KR20210043475A - Multi specific fusion protein and use thereof - Google Patents

Multi specific fusion protein and use thereof Download PDF

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KR20210043475A
KR20210043475A KR1020200130525A KR20200130525A KR20210043475A KR 20210043475 A KR20210043475 A KR 20210043475A KR 1020200130525 A KR1020200130525 A KR 1020200130525A KR 20200130525 A KR20200130525 A KR 20200130525A KR 20210043475 A KR20210043475 A KR 20210043475A
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amino acid
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박범찬
송재호
김나영
장세일
박정현
목진걸
송영자
김혜난
이재민
장창호
김응철
이은진
백기선
이현미
양소영
유재남
윤재봉
박영우
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주식회사 와이바이오로직스
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Abstract

The present invention provides a multispecific fusion protein that does not contain an Fc region and can specifically bind to two or more antigens. In one embodiment, a multispecific fusion protein comprising following structural formulas (I) and (II) is provided: N'-A-L1-X-C' (I); and N'-B-L1-Y-C' (II). The fusion protein may bind to cancer cells and immune cells, and may enhance the activity of immune cells. Therefore, the fusion protein can be used as an anticancer agent.

Description

다중 특이적 융합 단백질 및 이의 용도{MULTI SPECIFIC FUSION PROTEIN AND USE THEREOF}Multispecific fusion protein and its use {MULTI SPECIFIC FUSION PROTEIN AND USE THEREOF}

본 발명은 세포와 결합하는 다중 특이적 융합 단백질, 다중 특이적 융합 단백질의 제조방법, 다중 특이적 융합 단백질을 포함하는 조성물, 및 이의 용도에 관한 것이다.The present invention relates to a multispecific fusion protein that binds to cells, a method for preparing a multispecific fusion protein, a composition comprising the multispecific fusion protein, and uses thereof.

항체 및 항체를 기반으로 하는 개발된 물질들은 오늘날 다양한 질병 및 장애의 치료에 활용되고 있다. 현재 미국 및 유럽 연합에서 최소 70가지의 항체가 승인되었으며, 이와 함께 많은 수의 새로운 분자들이 전임상 연구 및 임상 시험 단계에 있다. 그러나, 연구 및 임상 커뮤니티 내에서 새롭고 더 좋고 안전한 치료제를 위한 지속적인 탐색이 이루어지고 있다. Antibodies and developed materials based on antibodies are used in the treatment of various diseases and disorders today. Currently, at least 70 antibodies have been approved in the United States and the European Union, with a large number of new molecules in the preclinical and clinical trial stages. However, there is an ongoing search for new, better and safer therapeutics within the research and clinical community.

통상 항체는 하나의 에피토프 또는 하나의 항원에 특이적으로 결합한다. 반면, 다중 특이적 항체는 두 개 이상의 항원 또는 두 개 이상의 에피토프에 결합하는 능력을 가지고 있다(대한민국 특허공개 10-2016-0035065). 그러나 많은 기술적 한계로 다중 특이적 항체의 개발에 난항을 겪고 있으며, 치료제로 승인된 다중 특이적 항체는 거의 없는 실정이다. 따라서, 여러 기능을 가지는 안정적인 다중 특이적 항체를 효율적으로 생산하기 위한 더 나은 다중 특이적 항체 및 방법이 여전히 필요한 상황이다.Usually, antibodies specifically bind to one epitope or one antigen. On the other hand, multispecific antibodies have the ability to bind two or more antigens or two or more epitopes (Korean Patent Publication 10-2016-0035065). However, the development of multispecific antibodies is difficult due to many technical limitations, and there are few multispecific antibodies approved as therapeutic agents. Therefore, there is still a need for better multispecific antibodies and methods for efficiently producing stable multispecific antibodies having multiple functions.

KRKR 10-2016-003506510-2016-0035065 AA

이에, 본 발명자들은 면역 활성을 증진시키는 새로운 구조의 다중 특이적 항체를 개발하기 위해 연구한 결과, 항체의 Fc 영역이 항체의 중쇄 가변 영역 및 경쇄 가변 영역으로 이루어진 항체 가변 영역으로 치환된 헤테로 다이머 형태의 다중 특이적 융합 단백질을 개발하였다. 또한, 상기 융합 단백질이 항암제로 효과가 있다는 점을 확인하여 본 발명을 완성하였다.Accordingly, the present inventors studied to develop a new structure of a multispecific antibody that enhances immune activity, as a result of the heterodimer form in which the Fc region of the antibody is substituted with the antibody variable region consisting of the heavy chain variable region and the light chain variable region of the antibody. The multispecific fusion protein of was developed. In addition, the present invention was completed by confirming that the fusion protein is effective as an anticancer agent.

상기 목적 달성을 위해, 본 발명의 일 측면은 하기 구조식 (I) 및 (II)를 포함하는 다중 특이적 융합 단백질을 제공한다:To achieve the above object, one aspect of the present invention provides a multispecific fusion protein comprising the following structural formulas (I) and (II):

N'-A-L1-X-C' (I); 및 N'-B-L1-Y-C' (II)N'-A-L1-X-C' (I); And N'-B-L1-Y-C' (II)

이때, 상기 구조식 (I) 및 (II)에 있어서, 상기 N'은 융합 단백질의 N-말단이고, 상기 C'은 융합 단백질의 C-말단이며, 상기 A 및 B는 각각 제1 항원에 특이적으로 결합하며, 상기 L1은 Cys을 적어도 하나 포함하는 펩타이드 링커이며, X는 항체 가변 중쇄(VH) 영역 또는 항체 가변 경쇄(VL) 영역이며, Y는 항체 가변 경쇄(VL) 영역 또는 항체 가변 중쇄(VH) 영역이며, 상기 X 및 Y는 제2 항원에 특이적으로 결합하는 항체 가변 영역을 형성한다.In this case, in the structural formulas (I) and (II), the N'is the N-terminus of the fusion protein, the C'is the C-terminus of the fusion protein, and A and B are each specific for a first antigen. And L1 is a peptide linker containing at least one Cys, X is an antibody variable heavy chain (VH) region or an antibody variable light chain (VL) region, and Y is an antibody variable light chain (VL) region or an antibody variable heavy chain ( VH) region, wherein X and Y form an antibody variable region that specifically binds to a second antigen.

본 발명의 또 다른 측면은, 상기 융합 단백질을 유효성분으로 포함하는 암 치료 또는 예방용 약학 조성물을 제공한다.Another aspect of the present invention provides a pharmaceutical composition for treating or preventing cancer comprising the fusion protein as an active ingredient.

본 발명에 따른 다중 특이적 융합 단백질은 두 개 이상의 항원에 특이적으로 결합할 수 있다. 또한, 면역세포에 특이적으로 결합하는 항체 가변영역과 암 항원에 특이적으로 결합하는 항체 가변영역을 포함하도록 제작된 다중 특이적 융합 단백질은 항암제로 활용이 가능하다.The multispecific fusion protein according to the present invention can specifically bind to two or more antigens. In addition, a multispecific fusion protein constructed to include an antibody variable region that specifically binds to immune cells and an antibody variable region that specifically binds to a cancer antigen can be used as an anticancer agent.

도 1은 항-CD3 UCHT1, 항-PD-L1 더발루맙, 항-CTLA-4 이필리무맙의 가변 도메인의 "Knob-in-Hole" 구조를 나타낸 도면이다. 여기서, CDR 루프(CDR loop)는 "VH CDR3", "VL CDR1", "VL CDR2", 및 "VL CDR3"로 표시하였다.
도 2는 UCHT1의 가변 도메인 단편 간의 상호작용을 확대하여 나타낸 도면이다. 상세하게는, VH-VL 특정 상호작용에 관련된 구조를 우측에 나타내었고, 정전기적 상호작용(상), 소수성 및 놉-인투-홀(Knob-into-Hole) 상호작용(하)에 의해 형성된 가변 도메인 단편을 나타내었다.
도 3a는 ALiCE의 구조를 도식화한 것이다.
도 3b, 도 3c, 도 3d, 도 3e 및 도 3f는 PD-L1 및 CD3 결합에 대한 가변 도메인을 나타내는 ACE-05, ACE-31, BiTE-05, YBL-007 및 UCHT1의 구조를 도식화한 것이다.
도 3g는 ACE-11 및 ACE-19의 구조를 도식화한 것이다.
도 3h는 ACE-28의 구조를 도식화한 것이다.
도 4는 PD-L1/PD-1 신호 차단능이 아벨루맙(avelumab)의 신호 차단능과 유사한 활성을 가진 항-PD-L1 항체(YBL-007)이다.
도 5a는 ACE-HC-VH, ACE-HC-VL 및 ACE-LC의 발현 여부를 SDS-PAGE 및 웨스턴 블롯팅으로 확인한 것이다.
도 5b는 ACE-18을 환원 및 비환원 조건에서 SDS-PAGE로 확인한 도면이다.
도 5c 및 도 5d는 ACE-11 및 ACE-19를 환원 및 비환원 조건에서 SDS-PAGE로 확인한 도면이다.
도 5e는 ACE-11 및 ACE-19를 환원 및 비환원 조건에서 모세관 전기영동(CE)으로 확인한 도면이다.
도 5f는 ACE-11 및 ACE-19를 SEC HPLC로 분석한 결과이다.
도 5g는 ACE-19를 SEC-HPLC로 분석한 결과이다.
도 5h는 ACE-19 fraction을 Native-PAGE로 확인한 것이다.
도 5i는 도 5g에서 얻은 ACE-19 fraction을 환원 및 비환원 조건에서 CE로 확인한 도면이다.
도 6은 PD-L1 및 CD3에 특이적으로 결합가능한 다중 특이적 융합 단백질의 모식도, 모세관 전기영동 분석 및 크기-배제 크로마토그래피를 통해 ACE-LC, ACE-HC-VH 및 ACE-HC-VL를 확인한 것이다.
도 7a는 모세관 전기영동 분석을 통해, ACE-05의 ACE-LC, ACE-HC-VH 및 ACE-HC-VL를 확인한 것이다. 분석 결과, ACE-LC, ACE-HC-VH 및 ACE-HC-VL이 2:1:1 비율로 존재함을 확인하였다.
도 7b는 ACE-10 및 ACE-18을 SEC-HPLC로 분석한 결과이다.
도 7c는 ACE-11 및 ACE-19를 환원 및 비환원 조건에서 CE로 확인한 결과이다.
도 7d는 ACE-11을 환원 및 비환원조건에서 CE로 확인한 결과이다.
도 7e는 ACE-19를 환원 및 비환원 조건에서 CE로 확인한 결과이다.
도 7f는 ACE-19를 SEC-HPLC로 분석한 결과이다.
도 7g는 SEC-FPLC를 이용하여 ACE-19를 complex와 ACE-19로 나누어 정제한 후, SEC-HPL로 분석한 결과이다.
도 7h는 SDS 존재 및 비존재, 가열 조건에 따른 ACE-19, complex를 Native-PAGE에서 확인한 도면이다.
도 8은 크기-배제 크로마토그래피 및 LC-ESI/TOF를 사용하여 질량분석(MS)한 결과이다. 그 결과, ACE-05가 균일한 이종사량체(heterotetramer)임을 확인하였다.
도 9는 ACE-00의 모식도, 모세관 전기영동 분석 및 크기-배제 크로마토그래피를 통해 ACE-LC, ACE-HC-VH 및 ACE-HC-VL를 확인한 것이다.
도 10은 서로 다른 조건에서 ACE-05를 양이온 교환 크로마토그래피(CEX)를 이용하여 분석한 것이다.
도 11a는 ACE-05의 열안정성을 확인한 것이다.
도 11b는 ACE-11 및 ACE-19의 열안정성을 확인한 것이다.
도 12는 CEX-HPLC 분석을 통해 ACE-05의 안정성을 확인한 것이다.
도 13은 ACE-05의 면역학적 시냅스 브리지를 도식화한 것이다.
도 14a는 ACE-05 및 ACE-31의 결합력을 확인한 것이다.
도 14b는 ACE-19의 결합력을 확인한 것이다.
도 14c는 ACE-11 및 ACE-19의 결합력을 확인한 것이다.
도 15a는 ACE-05 및 ACE-31의 결합력을 확인한 것이다.
도 15b는 ACE-19의 EGFR에 대한 결합력을 확인한 것이다.
도 15c는 ACE-19의 CD3에 대한 결합력을 확인한 것이다.
도 16a는 ACE-05의 PD-L1 및 CD3에 대한 동시결합을 확인한 것이다.
도 16b 및 도 16c는 ACE-19의 EGFR 및 CD3에 대한 동시 결합을 확인한 것이다.
도 17은 ACE-05 및 ACE-31의 Jrukat T 세포에 대한 결합력을 나타낸 것이다.
도 18a는 ACE-05 및 ACE-31의 Karpas-299 세포, Jrukat T 세포 및 Raji 세포에 대한 결합력을 나타낸 것이다.
도 18b는 ACE-18의 Raji 세포에 대한 결합력을 나타낸 것이다.
도 18c는 ACE-18의 CD20+ Raji 세포 또는 CD20- Raji 세포에 대한 결합력을 나타낸 것이다.
도 18d는 각 세포에서 항-CD20 항체의 세포 결합력을 이용하여 세포의 CD20 발현양을 나타낸 것이다.
도 18e는 ACE-18의 Karpass-299 세포에 대한 살상 능력을 확인한 것이다.
도 18f는 ACE-18의 Raji 세포에 대한 살상 능력을 확인한 것이다.
도 18g는 ACE-18의 Toledo 세포 및 Jeko-1 세포에 대한 살상 능력을 확인한 것이다.
도 18h는 ACE-19의 SW48 세포, HCT116 세포 및 HT29 세포에 대한 살상 능력 및 유세포 분석을 통해 종양에 존재하는 EGFR의 발현양을 확인한 것이다.
도 19는 PD-L1 발현 벡터가 도입된 HEK 세포를 확인한 것이다.
도 20은 NFAT-루시퍼라제 리포터 활성을 측정하여, ACE-05 및 ACE-31의 Jurkat T 세포 활성화를 평가하였다.
도 21은 NFAT-루시퍼라제 리포터 활성을 측정하여, ACE-05 및 ACE-31의 활성을 다른 물질과 비교하였다.
도 22는 ACE-05, ACE-31 및 BiTE-05의 PD-L1+ 종양 세포(HCC827)에 대한 세포 용해능(cytolytic ability)을 비교한 것이다.
도 23은 ACE-05, ACE-31 및 BiTE-05의 PD-L1+ 종양 세포(MDA-MB-231)에 대한 세포 용해능을 비교한 것이다.
도 24는 유세포 분석기를 통해 HCC827 및 MDA-MB-231에서 PD-L1 발현을 확인한 것이다.
도 25a는 ACE-05의 항암 활성을 측정한 것이다.
도 25b는 ACE-11 및 PBMC 동시 투여 후, 종양 세포에 대한 살해능을 측정한 것이다.
도 26a은 ACE-05가 표적 특이적으로 T 세포를 활성화시키는 능력이 있는지 여부를 확인한 것이다.
도 26b는 ACE-18가 표적 특이적으로 T 세포를 활성화시키는 능력이 있는지 여부를 확인한 것이다.
도 27은 ACE-05, ACE-31 및 BiTE-05가 T 세포를 활성화시키는 능력이 있는지 여부를 확인한 것이다.
도 28은 ACE-05, ACE-31 및 BiTE-05가 CD8+ T 세포에서 Granzyme B를 방출시키는데 미치는 영향을 확인한 것이다.
도 29는 ACE-05의 표적 특이적으로 T 세포를 활성화시키는 능력이 있는지 여부를 확인한 것이다.
도 30은 ACE-05, ACE-31 및 BiTE-05가 표적 특이적으로 T 세포를 활성화시키는 능력이 있는지 여부를 확인한 것이다.
도 31은 ACE-05, ACE-31 및 BiTE-05가 T 세포 응집 및 활성에 미치는 효과를 확인한 것이다.
도 32는 ACE-05, ACE-31 및 BiTE-05가 T 세포 자극에 미치는 영향을 확인한 것이다.
도 33은 ACE-05, ACE-31 및 BiTE-05 처리 후 PBMC에서 분비되는 사이토카인을 확인한 것이다.
도 34는 ACE-05 및 이의 변이체인 ACE-47(ACE-05의 K55Q 변이체), ACE-49(ACE-05의 D104N 변이체), ACE-56(ACE-05의 K55Q, D104N 변이체)의 결합 친화력을 측정한 것이다.
도 35는 ACE-05 및 이의 변이체의 비-표적(Off Target) Jurkat T 세포 활성화를 확인한 것이다.
도 36은 ACE-05 및 이의 변이체의 PD-L1 HCC827 암세포 살상 능력을 확인한 것이다.
도 37은 ACE-05, ACE-31 및 BiTE-05가 CD4+ 및 CD8+ T 세포에서 비-표적 사이토카인 분비능을 확인한 것이다.
도 38은 BiTE-05를 SEC-HPLC로 분석한 것이다.
도 39는 암 세포가 존재하지 않을 때, 본 실시예에 따른 융합 단백질의 비-표적 T 세포 활성화 정도를 확인한 것이다.
도 40은 본 실시예에 따른 융합 단백질이 암세포를 비 특이적으로 살상하는지 여부를 확인한 것이다.
도 41은 마우스에서 ACE-05, YBL-007 및 BiTE-05의 암세포 살상 효과를 확인한 것이다.
도 42는 ACE-05, YBL-007 및 BiTE-05 투여 후 마우스의 체중 변화를 나타낸 것이다.
도 43은 ACE-05 및 BiTE-05의 약동학을 분석한 것이다.
도 44는 ACE-05의 농도에 따른 항암 효과를 확인한 것이다.
도 45는 암을 보유하지 않은 마우스에서 ACE-05에 의한 사이토카인 분비를 확인한 것이다.
도 46은 암을 보유하지 않은 마우스에서 ACE-05에 의한 체중 변화를 확인한 것이다.
도 47은 ACE-05의 항암 효과를 확인한 것이다.
도 48은 ACE-05, YBL-007 및 UCHT1 투여 후 마우스의 체중 변화를 확인한 것이다.
도 49는 ACE-05, YBL-007 및 UCHT1 투여 후 종양 크기 변화를 확인한 것이다.
도 50은 ACE-05, YBL-007 및 UCHT1 투여 후 수득한 종양에 존재하는 CD45+ 림프구를 확인한 것이다.
도 51은 ACE-05, YBL-007 및 UCHT1 투여 후 CD45+ 림프구 수 및 CD3+ T 세포 비율을 확인한 것이다.
도 52는 ACE-05, YBL-007 및 UCHT1 투여 후 CD4+ 및 CD8+ T 세포 비율을 확인한 것이다.
도 53은 ACE-05, YBL-007 및 UCHT1 투여 후 유세포 분석을 통해 종양에 존재하는 CD4+ 및 CD8+ T 세포 비율을 확인한 것이다.
도 54는 유세포 분석을 통해 종양에 존재하는 EGFR 및 PD-L1의 발현양을 확인한 것이다.
도 55는 ACE-19가 SW48, HT29 및 HCT116 세포에 미치는 영향을 확인한 것이다.
도 56 및 도 57은 ACE-05-HC-VH 및 ACE-05-HC-VL의 면역원성을 확인하기 위해, MHC class I 분자 상에 제시될 수 있는 ACE-05-HC-VH 및 ACE-05-HC-VL 내의 펩티드를 분석한 것이다.
도 58 및 도 59는 ACE-02 및 ACE-03을 환원 및 비환원 조건에서 SDS-PAGE로 확인한 도면이다.
도 60은 ACE-05 및 ACE-16을 환원 및 비환원 조건에서 SDS-PAGE(좌측) 및 CE(우측)로 확인한 결과를 나타낸 도면이다.
도 61 내지 도 63은 ACE-06, ACE-10 및 ACE-11을 환원 및 비환원 조건에서 SDS-PAGE로 확인한 도면이다.
도 64는 ACE-15를 환원 및 비환원 조건에서 웨스턴블롯(상부 및 중간 패널) 및 SDS-PAGE(하단 패널)로 확인한 도면이다. 여기에서, Lane 1은 ACE-05 배양물의 총 상층액을, Lane 2는 ACE-15 배양물의 총 상층액을, Lane 3은 ACE-05의 정제된 단백질을 로딩한 것이다. 또한, 상단 패널은 항-CH1 항체를, 중간 패널은 항-Kappa 항체를 사용한 웨스턴 블롯 이미지를 나타낸 것이다.
도 65 및 도 66은 ACD-20 및 ACE21을 환원 및 비환원 조건에서 SDS-PAGE 및 웨스턴블롯으로 확인한 도면이다.
도 67은 ACE-23을 환원 및 비환원 조건에서 SDS-PAGE로 확인한 도면이다.
도 68은 ACE-25를 환원 및 비환원 조건에서 SDS-PAGE 및 CE로 분석한 결과 및 SEC-HPLC로 분석한 결과를 나타낸 도면이다.
도 69는 ACE-26의 ACE-VH-LC, ACE-VL-LC 및 ACE-VH-VL-LC를 환원 및 비환원 조건에서 SDS-PAGE 및 웨스턴블롯으로 확인한 도면이다.
도 70은 ACE-26을 환원 및 비환원 조건에서 SDS-PAGE 및 CE로 분석한 결과를 나타낸 도면이다.
도 71은 ACE-28을 환원 및 비환원 조건에서 SDS-PAGE, 웨스턴블롯 및 CE로 분석한 결과를 나타낸 도면이다.
도 72는 CH3 영역을 포함하는 ACE-28을 환원 및 비환원 조건에서 SDS-PAGE 및 웨스턴블롯으로 분석한 결과를 나타낸 도면이다.
도 73은 CH3 영역을 포함하는 ACE-28을 환원 및 비환원 조건에서 CE로 분석한 결과를 나타낸 도면이다.
도 74 및 도 75는 ACE-30 및 ACE-32를 환원 및 비환원 조건에서 SDS-PAGE, 웨스턴블롯 및 CE로 분석한 결과를 나타낸 도면이다.
도 76은 ACE-33을 환원 및 비환원 조건에서 SDS-PAGE 및 CE로 분석한 결과를 나타낸 도면이다.
1 is a diagram showing the "Knob-in-Hole" structure of the variable domains of anti-CD3 UCHT1, anti-PD-L1 dervalumab, and anti-CTLA-4 ipilimumab. Here, the CDR loops are denoted as "VH CDR3", "VL CDR1", "VL CDR2", and "VL CDR3".
2 is an enlarged view showing the interaction between the variable domain fragments of UCHT1. In detail, the structure related to the specific VH-VL interaction is shown on the right, and the variable formed by electrostatic interaction (top), hydrophobicity, and knob-into-hole interaction (bottom). Domain fragments are shown.
3A is a schematic diagram of the structure of ALiCE.
3b, 3c, 3d, 3e, and 3f are schematic structures of ACE-05, ACE-31, BiTE-05, YBL-007 and UCHT1 representing variable domains for PD-L1 and CD3 binding. .
Figure 3g is a schematic diagram of the structures of ACE-11 and ACE-19.
Figure 3h is a schematic diagram of the structure of ACE-28.
4 is an anti-PD-L1 antibody (YBL-007) having an activity similar to that of avelumab in PD-L1/PD-1 signal blocking ability.
Figure 5a shows whether the expression of ACE-HC-VH, ACE-HC-VL and ACE-LC was confirmed by SDS-PAGE and Western blotting.
Figure 5b is a view confirming ACE-18 by SDS-PAGE under reducing and non-reducing conditions.
5C and 5D are diagrams confirming ACE-11 and ACE-19 by SDS-PAGE under reducing and non-reducing conditions.
5E is a view confirming ACE-11 and ACE-19 by capillary electrophoresis (CE) under reducing and non-reducing conditions.
5F shows the results of analysis of ACE-11 and ACE-19 by SEC HPLC.
5G is a result of analyzing ACE-19 by SEC-HPLC.
5h shows the ACE-19 fraction confirmed by Native-PAGE.
5i is a view confirming the ACE-19 fraction obtained in FIG. 5g by CE under reducing and non-reducing conditions.
6 is a schematic diagram of a multispecific fusion protein capable of specifically binding to PD-L1 and CD3, ACE-LC, ACE-HC-VH and ACE-HC-VL through capillary electrophoresis analysis and size-exclusion chromatography. I confirmed it.
Figure 7a is through capillary electrophoresis analysis, confirming the ACE-LC, ACE-HC-VH and ACE-HC-VL of ACE-05. As a result of the analysis, it was confirmed that ACE-LC, ACE-HC-VH, and ACE-HC-VL were present in a 2:1:1 ratio.
7B is a result of analyzing ACE-10 and ACE-18 by SEC-HPLC.
7c is a result of confirming ACE-11 and ACE-19 with CE under reducing and non-reducing conditions.
7D is a result of confirming ACE-11 with CE in reducing and non-reducing conditions.
7E is a result of confirming ACE-19 with CE in reducing and non-reducing conditions.
7F is a result of analyzing ACE-19 by SEC-HPLC.
7G is a result of analysis by SEC-HPL after dividing ACE-19 into complex and ACE-19 using SEC-FPLC and purifying.
Figure 7h is a view confirming the presence and absence of SDS, ACE-19 and complex according to the heating conditions in Native-PAGE.
Figure 8 is the result of mass spectrometry (MS) using size-exclusion chromatography and LC-ESI/TOF. As a result, it was confirmed that ACE-05 is a homogeneous heterotetramer.
9 is a schematic diagram of ACE-00, capillary electrophoresis analysis, and size-exclusion chromatography to confirm ACE-LC, ACE-HC-VH and ACE-HC-VL.
10 is an analysis of ACE-05 using cation exchange chromatography (CEX) under different conditions.
Figure 11a confirms the thermal stability of ACE-05.
Figure 11b confirms the thermal stability of ACE-11 and ACE-19.
12 shows the stability of ACE-05 through CEX-HPLC analysis.
13 is a schematic diagram of the immunological synaptic bridge of ACE-05.
Figure 14a confirms the binding strength of ACE-05 and ACE-31.
Figure 14b confirms the binding force of ACE-19.
Figure 14c confirms the binding strength of ACE-11 and ACE-19.
Figure 15a confirms the binding strength of ACE-05 and ACE-31.
Figure 15b confirms the binding ability of ACE-19 to EGFR.
Figure 15c confirms the binding ability of ACE-19 to CD3.
Figure 16a confirms the simultaneous binding of ACE-05 to PD-L1 and CD3.
16B and 16C confirm the simultaneous binding of ACE-19 to EGFR and CD3.
Figure 17 shows the binding power of ACE-05 and ACE-31 to Jrukat T cells.
18A shows the binding power of ACE-05 and ACE-31 to Karpas-299 cells, Jrukat T cells, and Raji cells.
Figure 18b shows the binding power of ACE-18 to Raji cells.
Figure 18c shows the binding ability of ACE-18 to CD20 + Raji cells or CD20 - Raji cells.
18D shows the amount of CD20 expression in cells by using the cell avidity of the anti-CD20 antibody in each cell.
Fig. 18e shows the ability of ACE-18 to kill Karpass-299 cells.
Figure 18f confirms the killing ability of ACE-18 on Raji cells.
Fig. 18g is a confirmation of the killing ability of ACE-18 on Toledo cells and Jeko-1 cells.
18h is a view confirming the expression level of EGFR present in the tumor through flow cytometric analysis and the killing ability of ACE-19 on SW48 cells, HCT116 cells, and HT29 cells.
19 shows HEK cells into which the PD-L1 expression vector has been introduced.
20 shows NFAT-luciferase reporter activity was measured to evaluate the activation of Jurkat T cells of ACE-05 and ACE-31.
FIG. 21 shows the NFAT-luciferase reporter activity was measured, and the activities of ACE-05 and ACE-31 were compared with other substances.
Figure 22 is a comparison of the cytolytic ability of ACE-05, ACE-31 and BiTE-05 against PD-L1 + tumor cells (HCC827).
23 is a comparison of the cell lysis ability of ACE-05, ACE-31 and BiTE-05 against PD-L1 + tumor cells (MDA-MB-231).
24 is a flow cytometer confirming the expression of PD-L1 in HCC827 and MDA-MB-231.
Figure 25a is a measure of the anti-cancer activity of ACE-05.
Figure 25b is a measure of the killing ability against tumor cells after simultaneous administration of ACE-11 and PBMC.
Figure 26a confirms whether ACE-05 has the ability to specifically activate T cells.
Figure 26b confirms whether or not ACE-18 has the ability to specifically activate T cells.
Figure 27 confirms whether ACE-05, ACE-31 and BiTE-05 have the ability to activate T cells.
Fig. 28 shows the effect of ACE-05, ACE-31 and BiTE-05 on the release of Granzyme B in CD8 + T cells.
29 shows whether ACE-05 has the ability to specifically activate T cells.
FIG. 30 confirms whether ACE-05, ACE-31, and BiTE-05 have the ability to specifically activate T cells.
31 shows the effect of ACE-05, ACE-31 and BiTE-05 on T cell aggregation and activity.
Fig. 32 shows the effects of ACE-05, ACE-31 and BiTE-05 on T cell stimulation.
33 shows cytokines secreted from PBMCs after treatment with ACE-05, ACE-31 and BiTE-05.
Figure 34 shows the binding affinity of ACE-05 and its variants, ACE-47 (K55Q variant of ACE-05), ACE-49 (D104N variant of ACE-05), and ACE-56 (K55Q, D104N variant of ACE-05). Is measured.
Figure 35 confirms the non-target (Off Target) Jurkat T cell activation of ACE-05 and its variants.
Fig. 36 shows the ability of ACE-05 and its variants to kill PD-L1 HCC827 cancer cells.
Figure 37 shows that ACE-05, ACE-31, and BiTE-05 confirm the ability to secrete non-target cytokines in CD4 + and CD8 + T cells.
38 is an analysis of BiTE-05 by SEC-HPLC.
39 shows the degree of activation of non-target T cells of the fusion protein according to the present example when cancer cells are not present.
40 shows whether the fusion protein according to the present embodiment non-specifically kills cancer cells.
41 shows the cancer cell killing effects of ACE-05, YBL-007 and BiTE-05 in mice.
Figure 42 shows the change in body weight of mice after administration of ACE-05, YBL-007 and BiTE-05.
43 is an analysis of the pharmacokinetics of ACE-05 and BiTE-05.
44 shows the anticancer effect according to the concentration of ACE-05.
45 shows cytokine secretion by ACE-05 in mice that do not have cancer.
46 shows the change in body weight by ACE-05 in mice that do not have cancer.
47 shows the anticancer effect of ACE-05.
48 shows the change in body weight of mice after administration of ACE-05, YBL-007 and UCHT1.
49 shows changes in tumor size after administration of ACE-05, YBL-007 and UCHT1.
50 shows CD45 + lymphocytes present in tumors obtained after administration of ACE-05, YBL-007 and UCHT1.
FIG. 51 shows the confirmation of CD45 + lymphocyte count and CD3 + T cell ratio after administration of ACE-05, YBL-007 and UCHT1.
52 shows the percentage of CD4 + and CD8 + T cells after administration of ACE-05, YBL-007 and UCHT1.
53 shows the percentage of CD4 + and CD8 + T cells present in the tumor through flow cytometry after administration of ACE-05, YBL-007 and UCHT1.
54 shows the amount of expression of EGFR and PD-L1 present in the tumor through flow cytometry.
55 shows the effect of ACE-19 on SW48, HT29 and HCT116 cells.
56 and 57 show ACE-05-HC-VH and ACE-05 that can be presented on MHC class I molecules to confirm the immunogenicity of ACE-05-HC-VH and ACE-05-HC-VL. This is an analysis of the peptide in -HC-VL.
58 and 59 are views confirming ACE-02 and ACE-03 by SDS-PAGE under reducing and non-reducing conditions.
FIG. 60 is a diagram showing the results of confirming ACE-05 and ACE-16 by SDS-PAGE (left) and CE (right) under reducing and non-reducing conditions.
61 to 63 are views confirming ACE-06, ACE-10, and ACE-11 by SDS-PAGE under reducing and non-reducing conditions.
Figure 64 is a view confirmed by Western blot (top and middle panels) and SDS-PAGE (bottom panels) of ACE-15 under reducing and non-reducing conditions. Here, Lane 1 is the total supernatant of the ACE-05 culture, Lane 2 is the total supernatant of the ACE-15 culture, and Lane 3 is loaded with the purified protein of ACE-05. In addition, the upper panel shows an anti-CH1 antibody, and the middle panel shows a Western blot image using an anti-Kappa antibody.
65 and 66 are diagrams confirming ACD-20 and ACE21 by SDS-PAGE and Western blot under reducing and non-reducing conditions.
67 is a view confirming ACE-23 by SDS-PAGE under reducing and non-reducing conditions.
FIG. 68 is a diagram showing the results of analyzing ACE-25 by SDS-PAGE and CE under reducing and non-reducing conditions and by SEC-HPLC.
69 is a diagram showing ACE-VH-LC, ACE-VL-LC and ACE-VH-VL-LC of ACE-26 confirmed by SDS-PAGE and Western blot under reducing and non-reducing conditions.
FIG. 70 is a diagram showing the results of analyzing ACE-26 by SDS-PAGE and CE under reducing and non-reducing conditions.
71 is a diagram showing the results of analysis of ACE-28 by SDS-PAGE, Western blot and CE under reducing and non-reducing conditions.
72 is a view showing the results of SDS-PAGE and Western blot analysis of ACE-28 containing a CH3 region under reduced and non-reducing conditions.
73 is a diagram showing the results of CE analysis of ACE-28 containing a CH3 region under reduced and non-reducing conditions.
74 and 75 are diagrams showing the results of analysis of ACE-30 and ACE-32 by SDS-PAGE, Western blot, and CE under reducing and non-reducing conditions.
76 is a diagram showing the results of analysis of ACE-33 by SDS-PAGE and CE under reducing and non-reducing conditions.

용어의 정의Definition of Terms

본 명세서에서 사용된 용어, "다중 특이적 융합 단백질"은 적어도 하나 이상의 표적 또는 항원에 결합하는 물질을 의미한다. 구체적으로, 상기 융합 단백질은 예를 들어 해리 상수(KD)가 ≤10-7 M 일 때 항원에 특이적으로 결합하거나 선택적으로 결합할 수 있다. 일 구체예에서, 상기 융합 단백질은 KD가 ≤10-8 M이거나 KD가 ≤10-9 M일 때 높은 친화도로 항원에 특이적으로 결합할 수 있다. 상기 다중 특이적 융합 단백질은 항체 및 항체로부터 유래된 분자를 포함할 수 있다. As used herein, the term "multispecific fusion protein" refers to a substance that binds to at least one target or antigen. Specifically, the fusion protein may specifically bind or selectively bind to an antigen, for example, when the dissociation constant (KD) is ≤ 10 -7 M. In one embodiment, the fusion protein may specifically bind to an antigen with high affinity when the KD is ≤ 10 -8 M or the KD is ≤ 10 -9 M. The multispecific fusion protein may include an antibody and a molecule derived from the antibody.

일 구체예에서, 다중 특이적 융합 단백질 또는 이의 항원 결합 도메인은 천연 CDR을 포함하는 인간 면역글로불린을 포함하는 키메라 항체인 비인간 항체의 "인간화" 형태일 수 있다. 또한, 다중 특이적 융합 단백질 또는 항원 결합 도메인은 "완전 인간 항체" 또는 "인간 항체"의 일부를 포함할 수 있다. 또한, 일 구체예에서, 다중 특이적 융합 단백질 또는 항원 결합 도메인은 "단일 클론 항체" 또는 이의 일부일 수 있다.In one embodiment, the multispecific fusion protein or antigen binding domain thereof may be a "humanized" form of a non-human antibody that is a chimeric antibody comprising a human immunoglobulin comprising a native CDR. In addition, a multispecific fusion protein or antigen binding domain may comprise a portion of a “fully human antibody” or “human antibody”. Also, in one embodiment, the multispecific fusion protein or antigen binding domain may be a “monoclonal antibody” or a portion thereof.

본 명세서에서 사용된 용어, "항체"는 항원에 특이적으로 결합하여 항원-항체 반응을 일으키는 물질을 의미한다. 또한, 항체는 면역글로불린이라고 지칭되기도 한다. 항체는 IgG, IgE, IgM, IgD 및 IgA에서 선택되는 어느 하나를 의미할 수 있으며, IgG의 하위 부류인 IgG1, IgG2, IgG3, IgG4, IgA1 또는 IgA2일 수 있다. 또한, 항체는 작용 항체 또는 길항 항체일 수 있다. As used herein, the term "antibody" refers to a substance that specifically binds to an antigen and causes an antigen-antibody reaction. In addition, antibodies are also referred to as immunoglobulins. The antibody may mean any one selected from IgG, IgE, IgM, IgD and IgA, and may be IgG1, IgG2, IgG3, IgG4, IgA1 or IgA2, which are subclasses of IgG. In addition, the antibody may be an agonistic antibody or an antagonistic antibody.

본 명세서에서 사용된 용어, "Fab" 또는 "Fab 영역"은 항원에 결합하는 항체 영역을 지칭한다. 통상적인 IgG는 일반적으로 두 개의 Fab 영역을 포함한다. 각 Fab 영역은 전형적으로 각각의 중쇄 및 경쇄의 하나의 가변 영역 및 하나의 불변 영역으로 구성된다. 구체적으로, Fab 영역에서 중쇄의 가변 영역 및 불변 영역은 VH 및 CH1 영역이고, Fab 영역에서 경쇄의 가변 영역 및 불변 영역은 VL 및 CL 영역이다. Fab 영역의 VH, CH1, VL 및 CL은 본 개시 내용에 따른 항원 결합 능력을 부여하기 위해 다양한 방식으로 배열될 수 있다. As used herein, the term “Fab” or “Fab region” refers to an antibody region that binds to an antigen. Conventional IgG generally contains two Fab regions. Each Fab region typically consists of one variable region and one constant region of each heavy and light chain. Specifically, in the Fab region, the variable and constant regions of the heavy chain are VH and CH1 regions, and in the Fab region, the variable and constant regions of the light chain are VL and CL regions. The VH, CH1, VL and CL of the Fab region can be arranged in a variety of ways to confer antigen binding capacity according to the present disclosure.

본 명세서에서 사용된 용어, "중쇄"는 약 50-70 kDa의 폴리펩티드 사슬을 지칭한다. 여기서 아미노-말단 부분은 약 120 내지 130 개 이상의 아미노산의 가변 영역을 포함하고, 카르복시말단 부분은 불변 영역을 포함한다. 불변 영역은 알파(α), 델타(δ), 엡실론(ε), 감마(γ) 및 뮤(μ)의 5 가지 유형 중 하나일 수 있다. 이때, α, δ 및 γ는 약 450개의 아미노산을 포함하고 μ 및 ε은 약 550개의 아미노산을 포함한다. As used herein, the term “heavy chain” refers to a polypeptide chain of about 50-70 kDa. Here, the amino-terminal portion includes a variable region of about 120 to 130 or more amino acids, and the carboxy terminal portion includes a constant region. The constant region may be one of five types: alpha (α), delta (δ), epsilon (ε), gamma (γ), and mu (μ). Here, α, δ, and γ include about 450 amino acids, and μ and ε include about 550 amino acids.

본 명세서에서 사용된 용어, "경쇄"는 약 25kDa의 폴리펩티드 사슬을 지칭한다. 여기서 아미노-말단 부분은 약 100 내지 약 110개 이상의 아미노산의 가변 영역 및 카복시-말단 부분은 불변 영역을 포함한다. 경쇄 불변 도메인은 카파(κ) 또는 람다(λ) 두 가지 유형이 있다. 또한, 경쇄의 불변 영역을 "CL"이라고 한다. 중쇄 C 도메인 (CH 도메인)은 아미노-말단에서 카르복시-말단까지 번호가 매겨져 있다 (예 : CH1, CH2, CH3 등). 이들 항체 부류의 임의의 CL 및 CH1 영역이 본 개시 내용에 사용될 수 있다. 특정 구체 예에서, 본원에 제공된 CL 및 CH1 영역은 IgG 유형 (예를 들어, IgG1)이다. 본원에 제공된 Fab 영역의 대표적인 CL 영역은 다음 아미노산 서열을 갖는다: TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (서열번호: 59). 본원에 제공된 Fab 영역의 대표적인 CH1 영역은 다음과 같은 아미노산 서열을 가지고 있다 : ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKV (서열번호: 60). As used herein, the term “light chain” refers to a polypeptide chain of about 25 kDa. Wherein the amino-terminal portion includes a variable region of about 100 to about 110 or more amino acids and the carboxy-terminal portion includes a constant region. There are two types of light chain constant domains: kappa (κ) or lambda (λ). In addition, the constant region of the light chain is referred to as "CL". The heavy chain C domain (CH domain) is numbered from amino-terminus to carboxy-terminus (eg, CH1, CH2, CH3, etc.). Any of the CL and CH1 regions of these antibody classes can be used in the present disclosure. In certain embodiments, the CL and CH1 regions provided herein are of the IgG type (eg, IgG1). A representative CL region of the Fab region provided herein has the following amino acid sequence: TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 59). The representative CH1 region of the Fab region provided herein has the following amino acid sequence: ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKV (SEQ ID NO: 60).

본 명세서에서 사용된 용어, "Fc 영역"은 천연 Fc 영역, 재조합 Fc 영역 및 변이체 Fc 영역을 포함하는 면역글로불린 중쇄의 C-말단 영역을 의미한다. 일 구체예에서, 변이체 Fc 영역은 천연 서열 Fc 영역에 비해 적어도 하나의 아미노산 치환, 예를 들어 약 1개 내지 약 10개의 아미노산 치환, 또는 약 1개 내지 약 5개의 아미노산이 치환된 형태일 수 있다. 또한. 변이체 Fc 영역은 천연 서열 Fc 영역과 적어도 약 80% 상동성, 적어도 약 90% 상동성, 적어도 약 95% 상동성을 가질 수 있다.As used herein, the term "Fc region" refers to the C-terminal region of an immunoglobulin heavy chain including a native Fc region, a recombinant Fc region and a variant Fc region. In one embodiment, the variant Fc region may have at least one amino acid substitution, for example about 1 to about 10 amino acid substitutions, or about 1 to about 5 amino acids substitutions compared to the native sequence Fc region. . Also. The variant Fc region may have at least about 80% homology, at least about 90% homology, at least about 95% homology with the native sequence Fc region.

본 명세서에서 사용된 용어, "항원"은 항체에 선택적으로 결합할 수 있는 구조이다. 표적 항원은 폴리펩티드, 탄수화물, 핵산, 지질, 합텐 또는 기타 자연적으로 발생된 화합물이거나 합성된 화합물일 수 있다. 구체적으로, 항원은 폴리펩티드이며, 세포 상 또는 세포 내에 존재하는 단백질일 수 있다.As used herein, the term "antigen" is a structure capable of selectively binding to an antibody. The target antigen may be a polypeptide, carbohydrate, nucleic acid, lipid, hapten, or other naturally occurring compound or a synthetic compound. Specifically, the antigen is a polypeptide, and may be a protein present on or within a cell.

본 명세서에서 사용된 용어, "벡터"는 본 명세서에 기재된 다중 특이적 융합 단백질(예를 들어, 항체)을 코딩하는 핵산 서열을 포함하는 핵산 서열을 운반하거나 발현시키기 위한 물질을 의미한다. 구체적으로, 벡터는 발현 벡터, 플라스미드, 파지 벡터, 바이러스 벡터, 에피솜 및 인공 염색체를 포함한다. As used herein, the term “vector” refers to a material for carrying or expressing a nucleic acid sequence comprising a nucleic acid sequence encoding a multispecific fusion protein (eg, an antibody) described herein. Specifically, vectors include expression vectors, plasmids, phage vectors, viral vectors, episomes and artificial chromosomes.

본 명세서에서 사용된 용어, "폴리뉴클레오티드"는 "핵산"이라고도 지칭되며, 임의의 길이의 뉴클레오타이드의 중합체를 지칭한다. 구체적으로, 상기 폴리뉴클레오티드는 DNA 또는 RNA일 수 있다. As used herein, the term “polynucleotide” is also referred to as “nucleic acid” and refers to a polymer of nucleotides of any length. Specifically, the polynucleotide may be DNA or RNA.

다중 특이적 융합 단백질Multispecific fusion proteins

본 발명의 일 측면은, 항체의 Fc 영역이 항체의 가변영역으로 치환된 다중 특이적 융합 단백질을 제공한다.One aspect of the present invention provides a multispecific fusion protein in which the Fc region of an antibody is substituted with a variable region of an antibody.

본 발명은 세포에 결합하는 다중 결합 도메인을 갖는 신규 다중 특이적 융합 단백질을 제공한다. 이들 융합 단백질은 본 명세서에서 "항체 유사 세포 결합자(antibody like cell engagers; ALiCE)"로 지칭될 수 있다. 본 발명에서 제공되는 ALiCE 분자는 2개의 항원 결합 도메인을 갖는다. 제1 항원 결합 도메인은 2개의 Fab 영역을 가지며, 제2 항원 결합 도메인은 Fv 영역을 가진다. ALiCE 분자의 예시는 도 3a, 도 3b, 도 3c, 도 3g 및 도 3h에 나타내었다.The present invention provides a novel multispecific fusion protein having multiple binding domains that bind to cells. These fusion proteins may be referred to herein as "antibody like cell engagers (ALICE)". The ALiCE molecule provided in the present invention has two antigen binding domains. The first antigen binding domain has two Fab regions and the second antigen binding domain has an Fv region. Examples of ALiCE molecules are shown in FIGS. 3A, 3B, 3C, 3G, and 3H.

Fv 및 Fab 영역은 중쇄의 힌지 영역을 통해 연결될 수 있다. 일반적으로, 이러한 분자에서 제1 항원 결합 도메인은 Fab 영역을 포함하고, 제2 항원 결합 도메인은 CH2 및 CH3 도메인이 일반적으로 천연(native) 항체 구조 상에 위치할 위치에서 보통 제1 항원 결합 도메인에 (직접적으로 또는 간접적으로) 부착된다. 예를 들어, 일 구체예에서, 제1 중쇄의 C-말단은 CH2 도메인이 아닌 VH 도메인을 포함하고, 제2 중쇄의 C-말단은 CH2 도메인이 아닌 VL 도메인을 포함한다.The Fv and Fab regions can be linked through the hinge region of the heavy chain. Generally, in such molecules, the first antigen binding domain comprises a Fab region, and the second antigen binding domain is usually at a position where the CH2 and CH3 domains will be located on the native antibody structure. Attached (directly or indirectly). For example, in one embodiment, the C-terminus of the first heavy chain comprises a VH domain other than the CH2 domain, and the C-terminus of the second heavy chain comprises a VL domain other than the CH2 domain.

본 명세서에 개시된 다중 특이적 융합 단백질은 통상적인 항체 및 기존의 다중특이적 항체(예를 들어, 이중특이적 항체)에 비해 많은 이점을 제공한다. 다중 항원 결합 도메인 및 전반적인 구성 설계로 인해, 본 발명에서 제공된 다중 특이적 융합 단백질은 다수의 세포를 제공해주는 세포 결합자로서 사용될 수 있다. 예를 들어, 제1 항원 결합 도메인은 제1 세포 상에 발현된 항원에 결합할 수 있고, 제2 항원 결합 도메인은 제2 세포 상에 발현된 항원에 결합할 수 있다. 따라서, 본 다중 특이적 융합 단백질을 이용할 경우 두 세포를 효과적으로 연결할 수 있다.The multispecific fusion proteins disclosed herein provide many advantages over conventional antibodies and conventional multispecific antibodies (eg, bispecific antibodies). Due to the multiple antigen binding domains and overall configuration design, the multispecific fusion proteins provided in the present invention can be used as cell linkers providing multiple cells. For example, a first antigen binding domain can bind an antigen expressed on a first cell, and a second antigen binding domain can bind an antigen expressed on a second cell. Therefore, when the multispecific fusion protein is used, the two cells can be effectively linked.

본 발명에 제공된 다중 특이적 융합 단백질은 면역 세포에 결합하고, 이를 활성화하는데 유용할 수 있다. 예를 들어, 일 구체예에서, ALiCE 분자의 2가 Fab 부분은 통상적인 항체의 기능을 유지하지만, 제2 Fc-결손 1가 항원-결합 영역(즉, Fv 영역)은 면역 시스템의 이펙터 세포, 예컨대 T 세포를 인식, 결합, 재지시(redirect) 및/또는 활성화할 수 있다.The multispecific fusion proteins provided herein may be useful for binding and activating immune cells. For example, in one embodiment, the divalent Fab portion of the ALiCE molecule retains the function of a conventional antibody, while the second Fc-deficient monovalent antigen-binding region (i.e., the Fv region) is an effector cell of the immune system, For example, T cells can be recognized, bound, redirected and/or activated.

다른 구체예에서, ALiCE 분자의 Fv 부분은 통상적인 항체의 기능을 보유하고, Fab 영역은 면역 시스템의 이펙터 세포, 예컨대 T 세포를 인식, 결합, 재지시 및/또는 활성화할 수 있다. 예를 들어, ACE-05 및 ACE-31은 모두 항-PD-L1 및 항-CD3 도메인으로 구성된 ALiCE 분자이나, ACE-05는 Fab 영역을 통해 PD-L1에 결합하고, Fv 영역을 통해 CD3에 결합한다. 반면, ACE-31은 Fab 영역을 통해 CD3에 결합하고, Fv 영역을 통해 PD-L1에 결합한다.In another embodiment, the Fv portion of the ALiCE molecule retains the function of a conventional antibody, and the Fab region is capable of recognizing, binding, redirecting and/or activating effector cells, such as T cells, of the immune system. For example, ACE-05 and ACE-31 are both ALiCE molecules composed of anti-PD-L1 and anti-CD3 domains, but ACE-05 binds to PD-L1 through the Fab region and to CD3 through the Fv region. Combine. On the other hand, ACE-31 binds to CD3 through the Fab region and to PD-L1 through the Fv region.

일 구체예에서, 제대로 기능하는 Fc 영역의 부재 또는 완전한 CH2 및/또는 CH3 영역의 부재는 Fc-매개 이펙터 세포독성을 제거하거나 감소시킨다. 일 구체예에서, Fv 부분의 VH 및 VL 사슬 간의 자연적인 상호작용은 인공적인 조작을 통해 바람직하지 않은 면역원성을 부여하지 않으면서, ALiCE 분자의 이종이량체화(heterodimerization)를 촉진할 수 있다.In one embodiment, the absence of a properly functioning Fc region or the absence of a complete CH2 and/or CH3 region eliminates or reduces Fc-mediated effector cytotoxicity. In one embodiment, the natural interaction between the VH and VL chains of the Fv moiety can promote heterodimerization of ALiCE molecules without conferring undesirable immunogenicity through artificial manipulation.

상기 다중 특이적 융합 단백질의 일 구체예는 2개의 항원 결합 도메인을 포함하며, 여기서 제1 항원 결합 도메인은 2개의 항체 Fab 영역을 포함하고, 제2 항원 결합 도메인은 항체 Fv 영역을 포함하는 형태일 수 있다. 이때, 2개의 Fab 영역 각각은 2개의 부분을 포함한다. 제1 부분은 항체 가변 중쇄(VH) 영역 및 항체 CH1 영역을 포함한다. 또한, 제2 부분은 항체 가변 경쇄(VL) 영역 및 항체 경쇄 불변 영역(CL)을 포함한다. 두 개의 Fab 영역 각각은 항원에 결합할 수 있다. 제2 항원 결합 도메인의 Fv 영역은 VH 영역 및 VL 영역을 포함한다.One embodiment of the multispecific fusion protein comprises two antigen binding domains, wherein the first antigen binding domain comprises two antibody Fab regions and the second antigen binding domain comprises antibody Fv regions. I can. At this time, each of the two Fab regions includes two portions. The first portion comprises an antibody variable heavy chain (VH) region and an antibody CH1 region. In addition, the second portion comprises an antibody variable light chain (VL) region and an antibody light chain constant region (CL). Each of the two Fab regions is capable of binding an antigen. The Fv region of the second antigen binding domain comprises a VH region and a VL region.

또한, 상기 다중 특이적 융합 단백질의 일 구체예는 하기 4개의 폴리펩티드를 포함한 것일 수 있다:In addition, an embodiment of the multispecific fusion protein may include the following four polypeptides:

(a) 각각 항체 경쇄를 포함하는 제1 폴리펩티드 및 제2 폴리펩티드,(a) a first polypeptide and a second polypeptide each comprising an antibody light chain,

(b) 제1 VH 영역, 제1 CH1 영역, 및 제2 VH 영역을 포함하는 제3 폴리펩티드, 및(b) a third polypeptide comprising a first VH region, a first CH1 region, and a second VH region, and

(c) 제3 VH 영역, 제2 CH1 영역 및 VL 영역을 포함하는 제4 폴리펩티드.(c) a fourth polypeptide comprising a third VH region, a second CH1 region and a VL region.

이때, 제1 폴리펩티드 및 제3 폴리펩티드의 제1 VH 영역 및 제1 CH1 영역은 제1 항원 결합 Fab 영역을 형성하고, 제2 폴리펩티드 및 제4 폴리펩티드의 제3 VH 영역 및 제2 CH1 영역은 제2 항원 결합 Fab 영역을 형성하고, 제3 폴리펩티드의 제2 VH 영역 및 제4 폴리펩티드의 VL 영역은 항원 결합 Fv 영역을 형성한다. At this time, the first VH region and the first CH1 region of the first polypeptide and the third polypeptide form a first antigen-binding Fab region, and the third VH region and the second CH1 region of the second and fourth polypeptides are second. The antigen binding Fab region is formed, and the second VH region of the third polypeptide and the VL region of the fourth polypeptide form the antigen binding Fv region.

C-말단의 Fv도 2개의 상이한 중쇄 유사 사슬 (제3 및 제4 폴리펩티드)의 이종이량체화에 중요한 역할을 함을 확인하였다. VH와 VL 영역 사이의 상호 작용이 VL-VL 상호 작용보다 훨씬 강하기 때문에, VH-VL 결합을 한다. 따라서, 이종이량체화가 되어 본원의 다중 특이적 융합 단백질이 제조될 수 있다. 이종이량체화의 효율은 매우 높았으며, 포유류 세포에서 발현 및 정제된 대부분의 다중 특이적 융합 단백질은 이종이량체화된 형태이다. 이종이량체화 효율이 99% 이상 나타남을 확인하였다. It was confirmed that the C-terminal Fv also plays an important role in the heterodimerization of two different heavy chain-like chains (third and fourth polypeptides). Because the interaction between the VH and VL regions is much stronger than that of the VL-VL interaction, VH-VL binding occurs. Thus, it can be heterodimerized to produce the multispecific fusion protein of the present application. The efficiency of heterodimerization was very high, and most of the multispecific fusion proteins expressed and purified in mammalian cells are in heterodimerized form. It was confirmed that the heterodimerization efficiency was more than 99%.

또한, 이 구조는 표적 세포와 효과기 세포 사이의 최적의 시냅스 거리를 제공한다. N-말단 2개의 Fab 영역과 C-말단 Fv 영역의 거리는 40Å로 추정되었다. 더욱이, 본원에 제공된 다중 특이적 융합 단백질은 BiTE, DART 및 기타 ScFv 기반의 이중특이적 항체 형식과 같은 다른 공지된 이중특이적 항체보다 더 많은 접힘 복잡성(분자 크기)을 가지며, 따라서 개선된 열역학적 안정성을 가질 것으로 예상된다. 특히, Fv 영역의 VH 영역 및 VL 영역은 별개의 폴리펩티드 상에 존재한다. In addition, this structure provides an optimal synaptic distance between the target cell and the effector cell. The distance between the two N-terminal Fab regions and the C-terminal Fv region was estimated to be 40 Å. Moreover, the multispecific fusion proteins provided herein have more folding complexity (molecular size) than other known bispecific antibodies such as BiTE, DART and other ScFv based bispecific antibody formats, and thus improved thermodynamic stability. Is expected to have. In particular, the VH region and the VL region of the Fv region are on separate polypeptides.

다중 특이적 융합 단백질의 특징Characteristics of multispecific fusion proteins

일 구체예에서, 본원에 제공된 다중 특이적 융합 단백질에서 N-말단 2개의 Fab 영역과 C-말단 Fv 영역 사이의 거리는 약 40Å 내지 약 70Å의 범위에 있는 것으로 추정된다. 일 구체예에서, 본원에 제공된 다중 특이적 융합 단백질에서 N-말단 2개의 Fab 영역과 C-말단 Fv 영역 사이의 거리는 약 42Å 인 것으로 추정되었다. 일부 다른 실시 양태에서, 본원에 제공된 다중 특이적 융합 단백질에서 N-말단 2개의 Fab 영역과 C-말단 Fv 영역 사이의 거리는 약 60Å 인 것으로 추정되었다. In one embodiment, it is estimated that the distance between the two N-terminal Fab regions and the C-terminal Fv regions in the multispecific fusion proteins provided herein is in the range of about 40 Å to about 70 Å. In one embodiment, the distance between the two N-terminal Fab regions and the C-terminal Fv regions in the multispecific fusion proteins provided herein was estimated to be about 42 Å. In some other embodiments, the distance between the N-terminal two Fab regions and the C-terminal Fv regions in the multispecific fusion proteins provided herein was estimated to be about 60 Å.

다중 특이적 융합 단백질의 일 실시예로서, 제1 항원에 대한 제1 항원 결합 도메인의 결합 친화성은 제2 항원에 대한 제2 항원 결합 도메인의 결합 친화성보다 높을 수 있다. 예를 들어, 인간 PD-L1에 대한 ACE-05의 결합 역학은 모 항-PD-L1 항체(즉, Y-Biologics Inc.의 YBL-007)와 비슷했다. 대조적으로, CD3에 대한 ACE-05의 결합 친화성은 모 항-CD3 항체(미국 BioLegend의 UCHT1)보다 훨씬 낮았다.As an embodiment of the multispecific fusion protein, the binding affinity of the first antigen-binding domain for the first antigen may be higher than that of the second antigen-binding domain for the second antigen. For example, the binding kinetics of ACE-05 to human PD-L1 was similar to that of the parent anti-PD-L1 antibody (ie, YBL-007 from Y-Biologics Inc.). In contrast, the binding affinity of ACE-05 for CD3 was much lower than that of the parental anti-CD3 antibody (UCHT1, BioLegend, USA).

일 구체예에서, 본원에 제공된 다중 특이적 융합 단백질은 약 1 μM 이하, 약 100 nM 이하, 약 40 nM 이하, 약 20 nM 이하, 약 10 nM 이하, 약 1 nM 이하, 약 0.1 nM 이하, 50 pM 이하, 10 pM 이하, 또는 1 pM 이하의 해리 상수(KD)로 하나 이상의 표적, 항원 또는 에피토프에 결합할 수 있다. 일 실시예에서, 본원에 제공된 다중 특이적 융합 단백질은 약 20 nM 이하의 KD 로 표적, 항원 또는 에피토프에 결합할 수 있다. 일 실시예에서, 다중 특이적 융합 단백질은 약 10 nM 이하의 KD 로 표적, 항원 또는 에피토프에 결합할 수 있다. 일 실시예에서, 다중 특이적 융합 단백질은 약 1 nM 이하의 KD 로 표적, 항원 또는 에피토프에 결합할 수 있다. 일 실시예에서, 다중 특이적 융합 단백질은 약 0.5 nM 이하의 KD 로 표적, 항원 또는 에피토프에 결합할 수 있다. 일 실시예에서, 본원에 제공된 다중 특이적 융합 단백질은 약 0.1 nM 이하의 KD 로 표적, 항원 또는 에피토프에 결합할 수 있다. 일 실시예에서, 본원에 제공된 다중 특이적 융합 단백질은 약 50 pM 이하의 KD 로 표적, 항원 또는 에피토프에 결합할 수 있다. 일 실시예에서, 본원에 제공된 다중 특이적 융합 단백질은 약 25 pM 이하의 KD 로 표적, 항원 또는 에피토프에 결합할 수 있다. 일 실시예에서, 본원에 제공된 다중 특이적 융합 단백질은 약 10 pM 이하의 KD 로 표적, 항원 또는 에피토프에 결합할 수 있다. 일 실시예에서, 본원에 제공된 다중 특이적 융합 단백질은 약 1pM 이하의 KD 로 표적, 항원 또는 에피토프에 결합할 수 있다. In one embodiment, the multispecific fusion proteins provided herein are about 1 μM or less, about 100 nM or less, about 40 nM or less, about 20 nM or less, about 10 nM or less, about 1 nM or less, about 0.1 nM or less, 50 Can bind to one or more targets, antigens or epitopes with a dissociation constant (K D ) of pM or less, 10 pM or less, or 1 pM or less. In one embodiment, a multispecific fusion protein provided herein is capable of binding a target, antigen or epitope with a K D of about 20 nM or less. In one embodiment, the multispecific fusion protein is capable of binding to a target, antigen or epitope with a K D of about 10 nM or less. In one embodiment, the multispecific fusion protein is capable of binding to a target, antigen or epitope with a K D of about 1 nM or less. In one embodiment, the multispecific fusion protein is capable of binding to a target, antigen or epitope with a K D of about 0.5 nM or less. In one embodiment, a multispecific fusion protein provided herein is capable of binding a target, antigen or epitope with a K D of about 0.1 nM or less. In one embodiment, a multispecific fusion protein provided herein is capable of binding a target, antigen or epitope with a K D of about 50 pM or less. In one embodiment, a multispecific fusion protein provided herein is capable of binding a target, antigen or epitope with a K D of about 25 pM or less. In one embodiment, a multispecific fusion protein provided herein is capable of binding a target, antigen or epitope with a K D of about 10 pM or less. In one embodiment, a multispecific fusion protein provided herein is capable of binding a target, antigen or epitope with a K D of about 1 pM or less.

일 구체예에서, 제1 항원에 대한 다중 특이적 융합 단백질의 KD는 제2 항원에 대한 다중 특이적 융합 단백질 KD의 약 2 배, 3 배, 4 배, 5 배, 6 배, 7 배, 8 배, 9 배, 10 배, 15 배, 20 배, 50 배 이상일 수 있다. 일부 실시 양태에서, 제1 항원에 대한 다중 특이적 융합 단백질의 KD는 제2 항원에 대한 다중 특이적 융합 단백질 KD의 약 10, 102, 103 또는104 배일 수 있다.In one embodiment, the K D of the multispecific fusion protein for the first antigen is about 2 times, 3 times, 4 times, 5 times, 6 times, 7 times that of the multispecific fusion protein K D for the second antigen. , May be 8 times, 9 times, 10 times, 15 times, 20 times, 50 times or more. In some embodiments, the K D of the multispecific fusion protein for the first antigen may be about 10, 10 2 , 10 3 or 10 4 times that of the multispecific fusion protein K D for the second antigen.

본원 다중 특이적 융합 단백질은 화학적으로 변형된 형태일 수 있다. 일 실시예에서, 상기 융합 단백질은 글리코실화, 아세틸화, 페길화, 인산화, 아미드화, 공지된 보호기/차단기에 의한 유도체화, 단백질 분해 절단 및/또는 세포 리간드 또는 다른 단백질을 결합하여 화학적으로 변형될 수 있다. 이처럼 수많은 화학적 변형은 알려진 기술에 의해 수행될 수 있다.The multispecific fusion proteins herein may be in chemically modified form. In one embodiment, the fusion protein is chemically modified by glycosylation, acetylation, pegylation, phosphorylation, amidation, derivatization by known protecting groups/blockers, proteolytic cleavage and/or binding of cellular ligands or other proteins. Can be. Many of these chemical modifications can be performed by known techniques.

C 말단에 Fv가 존재하는 다중 특이적 융합 단백질Multispecific fusion protein with Fv at the C-terminus

상기 융합 단백질의 일 구체예는 하기 구조식 (I) 및 (II)를 포함하는 것일 수 있다:One embodiment of the fusion protein may include the following structural formulas (I) and (II):

N'-A-L1-X-C' (I); 및N'-A-L1-X-C' (I); And

N'-B-L1-Y-C' (II)N'-B-L1-Y-C' (II)

이때, 상기 구조식 (I) 및 (II)에 있어서,At this time, in the above structural formulas (I) and (II),

상기 N'은 융합 단백질의 N-말단이고,Wherein N'is the N-terminus of the fusion protein,

상기 C'은 융합 단백질의 C-말단이며,C'is the C-terminus of the fusion protein,

상기 A 및 B는 각각 제1 항원에 특이적이며,Each of A and B is specific for a first antigen,

상기 L1은 Cys을 적어도 하나 포함하는 펩타이드 링커이며,The L1 is a peptide linker containing at least one Cys,

X는 항체 가변 중쇄(VH) 영역 또는 항체 가변 경쇄(VL) 영역이며,X is an antibody variable heavy chain (VH) region or an antibody variable light chain (VL) region,

Y는 항체 가변 경쇄(VL) 영역 또는 항체 가변 중쇄(VH) 영역이며,Y is an antibody variable light chain (VL) region or an antibody variable heavy chain (VH) region,

상기 X 및 Y는 제2 항원에 특이적으로 결합하는 항체 가변 영역(Fv)을 형성한다.The X and Y form an antibody variable region (Fv) that specifically binds to the second antigen.

이때, 상기 A 및 B는 각각 항체 Fab 영역으로서, (i) 항체 가변 중쇄(VH) 영역 및 항체 CH1 영역을 포함하는 제1 부분; 및 (ii) 항체 가변 경쇄(VL) 영역 및 항체 경쇄 불변 영역(CL)을 포함하는 제2 부분으로 구성된 것일 수 있다.In this case, the A and B are each antibody Fab region, (i) a first portion including an antibody variable heavy chain (VH) region and an antibody CH1 region; And (ii) an antibody variable light chain (VL) region and an antibody light chain constant region (CL).

일 구체예에서, 상기 A 및 B는 2개의 Fab 영역으로 동일한 항원에 결합할 수 있다. 또한, 상기 A 및 B는 동일한 항원의 동일한 에피토프에 결합할 수 있다. 또한, 상기 A 및 B는 동일한 항원의 상이한 에피토프에 결합한다. 또 다른 구체예에서, 상기 A 및 B는 상이한 항원에 결합한다. In one embodiment, A and B may bind to the same antigen by two Fab regions. In addition, A and B may bind to the same epitope of the same antigen. In addition, A and B bind to different epitopes of the same antigen. In another embodiment, A and B bind different antigens.

다른 구체예에서, 제1 항원 결합 도메인 및 제2 항원 결합 도메인은 상이한 항원에 결합하고, 여기서 제1 항원 결합 도메인은 제1 항원에 결합하고 제2 항원 결합 도메인은 제2 항원에 결합할 수 있다. 도 3b 및 도 3c는 이러한 ALiCE 분자의 예시를 나타낸다. 여기서 ACE-05의 경우 첫 번째 항원 결합 도메인(2개의 Fab 영역)은 암 항원 (PD-L1)에 결합하고, 두 번째 항원 결합 도메인은 CD3와 같은 항원을 통해 T 세포와 같은 면역 세포에 결합한다. 또한, ACE-31의 경우 첫 번째 항원 결합 도메인(두 개의 Fab 영역)은 CD3와 같은 항원을 통해 T 세포와 같은 면역 세포에 결합한다. 또한, 두 번째 항원 결합 도메인은 암 항원 (PD-L1)에 결합한다. 이러한 ALiCE 분자는 면역 세포 (예를 들어, T 세포)를 암 세포에 결합시킬 수 있으므로 암 치료를 위한 치료제로 사용될 수 있다. In another embodiment, the first antigen binding domain and the second antigen binding domain bind different antigens, wherein the first antigen binding domain binds a first antigen and the second antigen binding domain is capable of binding a second antigen. . 3B and 3C show examples of such ALiCE molecules. Here, in the case of ACE-05, the first antigen-binding domain (two Fab regions) binds to the cancer antigen (PD-L1), and the second antigen-binding domain binds to immune cells such as T cells through antigens such as CD3. . In addition, in the case of ACE-31, the first antigen binding domain (two Fab regions) binds to immune cells such as T cells through antigens such as CD3. In addition, the second antigen binding domain binds to the cancer antigen (PD-L1). These ALiCE molecules can bind immune cells (eg, T cells) to cancer cells, and thus can be used as a therapeutic agent for cancer treatment.

구조식 (I)Structural Formula (I)

또한, 상기 구조식 (I)은 하기 구조식 (I') 및 (I'')을 포함하는 것일 수 있다:In addition, the structural formula (I) may include the following structural formulas (I') and (I''):

N'-A'-L1-X-C' (I'); 및 N'-A'-L1-X-C' (I'); And

N'-A''-C' (I'')N'-A''-C' (I'')

이때, 상기 구조식 (I') 및 (I'')에 있어서,At this time, in the above structural formulas (I') and (I''),

A'은 항체의 중쇄 영역으로서 가변영역 및 CH1 영역을 포함하거나, 또는 항체의 경쇄 영역이며;A'is a heavy chain region of an antibody and includes a variable region and a CH1 region, or is a light chain region of an antibody;

A''은 항체의 경쇄 영역이거나, 또는 항체의 중쇄 영역으로서 가변영역 및 CH1 영역을 포함하며,A'' is a light chain region of an antibody, or as a heavy chain region of an antibody, includes a variable region and a CH1 region,

이때, A' 및 A''은 결합하여 항체의 가변 영역을 형성하고, 이때 상기 가변 영역은 제1 항원에 특이적으로 결합한다. 이때, 상기 경쇄 영역은 경쇄 가변 영역 및 경쇄 불변 영역을 포함할 수 있다. 또한, N', L1, X 및 C'는 상기에서 정의한 바와 같다.At this time, A'and A'' bind to form a variable region of the antibody, wherein the variable region specifically binds to the first antigen. In this case, the light chain region may include a light chain variable region and a light chain constant region. In addition, N', L1, X and C'are as defined above.

구조식 (II)Structural Formula (II)

또한, 상기 구조식 (II)는 하기 구조식 (II') 및 (II'')을 포함하는 것일 수 있다:In addition, the structural formula (II) may include the following structural formulas (II') and (II''):

N'-B'-L1-Y-C' (II'); 및 N'-B'-L1-Y-C' (II'); And

N'-B''-C' (II'')N'-B''-C' (II'')

이때, 상기 구조식 (II') 및 (II'')에 있어서,At this time, in the above structural formulas (II') and (II''),

B'은 항체의 중쇄 영역으로서 가변영역 및 CH1 영역을 포함하거나, 또는 항체의 경쇄 영역이며;B'is a heavy chain region of an antibody and includes a variable region and a CH1 region, or is a light chain region of an antibody;

B''은 항체의 경쇄 영역이거나, 또는 항체의 중쇄 영역으로서 가변영역 및 CH1 영역을 포함하며;B'' is the light chain region of the antibody, or as the heavy chain region of the antibody comprises a variable region and a CH1 region;

이때, B' 및 B''은 결합하여 항체의 가변 영역을 형성하고, 이때 상기 가변 영역은 제1 항원에 특이적으로 결합한다. 이때, 상기 경쇄 영역은 경쇄 가변 영역 및 경쇄 불변 영역을 포함할 수 있다. 또한, N', L1, Y 및 C'는 상기에서 정의한 바와 같다.At this time, B'and B'' bind to form a variable region of the antibody, wherein the variable region specifically binds to the first antigen. In this case, the light chain region may include a light chain variable region and a light chain constant region. In addition, N', L1, Y and C'are as defined above.

N 말단에 Fv가 존재하는 다중 특이적 융합 단백질Multispecific fusion protein with Fv at the N-terminus

상기 융합 단백질의 또 다른 구체예는 하기 구조식 (III) 및 (IV)를 포함하는 것일 수 있다:Another embodiment of the fusion protein may be one comprising the following structural formulas (III) and (IV):

N'-X-L2-A-C' (III)N'-X-L2-A-C' (III)

N'-Y-L2-B-C' (IV)N'-Y-L2-B-C' (IV)

이때, 상기 구조식 (III) 및 (IV)에 있어서,In this case, in the structural formulas (III) and (IV),

상기 N'은 융합 단백질의 N-말단이고,Wherein N'is the N-terminus of the fusion protein,

상기 C'은 융합 단백질의 C-말단이며,C'is the C-terminus of the fusion protein,

상기 A 및 B는 각각 제1 항원에 특이적으로 결합하며,Each of A and B specifically binds to a first antigen,

상기 L2는 Cys을 적어도 하나 포함하는 펩타이드 링커이며,The L2 is a peptide linker containing at least one Cys,

X는 항체 가변 중쇄(VH) 영역 또는 항체 가변 경쇄(VL) 영역이며,X is an antibody variable heavy chain (VH) region or an antibody variable light chain (VL) region,

Y는 항체 가변 경쇄(VL) 영역 또는 항체 가변 중쇄(VH) 영역이며,Y is an antibody variable light chain (VL) region or an antibody variable heavy chain (VH) region,

상기 X 및 Y는 제2 항원에 특이적으로 결합하는 항체 가변 영역(Fv)을 형성한다.The X and Y form an antibody variable region (Fv) that specifically binds to the second antigen.

이때, 상기 A 및 B는 각각 항체 Fab 영역으로서, (i) 항체 가변 중쇄(VH) 영역 및 항체 CH1 영역을 포함하는 제1 부분; 및 (ii) 항체 가변 경쇄(VL) 영역 및 항체 경쇄 불변 영역(CL)을 포함하는 제2 부분으로 구성된 것일 수 있다.In this case, the A and B are each antibody Fab region, (i) a first portion including an antibody variable heavy chain (VH) region and an antibody CH1 region; And (ii) an antibody variable light chain (VL) region and an antibody light chain constant region (CL).

또한, 상기 구조식 (III)은 하기 구조식 (III') 및 (III'')을 포함하는 것일 수 있다:In addition, the structural formula (III) may include the following structural formulas (III') and (III"):

N'-X-L1-A'-C' (III'); 및 N'-X-L1-A'-C' (III'); And

N'-A''-C' (III'')N'-A''-C' (III'')

이때, 상기 구조식 (III') 및 (III'')에 있어서,At this time, in the above structural formulas (III') and (III''),

A'은 항체의 중쇄 영역으로서 가변영역 및 CH1 영역을 포함하거나, 또는 항체의 경쇄 영역이며;A'is a heavy chain region of an antibody and includes a variable region and a CH1 region, or is a light chain region of an antibody;

A''은 항체의 경쇄 영역이거나, 또는 항체의 중쇄 영역으로서 가변영역 및 CH1 영역을 포함하며;A'' is the light chain region of the antibody, or as the heavy chain region of the antibody comprises a variable region and a CH1 region;

이때, A' 및 A''은 결합하여 항체의 가변 영역을 형성하고, 이때 상기 가변 영역은 제1 항원에 특이적이다. At this time, A'and A'' combine to form a variable region of the antibody, wherein the variable region is specific for the first antigen.

또한, 상기 구조식 (IV)는 하기 구조식 (IV') 및 (IV'')을 포함하는 것일 수 있다:In addition, the structural formula (IV) may include the following structural formulas (IV') and (IV''):

N'-Y-L1-B'-C' (IV'); 및 N'-Y-L1-B'-C' (IV'); And

N'-B''-C' (IV'')N'-B''-C' (IV'')

이때, 상기 구조식 (IV') 및 (IV'')에 있어서,At this time, in the structural formulas (IV') and (IV''),

B'은 항체의 중쇄 영역으로서 가변영역 및 CH1 영역을 포함하거나, 또는 항체의 경쇄 영역이며;B'is a heavy chain region of an antibody and includes a variable region and a CH1 region, or is a light chain region of an antibody;

B''은 항체의 경쇄 영역이거나, 또는 항체의 중쇄 영역으로서 가변영역 및 CH1 영역을 포함하며;B'' is the light chain region of the antibody, or as the heavy chain region of the antibody comprises a variable region and a CH1 region;

이때, B' 및 B''은 결합하여 항체의 가변 영역을 형성하고, 이때 상기 가변 영역은 제1 항원에 특이적이다. At this time, B'and B'' bind to form a variable region of the antibody, wherein the variable region is specific for the first antigen.

링커Linker

이때, 상기 L1 및 L2는 면역글로불린 유래의 힌지 영역을 포함하는 것일 수 있다. 또한, 상기 L1 및 L2는 1개, 2개 또는 3개의 Cys을 포함할 수 있다. In this case, the L1 and L2 may include a hinge region derived from an immunoglobulin. In addition, the L1 and L2 may include 1, 2 or 3 Cys.

구체적으로, 상기 L1 및 L2는 각각 하기 구조식 (V)를 갖는 것일 수 있다:Specifically, each of L1 and L2 may have the following structural formula (V):

(L1')n-힌지-(L1'')m (V)(L1')n-hinge-(L1'')m (V)

이때, 상기 L1' 및 L1''은 각각 1 내지 15의 아미노산으로 구성된 링커이며,At this time, the L1' and L1'' are each a linker consisting of 1 to 15 amino acids,

n 및 m은 0 또는 1의 정수이며,n and m are integers of 0 or 1,

힌지는 면역글로불린 유래의 힌지 영역이다.The hinge is an immunoglobulin-derived hinge region.

일 구체예에서, 항체 힌지 영역은 IgG 힌지 영역이다. 본원에 제공된 IgG 힌지 영역은, 예를 들어 다양한 IgG 서브 타입의 항체 힌지 영역으로부터 선택될 수 있다. 아래 표는 본원에서 제공되는 유연한 펩티드 영역에 포함될 수 있는 코어 힌지 서열을 가진 예시적인 IgG 하위 유형을 나열한다.In one embodiment, the antibody hinge region is an IgG hinge region. The IgG hinge regions provided herein can be selected from, for example, antibody hinge regions of various IgG subtypes. The table below lists exemplary IgG subtypes with core hinge sequences that can be included in the flexible peptide regions provided herein.

IgG subtypeIgG subtype Core hinge sequenceCore hinge sequence 서열번호Sequence number IgG1IgG1 EPKSCDKTHTCPPCPEPKSCDKTHTCPPCP 5555 IgG2IgG2 ERKCCVECPPCPERKCCVECPPCP 5656 IgG3IgG3 ELKTPLDTTHTCPRCP(EPKSCDTPPPCPRCP)3 ELKTPLDTTHTCPRCP(EPKSCDTPPPCPRCP) 3 5757 IgG4IgG4 ESKYGPPCPSCPESKYGPPCPSCP 5858

Hinge Region SequenceHinge Region Sequence 서열번호Sequence number DKTHTCPPCPPCPAPELLGGPDKTHTCPPCPPCPAPELLGGP 385385 DKTHTCPPCPAPELLGGPDKTHTCPPCPAPELLGGP 386386 DKTHTCPPCPPCPAPELLGDKTHTCPPCPPCPAPELLG 387387

상기 힌지는 추가의 이황화 결합을 도입하도록 변형될 수 있다. 힌지 영역은 2개를 초과하는 이황화 결합을 포함할 수 있다. 힌지 영역은 예를 들어, 2, 4, 6, 8 또는 10개의 이황화 결합, 4, 6, 8, 10개의 이황화 결합, 4개의 이황화 결합과 같은 짝수의 이황화 결합을 포함할 수 있다. 일 실시예에서, 힌지 영역은 예를 들어 1, 3, 5, 7 또는 9개의 이황화 결합, 3, 5, 7 또는 9개의 이황화 결합, 3개의 이황화 결합과 같은 홀수 개의 이황화 결합을 포함할 수 있다. 도 3g는 다중 특이적 융합 단백질의 대표적인 예를 보여주며, 여기서 힌지 영역은 다중 특이적 융합 단백질의 중쇄 사이에 2개 및 3개의 이황화 결합이 형성되도록 제조되었다. The hinge can be modified to introduce additional disulfide bonds. The hinge region may contain more than two disulfide bonds. The hinge region may contain an even number of disulfide bonds such as, for example, 2, 4, 6, 8 or 10 disulfide bonds, 4, 6, 8, 10 disulfide bonds, and 4 disulfide bonds. In one embodiment, the hinge region may comprise an odd number of disulfide bonds such as 1, 3, 5, 7 or 9 disulfide bonds, 3, 5, 7 or 9 disulfide bonds, 3 disulfide bonds. . 3G shows a representative example of a multispecific fusion protein, wherein the hinge region was prepared such that two and three disulfide bonds were formed between the heavy chains of the multispecific fusion protein.

힌지 영역은 아미노산 서열 (PPC)n을 포함하며, 여기서 n은 정수이다. 일부 실시 양태에서, n은 예를 들어 2, 4, 6, 8 또는 10, 예를 들어 4, 6, 8 또는 10, 예를 들어 4와 같은 짝수일 수 있다. 다른 구체 예에서, n은 예를 들어 1, 3, 5, 7, 또는 9, 예를 들어 3, 5, 7, 또는 9, 예를 들어 3과 같은 홀수일 수 있다. 또한, 힌지 간 이황화 결합은 한 힌지 영역의 시스테인 잔기와 다른 힌지 영역의 시스테인 잔기 사이에 형성된다. The hinge region comprises an amino acid sequence (PPC) n , where n is an integer. In some embodiments, n can be an even number, such as 2, 4, 6, 8 or 10, for example 4, 6, 8 or 10, for example 4. In other embodiments, n can be an odd number, for example 1, 3, 5, 7, or 9, for example 3, 5, 7, or 9, for example 3. In addition, an inter-hinge disulfide bond is formed between a cysteine residue in one hinge region and a cysteine residue in another hinge region.

상기 L1' 및 L1''은 각각 1 내지 20개의 아미노산으로 이루어진 펩타이드일 수 있다. 구체적으로, 상기 L1' 및 L1''은 (G4S)p(p는 1 내지 10의 정수)와 같은 아미노산일 수 있다. 구체적으로, L1' 및 L1''은 (G4S)1, (G4S)2, (G4S)3, 또는 (G4S)4일 수 있다.Each of L1' and L1'' may be a peptide consisting of 1 to 20 amino acids. Specifically, the L1′ and L1″ may be amino acids such as (G4S)p (p is an integer of 1 to 10). Specifically, L1' and L1'' may be (G4S) 1 , (G4S) 2 , (G4S) 3 , or (G4S) 4 .

L1' 및/또는 L1''의 길이는 다양할 수 있다. 일부 구현 예에서, L1' 및/또는 L1''는 5 개 아미노산 길이이다. 다른 구체 예에서, L1' 및/또는 L1''는 9 개 아미노산 길이이다. 또 다른 구체 예에서, L1' 및/또는 L1''는 10 개 아미노산 길이이다. 아래 표는 L1' 및/또는 L1''의 대표적인 예를 보여준다.The length of L1′ and/or L1″ may vary. In some embodiments, LI' and/or LI'' is 5 amino acids long. In another embodiment, L1' and/or L1'' is 9 amino acids long. In another embodiment, L1' and/or L1'' is 10 amino acids long. The table below shows representative examples of L1' and/or L1''.

Linker SequenceLinker Sequence 서열번호Sequence number GGGGSGGGGS 112112 GGGGSGGGGSGGGGSGGGGS 113113 GGSGGGGSGGGSGGGGSG 114114

제1 항원First antigen

제1 항원은 암 항원(Tumor-Specific Antigens), 또는 면역세포 표면에 존재하는 단백질일 수 있으며, 또는 사이토카인일 수 있다. 제1 항원은 PD-L1, PD-1, EGFR, TNFR, BCMA, CD22, CD25, CD30, CD33, CD37, CD38, CD52, CD56, CD123, cMET, DLL3, GD2, Nectin-4, RANKL, SLAMF7, TROP2, Claudin 18.2, TNFR, TNF, CD3, HER2, CD20, CD19, CTLA-4, VEGFR, VEGF, NCAM1, ICAM-1, ICAM-2, CEACAM6, Carcinoembryonic antigen(CEA), CA-125, Alphafetoprotein (AFP), MUC-1, Epithelial tumor antigen (ETA), Melanoma-associated antigen (MAGE), Immature laminin receptor, TAG-72, HPV E6/E7, BING-4, Calcium-activated chloride channel 2, Cyclin-B1, 9D7, Ep-CAM, EphA3, Mesothelin, SAP-1, Survivin 또는 바이러스 유래 항원일 수 있다.The first antigen may be a cancer antigen (Tumor-Specific Antigens), or a protein present on the surface of an immune cell, or may be a cytokine. The first antigen is PD-L1, PD-1, EGFR, TNFR, BCMA, CD22, CD25, CD30, CD33, CD37, CD38, CD52, CD56, CD123, cMET, DLL3, GD2, Nectin-4, RANKL, SLAMF7, TROP2, Claudin 18.2, TNFR, TNF, CD3, HER2, CD20, CD19, CTLA-4, VEGFR, VEGF, NCAM1, ICAM-1, ICAM-2, CEACAM6, Carcinoembryonic antigen (CEA), CA-125, Alphafetoprotein (AFP ), MUC-1, Epithelial tumor antigen (ETA), Melanoma-associated antigen (MAGE), Immature laminin receptor, TAG-72, HPV E6/E7, BING-4, Calcium-activated chloride channel 2, Cyclin-B1, 9D7 , Ep-CAM, EphA3, Mesothelin, SAP-1, Survivin or virus-derived antigens.

구체적으로, 상기 제1 항원은 암 항원일 수 있다. 이때, 상기 암 항원은 PD-L1, EGFR, BCMA, CD19, CD20, CD22, CD25, CD30, CD33, CD37, CD38, CD52, CD56, CD123, HER2, cMET, DLL3, GD2, Nectin-4, RANKL, SLAMF7, TROP2, Claudin 18.2, MUC-1, Mesothelin, EpCAM 및 CEA로 이루어진 군에서 선택되는 어느 하나 일 수 있다.Specifically, the first antigen may be a cancer antigen. At this time, the cancer antigens are PD-L1, EGFR, BCMA, CD19, CD20, CD22, CD25, CD30, CD33, CD37, CD38, CD52, CD56, CD123, HER2, cMET, DLL3, GD2, Nectin-4, RANKL, It may be any one selected from the group consisting of SLAMF7, TROP2, Claudin 18.2, MUC-1, Mesothelin, EpCAM and CEA.

이때, 일 실시예에서, 제1 항원은 T 세포 기능을 조절하는 세포 표면 분자일 수 있다. 또 다른 실시예에서, 제1 항원은 면역 관문 억제제일 수 있다. 또한, 제1 항원은 암 항원일 수 있다.At this time, in one embodiment, the first antigen may be a cell surface molecule that regulates T cell function. In another embodiment, the first antigen may be an immune checkpoint inhibitor. In addition, the first antigen may be a cancer antigen.

또한, 제1 항원은 림프구 및 단핵구와 같은 면역세포 표면에 발현되는 단백질일 수 있다. 구체적으로, T 세포, B 세포, 수지상 세포, 과립구, 거핵구, 단핵구, 및 NK 세포 등의 세포에서 발현되는 단백질일 수 있다. 또한, 제1 항원은 CD8 + T 세포 또는 CD4 + T 세포에서 발현되는 단백질일 수 있다.In addition, the first antigen may be a protein expressed on the surface of immune cells such as lymphocytes and monocytes. Specifically, it may be a protein expressed in cells such as T cells, B cells, dendritic cells, granulocytes, megakaryocytes, monocytes, and NK cells. In addition, the first antigen may be a protein expressed on CD8 + T cells or CD4 + T cells.

상기 구조식에서 A 및 B가 동일한 항원을 인식할 수 있다. 또한, A 및 B가 서로 다른 항원을 인식할 수 있다.In the above structural formula, A and B can recognize the same antigen. In addition, A and B can recognize different antigens.

일 실시예로, 상기 A 및/또는 B는 PD-L1, HER2, CD19, CD20, EGFR, CD3, TNF 및 CTLA-4로 구성된 그룹에서 선택되는 어느 하나의 항원에 특이적으로 결합할 수 있다. 구체적으로, 상기 A 및/또는 B는 하기에서 선택되는 어느 하나의 가변 영역을 포함할 수 있다:In one embodiment, A and/or B may specifically bind to any one antigen selected from the group consisting of PD-L1, HER2, CD19, CD20, EGFR, CD3, TNF, and CTLA-4. Specifically, A and/or B may include any one variable region selected from:

PD-L1:PD-L1:

1) 서열번호 5(VH-CDR1), 서열번호 6(VH-CDR2) 및 서열번호 7(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 9(VL-CDR1), 서열번호 10(VL-CDR2) 및 서열번호 11(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;1) VH region comprising the amino acid sequence of SEQ ID NO: 5 (VH-CDR1), SEQ ID NO: 6 (VH-CDR2) and SEQ ID NO: 7 (VH-CDR3), and SEQ ID NO: 9 (VL-CDR1), SEQ ID NO: 10 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 11 (VL-CDR3);

2) 서열번호 159(VH-CDR1), 서열번호 160(VH-CDR2) 및 서열번호 161(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 171(VL-CDR1), 서열번호 172(VL-CDR2) 및 서열번호 173(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;2) a VH region comprising the amino acid sequence of SEQ ID NO: 159 (VH-CDR1), SEQ ID NO: 160 (VH-CDR2) and SEQ ID NO: 161 (VH-CDR3), and SEQ ID NO: 171 (VL-CDR1), SEQ ID NO: 172 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 173 (VL-CDR3);

3) 서열번호 159(VH-CDR1), 서열번호 160(VH-CDR2) 및 서열번호 161(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 314(VL-CDR1), 서열번호 315(VL-CDR2) 및 서열번호 316(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;3) VH region comprising the amino acid sequence of SEQ ID NO: 159 (VH-CDR1), SEQ ID NO: 160 (VH-CDR2) and SEQ ID NO: 161 (VH-CDR3), and SEQ ID NO: 314 (VL-CDR1), SEQ ID NO: 315 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 316 (VL-CDR3);

4) 서열번호 330(VH-CDR1), 서열번호 331(VH-CDR2) 및 서열번호 332(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 334(VL-CDR1), 서열번호 335(VL-CDR2) 및 서열번호 336(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;4) VH region comprising the amino acid sequence of SEQ ID NO: 330 (VH-CDR1), SEQ ID NO: 331 (VH-CDR2) and SEQ ID NO: 332 (VH-CDR3), and SEQ ID NO: 334 (VL-CDR1), SEQ ID NO: 335 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 336 (VL-CDR3);

HER2:HER2:

5) 서열번호 118(VH-CDR1), 서열번호 119(VH-CDR2) 및 서열번호 120(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 121(VL-CDR1), 서열번호 122(VL-CDR2) 및 서열번호 123(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;5) VH region comprising the amino acid sequence of SEQ ID NO: 118 (VH-CDR1), SEQ ID NO: 119 (VH-CDR2) and SEQ ID NO: 120 (VH-CDR3), and SEQ ID NO: 121 (VL-CDR1), SEQ ID NO: 122 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 123 (VL-CDR3);

6) 서열번호 276(VH-CDR1), 서열번호 277(VH-CDR2) 및 서열번호 278(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 288(VL-CDR1), 서열번호 289(VL-CDR2) 및 서열번호 290(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;6) VH region comprising the amino acid sequence of SEQ ID NO: 276 (VH-CDR1), SEQ ID NO: 277 (VH-CDR2) and SEQ ID NO: 278 (VH-CDR3), and SEQ ID NO: 288 (VL-CDR1), SEQ ID NO: 289 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 290 (VL-CDR3);

CD19:CD19:

7) 서열번호 140(VH-CDR1), 서열번호 141(VH-CDR2) 및 서열번호 142(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 152(VL-CDR1), 서열번호 153(VL-CDR2) 및 서열번호 154(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;7) VH region comprising the amino acid sequence of SEQ ID NO: 140 (VH-CDR1), SEQ ID NO: 141 (VH-CDR2) and SEQ ID NO: 142 (VH-CDR3), and SEQ ID NO: 152 (VL-CDR1), SEQ ID NO: 153 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 154 (VL-CDR3);

8) 서열번호 62(VH-CDR1), 서열번호 63(VH-CDR2) 및 서열번호 64(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 66(VL-CDR1), 서열번호 67(VL-CDR2) 및 서열번호 68(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;8) VH region comprising the amino acid sequence of SEQ ID NO: 62 (VH-CDR1), SEQ ID NO: 63 (VH-CDR2) and SEQ ID NO: 64 (VH-CDR3), and SEQ ID NO: 66 (VL-CDR1), SEQ ID NO: 67 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 68 (VL-CDR3);

CD20:CD20:

9) 서열번호 223(VH-CDR1), 서열번호 224(VH-CDR2) 및 서열번호 225(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 227(VL-CDR1), 서열번호 228(VL-CDR2) 및 서열번호 229(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;9) VH region comprising the amino acid sequence of SEQ ID NO: 223 (VH-CDR1), SEQ ID NO: 224 (VH-CDR2) and SEQ ID NO: 225 (VH-CDR3), and SEQ ID NO: 227 (VL-CDR1), SEQ ID NO: 228 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 229 (VL-CDR3);

10) 서열번호 436(VH-CDR1), 서열번호 437(VH-CDR2) 및 서열번호 438(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 441(VL-CDR1), 서열번호 442(VL-CDR2) 및 서열번호 443(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;10) VH region comprising the amino acid sequence of SEQ ID NO: 436 (VH-CDR1), SEQ ID NO: 437 (VH-CDR2) and SEQ ID NO: 438 (VH-CDR3), and SEQ ID NO: 441 (VL-CDR1), SEQ ID NO: 442 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 443 (VL-CDR3);

EGFR:EGFR:

11) 서열번호 234(VH-CDR1), 서열번호 235(VH-CDR2) 및 서열번호 236(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 238(VL-CDR1), 서열번호 239(VL-CDR2) 및 서열번호 240(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;11) VH region comprising the amino acid sequence of SEQ ID NO: 234 (VH-CDR1), SEQ ID NO: 235 (VH-CDR2) and SEQ ID NO: 236 (VH-CDR3), and SEQ ID NO: 238 (VL-CDR1), SEQ ID NO: 239 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 240 (VL-CDR3);

12) 서열번호 245(VH-CDR1), 서열번호 246(VH-CDR2) 및 서열번호 247(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 249(VL-CDR1), 서열번호 250(VL-CDR2) 및 서열번호 251(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;12) VH region comprising the amino acid sequence of SEQ ID NO: 245 (VH-CDR1), SEQ ID NO: 246 (VH-CDR2) and SEQ ID NO: 247 (VH-CDR3), and SEQ ID NO: 249 (VL-CDR1), SEQ ID NO: 250 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 251 (VL-CDR3);

13) 서열번호 256(VH-CDR1), 서열번호 257(VH-CDR2) 및 서열번호 258(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 260(VL-CDR1), 서열번호 261(VL-CDR2) 및 서열번호 262(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;13) VH region comprising the amino acid sequence of SEQ ID NO: 256 (VH-CDR1), SEQ ID NO: 257 (VH-CDR2) and SEQ ID NO: 258 (VH-CDR3), and SEQ ID NO: 260 (VL-CDR1), SEQ ID NO: 261 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 262 (VL-CDR3);

14) 서열번호 234(VH-CDR1), 서열번호 235(VH-CDR2) 및 서열번호 236(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 238(VL-CDR1), 서열번호 239(VL-CDR2) 및 서열번호 240(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;14) VH region comprising the amino acid sequence of SEQ ID NO: 234 (VH-CDR1), SEQ ID NO: 235 (VH-CDR2) and SEQ ID NO: 236 (VH-CDR3), and SEQ ID NO: 238 (VL-CDR1), SEQ ID NO: 239 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 240 (VL-CDR3);

CD3:CD3:

15) 서열번호 326(VH-CDR1), 서열번호 327(VH-CDR2) 및 서열번호 328(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 338(VL-CDR1), 서열번호 339(VL-CDR2) 및 서열번호 340(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;15) VH region comprising the amino acid sequence of SEQ ID NO: 326 (VH-CDR1), SEQ ID NO: 327 (VH-CDR2) and SEQ ID NO: 328 (VH-CDR3), and SEQ ID NO: 338 (VL-CDR1), SEQ ID NO: 339 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 340 (VL-CDR3);

16) 서열번호 330(VH-CDR1), 서열번호 331(VH-CDR2) 및 서열번호 332(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 334(VL-CDR1), 서열번호 335(VL-CDR2) 및 서열번호 336(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;16) VH region comprising the amino acid sequence of SEQ ID NO: 330 (VH-CDR1), SEQ ID NO: 331 (VH-CDR2) and SEQ ID NO: 332 (VH-CDR3), and SEQ ID NO: 334 (VL-CDR1), SEQ ID NO: 335 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 336 (VL-CDR3);

17) 서열번호 163(VH-CDR1), 서열번호 271(VH-CDR2) 및 서열번호 165(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 167(VL-CDR1), 서열번호 168(VL-CDR2) 및 서열번호 169(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;17) VH region comprising the amino acid sequence of SEQ ID NO: 163 (VH-CDR1), SEQ ID NO: 271 (VH-CDR2) and SEQ ID NO: 165 (VH-CDR3), and SEQ ID NO: 167 (VL-CDR1), SEQ ID NO: 168 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 169 (VL-CDR3);

18) 서열번호 396(VH-CDR1), 서열번호 397(VH-CDR2) 및 서열번호 398(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 402(VL-CDR1), 서열번호 403(VL-CDR2) 및 서열번호 404(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;18) VH region comprising the amino acid sequence of SEQ ID NO: 396 (VH-CDR1), SEQ ID NO: 397 (VH-CDR2) and SEQ ID NO: 398 (VH-CDR3), and SEQ ID NO: 402 (VL-CDR1), SEQ ID NO: 403 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 404 (VL-CDR3);

19) 서열번호 144(VH-CDR1), 서열번호 145(VH-CDR2) 및 서열번호 146(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 148(VL-CDR1), 서열번호 149(VL-CDR2) 및 서열번호 410(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;19) VH region comprising the amino acid sequence of SEQ ID NO: 144 (VH-CDR1), SEQ ID NO: 145 (VH-CDR2) and SEQ ID NO: 146 (VH-CDR3), and SEQ ID NO: 148 (VL-CDR1), SEQ ID NO: 149 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 410 (VL-CDR3);

20) 서열번호 144(VH-CDR1), 서열번호 145(VH-CDR2) 및 서열번호 146(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 148(VL-CDR1), 서열번호 149(VL-CDR2) 및 서열번호 150(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;20) VH region comprising the amino acid sequence of SEQ ID NO: 144 (VH-CDR1), SEQ ID NO: 145 (VH-CDR2) and SEQ ID NO: 146 (VH-CDR3), and SEQ ID NO: 148 (VL-CDR1), SEQ ID NO: 149 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 150 (VL-CDR3);

21) 서열번호 70(VH-CDR1), 서열번호 71(VH-CDR2) 및 서열번호 72(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 74(VL-CDR1), 서열번호 75(VL-CDR2) 및 서열번호 76(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;21) VH region comprising the amino acid sequence of SEQ ID NO: 70 (VH-CDR1), SEQ ID NO: 71 (VH-CDR2) and SEQ ID NO: 72 (VH-CDR3), and SEQ ID NO: 74 (VL-CDR1), SEQ ID NO: 75 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 76 (VL-CDR3);

22) 서열번호 78(VH-CDR1), 서열번호 79(VH-CDR2) 및 서열번호 80(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 82(VL-CDR1), 서열번호 83(VL-CDR2) 및 서열번호 84(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;22) VH region comprising the amino acid sequence of SEQ ID NO: 78 (VH-CDR1), SEQ ID NO: 79 (VH-CDR2) and SEQ ID NO: 80 (VH-CDR3), and SEQ ID NO: 82 (VL-CDR1), SEQ ID NO: 83 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 84 (VL-CDR3);

23) 서열번호 295(VH-CDR1), 서열번호 296(VH-CDR2) 및 서열번호 297(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 299(VL-CDR1), 서열번호 300(VL-CDR2) 및 서열번호 301(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;23) VH region comprising the amino acid sequence of SEQ ID NO: 295 (VH-CDR1), SEQ ID NO: 296 (VH-CDR2) and SEQ ID NO: 297 (VH-CDR3), and SEQ ID NO: 299 (VL-CDR1), SEQ ID NO: 300 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 301 (VL-CDR3);

24) 서열번호 78(VH-CDR1), 서열번호 79(VH-CDR2) 및 서열번호 80(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 82(VL-CDR1), 서열번호 83(VL-CDR2) 및 서열번호 87(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;24) VH region comprising the amino acid sequence of SEQ ID NO: 78 (VH-CDR1), SEQ ID NO: 79 (VH-CDR2) and SEQ ID NO: 80 (VH-CDR3), and SEQ ID NO: 82 (VL-CDR1), SEQ ID NO: 83 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 87 (VL-CDR3);

25) 서열번호 163(VH-CDR1), 서열번호 271(VH-CDR2) 및 서열번호 165(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 167(VL-CDR1), 서열번호 168(VL-CDR2) 및 서열번호 169(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;25) VH region comprising the amino acid sequence of SEQ ID NO: 163 (VH-CDR1), SEQ ID NO: 271 (VH-CDR2) and SEQ ID NO: 165 (VH-CDR3), and SEQ ID NO: 167 (VL-CDR1), SEQ ID NO: 168 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 169 (VL-CDR3);

26) 서열번호 177(VH-CDR1), 서열번호 178(VH-CDR2) 및 서열번호 179(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 181(VL-CDR1), 서열번호 182(VL-CDR2) 및 서열번호 183(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;26) VH region comprising the amino acid sequence of SEQ ID NO: 177 (VH-CDR1), SEQ ID NO: 178 (VH-CDR2) and SEQ ID NO: 179 (VH-CDR3), and SEQ ID NO: 181 (VL-CDR1), SEQ ID NO: 182 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 183 (VL-CDR3);

27) 서열번호 187(VH-CDR1), 서열번호 188(VH-CDR2) 및 서열번호 189(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 191(VL-CDR1), 서열번호 192(VL-CDR2) 및 서열번호 193(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;27) VH region comprising the amino acid sequence of SEQ ID NO: 187 (VH-CDR1), SEQ ID NO: 188 (VH-CDR2) and SEQ ID NO: 189 (VH-CDR3), and SEQ ID NO: 191 (VL-CDR1), SEQ ID NO: 192 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 193 (VL-CDR3);

28) 서열번호 177(VH-CDR1), 서열번호 178(VH-CDR2) 및 서열번호 179(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 181(VL-CDR1), 서열번호 182(VL-CDR2) 및 서열번호 207(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;28) VH region comprising the amino acid sequence of SEQ ID NO: 177 (VH-CDR1), SEQ ID NO: 178 (VH-CDR2) and SEQ ID NO: 179 (VH-CDR3), and SEQ ID NO: 181 (VL-CDR1), SEQ ID NO: 182 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 207 (VL-CDR3);

29) 서열번호 177(VH-CDR1), 서열번호 178(VH-CDR2) 및 서열번호 211(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 181(VL-CDR1), 서열번호 182(VL-CDR2) 및 서열번호 207(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;29) VH region comprising the amino acid sequence of SEQ ID NO: 177 (VH-CDR1), SEQ ID NO: 178 (VH-CDR2) and SEQ ID NO: 211 (VH-CDR3), and SEQ ID NO: 181 (VL-CDR1), SEQ ID NO: 182 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 207 (VL-CDR3);

30) 서열번호 306(VH-CDR1), 서열번호 307(VH-CDR2) 및 서열번호 308(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 310(VL-CDR1), 서열번호 311(VL-CDR2) 및 서열번호 312(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;30) VH region comprising the amino acid sequence of SEQ ID NO: 306 (VH-CDR1), SEQ ID NO: 307 (VH-CDR2) and SEQ ID NO: 308 (VH-CDR3), and SEQ ID NO: 310 (VL-CDR1), SEQ ID NO: 311 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 312 (VL-CDR3);

31) 서열번호 349(VH-CDR1), 서열번호 350(VH-CDR2) 및 서열번호 351(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 353(VL-CDR1), 서열번호 354(VL-CDR2) 및 서열번호 355(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;31) VH region comprising the amino acid sequence of SEQ ID NO: 349 (VH-CDR1), SEQ ID NO: 350 (VH-CDR2) and SEQ ID NO: 351 (VH-CDR3), and SEQ ID NO: 353 (VL-CDR1), SEQ ID NO: 354 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 355 (VL-CDR3);

32) 서열번호 359(VH-CDR1), 서열번호 360(VH-CDR2) 및 서열번호 361(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 363(VL-CDR1), 서열번호 364(VL-CDR2) 및 서열번호 365(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;32) VH region comprising the amino acid sequence of SEQ ID NO: 359 (VH-CDR1), SEQ ID NO: 360 (VH-CDR2) and SEQ ID NO: 361 (VH-CDR3), and SEQ ID NO: 363 (VL-CDR1), SEQ ID NO: 364 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 365 (VL-CDR3);

33) 서열번호 197(VH-CDR1), 서열번호 198(VH-CDR2) 및 서열번호 199(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 201(VL-CDR1), 서열번호 202(VL-CDR2) 및 서열번호 203(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;33) VH region comprising the amino acid sequence of SEQ ID NO: 197 (VH-CDR1), SEQ ID NO: 198 (VH-CDR2) and SEQ ID NO: 199 (VH-CDR3), and SEQ ID NO: 201 (VL-CDR1), SEQ ID NO: 202 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 203 (VL-CDR3);

TNF: TNF:

34) 서열번호 124(VH-CDR1), 서열번호 125(VH-CDR2) 및 서열번호 126(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 127(VL-CDR1), 서열번호 128(VL-CDR2) 및 서열번호 129(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;34) VH region comprising the amino acid sequence of SEQ ID NO: 124 (VH-CDR1), SEQ ID NO: 125 (VH-CDR2) and SEQ ID NO: 126 (VH-CDR3), and SEQ ID NO: 127 (VL-CDR1), SEQ ID NO: 128 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 129 (VL-CDR3);

35) 서열번호 280(VH-CDR1), 서열번호 281(VH-CDR2) 및 서열번호 282(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 284(VL-CDR1), 서열번호 285(VL-CDR2) 및 서열번호 286(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;35) VH region comprising the amino acid sequence of SEQ ID NO: 280 (VH-CDR1), SEQ ID NO: 281 (VH-CDR2) and SEQ ID NO: 282 (VH-CDR3), and SEQ ID NO: 284 (VL-CDR1), SEQ ID NO: 285 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 286 (VL-CDR3);

36) 서열번호 276(VH-CDR1), 서열번호 277(VH-CDR2) 및 서열번호 278(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 288(VL-CDR1), 서열번호 289(VL-CDR2) 및 서열번호 290(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역; 및36) VH region comprising the amino acid sequence of SEQ ID NO: 276 (VH-CDR1), SEQ ID NO: 277 (VH-CDR2) and SEQ ID NO: 278 (VH-CDR3), and SEQ ID NO: 288 (VL-CDR1), SEQ ID NO: 289 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 290 (VL-CDR3); And

CTLA-4:CTLA-4:

37) 서열번호 369(VH-CDR1), 서열번호 370(VH-CDR2) 및 서열번호 371(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 373(VL-CDR1), 서열번호 374(VL-CDR2) 및 서열번호 375(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역.37) VH region comprising the amino acid sequence of SEQ ID NO: 369 (VH-CDR1), SEQ ID NO: 370 (VH-CDR2) and SEQ ID NO: 371 (VH-CDR3), and SEQ ID NO: 373 (VL-CDR1), SEQ ID NO: 374 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 375 (VL-CDR3).

또한, 상기 A 또는 B는 하기의 그룹에서 선택되는 어느 하나의 가변영역을 포함할 수 있다:In addition, A or B may include any one variable region selected from the following group:

PD-L1:PD-L1:

1) 서열번호 4의 중쇄 가변 영역(VH) 및 서열번호 8의 경쇄 가변 영역(VL);1) the heavy chain variable region of SEQ ID NO: 4 (VH) and the light chain variable region of SEQ ID NO: 8 (VL);

2) 서열번호 158의 중쇄 가변 영역(VH) 및 서열번호 170의 경쇄 가변 영역(VL);2) the heavy chain variable region of SEQ ID NO: 158 (VH) and the light chain variable region of SEQ ID NO: 170 (VL);

3) 서열번호 158의 중쇄 가변 영역(VH) 및 서열번호 313의 경쇄 가변 영역(VL);3) the heavy chain variable region of SEQ ID NO: 158 (VH) and the light chain variable region of SEQ ID NO: 313 (VL);

4) 서열번호 329의 중쇄 가변 영역(VH) 및 서열번호 333의 경쇄 가변 영역(VL);4) the heavy chain variable region of SEQ ID NO: 329 (VH) and the light chain variable region of SEQ ID NO: 333 (VL);

5) 서열번호 329의 중쇄 가변 영역(VH) 및 서열번호 376의 경쇄 가변 영역(VL);5) the heavy chain variable region of SEQ ID NO: 329 (VH) and the light chain variable region of SEQ ID NO: 376 (VL);

HER2:HER2:

6) 서열번호 51의 중쇄 가변 영역(VH) 및 서열번호 52의 경쇄 가변 영역(VL);6) the heavy chain variable region of SEQ ID NO: 51 (VH) and the light chain variable region of SEQ ID NO: 52 (VL);

7) 서열번호 275의 중쇄 가변 영역(VH) 및 서열번호 287의 경쇄 가변 영역(VL);7) the heavy chain variable region of SEQ ID NO: 275 (VH) and the light chain variable region of SEQ ID NO: 287 (VL);

CD19:CD19:

8) 서열번호 139의 중쇄 가변 영역(VH) 및 서열번호 151의 경쇄 가변 영역(VL);8) the heavy chain variable region of SEQ ID NO: 139 (VH) and the light chain variable region of SEQ ID NO: 151 (VL);

9) 서열번호 61의 중쇄 가변 영역(VH) 및 서열번호 65의 경쇄 가변 영역(VL);9) the heavy chain variable region of SEQ ID NO: 61 (VH) and the light chain variable region of SEQ ID NO: 65 (VL);

CD20: CD20:

10) 서열번호 222의 중쇄 가변 영역(VH) 및 서열번호 226의 경쇄 가변 영역(VL);10) the heavy chain variable region of SEQ ID NO: 222 (VH) and the light chain variable region of SEQ ID NO: 226 (VL);

11) 서열번호 435의 중쇄 가변 영역(VH) 및 서열번호 440의 경쇄 가변 영역(VL);11) the heavy chain variable region of SEQ ID NO: 435 (VH) and the light chain variable region of SEQ ID NO: 440 (VL);

EGFR: EGFR:

12) 서열번호 233의 중쇄 가변 영역(VH) 및 서열번호 237의 경쇄 가변 영역(VL);12) the heavy chain variable region of SEQ ID NO: 233 (VH) and the light chain variable region of SEQ ID NO: 237 (VL);

13) 서열번호 244의 중쇄 가변 영역(VH) 및 서열번호 248의 경쇄 가변 영역(VL);13) the heavy chain variable region of SEQ ID NO: 244 (VH) and the light chain variable region of SEQ ID NO: 248 (VL);

14) 서열번호 255의 중쇄 가변 영역(VH) 및 서열번호 259의 경쇄 가변 영역(VL);14) the heavy chain variable region of SEQ ID NO: 255 (VH) and the light chain variable region of SEQ ID NO: 259 (VL);

CD3:CD3:

15) 서열번호 325의 중쇄 가변 영역(VH) 및 서열번호 337의 경쇄 가변 영역(VL);15) the heavy chain variable region of SEQ ID NO: 325 (VH) and the light chain variable region of SEQ ID NO: 337 (VL);

16) 서열번호 329의 중쇄 가변 영역(VH) 및 서열번호 376의 경쇄 가변 영역(VL);16) the heavy chain variable region of SEQ ID NO: 329 (VH) and the light chain variable region of SEQ ID NO: 376 (VL);

17) 서열번호 162의 중쇄 가변 영역(VH) 및 서열번호 166의 경쇄 가변 영역(VL);17) the heavy chain variable region of SEQ ID NO: 162 (VH) and the light chain variable region of SEQ ID NO: 166 (VL);

18) 서열번호 395의 중쇄 가변 영역(VH) 및 서열번호 401의 경쇄 가변 영역(VL);18) the heavy chain variable region of SEQ ID NO: 395 (VH) and the light chain variable region of SEQ ID NO: 401 (VL);

19) 서열번호 406의 중쇄 가변 영역(VH) 및 서열번호 409의 경쇄 가변 영역(VL);19) the heavy chain variable region of SEQ ID NO: 406 (VH) and the light chain variable region of SEQ ID NO: 409 (VL);

20) 서열번호 143의 중쇄 가변 영역(VH) 및 서열번호 147의 경쇄 가변 영역(VL);20) the heavy chain variable region of SEQ ID NO: 143 (VH) and the light chain variable region of SEQ ID NO: 147 (VL);

21) 서열번호 69의 중쇄 가변 영역(VH) 및 서열번호 73의 경쇄 가변 영역(VL);21) the heavy chain variable region of SEQ ID NO: 69 (VH) and the light chain variable region of SEQ ID NO: 73 (VL);

22) 서열번호 77의 중쇄 가변 영역(VH) 및 서열번호 81의 경쇄 가변 영역(VL);22) the heavy chain variable region of SEQ ID NO: 77 (VH) and the light chain variable region of SEQ ID NO: 81 (VL);

23) 서열번호 294의 중쇄 가변 영역(VH) 및 서열번호 298의 경쇄 가변 영역(VL);23) the heavy chain variable region of SEQ ID NO: 294 (VH) and the light chain variable region of SEQ ID NO: 298 (VL);

24) 서열번호 85의 중쇄 가변 영역(VH) 및 서열번호 86의 경쇄 가변 영역(VL);24) the heavy chain variable region of SEQ ID NO: 85 (VH) and the light chain variable region of SEQ ID NO: 86 (VL);

25) 서열번호 176의 중쇄 가변 영역(VH) 및 서열번호 180의 경쇄 가변 영역(VL);25) the heavy chain variable region of SEQ ID NO: 176 (VH) and the light chain variable region of SEQ ID NO: 180 (VL);

26) 서열번호 186의 중쇄 가변 영역(VH) 및 서열번호 190의 경쇄 가변 영역(VL);26) the heavy chain variable region of SEQ ID NO: 186 (VH) and the light chain variable region of SEQ ID NO: 190 (VL);

27) 서열번호 176의 중쇄 가변 영역(VH) 및 서열번호 206의 경쇄 가변 영역(VL);27) the heavy chain variable region of SEQ ID NO: 176 (VH) and the light chain variable region of SEQ ID NO: 206 (VL);

28) 서열번호 210의 중쇄 가변 영역(VH) 및 서열번호 212의 경쇄 가변 영역(VL);28) the heavy chain variable region of SEQ ID NO: 210 (VH) and the light chain variable region of SEQ ID NO: 212 (VL);

29) 서열번호 215의 중쇄 가변 영역(VH) 및 서열번호 216의 경쇄 가변 영역(VL);29) the heavy chain variable region of SEQ ID NO: 215 (VH) and the light chain variable region of SEQ ID NO: 216 (VL);

30) 서열번호 305의 중쇄 가변 영역(VH) 및 서열번호 309의 경쇄 가변 영역(VL);30) the heavy chain variable region of SEQ ID NO: 305 (VH) and the light chain variable region of SEQ ID NO: 309 (VL);

31) 서열번호 348의 중쇄 가변 영역(VH) 및 서열번호 352의 경쇄 가변 영역(VL);31) the heavy chain variable region of SEQ ID NO: 348 (VH) and the light chain variable region of SEQ ID NO: 352 (VL);

32) 서열번호 358의 중쇄 가변 영역(VH) 및 서열번호 362의 경쇄 가변 영역(VL);32) the heavy chain variable region of SEQ ID NO: 358 (VH) and the light chain variable region of SEQ ID NO: 362 (VL);

33) 서열번호 196의 중쇄 가변 영역(VH) 및 서열번호 200의 경쇄 가변 영역(VL);33) the heavy chain variable region of SEQ ID NO: 196 (VH) and the light chain variable region of SEQ ID NO: 200 (VL);

TNF:TNF:

34) 서열번호 53의 중쇄 가변 영역(VH) 및 서열번호 54의 경쇄 가변 영역(VL);34) the heavy chain variable region of SEQ ID NO: 53 (VH) and the light chain variable region of SEQ ID NO: 54 (VL);

35) 서열번호 279의 중쇄 가변 영역(VH) 및 서열번호 283의 경쇄 가변 영역(VL);35) the heavy chain variable region of SEQ ID NO: 279 (VH) and the light chain variable region of SEQ ID NO: 283 (VL);

36) 서열번호 275의 중쇄 가변 영역(VH) 및 서열번호 287의 경쇄 가변 영역(VL); 및36) the heavy chain variable region of SEQ ID NO: 275 (VH) and the light chain variable region of SEQ ID NO: 287 (VL); And

CTLA-4:CTLA-4:

37) 서열번호 368의 중쇄 가변 영역(VH) 및 서열번호 372의 경쇄 가변 영역(VL).37) The heavy chain variable region of SEQ ID NO: 368 (VH) and the light chain variable region of SEQ ID NO: 372 (VL).

제2 항원Second antigen

제2 항원은 암 항원(Tumor-Specific Antigens), 또는 면역세포 표면에 존재하는 단백질일 수 있으며, 또는 사이토카인일 수 있다. 제2 항원은 PD-L1, PD-1, EGFR, BCMA, CD22, CD25, CD30, CD33, CD37, CD38, CD52, CD56, CD123, cMET, DLL3, GD2, Nectin-4, RANKL, SLAMF7, TROP2, Claudin 18.2, TNFR, TNF, CD3, HER2, CD20, CD19, CTLA-4, VEGFR, VEGF, NCAM1, ICAM-1, ICAM-2, CEACAM6, Carcinoembryonic antigen(CEA), CA-125, Alphafetoprotein(AFP), MUC-1, Epithelial tumor antigen(ETA), Melanoma-associated antigen(MAGE), Immature laminin receptor, TAG-72, HPV E6/E7, BING-4, Calcium-activated chloride channel 2, Cyclin-B1, 9D7, Ep-CAM, EphA3, Mesothelin, SAP-1, Survivin 또는 바이러스 유래 항원일 수 있다. 구체적으로, 상기 제2 항원은 면역 세포 표면에 존재하는 단백질일 수 있다. The second antigen may be cancer antigens (Tumor-Specific Antigens), proteins present on the surface of immune cells, or cytokines. Second antigens are PD-L1, PD-1, EGFR, BCMA, CD22, CD25, CD30, CD33, CD37, CD38, CD52, CD56, CD123, cMET, DLL3, GD2, Nectin-4, RANKL, SLAMF7, TROP2, Claudin 18.2, TNFR, TNF, CD3, HER2, CD20, CD19, CTLA-4, VEGFR, VEGF, NCAM1, ICAM-1, ICAM-2, CEACAM6, Carcinoembryonic antigen (CEA), CA-125, Alphafetoprotein (AFP), MUC-1, Epithelial tumor antigen (ETA), Melanoma-associated antigen (MAGE), Immature laminin receptor, TAG-72, HPV E6/E7, BING-4, Calcium-activated chloride channel 2, Cyclin-B1, 9D7, Ep -CAM, EphA3, Mesothelin, SAP-1, Survivin or virus derived antigen. Specifically, the second antigen may be a protein present on the surface of immune cells.

Fv 형성 영역Fv formation area

상술한 X 및 Y는 결합하여 항체의 Fv를 형성하는 것을 특징으로 한다. 이때, 상기 Fv는 소정의 항원에 특이적으로 결합하는 것일 수 있다. 이때, 상기 X 및 Y는 항원에 특이적인 경쇄 가변 영역 또는 중쇄 가변 영역일 수 있다. 또한, 상기 X 및 Y는 경쇄 및 중쇄의 CDR을 포함할 수 있다.It is characterized in that the above-described X and Y combine to form the Fv of the antibody. In this case, the Fv may specifically bind to a predetermined antigen. In this case, X and Y may be a light chain variable region or a heavy chain variable region specific for an antigen. In addition, X and Y may include light chain and heavy chain CDRs.

상기 X 및 Y는 결합하여 Fv를 형성하고, 상기 Fv는 상술한 제2 항원에 특이적으로 결합할 수 있다. 일 실시예로, 상기 X 및 Y가 결합하여 형성한 Fv는 PD-L1, HER2, CD19, CD20, EGFR, CD3, TNF 및 CTLA-4로 구성된 그룹에서 선택되는 어느 하나의 항원에 특이적으로 결합할 수 있다. 구체적으로, X 및 Y는 각각 하기의 그룹에서 선택되는 어느 하나의 가변 영역 중의 가변 중쇄(VH) 영역 또는 가변 경쇄(VL) 영역을 포함할 수 있다:The X and Y combine to form Fv, and the Fv may specifically bind to the above-described second antigen. In one embodiment, the Fv formed by binding of X and Y specifically binds to any one antigen selected from the group consisting of PD-L1, HER2, CD19, CD20, EGFR, CD3, TNF, and CTLA-4. can do. Specifically, X and Y may each include a variable heavy chain (VH) region or a variable light chain (VL) region of any one variable region selected from the following group:

PD-L1:PD-L1:

1) 서열번호 5(VH-CDR1), 서열번호 6(VH-CDR2) 및 서열번호 7(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 9(VL-CDR1), 서열번호 10(VL-CDR2) 및 서열번호 11(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;1) VH region comprising the amino acid sequence of SEQ ID NO: 5 (VH-CDR1), SEQ ID NO: 6 (VH-CDR2) and SEQ ID NO: 7 (VH-CDR3), and SEQ ID NO: 9 (VL-CDR1), SEQ ID NO: 10 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 11 (VL-CDR3);

2) 서열번호 159(VH-CDR1), 서열번호 160(VH-CDR2) 및 서열번호 161(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 171(VL-CDR1), 서열번호 172(VL-CDR2) 및 서열번호 173(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;2) VH region comprising the amino acid sequence of SEQ ID NO: 159 (VH-CDR1), SEQ ID NO: 160 (VH-CDR2) and SEQ ID NO: 161 (VH-CDR3), and SEQ ID NO: 171 (VL-CDR1), SEQ ID NO: 172 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 173 (VL-CDR3);

3) 서열번호 159(VH-CDR1), 서열번호 160(VH-CDR2) 및 서열번호 161(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 314(VL-CDR1), 서열번호 315(VL-CDR2) 및 서열번호 316(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;3) VH region comprising the amino acid sequence of SEQ ID NO: 159 (VH-CDR1), SEQ ID NO: 160 (VH-CDR2) and SEQ ID NO: 161 (VH-CDR3), and SEQ ID NO: 314 (VL-CDR1), SEQ ID NO: 315 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 316 (VL-CDR3);

4) 서열번호 330(VH-CDR1), 서열번호 331(VH-CDR2) 및 서열번호 332(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 334(VL-CDR1), 서열번호 335(VL-CDR2) 및 서열번호 336(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;4) VH region comprising the amino acid sequence of SEQ ID NO: 330 (VH-CDR1), SEQ ID NO: 331 (VH-CDR2) and SEQ ID NO: 332 (VH-CDR3), and SEQ ID NO: 334 (VL-CDR1), SEQ ID NO: 335 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 336 (VL-CDR3);

HER2:HER2:

5) 서열번호 118(VH-CDR1), 서열번호 119(VH-CDR2) 및 서열번호 120(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 121(VL-CDR1), 서열번호 122(VL-CDR2) 및 서열번호 123(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;5) VH region comprising the amino acid sequence of SEQ ID NO: 118 (VH-CDR1), SEQ ID NO: 119 (VH-CDR2) and SEQ ID NO: 120 (VH-CDR3), and SEQ ID NO: 121 (VL-CDR1), SEQ ID NO: 122 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 123 (VL-CDR3);

6) 서열번호 276(VH-CDR1), 서열번호 277(VH-CDR2) 및 서열번호 278(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 288(VL-CDR1), 서열번호 289(VL-CDR2) 및 서열번호 290(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;6) VH region comprising the amino acid sequence of SEQ ID NO: 276 (VH-CDR1), SEQ ID NO: 277 (VH-CDR2) and SEQ ID NO: 278 (VH-CDR3), and SEQ ID NO: 288 (VL-CDR1), SEQ ID NO: 289 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 290 (VL-CDR3);

CD19:CD19:

7) 서열번호 140(VH-CDR1), 서열번호 141(VH-CDR2) 및 서열번호 142(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 152(VL-CDR1), 서열번호 153(VL-CDR2) 및 서열번호 154(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;7) VH region comprising the amino acid sequence of SEQ ID NO: 140 (VH-CDR1), SEQ ID NO: 141 (VH-CDR2) and SEQ ID NO: 142 (VH-CDR3), and SEQ ID NO: 152 (VL-CDR1), SEQ ID NO: 153 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 154 (VL-CDR3);

8) 서열번호 62(VH-CDR1), 서열번호 63(VH-CDR2) 및 서열번호 64(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 66(VL-CDR1), 서열번호 67(VL-CDR2) 및 서열번호 68(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;8) VH region comprising the amino acid sequence of SEQ ID NO: 62 (VH-CDR1), SEQ ID NO: 63 (VH-CDR2) and SEQ ID NO: 64 (VH-CDR3), and SEQ ID NO: 66 (VL-CDR1), SEQ ID NO: 67 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 68 (VL-CDR3);

CD20:CD20:

9) 서열번호 223(VH-CDR1), 서열번호 224(VH-CDR2) 및 서열번호 225(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 227(VL-CDR1), 서열번호 228(VL-CDR2) 및 서열번호 229(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;9) VH region comprising the amino acid sequence of SEQ ID NO: 223 (VH-CDR1), SEQ ID NO: 224 (VH-CDR2) and SEQ ID NO: 225 (VH-CDR3), and SEQ ID NO: 227 (VL-CDR1), SEQ ID NO: 228 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 229 (VL-CDR3);

10) 서열번호 436(VH-CDR1), 서열번호 437(VH-CDR2) 및 서열번호 438(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 441(VL-CDR1), 서열번호 442(VL-CDR2) 및 서열번호 443(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;10) VH region comprising the amino acid sequence of SEQ ID NO: 436 (VH-CDR1), SEQ ID NO: 437 (VH-CDR2) and SEQ ID NO: 438 (VH-CDR3), and SEQ ID NO: 441 (VL-CDR1), SEQ ID NO: 442 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 443 (VL-CDR3);

EGFR:EGFR:

11) 서열번호 234(VH-CDR1), 서열번호 235(VH-CDR2) 및 서열번호 236(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 238(VL-CDR1), 서열번호 239(VL-CDR2) 및 서열번호 240(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;11) VH region comprising the amino acid sequence of SEQ ID NO: 234 (VH-CDR1), SEQ ID NO: 235 (VH-CDR2) and SEQ ID NO: 236 (VH-CDR3), and SEQ ID NO: 238 (VL-CDR1), SEQ ID NO: 239 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 240 (VL-CDR3);

12) 서열번호 245(VH-CDR1), 서열번호 246(VH-CDR2) 및 서열번호 247(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 249(VL-CDR1), 서열번호 250(VL-CDR2) 및 서열번호 251(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;12) VH region comprising the amino acid sequence of SEQ ID NO: 245 (VH-CDR1), SEQ ID NO: 246 (VH-CDR2) and SEQ ID NO: 247 (VH-CDR3), and SEQ ID NO: 249 (VL-CDR1), SEQ ID NO: 250 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 251 (VL-CDR3);

13) 서열번호 256(VH-CDR1), 서열번호 257(VH-CDR2) 및 서열번호 258(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 260(VL-CDR1), 서열번호 261(VL-CDR2) 및 서열번호 262(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;13) VH region comprising the amino acid sequence of SEQ ID NO: 256 (VH-CDR1), SEQ ID NO: 257 (VH-CDR2) and SEQ ID NO: 258 (VH-CDR3), and SEQ ID NO: 260 (VL-CDR1), SEQ ID NO: 261 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 262 (VL-CDR3);

14) 서열번호 234(VH-CDR1), 서열번호 235(VH-CDR2) 및 서열번호 236(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 238(VL-CDR1), 서열번호 239(VL-CDR2) 및 서열번호 240(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;14) VH region comprising the amino acid sequence of SEQ ID NO: 234 (VH-CDR1), SEQ ID NO: 235 (VH-CDR2) and SEQ ID NO: 236 (VH-CDR3), and SEQ ID NO: 238 (VL-CDR1), SEQ ID NO: 239 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 240 (VL-CDR3);

CD3:CD3:

15) 서열번호 326(VH-CDR1), 서열번호 327(VH-CDR2) 및 서열번호 328(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 338(VL-CDR1), 서열번호 339(VL-CDR2) 및 서열번호 340(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;15) VH region comprising the amino acid sequence of SEQ ID NO: 326 (VH-CDR1), SEQ ID NO: 327 (VH-CDR2) and SEQ ID NO: 328 (VH-CDR3), and SEQ ID NO: 338 (VL-CDR1), SEQ ID NO: 339 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 340 (VL-CDR3);

16) 서열번호 330(VH-CDR1), 서열번호 331(VH-CDR2) 및 서열번호 332(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 334(VL-CDR1), 서열번호 335(VL-CDR2) 및 서열번호 336(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;16) VH region comprising the amino acid sequence of SEQ ID NO: 330 (VH-CDR1), SEQ ID NO: 331 (VH-CDR2) and SEQ ID NO: 332 (VH-CDR3), and SEQ ID NO: 334 (VL-CDR1), SEQ ID NO: 335 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 336 (VL-CDR3);

17) 서열번호 163(VH-CDR1), 서열번호 271(VH-CDR2) 및 서열번호 165(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 167(VL-CDR1), 서열번호 168(VL-CDR2) 및 서열번호 169(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;17) VH region comprising the amino acid sequence of SEQ ID NO: 163 (VH-CDR1), SEQ ID NO: 271 (VH-CDR2) and SEQ ID NO: 165 (VH-CDR3), and SEQ ID NO: 167 (VL-CDR1), SEQ ID NO: 168 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 169 (VL-CDR3);

18) 서열번호 396(VH-CDR1), 서열번호 397(VH-CDR2) 및 서열번호 398(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 402(VL-CDR1), 서열번호 403(VL-CDR2) 및 서열번호 404(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;18) VH region comprising the amino acid sequence of SEQ ID NO: 396 (VH-CDR1), SEQ ID NO: 397 (VH-CDR2) and SEQ ID NO: 398 (VH-CDR3), and SEQ ID NO: 402 (VL-CDR1), SEQ ID NO: 403 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 404 (VL-CDR3);

19) 서열번호 144(VH-CDR1), 서열번호 145(VH-CDR2) 및 서열번호 146(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 148(VL-CDR1), 서열번호 149(VL-CDR2) 및 서열번호 410(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;19) VH region comprising the amino acid sequence of SEQ ID NO: 144 (VH-CDR1), SEQ ID NO: 145 (VH-CDR2) and SEQ ID NO: 146 (VH-CDR3), and SEQ ID NO: 148 (VL-CDR1), SEQ ID NO: 149 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 410 (VL-CDR3);

20) 서열번호 144(VH-CDR1), 서열번호 145(VH-CDR2) 및 서열번호 146(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 148(VL-CDR1), 서열번호 149(VL-CDR2) 및 서열번호 150(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;20) VH region comprising the amino acid sequence of SEQ ID NO: 144 (VH-CDR1), SEQ ID NO: 145 (VH-CDR2) and SEQ ID NO: 146 (VH-CDR3), and SEQ ID NO: 148 (VL-CDR1), SEQ ID NO: 149 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 150 (VL-CDR3);

21) 서열번호 70(VH-CDR1), 서열번호 71(VH-CDR2) 및 서열번호 72(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 74(VL-CDR1), 서열번호 75(VL-CDR2) 및 서열번호 76(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;21) VH region comprising the amino acid sequence of SEQ ID NO: 70 (VH-CDR1), SEQ ID NO: 71 (VH-CDR2) and SEQ ID NO: 72 (VH-CDR3), and SEQ ID NO: 74 (VL-CDR1), SEQ ID NO: 75 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 76 (VL-CDR3);

22) 서열번호 78(VH-CDR1), 서열번호 79(VH-CDR2) 및 서열번호 80(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 82(VL-CDR1), 서열번호 83(VL-CDR2) 및 서열번호 84(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;22) VH region comprising the amino acid sequence of SEQ ID NO: 78 (VH-CDR1), SEQ ID NO: 79 (VH-CDR2) and SEQ ID NO: 80 (VH-CDR3), and SEQ ID NO: 82 (VL-CDR1), SEQ ID NO: 83 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 84 (VL-CDR3);

23) 서열번호 295(VH-CDR1), 서열번호 296(VH-CDR2) 및 서열번호 297(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 299(VL-CDR1), 서열번호 300(VL-CDR2) 및 서열번호 301(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;23) VH region comprising the amino acid sequence of SEQ ID NO: 295 (VH-CDR1), SEQ ID NO: 296 (VH-CDR2) and SEQ ID NO: 297 (VH-CDR3), and SEQ ID NO: 299 (VL-CDR1), SEQ ID NO: 300 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 301 (VL-CDR3);

24) 서열번호 78(VH-CDR1), 서열번호 79(VH-CDR2) 및 서열번호 80(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 82(VL-CDR1), 서열번호 83(VL-CDR2) 및 서열번호 87(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;24) VH region comprising the amino acid sequence of SEQ ID NO: 78 (VH-CDR1), SEQ ID NO: 79 (VH-CDR2) and SEQ ID NO: 80 (VH-CDR3), and SEQ ID NO: 82 (VL-CDR1), SEQ ID NO: 83 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 87 (VL-CDR3);

25) 서열번호 163(VH-CDR1), 서열번호 271(VH-CDR2) 및 서열번호 165(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 167(VL-CDR1), 서열번호 168(VL-CDR2) 및 서열번호 169(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;25) VH region comprising the amino acid sequence of SEQ ID NO: 163 (VH-CDR1), SEQ ID NO: 271 (VH-CDR2) and SEQ ID NO: 165 (VH-CDR3), and SEQ ID NO: 167 (VL-CDR1), SEQ ID NO: 168 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 169 (VL-CDR3);

26) 서열번호 177(VH-CDR1), 서열번호 178(VH-CDR2) 및 서열번호 179(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 181(VL-CDR1), 서열번호 182(VL-CDR2) 및 서열번호 183(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;26) VH region comprising the amino acid sequence of SEQ ID NO: 177 (VH-CDR1), SEQ ID NO: 178 (VH-CDR2) and SEQ ID NO: 179 (VH-CDR3), and SEQ ID NO: 181 (VL-CDR1), SEQ ID NO: 182 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 183 (VL-CDR3);

27) 서열번호 187(VH-CDR1), 서열번호 188(VH-CDR2) 및 서열번호 189(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 191(VL-CDR1), 서열번호 192(VL-CDR2) 및 서열번호 193(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;27) VH region comprising the amino acid sequence of SEQ ID NO: 187 (VH-CDR1), SEQ ID NO: 188 (VH-CDR2) and SEQ ID NO: 189 (VH-CDR3), and SEQ ID NO: 191 (VL-CDR1), SEQ ID NO: 192 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 193 (VL-CDR3);

28) 서열번호 177(VH-CDR1), 서열번호 178(VH-CDR2) 및 서열번호 179(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 181(VL-CDR1), 서열번호 182(VL-CDR2) 및 서열번호 207(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;28) VH region comprising the amino acid sequence of SEQ ID NO: 177 (VH-CDR1), SEQ ID NO: 178 (VH-CDR2) and SEQ ID NO: 179 (VH-CDR3), and SEQ ID NO: 181 (VL-CDR1), SEQ ID NO: 182 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 207 (VL-CDR3);

29) 서열번호 177(VH-CDR1), 서열번호 178(VH-CDR2) 및 서열번호 211(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 181(VL-CDR1), 서열번호 182(VL-CDR2) 및 서열번호 207(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;29) VH region comprising the amino acid sequence of SEQ ID NO: 177 (VH-CDR1), SEQ ID NO: 178 (VH-CDR2) and SEQ ID NO: 211 (VH-CDR3), and SEQ ID NO: 181 (VL-CDR1), SEQ ID NO: 182 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 207 (VL-CDR3);

30) 서열번호 306(VH-CDR1), 서열번호 307(VH-CDR2) 및 서열번호 308(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 310(VL-CDR1), 서열번호 311(VL-CDR2) 및 서열번호 312(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;30) VH region comprising the amino acid sequence of SEQ ID NO: 306 (VH-CDR1), SEQ ID NO: 307 (VH-CDR2) and SEQ ID NO: 308 (VH-CDR3), and SEQ ID NO: 310 (VL-CDR1), SEQ ID NO: 311 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 312 (VL-CDR3);

31) 서열번호 349(VH-CDR1), 서열번호 350(VH-CDR2) 및 서열번호 351(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 353(VL-CDR1), 서열번호 354(VL-CDR2) 및 서열번호 355(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;31) VH region comprising the amino acid sequence of SEQ ID NO: 349 (VH-CDR1), SEQ ID NO: 350 (VH-CDR2) and SEQ ID NO: 351 (VH-CDR3), and SEQ ID NO: 353 (VL-CDR1), SEQ ID NO: 354 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 355 (VL-CDR3);

32) 서열번호 359(VH-CDR1), 서열번호 360(VH-CDR2) 및 서열번호 361(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 363(VL-CDR1), 서열번호 364(VL-CDR2) 및 서열번호 365(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;32) VH region comprising the amino acid sequence of SEQ ID NO: 359 (VH-CDR1), SEQ ID NO: 360 (VH-CDR2) and SEQ ID NO: 361 (VH-CDR3), and SEQ ID NO: 363 (VL-CDR1), SEQ ID NO: 364 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 365 (VL-CDR3);

33) 서열번호 197(VH-CDR1), 서열번호 198(VH-CDR2) 및 서열번호 199(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 201(VL-CDR1), 서열번호 202(VL-CDR2) 및 서열번호 203(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;33) VH region comprising the amino acid sequence of SEQ ID NO: 197 (VH-CDR1), SEQ ID NO: 198 (VH-CDR2) and SEQ ID NO: 199 (VH-CDR3), and SEQ ID NO: 201 (VL-CDR1), SEQ ID NO: 202 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 203 (VL-CDR3);

TNF: TNF:

34) 서열번호 124(VH-CDR1), 서열번호 125(VH-CDR2) 및 서열번호 126(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 127(VL-CDR1), 서열번호 128(VL-CDR2) 및 서열번호 129(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;34) VH region comprising the amino acid sequence of SEQ ID NO: 124 (VH-CDR1), SEQ ID NO: 125 (VH-CDR2) and SEQ ID NO: 126 (VH-CDR3), and SEQ ID NO: 127 (VL-CDR1), SEQ ID NO: 128 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 129 (VL-CDR3);

35) 서열번호 280(VH-CDR1), 서열번호 281(VH-CDR2) 및 서열번호 282(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 284(VL-CDR1), 서열번호 285(VL-CDR2) 및 서열번호 286(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;35) VH region comprising the amino acid sequence of SEQ ID NO: 280 (VH-CDR1), SEQ ID NO: 281 (VH-CDR2) and SEQ ID NO: 282 (VH-CDR3), and SEQ ID NO: 284 (VL-CDR1), SEQ ID NO: 285 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 286 (VL-CDR3);

36) 서열번호 276(VH-CDR1), 서열번호 277(VH-CDR2) 및 서열번호 278(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 288(VL-CDR1), 서열번호 289(VL-CDR2) 및 서열번호 290(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역; 및36) VH region comprising the amino acid sequence of SEQ ID NO: 276 (VH-CDR1), SEQ ID NO: 277 (VH-CDR2) and SEQ ID NO: 278 (VH-CDR3), and SEQ ID NO: 288 (VL-CDR1), SEQ ID NO: 289 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 290 (VL-CDR3); And

CTLA-4:CTLA-4:

37) 서열번호 369(VH-CDR1), 서열번호 370(VH-CDR2) 및 서열번호 371(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 373(VL-CDR1), 서열번호 374(VL-CDR2) 및 서열번호 375(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역.37) VH region comprising the amino acid sequence of SEQ ID NO: 369 (VH-CDR1), SEQ ID NO: 370 (VH-CDR2) and SEQ ID NO: 371 (VH-CDR3), and SEQ ID NO: 373 (VL-CDR1), SEQ ID NO: 374 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 375 (VL-CDR3).

Fv 형성 영역Fv formation area

또한, 상기 X 또는 Y는 하기의 그룹에서 선택되는 어느 하나의 가변 영역 중의 가변 중쇄(VH) 영역 또는 가변 경쇄(VL) 영역일 수 있다:In addition, X or Y may be a variable heavy chain (VH) region or a variable light chain (VL) region of any one variable region selected from the following group:

PD-L1:PD-L1:

1) 서열번호 4의 중쇄 가변 영역(VH) 및 서열번호 8의 경쇄 가변 영역(VL);1) the heavy chain variable region of SEQ ID NO: 4 (VH) and the light chain variable region of SEQ ID NO: 8 (VL);

2) 서열번호 158의 중쇄 가변 영역(VH) 및 서열번호 170의 경쇄 가변 영역(VL);2) the heavy chain variable region of SEQ ID NO: 158 (VH) and the light chain variable region of SEQ ID NO: 170 (VL);

3) 서열번호 158의 중쇄 가변 영역(VH) 및 서열번호 313의 경쇄 가변 영역(VL);3) the heavy chain variable region of SEQ ID NO: 158 (VH) and the light chain variable region of SEQ ID NO: 313 (VL);

4) 서열번호 329의 중쇄 가변 영역(VH) 및 서열번호 333의 경쇄 가변 영역(VL);4) the heavy chain variable region of SEQ ID NO: 329 (VH) and the light chain variable region of SEQ ID NO: 333 (VL);

5) 서열번호 329의 중쇄 가변 영역(VH) 및 서열번호 376의 경쇄 가변 영역(VL);5) the heavy chain variable region of SEQ ID NO: 329 (VH) and the light chain variable region of SEQ ID NO: 376 (VL);

HER2:HER2:

6) 서열번호 51의 중쇄 가변 영역(VH) 및 서열번호 52의 경쇄 가변 영역(VL);6) the heavy chain variable region of SEQ ID NO: 51 (VH) and the light chain variable region of SEQ ID NO: 52 (VL);

7) 서열번호 275의 중쇄 가변 영역(VH) 및 서열번호 287의 경쇄 가변 영역(VL);7) the heavy chain variable region of SEQ ID NO: 275 (VH) and the light chain variable region of SEQ ID NO: 287 (VL);

CD19:CD19:

8) 서열번호 139의 중쇄 가변 영역(VH) 및 서열번호 151의 경쇄 가변 영역(VL);8) the heavy chain variable region of SEQ ID NO: 139 (VH) and the light chain variable region of SEQ ID NO: 151 (VL);

9) 서열번호 61의 중쇄 가변 영역(VH) 및 서열번호 65의 경쇄 가변 영역(VL);9) the heavy chain variable region of SEQ ID NO: 61 (VH) and the light chain variable region of SEQ ID NO: 65 (VL);

CD20: CD20:

10) 서열번호 222의 중쇄 가변 영역(VH) 및 서열번호 226의 경쇄 가변 영역(VL);10) the heavy chain variable region of SEQ ID NO: 222 (VH) and the light chain variable region of SEQ ID NO: 226 (VL);

11) 서열번호 435의 중쇄 가변 영역(VH) 및 서열번호 440의 경쇄 가변 영역(VL);11) the heavy chain variable region of SEQ ID NO: 435 (VH) and the light chain variable region of SEQ ID NO: 440 (VL);

EGFR: EGFR:

12) 서열번호 233의 중쇄 가변 영역(VH) 및 서열번호 237의 경쇄 가변 영역(VL);12) the heavy chain variable region of SEQ ID NO: 233 (VH) and the light chain variable region of SEQ ID NO: 237 (VL);

13) 서열번호 244의 중쇄 가변 영역(VH) 및 서열번호 248의 경쇄 가변 영역(VL);13) the heavy chain variable region of SEQ ID NO: 244 (VH) and the light chain variable region of SEQ ID NO: 248 (VL);

14) 서열번호 255의 중쇄 가변 영역(VH) 및 서열번호 259의 경쇄 가변 영역(VL);14) the heavy chain variable region of SEQ ID NO: 255 (VH) and the light chain variable region of SEQ ID NO: 259 (VL);

CD3:CD3:

15) 서열번호 325의 중쇄 가변 영역(VH) 및 서열번호 337의 경쇄 가변 영역(VL);15) the heavy chain variable region of SEQ ID NO: 325 (VH) and the light chain variable region of SEQ ID NO: 337 (VL);

16) 서열번호 329의 중쇄 가변 영역(VH) 및 서열번호 376의 경쇄 가변 영역(VL);16) the heavy chain variable region of SEQ ID NO: 329 (VH) and the light chain variable region of SEQ ID NO: 376 (VL);

17) 서열번호 162의 중쇄 가변 영역(VH) 및 서열번호 166의 경쇄 가변 영역(VL);17) the heavy chain variable region of SEQ ID NO: 162 (VH) and the light chain variable region of SEQ ID NO: 166 (VL);

18) 서열번호 395의 중쇄 가변 영역(VH) 및 서열번호 401의 경쇄 가변 영역(VL);18) the heavy chain variable region of SEQ ID NO: 395 (VH) and the light chain variable region of SEQ ID NO: 401 (VL);

19) 서열번호 406의 중쇄 가변 영역(VH) 및 서열번호 409의 경쇄 가변 영역(VL);19) the heavy chain variable region of SEQ ID NO: 406 (VH) and the light chain variable region of SEQ ID NO: 409 (VL);

20) 서열번호 143의 중쇄 가변 영역(VH) 및 서열번호 147의 경쇄 가변 영역(VL);20) the heavy chain variable region of SEQ ID NO: 143 (VH) and the light chain variable region of SEQ ID NO: 147 (VL);

21) 서열번호 69의 중쇄 가변 영역(VH) 및 서열번호 73의 경쇄 가변 영역(VL);21) the heavy chain variable region of SEQ ID NO: 69 (VH) and the light chain variable region of SEQ ID NO: 73 (VL);

22) 서열번호 77의 중쇄 가변 영역(VH) 및 서열번호 81의 경쇄 가변 영역(VL);22) the heavy chain variable region of SEQ ID NO: 77 (VH) and the light chain variable region of SEQ ID NO: 81 (VL);

23) 서열번호 294의 중쇄 가변 영역(VH) 및 서열번호 298의 경쇄 가변 영역(VL);23) the heavy chain variable region of SEQ ID NO: 294 (VH) and the light chain variable region of SEQ ID NO: 298 (VL);

24) 서열번호 85의 중쇄 가변 영역(VH) 및 서열번호 86의 경쇄 가변 영역(VL);24) the heavy chain variable region of SEQ ID NO: 85 (VH) and the light chain variable region of SEQ ID NO: 86 (VL);

25) 서열번호 176의 중쇄 가변 영역(VH) 및 서열번호 180의 경쇄 가변 영역(VL);25) the heavy chain variable region of SEQ ID NO: 176 (VH) and the light chain variable region of SEQ ID NO: 180 (VL);

26) 서열번호 186의 중쇄 가변 영역(VH) 및 서열번호 190의 경쇄 가변 영역(VL);26) the heavy chain variable region of SEQ ID NO: 186 (VH) and the light chain variable region of SEQ ID NO: 190 (VL);

27) 서열번호 176의 중쇄 가변 영역(VH) 및 서열번호 206의 경쇄 가변 영역(VL);27) the heavy chain variable region of SEQ ID NO: 176 (VH) and the light chain variable region of SEQ ID NO: 206 (VL);

28) 서열번호 210의 중쇄 가변 영역(VH) 및 서열번호 212의 경쇄 가변 영역(VL);28) the heavy chain variable region of SEQ ID NO: 210 (VH) and the light chain variable region of SEQ ID NO: 212 (VL);

29) 서열번호 215의 중쇄 가변 영역(VH) 및 서열번호 216의 경쇄 가변 영역(VL);29) the heavy chain variable region of SEQ ID NO: 215 (VH) and the light chain variable region of SEQ ID NO: 216 (VL);

30) 서열번호 305의 중쇄 가변 영역(VH) 및 서열번호 309의 경쇄 가변 영역(VL);30) the heavy chain variable region of SEQ ID NO: 305 (VH) and the light chain variable region of SEQ ID NO: 309 (VL);

31) 서열번호 348의 중쇄 가변 영역(VH) 및 서열번호 352의 경쇄 가변 영역(VL);31) the heavy chain variable region of SEQ ID NO: 348 (VH) and the light chain variable region of SEQ ID NO: 352 (VL);

32) 서열번호 358의 중쇄 가변 영역(VH) 및 서열번호 362의 경쇄 가변 영역(VL);32) the heavy chain variable region of SEQ ID NO: 358 (VH) and the light chain variable region of SEQ ID NO: 362 (VL);

33) 서열번호 196의 중쇄 가변 영역(VH) 및 서열번호 200의 경쇄 가변 영역(VL);33) the heavy chain variable region of SEQ ID NO: 196 (VH) and the light chain variable region of SEQ ID NO: 200 (VL);

TNF:TNF:

34) 서열번호 53의 중쇄 가변 영역(VH) 및 서열번호 54의 경쇄 가변 영역(VL);34) the heavy chain variable region of SEQ ID NO: 53 (VH) and the light chain variable region of SEQ ID NO: 54 (VL);

35) 서열번호 279의 중쇄 가변 영역(VH) 및 서열번호 283의 경쇄 가변 영역(VL);35) the heavy chain variable region of SEQ ID NO: 279 (VH) and the light chain variable region of SEQ ID NO: 283 (VL);

36) 서열번호 275의 중쇄 가변 영역(VH) 및 서열번호 287의 경쇄 가변 영역(VL); 및36) the heavy chain variable region of SEQ ID NO: 275 (VH) and the light chain variable region of SEQ ID NO: 287 (VL); And

CTLA-4:CTLA-4:

37) 서열번호 368의 중쇄 가변 영역(VH) 및 서열번호 372의 경쇄 가변 영역(VL).37) The heavy chain variable region of SEQ ID NO: 368 (VH) and the light chain variable region of SEQ ID NO: 372 (VL).

CH3이 추가된 Fv 영역 Fv area to which CH3 is added

상기 X 및/또는 Y는 CH3를 더 포함할 수 있다. 이때, CH3는 면역글로불린 유래의 CH3 영역일 수 있다. 이때, CH3는 X 및/또는 Y의 N 말단 또는 C 말단에 결합된 것일 수 있다. 구체적으로, CH3는 X 및 Y의 C 말단에 모두 포함될 수 있다. 또한, CH3는 X의 C 말단에만 포함되거나, Y의 C 말단에만 포함될 수 있다.The X and/or Y may further include CH3. At this time, CH3 may be an immunoglobulin-derived CH3 region. At this time, CH3 may be bonded to the N-terminus or C-terminus of X and/or Y. Specifically, CH3 may be included in both the C-terminus of X and Y. In addition, CH3 may be included only at the C-terminus of X, or may be included only at the C-terminus of Y.

CH3 영역의 존재는 다중 특이적 융합 단백질의 Fc 수용체 결합 능력을 제공할 수 있다. Fv 영역에 연결된 CH3 영역에는 KiH (knobs-into-holes) 구조가 도입될 수 있다. 도 1A는 항-CD3 UCHT1, 항-PD-L1 더발루맙, 항-CTLA-4 이필리무맙의 가변 도메인의 "Knob-in-Hole" 구조를 보여준다.The presence of the CH3 region can provide the ability of the multispecific fusion protein to bind to the Fc receptor. In the CH3 region connected to the Fv region, a kiH (knobs-into-holes) structure may be introduced. 1A shows the "Knob-in-Hole" structure of the variable domains of anti-CD3 UCHT1, anti-PD-L1 dervalumab, and anti-CTLA-4 ipilimumab.

A 및 B 및 X/Y의 조합 예시Examples of combinations of A and B and X/Y

상기 A 및 B는 상술한 제1 항원에서 선택된 어느 하나의 항원에 특이적으로 결합할 수 있도록 디자인될 수 있다. X/Y는 상술한 제2 항원에서 선택된 어느 하나의 항원에 특이적으로 결합할 수 있도록 디자인될 수 있다.The A and B may be designed to specifically bind to any one antigen selected from the above-described first antigen. X/Y may be designed to specifically bind to any one antigen selected from the above-described second antigen.

일 실시예에서, 상기 A 및 B는 PD-L1, EGFR, CD20, HER2, TNF, CD19, CD3 및 CTLA4로 구성된 군에서 선택되는 어느 하나의 제1 항원에 특이적으로 결합하며, X 및 Y가 결합하여 형성된 Fv는 PD-L1, EGFR, CD20, HER2, TNF, CD19, CD3 및 CTLA4로 구성된 군에서 선택되는 어느 하나의 제2 항원에 특이적으로 결합하되, 상기 A 및 B와 X 및 Y로 형성된 Fv는 동일한 항원에 결합하지 않는 것을 특징으로 할 수 있다.In one embodiment, the A and B specifically bind to any one first antigen selected from the group consisting of PD-L1, EGFR, CD20, HER2, TNF, CD19, CD3 and CTLA4, and X and Y are Fv formed by binding specifically binds to any one second antigen selected from the group consisting of PD-L1, EGFR, CD20, HER2, TNF, CD19, CD3 and CTLA4, but the A and B and X and Y The formed Fv can be characterized as not binding to the same antigen.

또 다른 구체예에서, 상기 다중 특이적 융합 단백질은 제1 항원으로 HER2에 특이적으로 결합하고, 제2 항원으로 TNF에 특이적으로 결합할 수 있다.In another embodiment, the multispecific fusion protein may specifically bind to HER2 as a first antigen and specifically bind to TNF as a second antigen.

일 구체예에서, 상기 다중 특이적 융합 단백질은 제1 항원으로 PD-L1에 특이적으로 결합하고, 제2 항원으로 CD3에 특이적으로 결합할 수 있다.In one embodiment, the multispecific fusion protein may specifically bind to PD-L1 as a first antigen and specifically bind to CD3 as a second antigen.

또 다른 구체예에서, 상기 다중 특이적 융합 단백질은 제1 항원으로 EGFR에 특이적으로 결합하고, 제2 항원으로 CD3에 특이적으로 결합할 수 있다.In another embodiment, the multispecific fusion protein may specifically bind to EGFR as a first antigen and specifically bind to CD3 as a second antigen.

또 다른 구체예에서, 상기 다중 특이적 융합 단백질은 제1 항원으로 CD20에 특이적으로 결합하고, 제2 항원으로 CD3에 특이적으로 결합할 수 있다.In another embodiment, the multispecific fusion protein may specifically bind to CD20 as a first antigen and specifically bind to CD3 as a second antigen.

일 구체예에서, 상기 다중 특이적 융합 단백질은 제1 항원으로 CD3에 특이적으로 결합하고, 제2 항원으로 PD-L1에 특이적으로 결합할 수 있다.In one embodiment, the multispecific fusion protein may specifically bind to CD3 as a first antigen and specifically to PD-L1 as a second antigen.

또 다른 구체예에서, 상기 다중 특이적 융합 단백질은 제1 항원으로 HER2에 특이적으로 결합하고, 제2 항원으로 CD3에 특이적으로 결합할 수 있다.In another embodiment, the multispecific fusion protein may specifically bind to HER2 as a first antigen and specifically bind to CD3 as a second antigen.

또 다른 구체예에서, 상기 다중 특이적 융합 단백질은 제1 항원으로 CD19에 특이적으로 결합하고, 제2 항원으로 CD3에 특이적으로 결합할 수 있다.In another embodiment, the multispecific fusion protein may specifically bind to CD19 as a first antigen and specifically bind to CD3 as a second antigen.

또 다른 구체예에서, 상기 다중 특이적 융합 단백질은 제1 항원으로 PD-L1에 특이적으로 결합하고, 제2 항원으로 CTLA-4에 특이적으로 결합할 수 있다.In another embodiment, the multispecific fusion protein may specifically bind to PD-L1 as a first antigen and specifically bind to CTLA-4 as a second antigen.

또 다른 구체예에서, 상기 다중 특이적 융합 단백질은 제1 항원으로 PD-L1에 특이적으로 결합하고, 제2 항원으로 PD-1에 특이적으로 결합할 수 있다.In another embodiment, the multispecific fusion protein may specifically bind to PD-L1 with a first antigen and specifically bind to PD-1 with a second antigen.

또 다른 구체예에서, 상기 다중 특이적 융합 단백질은 제1 항원으로 PD-1에 특이적으로 결합하고, 제2 항원으로 PD-L1에 특이적으로 결합할 수 있다.In another embodiment, the multispecific fusion protein may specifically bind to PD-1 with a first antigen and specifically bind to PD-L1 with a second antigen.

또 다른 구체예에서, 상기 다중 특이적 융합 단백질은 제1 항원으로 CD20에 특이적으로 결합하고, 제2 항원으로 CTLA-4에 특이적으로 결합할 수 있다.In another embodiment, the multispecific fusion protein may specifically bind to CD20 as a first antigen and to CTLA-4 as a second antigen.

다중 특이성 융합 단백질에 관한 실험 결과Experimental results on multispecific fusion proteins

VH-VL 이종이량체 형성에 기반한 ALiCE 분자 생성Generation of ALiCE molecules based on VH-VL heterodimer formation

항체 조립에서 CH3 도메인의 중요한 역할에도 불구하고, 본 발명자들은 VH 및 VL 도메인의 자율적 조립과 안정적인 Fv 복합체 형성이 두 HC의 특이적 이종이량체화를 촉진할 뿐만 아니라, 제2 항원을 결합하기 위한 추가 사이트를 도입하는 데에도 활용될 수 있다고 가정하였다. 이를 테스트하고자, 모(parent) IgG의 두 HC의 Fc 도메인을 제2 항원에 특이적인 IgG의 VH 및 VL 도메인으로 대체하여 각각 ACE-HC-VH 및 ACE-HC-VL을 생성하였다(도 3a).Despite the important role of the CH3 domain in antibody assembly, the present inventors found that the autonomous assembly of the VH and VL domains and the formation of a stable Fv complex not only promote the specific heterodimerization of the two HCs, but also to bind the second antigen. It is assumed that it can also be used to introduce additional sites. To test this, ACE-HC-VH and ACE-HC-VL were generated by replacing the Fc domains of the two HCs of the parent IgG with the VH and VL domains of the IgG specific for the second antigen (Fig. 3a). .

테스트 시스템으로서, 본 발명자들은 항-CD3 항체 UCHT1과 항-PD-L1 항체 YBL-007을 사용하였으며, 상기 YBL-007은 PD-L1/PD-1 신호 차단능이 아벨루맙(avelumab)의 신호 차단능과 유사한 본 발명자들에 의해 제작된 항-PD-L1 항체이다(도 4). 모 YBL-007의 LC는 ACE-LC에 사용되었으며, VH-CH1과 YBL-007 HC의 힌지 영역은 UCHT1의 VH 또는 VL에 융합되어 ALiCE의 두 HC를 생성하였다. ACE-HC-VH, ACE-HC-VL 및 ACE-LC를 암호화하는 다양한 조합의 발현 벡터를 FreeStyle 293-F 세포로 트랜스펙션시키고, 배양 배지에서 이러한 분자의 발현을 SDS-PAGE 및 웨스턴 블롯팅으로 분석하였다(도 5).As a test system, the present inventors used anti-CD3 antibody UCHT1 and anti-PD-L1 antibody YBL-007, and the YBL-007 has PD-L1/PD-1 signal blocking ability of avelumab. It is an anti-PD-L1 antibody produced by the present inventors similar to (Fig. 4). The LC of parent YBL-007 was used for ACE-LC, and the hinge regions of VH-CH1 and YBL-007 HC were fused to VH or VL of UCHT1 to generate two HCs of ALiCE. Expression vectors of various combinations encoding ACE-HC-VH, ACE-HC-VL and ACE-LC were transfected into FreeStyle 293-F cells, and the expression of these molecules in culture medium was SDS-PAGE and Western blotting. It was analyzed as (Fig. 5).

예상한 바와 같이, 접힘(folding) 및 분비 문제로 인해 각각의 사슬은 발현될 수 없었다(도 5, 레인 1 내지 3). 또한, UCHT1 VH 도메인의 CDR 3 루프(loop)에 놉(knob) 구조가 있는 ACE-HC-VH 사슬은 부적합한 놉-놉 상호작용으로 인해 동종이량체로 조립할 수 없는 반면(도 5, 레인 4), 동일한 ACE-HC-VL 사슬 간의 동종이량체 형성은 거의 검출되지 않았다(도 5, 레인 5).As expected, each chain could not be expressed due to folding and secretion problems (FIG. 5, lanes 1 to 3). In addition, the ACE-HC-VH chain having a knob structure in the CDR 3 loop of the UCHT1 VH domain cannot assemble into a homodimer due to an inappropriate knob-knob interaction (Fig. 5, lane 4). , Homodimer formation between the same ACE-HC-VL chains was hardly detected (Fig. 5, lane 5).

또한, 적합하게 조립된 복합체는 ACE-HC-VL, ACE-HC-VH 및 ACE-LC가 함께 존재하는 경우에만 고발현되어 분비되었다(도 5, 레인 6). 생성된 ALiCE(항-PD-L1 Fab × 항-CD3 Fv; 이하 ACE-05로 칭함)를 FreeStyle 293-F 세포에 일시적으로 발현시키고 CH1 친화성 크로마토그래피 정제하였으며, 그 수율은 약 20~30 ㎎/L이었다. 환원 및 비-환원 조건하에서 Bioanalyzer assay kit(P230 및 P80 kit)를 사용한 모세관 전기영동 분석은 ACE-LC, ACE-HC-VH 및 ACE-HC-VL 사슬이 ACE-05에서 2:1:1 비율로 존재함을 확인하였다(도 6 및 도 7).In addition, the suitably assembled complex was highly expressed and secreted only when ACE-HC-VL, ACE-HC-VH and ACE-LC were present together (FIG. 5, lane 6). The resulting ALiCE (anti-PD-L1 Fab × anti-CD3 Fv; hereinafter referred to as ACE-05) was transiently expressed in FreeStyle 293-F cells and purified by CH1 affinity chromatography, and the yield was about 20-30 mg. /L. Capillary electrophoresis analysis using the Bioanalyzer assay kit (P230 and P80 kit) under reducing and non-reducing conditions showed that the ACE-LC, ACE-HC-VH and ACE-HC-VL chains were in a 2:1:1 ratio in ACE-05. It was confirmed that it exists (Figs. 6 and 7).

크기-배제 크로마토그래피 및 LC-ESI/TOF를 사용한 질량분석법(MS)을 통한 분석 결과는 ACE-05가 균일한 이종사량체(heterotetramer)임을 나타내었다(도 6 및 도 8). 특히, 관찰된 주요 피크(123,997 Da)의 질량은 ACE-05(123,942 Da)의 이종사량체 구조의 이론적 질량에 매우 근접하였다. 이와 비교하여, 동종사량체(homotetramer) 구조인 ACE-05-HC-VH 동종이량체 + 2개의 ACE-05-LC의 질량은 125,597 Da이었고, ACE-05-HC-VL 동종이량체 + 2개의 ACE-05-LC의 질량은 122,287 Da이었다(도 8). 이러한 결과에서 정제된 ACE-05에서 검출 가능한 동종사량체 복합체가 존재하지 않음이 확인되었다.Analysis results through size-exclusion chromatography and mass spectrometry (MS) using LC-ESI/TOF indicated that ACE-05 was a homogeneous heterotetramer (FIGS. 6 and 8). In particular, the mass of the observed main peak (123,997 Da) was very close to the theoretical mass of the heterotetrameric structure of ACE-05 (123,942 Da). In comparison, the mass of ACE-05-HC-VH homodimer + two ACE-05-LC, which is a homotetramer structure, was 125,597 Da, and ACE-05-HC-VL homodimer + two The mass of ACE-05-LC was 122,287 Da (Fig. 8). From these results, it was confirmed that no homotetrameric complex detectable in purified ACE-05 was present.

또한, 본 발명자들은 ACE-31(UCHT1 및 YBL-007을 사용한 항-CD3 Fab × 항-PD-L1 Fv) 및 ACE-00(항-HER2 mAb[허셉틴] 및 항-TNF-α mAb[휴미라]를 사용한 항-HER2 Fab × 항-TNF-α Fv)을 생성하여 ALiCE 플랫폼이 일반적으로 다른 항체 쌍(pair)에 적용될 수 있는지의 여부를 조사하였다. ACE-05와 유사하게, ACE-31 및 ACE-00은 상응하는 이종사량체 복합체, ACE-HC-VL, ACE-HC-VH 및 2개의 ACE-LC로 조립되고, 균질한 형태로 분비되었다(도 6 및 도 9).In addition, the present inventors have ACE-31 (anti-CD3 Fab x anti-PD-L1 Fv using UCHT1 and YBL-007) and ACE-00 (anti-HER2 mAb [Herceptin] and anti-TNF-α mAb [Humira] Anti-HER2 Fab x anti-TNF-α Fv) was generated to investigate whether the ALiCE platform could be applied to other antibody pairs in general. Similar to ACE-05, ACE-31 and ACE-00 were assembled into the corresponding heterotetrameric complex, ACE-HC-VL, ACE-HC-VH and two ACE-LCs, and secreted in a homogeneous form ( 6 and 9).

단백질 발현 동안, 소량의 응집 (또는 올리고머의 오접힘(misfolding))이 발생하였다(도 10). 그러나, 이러한 응집체는 양이온 교환 크로마토그래피(cation exchange chromatography, CEX)에 의해 쉽게 제거되었으며, CEX 정제 후 추가 응집이 발생하지 않았다. 열 안정성 분석을 사용한 ACE-05의 안정성 테스트 및 다양한 pH 조건(pH6-8)에 대한 노출 또는 실온에서 장기간 배양(7 일)은 ACE-05가 IgG와 유사하게 안정적이고 균질한 구조임을 나타내었다(도 11 및 도 12).During protein expression, a small amount of aggregation (or oligomer misfolding) occurred (FIG. 10). However, these aggregates were easily removed by cation exchange chromatography (CEX), and further aggregation did not occur after CEX purification. Stability testing of ACE-05 using thermal stability analysis and exposure to various pH conditions (pH6-8) or long-term incubation at room temperature (7 days) showed that ACE-05 was of a stable and homogeneous structure similar to IgG ( 11 and 12).

T 세포 결합자로서 ALiCE의 결합 카이네틱스 및 동시 결합능Binding kinetics and simultaneous binding ability of ALiCE as a T cell combiner

ALiCE의 외부 및 내부 결합 도메인 간의 거리는 약 60Å인 것으로 밝혀졌으며, 이는 종양과 이펙터 세포 간의 면역학적 시냅스 브리지(synaptic bridge)가 형성될 가능성이 있는 거리이다(Arnett, K.L. et.al., Proc Natl Acad Sci U S A, 101:16268-16273, 2004)(도 3 및 도 13). 이러한 발견은 1가 BiTE와 달리, ALiCE의 2개의 Fab 암(arm)이 높은 결합력으로 종양 항원에 우선적으로 결합할 수 있고, 이어서 종양-침투 T 세포 상의 제2 항원에 조작된 스템(stem) Fv가 결합할 수 있음을 의미한다.The distance between the outer and inner binding domains of ALiCE was found to be about 60 Å, which is the likely distance for the formation of an immunological synaptic bridge between the tumor and effector cells (Arnett, KL et.al. , Proc Natl Acad. Sci USA , 101:16268-16273, 2004) (Figures 3 and 13). These findings suggest that unlike monovalent BiTE, two Fab arms of ALiCE can preferentially bind to tumor antigens with high avidity, followed by stem Fv engineered to a second antigen on tumor-penetrating T cells. Means can be combined.

따라서, 종양-특이적 T 세포 결합자 역할을 하는 ALiCE는 잠재적으로 비-표적(off-target) T-세포 세포독성을 감소시키면서 항-종양 효능을 향상시킬 수 있다. 이를 테스트하고자, PD-L1 및 CD3에 대한 ACE-05(항-PD-L1 Fab × 항-CD3 Fv) 및 ACE-31(항-CD3 Fab × 항-PD-L1 Fv)의 결합 카이네틱스를 Biacore 8K system(GE Healthcare)을 사용한 표면 플라즈몬 공명(surface plasmon resonance, SPR)으로 분석하였으며, 동일한 항원에 대한 YBL-007(항-PD-L1 모(parent) 항체), UCHT1(항-CD3 모 항체) 및 BiTE-05(항-PD-L1 × 항-CD3)의 결합 카이네틱스와 비교하였다(도 14 및 도 15).Thus, ALiCE, acting as a tumor-specific T cell linker, can potentially improve anti-tumor efficacy while reducing off-target T-cell cytotoxicity. To test this, the binding kinetics of ACE-05 (anti-PD-L1 Fab × anti-CD3 Fv) and ACE-31 (anti-CD3 Fab × anti-PD-L1 Fv) to PD-L1 and CD3 were evaluated. Analysis by surface plasmon resonance (SPR) using the Biacore 8K system (GE Healthcare), YBL-007 (anti-PD-L1 parent antibody), UCHT1 (anti-CD3 parent antibody) against the same antigen ) And BiTE-05 (anti-PD-L1 × anti-CD3) were compared with the binding kinetics (FIGS. 14 and 15 ).

본 발명자들은 PD-L1에 대한 ACE-05의 결합 친화도(KD) (6.78 × 10-10 M)가 YBL-007의 결합 친화도(6.46 × 10-10 M)와는 비슷하였으나, BiTE-05의 결합 친화도(1.39 × 10-9 M) 보다는 높음을 확인하였다. 이는, 아마도 ACE-05 및 YBL-007에서 2개의 PD-L1 결합 부위 때문일 것이다. 유사하게, 2가 항-CD3 Fab 암을 포함하는 ACE-31(2.39 × 10-10 M) 및 UCHT1(2.65 × 10-10 M) 둘 다의 CD3에 대한 결합 친화도는 BiTE-05(1.01 × 10-9 M)의 결합 친화도보다 더 높았다.The present inventors found that the binding affinity (K D ) of ACE-05 for PD-L1 (6.78 × 10 -10 M) was similar to that of YBL-007 (6.46 × 10 -10 M), but BiTE-05 It was confirmed to be higher than the binding affinity of (1.39 × 10 -9 M). This is probably due to the two PD-L1 binding sites in ACE-05 and YBL-007. Similarly, the binding affinity for CD3 of both ACE-31 (2.39 × 10 -10 M) and UCHT1 (2.65 × 10 -10 M), including bivalent anti-CD3 Fab cancer, is BiTE-05 (1.01 × It was higher than the binding affinity of 10 -9 M).

대조적으로, CD3에 대한 ACE-05(2.15 × 10-8 M) 및 PD-L1에 대한 ACE-31(2.72 × 10-8 M)의 1가 스템 Fv의 결합 친화도는 각각 CD3에 대한 모 항체 UCHT1의 결합 친화도(2.65 × 10-10 M) 및 PD-L1에 대한 모 항체 YBL-007의 결합 친화도(6.46 × 10-10 M)보다 40 내지 80배 낮았다. 또한, CD3에 대한 ACE-05 및 PD-L1에 대한 ACE-31의 스템 Fv의 결합 친화도는 CD3에 대한 BiTE-05의 결합 친화도(1.01 × 10-9 M) 및 PD-L1에 대한 BiTE-05의 결합 친화도(1.39 × 10-9 M)보다 훨씬 더 낮았으며, 이는 Fab 암과 스템 Fv의 제2 항원-결합 영역 간의 입체 장애 때문일 수 있다.In contrast, the binding affinity of the monovalent stem Fv of ACE-05 for CD3 (2.15 × 10 -8 M) and ACE-31 (2.72 × 10 -8 M) for PD-L1 is the parent antibody for CD3, respectively. The binding affinity of UCHT1 (2.65 × 10 -10 M) and that of the parent antibody YBL-007 for PD-L1 (6.46 × 10 -10 M) were 40 to 80 fold lower. In addition, the binding affinity of the stem Fv of ACE-05 to CD3 and of ACE-31 to PD-L1 is the binding affinity of BiTE-05 to CD3 (1.01 × 10 -9 M) and BiTE to PD-L1. It was much lower than the binding affinity of -05 (1.39 × 10 -9 M), which may be due to steric hindrance between the Fab cancer and the second antigen-binding region of stem Fv.

그러나, Octet QKe system(Pall Forte Bio)의 BLI(biolayer light interferometry) 및 유세포 분석기(GE Healthcare)를 사용하여, 본 발명자들은 PD-L1 및 CD3 둘 다에 대한 ACE-05 및 ACE-31의 동시 결합을 확인하였으며(도 16 및 도 17), 이는 2개의 각각의 항원에 대한 결합 친화도가 ALiCE 파라토프(paratope; 항원에 부착하는 항체분자 부위)의 원자가에 의존함을 나타낸다.However, using biolayer light interferometry (BLI) and flow cytometry (GE Healthcare) of the Octet QKe system (Pall Forte Bio), the present inventors have shown simultaneous binding of ACE-05 and ACE-31 to both PD-L1 and CD3. Was confirmed (FIGS. 16 and 17 ), which indicates that the binding affinity for each of the two antigens is dependent on the valency of the ALiCE paratope (an antibody molecule site attached to the antigen).

다음으로, 본 발명자들은 ALiCE 파라토프의 원자가가 종양 및 T-세포 결합에 미치는 영향을 조사하였다. Karpas-299 종양 세포의 PD-L1 및 Jurkat T 세포의 CD3에 대한 ACE-05 또는 ACE-31의 명백한 결합 친화도는 PD-L1 및 CD3에 대한 시험관내(in vitro) 결합 친화도와 일치하였다.Next, the present inventors investigated the effect of the valence of ALiCE paratope on tumor and T-cell binding. The apparent binding affinity of ACE-05 or ACE-31 for PD-L1 of Karpas-299 tumor cells and CD3 of Jurkat T cells was consistent with the in vitro binding affinity for PD-L1 and CD3.

구체적으로, ACE-05는 상응하는 ACE-31(PD-L1+ Karpas-299 세포에 대한 KD=20.58 nM 및 CD3+ Jurkat T 세포에 대한 KD=856 pM)의 결합 친화도와 비교하여, PD-L1에 대해 더 강한 결합(PD-L1+ Karpas-299 세포에 대한 KD=31.45 pM)을 보이고, CD3에 대해 더 약한 결합(CD3+ Jurkat T 세포에 대한 KD=52.44 nM)을 보였다. 한편, ACE-05와 ACE-31 모두는 PD-L1- Raji 세포에 결합하지 않았다(도 18a).Specifically, ACE-05 compared to the binding affinity of the corresponding ACE-31 ( K D =20.58 nM for PD-L1 + Karpas-299 cells and K D =856 pM for CD3 + Jurkat T cells), PD It showed stronger binding to -L1 (PD-L1 + K D =31.45 pM for Karpas-299 cells) and weaker binding to CD3 ( K D =52.44 nM for CD3 + Jurkat T cells). On the other hand, both ACE-05 and ACE-31 did not bind to PD-L1- Raji cells (FIG. 18A).

ACE-05의 종양세포 사멸 효과 향상 및 비-특이적 T-세포의 독성 감소Enhancement of tumor cell killing effect of ACE-05 and reduction of non-specific T-cell toxicity

ACE-05, ACE-31 및 BiTE-05에 의한 표적(on-target) 및 비-표적(off-target) T-세포 활성화를 비교하고자, 본 발명자들은 야생형(wild-type, WT) PD-L1- HEK 세포 또는 유전적으로 조작된 PD-L1+ HEK 세포를 NFAT-루시퍼라제 리포터 유전자를 발현하는 PD-1- Jurkat T 세포와 공배양하였다(도 19). 그 다음, T-세포 결합자 ACE-05, ACE-31 또는 BiTE-05를 처리한 후 NFAT-루시퍼라제 리포터 활성을 측정하여 Jurkat T 세포 활성화를 평가하였다. To compare the on-target and off-target T-cell activation by ACE-05, ACE-31 and BiTE-05, the present inventors described wild-type (WT) PD-L1 - HEK cells or maintain a fully operating the PD-L1 + HEK cells NFAT- luciferase reporter gene PD-1 expressing - Jurkat T cells were incubated with the ball (19). Then, after treatment with the T-cell binding agents ACE-05, ACE-31 or BiTE-05, NFAT-luciferase reporter activity was measured to evaluate Jurkat T cell activation.

흥미롭게도, ACE-05는 PD-L1+ HEK 세포 및 PD-1- Jurkat T 세포와 공배양시 가장 높은 표적(on-target) NFAT 활성화를 나타내었다. 반면, BiTE-05 및 ACE-31은 WT PD-L1- HEK 세포 및 PD-1- Jurkat T 세포와 공배양시 ACE-05보다 더 높은 비-표적(off-target) T-세포 활성화를 보였으며, 이는 PD-L1 표적화가 부재하여 Jurkat T 세포 상에서 CD3에 직접 결합에 의해 매개된다(도 20).Interestingly, ACE-05 showed the highest on-target NFAT activation when co-cultured with PD-L1 + HEK cells and PD-1 -Jurkat T cells. On the other hand, BiTE-05 and ACE-31 showed higher off-target T-cell activation than ACE-05 when co-cultured with WT PD-L1- HEK cells and PD-1 -Jurkat T cells. , It is mediated by direct binding to CD3 on Jurkat T cells in the absence of PD-L1 targeting (FIG. 20 ).

결합 친화도는 상이하지만, 전술한 바와 같이 ACE-05, ACE-31, BiTE-05 및 YBL-007이 PD-L1에 결합하였으므로, 본 발명자들은 PD-1 및 NFAT-루시퍼라제 리포터를 안정적으로 발현하는 Jurkat T 세포와 인간 PD-L1 및 조작된 세포 표면 단백질을 발현하는 CHO-K1 세포를 사용하여 PD-L1/PD-1 활성 억제능을 평가하였다. 이때, 상기 조작된 세포 표면 단백질은 항원에 무관한 방식(antigen-independent manner)으로 동족(cognate) T-세포 수용체(TCR)를 활성화 하도록 설계되었다(Cheng, Z.J.J. et al., Cancer Res., 75 (2015)).Although the binding affinity is different, as described above, since ACE-05, ACE-31, BiTE-05 and YBL-007 bound to PD-L1, the present inventors stably expressed PD-1 and NFAT-luciferase reporters. The ability to inhibit PD-L1/PD-1 activity was evaluated using Jurkat T cells and CHO-K1 cells expressing human PD-L1 and engineered cell surface proteins. At this time, the engineered cell surface protein was designed to activate cognate T-cell receptor (TCR) in an antigen-independent manner (Cheng, ZJJ et al., Cancer Res ., 75 (2015)).

또한, T-세포 활성화는 PD-L1/PD-1 상호작용만을 방해할 수 있는 YBL-007을 처리한 후보다 ACE-05 또는 BiTE-05를 세포 배양시 처리한 후 더 높았다(도 21). 이러한 결과는 PD-L1/PD-1 상호작용과 PD-L1/CD3-매개된 T-세포 리디렉션(redirection)을 동시에 억제할 수 있는 ACE-05 및 BiTE-05의 이중-표적 특이성에 기인한 것으로 보인다. In addition, T-cell activation was higher after treatment with ACE-05 or BiTE-05 during cell culture than after treatment with YBL-007, which can only interfere with PD-L1/PD-1 interaction (FIG. 21). These results are attributed to the dual-target specificity of ACE-05 and BiTE-05, which can simultaneously inhibit PD-L1/PD-1 interaction and PD-L1/CD3-mediated T-cell redirection. see.

또한, 2가 항-PD-L1 Fab 암을 포함하는 ACE-05의 T 세포 활성화 효율(EC50=0.21 nM)은 1가 항-PD-L1 scFv를 포함하는 BiTE-05의 T 세포 활성화 효율(EC50=1.09 nM) 보다 5배 더 높았다. 그러나, ACE-31은 T 세포를 재-활성화함에 있어서 ACE-05, BiTE-05 및 YBL-007보다 훨씬 덜 효과적이며, 다른 3개의 분자에 비해 PD-L1에 대한 ACE-31의 친화도가 낮음을 반영한다(도 21). In addition, the T cell activation efficiency (EC 50 =0.21 nM) of ACE-05 containing the bivalent anti-PD-L1 Fab cancer was determined by the T cell activation efficiency of BiTE-05 containing the monovalent anti-PD-L1 scFv ( EC 50 =1.09 nM) 5 times higher. However, ACE-31 is much less effective than ACE-05, BiTE-05 and YBL-007 in re-activating T cells, and the affinity of ACE-31 for PD-L1 is low compared to the other three molecules. Reflects (Fig. 21).

다음으로, 본 발명자들은 인간 이펙터 세포(말초 혈액 단핵세포(peripheral blood mononuclear cell, PBMC) 또는 분리된 T 세포)를 사용하여 PD-L1+ 종양 세포(HCC827 또는 MDA-MB-231)에 대한 ACE-05, ACE-31 및 BiTE-05의 세포 용해능(cytolytic ability)을 비교하였다. 조작된 CHO-K1 세포와 공동 배양된 PD-L1+ Jurkat T 세포의 NFAT 리포터 분석과 일치되게, 이펙터 세포(PBMC 또는 CD3+ T 세포)와 ACE-05의 인큐베이션은 PD-L1+ HCC827(EC50=1.97 pM) 및 MDA-MB-231(EC50=8.37 pM) 세포에 대해 가장 강력한 표적 사멸 활성을 나타내었다(도 22 내지 도 26). Next, the present inventors used human effector cells (peripheral blood mononuclear cells (PBMC) or isolated T cells) to ACE- for PD-L1 + tumor cells (HCC827 or MDA-MB-231). 05, the cytolytic ability of ACE-31 and BiTE-05 was compared. Consistent with NFAT reporter analysis of PD-L1 + Jurkat T cells co-cultured with engineered CHO-K1 cells, incubation of effector cells (PBMC or CD3 + T cells) and ACE-05 was performed using PD-L1 + HCC827 (EC 50 =1.97 pM) and MDA-MB-231 (EC 50 =8.37 pM) cells showed the strongest target killing activity (FIGS. 22 to 26 ).

CD8+ 세포독성 T 세포는 종종 고형 종양에서 주요 이펙터 세포로 간주되기 때문에, 본 발명자들은 ACE-05 처리시 PBMC로부터 분리된 CD8+ T 세포가 세포독성이 있는지의 여부를 테스트하였다. 일관되게, CD8+ T 세포 및 PD-L1+ MDA-MB-231과 ACE-05의 인큐베이션은 가장 강력한 세포 용해 활성을 보였으며, 퍼포린(perforin)과 협력하여 표적 종양 세포의 직접적인 단백질분해(proteolysis) 및 카스파제-매개 세포사멸을 유도하는 그랜자임 B(Granzyme B) 분비의 가장 높은 수준을 보였다(도 27 및 도 28).Since CD8 + cytotoxic T cells are often regarded as major effector cells in solid tumors, we tested whether CD8 + T cells isolated from PBMCs were cytotoxic upon ACE-05 treatment. Consistently, incubation of CD8 + T cells and PD-L1 + MDA-MB-231 and ACE-05 showed the most potent cytolytic activity, and direct proteolysis of target tumor cells in cooperation with perforin. ) And caspase-mediated apoptosis inducing granzyme B (Granzyme B) showed the highest level of secretion (FIGS. 27 and 28).

또한, 본 발명자들은 ACE-05가 PD-L1+ 종양 세포의 존재시 인간 이펙터 세포의 활성화 및 증식(expansion)을 자극할 수 있는지의 여부를 조사하였다. 이를 위해, 본 발명자들은 인간 CD3+ T 세포를 PD-L1+ MDA-MB-231 세포 및 1 nM ACE-05 또는 IgG와 24시간 동안 배양한 다음, 활성화 마커 CD69 및 CD25의 표면 발현을 모니터링하였다. 초기 활성화 마커 CD69는 ACE-05 및 PD-L1+ 종양 세포 존재시 CD4+ 및 CD8+ T 세포 모두에서 상향 조절되었으나, IgG에 의해서는 상향 조절되지 않았다(도 29).In addition, the present inventors investigated whether ACE-05 can stimulate the activation and expansion of human effector cells in the presence of PD-L1 + tumor cells. To this end, the present inventors cultured human CD3 + T cells with PD-L1 + MDA-MB-231 cells and 1 nM ACE-05 or IgG for 24 hours, and then monitored the surface expression of activation markers CD69 and CD25. Initial activation marker CD69 was upregulated in both CD4 + and CD8 + T cells in the presence of ACE-05 and PD-L1 + tumor cells, but not by IgG (FIG. 29 ).

또한, 후기 활성화 마커인 CD25는 PD-L1+ 종양 세포 존재시 ACE-05에 의해 CD3+ T 세포에서 고도로 상향 조절되었다(도 30). T 세포의 활성화 및 이펙터 세포로의 후속 분화도 T-세포 클러스터링(clustering) 및 응집과 관련이 있다(Zhou, J. et al., PLoS One, 13:e0191634, 2018). 따라서, 본 발명자들은 CytoLight-염색된 인간 CD3+ T 세포를 PD-L1+ MDA-MB-231 세포 및 1 nM ACE-05, ACE-31, BiTE-05 또는 IgG와 함께 90시간 동안 배양한 다음 클러스터 면적을 측정하였다.In addition, CD25, a late activation marker, was highly upregulated in CD3 + T cells by ACE-05 in the presence of PD-L1 + tumor cells (FIG. 30 ). Activation of T cells and subsequent differentiation into effector cells are also associated with T-cell clustering and aggregation (Zhou, J. et al. , PLoS One , 13:e0191634, 2018). Therefore, the present inventors cultured CytoLight-stained human CD3 + T cells with PD-L1 + MDA-MB-231 cells and 1 nM ACE-05, ACE-31, BiTE-05 or IgG for 90 hours and then cluster The area was measured.

그 결과, ACE-05가 PD-L1+ 종양 세포에 대하여 CD3+ T 세포의 클러스터링을 자극하고, ACE-31 또는 BiTE-05보다 더 효과적으로 T-세포 활성화를 유도할 수 있음을 확인하였다(도 31). 더욱이, ACE-05는 CD3+ T 세포 증식/확장을 강하게 유도하였다(도 32).As a result, it was confirmed that ACE-05 stimulates clustering of CD3 + T cells with respect to PD-L1 + tumor cells, and can induce T-cell activation more effectively than ACE-31 or BiTE-05 (FIG. 31 ). Moreover, ACE-05 strongly induced CD3 + T cell proliferation/expansion (Fig. 32).

한편, ACE-05의 표적(on-target) 종양-사멸능이 2종의 암 세포주(HCC827 및 MDA-MB-231)에 대해 BiTE-05의 표적 종양-사멸능보다 더 높았지만, 본 발명자들은 방출된 인터루킨(IL)-2 및 인터페론(IFN)-γ가 BiTE-05를 처리한 PBMC에서 ACE-05를 처리한 군보다 훨씬 더 높음을 예기치 않게 확인하였다(도 33). 이러한 결과는 활성화된 이펙터 세포로부터 방출된 사이토카인이 T-세포 세포독성을 담당하지만, PD-L1+ 종양 세포 존재하에서의 종양-살상 활성은 종양 세포에서 PD-L1에 대한 이중특이적 T-세포 결합자의 친화도에 따라 달라지며, 이는 T 세포의 리디렉션을 초래함을 시사한다.On the other hand, the on-target tumor-killing ability of ACE-05 was higher than that of BiTE-05 for the two cancer cell lines (HCC827 and MDA-MB-231), but the present inventors released It was unexpectedly confirmed that interleukin (IL)-2 and interferon (IFN)-γ were significantly higher in PBMC treated with BiTE-05 than in the group treated with ACE-05 (FIG. 33). These results show that cytokines released from activated effector cells are responsible for T-cell cytotoxicity, but tumor-killing activity in the presence of PD-L1 + tumor cells is bispecific T-cell binding to PD-L1 in tumor cells. It depends on the affinity of the child, suggesting that it results in the redirection of T cells.

이러한 가정을 추가로 확인하기 위해, 본 발명자들은 CD3에 대한 결합 친화도가 다르지만(ACE-05 > ACE-49 > ACE-47 > ACE-56), PD-L1에 대해 동일한 결합 친화도를 갖는 ACE-05 변이체를 제조하였다(도 34). CD3에 대해 가장 높은 친화도를 갖는 ACE-05는 NFAT 리포터 분석에서 가장 높은 비-표적(off-target) T-세포 활성화를 보였고, 비-표적 T-세포 활성화는 ACE-05 변이체의 경우 CD3에 대한 결합 친화도가 감소하면서 연속적으로 감소하였다.In order to further confirm this assumption, the inventors of the present invention have different binding affinity for CD3 (ACE-05> ACE-49> ACE-47> ACE-56), but ACE with the same binding affinity for PD-L1. The -05 variant was prepared (Figure 34). ACE-05, which has the highest affinity for CD3, showed the highest off-target T-cell activation in the NFAT reporter assay, and non-target T-cell activation was associated with CD3 in the case of the ACE-05 variant. The binding affinity for this decreased continuously with decreasing.

놀랍게도, PD-L1+ 종양세포 존재시 CD3+ T 세포의 표적 종양 살상능은 ACE-05 및 ACE-05 변이체의 경우 유사하였다(도 35 및 도 36). 항-HER2/CD3 이중특이적 항체에 의한 T 세포 세포용해 활성과 독성 사이토카인 방출의 언커플링(uncoupling)에 대한 이전 결과(Li, J. et al., Sci Transl Med, 11 (2019))와 일치되게, 사이토카인 방출은 분비된 그랜자임 B 및 퍼포린에 의해 주로 매개될 수 있는 ACE-05의 T 세포 세포용해 활성과 단절될 수 있다. 이러한 관찰은 ALiCE가 낮은 친화도로도 CD3에 결합하는 한, T-세포 결합 및 면역-관문 억제를 위해 종양 PD-L1에 결합하는 ALiCE의 능력이 항-종양 효과에 더 중요함을 종합적으로 시사한다. Surprisingly, the target tumor killing ability of CD3 + T cells in the presence of PD-L1 + tumor cells was similar for the ACE-05 and ACE-05 variants (FIGS. 35 and 36 ). Previous results on the uncoupling of T cytolytic activity and toxic cytokine release by anti-HER2/CD3 bispecific antibodies (Li, J. et al. , Sci Transl Med , 11 (2019)) Consistent with, cytokine release can be disrupted with the T cell cytolytic activity of ACE-05, which can be mediated primarily by secreted granzyme B and perforin. These observations collectively suggest that, as long as ALiCE binds to CD3 with low affinity, the ability of ALiCE to bind to tumor PD-L1 for T-cell binding and immune-checkout inhibition is more important for anti-tumor effects. .

ACE-05, ACE-31 및 BiTE-05에 의한 비-표적 T 세포 활성화를 평가하기 위해, PD-L1+ 종양 세포의 부재하에 CD4+ 또는 CD8+ T 세포에 ACE-05, ACE-31 또는 BiTE-05를 처리한 후 사이토카인 IL-2 및 IFN-γ의 분비를 측정하였다. 흥미롭게도, CD3에 대한 BiTE-05의 친화도가 ACE-31보다 낮다는 사실에도 불구하고, 오로지 BiTE-05 만이 CD4+ T 세포로부터 IL-2 및 IFN-γ의 분비를 강하게 유도하였다(도 37; IL-6 및 TNF-α는 검출되지 않음).To evaluate non-target T cell activation by ACE-05, ACE-31 and BiTE-05, ACE-05, ACE-31 or BiTE- on CD4 + or CD8 + T cells in the absence of PD-L1+ tumor cells. After treatment with 05, the secretion of cytokines IL-2 and IFN-γ was measured. Interestingly, despite the fact that the affinity of BiTE-05 for CD3 is lower than that of ACE-31, only BiTE-05 strongly induced the secretion of IL-2 and IFN-γ from CD4 + T cells (Figure 37 ; IL-6 and TNF-α were not detected).

CD3 항체 결합에 의해 유도된 CD3의 클러스터링 및/또는 멀티머화(multimerization)는 CD3 항체의 CD3 결합 친화도보다 T-세포 활성화에 더 중요하다고 보고된 바 있다(Minguet, S. et.al., Immunity, 26:43-54, 2007). 균일한 이종사량체 복합체인 ACE-05 및 ACE-31과 달리, 겔 여과 분석은 BiTE-05 제제가 다양한 오접힘된 다량체 형태를 포함하고 있는 것으로 나타났다(도 38). 실제로, BiTE-05의 이러한 다량체 성분은 종양 세포 없이도 CD4+ 및 CD8+ T 세포를 직접 활성화시킬 수 있으며(도 39), 비특이적 비-표적 T-세포 독성, 또는 사이토카인-방출 증후군(cytokine-release syndrome, CRS)을 유발할 수 있다.It has been reported that clustering and/or multimerization of CD3 induced by CD3 antibody binding is more important for T-cell activation than for CD3 binding affinity of CD3 antibodies (Minguet, S. et.al. , Immunity). , 26:43-54, 2007). Unlike ACE-05 and ACE-31, which are homogeneous heterotetrameric complexes, gel filtration analysis showed that the BiTE-05 formulation contained various misfolded multimeric forms (FIG. 38). Indeed, this multimeric component of BiTE-05 can directly activate CD4+ and CD8+ T cells without tumor cells (Figure 39), and nonspecific non-target T-cytotoxicity, or cytokine-release syndrome. , CRS).

또한, PBMC로부터 분리된 CD3+ T 세포와 PD-L1- Raji 종양 세포를 사용한 종양-살상 분석으로 ACE-05의 PD-L1+ 종양-특이적 T-세포 세포독성을 확인하였다(도 40). 종합하면, 이러한 발견은 종양 세포에 대한 ACE-05의 더 높은 친화도가 표적(on-target) T-세포 활성화를 증가시키고, 균일한 이종사량체 ACE-05가 BiTE-05에 비해 감소된 비특이적 T-세포 독성을 보임을 나타내었다.In addition, PD-L1 + tumor-specific T-cell cytotoxicity of ACE-05 was confirmed by tumor-killing analysis using CD3 + T cells and PD-L1 -Raji tumor cells isolated from PBMCs (FIG. 40). Taken together, these findings suggest that the higher affinity of ACE-05 for tumor cells increased on-target T-cell activation, and the homogeneous heterotetrameric ACE-05 was reduced compared to BiTE-05. It was shown to show T-cell toxicity.

인간화 마우스 모델에서 ALiCE의 생체 내 항-종양 효능In vivo anti-tumor efficacy of ALiCE in a humanized mouse model

ALiCE의 생체 내(in vivo) 항-종양 효능은 PD-L1+ HCC827 종양 세포를 이식한 PBMC-재구성된 NCG 마우스에서 조사하였다. 간략히, PD-L1+ HCC827 종양 세포를 우측 후방 옆구리에 피하 접종하기 3일 전에 2명의 건강한 기증자로부터 분리된 PBMC를 암컷 NCG 마우스에 이식하였다. 종양이 만져질 수 있을 때(4일째), 마우스에 3회 용량의 ACE-05 또는 BiTE-05(0.5 ㎎/㎏ 체중), 또는 3회 용량의 YBL-007 또는 IgG(5.0 ㎎/㎏ 체중)를 정맥주사하였다.The in vivo anti-tumor efficacy of ALiCE was investigated in PBMC-reconstituted NCG mice transplanted with PD-L1 + HCC827 tumor cells. Briefly, PBMCs isolated from two healthy donors were implanted into female NCG mice 3 days prior to subcutaneous inoculation of PD-L1 + HCC827 tumor cells in the right posterior flank. When the tumor is palpable (day 4), mice are given 3 doses of ACE-05 or BiTE-05 (0.5 mg/kg body weight), or 3 doses of YBL-007 or IgG (5.0 mg/kg body weight). It was injected intravenously.

ACE-05가 처리된 10 마리의 마우스 중 9 마리에서 12일째에 미리-확립된 종양이 완전히 퇴행하였다(도 41). 또한, 본 발명자들은 부작용의 징후로 체중 변화를 모니터링하였다. BiTE-05가 처리된 마우스는 체중의 상당한 감소(~20%)를 보인 반면, ACE-05 또는 YBL-007을 처리한 마우스에서는 현저한 체중 감소를 나타내지 않았다(도 42).In 9 of 10 mice treated with ACE-05, the pre-established tumors completely regressed on day 12 (FIG. 41 ). In addition, the present inventors monitored body weight changes as signs of side effects. Mice treated with BiTE-05 showed a significant decrease in body weight (~20%), whereas mice treated with ACE-05 or YBL-007 did not show significant weight loss (FIG. 42 ).

본 발명자들은 BiTE-05가 처리된 마우스의 체중 감소가 BiTE-05의 첫 번째 투여 후 사이토카인 방출의 급증에 기인한 것으로 추측하였다. 더욱이, 약동학적 분석은 ACE-05가 랫트 및 필리핀 원숭이(cynomolgus monkey)에서 BiTE-05보다 훨씬 더 긴 반감기를 가짐을 보여주었다(도 43). 용량 감소 분석(dose de-escalating analysis)은 매우 낮은 용량의 ACE-05(0.05 ㎎/㎏ 체중)에서도 PD-L1+ HCC827 종양이 완전히 퇴행하는 것으로 나타났다(도 44).The present inventors speculated that the weight loss in the mice treated with BiTE-05 was due to the rapid increase in cytokine release after the first administration of BiTE-05. Moreover, pharmacokinetic analysis showed that ACE-05 had a much longer half-life than BiTE-05 in rats and cynomolgus monkeys (FIG. 43 ). Dose de-escalating analysis revealed that PD-L1 + HCC827 tumors completely regressed even at very low doses of ACE-05 (0.05 mg/kg body weight) (FIG. 44).

본 발명자들은 hCD3ε 형질전환(TG) 마우스에서 ACE-05 및 BiTE-05의 생체 내 T 세포 독성 및 항-종양 효능을 추가로 조사하였으며, 여기서 상기 T 세포는 hCD3ε 및 mCD3ε 모두를 발현하도록 유전적으로 조작되었다. IL-2와 IFN-γ는 모두 다양한 메커니즘을 통해 항-종양 면역을 위한 중요한 이펙터 분자인 다면발현성(pleiotropic) 사이토카인이다.The present inventors further investigated the in vivo T cytotoxicity and anti-tumor efficacy of ACE-05 and BiTE-05 in hCD3ε transgenic (TG) mice, where the T cells were genetically engineered to express both hCD3ε and mCD3ε. Became. Both IL-2 and IFN-γ are pleiotropic cytokines, important effector molecules for anti-tumor immunity through various mechanisms.

그러나, IL-2의 면역 관련 부작용과 IFN-γ의 면역-회피 기능도 보고된 바 있다(Berraondo, P. et. al., Br J Cancer, 120:6-15, 2019). 또한, 활성화된 항원 제시 세포(APC), 예컨대 대식세포, 수지상 세포 또는 B 세포로부터 방출되는 전-염증성 사이토카인인 IL-6 및 TNF-α가 사이토카인-방출 증후군(CRS) 독성의 중심 매개체로 제안된 바 있다(Shimabukuro-Vornhagen, A. et. al., J Immunother Cancer, 6, 56 (2018)). 따라서, 비-표적 T-세포 독성을 평가하기 위해, 본 발명자들은 hCD3ε TG 마우스에 ACE-05, BiTE-05 또는 IgG의 단일 용량을 주입하고 6시간마다 혈청 사이토카인, IL-2, IFN-γ, IL-6 및 TNF-α를 측정하였다.However, immune-related side effects of IL-2 and immune-avoidance function of IFN-γ have also been reported (Berraondo, P. et. al. , Br J Cancer , 120:6-15, 2019). In addition, pro-inflammatory cytokines IL-6 and TNF-α, which are released from activated antigen presenting cells (APCs) such as macrophages, dendritic cells or B cells, are central mediators of cytokine-releasing syndrome (CRS) toxicity. It has been proposed (Shimabukuro-Vornhagen, A. et. al. , J Immunother Cancer , 6, 56 (2018)). Therefore, to evaluate non-target T-cell toxicity, we injected a single dose of ACE-05, BiTE-05 or IgG into hCD3ε TG mice and administered serum cytokines, IL-2, IFN-γ every 6 hours. , IL-6 and TNF-α were measured.

PBMC 및 HCC827 세포의 공동 배양에서 관찰된 사이토카인 방출과 유사하게, 비-종양 보유(non-tumor-bearing) hCD3ε 마우스에 BiTE-05를 투여한 경우 ACE-05 보다 더 높은 수준의 사이토카인, 특히 IL-2, IFN-γ 및 IL-6의 방출을 유도하였으며, 투여 6시간 후 최고 사이토카인 방출 수준을 보였다(도 45). 또한, BiTE-05를 처리한 비-종양 보유 hCD3ε 마우스는 심각한 체중 감소를 보였으며, 이에 반해 ACE-05 또는 IgG를 처리한 마우스는 훨씬 적은 체중 감소를 보여(도 46), ACE-05의 낮은 비-표적 세포독성을 입증하였다.Similar to the cytokine release observed in co-culture of PBMC and HCC827 cells, non-tumor-bearing hCD3ε mice received higher levels of cytokines than ACE-05 when administered BiTE-05, especially The release of IL-2, IFN-γ and IL-6 was induced, and the highest cytokine release level was shown 6 hours after administration (FIG. 45). In addition, the non-tumor bearing hCD3ε mice treated with BiTE-05 showed severe weight loss, whereas the mice treated with ACE-05 or IgG showed much less weight loss (Figure 46), and the low of ACE-05. Non-target cytotoxicity was demonstrated.

PD-L1+ HCC827 종양 세포를 이식한 PBMC-재구성된 NCG 마우스에서의 ACE-05의 항-종양 효능과 일치되게, hPD-L1+ CT26 종양을 이식한 hCD3ε TG 마우스에 ACE-05를 처리한 경우 종양 크기를 효과적으로 감소시켜 체중에 큰 변화를 일으키지 않고, 15일까지 6 마리의 마우스 중 1 마리의 마우스에서 완전한 퇴행을 일으킴을 확인하였다(도 47 및 도 48). 이후, 본 발명자들은 연구 종료 시점에 각 마우스로부터 종양을 수집하고, 종양-침윤 림프구(Tumor-infiltrating lymphocytes, TIL)를 분석하였다.Consistent with the anti-tumor efficacy of ACE-05 in PBMC-reconstituted NCG mice transplanted with PD-L1 + HCC827 tumor cells, hCD3ε TG mice transplanted with hPD-L1 + CT26 tumors treated with ACE-05 It was confirmed that the tumor size was effectively reduced so as not to cause a significant change in body weight, and complete regression was caused in 1 out of 6 mice by the 15th day (FIGS. 47 and 48). Thereafter, the present inventors collected tumors from each mouse at the end of the study, and analyzed tumor-infiltrating lymphocytes (TIL).

YBL-007 처리군 및 UCHT1 처리군으로부터 수집한 종양 샘플과 달리, ACE-05 처리군의 경우 남겨진 종양의 크기 및 무게가 작은 이유로 인해 2개의 종양 샘플만 분석할 수 있었다(도 49). 흥미롭게도, ACE-05를 처리한 경우 UCHT1를 처리한 경우와 비교하여 종양 미세환경에서 생존가능한 CD45+ 림프구 및 CD3+ T 세포의 수가 증가함을 확인하였다(도 50 및 도 51). 또한, ACE-05 및 YBL-007은 CD4+ T 세포가 아닌 CD8+ T 세포의 증식 및 확장을 유도하였으며(도 52 및 도 53), 이는 아마도 PD-1 및 PD-L1 상호작용의 억제 때문일 수 있다(Beyrend, G. et. al., J Immunother Cancer, 7, 217 (2019)).Unlike the tumor samples collected from the YBL-007 treatment group and the UCHT1 treatment group, in the case of the ACE-05 treatment group, only two tumor samples could be analyzed due to the small size and weight of the remaining tumor (FIG. 49 ). Interestingly, it was confirmed that the number of viable CD45 + lymphocytes and CD3 + T cells in the tumor microenvironment increased when ACE-05 was treated compared to UCHT1 (FIGS. 50 and 51). In addition, ACE-05 and YBL-007 is a CD4 + T cells are not induced the proliferation and expansion of CD8 + T cells (Fig. 52 and Fig. 53), which possibly PD-1 and PD-L1 be due to inhibition of the interaction (Beyrend, G. et. al. , J Immunother Cancer , 7 , 217 (2019)).

본 발명자들은 또한 인실리코(in silico) 면역원성 예측 도구를 사용하여 ACE-05-HC-VH 및 ACE-05-HC-VL 사슬의 T-세포 class I MHC 면역원성을 조사하였다. ACE-05-LC의 면역원성은 천연 항체(native antibody) LC와 동일하기 때문에 분석되지 않았다. 먼저, 본 발명자들은 백분위 수 순위(컷-오프 값 0.3 기준)를 사용하여 MHC class I 분자 상에 제시될 수 있는 ACE-05-HC-VH 및 ACE-05-HC-VL이 처리된 펩티드를 조사하였다(도 54 및 도 55, 좌측).The present inventors also investigated the T-cell class I MHC immunogenicity of the ACE-05-HC-VH and ACE-05-HC-VL chains using an in silico immunogenicity prediction tool. The immunogenicity of ACE-05-LC was not analyzed because it was identical to that of the native antibody LC. First, the present inventors investigated peptides treated with ACE-05-HC-VH and ACE-05-HC-VL that can be presented on MHC class I molecules using a percentile ranking (based on cut-off value of 0.3). (Fig. 54 and Fig. 55, left).

이후, MHC-I 결합 예측을 사용하여 수집된 펩티드 서열을 분석하여 면역원성 점수를 결정하였다. ACE-05-HC-VH 및 ACE-05-HC-VL 사슬 내에서 가능한 면역원성 펩티드(점수 > 0)를 도 56 및 도 57(우측)에 나열하여 나타내었다. ACE-05-HC-VH 및 ACE-05-HC-VL 사슬의 잠재적 면역원성 펩티드는 주로 가변 도메인 내의 CDR, FR 및 CH1에서 발견되었다.Thereafter, the collected peptide sequence was analyzed using MHC-I binding prediction to determine the immunogenicity score. Immunogenic peptides (score> 0) possible within the ACE-05-HC-VH and ACE-05-HC-VL chains are listed and shown in FIGS. 56 and 57 (right). Potential immunogenic peptides of the ACE-05-HC-VH and ACE-05-HC-VL chains were mainly found in the CDRs, FRs and CH1s within the variable domains.

ACE-05의 힌지와 제2 VH 또는 VL을 연결하는 인공적인 접합부(junction)는 면역원성 에피토프(epitope)인 것으로 밝혀지지 않았다. 종합하면, 이러한 결과는 ACE-05가 종양 특이적 표적(on-target) T-세포 활성화 및 연장된 약동학적 프로파일을 통해 덜 무차별적인 세포독성으로 향상된 항-종양 효능을 나타내며, 이는 종양 세포 상의 PD-L1에 대한 ACE-05의 2가 항-PD-L1 Fab 암(arm)의 고-친화성 결합 및 T 세포 상의 CD3에 대한 1가 항-CD3 스템(stem) Fv의 저-친화성 결합에 기인함을 입증하였다.The artificial junction connecting the hinge of ACE-05 and the second VH or VL has not been found to be an immunogenic epitope. Taken together, these results show that ACE-05 has improved anti-tumor efficacy with less promiscuous cytotoxicity through tumor-specific on-target T-cell activation and prolonged pharmacokinetic profile, indicating that PD on tumor cells On the high-affinity binding of the bivalent anti-PD-L1 Fab arm of ACE-05 to -L1 and the low-affinity binding of the monovalent anti-CD3 stem Fv to CD3 on T cells. It proved to be due.

다중 특이성 융합 단백질을 코딩하는 폴리뉴클레오티드Polynucleotides encoding multispecific fusion proteins

본 발명의 또 다른 측면은, 상기 구조식 (I), (I'), (I''), (II), (II') 또는 (II'')을 코딩하는 폴리뉴클레오티드를 제공하는 것이다.Another aspect of the present invention is to provide a polynucleotide encoding the structural formula (I), (I'), (I''), (II), (II') or (II'').

상기 폴리뉴클레오티드는 RNA 형태 또는 DNA 형태일 수 있다. 이중 가닥 또는 단일 가닥일 수 있으며, 단일 가닥인 경우 코딩 가닥 또는 비 코딩(안티센스) 가닥일 수 있다.The polynucleotide may be in the form of RNA or DNA. It may be double-stranded or single-stranded, and if single-stranded, it may be a coding strand or a non-coding (antisense) strand.

추가적으로, 상기 폴리뉴클레오티드는 마커 또는 태그 서열을 코딩하는 서열을 포함할 수 있다. 태그 서열의 일 구체예는 헥사-히스티딘 태그이다. Additionally, the polynucleotide may include a sequence encoding a marker or tag sequence. One embodiment of the tag sequence is a hexa-histidine tag.

뉴클레오티드 서열을 화학적으로 합성하여 제조하는 경우, 당업계에 널리 공지된 합성법, 예를 들어 문헌(Engels and Uhlmann, Angew Chem IntEd Engl., 37:73-127, 1988)에 기술된 방법을 이용할 수 있으며, 트리에스테르, 포스파이트, 포스포르아미다이트 및 H-포스페이트 방법, PCR 및 기타 오토프라이머 방법, 고체 지지체상의 올리고뉴클레오티드 합성법 등을 들 수 있다.When preparing by chemically synthesizing a nucleotide sequence, a synthetic method well known in the art, for example, a method described in Engels and Uhlmann, Angew Chem IntEd Engl., 37:73-127, 1988, can be used. , Tryester, phosphite, phosphoramidite and H-phosphate methods, PCR and other autoprimer methods, and oligonucleotide synthesis methods on a solid support.

일 구체예에 따르면, 상기 폴리펩티드는 구조식 (I), (I'), (I''), (II), (II') 또는 (II'')을 코딩하는 폴리뉴클레오티드와 적어도 약 70%, 적어도 약 75%, 적어도 약 80%, 적어도 약 85%, 적어도 약 86%, 적어도 약 87%, 적어도 약 88%, 적어도 약 89%, 적어도 약 90%, 적어도 약 91%, 적어도 약 92%, 적어도 약 93%, 적어도 약 94%, 적어도 약 95%, 적어도 약 96%, 적어도 약 97%, 적어도 약 98%, 적어도 약 99%, 또는 적어도 약 100%의 동일성을 가지는 핵산 서열을 포함할 수 있다.According to one embodiment, the polypeptide is at least about 70% with a polynucleotide encoding the formula (I), (I'), (I''), (II), (II') or (II''), At least about 75%, at least about 80%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, At least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% identity. have.

또한, 상기 폴리뉴클레오티드는 신호서열(signal sequence) 또는 리더 서열(leader sequence)을 코딩하는 핵산을 추가적으로 포함할 수 있다. 여기에서 사용된 용어 "신호서열"은 목적 단백질의 분비를 지시하는 신호펩타이드를 의미한다. 상기 신호펩타이드는 숙주 세포에서 번역된 후에 절단된다. 구체적으로, 상기 신호서열은 ER(endoplasmic reticulum) 막을 관통하는 단백질의 이동을 개시하는 아미노산 서열이다. In addition, the polynucleotide may additionally include a nucleic acid encoding a signal sequence or a leader sequence. The term "signal sequence" as used herein refers to a signal peptide that directs the secretion of a protein of interest. The signal peptide is cleaved after translation in the host cell. Specifically, the signal sequence is an amino acid sequence that initiates the movement of a protein through the ER (endoplasmic reticulum) membrane.

신호서열은 당업계에 그 특징이 잘 알려져 있으며, 통상 16 내지 30개의 아미노산 잔기를 포함하나, 그보다 더 많거나 적은 아미노산 잔기를 포함할 수 있다. 통상적인 신호 펩타이드는 기본 N-말단 영역, 중심의 소수성 영역, 및 보다 극성인(polar) C-말단 영역의 세 영역으로 구성된다. 중심 소수성 영역은 미성숙 폴리펩타이드가 이동하는 동안 막지질 이중층을 통하여 신호서열을 고정시키는 4 내지 12개의 소수성 잔기를 포함한다.The signal sequence is well known in the art, and usually includes 16 to 30 amino acid residues, but may include more or less amino acid residues. A typical signal peptide consists of three regions: a basic N-terminal region, a central hydrophobic region, and a more polar C-terminal region. The central hydrophobic region contains 4 to 12 hydrophobic residues that fix the signal sequence through the membrane lipid bilayer during migration of the immature polypeptide.

개시 이후에, 신호서열은 흔히 신호 펩티다아제(signal peptidases)로 알려진 세포 효소에 의하여 ER의 루멘(lumen) 내에서 절단된다. 이때, 상기 신호서열은 tPa(tissue Plasminogen Activation), HSV gDs(signal sequence of Herpes simplex virus glycoprotein D), 또는 성장 호르몬(growth hormone)의 분비신호서열일 수 있다. 바람직하게, 포유동물 등을 포함하는 고등 진핵 세포에서 사용되는 분비 신호서열을 사용할 수 있다. 또한, 숙주세포에서 발현 빈도가 높은 코돈으로 치환하여 사용할 수 있다.After initiation, the signal sequence is cleaved within the lumen of the ER by cellular enzymes commonly known as signal peptidases. In this case, the signal sequence may be a tissue plasma activation (tPa), a signal sequence of Herpes simplex virus glycoprotein D (HSV gDs), or a secretion signal sequence of growth hormone. Preferably, a secretion signal sequence used in higher eukaryotic cells including mammals and the like can be used. In addition, it can be used by substituting codons with high expression frequency in host cells.

융합 단백질을 코딩하는 폴리뉴클레오티드가 적재된 벡터Vector loaded with polynucleotides encoding fusion proteins

본 발명의 또 다른 측면은, 상술한 구조식 (I), (I'), (I''), (II), (II') 또는 (II'')을 코딩하는 폴리뉴클레오티드를 포함하는 벡터를 제공한다.Another aspect of the present invention is a vector comprising a polynucleotide encoding the above structural formula (I), (I'), (I''), (II), (II') or (II''). to provide.

상기 벡터는 숙주 세포에 도입되어 숙주 세포 유전체 내로 재조합 및 삽입될 수 있다. 또는 상기 벡터는 에피좀으로서 자발적으로 복제될 수 있는 폴리뉴클레오티드 서열을 포함하는 핵산 수단으로 이해된다. 상기 벡터는 선형 핵산, 플라스미드, 파지미드, 코스미드, RNA 벡터, 바이러스 벡터 및 이의 유사체들을 포함한다. 바이러스 벡터의 예로는 레트로바이러스, 아데노바이러스, 및 아데노-관련 바이러스를 포함하나 이에 제한되지 않는다. The vector can be introduced into a host cell and recombined and inserted into the host cell genome. Or the vector is understood as a nucleic acid means comprising a polynucleotide sequence capable of spontaneously replicating as an episome. Such vectors include linear nucleic acids, plasmids, phagemids, cosmids, RNA vectors, viral vectors, and analogs thereof. Examples of viral vectors include, but are not limited to, retroviruses, adenoviruses, and adeno-associated viruses.

구체적으로, 상기 벡터는 플라스미드 DNA, 파아지 DNA 등이 될 수 있고, 상업적으로 개발된 플라스미드(pUC18, pBAD, pIDTSAMRT-AMP 등), 대장균 유래 플라스미드(pYG601BR322, pBR325, pUC118, pUC119 등), 바실러스 서브틸리스 유래 플라스미드(pUB110, pTP5 등), 효모-유래 플라스미드(YEp13, YEp24, YCp50 등), 파아지 DNA(Charon4A, Charon21A, EMBL3, EMBL4, λgt10, λgt11, λZAP 등), 동물 바이러스 벡터(레트로바이러스(retrovirus), 아데노바이러스(adenovirus), 백시니아 바이러스(vaccinia virus) 등), 곤충 바이러스 벡터(배큘로바이러스(baculovirus) 등)이 될 수 있다. 상기 벡터는 숙주 세포에 따라서 단백질의 발현량과 수식 등이 다르게 나타나므로, 목적에 가장 적합한 숙주세포를 선택하여 사용함이 바람직하다.Specifically, the vector may be plasmid DNA, phage DNA, etc., commercially developed plasmids (pUC18, pBAD, pIDTSAMRT-AMP, etc.), E. coli-derived plasmids (pYG601BR322, pBR325, pUC118, pUC119, etc.), Bacillus subtilis S-derived plasmids (pUB110, pTP5, etc.), yeast-derived plasmids (YEp13, YEp24, YCp50, etc.), phage DNA (Charon4A, Charon21A, EMBL3, EMBL4, λgt10, λgt11, λZAP, etc.), animal virus vectors (retrovirus (retrovirus) ), adenovirus, vaccinia virus, etc.), insect virus vectors (baculovirus, etc.). Since the vector has different expression levels and modifications of proteins depending on the host cell, it is preferable to select and use the most suitable host cell for the purpose.

본 명세서에서 사용하는 용어, 목적 단백질의 "유전자 발현" 또는 "발현"은, DNA 서열의 전사, mRNA 전사체의 번역 및 융합 단백질 생산물 또는 이의 단편의 분비를 의미하는 것으로 이해된다. 유용한 발현 벡터는 RcCMV(Invitrogen, Carlsbad) 또는 이의 변이체일 수 있다. 상기 발현 벡터는 포유류 세포에서 목적 유전자의 연속적인 전사를 촉진하기 위한 인간 CMV(cytomegalovirus) 프로모터, 및 전사 후 RNA의 안정상태 수준을 높이기 위한 우태 성장 인자(bovine growth hormone) 폴리아데닐레이션 신호서열을 포함할 수 있다.As used herein, the term "gene expression" or "expression" of a protein of interest is understood to mean transcription of a DNA sequence, translation of an mRNA transcript, and secretion of a fusion protein product or fragment thereof. Useful expression vectors may be RcCMV (Invitrogen, Carlsbad) or a variant thereof. The expression vector includes a human CMV (cytomegalovirus) promoter for promoting the continuous transcription of a target gene in mammalian cells, and a bovine growth hormone polyadenylation signal sequence for increasing the stable state level of RNA after transcription. can do.

융합 단백질을 발현하는 형질전환된 세포Transformed cells expressing the fusion protein

본 발명의 또 다른 측면은, 상기 벡터가 도입된 형질전환 세포를 제공한다.Another aspect of the present invention provides a transformed cell into which the vector has been introduced.

상기 형질전환 세포의 숙주세포로서, 원핵세포, 진핵세포, 포유동물, 식물, 곤충, 균류 또는 세포성 기원의 세포를 포함할 수 있지만 이에 한정되지 않는다. 상기 원핵세포의 일 예로는 대장균을 사용할 수 있다. 또한, 진핵세포의 일 예로는 효모를 사용할 수 있다. 또한, 상기 포유동물 세포로 CHO 세포, F2N 세포, CSO 세포, BHK 세포, 바우스(Bowes) 흑색종 세포, HeLa 세포, 911 세포, AT1080 세포, A549 세포, HEK 293 세포 또는 HEK293T 세포 등을 사용할 수 있으나, 이에 한정되지 않으며, 당업자에게 알려진 포유동물 숙주세포로 사용 가능한 세포는 모두 이용 가능하다.The host cell of the transformed cell may include, but is not limited to, prokaryotic cells, eukaryotic cells, mammals, plants, insects, fungi, or cells of cellular origin. As an example of the prokaryotic cell, E. coli may be used. In addition, yeast may be used as an example of eukaryotic cells. In addition, CHO cells, F2N cells, CSO cells, BHK cells, Bowes melanoma cells, HeLa cells, 911 cells, AT1080 cells, A549 cells, HEK 293 cells, HEK293T cells, etc. can be used as the mammalian cells. However, the present invention is not limited thereto, and all cells that can be used as mammalian host cells known to those skilled in the art may be used.

또한, 숙주세포로 발현벡터를 도입하는 경우, CaCl2 침전법, CaCl2 침전법에 DMSO(dimethyl sulfoxide)라는 환원물질을 사용함으로써 효율을 높인 Hanahan 방법, 전기천공법(electroporation), 인산칼슘 침전법, 원형질 융합법, 실리콘 카바이드 섬유를 이용한 교반법, 아그로박테리아 매개된 형질전환법, PEG를 이용한 형질전환법, 덱스트란 설페이트, 리포펙타민 및 건조/억제 매개된 형질전환 방법 등이 사용될 수 있다.In addition, when introducing an expression vector into a host cell, the Hanahan method, electroporation, calcium phosphate precipitation method, which improved efficiency by using a reducing material called dimethyl sulfoxide (DMSO) in CaCl 2 precipitation method and CaCl 2 precipitation method. , Protoplasm fusion method, agitation method using silicon carbide fibers, Agrobacteria mediated transformation method, transformation method using PEG, dextran sulfate, lipofectamine and drying/inhibition mediated transformation method, and the like may be used.

전술한 바와 같이, 융합 단백질의 치료제로서의 특성을 최적화하거나 기타 다른 목적을 위해 호스트 세포가 갖고 있는 당화(glycosylation) 관련 유전자를 당업자에게 알려져 있는 방법을 통해 조작하여 융합 단백질의 당쇄 패턴(예를 들어, 시알산, 퓨코실화, 당화)을 조정할 수 있다. As described above, the glycosylation-related gene of the host cell for optimizing the properties of the fusion protein as a therapeutic agent or for other purposes is manipulated through a method known to those skilled in the art, and the sugar chain pattern of the fusion protein (e.g., Sialic acid, fucosylation, saccharification) can be adjusted.

융합 단백질을 포함하는 약학 조성물Pharmaceutical composition comprising a fusion protein

본 발명의 또 다른 측면은, 상술한 다중 특이적 융합 단백질을 유효성분으로 포함하는 암 치료 또는 예방용 약학 조성물을 제공하는 것이다.Another aspect of the present invention is to provide a pharmaceutical composition for the treatment or prevention of cancer comprising the above-described multi-specific fusion protein as an active ingredient.

구체적으로, 상기 암은 위암, 간암, 폐암, 대장암, 유방암, 전립선암, 난소암, 췌장암, 자궁경부암, 갑상선암, 후두암, 급성 골수성 백혈병, 뇌종양, 신경모세포종, 망막 모세포종, 두경부암, 침샘암 및 림프종으로 구성된 군에서 선택되는 어느 하나일 수 있다.Specifically, the cancer is gastric cancer, liver cancer, lung cancer, colon cancer, breast cancer, prostate cancer, ovarian cancer, pancreatic cancer, cervical cancer, thyroid cancer, laryngeal cancer, acute myelogenous leukemia, brain tumor, neuroblastoma, retinoblastoma, head and neck cancer, salivary gland cancer, and It may be any one selected from the group consisting of lymphoma.

이때, 상기 암은 PD-L1, EGFR, 및 HER2로 이루어진 군에서 선택되는 어느 하나의 단백질이 과발현된 것일 수 있다.In this case, the cancer may be overexpression of any one protein selected from the group consisting of PD-L1, EGFR, and HER2.

상기 약학 조성물의 바람직한 투여량은 환자의 상태 및 체중, 질병의 정도, 약물형태, 투여경로 및 기간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다. 본 발명의 암 또는 감염성 질환 치료용 또는 예방용 약학 조성물에서 그 유효성분은 항암 활성을 나타내거나, 감염성 질환에 치료 효과를 나타낼 수 있는 한, 용도, 제형, 배합 목적 등에 따라 임의의 양(유효량)으로 포함될 수 있는데, 통상적인 유효량은 조성물 전체 중량을 기준으로 할 때 0.001 중량 % 내지 20.0 중량% 범위 내에서 결정될 것이다. 여기서 "유효량"이란 항암 효과 또는 감염성 질환 치료(treatment) 효과를 유도할 수 있는 유효성분의 양을 말한다. 이러한 유효량은 당업자의 통상의 능력 범위 내에서 실험적으로 결정될 수 있다.The preferred dosage of the pharmaceutical composition varies depending on the condition and weight of the patient, the degree of the disease, the form of the drug, the route and duration of administration, but may be appropriately selected by those skilled in the art. In the pharmaceutical composition for the treatment or prevention of cancer or infectious diseases of the present invention, the active ingredient is an arbitrary amount (effective amount) according to the use, formulation, purpose of combination, etc., as long as it exhibits anti-cancer activity or can exhibit a therapeutic effect on infectious diseases. A typical effective amount will be determined within the range of 0.001% to 20.0% by weight based on the total weight of the composition. Here, "effective amount" refers to an amount of an active ingredient capable of inducing an anticancer effect or an infectious disease treatment effect. Such effective amounts can be determined empirically within the range of ordinary skill in the art.

본 명세서에서 사용된 용어, “치료”는 치료학적 처리 및 예방적 처리를 모두 포함하는 의미로 사용될 수 있다. 이때, 예방은 개체의 병리학적 상태 또는 질환을 완화시키거나 감소시키는 의미로 사용될 수 있다. 일 구체예에서, 용어 “치료”는 인간을 포함한 포유류에서 질환을 치료하기 위한 적용이나 어떠한 형태의 투약을 모두 포함한다. 또한, 상기 용어는 질환 또는 질환의 진행을 억제하거나 늦추는 것을 포함하며; 손상되거나, 결손된 기능을 회복시키거나, 수리하여, 질환을 부분적이거나 완전하게 완화시키거나; 또는 비효율적인 프로세스를 자극하거나; 질환의 심각함을 완화하는 의미를 포함한다.As used herein, the term “treatment” may be used to include both therapeutic treatment and prophylactic treatment. In this case, prevention may be used in the sense of alleviating or reducing a pathological condition or disease of an individual. In one embodiment, the term “treatment” encompasses any form of dosage or application to treat a disease in mammals, including humans. In addition, the term includes inhibiting or slowing the progression of a disease or disease; Restore or repair impaired or impaired function to partially or completely alleviate the disease; Or stimulating an inefficient process; Includes the meaning of alleviating the severity of the disease.

본 명세서에서 사용된 용어, “효능(efficacy)”은 1년, 5년, 또는 10년과 같이 일정 기간에 걸쳐 생존 또는 질병이 없는 상태에서 생존(disease-free survival)과 같은 하나 이상의 파라미터에 의해 결정될 수 있다. 뿐만 아니라, 상기 파라미터는 개체에서 적어도 하나의 종양의 크기가 억제되는 것을 포함할 수 있다.As used herein, the term “efficacy” refers to one or more parameters such as survival over a period of time, such as 1, 5, or 10 years, or disease-free survival. Can be determined. In addition, the parameter may include suppressing the size of at least one tumor in the individual.

생체이용률과 같은 약동학적 파라미터(Pharmacokinetic parameters) 및 클리어런스율(clearance rate)과 같은 기본적인 파라미터(underlying parameters)도 효능에 영향을 줄 수 있다. 따라서, “향상된 효능” (예를 들어, 효능의 개선)은 향상된 약동학적 파라미터 및 향상된 효능에 기인할 수 있으며, 시험 동물 또는 인간 대상체에서 클리어런스율 및 종양 성장을 비교하거나, 생존, 재발율 또는 질병이 없는 상태에서 생존과 같은 파라미터를 비교하여 측정될 수 있다.Pharmacokinetic parameters such as bioavailability and underlying parameters such as clearance rate can also affect efficacy. Thus, “enhanced efficacy” (eg, improved efficacy) can be attributed to improved pharmacokinetic parameters and improved efficacy, comparing clearance rates and tumor growth in test animals or human subjects, or survival, recurrence rates or disease. It can be measured by comparing parameters such as survival in the absence.

여기서 "치료학적으로 유효한 양" 또는 "약학적으로 유효한 양"이란 대상 질환을 예방 또는 치료하는데 유효한 화합물 또는 조성물의 양으로서, 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분하며 부작용을 일으키지 않을 정도의 양을 의미한다. 상기 유효량의 수준은 환자의 건강상태, 질환의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 방법, 투여 시간, 투여 경로 및 배출 비율, 치료 기간, 배합 또는 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 일 구체예에서 치료학적으로 유효한 양은 암을 치료하는데 효과적인 약물의 양을 의미한다.Herein, "therapeutically effective amount" or "pharmaceutically effective amount" is an amount of a compound or composition effective to prevent or treat the subject disease, which is sufficient to treat the disease at a reasonable benefit/risk ratio applicable to medical treatment, and It means the amount that does not cause side effects. The level of the effective amount is the health condition of the patient, the type of disease, the severity, the activity of the drug, the sensitivity to the drug, the method of administration, the time of administration, the route of administration and the rate of excretion, the duration of treatment, factors including the drugs used in combination or concurrently, and Other factors well known in the medical field can be determined. In one embodiment, a therapeutically effective amount refers to an amount of a drug effective to treat cancer.

이때, 상기 약학 조성물은 약학적으로 허용 가능한 담체를 더 포함할 수 있다. 상기 약학적으로 허용 가능한 담체는 환자에게 전달하기에 적절한 비-독성 물질이면 어떠한 담체라도 가능하다. 증류수, 알코올, 지방, 왁스 및 비활성 고체가 담체로 포함될 수 있다. 약물학적으로 허용되는 애쥬번트(완충제, 분산제) 또한 약학 조성물에 포함될 수 있다.In this case, the pharmaceutical composition may further include a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may be any carrier as long as it is a non-toxic material suitable for delivery to a patient. Distilled water, alcohols, fats, waxes and inert solids may be included as carriers. Pharmaceutically acceptable adjuvants (buffers, dispersants) may also be included in the pharmaceutical composition.

구체적으로, 상기 약학 조성물은 유효성분 이외에 약제학적으로 허용되는 담체를 포함하여 당업계에 공지된 통상의 방법으로 투여 경로에 따라 비경구용 제형으로 제조될 수 있다. 여기서 "약제학적으로 허용되는" 의미는 유효성분의 활성을 억제하지 않으면서 적용(처방) 대상이 적응 가능한 이상의 독성을 지니지 않는다는 의미이다.Specifically, the pharmaceutical composition may be prepared in a parenteral formulation according to an administration route by a conventional method known in the art, including a pharmaceutically acceptable carrier in addition to the active ingredient. Here, "pharmaceutically acceptable" means that the application (prescription) does not have toxicity beyond adaptable without inhibiting the activity of the active ingredient.

상기 약학 조성물이 비경구용 제형으로 제조될 경우, 적합한 담체와 함께 당업계에 공지된 방법에 따라 주사제, 경피 투여제, 비강 흡입제 및 좌제의 형태로 제제화될 수 있다. 주사제로 제제화할 경우 적합한 담체로서는 멸균수, 에탄올, 글리세롤이나 프로필렌 글리콜 등의 폴리올 또는 이들의 혼합물을 사용할 수 있으며, 바람직하게는 링거 용액, 트리에탄올 아민이 함유된 PBS(phosphate buffered saline)나 주사용 멸균수, 5% 덱스트로스 같은 등장 용액 등을 사용할 수 있다. 약제학적 조성물의 제제화와 관련하여서는 당업계에 공지되어 있으며, 구체적으로 문헌[Remington's Pharmaceutical Sciences(19th ed., 1995)] 등을 참조할 수 있다. 상기 문헌은 본 명세서의 일부로서 간주된다.When the pharmaceutical composition is prepared in a parenteral formulation, it may be formulated in the form of an injection, a transdermal administration, a nasal inhalation, and a suppository according to a method known in the art together with a suitable carrier. When formulated as an injection, sterile water, ethanol, polyols such as glycerol or propylene glycol, or mixtures thereof may be used as suitable carriers, preferably Ringer's solution, PBS (phosphate buffered saline) containing triethanol amine, or sterilization for injection. Water, isotonic solutions such as 5% dextrose, etc. can be used. Regarding the formulation of a pharmaceutical composition, it is known in the art, and specifically, reference may be made to Remington's Pharmaceutical Sciences (19th ed., 1995). This document is considered part of this specification.

상기 약학 조성물의 바람직한 투여량은 환자의 상태, 체중, 성별, 연령, 환자의 중증도, 투여 경로에 따라 1일 체중 1 kg당 0.01 ㎍ 내지 10 g 범위, 또는 0.01 mg 내지 1 g 범위일 수 있다. 투여는 1일 1회 또는 수회로 나누어 이루어질 수 있다. 이러한 투여량은 어떠한 측면으로든 본원 발명의 범위를 제한하는 것으로 해석되어서는 안된다. The preferred dosage of the pharmaceutical composition may be in the range of 0.01 µg to 10 g per 1 kg of body weight per day, or in the range of 0.01 mg to 1 g, depending on the patient's condition, weight, sex, age, patient severity, and route of administration. Administration can be made once a day or divided into several times. Such dosage should not be construed as limiting the scope of the invention in any aspect.

상기 약학 조성물이 적용(처방)될 수 있는 대상은 포유동물 및 사람이며, 특히 사람인 경우가 바람직하다. 본원의 약학 조성물은 유효성분 이외에, 항암 활성의 상승·보강을 위하여 이미 안전성이 검증되고 항암 활성 또는 감염성 질환에 치료 효과를 갖는 것으로 공지된 임의의 화합물이나 천연 추출물을 추가로 포함할 수 있다. Subjects to which the pharmaceutical composition can be applied (prescribed) are mammals and humans, particularly preferably humans. In addition to the active ingredient, the pharmaceutical composition of the present application may further include any compound or natural extract, which has already been verified for safety and has a therapeutic effect on anti-cancer activity or infectious disease, in order to increase and reinforce anti-cancer activity.

병용 투여용 약학 조성물Pharmaceutical composition for combined administration

본 발명의 또 다른 측면은, 상술한 다중 특이적 융합 단백질 및 항암제를 더 포함하는 약학 조성물을 제공한다.Another aspect of the present invention provides a pharmaceutical composition further comprising the above-described multispecific fusion protein and an anticancer agent.

상기 융합 단백질은 약제학적으로 허용되는 담체를 포함한다. 이때, 약제학적 조성물은 대상체에 대한 투여 경로에 적합하도록 제형화될 수 있다.The fusion protein includes a pharmaceutically acceptable carrier. At this time, the pharmaceutical composition may be formulated to be suitable for the route of administration to the subject.

다중 특이적 융합 단백질의 용도Use of multispecific fusion proteins

본 발명의 또 다른 측면은, 암을 치료 또는 예방하기 위한 상기 다중 특이적 융합 단백질의 용도를 제공한다.Another aspect of the present invention provides the use of the multispecific fusion protein for treating or preventing cancer.

상기 암은 위암, 간암, 폐암, 대장암, 유방암, 전립선암, 난소암, 췌장암, 자궁경부암, 갑상선암, 후두암, 급성 골수성 백혈병, 뇌종양, 신경모세포종, 망막 모세포종, 두경부암, 침샘암 및 림프종으로 구성된 군에서 선택될 수 있다.The cancer is gastric cancer, liver cancer, lung cancer, colon cancer, breast cancer, prostate cancer, ovarian cancer, pancreatic cancer, cervical cancer, thyroid cancer, laryngeal cancer, acute myelogenous leukemia, brain tumor, neuroblastoma, retinoblastoma, head and neck cancer, salivary gland cancer and lymphoma. Can be selected from the group.

본 발명의 또 다른 측면은, 세포결합자(cell engager)로서 이용하기 위한 상기 다중 특이적 융합 단백질의 용도를 제공한다.Another aspect of the present invention provides the use of the multispecific fusion protein for use as a cell engager.

암 예방 및 치료 방법Cancer prevention and treatment methods

본 발명의 또 다른 측면은, 상기 다중 특이적 융합 단백질을 개체에 투여하는 단계를 포함하는 암 치료 또는 예방 방법을 제공한다.Another aspect of the present invention provides a method for treating or preventing cancer comprising administering the multispecific fusion protein to an individual.

상기 개체는 암 또는 감염성 질환을 앓고 있는 개체일 수 있다. 또한 상기 개체는 포유동물일 수 있으며, 바람직하게는 인간일 수 있다. 다중 특이적 융합 단백질은 상술한 바와 같다.The subject may be a subject suffering from cancer or an infectious disease. In addition, the individual may be a mammal, preferably a human. The multispecific fusion protein is as described above.

상기 다중 특이적 융합 단백질은 환자의 상태 및 부작용의 유무에 따라 다양한 방법 및 양으로 대상에게 투여될 수 있고, 최적의 투여경로, 투여량 및 투여횟수는 통상의 기술자가 적절한 범위로 선택할 수 있다. 또한, 상기 융합 단백질은 치료하고자 하는 질환에 대하여 치료효과가 공지된 다른 약물 또는 생리학적 활성물질과 병용하여 투여되거나, 다른 약물과의 조합 제제 형태로 제형화될 수 있다.The multispecific fusion protein may be administered to a subject in various methods and amounts depending on the condition of the patient and the presence or absence of side effects, and the optimal administration route, dosage, and frequency of administration may be selected within an appropriate range by a person skilled in the art. In addition, the fusion protein may be administered in combination with other drugs or physiologically active substances known to have a therapeutic effect on the disease to be treated, or may be formulated in the form of a combination formulation with other drugs.

융합 단백질 생산 방법Fusion protein production method

본 발명의 또 다른 측면은, 상술한 형질전환된 세포를 배양하는 단계를 포함하는 다중 특이적 융합 단백질을 생산하는 방법을 제공한다. 구체적으로, 상기 생산 방법은 i) 상기 형질전환 세포를 배양하여 배양물을 수득하는 단계; 및 ii) 상기 배양물로부터 융합 단백질을 회수하는 단계를 포함할 수 있다.Another aspect of the present invention provides a method for producing a multispecific fusion protein comprising culturing the transformed cells described above. Specifically, the production method comprises the steps of: i) culturing the transformed cells to obtain a culture; And ii) recovering the fusion protein from the culture.

상기 형질전환 세포를 배양하는 방법은 당업계에 널리 알려져 있는 방법을 이용하여 수행할 수 있다. 구체적으로, 상기 배양은 배치 공정 또는 주입 배치 또는 반복 주입 배치 공정(fed batch or repeated fed batch process)에서 연속식으로 배양할 수 있다. The method of culturing the transformed cells may be performed using a method well known in the art. Specifically, the culture may be continuously cultured in a batch process or in a fed batch or repeated fed batch process.

상기 융합 단백질을 회수하기 위하여 면역글로불린의 정제를 위해 당 업계에 공지된 임의의 방법, 예를 들어 크로마토그래피 (이온 교환, 친화성, 특히 Protein A, 사이징 컬럼 크로마토그래피 및 kappa-select 친화성 크로마토그래피 이 후 특정 항원의 경우에 있어서 친화성에 의한 정제), 원심 분리, 차등 용해도 또는 단백질 정제를 위한 기타 표준 기술이 사용될 수 있다. 특정 구체 예에서, 카파-셀렉트(예를 들어, GE Healthcare Life Science에 의해 개발된 카파 셀렉트)는 Fab (카파) 단편 또는 Fab 단편을 함유하는 다중 특이적 융합 단백질의 정제에 사용된다. 추가로, 본원에 제공된 다중 특이적 융합 단백질은 정제를 용이하게 하기 위해 본원에 기재된 이종 폴리펩티드 서열 또는 당업계에 공지된 다른 서열에 융합될 수 있다.Any method known in the art for purification of immunoglobulins to recover the fusion protein, for example chromatography (ion exchange, affinity, especially Protein A, sizing column chromatography and kappa-select affinity chromatography Thereafter, in the case of specific antigens, purification by affinity), centrifugation, differential solubility or other standard techniques for protein purification can be used. In certain embodiments, kappa-select (eg, kappa select developed by GE Healthcare Life Science) is used for purification of a Fab (kappa) fragment or a multispecific fusion protein containing a Fab fragment. Additionally, the multispecific fusion proteins provided herein can be fused to heterologous polypeptide sequences described herein or other sequences known in the art to facilitate purification.

이하, 본 발명을 하기 실시예를 통하여 보다 상세하게 설명한다. 그러나 이들 실시예는 본 발명을 예시적으로 설명하기 위한 것으로 본 발명의 범위가 이들 실시예만으로 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail through the following examples. However, these examples are for illustrative purposes only, and the scope of the present invention is not limited to these examples.

I. 다중 특이적 융합 단백질의 제조I. Preparation of multiple specific fusion proteins

실시예 1. 다중 특이적 융합 단백질 ALiCE의 제조Example 1. Preparation of multispecific fusion protein ALiCE

ALiCE 변이체인 ACE-05(항-PD-L1 Fab × 항-CD3 Fv), ACE-31(항-CD3 Fab × 항-PD-L1 Fv), ACE-18(항-CD20 Fab × CD3 Fv) 및 ACE-00(항-HER2 Fab × 항-TNF-α Fv)의 HC 쌍, ACE-HC-VH 및 ACE-HC-VL은 모(parent) 항체인 YBL-007(항-PD-L1), UCHT1(항-CD3), 리툭시맙(항-CD20), 허셉틴(항-HER2) 및 휴미라(항-TNF-α)를 주형으로 사용하고, VHA-CH1-힌지(hinge), VHB 및 VLB를 암호화하는 서열을 PCR로 증폭하였다. ALiCE variants ACE-05 (anti-PD-L1 Fab × anti-CD3 Fv), ACE-31 (anti-CD3 Fab × anti-PD-L1 Fv), ACE-18 (anti-CD20 Fab × CD3 Fv) and HC pair of ACE-00 (anti-HER2 Fab × anti-TNF-α Fv), ACE-HC-VH and ACE-HC-VL are parent antibodies YBL-007 (anti-PD-L1), UCHT1 (Anti-CD3), Rituximab (anti-CD20), Herceptin (anti-HER2) and Humira (anti-TNF-α) were used as templates, and VHA-CH1-hinge, VHB and VLB were encoded The sequence was amplified by PCR.

두 개의 PCR 단편 쌍인 VHA-CH1-힌지 및 VHB 또는 VHA-CH1-힌지 및 VLB는 제조업체의 프로토콜에 따라 ElectraTM 클로닝 시스템(ElectraTM cloning system; ATUM) (Engler, C. et.al., PloS one, 3, e3647 (2008))을 사용하여 사내(in-house) 제조된 포유류 발현 벡터 p293F에 서브클로닝(sub-cloning)하였다. 그 후, DH5α 컴피턴트 세포(competent cell; # CP010, Enzynomics)로 형질전환시켰다. ALiCE HC 구축을 위한 PCR 프라이머는 힌지와 5' 말단에 VHB 또는 VLB 사이에 짧은 링커(G4S), 및 3' 말단에, ElectraTM 클로닝 시스템에 필요한 SapI 제한 부위를 포함하도록 설계하였다.Two PCR fragment pairs VHA-VHB and CH1- hinge or VHA-VLB and CH1- hinge according to the manufacturer's protocol Electra TM cloning system (Electra TM cloning system; ATUM) (Engler, C. et.al., PloS one , 3 , e3647 (2008)) was used to sub-cloning into the mammalian expression vector p293F prepared in-house. Then, it was transformed into DH5α competent cells (# CP010, Enzynomics). PCR primers for constructing ALiCE HC were designed to contain a short linker (G4S) between the VHB or VLB at the hinge and 5'end, and the Sap I restriction site required for the Electra TM cloning system at the 3'end.

ALiCE 구축에 사용된 LC인 ACE-LC는 모 항체의 광(light) 변화와 동일하였다. N-말단에 리더 펩티드를 포함하는 LC를 암호화하는 서열을 PCR-증폭하고, NheI/XhoI 제한 부위를 포함하는 p293 발현 벡터에 서브클로닝하였다. 생성된 구조물(constructs)을 DH5α 컴피턴트 세포(# CP010, Enzynomics)로 형질전환시키고, 시퀀싱을 통해 확인하였다.ACE-LC, the LC used to construct ALiCE, was the same as the change in light of the parent antibody. The sequence encoding the LC containing the leader peptide at the N-terminus was PCR-amplified and subcloned into the p293 expression vector containing the Nhe I/ Xho I restriction site. The resulting constructs were transformed with DH5α competent cells (# CP010, Enzynomics) and confirmed through sequencing.

또한, 다른 ALiCE 변이체인 ACE-02, ACE-03, ACE-06, ACE-10, ACE-11, ACE-16, ACE-20, ACE-21, ACE-23, ACE-25, ACE-26, ACE-28, ACE-30, ACE-32 및 ACE-33도 실시예 21에 기재된 서열을 기반으로 상기와 같은 방법으로 클로닝하였다.In addition, other ALiCE variants ACE-02, ACE-03, ACE-06, ACE-10, ACE-11, ACE-16, ACE-20, ACE-21, ACE-23, ACE-25, ACE-26, ACE-28, ACE-30, ACE-32 and ACE-33 were also cloned in the same manner as described above based on the sequence described in Example 21.

실시예 2. ALiCE의 발현 및 정제Example 2. Expression and purification of ALiCE

C-말단에 6×-His 태그를 포함하는 ALiCE 변이체인 ACE-00, ACE-05, ACE-18, ACE-31 및 BiTE-05를 생산하기 위해, 1:1:2 비율의 ACE-HC-VH, ACE-HC-VL 및 ACE-LC, 또는 BiTE-05를 암호화하는 플라스미드를 FreeStyle 293-F 세포(#R79007, ThermoFisher)로 1:4(w/w)의 DNA 대 PEI 비율로 폴리에틸렌이민(PEI; #23996-1, Polysciences)을 사용하여 트랜스펙션시켜 폴리플렉스(polyplex)를 형성하였다(Xie, Q. et.al., Cytotechnology, 65:263-271, 2013). 일시적 트랜스펙션의 경우, 1 ㎎의 플라스미드 DNA를 2×106 개의 Freestyle 203-F 세포로 트랜스펙션시킨 후, 37℃ 및 5% CO2 조건하에서 FreeStyle 293 발현 배지(#12338018, Gibco)를 이용하여 쉐이킹(120 rpm) 하면서 배양하였다.To produce ALiCE variants ACE-00, ACE-05, ACE-18, ACE-31 and BiTE-05 containing a 6×-His tag at the C-terminus, ACE-HC- in a 1:1:2 ratio Plasmids encoding VH, ACE-HC-VL and ACE-LC, or BiTE-05 were transferred to FreeStyle 293-F cells (#R79007, ThermoFisher) in a 1:4 (w/w) DNA to PEI ratio of polyethyleneimine ( PEI; #23996-1, Polysciences) was used to form a polyplex (Xie, Q. et.al. , Cytotechnology , 65:263-271, 2013). For transient transfection, 1 mg of plasmid DNA was added to 2×10 6 After transfection with Freestyle 203-F cells, they were cultured while shaking (120 rpm) using FreeStyle 293 expression medium (#12338018, Gibco) under conditions of 37° C. and 5% CO 2.

ALiCE 분자와 BiTE-05는 배양물을 4℃에서 30분 동안 4,800 rpm으로 원심분리한 후, 0.22 ㎛ TOP-필터(Millipore)를 사용하여 상층액을 여과하여 데브리스(debris)를 제거함에 의해 정제하였다. ALiCE 분자를 포함하는 상층액은 CaptureSelect CH1-XL 프리-팩킹된 컬럼(CaptureSelect CH1-XL pre-packed column; #494346201, ThermoFisher)에 로딩하였으며, BiTE-05를 포함하는 상층액은 Ni-NTA 아가로오스 레진(Ni-NTA agarose resin, # R90101, ThermoFisher)에 로딩하였다. ALiCE molecule and BiTE-05 were purified by centrifuging the culture at 4°C for 30 minutes at 4,800 rpm, and then filtering the supernatant using a 0.22 μm TOP-filter to remove debris. I did. The supernatant containing ALiCE molecules was loaded on a CaptureSelect CH1-XL pre-packed column (#494346201, ThermoFisher), and the supernatant containing BiTE-05 was Ni-NTA agar. It was loaded on OS resin (Ni-NTA agarose resin, # R90101, ThermoFisher).

ALiCE 분자는 0.1 M 글리신(pH 3.0)을 이용하여 컬럼에서 용출시켰으며, BiTE-05는 3 M 이미다졸/20 mM 인산나트륨(pH 6.0)을 이용하여 용출하였다. 용출된 ALiCE 분자 및 BiTE-05는 Slide-A-Lyzer 투석 카세트 키트(Slide-A-Lyzer Dialysis Cassette Kits; #66372, ThermoFisher)를 사용하여 인산염 완충 식염수(PBS; pH 7.4)로 투석하였다. SPR 결합 카이네틱 분석(Surface plasmon resonance binding kinetic assay)을 위해, 트롬빈 절단 캡쳐 키트(Thrombin Cleavage Capture kit; # 69022, Merck)를 사용하여 BiTE-05에서 6×-His-태그를 제거하였다. ALiCE molecule was eluted from the column using 0.1 M glycine (pH 3.0), and BiTE-05 was eluted using 3 M imidazole/20 mM sodium phosphate (pH 6.0). The eluted ALiCE molecules and BiTE-05 were dialyzed with phosphate buffered saline (PBS; pH 7.4) using Slide-A-Lyzer Dialysis Cassette Kits (#66372, ThermoFisher). For SPR binding kinetic assay (Surface plasmon resonance binding kinetic assay), a 6×-His-tag was removed from BiTE-05 using a Thrombin Cleavage Capture kit (#69022, Merck).

또한, 다른 ALiCE 변이체인 ACE-02, ACE-03, ACE-06, ACE-10, ACE-11, ACE-16, ACE-20, ACE-21, ACE-23, ACE-25, ACE-26, ACE-28, ACE-30, ACE-32 및 ACE-33도 상기와 같은 방법으로 수득하였다.In addition, other ALiCE variants ACE-02, ACE-03, ACE-06, ACE-10, ACE-11, ACE-16, ACE-20, ACE-21, ACE-23, ACE-25, ACE-26, ACE-28, ACE-30, ACE-32 and ACE-33 were also obtained in the same manner as above.

실시예 3. ALiCE 구조 분석Example 3. ALiCE structure analysis

실험예 1. 항체 구조의 PyMOL 분석Experimental Example 1. PyMOL analysis of antibody structure

항-CD3 항체 UCHT(PBD ID: 1XIW), 항-PD-L1 항체 더발루맙 및 항-CTLA-1 항체 이필리무맙(PBD ID: 5TRU)의 구조는 Protein Data Bank(PBD, www.rcsb.org)에서 다운로드하고, PyMOL 소프트웨어를 사용하여 시각화하였다(Schrodinger, LLC The PyMOL Molecular Graphics System, Version 1.8. (2015)).The structures of anti-CD3 antibody UCHT (PBD ID: 1XIW), anti-PD-L1 antibody dervalumab, and anti-CTLA-1 antibody ipilimumab (PBD ID: 5TRU) are described in Protein Data Bank (PBD, www.rcsb. org) and visualized using PyMOL software (Schrodinger, LLC The PyMOL Molecular Graphics System, Version 1.8. (2015)).

실험예 3.2. 이종 이량체 ALiCE의 구조 분석Experimental Example 3.2. Structural analysis of heterodimer ALiCE

ALiCE 분자는 SDS-PAGE; Agilent 2100 Bioanalyzer(Agilent Technology)를 사용한 전자동 모세관 전기영동(CE); Superdex 200A 컬럼(GE Healthcare Life Science)을 사용한 분석적 크기-배제 크로마토그래피(SEC); 및 MabPac SCX-10 컬럼(ThermoFisher)을 사용한 분석적 양이온 교환 크로마토그래피(CEX)로 특성을 분석하였다. 2개의 상이한 ALiCE HC에 의한 이종이량체 형성은 환원 및 비-환원 조건하에서 SDS-PAGE 및 CE로 ALiCE 분자를 분석하여 평가하였다.The ALiCE molecule was SDS-PAGE; Fully automated capillary electrophoresis (CE) using an Agilent 2100 Bioanalyzer (Agilent Technology); Analytical Size-Exclusion Chromatography (SEC) using a Superdex 200A column (GE Healthcare Life Science); And analytical cation exchange chromatography (CEX) using a MabPac SCX-10 column (ThermoFisher). Heterodimer formation by two different ALiCE HCs was evaluated by analyzing ALiCE molecules by SDS-PAGE and CE under reducing and non-reducing conditions.

CE 분석을 위해, 단백질-분석적 용액 혼합물을 미세유체 단백질 칩(microfluidic protein chip)에 로딩하고, 제조업체의 프로토콜에 따라 환원 및 비-환원 조건하에서 Bioanalyzer Protein 230 assay kit(Agilent)를 사용하여 분자량별로 분리하였다. 또한, ACE-05에서 다양한 사슬의 화학양론 비율(stoichiometric ratio)은 Bioanalyzer Protein 80 assay kit(Agilent)를 사용하여 환원 조건하에서 결정하였다.For CE analysis, the protein-analytical solution mixture was loaded onto a microfluidic protein chip and separated by molecular weight using the Bioanalyzer Protein 230 assay kit (Agilent) under reducing and non-reducing conditions according to the manufacturer's protocol. I did. In addition, the stoichiometric ratio of various chains in ACE-05 was determined under reducing conditions using a Bioanalyzer Protein 80 assay kit (Agilent).

5개의 독립적인 실험에서 결정된 ACE-05에 대한 각 사슬의 기여도(% 총계)에 대한 평균 및 상대표준편차(% CV)는 2100 Expert Software(Agilent Technology)를 사용하여 분석하고, GraphPad Prism 8 소프트웨어를 사용하여 플로팅하였다. ALiCE 분자의 품질 및 형태는 Superdex 200A 컬럼(GE Healthcare Life Science)을 사용한 SEC(버퍼, PBS pH 7.4) 및 MabPac SCX-10 컬럼(ThermoFisher)을 사용한 CEX(버퍼, 50 mM 아세트산 나트륨 pH 5.0)로 분석하였다. 데이터는 GraphPad Prism 8 소프트웨어를 사용하여 플로팅하고 분석하였다.The mean and relative standard deviation (% CV) of each chain's contribution (% total) to ACE-05 determined in five independent experiments were analyzed using 2100 Expert Software (Agilent Technology), and GraphPad Prism 8 software was used. Plotted using. The quality and morphology of ALiCE molecules were analyzed by SEC (buffer, PBS pH 7.4) using Superdex 200A column (GE Healthcare Life Science) and CEX (buffer, 50 mM sodium acetate pH 5.0) using MabPac SCX-10 column (ThermoFisher). I did. Data were plotted and analyzed using GraphPad Prism 8 software.

그 결과, 항-CD3 항체 UCHT1(PDB ID: 1XIW), 항-PD-L1 항체 더발루맙(PDB ID : 5X8M) 및 항-CTLA4 항체 이필리무맙(PDB ID: 5TRU)을 포함한 다양한 VH 및 VL 복합체의 결정 구조는 VH 및 VL 상호작용의 핵심 결정인자가 "놉-인투-홀(Knob-into-Hole)"구조를 형성하여 VL의 CDR1, CDR2 및 CDR3 영역에 결합하는 VH의 CDR3 영역임을 명확하게 입증하였다(도 1). 또한, VH-VL 공유영역(interface)에서 정전기적 상호작용으로 둘러싸인 소수성 상호작용은 VH 및 VL 도메인의 자율적 조립(autonomous assembly)과 Fv 복합체의 안정화에 기여함을 확인하였다(도 2).As a result, various VH and VL including anti-CD3 antibody UCHT1 (PDB ID: 1XIW), anti-PD-L1 antibody dervalumab (PDB ID: 5X8M) and anti-CTLA4 antibody ipilimumab (PDB ID: 5TRU) The crystal structure of the complex is clear that the key determinant of VH and VL interaction is the CDR3 region of VH, which forms a "knob-into-Hole" structure and binds to the CDR1, CDR2 and CDR3 regions of VL. Proved to be (Fig. 1). In addition, it was confirmed that the hydrophobic interaction surrounded by electrostatic interactions in the VH-VL interface contributes to the autonomous assembly of the VH and VL domains and the stabilization of the Fv complex (FIG. 2).

실험예 4. ALiCE의 질량 분석Experimental Example 4. ALiCE mass spectrometry

정제된 ACE-05의 분자량은 ZORBAX 300SB-C8(2.1×50 ㎚; Agilent) 컬럼을 사용하여 TOF(time-of-flight) 분석을 통한 액체크로마토그래피-전자분무이온화(LC-ESI/TOF)로 확인하였다. 전체 실행에 걸쳐 포름산 농도는 0.2%로 일정하되, 이동상은 5% 아세토니트릴(초기 조건)로 시작하여 100% 아세토니트릴까지 35분에 걸쳐 물 및 아세토니트릴의 구배로 구성하였다.The molecular weight of purified ACE-05 was determined by liquid chromatography-electrospray ionization (LC-ESI/TOF) through time-of-flight (TOF) analysis using a ZORBAX 300SB-C8 (2.1×50 nm; Agilent) column. Confirmed. The formic acid concentration was constant over the entire run at 0.2%, while the mobile phase consisted of a gradient of water and acetonitrile over 35 minutes, starting with 5% acetonitrile (initial conditions) to 100% acetonitrile.

유속은 0.1 ㎖/분(min)이었다. 마이크로 A-TOF Ⅲ 질량 분석기(Micro A-TOF Ⅲ mass spectrometer; Bruker Daltonics, Germany)를 사용하여 전자분무이온화(electrospray ionization, ESI)를 음성 모드로 사용하여 질량 분석법 검출을 수행하였다. 다음의 MS 파라미터(parameter)가 사용되었다: 모세관 전압, 4500 V; 분무기(nebulizer) 압력, 0.8 psi; 건조 가스 흐름, 5.5/분; 건조 가스 온도, 190℃.The flow rate was 0.1 ml/min (min). Mass spectrometry detection was performed using a micro A-TOF III mass spectrometer (Bruker Daltonics, Germany) using electrospray ionization (ESI) as a negative mode. The following MS parameters were used: capillary voltage, 4500 V; Nebulizer pressure, 0.8 psi; Dry gas flow, 5.5/min; Dry gas temperature, 190°C.

실험예 5. ALiCE의 안정성 분석Experimental Example 5. Stability Analysis of ALiCE

ACE-05, BiTE-05, YBL-007 및 UCHT1의 열 안정성은 SYPRO 주황색 염료(dye)를 이용한 Thermofluor assay(Lavinder, J.J. et.al., J Am Chem Soc, 131:3794-3795, 2009)를 사용하여 분석하였다. 구체적으로, 정제된 각 항체의 3μM 용액을 1:25로 희석한 SYPRO 주황색 염료(#S6650, ThermoFisher) 10㎕와 혼합하고, 각 혼합물 50 ㎕를 25℃에서 30분 동안 인큐베이션하였다. 샘플은 C100 Thermal Cycler를 사용하여 실온에서 99℃까지 1℃/분(min)의 속도로 가열하여 변성시키고, CYPRO 염료로 염색된 변성 단백질의 양을 1 분마다 기록하였다(즉, 각 1℃ 온도 변화). 용융 온도(TM)는 CFX 96 ORM 시스템(BioRad)을 사용하여 계산하였다. 단백질 안정성은 CEX로 정제된 ACE-05를 다양한 pH 조건(pH 6, 20 mM 인산나트륨; pH 7.4, PBS; pH 8, 20 mM Tris-HCl)에 노출시키거나 실온에서 장기간 인큐베이션(7 일)한 후 MabPac SCX-10 분석 컬럼(ThermoFisher)을 사용하여 CEX-HPLC로 분석하여 평가하였다. 데이터는 GraphPad Prism 8 소프트웨어를 사용하여 플로팅하였다.The thermal stability of ACE-05, BiTE-05, YBL-007 and UCHT1 was determined by Thermofluor assay (Lavinder, JJ et.al. , J Am Chem Soc , 131:3794-3795, 2009) using SYPRO orange dye (dye). Analyzed using. Specifically, 3 μM solution of each purified antibody was mixed with 10 μl of SYPRO orange dye (#S6650, ThermoFisher) diluted 1:25, and 50 μl of each mixture was incubated at 25° C. for 30 minutes. Samples were denatured by heating at a rate of 1°C/min (min) from room temperature to 99°C using a C100 Thermal Cycler, and the amount of denatured protein stained with CYPRO dye was recorded every minute (i.e., each 1°C temperature). change). Melting temperature (TM) was calculated using the CFX 96 ORM system (BioRad). Protein stability was determined by exposing CEX-purified ACE-05 to various pH conditions (pH 6, 20 mM sodium phosphate; pH 7.4, PBS; pH 8, 20 mM Tris-HCl) or long-term incubation at room temperature (7 days). After the analysis was evaluated by CEX-HPLC using a MabPac SCX-10 analysis column (ThermoFisher). Data were plotted using GraphPad Prism 8 software.

실시예 6. ALiCE의 결합력 측정Example 6. Measurement of binding force of ALiCE

실시예 6.1. ALiCE 분자의 결합 카이네틱스 분석Example 6.1. Binding kinetics analysis of ALiCE molecules

다양한 항원에 대한 ALiCE 분자의 결합 카이네틱스는 인증 등급(certified-grade) CM5 시리즈 S 센서 칩(# BR100399, GE Healthcare)이 장착된 Biacore 8K 시스템을 사용하여 표면 플라즈몬 공명으로 측정하였다. 3 mM 에틸렌디아민테트라아세트산(EDTA) 및 0.05%(v/v) P20 계면활성제(HBS-EP+)를 함유하는 HEPES-완충 식염수(0.01 M HEPES, 0.15 M NaCl)를 반응 및 러닝 버퍼(running buffer) (#BR100669, GE Healthcare)로 사용하였다.Binding kinetics of ALiCE molecules to various antigens was measured by surface plasmon resonance using a Biacore 8K system equipped with a certified-grade CM5 series S sensor chip (# BR100399, GE Healthcare). HEPES-buffered saline (0.01 M HEPES, 0.15 M NaCl) containing 3 mM ethylenediaminetetraacetic acid (EDTA) and 0.05% (v/v) P20 surfactant (HBS-EP+) was added to the reaction and running buffer. (#BR100669, GE Healthcare).

항원 PD-L1-his(0.1 ㎍/㎖; 사내에서 자체 합성함) 및 CD3εδ-플래그(flag)-his(0.2 ㎍/㎖; #CT038-H2508H, Sino Biological)를 제조업체의 지침에 따라 CM5 센서 칩(#BR100399, GE Healthcare)의 표면 상에 고정하였다. 그 후에 HBS-EP + 버퍼(buffer)에 희석된, 이중특이적 T-세포 결합자(ACE-05, BiTE-05, 및 ACE-31) 및 모(parent) mAb (YBL-007 및 UCHT1)를 30 ㎕/분(min)의 유속으로 300초 동안 12개의 상이한 농도(0, 0.5, 1, 2, 4, 8, 16, 32, 64, 128, 256, 및 512 nM)로 항원이 고정된 센서 칩(antigen-immobilized sensor chip) 위에 적용하였다. 센서 칩에 결합된 분석물은 HBS-EP + 러닝 버퍼로 300초 동안 세척하여 해리되었다. Antigens PD-L1-his (0.1 μg/ml; self-synthesizing in-house) and CD3εδ-flag-his (0.2 μg/ml; #CT038-H2508H, Sino Biological) were assigned to the CM5 sensor chip according to the manufacturer's instructions. It was fixed on the surface of (#BR100399, GE Healthcare). Thereafter, bispecific T-cell linkers (ACE-05, BiTE-05, and ACE-31) and parent mAb (YBL-007 and UCHT1) diluted in HBS-EP + buffer were added. Sensors immobilized with antigens at 12 different concentrations (0, 0.5, 1, 2, 4, 8, 16, 32, 64, 128, 256, and 512 nM) for 300 seconds at a flow rate of 30 μl/min (min) It was applied on a chip (antigen-immobilized sensor chip). The analyte bound to the sensor chip was dissociated by washing with HBS-EP + running buffer for 300 seconds.

결합(M-1s-1, Ka) 및 해리(S-1, Kd)는 모두 300초 간격으로 측정되었다. 평형 해리 상수(M, KD)는 오프-레이트(off-rate) 대 온-레이트(on-rate)의 비율(kd/ka)로 계산하였다. 1가 리간드(monovalent ligand)-분석물 상호작용의 경우 1:1 결합 모델을, 그리고 2가 리간드(bivalent ligand)-분석물 상호작용의 경우 1:2 결합 모델을 이용하는 Biacore Insight Evaluation Software의 글로벌 피팅 기능으로 카이네틱 파라미터를 결정하였다.Both binding (M -1 s -1 , K a ) and dissociation (S -1 , K d ) were measured at 300 second intervals. The equilibrium dissociation constant (M, K D ) was calculated as the ratio of off-rate to on-rate (k d /k a ). Global fitting of Biacore Insight Evaluation Software using a 1:1 binding model for monovalent ligand-analyte interactions and a 1:2 binding model for bivalent ligand-analyte interactions. The kinetic parameters were determined by function.

실시예 6.2. 동시 결합 분석Example 6.2. Simultaneous binding analysis

CD3 및 PD-L1에 대한 ACE-05 및 ACE-31의 동시 이중 결합 분석을 위해, BLI(biolayer light interferometry)는 Octet QKe system(Pall Forte Bio)으로 수행하였다(Abdiche, Y. et.al., Anal Biochem, 377:209-217, 2008). 제1 리간드인 PD-L1-Fc(2 ㎍/㎖; 사내에서 자체 합성함) 및 CD3εδ-플래그(flag)-his(3 ㎍/㎖; #CT038-H2508H, Sino Biological)를 결합이 0.5 내지 1.0 nM에 도달할 때까지 각각 수화된(hydrated) AHC(#18-5064, Pall Forte Bio) 또는 Ni-NTA(#18-5013, Pall Forte Bio) 바이오센서에 로딩하였다.For simultaneous double binding analysis of ACE-05 and ACE-31 to CD3 and PD-L1, biolayer light interferometry (BLI) was performed with the Octet QKe system (Pall Forte Bio) (Abdiche, Y. et.al. , Anal Biochem , 377:209-217, 2008). The first ligand, PD-L1-Fc (2 µg/ml; synthesized in-house) and CD3εδ-flag-his (3 µg/ml; #CT038-H2508H, Sino Biological) have a binding of 0.5 to 1.0 Each hydrated AHC (#18-5064, Pall Forte Bio) or Ni-NTA (#18-5013, Pall Forte Bio) biosensor was loaded until nM was reached.

이후, 바이오센서를 2분(ACE-05) 또는 1분(ACE-31) 동안 카이네틱스 버퍼(0.1% 소 혈청 알부민[BSA] 및 0.02% Tween-20 함유 PBS)로 세척하여 결합되지 않은 단백질을 제거하고, 30 nM ACE-05 또는 15 nM ACE-31에 침지시켜 결합(association)을 분석하였으며, PBS로 7분(ACE-05) 또는 2분(ACE-31) 동안 세척하여 해리를 측정하였다. 뒤이어, 제1 리간드와 ACE-05 또는 ACE-31이 로딩된 바이오센서에 제2 리간드, 즉 200 nM CD3εδ-플래그-his(ACE-05) 또는 120 nM PD-L1-Fc(ACE-31)를 포함하는 용액에 침지시켜 결합을 측정한 다음, 3분(ACE-05) 또는 2분(ACE-31) 동안 PBS로 세척하여 해리를 측정하였다. 센서그램(sensorgram) 데이터는 GraphPad Prism 8 소프트웨어를 사용하여 플롯팅하였다.Thereafter, the biosensor was washed with kinetics buffer (0.1% bovine serum albumin [BSA] and 0.02% Tween-20-containing PBS) for 2 minutes (ACE-05) or 1 minute (ACE-31) to obtain unbound protein. Was removed and immersed in 30 nM ACE-05 or 15 nM ACE-31 to analyze association, and was washed with PBS for 7 minutes (ACE-05) or 2 minutes (ACE-31) to measure dissociation. . Subsequently, a second ligand, that is, 200 nM CD3εδ-flag-his (ACE-05) or 120 nM PD-L1-Fc (ACE-31), was added to the biosensor loaded with the first ligand and ACE-05 or ACE-31. The binding was measured by immersion in the containing solution, followed by washing with PBS for 3 minutes (ACE-05) or 2 minutes (ACE-31) to measure dissociation. Sensorgram data was plotted using GraphPad Prism 8 software.

II. ALiCE의 효능 확인 : In vitro assayII. Confirmation of the efficacy of ALiCE: In vitro assay

실시예 7. 유세포 분석Example 7. Flow cytometry

세포 표면 PD-L1의 수준을 평가하기 위해, 본 발명자들은 PD-L1+ 암 세포(HCC827, MDA-MB-231, 및 Karpas-299)와 PD-L1- Raji 세포를 모두 0.5×106 cells/100 ㎕로 하고, 1:50(v/v)으로 희석된 피코에리트린(phycoerythrin, PE)-Cy7이 컨쥬게이션된 항-PD-L1 항체(#55817, BD Bioscience)와 인큐베이션하였다. FITC(fluorescein isothiocyanate)가 컨쥬게이션된 항-CD3 항체(#130-113-138, Miltenyi Biotech)를 사용하여 Jurkat T 세포(0.5×106 cells/100 ㎕) 상의 CD3 수준을 평가하였다.In order to evaluate the level of cell surface PD-L1, we used both PD-L1 + cancer cells (HCC827, MDA-MB-231, and Karpas-299) and PD-L1 - Raji cells at 0.5×10 6 cells/ It was 100 μl and incubated with an anti-PD-L1 antibody (#55817, BD Bioscience) conjugated with phycoerythrin (PE)-Cy7 diluted 1:50 (v/v). FITC (fluorescein isothiocyanate) conjugated anti-CD3 antibody (#130-113-138, Miltenyi Biotech) was used to evaluate CD3 levels on Jurkat T cells (0.5×10 6 cells/100 μl).

1 ㎖의 FACS 버퍼(1% 우태아 혈청[FBS]을 함유하는 PBS)로 세포를 2회 세척하고, PD-L1 또는 CD3의 세포 표면 발현을 유세포 분석기(BD FACSCanto Ⅱ)로 분석하였다. 세포 표면에서 PD-L1 및 CD3에 대한 ACE-05 및 ACE-31의 이중 결합능은 CD3+ Jurkat T 세포와 20 nM ACE-05, ACE-31 또는 ACE-18(CD20 Fab × CD3 Fv, Ctrl-ACE)을 1시간 동안 인큐베이션하여 조사하였다. 1 ㎖의 FACS 버퍼로 2회 세척한 후, 세포를 PD-L1-Fc(75 ㎍/100 ㎕)와 인큐베이션하고 1 ㎖의 FACS 버퍼로 2회 세척하였다.Cells were washed twice with 1 ml of FACS buffer (PBS containing 1% fetal bovine serum [FBS]), and cell surface expression of PD-L1 or CD3 was analyzed by flow cytometry (BD FACSCanto II). The double binding capacity of ACE-05 and ACE-31 to PD-L1 and CD3 on the cell surface was determined by CD3 + Jurkat T cells and 20 nM ACE-05, ACE-31 or ACE-18 (CD20 Fab × CD3 Fv, Ctrl-ACE). ) Was investigated by incubating for 1 hour. After washing twice with 1 ml of FACS buffer, cells were incubated with PD-L1-Fc (75 μg/100 μl) and washed twice with 1 ml of FACS buffer.

이후, PD-L1-Fc는 Alexa 647이 컨쥬게이션된 항-인간 Fc 항체(#109-605-098, Jackson ImmunoResearch)를 사용하여 검출되었다. PD-L1+ Karpas-299 및 PD-L1- Raji 암 세포와 CD3+ Jurkat T 세포에 대한 ALiCE(ACE-05 및 ACE-31)의 명백한 결합 친화도는 상기 세포들(0.5×106 cells/100 ㎕)에 ACE-05(Karpas-299 세포의 경우 0.000932, 0.003729, 0.014915, 0.059662, 0.59459, 3.81, 및 15.27 nM; Raji 세포의 경우 1.56, 15.625, 156.25, 및 1562 nM; Jurkat 세포의 경우 1.1, 3.3, 9.9, 29.6, 88.9, 266.7, 800, 및 2400 nM) 또는 ACE-31(Karpas-299 세포의 경우 0.594, 3.81, 15.27, 61.03, 244.37, 977.5, 및 3910 nM; Raji 세포의 경우 1.56, 15.625, 156.25, 및 1562 nM; Jurkat 세포의 경우 0.011, 0.033, 0.101, 0.304, 0.914, 2.743, 8.320, 24.691, 및 74.074 nM)를 표시된 농도로 처리하여 측정하였다.Thereafter, PD-L1-Fc was detected using an anti-human Fc antibody conjugated with Alexa 647 (#109-605-098, Jackson ImmunoResearch). The apparent binding affinity of ALiCE (ACE-05 and ACE-31) to PD-L1 + Karpas-299 and PD-L1 - Raji cancer cells and CD3 + Jurkat T cells was determined by the above cells (0.5×10 6 cells/100). ΜL) in ACE-05 (0.000932, 0.003729, 0.014915, 0.059662, 0.59459, 3.81, and 15.27 nM for Raji cells; 1.56, 15.625, 156.25, and 1562 nM for Raji cells; 1.1, 3.3 for Jurkat cells). , 9.9, 29.6, 88.9, 266.7, 800, and 2400 nM) or ACE-31 (0.594, 3.81, 15.27, 61.03, 244.37, 977.5, and 3910 nM for Karpas-299 cells; 1.56, 15.625, for Raji cells; 156.25, and 1562 nM; for Jurkat cells 0.011, 0.033, 0.101, 0.304, 0.914, 2.743, 8.320, 24.691, and 74.074 nM) were measured by treatment at the indicated concentrations.

세포 표면에 결합된 ACE-05 또는 ACE-31은 인간 Fab 단편에 대한 Alexa 647이 컨쥬게이션된 항체(# 109-606-097, Jackson Immunoresearch)와 인큐베이션한 후 유세포 분석기(CytoPLEX-LX)로 검출하였다. 유세포 분석 데이터는 FlowJo 10 소프트웨어(FlowJo, LLC)를 사용하여 분석하고, 기하학적 평균은 GraphPad Prism 8 소프트웨어를 사용하여 플롯팅하였다.ACE-05 or ACE-31 bound to the cell surface was detected with a flow cytometer (CytoPLEX-LX) after incubation with an antibody conjugated with Alexa 647 to a human Fab fragment (#109-606-097, Jackson Immunoresearch). . Flow cytometric data was analyzed using FlowJo 10 software (FlowJo, LLC), and geometric mean plotted using GraphPad Prism 8 software.

실시예 8. ALiCE(ACE-05 및 ACE-31)에 의한 Jurkat T 세포 활성화 분석Example 8. Analysis of Jurkat T cell activation by ALiCE (ACE-05 and ACE-31)

ACE-05 및 ACE-31이 표적 세포 표면에서 PD-L1에 대해 T-세포 활성화를 리디렉션(redirection) 하는지의 여부를 평가하고자, PD-L1- WT HEK 세포 또는 유전적으로 조작된 PD-L1+ HEK 세포(7×104 cells/well)를 폴리-L-라이신(#P4707, Sigma)으로 코팅된 화이트-바텀 플레이트에 시딩(seeding) 하였다. 상기 세포를 24시간 동안 전-배양한 후, NFAT-반응 요소의 제어하에 반딧불이 루시퍼라제 유전자(firefly luciferase gene)를 발현하는 PD-1- Jurkat T 세포(2×105 cells/well) 및 ACE-05, ACE-31 또는 BiTE-05의 연속 희석액을 첨가하고, 세포를 37℃ 및 5% CO2 조건하에서 6시간 동안 인큐베이션하였다. T 세포 활성화에 의해 유도된 루시퍼라제 축적은 제조업체의 프로토콜에 따라 Bio-Glo Luciferase assay(#G7940, Promega)를 수행하여 측정하였다. RLU(relative light units)로 표현된 결과 데이터는 GraphPad Prism 8 소프트웨어를 사용하여 플롯팅하고 분석되었다.To evaluate whether ACE-05 and ACE-31 redirect T-cell activation to PD-L1 on the target cell surface, PD-L1 - WT HEK cells or genetically engineered PD-L1 + HEK Cells (7×10 4 cells/well) were seeded on a white-bottom plate coated with poly-L-lysine (#P4707, Sigma). After pre-culturing the cells for 24 hours, PD-1 expressing firefly luciferase gene - Jurkat T cells (2×10 5 cells/well) and ACE- under the control of NFAT-responsive elements 05, serial dilutions of ACE-31 or BiTE-05 were added, and the cells were incubated for 6 hours under conditions of 37°C and 5% CO 2. Luciferase accumulation induced by T cell activation was measured by performing a Bio-Glo Luciferase assay (#G7940, Promega) according to the manufacturer's protocol. The resulting data expressed in relative light units (RLU) was plotted and analyzed using GraphPad Prism 8 software.

실시예 9. 표적 T-세포 활성화 분석Example 9. Target T-cell activation assay

표적(on-target) 특이적 T 세포 활성화를 평가하고자, 5% FBS를 포함하는 배지에서 PD-L1+ MDA-BM-231 암 세포(1×105 cells/well) 및 인간 PBMC(#SER-PBMC-200-F, Zenbio)로부터 분리된 CD3+ T 세포(1×106 cells/well)를 공동 배양하되, 1 nM ACE-05, BiTE-05, ACE-31 또는 IgG를 첨가하였다. CD3+ T 세포를 제조업체의 지침에 따라 Trace Far Red (#C34564, ThermoFisher)로 염색하였다. 24시간 또는 48시간 동안 배양한 후 T 세포를 수확하고, APC가 컨쥬게이션된 항-CD4 항체(#130-113-210, MiltenyBiotec), FITC가 컨쥬게이션된 항-CD8 항체(#130-110-677, MiltenyBiotec), PE-Vio 770이 컨쥬게이션된 항-CD69 항체(#130-122-5-4, MiltenyBiotec) 및 PE가 컨쥬게이션된 항-CD25 항체(#341009, BD Bioscience)로 표지하였다. T 세포 서브세트(subset) 및 활성화된 T 세포는 FlowJo 10 소프트웨어(FlowJo, LLC)를 이용하여 유세포 분석기(BD FACSCanto Ⅱ)로 확인하였다.To evaluate on-target specific T cell activation, PD-L1 + MDA-BM-231 cancer cells (1×10 5 cells/well) and human PBMC (#SER- PBMC-200-F, Zenbio) isolated CD3 + T cells (1×10 6 cells/well) were co-cultured, but 1 nM ACE-05, BiTE-05, ACE-31 or IgG was added. CD3 + T cells were stained with Trace Far Red (#C34564, ThermoFisher) according to the manufacturer's instructions. After incubation for 24 or 48 hours, T cells were harvested, and APC conjugated anti-CD4 antibody (#130-113-210, MiltenyBiotec), FITC conjugated anti-CD8 antibody (#130-110- 677, MiltenyBiotec), PE-Vio 770 conjugated anti-CD69 antibody (#130-122-5-4, MiltenyBiotec) and PE conjugated anti-CD25 antibody (#341009, BD Bioscience). T cell subsets and activated T cells were identified by flow cytometry (BD FACSCanto II) using FlowJo 10 software (FlowJo, LLC).

실시예 10. PD-1/PD-L1 차단에 대한 생물학적 검정Example 10. Bioassay for PD-1/PD-L1 blockade

PD-1/PD-L1 차단 바이오어세이(PD-1/PD-L1 blockade bioassay)는 제조업체의 프로토콜(#J1250, Promega)에 따라 수행하였다. 간략하게, 바이오어세이 키트에 포함되어 있는 PD-L1/aAPC+ CHO-K1 세포 바이알 하나를 냉동 스톡(stock)으로부터의 회수 배지(10% FBS를 포함하는 90% Ham's F-12)에 현탁시키고, 이를 화이트 바텀 플레이트에 시딩하여 37℃에서 밤새 배양하였다. 각각의 웰(well)에 0, 0.006, 0.032, 0.16, 0.8, 4 또는 20 nM 농도의 ACE-05, BiTE-05, ACE-31, YBL-007 또는 IgG와 함께, 어세이 버퍼(1% FBS를 포함하는 RPM 1640)에서 인간 PD-1 및 NFAT-루시퍼라제 리포터를 안정적으로 발현하는 Jurkat T 세포를 첨가하였다. 6시간 후, Bio-Glo Luciferase assay system(#G7940, Promega)을 사용하여 NFAT-매개 루시퍼라제 활성을 측정하였다. RLU(relative light units) 데이터는 GraphPad Prism 8 소프트웨어를 사용하여 플롯팅하고 분석되었다.The PD-1/PD-L1 blockade bioassay was performed according to the manufacturer's protocol (#J1250, Promega). Briefly, one vial of PD-L1/aAPC + CHO-K1 cells included in the bioassay kit was suspended in recovery medium from a frozen stock (90% Ham's F-12 containing 10% FBS) and , This was seeded on a white bottom plate and incubated overnight at 37°C. Assay buffer (1% FBS) with ACE-05, BiTE-05, ACE-31, YBL-007 or IgG at concentrations of 0, 0.006, 0.032, 0.16, 0.8, 4 or 20 nM in each well. RPM 1640) containing Jurkat T cells stably expressing human PD-1 and NFAT-luciferase reporters were added. After 6 hours, NFAT-mediated luciferase activity was measured using a Bio-Glo Luciferase assay system (#G7940, Promega). RLU (relative light units) data were plotted and analyzed using GraphPad Prism 8 software.

실시예 11. 종양 살상 분석(Tumor-killing assay)Example 11. Tumor killing assay (Tumor-killing assay)

HCC827(ATCC CRL2868), MDA-MB-231(ATCC HTB-26), Karpas-299(# 06072604, Sigma) 및 Raji(ATCC CCL86) 암 세포는 37℃ 및 5% CO2 조건하에서 10% FBS가 첨가된 RPMI-1640 배지를 이용하여 배양하였다. 본 발명에 사용된 모든 건강한 기증자의 PBMC 및 CD8+ T 세포는 AllCells(#PB004F 및 #PB009-3F), Zenbio(#SER-PBMC-200-F), 및 Lonza(#3W-270)에서 구입하였다. CD3+ T 세포 및 CD8+ T 세포는 Pan T-cell isolation kit(#130-096-535, Miltenyi Biotec) 및 CD8+ T-cell isolation kit(#130-096-495, Miltenyi Biotec)를 사용하여 인간 PBMC 제제(preparation)로부터 분리하였다.HCC827 (ATCC CRL2868), MDA-MB-231 (ATCC HTB-26), Karpas-299 (# 06072604, Sigma) and Raji (ATCC CCL86) cancer cells were added with 10% FBS under conditions of 37°C and 5% CO 2 It was cultured using the RPMI-1640 medium. PBMC and CD8 + T cells of all healthy donors used in the present invention were purchased from AllCells (#PB004F and #PB009-3F), Zenbio (#SER-PBMC-200-F), and Lonza (#3W-270). . CD3 + T cells and CD8 + T cells were human using Pan T-cell isolation kit (#130-096-535, Miltenyi Biotec) and CD8 + T-cell isolation kit (#130-096-495, Miltenyi Biotec). It was isolated from PBMC preparation.

PD-L1을 발현하는 암 세포에 대한 PBMC 또는 T-세포의 세포독성(cytotoxicity)은 사멸된 암 세포로부터 방출된 젖산 탈수소효소(lactate dehydrogenase, LDH)를 측정함에 의해 평가하였다. 이중특이적 T 세포 결합자의 표적(on-target) 종양 세포-살상 능력은 10:1(CD3+ T 세포) 또는 5:1(CD8+ T 세포)의 E:T(이펙터(effector):표적(target)) 비율로 PD-L1+ MDA-MB-231 암 세포(1×104 cells/well) 및 T 세포를 표시된 단백질(ACE-05, ACE-31, BiTE-05, 또는 IgG)과 함께 공동 배양하여 조사하였다.The cytotoxicity of PBMCs or T-cells against cancer cells expressing PD-L1 was evaluated by measuring lactate dehydrogenase (LDH) released from killed cancer cells. The on-target tumor cell-killing ability of the bispecific T cell linker is 10:1 (CD3 + T cells) or 5:1 (CD8 + T cells) of E:T (effector: target ( target)) PD-L1 + MDA-MB-231 cancer cells (1×10 4 cells/well) and T cells with the indicated protein (ACE-05, ACE-31, BiTE-05, or IgG) It was investigated by culturing.

48~72시간 배양 후, 사멸된 종양 세포에서 방출된 LDH를 제조업체의 지침에 따라 CytoTox96 non-radioactive cytotoxicity assay kit(#G1780, Promega)를 사용하여 측정하였다. 사멸된 종양 세포의 퍼센티지는 다음의 수학식을 사용하여 계산하였다:After 48-72 hours incubation, LDH released from the killed tumor cells was measured using a CytoTox96 non-radioactive cytotoxicity assay kit (#G1780, Promega) according to the manufacturer's instructions. The percentage of tumor cells killed was calculated using the following equation:

[수학식 1][Equation 1]

% 세포독성(% 사멸된 종양 세포)=(실험적 - 표적 자발적 - 이펙터 자발적)/(표적 최대값 - 표적 자발적)×100%. % Cytotoxicity (% killed tumor cells) = (experimental-target spontaneous-effector spontaneous) / (target maximum-target spontaneous) x 100%.

또한, PBMC는 PD-L1+ HCC827 종양 세포-살상 능력을 조사하기 위해 이펙터 세포(E:T 비율, 25:1)로도 사용되었다. 비-표적 T-세포 세포독성을 평가하고자, PD-L1- HEK293 또는 Raji 암 세포를 CD3+ T 세포 및 1 nM ACE-05, BiTE-05, ACE-31, IgG 또는 ACE-18과 공동 배양하였다. 48~72 시간 배양 후, PD-L1- 세포로부터 방출된 LDH를 전술한 바와 같이 위에서 측정하고 계산하였다.In addition, PBMC were also used as effector cells (E:T ratio, 25:1) to investigate PD-L1 + HCC827 tumor cell-killing ability. To evaluate non-target T-cell cytotoxicity, PD-L1 - HEK293 or Raji cancer cells were co-cultured with CD3 + T cells and 1 nM ACE-05, BiTE-05, ACE-31, IgG or ACE-18. . After 48-72 hours incubation, LDH released from PD-L1- cells was measured and calculated as described above.

실시예 12. T-세포 클러스터링Example 12. T-cell clustering

T-세포 활성화 및 분화는 IncuCyte 생-세포 분석 시스템(IncuCyte live-cell analysis system; Sartorius, USA)을 사용하여 T 세포 및 PD-L1+ 종양 세포 클러스터링을 정확하게 정량화하여 평가하였다. CD3+ T 세포를 인간 PBMC로부터 분리하고, 제조업체의 프로토콜에 따라 CytoLight 시약(#4706, Sartorius)으로 표지하였다. PD-L1+ MDA-MB-231 세포(4×103 cells/well) 및 CD3+ T 세포를 10:1의 E:T 비율로 1 nM ACE-05, ACE-31, BiTE-05 또는 IgG와 함께 공동 배양하였다. 생-세포 이미지는 90시간의 배양 기간 동안 6 시간마다 수득하였으며, T-세포 활성화를 나타내는 적색 형광 클러스터의 평균 면적(㎟)은 IncuCyte 소프트웨어를 사용하여 측정하였다. 4반복(quadruplicate)으로 얻은 데이터는 GraphPad Prism 8 소프트웨어를 사용하여 플롯팅하였다.T-cell activation and differentiation was evaluated by accurately quantifying T cells and PD-L1 + tumor cell clustering using the IncuCyte live-cell analysis system (Sartorius, USA). CD3 + T cells were isolated from human PBMCs and labeled with CytoLight reagent (#4706, Sartorius) according to the manufacturer's protocol. PD-L1 + MDA-MB-231 cells (4×10 3 cells/well) and CD3 + T cells with 1 nM ACE-05, ACE-31, BiTE-05 or IgG at an E:T ratio of 10:1. Co-cultured together. Live-cell images were obtained every 6 hours during the 90-hour culture period, and the average area (mm 2) of red fluorescent clusters representing T-cell activation was measured using IncuCyte software. Data obtained in quadruplicate were plotted using GraphPad Prism 8 software.

실시예 13. T-세포 확장 분석Example 13. T-cell expansion assay

PD-L1+ 종양 세포의 존재하에서 ACE-05로 유도된 일차(primary) 인간 T-세포 확장(expansion)은 T-세포 증식 분석법을 사용하여 조사하였다. PBMC로부터 분리된 CD3+ T 세포를 제조업체의 지침에 따라 Cell Trace Far Red(#C34564, ThermoFisher)로 염색하였다. PD-L1+ MDA-MB-231 암세포를 1×105 cells/well의 농도로 24-웰 플레이트에 시딩하였다. 다음날, 전-배양된 MDA-MB-231 세포를 미리 데워둔 Dulbecco's PBS로 1회 세척한 후, 분석 배지(1% FBS를 포함하는 RPMI-1640)로 교체하였다. Cell Trace로 염색된 CD3+ T 세포(1×106 cells/well) 및 1 nM ACE-05, IgG 또는 ACE-18(음성 대조군으로서 CD20 × CD3)을 포함하는 혼합물을 24-웰 플레이트의 MDA-MB-231 세포에 첨가하였다. 96시간 동안 배양한 후 T 세포를 수확하고, BD FACSCanto Ⅱ 시스템을 사용하여 유세포 분석기로 분석하였다. FlowJo 10 소프트웨어(FlowJo, LLC)를 사용하여 얻은 유세포 분석 데이터를 기반으로 T 세포의 확장을 시각화하였다.Primary human T-cell expansion induced with ACE-05 in the presence of PD-L1 + tumor cells was investigated using a T-cell proliferation assay. CD3 + T cells isolated from PBMC were stained with Cell Trace Far Red (#C34564, ThermoFisher) according to the manufacturer's instructions. PD-L1 + MDA-MB-231 cancer cells were seeded in a 24-well plate at a concentration of 1×10 5 cells/well. The next day, the pre-cultured MDA-MB-231 cells were washed once with Dulbecco's PBS, which had been pre-warmed, and then replaced with an assay medium (RPMI-1640 containing 1% FBS). A mixture containing CD3 + T cells (1 × 10 6 cells/well) stained with Cell Trace and 1 nM ACE-05, IgG or ACE-18 (CD20 × CD3 as negative control) was prepared in MDA- It was added to MB-231 cells. After culturing for 96 hours, T cells were harvested and analyzed by flow cytometry using the BD FACSCanto II system. The expansion of T cells was visualized based on flow cytometric data obtained using FlowJo 10 software (FlowJo, LLC).

실시예 14. 종양 세포의 부재시 다량체 T-세포 결합자에 의한 비-표적 T-세포 활성화 분석Example 14. Non-target T-cell activation assay by multimeric T-cell combiner in the absence of tumor cells

표적 종양 세포의 부재시, T-세포 결합자에 의한 비특이적 비-표적(off-target) T-세포 활성화를 평가하고자, 인간 PBMC(#4W-270C, Lonza)로부터 분리된 CD3+ T 세포(1×106 cells/well)를 5% FBS를 포함하는 배지에서 배양하되, 1 nM ACE-05, BiTE-05 또는 다량체 ACE-05를 직접 첨가하였다. 클러스터링된 ACE-05는 5 ㎕ CH1 비드(#1943462250, ThermoFisher)를 1 nM ACE-05와 혼합하여 준비하였다. 48시간 동안 배양한 후 T 세포를 수확하고, FITC가 컨쥬게이션된 CD4 항체(#130-114-531, MiltenyBiotec) 및 CD69-PE-Vio 770 항체(#130-122-5-4, MiltenyBiotec)로 표지하였다. T 세포 서브세트(subset) 및 활성화된 T 세포는 FlowJo 10 소프트웨어(FlowJo, LLC)를 이용하여 유세포 분석기(BD FACSCanto Ⅱ)로 확인하였다. In the absence of target tumor cells, CD3 + T cells isolated from human PBMC (#4W-270C, Lonza) (1× 10 6 cells/well) were cultured in a medium containing 5% FBS, but 1 nM ACE-05, BiTE-05 or multimer ACE-05 was added directly. Clustered ACE-05 was prepared by mixing 5 μl CH1 beads (#1943462250, ThermoFisher) with 1 nM ACE-05. After incubation for 48 hours, T cells were harvested, and FITC conjugated with CD4 antibody (#130-114-531, MiltenyBiotec) and CD69-PE-Vio 770 antibody (#130-122-5-4, MiltenyBiotec). Labeled. T cell subsets and activated T cells were identified by flow cytometry (BD FACSCanto II) using FlowJo 10 software (FlowJo, LLC).

실시예 15. 면역세포가 분비하는 사이토카인 분석Example 15. Analysis of cytokines secreted by immune cells

PD-L1 + 종양 세포가 존재 또는 부존재 시에, 활성화된 면역 세포 (PBMC 및 CD4 + T 세포)에서 방출하는 사이토카인인, IL-2, IFN-γ, IL-6 및 TNF-α의 수준을 조사하였다. 구체적으로, PD-L1+ HCC827 암세포가 존재하는 표적 조건으로, 1 nM ACE-05, BiTE-05, ACE-31, 또는 IgG과 함께, 인간 PBMC를 HCC827 암 세포와 함께 25 : 1의 E : T 비율로 72 시간 동안 공동 배양하였다. 약물 투여 후, 0, 6, 12, 18, 24, 48 및 72 시간에서 샘플을 수집하였다. 그 후, IL-2(#431004, BioLegend), IFN-γ(#431004, BioLegend) 용 ELISA 키트를 사용하여 사이토카인의 농도를 분석하였다.Levels of cytokines, IL-2, IFN-γ, IL-6 and TNF-α, released by activated immune cells (PBMC and CD4 + T cells) in the presence or absence of PD-L1 + tumor cells Investigated. Specifically, as a target condition in which PD-L1 + HCC827 cancer cells are present, with 1 nM ACE-05, BiTE-05, ACE-31, or IgG, human PBMCs with HCC827 cancer cells 25:1 E:T Co-cultured for 72 hours at a rate. Samples were collected at 0, 6, 12, 18, 24, 48 and 72 hours after drug administration. Thereafter, the concentration of cytokines was analyzed using an ELISA kit for IL-2 (#431004, BioLegend) and IFN-γ (#431004, BioLegend).

비-표적 조건으로, CD4+ T 세포 분리 키트를 사용하여 인간 PBMC에서 분리한 CD4+ T 세포에 1 nM의 ACE-05, BiTE-05, ACE-31 또는 IgG를 직접 첨가하였다(#130-096-533, Miltenyi Biotec). 72 시간 동안 인큐베이션 한 후, 방출된 사이토카인을 상술한 바와 같이 ELISA로 분석하였다.As a non-target condition, 1 nM of ACE-05, BiTE-05, ACE-31 or IgG was directly added to CD4 + T cells isolated from human PBMC using a CD4 + T cell separation kit (#130-096 -533, Miltenyi Biotec). After incubation for 72 hours, the released cytokines were analyzed by ELISA as described above.

그랜자임 B 분석을 위해, 다양한 농도의 ACE-05, BiTE-05, ACE-31 또는 IgG 존재하에(0, 6.4, 32, 160, 800, 4000 pM), PBMC 유래 CD8+ T 세포와 MDA-MB-231 세포를 5:1의 E:T 비율로 공동 배양하였다. 48 시간 후, ELISA 키트(#DGZB00, R & D Systems)를 사용하여 분석 배지에 축적된 그랜자임 B를 분석하였다. 각 상층액의 광학 밀도 (OD)는 마이크로 플레이트 리더를 사용하여 측정하였고, 사이토카인의 농도는 GraphPad Prism 8 소프트웨어를 사용하여 분석하였다.For Granzyme B analysis, in the presence of various concentrations of ACE-05, BiTE-05, ACE-31 or IgG (0, 6.4, 32, 160, 800, 4000 pM), PBMC-derived CD8 + T cells and MDA-MB -231 cells were co-cultured at an E:T ratio of 5:1. After 48 hours, Granzyme B accumulated in the assay medium was analyzed using an ELISA kit (#DGZB00, R & D Systems). The optical density (OD) of each supernatant was measured using a microplate reader, and the concentration of cytokines was analyzed using GraphPad Prism 8 software.

III. ALiCE의 효능 확인 : In vivo assayIII. Checking the efficacy of ALiCE: In vivo assay

실시예 16. 래트 및 원숭이에서 약동학 분석Example 16. Pharmacokinetic analysis in rats and monkeys

6-7 주령의 수컷 Sprague-Dawley 래트에 꼬리 정맥을 통해 10 mg/kg 용량으로 ACE-05, BiTE-05 또는 hIgG를 주사하였다(n = 3 / 그룹). 혈액 샘플 (각각 150 μl)을 약물 투여 후 10 분 및 30 분; 1, 2, 4, 8 및 24 시간; 3 일, 5 일, 9 일에 각 래트로부터 수집 하였다. 그 후, 10,000-13,000 rpm에서 2 분 동안 원심 분리하였다. 각 혈장 샘플을 70 μl씩 나누어 -80℃에 보관하였다.Male Sprague-Dawley rats aged 6-7 weeks were injected with ACE-05, BiTE-05 or hIgG at a dose of 10 mg/kg via tail vein (n = 3 / group). Blood samples (150 μl each) 10 and 30 minutes after drug administration; 1, 2, 4, 8 and 24 hours; It was collected from each rat on the 3rd, 5th, and 9th days. Then, it was centrifuged for 2 minutes at 10,000-13,000 rpm. Each plasma sample was divided into 70 μl and stored at -80°C.

또한, 20-24 개월된 수컷 필리핀 원숭이(cynomolgus monkey)에 5 mg/kg 용량으로 ACE-05, BiTE-05 또는 hIgG를 정맥 내 투여했습니다(n = 3 / 그룹). 혈액 샘플(각각 150 μl)을 약물 투여 후 10 분 및 30 분; 1, 2, 4, 8 및 24 시간; 2, 3, 4, 8, 12 및 15일에 각 원숭이부터 수집 하였다. 약동학적 분석은 Gyrolab xPlore 자동 면역 분석 시스템을 이용하여 수행하였다.In addition, 20-24 month-old male cynomolgus monkeys were administered ACE-05, BiTE-05 or hIgG intravenously at a dose of 5 mg/kg (n = 3 / group). Blood samples (150 μl each) 10 and 30 minutes after drug administration; 1, 2, 4, 8 and 24 hours; Collected from each monkey on the 2nd, 3rd, 4th, 8th, 12th and 15th days. Pharmacokinetic analysis was performed using the Gyrolab xPlore automated immunoassay system.

ACE-05 또는 인간 IgG를 분리하기 위해, 비오틴화된 항-인간 IgG CH1 나노 바디를 streptavidin으로 코팅된 Gyrolab Bioaffy CD200(#P0004180, Gyros Protein Technologies)의 표면에 고정하고, 혈청 샘플을 적재하였다. 유사하게, 비오틴화된 PD-L1-Fc를 사용하여 BiTE-05를 포획했다. 포획된 ACE-05 및 인간 IgG는 Alexa 647- 접합된 항-카파 항체(#316514, Novus)를 사용하여 검출하였다. 또한, BiTE-05는 Alexa 647-접합된 항-His 항체(#362611, Novus)를 이용하여 검출하였다. To isolate ACE-05 or human IgG, biotinylated anti-human IgG CH1 nanobodies were immobilized on the surface of streptavidin-coated Gyrolab Bioaffy CD200 (#P0004180, Gyros Protein Technologies), and serum samples were loaded. Similarly, biotinylated PD-L1-Fc was used to capture BiTE-05. Captured ACE-05 and human IgG were detected using an Alexa 647-conjugated anti-kappa antibody (#316514, Novus). In addition, BiTE-05 was detected using an Alexa 647-conjugated anti-His antibody (#362611, Novus).

샘플 농도는 Gyrolab 소프트웨어를 사용하여 계산하였고, t1/2 값은 Phoenix WinNonlin 소프트웨어를 사용하여 계산하였다.Sample concentrations were calculated using Gyrolab software, and t 1/2 values were calculated using Phoenix WinNonlin software.

실시예 17. 인간화 마우스 모델에서 ALiCE의 항암 효과 확인Example 17. Confirmation of anticancer effect of ALiCE in humanized mouse model

PD-L1 + HCC827 종양에 대한 ALiCE의 항 종양 효능을 PBMC-재구성된 인간화 NCG(NOD/scid IL-2Rγ null) 마우스 모델에서 평가하였다. 구체적으로, 7-8 주령의 암컷 NCG 마우스(Crown Bioscience)를 각각 10 마리씩 4 개의 그룹으로 무작위로 나누었다. 2 명의 건강한 공여자로부터 수득한 5 × 106 세포/100μl의 PBMC를 각각의 마우스의 정맥에 이식하였다. 3 일 후, 마우스의 오른쪽 옆구리에 5 Х106 PD-L1+ HCC827 종양 세포를 피하로 접종하였다. 종양 부피가 ~ 50 mm3에 도달하면 (4 일 후), 마우스에게 격일로 ACE-05 또는 BiTE-05를 주사하거나(Q2d, 총 3 회 용량), 3 일마다 YBL-007 또는 IgG를 주사하였다(Q3d, 총 3 회 용량). 종양 직경 및 체중을 2 일마다 측정하였고, GraphPad Prism 8 소프트웨어를 사용하여 분석하였다.The anti-tumor efficacy of ALiCE against PD-L1 + HCC827 tumors was evaluated in a PBMC-reconstituted humanized NCG (NOD/scid IL-2Rγ null) mouse model. Specifically, 7-8 week old female NCG mice (Crown Bioscience) were randomly divided into 4 groups of 10 mice each. PBMCs of 5×10 6 cells/100 μl obtained from two healthy donors were implanted into the veins of each mouse. After 3 days, 5 Х10 6 PD-L1 + HCC827 tumor cells were inoculated subcutaneously on the right flank of the mouse. When the tumor volume reached ~ 50 mm 3 (after 4 days), mice were injected with ACE-05 or BiTE-05 every other day (Q2d, total 3 doses), or YBL-007 or IgG every 3 days. (Q3d, total 3 doses). Tumor diameter and body weight were measured every 2 days and analyzed using GraphPad Prism 8 software.

실시예 18. In vivo에서 사이토카인 분석Example 18. In vivo cytokine analysis

6-7 주령의 암컷 비 종양 보유 hCD3ε TG 마우스를 각각 6 마리씩 4 개 그룹으로 구분하였다. 그 후, 각각의 그룹에 꼬리 정맥혈에 ACE-05 및 BiTE-05를 0.5 mg/kg 투여하였고, IgG 5 mg/kg을 투여하였다. 사이토 카인 분석을 위한 혈액 샘플을 0, 6, 12, 24 및 48 시간에 각 동물로부터 수집하고 -80℃에서 보관하였다. 수집한 각 혈장 샘플에 존재하는 다양한 사이토카인을 BD Cytometric Bead Array (CBA) Mouse Inflammation Kit (# 552364, BD Bioscience) 및 Mouse Th1 / Th2 Cytokine Kit (# 551287, BD Bioscience)의 프로토콜에 따라 분석하였다. 사이토 카인 수준은 GraphPad Prism 8 소프트웨어를 사용하여 분석하였다.6-7 week old female non-tumor-bearing hCD3ε TG mice were divided into 4 groups of 6 mice each. Thereafter, 0.5 mg/kg of ACE-05 and BiTE-05 were administered to tail venous blood to each group, and 5 mg/kg of IgG was administered. Blood samples for cytokine analysis were collected from each animal at 0, 6, 12, 24 and 48 hours and stored at -80°C. Various cytokines present in each collected plasma sample were analyzed according to the protocols of the BD Cytometric Bead Array (CBA) Mouse Inflammation Kit (# 552364, BD Bioscience) and the Mouse Th1 / Th2 Cytokine Kit (# 551287, BD Bioscience). Cytokine levels were analyzed using GraphPad Prism 8 software.

실시예 19. 종양 침투 림프구 분석Example 19. Tumor Penetrating Lymphocyte Analysis

종양 침투 림프구(TIL)는 hPD-L1을 발현하는 CT26 종양을 보유하고 있는 hCD3ε TG 마우스에서 분석되었다. 구체적으로, 마우스의 오른쪽 옆구리에 5×105 CT26-hPD-L1 세포를 피하로 접종하였다. 피하 종양 부피가 ~ 90 mm3에 도달하면, 시험 제제 (ACE-05, 1 mg / kg; YBL-007, 3 mg / kg; UCHT1, 2 mg / kg)의 복강 내 (ip) 투여를 시작하고, 주 2회로 2주동안 투여하였다(BIW, 총 4 회 투여). 마지막 주사 후 1 주일 후에 마우스에서 종양을 수득하였다. 종양 조직에서 살아있는 림프구 및 T 세포를 림프구 마커 (mCD45, mCD4, mCD8 및 hCD3)를 사용하여 유세포 분석으로 분석하였다. 그 결과는 GraphPad Prism 8 소프트웨어를 사용하여 분석하였다.Tumor-infiltrating lymphocytes (TIL) were analyzed in hCD3ε TG mice bearing CT26 tumors expressing hPD-L1. Specifically, 5×10 5 CT26-hPD-L1 cells were inoculated subcutaneously on the right flank of the mouse. When the subcutaneous tumor volume reaches ~90 mm 3 , start the intraperitoneal (ip) administration of the test formulation (ACE-05, 1 mg/kg; YBL-007, 3 mg/kg; UCHT1, 2 mg/kg) and , It was administered twice a week for 2 weeks (BIW, a total of 4 administrations). Tumors were obtained from mice one week after the last injection. Live lymphocytes and T cells in tumor tissue were analyzed by flow cytometry using lymphocyte markers (mCD45, mCD4, mCD8 and hCD3). The results were analyzed using GraphPad Prism 8 software.

실시예 20. In silico 면역원성 예측Example 20. In silico immunogenicity prediction

ACE-05-HC-VH 및 ACE-05-HC-VL 사슬의 Class I 면역원성을 in silico 웹 베이스 예측 프로그램인 MHC-I Binding Predictions (http://tools.iedb.org/mhci/) and Class I Immunogenicity (http://tools.iedb.org/immunogenicity/)을 이용하여 분석하였다. MHC-I 결합을 위해, ACE-05-HC-VH 및 ACE-05-HC-VL의 에피토프 후보는 IEDB (Immune Epitope Database)을 이용하여 예측되었다. MHC class-I 분자에 제시 가능한 펩타이드로서 0.3 백분위수를 컷오프로 하여 8-10머의 펩티드가 선정되었다. 면역원성 점수는 MHC-I 결합 예측 프로그램을 이용하여 수득하였다. ACE-05-HC-VH 및 ACE-05-HC-VL 내에 존재하는 면역원성이 있는 펩티드 및 이의 위치를 확인하였다.MHC-I Binding Predictions ( http://tools.iedb.org/mhci/ ) and Class , an in silico web-based prediction program, for Class I immunogenicity of ACE-05-HC-VH and ACE-05-HC-VL chains I Immunogenicity ( http://tools.iedb.org/immunogenicity/ ) was used to analyze. For MHC-I binding, epitope candidates of ACE-05-HC-VH and ACE-05-HC-VL were predicted using IEDB (Immune Epitope Database). As a peptide that can be presented to the MHC class-I molecule, 8-10 mer peptides were selected with the 0.3 percentile cutoff. Immunogenicity scores were obtained using the MHC-I binding prediction program. Immunogenic peptides present in ACE-05-HC-VH and ACE-05-HC-VL and their position were identified.

IV. 다중 특이적 융합 단백질의 예시IV. Examples of multispecific fusion proteins

실시예 21. 표적에 따른 융합 단백질의 실시예Example 21. Examples of fusion proteins according to targets

이 실시예는 본 발명에 제공된 바와 같은 예시적인 다중 특이적 융합 단백질, 특히 다중 특이적 융합 단백질 ACE-00, ACE-02, ACE-03, ACE-04, ACE-05, ACE-09, ACE-10, ACE-11, ACE-12, ACE-18, ACE-19, ACE-31 외 다수의 다중 특이적 융합 단백질이 개시되어 있다. 뿐만 아니라, 상기 융합 단백질과 제1항원과 제2항원의 결합 부위가 뒤바뀐, ACE-00r, ACE-02r, ACE-03r, ACE-04r, ACE-05r, ACE-09r, ACE-10r, ACE-11r, ACE-12r, ACE-18r, ACE-19r, ACE-31r 외 다수의 다중 특이적 융합 단백질의 구성 및 발현을 예시한다. 각각의 예시적인 다중 특이적 융합 단백질에서 제1 및 제2 항원을 타겟팅하는 구성요소는 하기 표 4에 요약하여 나타내었다.This example shows exemplary multispecific fusion proteins as provided herein, in particular multispecific fusion proteins ACE-00, ACE-02, ACE-03, ACE-04, ACE-05, ACE-09, ACE- 10, ACE-11, ACE-12, ACE-18, ACE-19, ACE-31 and many other multispecific fusion proteins have been disclosed. In addition, ACE-00r, ACE-02r, ACE-03r, ACE-04r, ACE-05r, ACE-09r, ACE-10r, ACE- 11r, ACE-12r, ACE-18r, ACE-19r, ACE-31r, and many other multispecific fusion proteins are illustrated. Components targeting the first and second antigens in each exemplary multispecific fusion protein are summarized in Table 4 below.

다중 특이적 융합 단백질Multispecific fusion proteins 타겟팅 구성요소(Targeting component)Targeting component 제1 항원 결합 도메인First antigen binding domain 제2 항원 결합 도메인Second antigen binding domain ACE-00ACE-00 Trastuzumab(Anti-Her2 Ab)Trastuzumab (Anti-Her2 Ab) AdalimumabAdalimumab ACE-01ACE-01 Anti-CD19 AbAnti-CD19 Ab Anti-CD3 mouse OKT3Anti-CD3 mouse OKT3 ACE-02ACE-02 Anti-CD19 AbAnti-CD19 Ab Anti-CD3 humanized 12F6Anti-CD3 humanized 12F6 ACE-03ACE-03 Anti-CD19 AbAnti-CD19 Ab Anti-CD3 humanized OKT3Anti-CD3 humanized OKT3 ACE-04ACE-04 Anti-PD-L1 AbAnti-PD-L1 Ab Anti-CD3 chimeric OKT3 FabAnti-CD3 chimeric OKT3 Fab ACE-05ACE-05 Anti-PD-L1 AbAnti-PD-L1 Ab Anti-CD3 AbAnti-CD3 Ab ACE-06ACE-06 Anti-PD-L1 AbAnti-PD-L1 Ab ForalumabForalumab ACE-07ACE-07 Anti-PD-L1 AbAnti-PD-L1 Ab Anti-CD3 UCHT1Anti-CD3 UCHT1 ACE-08ACE-08 Anti-PD-L1 AbAnti-PD-L1 Ab Anti-CD3 2C11Anti-CD3 2C11 ACE-09ACE-09 Anti-PD-L1 AbAnti-PD-L1 Ab Anti-CD3 UCHT1Anti-CD3 UCHT1 ACE-10ACE-10 Anti-CD20Anti-CD20 Anti-CD3 UCHT1Anti-CD3 UCHT1 ACE-11ACE-11 Cetuximab(Anti-EGFR Ab)Cetuximab (Anti-EGFR Ab) Anti-CD3 UCHT1Anti-CD3 UCHT1 ACE-12ACE-12 Anti-PD-L1 AbAnti-PD-L1 Ab Anti-CD3 UCHT1Anti-CD3 UCHT1 ACE-13ACE-13 Anti-PD-L1 AbAnti-PD-L1 Ab Anti-PD-1 AbAnti-PD-1 Ab ACE-14ACE-14 Anti-PD-L1 AbAnti-PD-L1 Ab Anti-CD3 UCHT1Anti-CD3 UCHT1 ACE-15ACE-15 Anti-PD-L1 AbAnti-PD-L1 Ab Anti-CD3 UCHT1Anti-CD3 UCHT1 ACE-16ACE-16 Anti-PD-L1 AbAnti-PD-L1 Ab Anti-CD3 UCHT1Anti-CD3 UCHT1 ACE-17ACE-17 Anti-PD-L1 AbAnti-PD-L1 Ab Anti-CD3 UCHT1Anti-CD3 UCHT1 ACE-18ACE-18 Anti-CD20 AbAnti-CD20 Ab Anti-CD3 UCHT1Anti-CD3 UCHT1 ACE-19ACE-19 Anti-EGFR AbAnti-EGFR Ab Anti-CD3 UCHT1Anti-CD3 UCHT1 ACE-20ACE-20 Matuzumab(Anti-EGFR Ab)Matuzumab (Anti-EGFR Ab) Anti-CD3 UCHT1Anti-CD3 UCHT1 ACE-21ACE-21 Zalutumumab(Anti-EGFR Ab)Zalutumumab (Anti-EGFR Ab) Anti-CD3 UCHT1Anti-CD3 UCHT1 ACE-22ACE-22 Rituximab(Anti-CD20 Ab)Rituximab (Anti-CD20 Ab) Anti-CD3 UCHT1Anti-CD3 UCHT1 ACE-23ACE-23 Anti-PD-L1 AbAnti-PD-L1 Ab Foralumab(Anti-CD3 Ab)Foralumab (Anti-CD3 Ab) ACE-24ACE-24 Trastuzumab(Anti-Her2 Ab)Trastuzumab (Anti-Her2 Ab) Adalimumab(Anti-TNF Ab)Adalimumab (Anti-TNF Ab) ACE-25ACE-25 Trastuzumab(Anti-Her2 Ab)Trastuzumab (Anti-Her2 Ab) Adalimumab(Anti-TNF Ab)Adalimumab (Anti-TNF Ab) ACE-26ACE-26 Cetuximab(Anti-EGFR Ab)Cetuximab (Anti-EGFR Ab) Anti-CD3 SP34Anti-CD3 SP34 ACE-27ACE-27 Anti-PD-L1 AbAnti-PD-L1 Ab Anti-CD3 SP34Anti-CD3 SP34 ACE-28ACE-28 Cetuximab(Anti-EGFR Ab)Cetuximab (Anti-EGFR Ab) Anti-CD3 UCHT1Anti-CD3 UCHT1 ACE-29ACE-29 Cetuximab(Anti-EGFR Ab)Cetuximab (Anti-EGFR Ab) Anti-CD3 SP34Anti-CD3 SP34 ACE-30ACE-30 Anti-CD3 UCHT1Anti-CD3 UCHT1 Anti-PD-L1 AbAnti-PD-L1 Ab ACE-31ACE-31 Anti-CD3 UCHT1Anti-CD3 UCHT1 Anti-PD-L1 AbAnti-PD-L1 Ab ACE-32ACE-32 Cetuximab(Anti-EGFR Ab)Cetuximab (Anti-EGFR Ab) Anti-CD3 SP34Anti-CD3 SP34 ACE-33ACE-33 Anti-CD3 UCHTAnti-CD3 UCHT Anti-PD-L1 AbAnti-PD-L1 Ab ACE-34ACE-34 Anti-PD-L1 AbAnti-PD-L1 Ab Mouse Anti-CD3 Mouse Anti-CD3 ACE-35ACE-35 Anti-PD-L1 AbAnti-PD-L1 Ab Mouse Anti-CD3 Mouse Anti-CD3 ACE-36ACE-36 Anti-PD-L1 AbAnti-PD-L1 Ab Ipilimumab(Anti-CTLA4 Ab)Ipilimumab (Anti-CTLA4 Ab) ACE-37ACE-37 Rituximab(Anti-CD20 Ab)Rituximab (Anti-CD20 Ab) Ipilimumab(Anti-CTLA4 Ab)Ipilimumab (Anti-CTLA4 Ab) ACE-38ACE-38 Cetuximab(Anti-EGFR Ab)Cetuximab (Anti-EGFR Ab) Anti-CD3 UCHT1Anti-CD3 UCHT1 ACE-39ACE-39 Cetuximab(Anti-EGFR Ab)Cetuximab (Anti-EGFR Ab) Anti-CD3 UCHT1Anti-CD3 UCHT1 ACE-40ACE-40 Cetuximab(Anti-EGFR Ab)Cetuximab (Anti-EGFR Ab) Anti-CD3 UCHT1Anti-CD3 UCHT1 ACE-00rACE-00r Adalimumab(Anti-TNF Ab)Adalimumab (Anti-TNF Ab) Trastuzumab(Anti-Her2 Ab)Trastuzumab (Anti-Her2 Ab) ACE-01rACE-01r Anti-CD3 mouse OKT3Anti-CD3 mouse OKT3 Anti-CD19 AbAnti-CD19 Ab ACE-02rACE-02r Anti-CD3 humanized 12F6Anti-CD3 humanized 12F6 Anti-CD19 AbAnti-CD19 Ab ACE-03rACE-03r Anti-CD3 humanized OKT3Anti-CD3 humanized OKT3 Anti-CD19 AbAnti-CD19 Ab ACE-04rACE-04r Anti-CD3 chimetic OKT3 FabAnti-CD3 chimetic OKT3 Fab Anti-PD-L1 AbAnti-PD-L1 Ab ACE-05rACE-05r Anti-CD3 UCHT1Anti-CD3 UCHT1 Anti-PD-L1 AbAnti-PD-L1 Ab ACE-06rACE-06r Foralumab(Anti-CD3 Ab)Foralumab (Anti-CD3 Ab) Anti-PD-L1 AbAnti-PD-L1 Ab ACE-07rACE-07r Anti-CD3 UCHT1Anti-CD3 UCHT1 Anti-PD-L1 AbAnti-PD-L1 Ab ACE-08rACE-08r Anti-CD3 2C11Anti-CD3 2C11 Anti-PD-L1 AbAnti-PD-L1 Ab ACE-09rACE-09r Anti-CD3 UCHT1Anti-CD3 UCHT1 Anti-PD-L1 AbAnti-PD-L1 Ab ACE-10rACE-10r Anti-CD3 UCHT1Anti-CD3 UCHT1 Anti-CD20 AbAnti-CD20 Ab ACE-11rACE-11r Anti-CD3 UCHT1Anti-CD3 UCHT1 Cetuximab(Anti-EGFR Ab)Cetuximab (Anti-EGFR Ab) ACE-12rACE-12r Anti-CD3 UCHT1Anti-CD3 UCHT1 Anti-PD-L1 AbAnti-PD-L1 Ab ACE-13rACE-13r Anti-PD-1 AbAnti-PD-1 Ab Anti-PD-L1 AbAnti-PD-L1 Ab ACE-14rACE-14r Anti-CD3 UCHT1Anti-CD3 UCHT1 Anti-PD-L1 AbAnti-PD-L1 Ab ACE-15rACE-15r Anti-CD3 UCHT1Anti-CD3 UCHT1 Anti-PD-L1 AbAnti-PD-L1 Ab ACE-16rACE-16r Anti-CD3 UCHT1Anti-CD3 UCHT1 Anti-PD-L1 AbAnti-PD-L1 Ab ACE-17rACE-17r Anti-CD3 UCHT1Anti-CD3 UCHT1 Anti-PD-L1 AbAnti-PD-L1 Ab ACE-18rACE-18r Anti-CD3 UCHT1Anti-CD3 UCHT1 Anti-CD20 AbAnti-CD20 Ab ACE-19rACE-19r Anti-CD3 UCHT1Anti-CD3 UCHT1 Anti-EGFR AbAnti-EGFR Ab ACE-20rACE-20r Anti-CD3 UCHT1Anti-CD3 UCHT1 Matuzumab(Anti-EGFR Ab)Matuzumab (Anti-EGFR Ab) ACE-21rACE-21r Anti-CD3 UCHT1Anti-CD3 UCHT1 Zalutumumab(Anti-EGFR Ab)Zalutumumab (Anti-EGFR Ab) ACE-22rACE-22r Anti-CD3 UCHT1Anti-CD3 UCHT1 Rituximab(Anti-CD20 Ab)Rituximab (Anti-CD20 Ab) ACE-23rACE-23r Foralumab(Anti-CD3 Ab)Foralumab (Anti-CD3 Ab) Anti-PD-L1 AbAnti-PD-L1 Ab ACE-24rACE-24r Adalimumab(Anti-TNF Ab)Adalimumab (Anti-TNF Ab) Trastuzumab(Anti-Her2 Ab)Trastuzumab (Anti-Her2 Ab) ACE-25rACE-25r Adalimumab(Anti-TNF Ab)Adalimumab (Anti-TNF Ab) Trastuzumab(Anti-Her2 Ab)Trastuzumab (Anti-Her2 Ab) ACE-26rACE-26r Anti-CD3 SP34Anti-CD3 SP34 Cetuximab(Anti-EGFR Ab)Cetuximab (Anti-EGFR Ab) ACE-27rACE-27r Anti-CD3 SP34Anti-CD3 SP34 Anti-PD-L1 AbAnti-PD-L1 Ab ACE-28rACE-28r Anti-CD3 UCHT1Anti-CD3 UCHT1 CetuximabCetuximab ACE-29rACE-29r Anti-CD3 SP34Anti-CD3 SP34 CetuximabCetuximab ACE-30rACE-30r Anti-PD-L1 AbAnti-PD-L1 Ab Anti-CD3 UCHTAnti-CD3 UCHT ACE-31rACE-31r Anti-PD-L1 AbAnti-PD-L1 Ab Anti-CD3 UCHTAnti-CD3 UCHT ACE-32rACE-32r Anti-CD3 SP34Anti-CD3 SP34 CetuximabCetuximab ACE-33rACE-33r Anti-PD-L1 AbAnti-PD-L1 Ab Anti-CD3 UCHTAnti-CD3 UCHT ACE-34rACE-34r Mouse Anti-CD3 Mouse Anti-CD3 Anti-PD-L1 AbAnti-PD-L1 Ab ACE-35rACE-35r Mouse Anti-CD3 Mouse Anti-CD3 Anti-PD-L1 AbAnti-PD-L1 Ab ACE-36rACE-36r IpilimumabIpilimumab Anti-PD-L1 AbAnti-PD-L1 Ab ACE-37rACE-37r IpilimumabIpilimumab RituximabRituximab ACE-38rACE-38r Anti-CD3 UCHT1Anti-CD3 UCHT1 CetuximabCetuximab ACE-39rACE-39r Anti-CD3 UCHT1Anti-CD3 UCHT1 CetuximabCetuximab ACE-40rACE-40r Anti-CD3 UCHT1Anti-CD3 UCHT1 CetuximabCetuximab

Formats used in amino acid sequences: BOLD: VH or VL;Formats used in amino acid sequences: BOLD : VH or VL;

BOLD and UNDERLINED : CDR; BOLD and UNDERLINED : CDR;

ITALICIZED: antibody hinge region; ITALICIZED : antibody hinge region;

lower case: flexible linker;lower case: flexible linker;

[BRACKET]: CH1;[BRACKET]: CH1;

[BRACKET and UNDERLINED]: CL.[ BRACKET and UNDERLINED ]: CL.

Double underlined: CH3Double underlined: CH3

실시예 21.1. ACE-00의 제조Example 21.1. Preparation of ACE-00

ACE-00은 2개의 상이한 중쇄 유사 사슬 (ACE-00-VH 및 ACE-00-VL) 및 2개의 동일한 경쇄 (ACE-00-LC)를 포함한다. ACE-00의 항 -Her2 도메인 구축에 사용되는 모 항체는 트라스투주맙이고 ACE-00의 항-TNF 알파 도메인 구축에 사용되는 모 항체는 아달리무맙이다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다: ACE-00 contains two different heavy chain-like chains (ACE-00-VH and ACE-00-VL) and two identical light chains (ACE-00-LC). The parent antibody used to construct the anti-Her2 domain of ACE-00 is trastuzumab, and the parent antibody used to construct the anti-TNF alpha domain of ACE-00 is adalimumab. The amino acid sequences of these three types of polypeptides are as follows:

ACE-00-VH amino acid sequence:ACE-00-VH amino acid sequence:

EVQLVESGGGLVQPGGSLRLSCAAS GFNIKDTY IHWVRQAPGKGLEWVAR IYPTNGYT RYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYC SRWGGDGFYAMDY WGQGTLVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC]DKTHTCPPCPAPELLGGP EVQLVESGGGLVQPGRSLRLSCAAS GFTFDDYA MHWVRQAPGKGLEWVSA ITWNSGHI DYADSVEGRFTISRDNAKNSLYLQMNSLRAEDTAVYYC AKVSYLSTASSLDY WGQGTLVTVSS(서열번호: 115) EVQLVESGGGLVQPGGSLRLSCAAS GFNIKDTY IHWVRQAPGKGLEWVAR IYPTNGYT RYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYC SRWGGDGFYAMDY WGQGTLVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC] DKTHTCPPCPAPELLGGP EVQLVESGGGLVQPGRSLRLSCAAS GFTFDDYA MHWVRQAPGKGLEWVSA ITWNSGHI DYADSVEGRFTISRDNAKNSLYLQMNSLRAEDTAVYYC AKVSYLSTASSLDY WGQGTLVTVSS (SEQ ID NO: 115)

ACE-00-VL amino acid sequence:ACE-00-VL amino acid sequence:

EVQLVESGGGLVQPGGSLRLSCAAS GFNIKDTY IHWVRQAPGKGLEWVAR IYPTNGYT RYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYC SRWGGDGFYAMDY WGQGTLVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC]DKTHTCPPCPAPELLGGP DIQMTQSPSSLSASVGDRVTITCRAS QGIRNY LAWYQQKPGKAPKLLIY AAS TLQSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYC QRYNRAPYT FGQGTKVEIKR(서열번호: 116) EVQLVESGGGLVQPGGSLRLSCAAS GFNIKDTY IHWVRQAPGKGLEWVAR IYPTNGYT RYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYC SRWGGDGFYAMDY WGQGTLVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC] DKTHTCPPCPAPELLGGP DIQMTQSPSSLSASVGDRVTITCRAS QGIRNY LAWYQQKPGKAPKLLIY AAS TLQSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYC QRYNRAPYT FGQGTKVEIKR (SEQ ID NO: 116)

ACE-00-LC amino acid sequence (anti-CD19 antibody light chain): ACE-00-LC amino acid sequence (anti-CD19 antibody light chain) :

DIQMTQSPSSLSASVGDRVTITCRAS QDVNTA VAWYQQKPGKAPKLLIY SAS FLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYC QQHYTTPPT FGQGTKVEIK[ RSVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC](서열번호: 117) DIQMTQSPSSLSASVGDRVTITCRAS QDVNTA VAWYQQKPGKAPKLLIY SAS FLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYC QQHYTTPPT FGQGTKVEIK[ RSVAAPSVFIFPPSDEQLKSGTASVVCLLNNVDYPREAKSQGNSVSTYPREAKVQWKSDNSVDYPREAKVQWKDS

Her2를 표적으로하는 2가 Fab 영역 및 TNF 알파를 표적으로하는 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열은 표 5에 나열되어있다: The VH and VL amino acid sequences for the bivalent Fab region targeting Her2 and the monovalent Fv region targeting TNF alpha are listed in Table 5:

Fab region
(Anti-Her2)
Fab region
(Anti-Her2)
VH: EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS (서열번호: 51)VH: EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS (SEQ ID NO: 51) VL:
DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKR (서열번호: 52)
VL:
DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKR (SEQ ID NO: 52)
CDR H1: GFNIKDTY (서열번호: 118)CDR H1: GFNIKDTY (SEQ ID NO: 118) CDR L1: QDVNTA (서열번호: 121)CDR L1: QDVNTA (SEQ ID NO: 121) CDR H2: IYPTNGYT (서열번호: 119)CDR H2: IYPTNGYT (SEQ ID NO: 119) CDR L2: SAS (서열번호: 122)CDR L2: SAS (SEQ ID NO: 122) CDR H3: SRWGGDGFYAMDY (서열번호: 120)CDR H3: SRWGGDGFYAMDY (SEQ ID NO: 120) CDR L3: QQHYTTPPT (서열번호: 123)CDR L3: QQHYTTPPT (SEQ ID NO: 123) Fv region
(Anti-TNF alpha)
Fv region
(Anti-TNF alpha)
VH:
EVQLVESGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSAITWNSGHIDYADSVEGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAKVSYLSTASSLDYWGQGTLVTVSS (서열번호: 53)
VH:
EVQLVESGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSAITWNSGHIDYADSVEGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAKVSYLSTASSLDYWGQGTLVTVSS (SEQ ID NO: 53)
VL:
DIQMTQSPSSLSASVGDRVTITCRASQGIRNYLAWYQQKPGKAPKLLIYAASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQRYNRAPYTFGQGTKVEIKR (서열번호: 54)
VL:
DIQMTQSPSSLSASVGDRVTITCRASQGIRNYLAWYQQKPGKAPKLLIYAASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQRYNRAPYTFGQGTKVEIKR (SEQ ID NO: 54)
CDR H1: GFTFDDYA (서열번호: 124)CDR H1: GFTFDDYA (SEQ ID NO: 124) CDR L1: QGIRNY (서열번호: 127)CDR L1: QGIRNY (SEQ ID NO: 127) CDR H2: ITWNSGHI (서열번호: 125)CDR H2: ITWNSGHI (SEQ ID NO: 125) CDR L2: AAS (서열번호: 128)CDR L2: AAS (SEQ ID NO: 128) CDR H3: AKVSYLSTASSLDY (서열번호: 126)CDR H3: AKVSYLSTASSLDY (SEQ ID NO: 126) CDR L3: QRYNRAPYT (서열번호: 129)CDR L3: QRYNRAPYT (SEQ ID NO: 129)

실시예 21.2. ACE-01의 제조 Example 21.2. Preparation of ACE-01

ACE-01은 2개의 상이한 중쇄 유사 사슬 (ACE-01-VH 및 ACE-01-VL) 및 2개의 동일한 경쇄 (ACE-01-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다: ACE-01 contains two different heavy chain-like chains (ACE-01-VH and ACE-01-VL) and two identical light chains (ACE-01-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-01-VH amino acid sequence (서열번호: 136)ACE-01-VH amino acid sequence (SEQ ID NO: 136)

QVQLQQSGAELVRPGSSVKISCKASGYAFS SYWMN WVKQRPGQGLEWIGQ IWPGDGDT NYNGKFKGKATLTADESSSTAYMQLSSLASEDSAVYFC ARRETTTVGRYYYAMDY WGQGTTVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC]DKTHTCPPCPAPELLGGP QVQLQQSGAELARPGASVKMSCKAS GYTFTRYT MHWVKQRPGQGLEWIGY INPSRGYT NYNQKFKDKATLTTDKSSSTAYMQLSSLTSEDSAVYYC ARYYDDHYCLDY WGQGTTVTVSS QVQLQQSGAELVRPGSSVKISCKASGYAFS SYWMN WVKQRPGQGLEWIGQ IWPGDGDT NYNGKFKGKATLTADESSSTAYMQLSSLASEDSAVYFC ARRETTTVGRYYYAMDY WGQGTTVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC] DKTHTCPPCPAPELLGGP QVQLQQSGAELARPGASVKMSCKAS GYTFTRYT MHWVKQRPGQGLEWIGY INPSRGYT NYNQKFKDKATLTTDKSSSTAYMQLSSLTSEDSAVYYC ARYYDDHYCLDY WGQGTTVTVSS

ACE-01- VL amino acid sequence (서열번호: 137)ACE-01- VL amino acid sequence (SEQ ID NO: 137)

QVQLQQSGAELVRPGSSVKISCKASGYAFSSYWMNWVKQRPGQGLEWIGQIWPGDGDTNYNGKFKGKATLTADESSSTAYMQLSSLASEDSAVYFCARRETTTVGRYYYAMDYWGQGTTVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC]DKTHTCPPCPAPELLGGPQIVLTQSPAIMSASPGEKVTMTCSAS SSVSY MNWYQQKSGTSPKRWIY DTS KLASGVPAHFRGSGSGTSYSLTISGMEAEDAATYYC QQWSSNPFTF GSGTKLEINR QVQLQQSGAELVRPGSSVKISCKASGYAFSSYWMNWVKQRPGQGLEWIGQIWPGDGDTNYNGKFKGKATLTADESSSTAYMQLSSLASEDSAVYFCARRETTTVGRYYYAMDYWGQGTTVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC] DKTHTCPPCPAPELLGGP QIVLTQSPAIMSASPGEKVTMTCSAS SSVSY MNWYQQKSGTSPKRWIY DTS KLASGVPAHFRGSGSGTSYSLTISGMEAEDAATYYC QQWSSNPFTF GSGTKLEINR

ACE-01-LC amino acid sequence (서열번호: 138)ACE-01-LC amino acid sequence (SEQ ID NO: 138)

DIQLTQSPASLAVSLGQRATISCKAS QSVDYDGDSY LNWYQQIPGQPPKLLIY DAS NLVSGIPPRFSGSGSGTDFTLNIHPVEKVDAATYHC QQSTEDPWT FGGGTKLEIK[RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] DIQLTQSPASLAVSLGQRATISCKAS QSVDYDGDSY LNWYQQIPGQPPKLLIY DAS NLVSGIPPRFSGSGSGTDFTLNIHPVEKVDAATYHC QQSTEDPWT FGGGTKLEIK [ RTVAAPSVFIFPPSDEQLKSGTASVVCSQVLTQLKSGTASVVCSKNFQLKSGTASVVCSKNFREADS

제1 항원 결합 도메인 (CD19를 표적으로하는 2가 Fab 영역) 및 제2 항원 결합 도메인 (CD3를 표적으로하는 1가 Fv 영역)에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 6에 나열되어있다: The VH and VL amino acid sequences and CDR sequences therein for the first antigen-binding domain (divalent Fab region targeting CD19) and the second antigen-binding domain (monovalent Fv region targeting CD3) are shown in Table 6 below. Are listed:

Fab region
(Anti-CD19)
Fab region
(Anti-CD19)
VH: QVQLQQSGAELVRPGSSVKISCKASGYAFSSYWMNWVKQRPGQGLEWIGQIWPGDGDTNYNGKFKGKATLTADESSSTAYMQLSSLASEDSAVYFCARRETTTVGRYYYAMDYWGQGTTVTVSS (서열번호: 139)VH: QVQLQQSGAELVRPGSSVKISCKASGYAFSSYWMNWVKQRPGQGLEWIGQIWPGDGDTNYNGKFKGKATLTADESSSTAYMQLSSLASEDSAVYFCARRETTTVGRYYYAMDYWGQGTTVTVSS (SEQ ID NO: 139) VL:
DIQLTQSPASLAVSLGQRATISCKASQSVDYDGDSYLNWYQQIPGQPPKLLIYDASNLVSGIPPRFSGSGSGTDFTLNIHPVEKVDAATYHCQQSTEDPWTFGGGTKLEIK (서열번호: 151)
VL:
DIQLTQSPASLAVSLGQRATISCKASQSVDYDGDSYLNWYQQIPGQPPKLLIYDASNLVSGIPPRFSGSGSGTDFTLNIHPVEKVDAATYHCQQSTEDPWTFGGGTKLEIK (SEQ ID NO: 151)
CDR H1: SYWMN (서열번호: 140)CDR H1: SYWMN (SEQ ID NO: 140) CDR L1: QSVDYDGDSY (서열번호: 152)CDR L1: QSVDYDGDSY (SEQ ID NO: 152) CDR H2: IWPGDGDT (서열번호: 141)CDR H2: IWPGDGDT (SEQ ID NO: 141) CDR L2: DAS (서열번호: 153)CDR L2: DAS (SEQ ID NO: 153) CDR H3: ARRETTTVGRYYYAMDY (서열번호: 142)CDR H3: ARRETTTVGRYYYAMDY (SEQ ID NO: 142) CDR L3: QQSTEDPWT (서열번호: 154)CDR L3: QQSTEDPWT (SEQ ID NO: 154) Fv region
(Anti-CD3)
Fv region
(Anti-CD3)
VH:
QVQLQQSGAELARPGASVKMSCKASGYTFTRYTMHWVKQRPGQGLEWIGYINPSRGYTNYNQKFKDKATLTTDKSSSTAYMQLSSLTSEDSAVYYCARYYDDHYCLDYWGQGTTVTVSS (서열번호: 143)
VH:
QVQLQQSGAELARPGASVKMSCKASGYTFTRYTMHWVKQRPGQGLEWIGYINPSRGYTNYNQKFKDKATLTTDKSSSTAYMQLSSLTSEDSAVYYCARYYDDHYCLDYWGQGTTVTVSS (SEQ ID NO: 143)
VL:
QIVLTQSPAIMSASPGEKVTMTCSASSSVSYMNWYQQKSGTSPKRWIYDTSKLASGVPAHFRGSGSGTSYSLTISGMEAEDAATYYCQQWSSNPFTFGSGTKLEINR (서열번호: 147)
VL:
QIVLTQSPAIMSASPGEKVTMTCSASSSVSYMNWYQQKSGTSPKRWIYDTSKLASGVPAHFRGSGSGTSYSLTISGMEAEDAATYYCQQWSSNPFTFGSGTKLEINR (SEQ ID NO: 147)
CDR H1: GYTFTRYT (서열번호: 144)CDR H1: GYTFTRYT (SEQ ID NO: 144) CDR L1: SSVSY (서열번호: 148)CDR L1: SSVSY (SEQ ID NO: 148) CDR H2: INPSRGYT (서열번호: 145)CDR H2: INPSRGYT (SEQ ID NO: 145) CDR L2: DTS (서열번호: 149)CDR L2: DTS (SEQ ID NO: 149) CDR H3: ARYYDDHYCLDY (서열번호: 146)CDR H3: ARYYDDHYCLDY (SEQ ID NO: 146) CDR L3: QQWSSNPFTF (서열번호: 150)CDR L3: QQWSSNPFTF (SEQ ID NO: 150)

실시예 21.3. ACE-02의 제조 Example 21.3. Preparation of ACE-02

ACE-02는 2개의 상이한 중쇄 유사 사슬 (ACE-02-VH 및 ACE-02-VL) 및 2개의 동일한 경쇄 (ACE-02-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다: ACE-02 contains two different heavy chain-like chains (ACE-02-VH and ACE-02-VL) and two identical light chains (ACE-02-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-02-VH amino acid sequence: ACE-02-VH amino acid sequence :

QVQLQQSGAELVRPGSSVKISCKASGYAFS SYWM NWVKQRPGQGLEWIG QIWPGDGDTNYNGKFKG KATLTADESSSTAYMQLSSLASEDSAVYFCAR RETTTVGRYYYAMDY WGQGTTVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC]DKTHTCPPCPAPELLGGP QVQLVQSGGGVVQPGRSLRLSCKAS GYTFTSYT MHWVRQAPGKGLEWIGY INPSSGYT KYNQKFKDRFTISADKSKSTAFLQMDSLRPEDTGVYFC ARWQDYDVYFDY WGQGTPVTVSS(서열번호: 88) QVQLQQSGAELVRPGSSVKISCKASGYAFS SYWM NWVKQRPGQGLEWIG QIWPGDGDTNYNGKFKG KATLTADESSSTAYMQLSSLASEDSAVYFCAR RETTTVGRYYYAMDY WGQGTTVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC] DKTHTCPPCPAPELLGGP QVQLVQSGGGVVQPGRSLRLSCKAS GYTFTSYT MHWVRQAPGKGLEWIGY INPSSGYT KYNQKFKDRFTISADKSKSTAFLQMDSLRPEDTGVYFC ARWQDYDVYFDY WGQGTPVTVSS (SEQ ID NO: 88)

ACE-02-VL amino acid sequence: ACE-02-VL amino acid sequence :

QVQLQQSGAELVRPGSSVKISCKASGYAFS SYWMN WVKQRPGQGLEWIG QIWPGDGDTNYNGKFKG KATLTADESSSTAYMQLSSLASEDSAVYFCAR RETTTVGRYYYAMDY WGQGTTVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC]DKTHTCPPCPAPELLGGP DIQMTQSPSSLSASVGDRVTMTCRA SSSVSY MHWYQQTPGKAPKPWIY ATS NLASGVPSRFSGSGSGTDYTLTISSLQPEDIATYYC QQWSSNPPT FGQGTKLQITR(서열번호: 89) QVQLQQSGAELVRPGSSVKISCKASGYAFS SYWMN WVKQRPGQGLEWIG QIWPGDGDTNYNGKFKG KATLTADESSSTAYMQLSSLASEDSAVYFCAR RETTTVGRYYYAMDY WGQGTTVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC] DKTHTCPPCPAPELLGGP DIQMTQSPSSLSASVGDRVTMTCRA SSSVSY MHWYQQTPGKAPKPWIY ATS NLASGVPSRFSGSGSGTDYTLTISSLQPEDIATYYC QQWSSNPPT FGQGTKLQITR (SEQ ID NO: 89)

ACE-02-LC amino acid sequence (anti-CD19 antibody light chain): ACE-02-LC amino acid sequence (anti-CD19 antibody light chain) :

DIQLTQSPASLAVSLGQRATISCKAS QSVDYDGDSY LNWYQQIPGQPPKLLIY DAS NLVSGIPPRFSGSGSGTDFTLNIHPVEKVDAATYHC QQSTEDPWT FGGGTKLEIK[ RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC](서열번호: 90) DIQLTQSPASLAVSLGQRATISCKAS QSVDYDGDSY LNWYQQIPGQPPKLLIY DAS NLVSGIPPRFSGSGSGTDFTLNIHPVEKVDAATYHC QQSTEDPWT FGGGTKLEIK [RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] (SEQ ID NO: 90)

CD19를 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 인간화 12F6의 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 7에 나열되어있다: The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting CD19 and the second antigen binding domain monovalent Fv region of humanized 12F6 are listed in Table 7 below:

Fab region
(Anti-CD19)
Fab region
(Anti-CD19)
VH: QVQLQQSGAELVRPGSSVKISCKASGYAFSSYWMNWVKQRPGQGLEWIGQIWPGDGDTNYNGKFKGKATLTADESSSTAYMQLSSLASEDSAVYFCARRETTTVGRYYYAMDYWGQGTTVTVSS (서열번호: 61)VH: QVQLQQSGAELVRPGSSVKISCKASGYAFSSYWMNWVKQRPGQGLEWIGQIWPGDGDTNYNGKFKGKATLTADESSSTAYMQLSSLASEDSAVYFCARRETTTVGRYYYAMDYWGQGTTVTVSS (SEQ ID NO: 61) VL:
DIQLTQSPASLAVSLGQRATISCKASQSVDYDGDSYLNWYQQIPGQPPKLLIYDASNLVSGIPPRFSGSGSGTDFTLNIHPVEKVDAATYHCQQSTEDPWTFGGGTKLEIK (서열번호: 65)
VL:
DIQLTQSPASLAVSLGQRATISCKASQSVDYDGDSYLNWYQQIPGQPPKLLIYDASNLVSGIPPRFSGSGSGTDFTLNIHPVEKVDAATYHCQQSTEDPWTFGGGTKLEIK (SEQ ID NO: 65)
CDR H1: SYWMN (서열번호: 62)CDR H1: SYWMN (SEQ ID NO: 62) CDR L1: QSVDYDGDSY (서열번호: 66)CDR L1: QSVDYDGDSY (SEQ ID NO: 66) CDR H2: QIWPGDGDTNYNGKFKG (서열번호: 63)CDR H2: QIWPGDGDTNYNGKFKG (SEQ ID NO: 63) CDR L2: DAS (서열번호: 67)CDR L2: DAS (SEQ ID NO: 67) CDR H3: RETTTVGRYYYAMDY (서열번호: 64)CDR H3: RETTTVGRYYYAMDY (SEQ ID NO: 64) CDR L3: QQSTEDPWT (서열번호: 68)CDR L3: QQSTEDPWT (SEQ ID NO: 68) Fv region
(Anti-CD3)
Fv region
(Anti-CD3)
VH:
QVQLVQSGGGVVQPGRSLRLSCKASGYTFTSYTMHWVRQAPGKGLEWIGYINPSSGYTKYNQKFKDRFTISADKSKSTAFLQMDSLRPEDTGVYFCARWQDYDVYFDYWGQGTPVTVSS (서열번호: 69)
VH:
QVQLVQSGGGVVQPGRSLRLSCKASGYTFTSYTMHWVRQAPGKGLEWIGYINPSSGYTKYNQKFKDRFTISADKSKSTAFLQMDSLRPEDTGVYFCARWQDYDVYFDYWGQGTPVTVSS (SEQ ID NO: 69)
VL:
DIQMTQSPSSLSASVGDRVTMTCRASSSVSYMHWYQQTPGKAPKPWIYATSNLASGVPSRFSGSGSGTDYTLTISSLQPEDIATYYCQQWSSNPPTFGQGTKLQITR (서열번호: 73)
VL:
DIQMTQSPSSLSASVGDRVTMTCRASSSVSYMHWYQQTPGKAPKPWIYATSNLASGVPSRFSGSGSGTDYTLTISSLQPEDIATYYCQQWSSNPPTFGQGTKLQITR (SEQ ID NO: 73)
CDR H1: GYTFTSYT (서열번호: 70)CDR H1: GYTFTSYT (SEQ ID NO: 70) CDR L1: SSSVSY (서열번호: 74)CDR L1: SSSVSY (SEQ ID NO: 74) CDR H2: INPSSGYT (서열번호: 71)CDR H2: INPSSGYT (SEQ ID NO: 71) CDR L2: ATS (서열번호: 75)CDR L2: ATS (SEQ ID NO: 75) CDR H3: ARWQDYDVYFDY (서열번호: 72)CDR H3: ARWQDYDVYFDY (SEQ ID NO: 72) CDR L3: QQWSSNPPT (서열번호: 76)CDR L3: QQWSSNPPT (SEQ ID NO: 76)

ACE-02-VH, ACE-02-VL 및 ACE-02-LC를 암호화하는 DNA 서열은 각각 서열번호 100 내지 102의 핵산 서열을 가진다.DNA sequences encoding ACE-02-VH, ACE-02-VL and ACE-02-LC have nucleic acid sequences of SEQ ID NOs: 100 to 102, respectively.

실시예 21.4. ACE-03의 제조 Example 21.4. Preparation of ACE-03

ACE-03은 항 -CD19 및 인간화 항 -CD3 OKT3 도메인으로 구성된다. ACE-03은 두 개의 다른 중쇄 유사 사슬 (ACE-03-VH 및 ACE-03-VL)과 두 개의 동일한 경쇄 (ACE-03-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다: ACE-03 consists of anti-CD19 and humanized anti-CD3 OKT3 domains. ACE-03 contains two different heavy chain-like chains (ACE-03-VH and ACE-03-VL) and two identical light chains (ACE-03-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-03-VH amino acid sequence:ACE-03-VH amino acid sequence:

QVQLQQSGAELVRPGSSVKISCKASGYAFS SYWMN WVKQRPGQGLEWIG QIWPGDGDTNYNGKFKG KATLTADESSSTAYMQLSSLASEDSAVYFCAR RETTTVGRYYYAMDY WGQGTTVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC]DKTHTCPPCPAPELLGGP VQLVQSGGGVVQPGRSLRLSCKAS GYTFTRYT MHWVRQAPGKGLEWIGY INPSRGYT NYNQKVKDRFTISTDKSKSTAFLQMDSLRPEDTAVYYC ARYYDDHYCLDY WGQGTPVTVSS (서열번호: 91) QVQLQQSGAELVRPGSSVKISCKASGYAFS SYWMN WVKQRPGQGLEWIG QIWPGDGDTNYNGKFKG KATLTADESSSTAYMQLSSLASEDSAVYFCAR RETTTVGRYYYAMDY WGQGTTVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC] DKTHTCPPCPAPELLGGP VQLVQSGGGVVQPGRSLRLSCKAS GYTFTRYT MHWVRQAPGKGLEWIGY INPSRGYT NYNQKVKDRFTISTDKSKSTAFLQMDSLRPEDTAVYYC ARYYDDHYCLDY WGQGTPVTVSS (SEQ ID NO: 91)

ACE-03-VL amino acid sequence: ACE-03-VL amino acid sequence :

QVQLQQSGAELVRPGSSVKISCKASGYAFS SYWMN WVKQRPGQGLEWIG QIWPGDGDTNYNGKFKG KATLTADESSSTAYMQLSSLASEDSAVYFCAR RETTTVGRYYYAMDY WGQGTTVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC]DKTHTCPPCPAPELLGGP DIQMTQSPSSLSASVGDRVTITCSAS SSVSY MNWYQQTPGKAPKRWIY DTS KLASGVPSRFSGSGSGTDYTFTISSLQPEDIATYYC QQWSSNPFT FGQGTKLQITR (서열번호: 92) QVQLQQSGAELVRPGSSVKISCKASGYAFS SYWMN WVKQRPGQGLEWIG QIWPGDGDTNYNGKFKG KATLTADESSSTAYMQLSSLASEDSAVYFCAR RETTTVGRYYYAMDY WGQGTTVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC] DKTHTCPPCPAPELLGGP DIQMTQSPSSLSASVGDRVTITCSAS SSVSY MNWYQQTPGKAPKRWIY DTS KLASGVPSRFSGSGSGTDYTFTISSLQPEDIATYYC QQWSSNPFT FGQGTKLQITR (SEQ ID NO: 92)

ACE-03-LC amino acid sequence (anti-CD19 antibody light chain): ACE-03-LC amino acid sequence (anti-CD19 antibody light chain) :

DIQLTQSPASLAVSLGQRATISCKAS QSVDYDGDSY LNWYQQIPGQPPKLLIY DAS NLVSGIPPRFSGSGSGTDFTLNIHPVEKVDAATYHC QQSTEDPWT FGGGTKLEIK[ RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] (서열번호: 90) DIQLTQSPASLAVSLGQRATISCKAS QSVDYDGDSY LNWYQQIPGQPPKLLIY DAS NLVSGIPPRFSGSGSGTDFTLNIHPVEKVDAATYHC QQSTEDPWT FGGGTKLEIK [RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] (SEQ ID NO: 90)

CD19를 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 인간화 OKT3의 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 8에 나열되어있다: The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting CD19 and the second antigen binding domain monovalent Fv region of humanized OKT3 are listed in Table 8 below:

Fab region
(Anti-CD19)
Fab region
(Anti-CD19)
VH: QVQLQQSGAELVRPGSSVKISCKASGYAFSSYWMNWVKQRPGQGLEWIGQIWPGDGDTNYNGKFKGKATLTADESSSTAYMQLSSLASEDSAVYFCARRETTTVGRYYYAMDYWGQGTTVTVSS (서열번호: 61)VH: QVQLQQSGAELVRPGSSVKISCKASGYAFSSYWMNWVKQRPGQGLEWIGQIWPGDGDTNYNGKFKGKATLTADESSSTAYMQLSSLASEDSAVYFCARRETTTVGRYYYAMDYWGQGTTVTVSS (SEQ ID NO: 61) VL:
DIQLTQSPASLAVSLGQRATISCKASQSVDYDGDSYLNWYQQIPGQPPKLLIYDASNLVSGIPPRFSGSGSGTDFTLNIHPVEKVDAATYHCQQSTEDPWTFGGGTKLEIK (서열번호: 65)
VL:
DIQLTQSPASLAVSLGQRATISCKASQSVDYDGDSYLNWYQQIPGQPPKLLIYDASNLVSGIPPRFSGSGSGTDFTLNIHPVEKVDAATYHCQQSTEDPWTFGGGTKLEIK (SEQ ID NO: 65)
CDR H1: SYWMN (서열번호: 62)CDR H1: SYWMN (SEQ ID NO: 62) CDR L1: QSVDYDGDSY (서열번호: 66)CDR L1: QSVDYDGDSY (SEQ ID NO: 66) CDR H2: QIWPGDGDTNYNGKFKG (서열번호: 63)CDR H2: QIWPGDGDTNYNGKFKG (SEQ ID NO: 63) CDR L2: DAS (서열번호: 67)CDR L2: DAS (SEQ ID NO: 67) CDR H3: RETTTVGRYYYAMDY (서열번호: 64)CDR H3: RETTTVGRYYYAMDY (SEQ ID NO: 64) CDR L3: QQSTEDPWT (서열번호: 68)CDR L3: QQSTEDPWT (SEQ ID NO: 68) Fv region
(Anti-CD3)
Fv region
(Anti-CD3)
VH:
VQLVQSGGGVVQPGRSLRLSCKASGYTFTRYTMHWVRQAPGKGLEWIGYINPSRGYTNYNQKVKDRFTISTDKSKSTAFLQMDSLRPEDTAVYYCARYYDDHYCLDYWGQGTPVTVSS (서열번호: 77)
VH:
VQLVQSGGGVVQPGRSLRLSCKASGYTFTRYTMHWVRQAPGKGLEWIGYINPSRGYTNYNQKVKDRFTISTDKSKSTAFLQMDSLRPEDTAVYYCARYYDDHYCLDYWGQGTPVTVSS (SEQ ID NO: 77)
VL:
DIQMTQSPSSLSASVGDRVTITCSASSSVSYMNWYQQTPGKAPKRWIYDTSKLASGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQQWSSNPFTFGQGTKLQITR (서열번호: 81)
VL:
DIQMTQSPSSLSASVGDRVTITCSASSSVSYMNWYQQTPGKAPKRWIYDTSKLASGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQQWSSNPFTFGQGTKLQITR (SEQ ID NO: 81)
CDR H1: GYTFTRYT (서열번호: 78)CDR H1: GYTFTRYT (SEQ ID NO: 78) CDR L1: SSVSY (서열번호: 82)CDR L1: SSVSY (SEQ ID NO: 82) CDR H2: INPSRGYT (서열번호: 79)CDR H2: INPSRGYT (SEQ ID NO: 79) CDR L2: DTS (서열번호: 83)CDR L2: DTS (SEQ ID NO: 83) CDR H3: ARYYDDHYCLDY (서열번호: 80)CDR H3: ARYYDDHYCLDY (SEQ ID NO: 80) CDR L3: QQWSSNPFT (서열번호: 84)CDR L3: QQWSSNPFT (SEQ ID NO: 84)

ACE-03-VH, ACE-03-VL 및 ACE-03-LC를 암호화하는 DNA 서열은 각각 서열번호 103, 104 및 102의 핵산 서열을 가진다.DNA sequences encoding ACE-03-VH, ACE-03-VL and ACE-03-LC have the nucleic acid sequences of SEQ ID NOs: 103, 104 and 102, respectively.

실시예 21.5. ACE-04의 제조 Example 21.5. Preparation of ACE-04

ACE-04는 ACE-04-VH (VL-CL-VH-CH1) 및 ACE-04-VL (VH-CH1-VL-CL)과 같은 2개의 상이한 중쇄 및 2개의 동일한 경쇄 (ACE- 04-LC). 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다: ACE-04 has two different heavy chains such as ACE-04-VH (VL-CL-VH-CH1) and ACE-04-VL (VH-CH1-VL-CL) and two identical light chains (ACE-04-LC ). The amino acid sequences of these three types of polypeptides are as follows:

ACE-04-VH amino acid sequence: ACE-04-VH amino acid sequence :

QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGI ANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPAPELLGGPggggsQVQLQQSGAELARPGASVKMSCKAS GYTFTRYT MHWVKQRPGQGLEWIGY INPSRGYT NYNQKFKDKATLTTDKSSSTAYMQLSSLTSEDSAVYYC ARYYDDHYCLDY WGQGTTVTVSA[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC] (서열번호: 93) QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGI ANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS [ ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPAPELLGGP ggggs QVQLQQSGAELARPGASVKMSCKAS GYTFTRYT MHWVKQRPGQGLEWIGY INPSRGYT NYNQKFKDKATLTTDKSSSTAYMQLSSLTSEDSAVYYC ARYYDDHYCLDY WGQGTTVTVSA [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC] ( SEQ ID NO: 93)

ACE-04-VL amino acid sequence: ACE-04-VL amino acid sequence :

QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGR IIPILGI ANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPAPELLGGPggggsQIVLTQSPAIMSASPGEKVTMTCSAS SSVSY MNWYQQKSGTSPKRWIY DTS KLASGVPAHFRGSGSGTSYSLTISGMEAEDAATYYC QQWSSNPF TFGSGTKLEIN[RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC](서열번호: 94) QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGR IIPILGI ANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPAPELLGGP ggggs QIVLTQSPAIMSASPGEKVTMTCSAS SSVSY MNWYQQKSGTSPKRWIY DTS KLASGVPAHFRGSGSGTSYSLTISGMEAEDAATYYC QQWSSNPF TFGSGTKLEIN [RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] ( SEQ ID NO: 94)

ACE-04-LC amino acid sequence (anti-PD-L1 antibody light chain): ACE-04-LC amino acid sequence (anti-PD-L1 antibody light chain) :

QLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVL[RSVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] (서열번호: 95) QLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVL [RSVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] (SEQ ID NO: 95)

PD-L1을 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 키메라 OKT3 Fab 영역의 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 9에 나열되어있다: The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting PD-L1 and the second antigen binding domain monovalent Fv region of the chimeric OKT3 Fab region are listed in Table 9 below. have:

Fab region
(Anti-PD-L1)
Fab region
(Anti-PD-L1)
VH: QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (서열번호: 4)VH: QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (SEQ ID NO: 4) VL:
QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLR (서열번호: 8)
VL:
QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLR (SEQ ID NO: 8)
CDR H1: GGTFSSYA (서열번호: 5)CDR H1: GGTFSSYA (SEQ ID NO: 5) CDR L1: SSNIGAGYD (서열번호: 9)CDR L1: SSNIGAGYD (SEQ ID NO: 9) CDR H2: IIPILGIA (서열번호: 6)CDR H2: IIPILGIA (SEQ ID NO: 6) CDR L2: GDI (서열번호: 10)CDR L2: GDI (SEQ ID NO: 10) CDR H3: AKPRDGYNLVAFDI (서열번호: 7)CDR H3: AKPRDGYNLVAFDI (SEQ ID NO: 7) CDR L3: QSYDSSLSGGV (서열번호: 11)CDR L3: QSYDSSLSGGV (SEQ ID NO: 11) Fv region
(Anti-CD3)
Fv region
(Anti-CD3)
VH:
QVQLQQSGAELARPGASVKMSCKASGYTFTRYTMHWVKQRPGQGLEWIGYINPSRGYTNYNQKFKDKATLTTDKSSSTAYMQLSSLTSEDSAVYYCARYYDDHYCLDYWGQGTTVTVSA (서열번호: 85)
VH:
QVQLQQSGAELARPGASVKMSCKASGYTFTRYTMHWVKQRPGQGLEWIGYINPSRGYTNYNQKFKDKATLTTDKSSSTAYMQLSSLTSEDSAVYYCARYYDDHYCLDYWGQGTTVTVSA (SEQ ID NO: 85)
VL:
QIVLTQSPAIMSASPGEKVTMTCSASSSVSYMNWYQQKSGTSPKRWIYDTSKLASGVPAHFRGSGSGTSYSLTISGMEAEDAATYYCQQWSSNPFTFGSGTKLEINR (서열번호: 86)
VL:
QIVLTQSPAIMSASPGEKVTMTCSASSSVSYMNWYQQKSGTSPKRWIYDTSKLASGVPAHFRGSGSGTSYSLTISGMEAEDAATYYCQQWSSNPFTFGSGTKLEINR (SEQ ID NO: 86)
CDR H1: GYTFTRYT (서열번호: 78)CDR H1: GYTFTRYT (SEQ ID NO: 78) CDR L1: SSVSY (서열번호: 82)CDR L1: SSVSY (SEQ ID NO: 82) CDR H2: INPSRGYT (서열번호: 79)CDR H2: INPSRGYT (SEQ ID NO: 79) CDR L2: DTS (서열번호: 83)CDR L2: DTS (SEQ ID NO: 83) CDR H3: ARYYDDHYCLDY (서열번호: 80)CDR H3: ARYYDDHYCLDY (SEQ ID NO: 80) CDR L3: QQWSSNPF (서열번호: 87)CDR L3: QQWSSNPF (SEQ ID NO: 87)

ACE-04-VH, ACE-04-VL 및 ACE-04-LC를 암호화하는 DNA 서열은 각각 서열번호 105, 106 및 107의 핵산 서열을 가진다.DNA sequences encoding ACE-04-VH, ACE-04-VL and ACE-04-LC have nucleic acid sequences of SEQ ID NOs: 105, 106 and 107, respectively.

실시예 21.6. ACE-05의 제조 Example 21.6. Preparation of ACE-05

ACE-05는 2개의 상이한 중쇄 유사 사슬 (ACE-05-VH 및 ACE-05-VL) 및 2개의 동일한 경쇄 (ACE-05-LC)를 포함한다. ACE-05는 유연한 펩타이드 영역에 G4S 링커 (GGGS의 아미노산 서열, 서열번호: 112)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다: ACE-05 contains two different heavy chain-like chains (ACE-05-VH and ACE-05-VL) and two identical light chains (ACE-05-LC). ACE-05 contains a G4S linker (amino acid sequence of GGGS, SEQ ID NO: 112) in the flexible peptide region. The amino acid sequences of these three types of polypeptides are as follows:

ACE-05-VH amino acid sequence (서열번호: 213)ACE-05-VH amino acid sequence (SEQ ID NO: 213)

QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPPCPAPELLGGPggggsEVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFS QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPPCPAPELLGGP ggggs EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFS

ACE-05-VL amino acid sequence (서열번호: 214)ACE-05-VL amino acid sequence (SEQ ID NO: 214)

QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPPCPAPELLGGPggggsDIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPPCPAPELLGGP ggggs DIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR

ACE-05-LC amino acid sequence (서열번호: 157)ACE-05-LC amino acid sequence (SEQ ID NO: 157)

QLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVLR[SVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] QLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVLR [ SVAAPSVFIFPPSDEQLKSGTASVVCSKSVLTQLKSGTASVVCSKNFQLKSGTASVVCSKNFREADS

PD-L1을 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 CD3를 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 10에 열거되어있다: The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting PD-L1 and the second antigen binding domain monovalent Fv region targeting CD3 are listed in Table 10 below. have:

Fab region
(Anti-PD-L1)
Fab region
(Anti-PD-L1)
VH: QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (서열번호: 158)VH: QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (SEQ ID NO: 158) VL:
QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLR (서열번호: 170)
VL:
QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLR (SEQ ID NO: 170)
CDR H1: GGTFSSYA (서열번호: 159)CDR H1: GGTFSSYA (SEQ ID NO: 159) CDR L1: SSNIGAGYD (서열번호: 171)CDR L1: SSNIGAGYD (SEQ ID NO: 171) CDR H2: IIPILGIA (서열번호: 160)CDR H2: IIPILGIA (SEQ ID NO: 160) CDR L2: GDI (서열번호: 172)CDR L2: GDI (SEQ ID NO: 172) CDR H3: AKPRDGYNLVAFDI (서열번호: 161)CDR H3: AKPRDGYNLVAFDI (SEQ ID NO: 161) CDR L3: QSYDSSLSGGV (서열번호: 173)CDR L3: QSYDSSLSGGV (SEQ ID NO: 173) Fv region
(Anti-CD3)
Fv region
(Anti-CD3)
VH: EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (서열번호: 215)VH: EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (SEQ ID NO: 215) VL: DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (서열번호: 216)VL: DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (SEQ ID NO: 216)
CDR H1: GYSFTGYT (서열번호: 177)CDR H1: GYSFTGYT (SEQ ID NO: 177) CDR L1: QDIRNY (서열번호: 181)CDR L1: QDIRNY (SEQ ID NO: 181) CDR H2: INPYKGVS (서열번호: 178)CDR H2: INPYKGVS (SEQ ID NO: 178) CDR L2: YTS (서열번호: 182)CDR L2: YTS (SEQ ID NO: 182) CDR H3: ARSGYYGDSDWYFD (서열번호: 211)CDR H3: ARSGYYGDSDWYFD (SEQ ID NO: 211) CDR L3: QQGNTLPWT (서열번호: 207)CDR L3: QQGNTLPWT (SEQ ID NO: 207)

숙주 세포를 ACE-05-VH, ACE-05-VL 및 ACE-05-LC (0.5 : 0.5 : 1 w / w 비율)의 DNA로 형질 감염시키기 위해 삼중 형질 감염을 수행하였다. ACE-05-VH, ACE-05-VL 및 ACE-05-LC를 암호화하는 DNA 서열은 각각 서열번호 20, 21 및 22의 핵산 서열을 가진다.Triple transfection was performed to transfect host cells with DNA of ACE-05-VH, ACE-05-VL and ACE-05-LC (0.5: 0.5: 1 w / w ratio). DNA sequences encoding ACE-05-VH, ACE-05-VL and ACE-05-LC have nucleic acid sequences of SEQ ID NOs: 20, 21 and 22, respectively.

실시예 21.7. ACE-06의 제조 Example 21.7. Preparation of ACE-06

ACE-06은 2개의 상이한 중쇄 유사 사슬 (ACE-06-VH 및 ACE-06-VL) 및 2개의 동일한 경쇄 (ACE-06-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다: ACE-06 contains two different heavy chain-like chains (ACE-06-VH and ACE-06-VL) and two identical light chains (ACE-06-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-06-VH amino acid sequence (서열번호: 155)ACE-06-VH amino acid sequence (SEQ ID NO: 155)

QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPAPELLGGPggggsQVQLVESGGGVVQPGRSLRLSCAAS GFKFSGYG MHWVRQAPGKGLEWVAVI WYDGSKK YYVDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC ARQMGYWHFDL WGRGTLVTVSS QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPAPELLGGP ggggs QVQLVESGGGVVQPGRSLRLSCAAS GFKFSGYG MHWVRQAPGKGLEWVAVI WYDGSKK YYVDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC ARQMGYWHFDL WGRGTLVTVSS

ACE-06-VL amino acid sequence (서열번호: 156)ACE-06-VL amino acid sequence (SEQ ID NO: 156)

QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPAPELLGGPggggsEIVLTQSPATLSLSPGERATLSCRAS QSVSSY LAWYQQKPGQAPRLLIY DAS NRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYC QQRSNWPPLT FGGGTKVEIKR QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPAPELLGGP ggggs EIVLTQSPATLSLSPGERATLSCRAS QSVSSY LAWYQQKPGQAPRLLIY DAS NRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYC QQRSNWPPLT FGGGTKVEIKR

ACE-06-LC (amino acid sequence (서열번호: 157)ACE-06-LC (amino acid sequence (SEQ ID NO: 157)

QLVLTQPPSVSGAPGQRVTISCTGSQLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYDSSNIGAGYD VHWYQQLPGAAPKLLIYVHWYQQLPGAAPKLLIY GDIGDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCNRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGVQSYDSSLSGGV FGGGTKLTVLR[FGGGTKLTVLR[ SVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC]SVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC]

PD-L1을 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 CD3를 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 11에 열거되어있다: The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting PD-L1 and the second antigen binding domain monovalent Fv region targeting CD3 are listed in Table 11 below. have:

Fab region
(Anti-PD-L1)
Fab region
(Anti-PD-L1)
VH:
QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (서열번호: 158)
VH:
QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (SEQ ID NO: 158)
VL:
QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLR (서열번호: 170)
VL:
QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLR (SEQ ID NO: 170)
CDR H1: GGTFSSYA (서열번호: 159)CDR H1: GGTFSSYA (SEQ ID NO: 159) CDR L1: SSNIGAGYD (서열번호: 171)CDR L1: SSNIGAGYD (SEQ ID NO: 171) CDR H2: IIPILGIA (서열번호: 160)CDR H2: IIPILGIA (SEQ ID NO: 160) CDR L2: GDI (서열번호: 172)CDR L2: GDI (SEQ ID NO: 172) CDR H3: AKPRDGYNLVAFDI (서열번호: 161)CDR H3: AKPRDGYNLVAFDI (SEQ ID NO: 161) CDR L3: QSYDSSLSGGV (서열번호: 173)
CDR L3: QSYDSSLSGGV (SEQ ID NO: 173)
Fv region
(Anti-CD3)
Fv region
(Anti-CD3)
VH:
QVQLVESGGGVVQPGRSLRLSCAASGFKFSGYGMHWVRQAPGKGLEWVAVIWYDGSKKYYVDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARQMGYWHFDLWGRGTLVTVSS (서열번호: 162)
VH:
QVQLVESGGGVVQPGRSLRLSCAASGFKFSGYGMHWVRQAPGKGLEWVAVIWYDGSKKYYVDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARQMGYWHFDLWGRGTLVTVSS (SEQ ID NO: 162)
VL:
EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPPLTFGGGTKVEIKR (서열번호: 166)
VL:
EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPPLTFGGGTKVEIKR (SEQ ID NO: 166)
CDR H1: GFKFSGYG (서열번호: 163)CDR H1: GFKFSGYG (SEQ ID NO: 163) CDR L1:
QSVSSY (서열번호: 167)
CDR L1:
QSVSSY (SEQ ID NO: 167)
CDR H2: IWYDGSKK (서열번호: 271)CDR H2: IWYDGSKK (SEQ ID NO: 271) CDR L2: DAS (서열번호: 168)CDR L2: DAS (SEQ ID NO: 168) CDR H3: ARQMGYWHFDL (서열번호: 165)CDR H3: ARQMGYWHFDL (SEQ ID NO: 165) CDR L3: QQRSNWPPLT (서열번호: 169)CDR L3: QQRSNWPPLT (SEQ ID NO: 169)

실시예 21.8. ACE-07의 제조 Example 21.8. Preparation of ACE-07

ACE-07은 2개의 상이한 중쇄 유사 사슬 (ACE-07-VH 및 ACE-07-VL) 및 2개의 동일한 경쇄 (ACE-07-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다:ACE-07 contains two different heavy chain-like chains (ACE-07-VH and ACE-07-VL) and two identical light chains (ACE-07-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-07-VH amino acid sequence (서열번호: 174)ACE-07-VH amino acid sequence (SEQ ID NO: 174)

QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPAPELLGGPggggsEVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKCLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFDV WGQGTTLTVFS QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPAPELLGGP ggggs EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKCLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFDV WGQGTTLTVFS

ACE-07-VL amino acid sequence (서열번호: 175)ACE-07-VL amino acid sequence (SEQ ID NO: 175)

QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPAPELLGGPggggsDIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPW TFAGCTKLEIKR QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPAPELLGGP ggggs DIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPW TFAGCTKLEIKR

ACE-07-LC amino acid sequence (서열번호: 157)ACE-07-LC amino acid sequence (SEQ ID NO: 157)

QLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVLR[SVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] QLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVLR [ SVAAPSVFIFPPSDEQLKSGTASVVCSKSVLTQLKSGTASVVCSKNFQLKSGTASVVCSKNFREADS

PD-L1을 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 CD3를 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 12에 열거되어있다: The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting PD-L1 and the second antigen binding domain monovalent Fv region targeting CD3 are listed in Table 12 below. have:

Fab region
(Anti-PD-L1)
Fab region
(Anti-PD-L1)
VH:
QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (서열번호: 158)
VH:
QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (SEQ ID NO: 158)
VL:
QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLR (서열번호: 170)
VL:
QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLR (SEQ ID NO: 170)
CDR H1: GGTFSSYA (서열번호: 159)
CDR H1: GGTFSSYA (SEQ ID NO: 159)
CDR L1: SSNIGAGYD (서열번호: 171)
CDR L1: SSNIGAGYD (SEQ ID NO: 171)
CDR H2: IIPILGIA (서열번호: 160)CDR H2: IIPILGIA (SEQ ID NO: 160) CDR L2: GDI (서열번호: 172)CDR L2: GDI (SEQ ID NO: 172) CDR H3: AKPRDGYNLVAFDI (서열번호: 161)CDR H3: AKPRDGYNLVAFDI (SEQ ID NO: 161) CDR L3: QSYDSSLSGGV (서열번호: 173)CDR L3: QSYDSSLSGGV (SEQ ID NO: 173) Fv region
(Anti-CD3)
Fv region
(Anti-CD3)
VH: EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKCLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (서열번호: 176)VH: EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKCLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (SEQ ID NO: 176) VL: DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGCTKLEIKR (서열번호: 180)VL: DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGCTKLEIKR (SEQ ID NO: 180)
CDR H1: GYSFTGYT (서열번호: 177)CDR H1: GYSFTGYT (SEQ ID NO: 177) CDR L1: QDIRNY (서열번호: 181)CDR L1: QDIRNY (SEQ ID NO: 181) CDR H2: INPYKGVS (서열번호: 178)CDR H2: INPYKGVS (SEQ ID NO: 178) CDR L2: YTS (서열번호: 182)CDR L2: YTS (SEQ ID NO: 182) CDR H3: ARSGYYGDSDWYFDV (서열번호: 179)CDR H3: ARSGYYGDSDWYFDV (SEQ ID NO: 179) CDR L3: QQGNTLPW (서열번호: 183)CDR L3: QQGNTLPW (SEQ ID NO: 183)

실시예 21.9. ACE-08의 제조 Example 21.9. Preparation of ACE-08

ACE-08은 2개의 상이한 중쇄 유사 사슬 (ACE-08-VH 및 ACE-08-VL) 및 2개의 동일한 경쇄 (ACE-08-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다:ACE-08 contains two different heavy chain-like chains (ACE-08-VH and ACE-08-VL) and two identical light chains (ACE-08-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-08-VH amino acid sequence (서열번호: 184)ACE-08-VH amino acid sequence (SEQ ID NO: 184)

QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPAPELLGGPggggsEVQLVESGGGLVQPGKSLKLSCEAS GFTFSGYG MHWVRQAPGRCLESVAY ITSSSINI KYADAVKGRFTVSRDNAKNLLFLQMNILKSEDTAMYYC ARFDWDKNY WGQGTMVTVSS QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPAPELLGGP ggggs EVQLVESGGGLVQPGKSLKLSCEAS GFTFSGYG MHWVRQAPGRCLESVAY ITSSSINI KYADAVKGRFTVSRDNAKNLLFLQMNILKSEDTAMYYC ARFDWDKNY WGQGTMVTVSS

ACE-08-VL amino acid sequence (서열번호: 185)ACE-08-VL amino acid sequence (SEQ ID NO: 185)

QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPAPELLGGPggggsQMTQSPSSLPASLGDRVTINCQAS QDISNY LNWYQQKPGKAPKLLIY YTN KLADGVPSRFSGSGSGRDSSFTISSLESEDIGSYYC QQYYNYPWT FGPCTKLEIKR QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPAPELLGGP ggggs QMTQSPSSLPASLGDRVTINCQAS QDISNY LNWYQQKPGKAPKLLIY YTN KLADGVPSRFSGSGSGRDSSFTISSLESEDIGSYYC QQYYNYPWT FGPCTKLEIKR

ACE-08-LC amino acid sequence (서열번호: 157)ACE-08-LC amino acid sequence (SEQ ID NO: 157)

QLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVLR[SVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] QLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVLR [ SVAAPSVFIFPPSDEQLKSGTASVVCSKSVLTQLKSGTASVVCSKNFQLKSGTASVVCSKNFREADS

PD-L1을 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 CD3를 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 13에 열거되어있다: The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting PD-L1 and the second antigen binding domain monovalent Fv region targeting CD3 are listed in Table 13 below. have:

Fab region
(Anti-PD-L1)
Fab region
(Anti-PD-L1)
VH: QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (서열번호: 158)VH: QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (SEQ ID NO: 158) VL:
QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLR (서열번호: 170)
VL:
QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLR (SEQ ID NO: 170)
CDR H1: GGTFSSYA (서열번호: 159)CDR H1: GGTFSSYA (SEQ ID NO: 159) CDR L1: SSNIGAGYD (서열번호: 171)
CDR L1: SSNIGAGYD (SEQ ID NO: 171)
CDR H2: IIPILGIA (서열번호: 160)CDR H2: IIPILGIA (SEQ ID NO: 160) CDR L2: GDI (서열번호: 172)CDR L2: GDI (SEQ ID NO: 172) CDR H3: AKPRDGYNLVAFDI (서열번호: 161)CDR H3: AKPRDGYNLVAFDI (SEQ ID NO: 161) CDR L3: QSYDSSLSGGV (서열번호: 173)CDR L3: QSYDSSLSGGV (SEQ ID NO: 173) Fv region
(Anti-CD3)
Fv region
(Anti-CD3)
VH:
EVQLVESGGGLVQPGKSLKLSCEASGFTFSGYGMHWVRQAPGRCLESVAYITSSSINIKYADAVKGRFTVSRDNAKNLLFLQMNILKSEDTAMYYCARFDWDKNYWGQGTMVTVSS (서열번호: 186)
VH:
EVQLVESGGGLVQPGKSLKLSCEASGFTFSGYGMHWVRQAPGRCLESVAYITSSSINIKYADAVKGRFTVSRDNAKNLLFLQMNILKSEDTAMYYCARFDWDKNYWGQGTMVTVSS (SEQ ID NO: 186)
VL: QMTQSPSSLPASLGDRVTINCQASQDISNYLNWYQQKPGKAPKLLIYYTNKLADGVPSRFSGSGSGRDSSFTISSLESEDIGSYYCQQYYNYPWTFGPCTKLEIKR (서열번호: 190)VL: QMTQSPSSLPASLGDRVTINCQASQDISNYLNWYQQKPGKAPKLLIYYTNKLADGVPSRFSGSGSGRDSSFTISSLESEDIGSYYCQQYYNYPWTFGPCTKLEIKR (SEQ ID NO: 190)
CDR H1: GFTFSGYG (서열번호: 187)CDR H1: GFTFSGYG (SEQ ID NO: 187) CDR L1: QDISNY (서열번호: 191)
CDR L1: QDISNY (SEQ ID NO: 191)
CDR H2: ITSSSINI (서열번호: 188)CDR H2: ITSSSINI (SEQ ID NO: 188) CDR L2: YTN (서열번호: 192)CDR L2: YTN (SEQ ID NO: 192) CDR H3: ARFDWDKNY (서열번호: 189)CDR H3: ARFDWDKNY (SEQ ID NO: 189) CDR L3: QQYYNYPWT (서열번호: 193)CDR L3: QQYYNYPWT (SEQ ID NO: 193)

실시예 21.10. ACE-09의 제조Example 21.10. Preparation of ACE-09

ACE-09는 두 개의 다른 중쇄 유사 사슬 (ACE-09-VH 및 ACE-09-VL) 및 두 개의 동일한 경쇄 (ACE-09-LC)를 포함한다. ACE-05와 비교하여 ACE-09는 유연한 펩타이드 영역에 G4S 링커 (GGGS의 아미노산 서열)를 포함하지 않는다. 이 세 가지 유형의 폴리 펩타이드의 아미노산 서열은 다음과 같다: ACE-09 contains two different heavy chain-like chains (ACE-09-VH and ACE-09-VL) and two identical light chains (ACE-09-LC). Compared to ACE-05, ACE-09 does not contain a G4S linker (amino acid sequence of GGGS) in the flexible peptide region. The amino acid sequences of these three types of polypeptides are as follows:

ACE-09-VH amino acid sequence (without the G4S linker): ACE-09-VH amino acid sequence (without the G4S linker) :

QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPAPELLGGP EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYTMN WVKQSHGKNLEWMG LINPYKGVST YNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCAR SGYYGDSDWYFDV WGQGTTLTVFS (서열번호: 96) QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPAPELLGGP EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYTMN WVKQSHGKNLEWMG LINPYKGVST YNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCAR SGYYGDSDWYFDV WGQGTTLTVFS (SEQ ID NO: 96)

ACE-09-VL amino acid sequence (without the G4S linker): ACE-09-VL amino acid sequence (without the G4S linker) :

QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPAPELLGGP DIQMTQTTSSLSASLGDRVTISC RASQDIRNYLN WYQQKPDGTVKLLIY YTSRLHS GVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR (서열번호: 97) QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPAPELLGGP DIQMTQTTSSLSASLGDRVTISC RASQDIRNYLN WYQQKPDGTVKLLIY YTSRLHS GVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR (SEQ ID NO: 97)

ACE-09-LC amino acid sequence (anti-PD-L1 antibody light chain): QLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVL[RSVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] (서열번호: 95) ACE-09-LC amino acid sequence (anti-PD-L1 antibody light chain): QLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVL [RSVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] ( SEQ ID NO: 95)

PD-L1을 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 CD3를 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 14에 열거되어있다: The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting PD-L1 and the second antigen binding domain monovalent Fv region targeting CD3 are listed in Table 14 below. have:

Fab region
(Anti-PD-L1)
Fab region
(Anti-PD-L1)
VH: QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (서열번호: 4)VH: QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (SEQ ID NO: 4) VL:
QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLR (서열번호: 8)
VL:
QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLR (SEQ ID NO: 8)
CDR H1: GGTFSSYA (서열번호: 5)CDR H1: GGTFSSYA (SEQ ID NO: 5) CDR L1: SSNIGAGYD (서열번호: 9)CDR L1: SSNIGAGYD (SEQ ID NO: 9) CDR H2: IIPILGIA (서열번호: 6)CDR H2: IIPILGIA (SEQ ID NO: 6) CDR L2: GDI (서열번호: 10)CDR L2: GDI (SEQ ID NO: 10) CDR H3: AKPRDGYNLVAFDI (서열번호: 7)CDR H3: AKPRDGYNLVAFDI (SEQ ID NO: 7) CDR L3: QSYDSSLSGGV (서열번호: 11)CDR L3: QSYDSSLSGGV (SEQ ID NO: 11) Fv region
(Anti-CD3)
Fv region
(Anti-CD3)
VH:
EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (서열번호: 12)
VH:
EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (SEQ ID NO: 12)
VL:
DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (서열번호: 16)
VL:
DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (SEQ ID NO: 16)
CDR H1: GYSFTGYTMN (서열번호: 13)CDR H1: GYSFTGYTMN (SEQ ID NO: 13) CDR L1: RASQDIRNYLN (서열번호: 17)CDR L1: RASQDIRNYLN (SEQ ID NO: 17) CDR H2: LINPYKGVST (서열번호: 14)CDR H2: LINPYKGVST (SEQ ID NO: 14) CDR L2: YTSRLHS (서열번호: 18)CDR L2: YTSRLHS (SEQ ID NO: 18) CDR H3: SGYYGDSDWYFDV (서열번호: 15)CDR H3: SGYYGDSDWYFDV (SEQ ID NO: 15) CDR L3: QQGNTLPWT (서열번호: 19)CDR L3: QQGNTLPWT (SEQ ID NO: 19)

ACE-09-VH, ACE-09-VL 및 ACE-09-LC를 암호화하는 DNA 서열은 각각 서열번호 108, 109 및 107의 핵산 서열을 가진다.The DNA sequences encoding ACE-09-VH, ACE-09-VL and ACE-09-LC have the nucleic acid sequences of SEQ ID NOs: 108, 109 and 107, respectively.

실시예 21.11. ACE-10의 제조Example 21.11. Preparation of ACE-10

ACE-10은 2개의 상이한 중쇄 유사 사슬 (ACE-10-VH 및 ACE-10-VL) 및 2개의 동일한 경쇄 (ACE-10-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다: ACE-10 contains two different heavy chain-like chains (ACE-10-VH and ACE-10-VL) and two identical light chains (ACE-10-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-10-VH amino acid sequence (서열번호: 23)ACE-10-VH amino acid sequence (SEQ ID NO: 23)

QVQLQQPGAELVKPGASVKMSCKAS GYTFTSYN MHWVKQTPGRGLEWIGA IYPGNGDT SYNQKFKGKATLTADKSSSTAYMQLSSLTSEDSAVYYC ARSTYYGGDWYFNV WGAGTTVTVSA[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPAPELLGGPggggsEVQLQQSGPELVKPGPSMKISCKAS GYSFTGYTMN WVKQSHGKNLEWMG LINPYKGVST YNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFDV WGQGTTLTVFS QVQLQQPGAELVKPGASVKMSCKAS GYTFTSYN MHWVKQTPGRGLEWIGA IYPGNGDT SYNQKFKGKATLTADKSSSTAYMQLSSLTSEDSAVYYC ARSTYYGGDWYFNV WGAGTTVTVSA [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPAPELLGGP ggggs EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYTMN WVKQSHGKNLEWMG LINPYKGVST YNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFDV WGQGTTLTVFS

ACE-10-VL amino acid sequence (서열번호: 24)ACE-10-VL amino acid sequence (SEQ ID NO: 24)

QVQLQQPGAELVKPGASVKMSCKAS GYTFTSYN MHWVKQTPGRGLEWIGA IYPGNGDT SYNQKFKGKATLTADKSSSTAYMQLSSLTSEDSAVYYC ARSTYYGGDWYFNV WGAGTTVTVSA[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPAPELLGGPggggsDIQMTQTTSSLSASLGDRVTISC RASQDIRNYLN WYQQKPDGTVKLLIY YTSRLHS GVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR QVQLQQPGAELVKPGASVKMSCKAS GYTFTSYN MHWVKQTPGRGLEWIGA IYPGNGDT SYNQKFKGKATLTADKSSSTAYMQLSSLTSEDSAVYYC ARSTYYGGDWYFNV WGAGTTVTVSA [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPAPELLGGP ggggs DIQMTQTTSSLSASLGDRVTISC RASQDIRNYLN WYQQKPDGTVKLLIY YTSRLHS GVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR

ACE-10-LC amino acid sequence (서열번호: 25)ACE-10-LC amino acid sequence (SEQ ID NO: 25)

QIVLSQSPAILSASPGEKVTMTCRAS SSVSY IHWFQQKPGSSPKPWIY ATS NLASGVPVRFSGSGSGTSYSLTISRVEAEDAATYYC QQWTSNPPT FGGGTKLEIK[RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] QIVLSQSPAILSASPGEKVTMTCRAS SSVSY IHWFQQKPGSSPKPWIY ATS NLASGVPVRFSGSGSGTSYSLTISRVEAEDAATYYC QQWTSNPPT FGGGTKLEIK [ RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPYPREAKVQWKVDTLSKVQWKLSKDSKSKLSVDS

CD20을 표적으로하는 2가 Fab 영역 및 CD3을 표적으로하는 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 아래 표 15에 나열되어 있다: The VH and VL amino acid sequences and CDR sequences therein for the bivalent Fab region targeting CD20 and the monovalent Fv region targeting CD3 are listed in Table 15 below:

Fab region
(Anti-CD20)
Fab region
(Anti-CD20)
VH: QVQLQQPGAELVKPGASVKMSCKASGYTFTSYNMHWVKQTPGRGLEWIGAIYPGNGDTSYNQKFKGKATLTADKSSSTAYMQLSSLTSEDSAVYYCARSTYYGGDWYFNVWGAGTTVTVSA (서열번호: 26)VH: QVQLQQPGAELVKPGASVKMSCKASGYTFTSYNMHWVKQTPGRGLEWIGAIYPGNGDTSYNQKFKGKATLTADKSSSTAYMQLSSLTSEDSAVYYCARSTYYGGDWYFNVWGAGTTVTVSA (SEQ ID NO: 26) VL:
QIVLSQSPAILSASPGEKVTMTCRASSSVSYIHWFQQKPGSSPKPWIYATSNLASGVPVRFSGSGSGTSYSLTISRVEAEDAATYYCQQWTSNPPTFGGGTKLEIKR (서열번호: 30)
VL:
QIVLSQSPAILSASPGEKVTMTCRASSSVSYIHWFQQKPGSSPKPWIYATSNLASGVPVRFSGSGSGTSYSLTISRVEAEDAATYYCQQWTSNPPTFGGGTKLEIKR (SEQ ID NO: 30)
CDR H1: GYTFTSYN (서열번호: 27)CDR H1: GYTFTSYN (SEQ ID NO: 27) CDR L1: SSVSY (서열번호: 31)CDR L1: SSVSY (SEQ ID NO: 31) CDR H2: IYPGNGDT (서열번호: 28)CDR H2: IYPGNGDT (SEQ ID NO: 28) CDR L2: ATS (서열번호: 32)CDR L2: ATS (SEQ ID NO: 32) CDR H3: ARSTYYGGDWYFNV (서열번호: 29)CDR H3: ARSTYYGGDWYFNV (SEQ ID NO: 29) CDR L3: QQWTSNPPT (서열번호: 33)CDR L3: QQWTSNPPT (SEQ ID NO: 33) Fv region
(Anti-CD3)
Fv region
(Anti-CD3)
VH:
EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (서열번호: 12)
VH:
EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (SEQ ID NO: 12)
VL:
DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (서열번호: 16)
VL:
DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (SEQ ID NO: 16)
CDR H1: GYSFTGYTMN (서열번호: 13)CDR H1: GYSFTGYTMN (SEQ ID NO: 13) CDR L1: RASQDIRNYLN (서열번호: 17)CDR L1: RASQDIRNYLN (SEQ ID NO: 17) CDR H2: LINPYKGVST (서열번호: 14)CDR H2: LINPYKGVST (SEQ ID NO: 14) CDR L2: YTSRLHS (서열번호: 18)CDR L2: YTSRLHS (SEQ ID NO: 18) CDR H3: SGYYGDSDWYFDV (서열번호: 15)CDR H3: SGYYGDSDWYFDV (SEQ ID NO: 15) CDR L3: QQGNTLPWT (서열번호: 19)CDR L3: QQGNTLPWT (SEQ ID NO: 19)

ACE-10-VH, ACE-10-VL 및 ACE-10-LC를 암호화하는 DNA 서열은 각각 서열번호 34, 35 및 36의 핵산 서열을 가진다.DNA sequences encoding ACE-10-VH, ACE-10-VL and ACE-10-LC have nucleic acid sequences of SEQ ID NOs: 34, 35 and 36, respectively.

실시예 21.12. ACE-11의 제조Example 21.12. Preparation of ACE-11

ACE-11은 ACE-05 및 ACE-10과 동일한 전체 구조를 가지며, 두 개의 다른 중쇄 유사 사슬 (ACE-11-VH 및 ACE-11-VL) 및 두 개의 동일한 경쇄 (ACE-11-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다: ACE-11 has the same overall structure as ACE-05 and ACE-10, and has two different heavy chain-like chains (ACE-11-VH and ACE-11-VL) and two identical light chains (ACE-11-LC). Includes. The amino acid sequences of these three types of polypeptides are as follows:

ACE-11-VH amino acid sequence (서열번호: 37)ACE-11-VH amino acid sequence (SEQ ID NO: 37)

QVQLKQSGPGLVQPSQSLSITCTVS GFSLTNYG VHWVRQSPGKGLEWLGV IWSGGNT DYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYC ARALTYYDYEFAY WGQGTLVTVSA[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPAPELLGGPggggsEVQLQQSGPELVKPGPSMKISCKAS GYSFTGYTMN WVKQSHGKNLEWMG LINPYKGVST YNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFDV WGQGTTLTVFS QVQLKQSGPGLVQPSQSLSITCTVS GFSLTNYG VHWVRQSPGKGLEWLGV IWSGGNT DYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYC ARALTYYDYEFAY WGQGTLVTVSA [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPAPELLGGP ggggs EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYTMN WVKQSHGKNLEWMG LINPYKGVST YNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFDV WGQGTTLTVFS

ACE-11-VL amino acid sequence (서열번호: 38)ACE-11-VL amino acid sequence (SEQ ID NO: 38)

QVQLKQSGPGLVQPSQSLSITCTVS GFSLTNYG VHWVRQSPGKGLEWLGV IWSGGNT DYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYC ARALTYYDYEFAY WGQGTLVTVSA[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPAPELLGGPggggsDIQMTQTTSSLSASLGDRVTISC RASQDIRNYLN WYQQKPDGTVKLLIY YTSRLHS GVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR QVQLKQSGPGLVQPSQSLSITCTVS GFSLTNYG VHWVRQSPGKGLEWLGV IWSGGNT DYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYC ARALTYYDYEFAY WGQGTLVTVSA [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPAPELLGGP ggggs DIQMTQTTSSLSASLGDRVTISC RASQDIRNYLN WYQQKPDGTVKLLIY YTSRLHS GVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR

ACE-11-LC amino acid sequence (서열번호: 39)ACE-11-LC amino acid sequence (SEQ ID NO: 39)

DILLTQSPVILSVSPGERVSFSCRASDILLTQSPVILSVSPGERVSFSCRAS QSIGTNQSIGTN IHWYQQRTNGSPRLLIKIHWYQQRTNGSPRLLIK YASYAS ESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYC QQNNNWPTTQQNNNWPTT FGAGTKLELK[FGAGTKLELK[ RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC]RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC]

EGFR을 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 CD3를 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 16에 열거되어있다: The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting EGFR and the second antigen binding domain monovalent Fv region targeting CD3 are listed in Table 16 below:

Fab region
(Anti-EGFR)
Fab region
(Anti-EGFR)
VH: QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSA (서열번호: 40)VH: QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSA (SEQ ID NO: 40) VL:
DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELKR (서열번호: 44)
VL:
DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELKR (SEQ ID NO: 44)
CDR H1: GFSLTNYG (서열번호: 41)CDR H1: GFSLTNYG (SEQ ID NO: 41) CDR L1: QSIGTN (서열번호: 45)CDR L1: QSIGTN (SEQ ID NO: 45) CDR H2: IWSGGNT (서열번호: 42) CDR H2: IWSGGNT (SEQ ID NO: 42) CDR L2: YAS (서열번호: 46)CDR L2: YAS (SEQ ID NO: 46) CDR H3: ARALTYYDYEFAY (서열번호: 43) CDR H3: ARALTYYDYEFAY (SEQ ID NO: 43) CDR L3: QQNNNWPTT (서열번호: 47)CDR L3: QQNNNWPTT (SEQ ID NO: 47) Fv region
(Anti-CD3)
Fv region
(Anti-CD3)
VH:
EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (서열번호: 12)
VH:
EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (SEQ ID NO: 12)
VL:
DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (서열번호: 16)
VL:
DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (SEQ ID NO: 16)
CDR H1: GYSFTGYTMN (서열번호: 13)CDR H1: GYSFTGYTMN (SEQ ID NO: 13) CDR L1: RASQDIRNYLN (서열번호: 17)CDR L1: RASQDIRNYLN (SEQ ID NO: 17) CDR H2: LINPYKGVST (서열번호: 14)CDR H2: LINPYKGVST (SEQ ID NO: 14) CDR L2: YTSRLHS (서열번호: 18)CDR L2: YTSRLHS (SEQ ID NO: 18) CDR H3: SGYYGDSDWYFDV (서열번호: 15)CDR H3: SGYYGDSDWYFDV (SEQ ID NO: 15) CDR L3: QQGNTLPWT (서열번호: 19)CDR L3: QQGNTLPWT (SEQ ID NO: 19)

ACE-11-VH, ACE-11-VL 및 ACE-11-LC를 암호화하는 DNA 서열은 각각 서열번호 48, 49 및 50의 핵산 서열을 가진다.DNA sequences encoding ACE-11-VH, ACE-11-VL and ACE-11-LC have nucleic acid sequences of SEQ ID NOs: 48, 49 and 50, respectively.

실시예 21.13. ACE-12의 제조Example 21.13. Preparation of ACE-12

ACE-12는 GGGGSGGGGS (서열번호: 113) 및 GGSGGGGSG (서열번호: 114)의 아미노산 서열을 갖는 G4S 링커를 포함하는 반면, ACE-05는 유연한 펩티드 영역의 GGGGS 아미노산 서열을 갖는 G4S 링커를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다: ACE-12 comprises a G4S linker with the amino acid sequence of GGGGSGGGGS (SEQ ID NO: 113) and GGSGGGGSG (SEQ ID NO: 114), while ACE-05 comprises a G4S linker with the GGGGS amino acid sequence of the flexible peptide region. The amino acid sequences of these three types of polypeptides are as follows:

ACE-12-VH amino acid sequence (with 10 residues GGGGSGGGGS): ACE-12-VH amino acid sequence (with 10 residues GGGGSGGGGS) :

QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPAPELLGGPggggsggggsEVQLQQSGPELVKPGPSMKISCKAS GYSFTGYTMN WVKQSHGKNLEWMG LINPYKGVST YNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCAR SGYYGDSDWYFDV WGQGTTLTVFS (서열번호: 98) QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPAPELLGGP ggggsggggs EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYTMN WVKQSHGKNLEWMG LINPYKGVST YNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCAR SGYYGDSDWYFDV WGQGTTLTVFS (SEQ ID NO: 98)

ACE-12-VL amino acid sequence (with 9 residues GGSGGGGSG): ACE-12-VL amino acid sequence (with 9 residues GGSGGGGSG) :

QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPAPELLGGPggsggggsgDIQMTQTTSSLSASLGDRVTISC RASQDIRNYLN WYQQKPDGTVKLLIY YTSRLHS GVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR (서열번호: 99) QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPAPELLGGP ggsggggsg DIQMTQTTSSLSASLGDRVTISC RASQDIRNYLN WYQQKPDGTVKLLIY YTSRLHS GVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR (SEQ ID NO: 99)

ACE-12-LC amino acid sequence (anti-PD-L1 antibody light chain): ACE-12-LC amino acid sequence (anti-PD-L1 antibody light chain) :

QLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVL[ RSVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] (서열번호: 95) QLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVL [RSVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] (SEQ ID NO: 95)

PD-L1을 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 UCHT1의 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 17에 나열되어있다: The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting PD-L1 and the second antigen binding domain monovalent Fv region of UCHT1 are listed in Table 17 below:

Fab region
(Anti-PD-L1)
Fab region
(Anti-PD-L1)
VH: QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (서열번호: 4)VH: QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (SEQ ID NO: 4) VL:
QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLR (서열번호: 8)
VL:
QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLR (SEQ ID NO: 8)
CDR H1: GGTFSSYA (서열번호: 5)CDR H1: GGTFSSYA (SEQ ID NO: 5) CDR L1: SSNIGAGYD (서열번호: 9)CDR L1: SSNIGAGYD (SEQ ID NO: 9) CDR H2: IIPILGIA (서열번호: 6)CDR H2: IIPILGIA (SEQ ID NO: 6) CDR L2: GDI (서열번호: 10)CDR L2: GDI (SEQ ID NO: 10) CDR H3: AKPRDGYNLVAFDI (서열번호: 7)CDR H3: AKPRDGYNLVAFDI (SEQ ID NO: 7) CDR L3: QSYDSSLSGGV (서열번호: 11)CDR L3: QSYDSSLSGGV (SEQ ID NO: 11) Fv region
(Anti-CD3)
Fv region
(Anti-CD3)
VH:
EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (서열번호: 12)
VH:
EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (SEQ ID NO: 12)
VL:
DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (서열번호: 16)
VL:
DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (SEQ ID NO: 16)
CDR H1: GYSFTGYTMN (서열번호: 13)CDR H1: GYSFTGYTMN (SEQ ID NO: 13) CDR L1: RASQDIRNYLN (서열번호: 17)CDR L1: RASQDIRNYLN (SEQ ID NO: 17) CDR H2: LINPYKGVST (서열번호: 14)CDR H2: LINPYKGVST (SEQ ID NO: 14) CDR L2: YTSRLHS (서열번호: 18)CDR L2: YTSRLHS (SEQ ID NO: 18) CDR H3: SGYYGDSDWYFDV (서열번호: 15)CDR H3: SGYYGDSDWYFDV (SEQ ID NO: 15) CDR L3: QQGNTLPWT (서열번호: 19)CDR L3: QQGNTLPWT (SEQ ID NO: 19)

ACE-12-VH, ACE-12-VL 및 ACE-12-LC를 암호화하는 DNA 서열은 각각 서열번호 110, 111 및 107의 핵산 서열을 가진다.DNA sequences encoding ACE-12-VH, ACE-12-VL and ACE-12-LC have nucleic acid sequences of SEQ ID NOs: 110, 111 and 107, respectively.

실시예 21.14. ACE-13의 제조Example 21.14. Preparation of ACE-13

ACE-13은 두 개의 다른 중쇄 유사 사슬 (ACE-13-VH 및 ACE-13-VL) 및 두 개의 동일한 경쇄 (ACE-13-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다: ACE-13 contains two different heavy chain-like chains (ACE-13-VH and ACE-13-VL) and two identical light chains (ACE-13-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-13-VH amino acid sequence (서열번호: 194)ACE-13-VH amino acid sequence (SEQ ID NO: 194)

QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPAPELLGGPggggsQVQLVESGGGVVQPGRSLRLSCAAS GFTFLRYA MHWVRQAPGKGLEWVAV ISYDGRYK YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC TTTTFDS WGQGTLVTVSS QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPAPELLGGP ggggs QVQLVESGGGVVQPGRSLRLSCAAS GFTFLRYA MHWVRQAPGKGLEWVAV ISYDGRYK YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC TTTTFDS WGQGTLVTVSS

ACE-13-VL amino acid sequence (서열번호: 195)ACE-13-VL amino acid sequence (SEQ ID NO: 195)

QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPAPELLGGPggggsDIVMTQTPLSLPVTPGEAASISCRSS QSLLDSEDGNTY LDWYLQKPGQSPQLLIY TLS HRASGVPDRFSGSGSGTDFTLEISRVEAEDVGVYYC MQRRDFPFT FGQGTKVDIKR QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPAPELLGGP ggggs DIVMTQTPLSLPVTPGEAASISCRSS QSLLDSEDGNTY LDWYLQKPGQSPQLLIY TLS HRASGVPDRFSGSGSGTDFTLEISRVEAEDVGVYYC MQRRDFPFT FGQGTKVDIKR

ACE-13-LC amino acid sequence (서열번호: 157)ACE-13-LC amino acid sequence (SEQ ID NO: 157)

QLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVLR[SVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] QLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVLR [ SVAAPSVFIFPPSDEQLKSGTASVVCSKSVLTQLKSGTASVVCSKNFQLKSGTASVVCSKNFREADS

PD-L1을 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 PD-1를 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 18에 열거되어있다: The VH and VL amino acid sequences and CDR sequences therein for the first antigen-binding domain bivalent Fab region targeting PD-L1 and the second antigen-binding domain monovalent Fv region targeting PD-1 are shown in Table 18 below. It is listed:

Fab region
(Anti-PD-L1)
Fab region
(Anti-PD-L1)
VH: QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (서열번호: 158)VH: QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (SEQ ID NO: 158) VL:
QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLR (서열번호: 170)
VL:
QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLR (SEQ ID NO: 170)
CDR H1: GGTFSSYA (서열번호: 159)CDR H1: GGTFSSYA (SEQ ID NO: 159) CDR L1: SSNIGAGYD (서열번호: 171)CDR L1: SSNIGAGYD (SEQ ID NO: 171) CDR H2: IIPILGIA (서열번호: 160)CDR H2: IIPILGIA (SEQ ID NO: 160) CDR L2: GDI (서열번호: 172)CDR L2: GDI (SEQ ID NO: 172) CDR H3: AKPRDGYNLVAFDI (서열번호: 161)CDR H3: AKPRDGYNLVAFDI (SEQ ID NO: 161) CDR L3: QSYDSSLSGGV (서열번호: 173)CDR L3: QSYDSSLSGGV (SEQ ID NO: 173) Fv region
(Anti-PD-1)
Fv region
(Anti-PD-1)
VH: QVQLVESGGGVVQPGRSLRLSCAASGFTFLRYAMHWVRQAPGKGLEWVAVISYDGRYKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCTTTTFDSWGQGTLVTVSS (서열번호: 196)VH: QVQLVESGGGVVQPGRSLRLSCAASGFTFLRYAMHWVRQAPGKGLEWVAVISYDGRYKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCTTTTFDSWGQGTLVTVSS (SEQ ID NO: 196) VL:
DIVMTQTPLSLPVTPGEAASISCRSSQSLLDSEDGNTYLDWYLQKPGQSPQLLIYTLSHRASGVPDRFSGSGSGTDFTLEISRVEAEDVGVYYCMQRRDFPFTFGQGTKVDIKR (서열번호: 200)
VL:
DIVMTQTPLSLPVTPGEAASISCRSSQSLLDSEDGNTYLDWYLQKPGQSPQLLIYTLSHRASGVPDRFSGSGSGTDFTLEISRVEAEDVGVYYCMQRRDFPFTFGQGTKVDIKR (SEQ ID NO: 200)
CDR H1: GFTFLRYA (서열번호: 197)CDR H1: GFTFLRYA (SEQ ID NO: 197) CDR L1: QSLLDSEDGNTY (서열번호: 201)CDR L1: QSLLDSEDGNTY (SEQ ID NO: 201) CDR H2: ISYDGRYK (서열번호: 198)CDR H2: ISYDGRYK (SEQ ID NO: 198) CDR L2: TLS (서열번호: 202)CDR L2: TLS (SEQ ID NO: 202) CDR H3: TTTTFDS (서열번호: 199)CDR H3: TTTTFDS (SEQ ID NO: 199) CDR L3: MQRRDFPFT (서열번호: 203)CDR L3: MQRRDFPFT (SEQ ID NO: 203)

실시예 21.15. ACE-14의 제조Example 21.15. Preparation of ACE-14

ACE-14는 두 개의 다른 중쇄 유사 사슬 (ACE-14-VH 및 ACE-14-VL) 및 두 개의 동일한 경쇄 (ACE-14-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다: ACE-14 contains two different heavy chain-like chains (ACE-14-VH and ACE-14-VL) and two identical light chains (ACE-14-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-14-VH amino acid sequence (서열번호: 204)ACE-14-VH amino acid sequence (SEQ ID NO: 204)

QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPAPELLGGPggggsggggsEVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKCLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFDV WGQGTTLTVFS QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPAPELLGGP ggggsggggs EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKCLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFDV WGQGTTLTVFS

ACE-14-VL amino acid sequence (서열번호: 205)ACE-14-VL amino acid sequence (SEQ ID NO: 205)

QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPAPELLGGPggggsggggsDIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FACGTKLEIKR QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPAPELLGGP ggggsggggs DIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FACGTKLEIKR

ACE-14-LC amino acid sequence (서열번호: 157)ACE-14-LC amino acid sequence (SEQ ID NO: 157)

QLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVLR[SVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] QLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVLR [ SVAAPSVFIFPPSDEQLKSGTASVVCSKSVLTQLKSGTASVVCSKNFQLKSGTASVVCSKNFREADS

PD-L1을 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 CD3를 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 19에 열거되어있다: The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting PD-L1 and the second antigen binding domain monovalent Fv region targeting CD3 are listed in Table 19 below. Has :

Fab region
(Anti-PD-L1)
Fab region
(Anti-PD-L1)
VH: QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (서열번호: 158)VH: QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (SEQ ID NO: 158) VL:
QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLR (서열번호: 170)
VL:
QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLR (SEQ ID NO: 170)
CDR H1: GGTFSSYA (서열번호: 159)CDR H1: GGTFSSYA (SEQ ID NO: 159) CDR L1: SSNIGAGYD (서열번호: 171)CDR L1: SSNIGAGYD (SEQ ID NO: 171) CDR H2: IIPILGIA (서열번호: 160)CDR H2: IIPILGIA (SEQ ID NO: 160) CDR L2: GDI (서열번호: 172)CDR L2: GDI (SEQ ID NO: 172) CDR H3: AKPRDGYNLVAFDI (서열번호: 161)CDR H3: AKPRDGYNLVAFDI (SEQ ID NO: 161) CDR L3: QSYDSSLSGGV (서열번호: 173)CDR L3: QSYDSSLSGGV (SEQ ID NO: 173) Fv region
(Anti-CD3)
Fv region
(Anti-CD3)
VH: EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKCLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (서열번호: 176)VH: EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKCLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (SEQ ID NO: 176) VL: DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFACGTKLEIKR (서열번호: 206)VL: DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFACGTKLEIKR (SEQ ID NO: 206)
CDR H1: GYSFTGYT (서열번호: 177)CDR H1: GYSFTGYT (SEQ ID NO: 177) CDR L1: QDIRNY (서열번호: 181)CDR L1: QDIRNY (SEQ ID NO: 181) CDR H2: INPYKGVS (서열번호: 178)CDR H2: INPYKGVS (SEQ ID NO: 178) CDR L2: YTS (서열번호: 182)CDR L2: YTS (SEQ ID NO: 182) CDR H3: ARSGYYGDSDWYFDV (서열번호: 179)CDR H3: ARSGYYGDSDWYFDV (SEQ ID NO: 179) CDR L3: QQGNTLPWT (서열번호: 207)CDR L3: QQGNTLPWT (SEQ ID NO: 207)

실시예 21.16. ACE-15의 제조Example 21.16. Preparation of ACE-15

ACE-15는 두 개의 다른 중쇄 유사 사슬 (ACE-15-VH 및 ACE-15-VL) 및 두 개의 동일한 경쇄 (ACE-15-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다: ACE-15 contains two different heavy chain-like chains (ACE-15-VH and ACE-15-VL) and two identical light chains (ACE-15-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-15-VH amino acid sequence (서열번호: 208)ACE-15-VH amino acid sequence (SEQ ID NO: 208)

QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPAPELLGGPggggsEVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGCGTTLTVFS QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPAPELLGGP ggggs EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGCGTTLTVFS

ACE-15-VL amino acid sequence (서열번호: 209)ACE-15-VL amino acid sequence (SEQ ID NO: 209)

QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPAPELLGGPggggsDIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGCVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPAPELLGGP ggggs DIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGCVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR

ACE-15-LC amino acid sequence (서열번호: 157)ACE-15-LC amino acid sequence (SEQ ID NO: 157)

QLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVLR[SVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] QLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVLR [ SVAAPSVFIFPPSDEQLKSGTASVVCSKSVLTQLKSGTASVVCSKNFQLKSGTASVVCSKNFREADS

PD-L1을 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 CD3를 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 20에 열거되어있다: The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting PD-L1 and the second antigen binding domain monovalent Fv region targeting CD3 are listed in Table 20 below. have:

Fab region
(Anti-PD-L1)
Fab region
(Anti-PD-L1)
VH: QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (서열번호: 158)VH: QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (SEQ ID NO: 158) VL:
QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLR (서열번호: 170)
VL:
QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLR (SEQ ID NO: 170)
CDR H1: GGTFSSYA (서열번호: 159)CDR H1: GGTFSSYA (SEQ ID NO: 159) CDR L1: SSNIGAGYD (서열번호: 171)CDR L1: SSNIGAGYD (SEQ ID NO: 171) CDR H2: IIPILGIA (서열번호: 160)CDR H2: IIPILGIA (SEQ ID NO: 160) CDR L2: GDI (서열번호: 172)CDR L2: GDI (SEQ ID NO: 172) CDR H3: AKPRDGYNLVAFDI (서열번호: 161)CDR H3: AKPRDGYNLVAFDI (SEQ ID NO: 161) CDR L3: QSYDSSLSGGV (서열번호: 173)CDR L3: QSYDSSLSGGV (SEQ ID NO: 173) Fv region
(Anti-CD3)
Fv region
(Anti-CD3)
VH:
EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGCGTTLTVFS (서열번호: 210)
VH:
EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGCGTTLTVFS (SEQ ID NO: 210)
VL:
DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGCVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (서열번호: 212)
VL:
DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGCVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (SEQ ID NO: 212)
CDR H1: GYSFTGYT (서열번호: 177)CDR H1: GYSFTGYT (SEQ ID NO: 177) CDR L1: QDIRNY (서열번호: 181)CDR L1: QDIRNY (SEQ ID NO: 181) CDR H2: INPYKGVS (서열번호: 178)CDR H2: INPYKGVS (SEQ ID NO: 178) CDR L2: YTS (서열번호: 182)CDR L2: YTS (SEQ ID NO: 182) CDR H3: ARSGYYGDSDWYFD (서열번호: 211)CDR H3: ARSGYYGDSDWYFD (SEQ ID NO: 211) CDR L3: QQGNTLPWT (서열번호: 207)CDR L3: QQGNTLPWT (SEQ ID NO: 207)

실시예 21.17. ACE-16의 제조Example 21.17. Preparation of ACE-16

ACE-16은 2개의 상이한 중쇄 유사 사슬 (ACE-16-VH 및 ACE-16-VL) 및 2개의 동일한 경쇄 (ACE-16-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다: ACE-16 contains two different heavy chain-like chains (ACE-16-VH and ACE-16-VL) and two identical light chains (ACE-16-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-16-VH amino acid sequence (서열번호: 1)ACE-16-VH amino acid sequence (SEQ ID NO: 1)

QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPAPELLGGPggggsEVQLQQSGPELVKPGPSMKISCKAS GYSFTGYTMN WVKQSHGKNLEWMG LINPYKGVST YNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFDV WGQGTTLTVFS QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPAPELLGGP ggggs EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYTMN WVKQSHGKNLEWMG LINPYKGVST YNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFDV WGQGTTLTVFS

ACE-16-VL amino acid sequence (서열번호: 2)ACE-16-VL amino acid sequence (SEQ ID NO: 2)

QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPAPELLGGPggggsDIQMTQTTSSLSASLGDRVTISC RASQDIRNYLN WYQQKPDGTVKLLIY YTSRLHS GVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPAPELLGGP ggggs DIQMTQTTSSLSASLGDRVTISC RASQDIRNYLN WYQQKPDGTVKLLIY YTSRLHS GVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR

ACE-16-LC amino acid sequence (서열번호: 3)ACE-16-LC amino acid sequence (SEQ ID NO: 3)

QLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVL[RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] QLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVL [ RTVAAPSVFIFPPSDEQLKSGTASVVCSKNFLTQLKSGTASVVCSKNFQLKSGTASVVCSKNFREADS

PD-L1을 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 CD3를 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 21에 열거되어있다:The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting PD-L1 and the second antigen binding domain monovalent Fv region targeting CD3 are listed in Table 21 below. have:

Fab region
(Anti-PD-L1)
Fab region
(Anti-PD-L1)
VH: QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (서열번호: 4)VH: QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (SEQ ID NO: 4) VL:
QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLR (서열번호: 8)
VL:
QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLR (SEQ ID NO: 8)
CDR H1: GGTFSSYA (서열번호: 5)CDR H1: GGTFSSYA (SEQ ID NO: 5) CDR L1: SSNIGAGYD (서열번호: 9)CDR L1: SSNIGAGYD (SEQ ID NO: 9) CDR H2: IIPILGIA (서열번호: 6)CDR H2: IIPILGIA (SEQ ID NO: 6) CDR L2: GDI (서열번호: 10)CDR L2: GDI (SEQ ID NO: 10) CDR H3: AKPRDGYNLVAFDI (서열번호: 7)
CDR H3: AKPRDGYNLVAFDI (SEQ ID NO: 7)
CDR L3: QSYDSSLSGGV (서열번호: 11)CDR L3: QSYDSSLSGGV (SEQ ID NO: 11)
Fv region
(Anti-CD3)
Fv region
(Anti-CD3)
VH:
EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (서열번호: 12)
VH:
EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (SEQ ID NO: 12)
VL:
DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (서열번호: 16)
VL:
DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (SEQ ID NO: 16)
CDR H1: GYSFTGYTMN (서열번호: 13)CDR H1: GYSFTGYTMN (SEQ ID NO: 13) CDR L1: RASQDIRNYLN (서열번호: 17)CDR L1: RASQDIRNYLN (SEQ ID NO: 17) CDR H2: LINPYKGVST (서열번호: 14)CDR H2: LINPYKGVST (SEQ ID NO: 14) CDR L2: YTSRLHS (서열번호: 18)CDR L2: YTSRLHS (SEQ ID NO: 18) CDR H3: SGYYGDSDWYFDV (서열번호: 15)CDR H3: SGYYGDSDWYFDV (SEQ ID NO: 15) CDR L3: QQGNTLPWT (서열번호: 19)CDR L3: QQGNTLPWT (SEQ ID NO: 19)

실시예 21.18. ACE-17의 제조Example 21.18. Preparation of ACE-17

ACE-17은 2개의 상이한 중쇄 유사 사슬 (ACE-17-VH 및 ACE-17-VL) 및 2개의 동일한 경쇄 (ACE-17-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다: ACE-17 contains two different heavy chain-like chains (ACE-17-VH and ACE-17-VL) and two identical light chains (ACE-17-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-17-VH amino acid sequence (서열번호: 217)ACE-17-VH amino acid sequence (SEQ ID NO: 217)

QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPPCPAPELLGGP EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFS QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPPCPAPELLGGP EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFS

ACE-17-VL amino acid sequence (서열번호: 218) ACE-17-VL amino acid sequence (SEQ ID NO: 218)

QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPPCPAPELLGGP DIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPPCPAPELLGGP DIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR

ACE-17-LC amino acid sequence (서열번호: 157)ACE-17-LC amino acid sequence (SEQ ID NO: 157)

QLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVLR[SVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] QLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVLR [ SVAAPSVFIFPPSDEQLKSGTASVVCSKSVLTQLKSGTASVVCSKNFQLKSGTASVVCSKNFREADS

PD-L1을 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 CD3를 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 22에 열거되어있다:The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting PD-L1 and the second antigen binding domain monovalent Fv region targeting CD3 are listed in Table 22 below. have:

Fab region
(Anti-PD-L1)
Fab region
(Anti-PD-L1)
VH: QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (서열번호: 158)VH: QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (SEQ ID NO: 158) VL:
QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLR (서열번호: 170)
VL:
QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLR (SEQ ID NO: 170)
CDR H1: GGTFSSYA (서열번호: 159)CDR H1: GGTFSSYA (SEQ ID NO: 159) CDR L1: SSNIGAGYD (서열번호: 171)CDR L1: SSNIGAGYD (SEQ ID NO: 171) CDR H2: IIPILGIA (서열번호: 160)CDR H2: IIPILGIA (SEQ ID NO: 160) CDR L2: GDI (서열번호: 172)CDR L2: GDI (SEQ ID NO: 172) CDR H3: AKPRDGYNLVAFDI (서열번호: 161)CDR H3: AKPRDGYNLVAFDI (SEQ ID NO: 161) CDR L3: QSYDSSLSGGV (서열번호: 173)CDR L3: QSYDSSLSGGV (SEQ ID NO: 173) Fv region
(Anti-CD3)
Fv region
(Anti-CD3)
VH:
EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (서열번호: 215)
VH:
EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (SEQ ID NO: 215)
VL:
DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (서열번호: 216)
VL:
DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (SEQ ID NO: 216)
CDR H1: GYSFTGYT (서열번호: 177)CDR H1: GYSFTGYT (SEQ ID NO: 177) CDR L1: QDIRNY (서열번호: 181)CDR L1: QDIRNY (SEQ ID NO: 181) CDR H2: INPYKGVS (서열번호: 178)CDR H2: INPYKGVS (SEQ ID NO: 178) CDR L2: YTS (서열번호: 182)CDR L2: YTS (SEQ ID NO: 182) CDR H3: ARSGYYGDSDWYFD (서열번호: 211)CDR H3: ARSGYYGDSDWYFD (SEQ ID NO: 211) CDR L3: QQGNTLPWT (서열번호: 207)CDR L3: QQGNTLPWT (SEQ ID NO: 207)

실시예 21.19. ACE-18의 제조Example 21.19. Preparation of ACE-18

ACE-18은 2개의 다른 중쇄 유사 사슬 (ACE-18-VH 및 ACE-18-VL) 및 2개의 동일한 경쇄 (ACE-18-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다: ACE-18 contains two different heavy chain-like chains (ACE-18-VH and ACE-18-VL) and two identical light chains (ACE-18-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-18-VH amino acid sequence (서열번호: 219)ACE-18-VH amino acid sequence (SEQ ID NO: 219)

QVQLQQPGAELVKPGASVKMSCKAS GYTFTSYN MHWVKQTPGRGLEWIGA IYPGNGDT SYNQKFKGKATLTADKSSSTAYMQLSSLTSEDSAVYYC ARSTYYGGDWYFNV WGAGTTVTVSA[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC]DKTHTCPPCPPCPAPELLGGPGGGGSEVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFS QVQLQQPGAELVKPGASVKMSCKAS GYTFTSYN MHWVKQTPGRGLEWIGA IYPGNGDT SYNQKFKGKATLTADKSSSTAYMQLSSLTSEDSAVYYC ARSTYYGGDWYFNV WGAGTTVTVSA [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC] DKTHTCPPCPPCPAPELLGGP GGGGS EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFS

ACE-18-VL amino acid sequence (서열번호: 220)ACE-18-VL amino acid sequence (SEQ ID NO: 220)

QVQLQQPGAELVKPGASVKMSCKAS GYTFTSYN MHWVKQTPGRGLEWIGA IYPGNGDT SYNQKFKGKATLTADKSSSTAYMQLSSLTSEDSAVYYC ARSTYYGGDWYFNV WGAGTTVTVSA[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC]DKTHTCPPCPPCPAPELLGGPGGGGSDIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR QVQLQQPGAELVKPGASVKMSCKAS GYTFTSYN MHWVKQTPGRGLEWIGA IYPGNGDT SYNQKFKGKATLTADKSSSTAYMQLSSLTSEDSAVYYC ARSTYYGGDWYFNV WGAGTTVTVSA [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC] DKTHTCPPCPPCPAPELLGGP GGGGS DIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR

ACE-18-LC amino acid sequence (서열번호: 221)ACE-18-LC amino acid sequence (SEQ ID NO: 221)

QIVLSQSPAILSASPGEKVTMTCRAS SSVSY IHWFQQKPGSSPKPWIY ATS NLASGVPVRFSGSGSGTSYSLTISRVEAEDAATYYC QQWTSNPPT FGGGTKLEIK[RSVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC*] QIVLSQSPAILSASPGEKVTMTCRAS SSVSY IHWFQQKPGSSPKPWIY ATS NLASGVPVRFSGSGSGTSYSLTISRVEAEDAATYYC QQWTSNPPT FGGGTKLEIK [ RSVAAPSVFIFPPSDEQLKSGTKLEIK [RSVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPYPREAKVQWKVDTLSKVQWKVDTLSKVQWKVT

CD20을 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 CD3을 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 23에 열거되어있다:The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting CD20 and the second antigen binding domain monovalent Fv region targeting CD3 are listed in Table 23 below:

Fab region
(Anti-CD20)
Fab region
(Anti-CD20)
VH: QVQLQQPGAELVKPGASVKMSCKASGYTFTSYNMHWVKQTPGRGLEWIGAIYPGNGDTSYNQKFKGKATLTADKSSSTAYMQLSSLTSEDSAVYYCARSTYYGGDWYFNVWGAGTTVTVSA (서열번호: 222)VH: QVQLQQPGAELVKPGASVKMSCKASGYTFTSYNMHWVKQTPGRGLEWIGAIYPGNGDTSYNQKFKGKATLTADKSSSTAYMQLSSLTSEDSAVYYCARSTYYGGDWYFNVWGAGTTVTVSA (SEQ ID NO: 222) VL:
QIVLSQSPAILSASPGEKVTMTCRASSSVSYIHWFQQKPGSSPKPWIYATSNLASGVPVRFSGSGSGTSYSLTISRVEAEDAATYYCQQWTSNPPTFGGGTKLEIK (서열번호: 226)
VL:
QIVLSQSPAILSASPGEKVTMTCRASSSVSYIHWFQQKPGSSPKPWIYATSNLASGVPVRFSGSGSGTSYSLTISRVEAEDAATYYCQQWTSNPPTFGGGTKLEIK (SEQ ID NO: 226)
CDR H1: GYTFTSYN (서열번호: 223)CDR H1: GYTFTSYN (SEQ ID NO: 223) CDR L1: SSVSY (서열번호: 227)CDR L1: SSVSY (SEQ ID NO: 227) CDR H2: IYPGNGDT (서열번호: 224)CDR H2: IYPGNGDT (SEQ ID NO: 224) CDR L2: ATS (서열번호: 228)CDR L2: ATS (SEQ ID NO: 228) CDR H3: ARSTYYGGDWYFNV (서열번호: 225)CDR H3: ARSTYYGGDWYFNV (SEQ ID NO: 225) CDR L3: QQWTSNPPT (서열번호: 229)CDR L3: QQWTSNPPT (SEQ ID NO: 229) Fv region
(Anti-CD3)
Fv region
(Anti-CD3)
VH: EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (서열번호: 215)VH: EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (SEQ ID NO: 215) VL:
DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (서열번호: 216)
VL:
DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (SEQ ID NO: 216)
CDR H1: GYSFTGYT (서열번호: 177)CDR H1: GYSFTGYT (SEQ ID NO: 177) CDR L1: QDIRNY (서열번호: 181)CDR L1: QDIRNY (SEQ ID NO: 181) CDR H2: INPYKGVS (서열번호: 178)CDR H2: INPYKGVS (SEQ ID NO: 178) CDR L2: YTS (서열번호: 182)CDR L2: YTS (SEQ ID NO: 182) CDR H3: ARSGYYGDSDWYFD (서열번호: 211)CDR H3: ARSGYYGDSDWYFD (SEQ ID NO: 211) CDR L3: QQGNTLPWT (서열번호: 207)CDR L3: QQGNTLPWT (SEQ ID NO: 207)

실시예 21.20. ACE-19의 제조Example 21.20. Preparation of ACE-19

ACE-19는 2개의 상이한 중쇄 유사 사슬 (ACE-19-VH 및 ACE-19-VL) 및 2개의 동일한 경쇄 (ACE-19-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다: ACE-19 contains two different heavy chain-like chains (ACE-19-VH and ACE-19-VL) and two identical light chains (ACE-19-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-19-VH amino acid sequence (서열번호: 230)ACE-19-VH amino acid sequence (SEQ ID NO: 230)

QVQLKQSGPGLVQPSQSLSITCTVS GFSLTNYG VHWVRQSPGKGLEWLGV IWSGGNT DYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYC ARALTYYDYEFAY WGQGTLVTVSA[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC]DKTHTCPPCPPCPAPELLGGPGGGGSEVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFS QVQLKQSGPGLVQPSQSLSITCTVS GFSLTNYG VHWVRQSPGKGLEWLGV IWSGGNT DYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYC ARALTYYDYEFAY WGQGTLVTVSA [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC] DKTHTCPPCPPCPAPELLGGP GGGGS EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFS

ACE-19-VL amino acid sequence (서열번호: 231)ACE-19-VL amino acid sequence (SEQ ID NO: 231)

QVQLKQSGPGLVQPSQSLSITCTVS GFSLTNYG VHWVRQSPGKGLEWLGV IWSGGNT DYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYC ARALTYYDYEFAY WGQGTLVTVSA[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC]DKTHTCPPCPPCPAPELLGGPGGGGSDIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR QVQLKQSGPGLVQPSQSLSITCTVS GFSLTNYG VHWVRQSPGKGLEWLGV IWSGGNT DYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYC ARALTYYDYEFAY WGQGTLVTVSA [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC] DKTHTCPPCPPCPAPELLGGP GGGGS DIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR

ACE-19-LC amino acid sequence (서열번호: 232)ACE-19-LC amino acid sequence (SEQ ID NO: 232)

DILLTQSPVILSVSPGERVSFSCRAS QSIGTN IHWYQQRTNGSPRLLIK YAS ESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYC QQNNNWPTT FGAGTKLELK[RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] DILLTQSPVILSVSPGERVSFSCRAS QSIGTN IHWYQQRTNGSPRLLIK YAS ESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYC QQNNNWPTT FGAGTKLELK [ RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWHKVDNALKAQSGNSHKVDNALKLSQS

EGFR을 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 CD3를 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 24에 열거되어있다:The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting EGFR and the second antigen binding domain monovalent Fv region targeting CD3 are listed in Table 24 below:

Fab region
(Anti-EGFR)
Fab region
(Anti-EGFR)
VH: QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSA (서열번호: 233)VH: QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSA (SEQ ID NO: 233) VL:
DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELK (서열번호: 237)
VL:
DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELK (SEQ ID NO: 237)
CDR H1: GFSLTNYG (서열번호: 234)CDR H1: GFSLTNYG (SEQ ID NO: 234) CDR L1: QSIGTN (서열번호: 238)CDR L1: QSIGTN (SEQ ID NO: 238) CDR H2: IWSGGNT (서열번호: 235)CDR H2: IWSGGNT (SEQ ID NO: 235) CDR L2: YAS (서열번호: 239)CDR L2: YAS (SEQ ID NO: 239) CDR H3: ARALTYYDYEFAY (서열번호: 236)CDR H3: ARALTYYDYEFAY (SEQ ID NO: 236) CDR L3: QQNNNWPTT (서열번호: 240)CDR L3: QQNNNWPTT (SEQ ID NO: 240) Fv region
(Anti-CD3)
Fv region
(Anti-CD3)
VH:
EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (서열번호: 215)
VH:
EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (SEQ ID NO: 215)
VL:
DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (서열번호: 216)
VL:
DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (SEQ ID NO: 216)
CDR H1: GYSFTGYT (서열번호: 177)CDR H1: GYSFTGYT (SEQ ID NO: 177) CDR L1: QDIRNY (서열번호: 181)CDR L1: QDIRNY (SEQ ID NO: 181) CDR H2: INPYKGVS (서열번호: 178)CDR H2: INPYKGVS (SEQ ID NO: 178) CDR L2: YTS (서열번호: 182)CDR L2: YTS (SEQ ID NO: 182) CDR H3: ARSGYYGDSDWYFD (서열번호: 211)CDR H3: ARSGYYGDSDWYFD (SEQ ID NO: 211) CDR L3: QQGNTLPWT (서열번호: 207)CDR L3: QQGNTLPWT (SEQ ID NO: 207)

실시예 21.21. ACE-20의 제조Example 21.21. Preparation of ACE-20

ACE-20은 두 개의 다른 중쇄 유사 사슬 (ACE-20-VH 및 ACE-20-VL) 및 두 개의 동일한 경쇄 (ACE-20-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다: ACE-20 contains two different heavy chain-like chains (ACE-20-VH and ACE-20-VL) and two identical light chains (ACE-20-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-20-VH amino acid sequence (서열번호: 241)ACE-20-VH amino acid sequence (SEQ ID NO: 241)

QVQLVQSGAEVKKPGASVKVSCKAS GYTFTSHW MHWVRQAPGQGLEWIGE FNPSNGRT NYNEKFKSKATMTVDTSTNTAYMELSSLRSEDTAVYYC ASRDYDYDCRYFDY WGQGTLVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPPCPAPELLGGPggggsEVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFS* QVQLVQSGAEVKKPGASVKVSCKAS GYTFTSHW MHWVRQAPGQGLEWIGE FNPSNGRT NYNEKFKSKATMTVDTSTNTAYMELSSLRSEDTAVYYC ASRDYDYDCRYFDY WGQGTLVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPPCPAPELLGGP ggggs EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFS *

ACE-20-VL amino acid sequence (서열번호: 242)ACE-20-VL amino acid sequence (SEQ ID NO: 242)

QVQLVQSGAEVKKPGASVKVSCKAS GYTFTSHW MHWVRQAPGQGLEWIGE FNPSNGRT NYNEKFKSKATMTVDTSTNTAYMELSSLRSEDTAVYYC ASRDYDYDCRYFDY WGQGTLVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPPCPAPELLGGPggggsDIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR QVQLVQSGAEVKKPGASVKVSCKAS GYTFTSHW MHWVRQAPGQGLEWIGE FNPSNGRT NYNEKFKSKATMTVDTSTNTAYMELSSLRSEDTAVYYC ASRDYDYDCRYFDY WGQGTLVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPPCPAPELLGGP ggggs DIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR

ACE-20-LC amino acid sequence (서열번호: 243)ACE-20-LC amino acid sequence (SEQ ID NO: 243)

DIQMTQSPSSLSASVGDRVTITCSAS SSVTY MYWYQQKPGKAPKLLIY DTS NLASGVPSRFSGSGSGTDYTFTISSLQPEDIATYYC QQWSSHIFT FGQGTKVEIKR[TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] DIQMTQSPSSLSASVGDRVTITCSAS SSVTY MYWYQQKPGKAPKLLIY DTS NLASGVPSRFSGSGSGTDYTFTISSLQPEDIATYYC QQWSSHIFT FGQGTKVEIKR [ TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPYPREAKVQSKLSVDSKVQWKVDTLSKSKLSVD

EGFR을 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 CD3를 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 25에 열거되어있다:The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting EGFR and the second antigen binding domain monovalent Fv region targeting CD3 are listed in Table 25 below:

Fab region
(Anti-EGFR)
Fab region
(Anti-EGFR)
VH: QVQLVQSGAEVKKPGASVKVSCKASGYTFTSHWMHWVRQAPGQGLEWIGEFNPSNGRTNYNEKFKSKATMTVDTSTNTAYMELSSLRSEDTAVYYCASRDYDYDCRYFDYWGQGTLVTVSS (서열번호: 244)VH: QVQLVQSGAEVKKPGASVKVSCKASGYTFTSHWMHWVRQAPGQGLEWIGEFNPSNGRTNYNEKFKSKATMTVDTSTNTAYMELSSLRSEDTAVYYCASRDYDYDCRYFDYWGQGTLVTVSS (SEQ ID NO: 244) VL:
DIQMTQSPSSLSASVGDRVTITCSASSSVTYMYWYQQKPGKAPKLLIYDTSNLASGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQQWSSHIFTFGQGTKVEIKR (서열번호: 248)
VL:
DIQMTQSPSSLSASVGDRVTITCSASSSVTYMYWYQQKPGKAPKLLIYDTSNLASGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQQWSSHIFTFGQGTKVEIKR (SEQ ID NO: 248)
CDR H1: GYTFTSHW (서열번호: 245)CDR H1: GYTFTSHW (SEQ ID NO: 245) CDR L1: SSVTY (서열번호: 249)CDR L1: SSVTY (SEQ ID NO: 249) CDR H2: FNPSNGRT (서열번호: 246)CDR H2: FNPSNGRT (SEQ ID NO: 246) CDR L2: DTS (서열번호: 250)CDR L2: DTS (SEQ ID NO: 250) CDR H3: ASRDYDYDCRYFDY (서열번호: 247)CDR H3: ASRDYDYDCRYFDY (SEQ ID NO: 247) CDR L3: QQWSSHIFT (서열번호: 251)CDR L3: QQWSSHIFT (SEQ ID NO: 251) Fv region
(Anti-CD3)
Fv region
(Anti-CD3)
VH: EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (서열번호: 215)VH: EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (SEQ ID NO: 215) VL:
DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (서열번호: 216)
VL:
DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (SEQ ID NO: 216)
CDR H1: GYSFTGYT (서열번호: 177)CDR H1: GYSFTGYT (SEQ ID NO: 177) CDR L1: QDIRNY (서열번호: 181)CDR L1: QDIRNY (SEQ ID NO: 181) CDR H2: INPYKGVS (서열번호: 178)CDR H2: INPYKGVS (SEQ ID NO: 178) CDR L2: YTS (서열번호: 182)CDR L2: YTS (SEQ ID NO: 182) CDR H3: ARSGYYGDSDWYFD (서열번호: 211)CDR H3: ARSGYYGDSDWYFD (SEQ ID NO: 211) CDR L3: QQGNTLPWT (서열번호: 207)CDR L3: QQGNTLPWT (SEQ ID NO: 207)

실시예 21.22. ACE-21의 제조Example 21.22. Preparation of ACE-21

ACE-21은 2개의 상이한 중쇄 유사 사슬 (ACE-21-VH 및 ACE-21-VL) 및 2개의 동일한 경쇄 (ACE-21-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다: ACE-21 contains two different heavy chain-like chains (ACE-21-VH and ACE-21-VL) and two identical light chains (ACE-21-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-21-VH amino acid sequence (서열번호: 252)ACE-21-VH amino acid sequence (SEQ ID NO: 252)

QVQLVESGGGVVQPGRSLRLSCAAS GFTFSTYG MHWVRQAPGKGLEWVAV IWDDGSYK YYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC ARDGITMVRGVMKDYFDY WGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPPCPAPELLGGPggggsEVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFS QVQLVESGGGVVQPGRSLRLSCAAS GFTFSTYG MHWVRQAPGKGLEWVAV IWDDGSYK YYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC ARDGITMVRGVMKDYFDY WGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPPCPAPELLGGPggggs EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFS

ACE-21-VL amino acid sequence (서열번호: 253)ACE-21-VL amino acid sequence (SEQ ID NO: 253)

QVQLVESGGGVVQPGRSLRLSCAAS GFTFSTYG MHWVRQAPGKGLEWVAV IWDDGSYK YYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC ARDGITMVRGVMKDYFDY WGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPPCPAPELLGGPggggsDIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR QVQLVESGGGVVQPGRSLRLSCAAS GFTFSTYG MHWVRQAPGKGLEWVAV IWDDGSYK YYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC ARDGITMVRGVMKDYFDY WGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPPCPAPELLGGPggggs DIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR

ACE-21-LC amino acid sequence (서열번호: 254)ACE-21-LC amino acid sequence (SEQ ID NO: 254)

AIQLTQSPSSLSASVGDRVTITCRASAIQLTQSPSSLSASVGDRVTITCRAS QDISSAQDISSA LVWYQQKPGKAPKLLIYLVWYQQKPGKAPKLLIY DASDAS SLESGVPSRFSGSESGTDFTLTISSLQPEDFATYYCSLESGVPSRFSGSESGTDFTLTISSLQPEDFATYYC QQFNSYPLTQQFNSYPLT FGGGTKVEIKRFGGGTKVEIKR TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

EGFR을 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 CD3를 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 26에 열거되어있다:The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting EGFR and the second antigen binding domain monovalent Fv region targeting CD3 are listed in Table 26 below:

Fab region
(Anti-EGFR)
Fab region
(Anti-EGFR)
VH: QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWDDGSYKYYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGITMVRGVMKDYFDYWGQGTLVTVSS (서열번호: 255)VH: QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWDDGSYKYYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGITMVRGVMKDYFDYWGQGTLVTVSS (SEQ ID NO: 255) VL:
AIQLTQSPSSLSASVGDRVTITCRASQDISSALVWYQQKPGKAPKLLIYDASSLESGVPSRFSGSESGTDFTLTISSLQPEDFATYYCQQFNSYPLTFGGGTKVEIKR (서열번호: 259)
VL:
AIQLTQSPSSLSASVGDRVTITCRASQDISSALVWYQQKPGKAPKLLIYDASSLESGVPSRFSGSESGTDFTLTISSLQPEDFATYYCQQFNSYPLTFGGGTKVEIKR (SEQ ID NO: 259)
CDR H1: GFTFSTYG (서열번호: 256)CDR H1: GFTFSTYG (SEQ ID NO: 256) CDR L1: QDISSA (서열번호: 260)CDR L1: QDISSA (SEQ ID NO: 260) CDR H2: IWDDGSYK (서열번호: 257)CDR H2: IWDDGSYK (SEQ ID NO: 257) CDR L2: DAS (서열번호: 261)CDR L2: DAS (SEQ ID NO: 261) CDR H3: ARDGITMVRGVMKDYFDY (서열번호: 258)CDR H3: ARDGITMVRGVMKDYFDY (SEQ ID NO: 258) CDR L3: QQFNSYPLT (서열번호: 262)CDR L3: QQFNSYPLT (SEQ ID NO: 262) Fv region
(Anti-CD3)
Fv region
(Anti-CD3)
VH:
EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (서열번호: 215)
VH:
EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (SEQ ID NO: 215)
VL: DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (서열번호: 216)VL: DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (SEQ ID NO: 216)
CDR H1: GYSFTGYT (서열번호: 177)CDR H1: GYSFTGYT (SEQ ID NO: 177) CDR L1: QDIRNY (서열번호: 181)CDR L1: QDIRNY (SEQ ID NO: 181) CDR H2: INPYKGVS (서열번호: 178)CDR H2: INPYKGVS (SEQ ID NO: 178) CDR L2: YTS (서열번호: 182)CDR L2: YTS (SEQ ID NO: 182) CDR H3: ARSGYYGDSDWYFD (서열번호: 211)CDR H3: ARSGYYGDSDWYFD (SEQ ID NO: 211) CDR L3: QQGNTLPWT (서열번호: 207)CDR L3: QQGNTLPWT (SEQ ID NO: 207)

실시예 21.23. ACE-22의 제조Example 21.23. Preparation of ACE-22

ACE-22는 두 개의 다른 중쇄 유사 사슬 (ACE-22-VH 및 ACE-22-VL) 및 두 개의 동일한 경쇄 (ACE-22-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다:ACE-22 contains two different heavy chain-like chains (ACE-22-VH and ACE-22-VL) and two identical light chains (ACE-22-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-22-VH amino acid sequence (서열번호: 263)ACE-22-VH amino acid sequence (SEQ ID NO: 263)

QVQLQQPGAELVKPGASVKMSCKAS GYTFTSYN MHWVKQTPGRGLEWIGA IYPGNGDT SYNQKFKGKATLTADKSSSTAYMQLSSLTSEDSAVYYC ARSTYYGGDWYFNV WGAGTTVTVSA[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC]DKTHTCPPCPPCPAPELLGGP EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFS QVQLQQPGAELVKPGASVKMSCKAS GYTFTSYN MHWVKQTPGRGLEWIGA IYPGNGDT SYNQKFKGKATLTADKSSSTAYMQLSSLTSEDSAVYYC ARSTYYGGDWYFNV WGAGTTVTVSA [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC] DKTHTCPPCPPCPAPELLGGP EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFS

ACE-22-VL amino acid sequence (서열번호: 264)ACE-22-VL amino acid sequence (SEQ ID NO: 264)

QVQLQQPGAELVKPGASVKMSCKASGYTFTSYNMHWVKQTPGRGLEWIGAIYPGNGDTSYNQKFKGKATLTADKSSSTAYMQLSSLTSEDSAVYYCARSTYYGGDWYFNVWGAGTTVTVSA[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC]DKTHTCPPCPPCPAPELLGGP DIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR QVQLQQPGAELVKPGASVKMSCKASGYTFTSYNMHWVKQTPGRGLEWIGAIYPGNGDTSYNQKFKGKATLTADKSSSTAYMQLSSLTSEDSAVYYCARSTYYGGDWYFNVWGAGTTVTVSA [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC] DKTHTCPPCPPCPAPELLGGP DIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR

ACE-22-LC amino acid sequence (서열번호: 221)ACE-22-LC amino acid sequence (SEQ ID NO: 221)

QIVLSQSPAILSASPGEKVTMTCRAS SSVSY IHWFQQKPGSSPKPWIY ATS NLASGVPVRFSGSGSGTSYSLTISRVEAEDAATYYC QQWTSNPPT FGGGTKLEIK[RSVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] QIVLSQSPAILSASPGEKVTMTCRAS SSVSY IHWFQQKPGSSPKPWIY ATS NLASGVPVRFSGSGSGTSYSLTISRVEAEDAATYYC QQWTSNPPT FGGGTKLEIK [ RSVAAPSVFIFPPSDEQLKSGTKLEIK [RSVAAPSVFIFPPSDEQLKSGTKLEIK [RSVAAPSVFIFPPSDEQLKSGTKLEIK [RSVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPYPREAKVQWKVSTLSKVQWKVDTLSKADSKWKVT

CD20을 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 CD3을 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 27에 열거되어있다:The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting CD20 and the second antigen binding domain monovalent Fv region targeting CD3 are listed in Table 27 below:

Fab region
(Anti-CD20)
Fab region
(Anti-CD20)
VH: QVQLQQPGAELVKPGASVKMSCKASGYTFTSYNMHWVKQTPGRGLEWIGAIYPGNGDTSYNQKFKGKATLTADKSSSTAYMQLSSLTSEDSAVYYCARSTYYGGDWYFNVWGAGTTVTVSA (서열번호: 222)VH: QVQLQQPGAELVKPGASVKMSCKASGYTFTSYNMHWVKQTPGRGLEWIGAIYPGNGDTSYNQKFKGKATLTADKSSSTAYMQLSSLTSEDSAVYYCARSTYYGGDWYFNVWGAGTTVTVSA (SEQ ID NO: 222) VL:
QIVLSQSPAILSASPGEKVTMTCRASSSVSYIHWFQQKPGSSPKPWIYATSNLASGVPVRFSGSGSGTSYSLTISRVEAEDAATYYCQQWTSNPPTFGGGTKLEIK (서열번호: 226)
VL:
QIVLSQSPAILSASPGEKVTMTCRASSSVSYIHWFQQKPGSSPKPWIYATSNLASGVPVRFSGSGSGTSYSLTISRVEAEDAATYYCQQWTSNPPTFGGGTKLEIK (SEQ ID NO: 226)
CDR H1: GYTFTSYN (서열번호: 223)CDR H1: GYTFTSYN (SEQ ID NO: 223) CDR L1: SSVSY (서열번호: 227)CDR L1: SSVSY (SEQ ID NO: 227) CDR H2: IYPGNGDT (서열번호: 224)CDR H2: IYPGNGDT (SEQ ID NO: 224) CDR L2: ATS (서열번호: 228)CDR L2: ATS (SEQ ID NO: 228) CDR H3: ARSTYYGGDWYFNV (서열번호: 225)CDR H3: ARSTYYGGDWYFNV (SEQ ID NO: 225) CDR L3: QQWTSNPPT (서열번호: 229)CDR L3: QQWTSNPPT (SEQ ID NO: 229) Fv region
(Anti-CD3)
Fv region
(Anti-CD3)
VH: EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (서열번호: 215)VH: EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (SEQ ID NO: 215) VL: DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (서열번호: 216)VL: DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (SEQ ID NO: 216)
CDR H1: GYSFTGYT (서열번호: 177)CDR H1: GYSFTGYT (SEQ ID NO: 177) CDR L1: QDIRNY (서열번호: 181)CDR L1: QDIRNY (SEQ ID NO: 181) CDR H2: INPYKGVS (서열번호: 178)CDR H2: INPYKGVS (SEQ ID NO: 178) CDR L2: YTS (서열번호: 182)CDR L2: YTS (SEQ ID NO: 182) CDR H3: ARSGYYGDSDWYFD (서열번호: 211)CDR H3: ARSGYYGDSDWYFD (SEQ ID NO: 211) CDR L3: QQGNTLPWT (서열번호: 207)CDR L3: QQGNTLPWT (SEQ ID NO: 207)

실시예 21.24. ACE-23의 제조Example 21.24. Preparation of ACE-23

ACE-23은 두 개의 다른 중쇄 유사 사슬 (ACE-23-VH 및 ACE-23-VL) 및 두 개의 동일한 경쇄 (ACE-23-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다: ACE-23 contains two different heavy chain-like chains (ACE-23-VH and ACE-23-VL) and two identical light chains (ACE-23-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-23-VH amino acid sequence (서열번호: 269)ACE-23-VH amino acid sequence (SEQ ID NO: 269)

QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPPCPAPELLGGPggggsQVQLVESGGGVVQPGRSLRLSCAAS GFKFSGYG MHWVRQAPGKGLEWVAV IWYDGSKK YYVDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC ARQMGYWHFDL WGRGTLVTVSS QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPPCPAPELLGGP ggggs QVQLVESGGGVVQPGRSLRLSCAAS GFKFSGYG MHWVRQAPGKGLEWVAV IWYDGSKK YYVDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC ARQMGYWHFDL WGRGTLVTVSS

ACE-23-VL amino acid sequence (서열번호: 270)ACE-23-VL amino acid sequence (SEQ ID NO: 270)

QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYAI SWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYY CAKPRDGYNLVAFDI WGQGTMVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPPCPAPELLGGPggggsEIVLTQSPATLSLSPGERATLSCRAS QSVSSY LAWYQQKPGQAPRLLIY DAS NRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYC QQRSNWPPLT FGGGTKVEIKR QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYAI SWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYY CAKPRDGYNLVAFDI WGQGTMVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPPCPAPELLGGP ggggs EIVLTQSPATLSLSPGERATLSCRAS QSVSSY LAWYQQKPGQAPRLLIY DAS NRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYC QQRSNWPPLT FGGGTKVEIKR

ACE-23-LC amino acid sequence (서열번호: 157)ACE-23-LC amino acid sequence (SEQ ID NO: 157)

QLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVLR[SVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] QLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVLR [ SVAAPSVFIFPPSDEQLKSGTASVVCSKSVLTQLKSGTASVVCSKNFQLKSGTASVVCSKNFREADS

PD-L1을 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 CD3를 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 28에 열거되어있다:The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting PD-L1 and the second antigen binding domain monovalent Fv region targeting CD3 are listed in Table 28 below. have:

Fab region
(Anti-PD-L1)
Fab region
(Anti-PD-L1)
VH: QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (서열번호: 158)VH: QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (SEQ ID NO: 158) VL:
QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLR (서열번호: 170)
VL:
QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLR (SEQ ID NO: 170)
CDR H1: GGTFSSYA (서열번호: 159)CDR H1: GGTFSSYA (SEQ ID NO: 159) CDR L1: SSNIGAGYD (서열번호: 171)CDR L1: SSNIGAGYD (SEQ ID NO: 171) CDR H2: IIPILGIA (서열번호: 160)CDR H2: IIPILGIA (SEQ ID NO: 160) CDR L2: GDI (서열번호: 172)CDR L2: GDI (SEQ ID NO: 172) CDR H3: AKPRDGYNLVAFDI (서열번호: 161)CDR H3: AKPRDGYNLVAFDI (SEQ ID NO: 161) CDR L3: QSYDSSLSGGV (서열번호: 173)CDR L3: QSYDSSLSGGV (SEQ ID NO: 173) Fv region
(Anti-CD3)
Fv region
(Anti-CD3)
VH: QVQLVESGGGVVQPGRSLRLSCAASGFKFSGYGMHWVRQAPGKGLEWVAVIWYDGSKKYYVDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARQMGYWHFDLWGRGTLVTVSS (서열번호: 162)VH: QVQLVESGGGVVQPGRSLRLSCAASGFKFSGYGMHWVRQAPGKGLEWVAVIWYDGSKKYYVDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARQMGYWHFDLWGRGTLVTVSS (SEQ ID NO: 162) VL:
EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPPLTFGGGTKVEIKR (서열번호: 166)
VL:
EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPPLTFGGGTKVEIKR (SEQ ID NO: 166)
CDR H1: GFKFSGYG (서열번호: 163)CDR H1: GFKFSGYG (SEQ ID NO: 163) CDR L1: QSVSSY (서열번호: 167)CDR L1: QSVSSY (SEQ ID NO: 167) CDR H2: IWYDGSKK (서열번호: 271)CDR H2: IWYDGSKK (SEQ ID NO: 271) CDR L2: DAS (서열번호: 168)CDR L2: DAS (SEQ ID NO: 168) CDR H3: ARQMGYWHFDL (서열번호: 165)CDR H3: ARQMGYWHFDL (SEQ ID NO: 165) CDR L3: QQRSNWPPLT (서열번호: 169)CDR L3: QQRSNWPPLT (SEQ ID NO: 169)

실시예 21.25. ACE-24의 제조Example 21.25. Preparation of ACE-24

ACE-24는 2개의 상이한 중쇄 유사 사슬 (ACE-24-VH 및 ACE-24-VL) 및 2개의 동일한 경쇄 (ACE-24-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다: ACE-24 contains two different heavy chain-like chains (ACE-24-VH and ACE-24-VL) and two identical light chains (ACE-24-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-24-VH amino acid sequence (서열번호: 272)ACE-24-VH amino acid sequence (SEQ ID NO: 272)

EVQLVESGGGLVQPGGSLRLSCAAS GFNIKDTY IHWVRQAPGKGLEWVAR IYPTNGYT RYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYC SRWGGDGFYAMDY WGQGTLVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPAPELLGGPggggsEVQLVESGGGLVQPGRSLRLSCAAS GFTFDDYA MHWVRQAPGKGLEWVSA ITWNSGHI DYADSVEGRFTISRDNAKNSLYLQMNSLRAEDTAVYYC AKVSYLSTASSLDY WGQGTLVTVSS EVQLVESGGGLVQPGGSLRLSCAAS GFNIKDTY IHWVRQAPGKGLEWVAR IYPTNGYT RYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYC SRWGGDGFYAMDY WGQGTLVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPAPELLGGP ggggs EVQLVESGGGLVQPGRSLRLSCAAS GFTFDDYA MHWVRQAPGKGLEWVSA ITWNSGHI DYADSVEGRFTISRDNAKNSLYLQMNSLRAEDTAVYYC AKVSYLSTASSLDY WGQGTLVTVSS

ACE-24-VL amino acid sequence (서열번호: 273)ACE-24-VL amino acid sequence (SEQ ID NO: 273)

EVQLVESGGGLVQPGGSLRLSCAAS GFNIKDTY IHWVRQAPGKGLEWVAR IYPTNGYT RYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYC SRWGGDGFYAMDY WGQGTLVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC]DKTHTCPPCPAPELLGGP DIQMTQSPSSLSASVGDRVTITCRAS QGIRNY LAWYQQKPGKAPKLLIY AAS TLQSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYC QRYNRAPYT FGQGTKVEIKR EVQLVESGGGLVQPGGSLRLSCAAS GFNIKDTY IHWVRQAPGKGLEWVAR IYPTNGYT RYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYC SRWGGDGFYAMDY WGQGTLVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC] DKTHTCPPCPAPELLGGP DIQMTQSPSSLSASVGDRVTITCRAS QGIRNY LAWYQQKPGKAPKLLIY AAS TLQSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYC QRYNRAPYT FGQGTKVEIKR

ACE-24-LC amino acid sequence (서열번호: 274)ACE-24-LC amino acid sequence (SEQ ID NO: 274)

DIQMTQSPSSLSASVGDRVTITCRAS QDVNTA VAWYQQKPGKAPKLLIY SAS FLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYC QQHYTTPPT FGQGTKVEIK[RSVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] DIQMTQSPSSLSASVGDRVTITCRAS QDVNTA VAWYQQKPGKAPKLLIY SAS FLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYC QQHYTTPPT FGQGTKVEIK [ RSVAAPSVFIFPPSDEQLKSGTASVVCLLNNVDYPREAKSQGNSVDYPREAKVQWKTHKDS

HER2를 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 TNF를 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 29에 열거되어있다:The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting HER2 and the second antigen binding domain monovalent Fv region targeting TNF are listed in Table 29 below:

Fab region
(Anti-HER2)
Fab region
(Anti-HER2)
VH: EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS (서열번호: 275)VH: EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS (SEQ ID NO: 275) VL:
DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIK (서열번호: 287)
VL:
DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIK (SEQ ID NO: 287)
CDR H1: GFNIKDTY (서열번호: 276)CDR H1: GFNIKDTY (SEQ ID NO: 276) CDR L1: QDVNTA (서열번호: 288)
CDR L1: QDVNTA (SEQ ID NO: 288)
CDR H2: IYPTNGYT (서열번호: 277)CDR H2: IYPTNGYT (SEQ ID NO: 277) CDR L2: SAS (서열번호: 289)CDR L2: SAS (SEQ ID NO: 289) CDR H3: SRWGGDGFYAMDY (서열번호: 278)CDR H3: SRWGGDGFYAMDY (SEQ ID NO: 278) CDR L3: QQHYTTPPT (서열번호: 290)CDR L3: QQHYTTPPT (SEQ ID NO: 290) Fv region
(Anti-TNF)
Fv region
(Anti-TNF)
VH: EVQLVESGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSAITWNSGHIDYADSVEGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAKVSYLSTASSLDYWGQGTLVTVSS (서열번호: 279)VH: EVQLVESGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSAITWNSGHIDYADSVEGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAKVSYLSTASSLDYWGQGTLVTVSS (SEQ ID NO: 279) VL:
DIQMTQSPSSLSASVGDRVTITCRASQGIRNYLAWYQQKPGKAPKLLIYAASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQRYNRAPYTFGQGTKVEIKR (서열번호: 283)
VL:
DIQMTQSPSSLSASVGDRVTITCRASQGIRNYLAWYQQKPGKAPKLLIYAASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQRYNRAPYTFGQGTKVEIKR (SEQ ID NO: 283)
CDR H1: GFTFDDYA (서열번호: 280)CDR H1: GFTFDDYA (SEQ ID NO: 280) CDR L1: QGIRNY (서열번호: 284)
CDR L1: QGIRNY (SEQ ID NO: 284)
CDR H2: ITWNSGHI (서열번호: 281)CDR H2: ITWNSGHI (SEQ ID NO: 281) CDR L2: AAS (서열번호: 285)CDR L2: AAS (SEQ ID NO: 285) CDR H3: AKVSYLSTASSLDY (서열번호: 282)CDR H3: AKVSYLSTASSLDY (SEQ ID NO: 282) CDR L3: QRYNRAPYT (서열번호: 286)CDR L3: QRYNRAPYT (SEQ ID NO: 286)

실시예 21.26. ACE-25의 제조Example 21.26. Preparation of ACE-25

ACE-25는 2개의 상이한 중쇄 유사 사슬 (ACE-25-VH 및 ACE-25-VL) 및 2개의 동일한 경쇄 (ACE-25-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다: ACE-25 contains two different heavy chain-like chains (ACE-25-VH and ACE-25-VL) and two identical light chains (ACE-25-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-25-VH amino acid sequence (서열번호: 291)ACE-25-VH amino acid sequence (SEQ ID NO: 291)

EVQLVESGGGLVQPGGSLRLSCAAS GFNIKDTY IHWVRQAPGKGLEWVAR IYPTNGYT RYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYC SRWGGDGFYAMDY WGQGTLVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPAPELLGGPggggsggggs EVQLVESGGGLVQPGRSLRLSCAAS GFTFDDYA MHWVRQAPGKGLEWVSA ITWNSGHI DYADSVEGRFTISRDNAKNSLYLQMNSLRAEDTAVYYC AKVSYLSTASSLDY WGQGTLVTVSS EVQLVESGGGLVQPGGSLRLSCAAS GFNIKDTY IHWVRQAPGKGLEWVAR IYPTNGYT RYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYC SRWGGDGFYAMDY WGQGTLVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPAPELLGGPggggsggggs EVQLVESGGGLVQPGRSLRLSCAAS GFTFDDYA MHWVRQAPGKGLEWVSA ITWNSGHI DYADSVEGRFTISRDNAKNSLYLQMNSLRAEDTAVYYC AKVSYLSTASSLDY WGQGTLVTVSS

ACE-25-VL amino acid sequence (서열번호: 273)ACE-25-VL amino acid sequence (SEQ ID NO: 273)

EVQLVESGGGLVQPGGSLRLSCAAS GFNIKDTY IHWVRQAPGKGLEWVAR IYPTNGYT RYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYC SRWGGDGFYAMDY WGQGTLVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC]DKTHTCPPCPAPELLGGP DIQMTQSPSSLSASVGDRVTITCRAS QGIRNY LAWYQQKPGKAPKLLIY AAS TLQSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYC QRYNRAPYT FGQGTKVEIKR EVQLVESGGGLVQPGGSLRLSCAAS GFNIKDTY IHWVRQAPGKGLEWVAR IYPTNGYT RYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYC SRWGGDGFYAMDY WGQGTLVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC] DKTHTCPPCPAPELLGGP DIQMTQSPSSLSASVGDRVTITCRAS QGIRNY LAWYQQKPGKAPKLLIY AAS TLQSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYC QRYNRAPYT FGQGTKVEIKR

ACE-25-LC amino acid sequence (서열번호: 274)ACE-25-LC amino acid sequence (SEQ ID NO: 274)

DIQMTQSPSSLSASVGDRVTITCRAS QDVNTA VAWYQQKPGKAPKLLIY SAS FLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYC QQHYTTPPT FGQGTKVEIK[RSVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] DIQMTQSPSSLSASVGDRVTITCRAS QDVNTA VAWYQQKPGKAPKLLIY SAS FLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYC QQHYTTPPT FGQGTKVEIK [ RSVAAPSVFIFPPSDEQLKSGTASVVCLLNNVDYPREAKSQGNSVDYPREAKVQWKTHKDS

HER2를 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 TNF를 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 30에 열거되어있다:The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting HER2 and the second antigen binding domain monovalent Fv region targeting TNF are listed in Table 30 below:

Fab region
(Anti-HER2)
Fab region
(Anti-HER2)
VH: EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS (서열번호: 275)VH: EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS (SEQ ID NO: 275) VL:
DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIK (서열번호: 287)
VL:
DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIK (SEQ ID NO: 287)
CDR H1: GFNIKDTY (서열번호: 276)CDR H1: GFNIKDTY (SEQ ID NO: 276) CDR L1: QDVNTA (서열번호: 288)CDR L1: QDVNTA (SEQ ID NO: 288) CDR H2: IYPTNGYT (서열번호: 277)CDR H2: IYPTNGYT (SEQ ID NO: 277) CDR L2: SAS (서열번호: 289)CDR L2: SAS (SEQ ID NO: 289) CDR H3: SRWGGDGFYAMDY (서열번호: 278)CDR H3: SRWGGDGFYAMDY (SEQ ID NO: 278) CDR L3: QQHYTTPPT (서열번호: 290)CDR L3: QQHYTTPPT (SEQ ID NO: 290) Fv region
(Anti-TNF)
Fv region
(Anti-TNF)
VH: EVQLVESGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSAITWNSGHIDYADSVEGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAKVSYLSTASSLDYWGQGTLVTVSS (서열번호: 279)VH: EVQLVESGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSAITWNSGHIDYADSVEGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAKVSYLSTASSLDYWGQGTLVTVSS (SEQ ID NO: 279) VL:
DIQMTQSPSSLSASVGDRVTITCRASQGIRNYLAWYQQKPGKAPKLLIYAASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQRYNRAPYTFGQGTKVEIKR (서열번호: 283)
VL:
DIQMTQSPSSLSASVGDRVTITCRASQGIRNYLAWYQQKPGKAPKLLIYAASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQRYNRAPYTFGQGTKVEIKR (SEQ ID NO: 283)
CDR H1: GFTFDDYA (서열번호: 280)CDR H1: GFTFDDYA (SEQ ID NO: 280) CDR L1: QGIRNY (서열번호: 284)CDR L1: QGIRNY (SEQ ID NO: 284) CDR H2: ITWNSGHI (서열번호: 281)CDR H2: ITWNSGHI (SEQ ID NO: 281) CDR L2: AAS (서열번호: 285)CDR L2: AAS (SEQ ID NO: 285) CDR H3: AKVSYLSTASSLDY (서열번호: 282)CDR H3: AKVSYLSTASSLDY (SEQ ID NO: 282) CDR L3: QRYNRAPYT (서열번호: 286)CDR L3: QRYNRAPYT (SEQ ID NO: 286)

실시예 21.27. ACE-26의 제조Example 21.27. Preparation of ACE-26

ACE-26은 2개의 상이한 중쇄 유사 사슬 (ACE-26-VH 및 ACE-26-VL) 및 2개의 동일한 경쇄 (ACE-26-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다: ACE-26 contains two different heavy chain-like chains (ACE-26-VH and ACE-26-VL) and two identical light chains (ACE-26-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-26-VH amino acid sequence (서열번호: 292)ACE-26-VH amino acid sequence (SEQ ID NO: 292)

QVQLKQSGPGLVQPSQSLSITCTVS GFSLTNYG VHWVRQSPGKGLEWLGV IWSGGNT DYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYC ARALTYYDYEFAY WGQGTLVTVSA[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPPCPAPELLGGPggggsEVKLLESGGGLVQPKGSLKLSCAAS GFTFNTYA MNWVRQAPGKGLEWVAR IRSKYNNYAT YYADSVKDRFTISRDDSQSILYLQMNNLKTEDTAMYYC VRHGNFGNSYVSWFAY WGQGTLVTVSA QVQLKQSGPGLVQPSQSLSITCTVS GFSLTNYG VHWVRQSPGKGLEWLGV IWSGGNT DYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYC ARALTYYDYEFAY WGQGTLVTVSA [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPPCPAPELLGGP ggggs EVKLLESGGGLVQPKGSLKLSCAAS GFTFNTYA MNWVRQAPGKGLEWVAR IRSKYNNYAT YYADSVKDRFTISRDDSQSILYLQMNNLKTEDTAMYYC VRHGNFGNSYVSWFAY WGQGTLVTVSA

ACE-26-VL amino acid sequence (서열번호: 293)ACE-26-VL amino acid sequence (SEQ ID NO: 293)

QVQLKQSGPGLVQPSQSLSITCTVS GFSLTNYG VHWVRQSPGKGLEWLGV IWSGGNT DYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYC ARALTYYDYEFAY WGQGTLVTVSA[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPPCPAPELLGGPggggsQAVVTQESALTTSPGETVTLTCRSS TGAVTTSNY ANWVQEKPDHLFTGLIG GTN KRAPGVPARFSGSLIGDKAALTITGAQTEDEAIYFC ALWYSNLWV FGGGTKLTVL QVQLKQSGPGLVQPSQSLSITCTVS GFSLTNYG VHWVRQSPGKGLEWLGV IWSGGNT DYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYC ARALTYYDYEFAY WGQGTLVTVSA [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPPCPAPELLGGP ggggs QAVVTQESALTTSPGETVTLTCRSS TGAVTTSNY ANWVQEKPDHLFTGLIG GTN KRAPGVPARFSGSLIGDKAALTITGAQTEDEAIYFC ALWYSNLWV FGGGTKLTVL

ACE-26-LC amino acid sequence (서열번호: 232)ACE-26-LC amino acid sequence (SEQ ID NO: 232)

DILLTQSPVILSVSPGERVSFSCRAS QSIGTN IHWYQQRTNGSPRLLIK YAS ESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYC QQNNNWPTT FGAGTKLELK[RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] DILLTQSPVILSVSPGERVSFSCRAS QSIGTN IHWYQQRTNGSPRLLIK YAS ESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYC QQNNNWPTT FGAGTKLELK [ RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWHKVDNALKAQSGNSHKVDNALKLSQS

EGFR을 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 CD3를 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 31에 열거되어있다:The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting EGFR and the second antigen binding domain monovalent Fv region targeting CD3 are listed in Table 31 below:

Fab region
(Anti-EGFR)
Fab region
(Anti-EGFR)
VH: QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSA (서열번호: 233)VH: QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSA (SEQ ID NO: 233) VL:
DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELK (서열번호: 237)
VL:
DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELK (SEQ ID NO: 237)
CDR H1: GFSLTNYG (서열번호: 234)CDR H1: GFSLTNYG (SEQ ID NO: 234) CDR L1: QSIGTN (서열번호: 238)CDR L1: QSIGTN (SEQ ID NO: 238) CDR H2: IWSGGNT (서열번호: 235)CDR H2: IWSGGNT (SEQ ID NO: 235) CDR L2: YAS (서열번호: 239)CDR L2: YAS (SEQ ID NO: 239) CDR H3: ARALTYYDYEFAY (서열번호: 236)CDR H3: ARALTYYDYEFAY (SEQ ID NO: 236) CDR L3: QQNNNWPTT (서열번호: 240)CDR L3: QQNNNWPTT (SEQ ID NO: 240) Fv region
(Anti-CD3)
Fv region
(Anti-CD3)
VH: EVKLLESGGGLVQPKGSLKLSCAASGFTFNTYAMNWVRQAPGKGLEWVARIRSKYNNYATYYADSVKDRFTISRDDSQSILYLQMNNLKTEDTAMYYCVRHGNFGNSYVSWFAYWGQGTLVTVSA (서열번호: 294)VH: EVKLLESGGGLVQPKGSLKLSCAASGFTFNTYAMNWVRQAPGKGLEWVARIRSKYNNYATYYADSVKDRFTISRDDSQSILYLQMNNLKTEDTAMYYCVRHGNFGNSYVSWFAYWGQGTLVTVSA (SEQ ID NO: 294) VL:
QAVVTQESALTTSPGETVTLTCRSSTGAVTTSNYANWVQEKPDHLFTGLIGGTNKRAPGVPARFSGSLIGDKAALTITGAQTEDEAIYFCALWYSNLWVFGGGTKLTVL (서열번호: 298)
VL:
QAVVTQESALTTSPGETVTLTCRSSTGAVTTSNYANWVQEKPDHLFTGLIGGTNKRAPGVPARFSGSLIGDKAALTITGAQTEDEAIYFCALWYSNLWVFGGGTKLTVL (SEQ ID NO: 298)
CDR H1: GFTFNTYA (서열번호: 295)CDR H1: GFTFNTYA (SEQ ID NO: 295) CDR L1: TGAVTTSNY (서열번호: 299)CDR L1: TGAVTTSNY (SEQ ID NO: 299) CDR H2: IRSKYNNYAT (서열번호: 296)CDR H2: IRSKYNNYAT (SEQ ID NO: 296) CDR L2: GTN (서열번호: 300)CDR L2: GTN (SEQ ID NO: 300) CDR H3: VRHGNFGNSYVSWFAY (서열번호: 297)CDR H3: VRHGNFGNSYVSWFAY (SEQ ID NO: 297) CDR L3: ALWYSNLWV (서열번호: 301)CDR L3: ALWYSNLWV (SEQ ID NO: 301)

실시예 21.28. ACE-27의 제조Example 21.28. Preparation of ACE-27

ACE-27은 2개의 상이한 중쇄 유사 사슬 (ACE-27-VH 및 ACE-27-VL) 및 2개의 동일한 경쇄 (ACE-27-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다:ACE-27 contains two different heavy chain-like chains (ACE-27-VH and ACE-27-VL) and two identical light chains (ACE-27-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-27-VH amino acid sequence (서열번호: 302)ACE-27-VH amino acid sequence (SEQ ID NO: 302)

QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPPCPAPELLGGPggggs EVKLLESGGGLVQPKGSLKLSCAAS GFTFNTYA MNWVRQAPGKGLEWVAR IRSKYNNYAT YYADSVKDRFTISRDDSQSILYLQMNNLKTEDTAMYYC VRHGNFGNSYVSWFAY WGQGTLVTVSA QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPPCPAPELLGGPggggs EVKLLESGGGLVQPKGSLKLSCAAS GFTFNTYA MNWVRQAPGKGLEWVAR IRSKYNNYAT YYADSVKDRFTISRDDSQSILYLQMNNLKTEDTAMYYC VRHGNFGNSYVSWFAY WGQGTLVTVSA

ACE-27-VL amino acid sequence (서열번호: 303)ACE-27-VL amino acid sequence (SEQ ID NO: 303)

QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPPCPAPELLGGPggggsQAVVTQESALTTSPGETVTLTCRSS TGAVTTSNY ANWVQEKPDHLFTGLIG GTN KRAPGVPARFSGSLIGDKAALTITGAQTEDEAIYFC ALWYSNLWV FGGGTKLTVL QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPPCPAPELLGGP ggggs QAVVTQESALTTSPGETVTLTCRSS TGAVTTSNY ANWVQEKPDHLFTGLIG GTN KRAPGVPARFSGSLIGDKAALTITGAQTEDEAIYFC ALWYSNLWV FGGGTKLTVL

ACE-27-LC amino acid sequence (서열번호: 304)ACE-27-LC amino acid sequence (SEQ ID NO: 304)

QAVVTQESALTTSPGETVTLTCRSSTGAVTTSNYANWVQEKPDHLFTGLIGGTNKRAPGVPARFSGSLIGDKAALTITGAQTEDEAIYFCALWYSNLWVFGGGTKLTVL[RSVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC]* QAVVTQESALTTSPGETVTLTCRSS TGAVTTSNY ANWVQEKPDHLFTGLIG GTN KRAPGVPARFSGSLIGDKAALTITGAQTEDEAIYFC ALWYSNLWV FGGGTKLTVL[ RSVAAPSVFIFPPSDEQLKSGTKLTVL[ RSVAAPSVFIFPPSDEQLKSGTGGNASVVCLLNNFYPREAKSKVQSKVLTQDSKVQWKVDSKLSKVD

PD-L1을 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 CD3를 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 32에 열거되어있다:The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting PD-L1 and the second antigen binding domain monovalent Fv region targeting CD3 are listed in Table 32 below. have:

Fab region
(Anti-PD-L1)
Fab region
(Anti-PD-L1)
VH: QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (서열번호: 158)VH: QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (SEQ ID NO: 158) VL:
QAVVTQESALTTSPGETVTLTCRSSTGAVTTSNYANWVQEKPDHLFTGLIGGTNKRAPGVPARFSGSLIGDKAALTITGAQTEDEAIYFCALWYSNLWVFGGGTKLTVL (서열번호: 313)
VL:
QAVVTQESALTTSPGETVTLTCRSSTGAVTTSNYANWVQEKPDHLFTGLIGGTNKRAPGVPARFSGSLIGDKAALTITGAQTEDEAIYFCALWYSNLWVFGGGTKLTVL (SEQ ID NO: 313)
CDR H1: GGTFSSYA (서열번호: 159)CDR H1: GGTFSSYA (SEQ ID NO: 159) CD TGAVTTSNY (서열번호: 314)
R L1:
CD TGAVTTSNY (SEQ ID NO: 314)
R L1:
CDR H2: IIPILGIA (서열번호: 160)CDR H2: IIPILGIA (SEQ ID NO: 160) CDR L2: GTN (서열번호: 315)CDR L2: GTN (SEQ ID NO: 315) CDR H3: AKPRDGYNLVAFDI (서열번호: 161)CDR H3: AKPRDGYNLVAFDI (SEQ ID NO: 161) CDR L3: ALWYSNLWV (서열번호: 316)CDR L3: ALWYSNLWV (SEQ ID NO: 316) Fv region
(Anti-CD3)
Fv region
(Anti-CD3)
VH: EVKLLESGGGLVQPKGSLKLSCAASGFTFNTYAMNWVRQAPGKGLEWVARIRSKYNNYATYYADSVKDRFTISRDDSQSILYLQMNNLKTEDTAMYYCVRHGNFGNSYVSWFAYWGQGTLVTVSA (서열번호: 305)VH: EVKLLESGGGLVQPKGSLKLSCAASGFTFNTYAMNWVRQAPGKGLEWVARIRSKYNNYATYYADSVKDRFTISRDDSQSILYLQMNNLKTEDTAMYYCVRHGNFGNSYVSWFAYWGQGTLVTVSA (SEQ ID NO: 305) VL:
QAVVTQESALTTSPGETVTLTCRSSTGAVTTSNYANWVQEKPDHLFTGLIGGTNKRAPGVPARFSGSLIGDKAALTITGAQTEDEAIYFCALWYSNLWVFGGGTKLTVL (서열번호: 309)
VL:
QAVVTQESALTTSPGETVTLTCRSSTGAVTTSNYANWVQEKPDHLFTGLIGGTNKRAPGVPARFSGSLIGDKAALTITGAQTEDEAIYFCALWYSNLWVFGGGTKLTVL (SEQ ID NO: 309)
CDR H1: GFTFNTYA (서열번호: 306)CDR H1: GFTFNTYA (SEQ ID NO: 306) CDR L1: TGAVTTSNY (서열번호: 310)CDR L1: TGAVTTSNY (SEQ ID NO: 310) CDR H2: IRSKYNNYAT (서열번호: 307)CDR H2: IRSKYNNYAT (SEQ ID NO: 307) CDR L2: GTN (서열번호: 311)CDR L2: GTN (SEQ ID NO: 311) CDR H3: VRHGNFGNSYVSWFAY (서열번호: 308)CDR H3: VRHGNFGNSYVSWFAY (SEQ ID NO: 308) CDR L3: ALWYSNLWV (서열번호: 312)CDR L3: ALWYSNLWV (SEQ ID NO: 312)

실시예 21.29. ACE-28의 제조Example 21.29. Preparation of ACE-28

ACE-28은 2개의 상이한 중쇄 유사 사슬 (ACE-28-VH 및 ACE-28-VL) 및 2개의 동일한 경쇄 (ACE-28-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다:ACE-28 contains two different heavy chain-like chains (ACE-28-VH and ACE-28-VL) and two identical light chains (ACE-28-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-28-VH amino acid sequence (서열번호: 317)ACE-28-VH amino acid sequence (SEQ ID NO: 317)

QVQLKQSGPGLVQPSQSLSITCTVS GFSLTNYG VHWVRQSPGKGLEWLGV IWSGGNT DYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYC ARALTYYDYEFAY WGQGTLVTVSA[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPPCPAPELLGGPggggsEVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFS GQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK QVQLKQSGPGLVQPSQSLSITCTVS GFSLTNYG VHWVRQSPGKGLEWLGV IWSGGNT DYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYC ARALTYYDYEFAY WGQGTLVTVSA [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPPCPAPELLGGP ggggs EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFS GQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

ACE-28-VL amino acid sequence (서열번호: 318)ACE-28-VL amino acid sequence (SEQ ID NO: 318)

QVQLKQSGPGLVQPSQSLSITCTVS GFSLTNYG VHWVRQSPGKGLEWLGV IWSGGNT DYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCAR ALTYYDYEFAY WGQGTLVTVSA[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPPCPAPELLGGPggggsDIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR GQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK QVQLKQSGPGLVQPSQSLSITCTVS GFSLTNYG VHWVRQSPGKGLEWLGV IWSGGNT DYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCAR ALTYYDYEFAY WGQGTLVTVSA [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPPCPAPELLGGP ggggs DIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR GQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

ACE-28-LC amino acid sequence (서열번호: 232)ACE-28-LC amino acid sequence (SEQ ID NO: 232)

DILLTQSPVILSVSPGERVSFSCRAS QSIGTN IHWYQQRTNGSPRLLIK YAS ESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYC QQNNNWPTT FGAGTKLELK[RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] DILLTQSPVILSVSPGERVSFSCRAS QSIGTN IHWYQQRTNGSPRLLIK YAS ESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYC QQNNNWPTT FGAGTKLELK [ RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWHKVDNALKAQSGNSHKVDNALKLSQS

EGFR을 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 CD3를 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 33에 열거되어있다:The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting EGFR and the second antigen binding domain monovalent Fv region targeting CD3 are listed in Table 33 below:

Fab region
(Anti-EGFR)
Fab region
(Anti-EGFR)
VH: QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSA (서열번호: 233)VH: QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSA (SEQ ID NO: 233) VL:
DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELK (서열번호: 237)
VL:
DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELK (SEQ ID NO: 237)
CDR H1: GFSLTNYG (서열번호: 234)CDR H1: GFSLTNYG (SEQ ID NO: 234) CDR L1: QSIGTN (서열번호: 238)CDR L1: QSIGTN (SEQ ID NO: 238) CDR H2: IWSGGNT (서열번호: 235)CDR H2: IWSGGNT (SEQ ID NO: 235) CDR L2: YAS (서열번호: 239)CDR L2: YAS (SEQ ID NO: 239) CDR H3: ARALTYYDYEFAY (서열번호: 236)CDR H3: ARALTYYDYEFAY (SEQ ID NO: 236) CDR L3: QQNNNWPTT (서열번호: 240)CDR L3: QQNNNWPTT (SEQ ID NO: 240) Fv region
(Anti-CD3)
Fv region
(Anti-CD3)
VH: EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (서열번호: 215)VH: EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (SEQ ID NO: 215) VL:
DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (서열번호: 216)
VL:
DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (SEQ ID NO: 216)
CDR H1: GYSFTGYT (서열번호: 177)CDR H1: GYSFTGYT (SEQ ID NO: 177) CDR L1: QDIRNY (서열번호: 181)CDR L1: QDIRNY (SEQ ID NO: 181) CDR H2: INPYKGVS (서열번호: 178)CDR H2: INPYKGVS (SEQ ID NO: 178) CDR L2: YTS (서열번호: 182)CDR L2: YTS (SEQ ID NO: 182) CDR H3: ARSGYYGDSDWYFD (서열번호: 211)CDR H3: ARSGYYGDSDWYFD (SEQ ID NO: 211) CDR L3: QQGNTLPWT (서열번호: 207)CDR L3: QQGNTLPWT (SEQ ID NO: 207)

실시예 21.30. ACE-29의 제조Example 21.30. Preparation of ACE-29

ACE-29는 2개의 상이한 중쇄 유사 사슬 (ACE-29-VH 및 ACE-29-VL) 및 2개의 동일한 경쇄 (ACE-29-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다:ACE-29 contains two different heavy chain-like chains (ACE-29-VH and ACE-29-VL) and two identical light chains (ACE-29-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-29-VH amino acid sequence (서열번호: 319)ACE-29-VH amino acid sequence (SEQ ID NO: 319)

QVQLKQSGPGLVQPSQSLSITCTVS GFSLTNYG VHWVRQSPGKGLEWLGV IWSGGNT DYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYC ARALTYYDYEFAY WGQGTLVTVSA[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPPCPAPELLGGP]ggggsEVKLLESGGGLVQPKGSLKLSCAAS GFTFNTYA MNWVRQAPGKGLEWVAR IRSKYNNYAT YYADSVKDRFTISRDDSQSILYLQMNNLKTEDTAMYYC VRHGNFGNSYVSWFAY WGQGTLVTVSA GQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK QVQLKQSGPGLVQPSQSLSITCTVS GFSLTNYG VHWVRQSPGKGLEWLGV IWSGGNT DYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYC ARALTYYDYEFAY WGQGTLVTVSA [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPPCPAPELLGGP] ggggs EVKLLESGGGLVQPKGSLKLSCAAS GFTFNTYA MNWVRQAPGKGLEWVAR IRSKYNNYAT YYADSVKDRFTISRDDSQSILYLQMNNLKTEDTAMYYC VRHGNFGNSYVSWFAY WGQGTLVTVSA GQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

ACE-29-VL amino acid sequence (서열번호: 320)ACE-29-VL amino acid sequence (SEQ ID NO: 320)

QVQLKQSGPGLVQPSQSLSITCTVS GFSLTNYG VHWVRQSPGKGLEWLGV IWSGGNT DYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYC ARALTYYDYEFAY WGQGTLVTVSA[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPPCPAPELLGGP]ggggsQAVVTQESALTTSPGETVTLTCRSS TGAVTTSNY ANWVQEKPDHLFTGLIG GTN KRAPGVPARFSGSLIGDKAALTITGAQTEDEAIYFC ALWYSNLWV FGGGTKLTVL GQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK QVQLKQSGPGLVQPSQSLSITCTVS GFSLTNYG VHWVRQSPGKGLEWLGV IWSGGNT DYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYC ARALTYYDYEFAY WGQGTLVTVSA [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPPCPAPELLGGP] ggggs QAVVTQESALTTSPGETVTLTCRSS TGAVTTSNY ANWVQEKPDHLFTGLIG GTN KRAPGVPARFSGSLIGDKAALTITGAQTEDEAIYFC ALWYSNLWV FGGGTKLTVL GQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

ACE-29-LC amino acid sequence (서열번호: 232)ACE-29-LC amino acid sequence (SEQ ID NO: 232)

DILLTQSPVILSVSPGERVSFSCRAS QSIGTN IHWYQQRTNGSPRLLIK YAS ESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYC QQNNNWPTT FGAGTKLELK[RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] DILLTQSPVILSVSPGERVSFSCRAS QSIGTN IHWYQQRTNGSPRLLIK YAS ESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYC QQNNNWPTT FGAGTKLELK [ RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWHKVDNALKAQSGNSHKVDNALKLSQS

EGFR을 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 CD3를 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 34에 열거되어있다:The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting EGFR and the second antigen binding domain monovalent Fv region targeting CD3 are listed in Table 34 below:

Fab region
(Anti-EGFR)
Fab region
(Anti-EGFR)
VH: QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSA (서열번호: 233)VH: QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSA (SEQ ID NO: 233) VL:
DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELK (서열번호: 237)
VL:
DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELK (SEQ ID NO: 237)
CDR H1: GFSLTNYG (서열번호: 234)CDR H1: GFSLTNYG (SEQ ID NO: 234) CDR L1: QSIGTN (서열번호: 238)CDR L1: QSIGTN (SEQ ID NO: 238) CDR H2: IWSGGNT (서열번호: 235)CDR H2: IWSGGNT (SEQ ID NO: 235) CDR L2: YAS (서열번호: 239)CDR L2: YAS (SEQ ID NO: 239) CDR H3: ARALTYYDYEFAY (서열번호: 236)CDR H3: ARALTYYDYEFAY (SEQ ID NO: 236) CDR L3: QQNNNWPTT (서열번호: 240)CDR L3: QQNNNWPTT (SEQ ID NO: 240) Fv region
(Anti-CD3)
Fv region
(Anti-CD3)
VH:
EVKLLESGGGLVQPKGSLKLSCAASGFTFNTYAMNWVRQAPGKGLEWVARIRSKYNNYATYYADSVKDRFTISRDDSQSILYLQMNNLKTEDTAMYYCVRHGNFGNSYVSWFAYWGQGTLVTVSA (서열번호: 294)
VH:
EVKLLESGGGLVQPKGSLKLSCAASGFTFNTYAMNWVRQAPGKGLEWVARIRSKYNNYATYYADSVKDRFTISRDDSQSILYLQMNNLKTEDTAMYYCVRHGNFGNSYVSWFAYWGQGTLVTVSA (SEQ ID NO: 294)
VL:
QAVVTQESALTTSPGETVTLTCRSSTGAVTTSNYANWVQEKPDHLFTGLIGGTNKRAPGVPARFSGSLIGDKAALTITGAQTEDEAIYFCALWYSNLWVFGGGTKLTVL (서열번호: 298)
VL:
QAVVTQESALTTSPGETVTLTCRSSTGAVTTSNYANWVQEKPDHLFTGLIGGTNKRAPGVPARFSGSLIGDKAALTITGAQTEDEAIYFCALWYSNLWVFGGGTKLTVL (SEQ ID NO: 298)
CDR H1: GFTFNTYA (서열번호: 295)CDR H1: GFTFNTYA (SEQ ID NO: 295) CDR L1: TGAVTTSNY (서열번호: 299)CDR L1: TGAVTTSNY (SEQ ID NO: 299) CDR H2: IRSKYNNYAT (서열번호: 296)CDR H2: IRSKYNNYAT (SEQ ID NO: 296) CDR L2: GTN (서열번호: 300)CDR L2: GTN (SEQ ID NO: 300) CDR H3: VRHGNFGNSYVSWFAY (서열번호: 297)CDR H3: VRHGNFGNSYVSWFAY (SEQ ID NO: 297) CDR L3: ALWYSNLWV (서열번호: 301)CDR L3: ALWYSNLWV (SEQ ID NO: 301)

실시예 21.31. ACE-30의 제조Example 21.31. Preparation of ACE-30

ACE-30은 2개의 상이한 중쇄 유사 사슬 (ACE-30-VH 및 ACE-30-VL) 및 2개의 동일한 경쇄 (ACE-30-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다:ACE-30 contains two different heavy chain-like chains (ACE-30-VH and ACE-30-VL) and two identical light chains (ACE-30-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-30-VH amino acid sequence (서열번호: 322)ACE-30-VH amino acid sequence (SEQ ID NO: 322)

EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFDV WGQGTTLTVFS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPAPELLGGPggggsQMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFDV WGQGTTLTVFS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPAPELLGGP ggggs QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS

ACE-30-VL amino acid sequence (서열번호: 323)ACE-30-VL amino acid sequence (SEQ ID NO: 323)

EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFDV WGQGTTLTVFS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPAPELLGGPggggsQLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVLR EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFDV WGQGTTLTVFS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPAPELLGGP ggggs QLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVLR

ACE-30-LC amino acid sequence (서열번호: 324)ACE-30-LC amino acid sequence (SEQ ID NO: 324)

DIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR[TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] DIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR [ TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPYPREAKVQWKVDTLSKVQWKLSKDSKSKLSVT

CD3를 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 PD-L1을 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 35에 열거되어있다:The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting CD3 and the second antigen binding domain monovalent Fv region targeting PD-L1 are listed in Table 35 below. have:

Fab region
(Anti-CD3)
Fab region
(Anti-CD3)
VH: EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (서열번호: 325)VH: EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (SEQ ID NO: 325) VL:
DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (서열번호: 337)
VL:
DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (SEQ ID NO: 337)
CDR H1: GYSFTGYT (서열번호: 326)CDR H1: GYSFTGYT (SEQ ID NO: 326) CDR L1: QDIRNY (서열번호: 338)CDR L1: QDIRNY (SEQ ID NO: 338) CDR H2: INPYKGVS (서열번호: 327)CDR H2: INPYKGVS (SEQ ID NO: 327) CDR L2: YTS (서열번호: 339)CDR L2: YTS (SEQ ID NO: 339) CDR H3: ARSGYYGDSDWYFDV (서열번호: 328)CDR H3: ARSGYYGDSDWYFDV (SEQ ID NO: 328) CDR L3: QQGNTLPWT (서열번호: 340)CDR L3: QQGNTLPWT (SEQ ID NO: 340) Fv region
(Anti-PD-L1)
Fv region
(Anti-PD-L1)
VH:
QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (서열번호: 329)
VH:
QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (SEQ ID NO: 329)
VL: QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLR (서열번호: 333)VL: QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLR (SEQ ID NO: 333)
CDR H1: GGTFSSYA (서열번호: 330)CDR H1: GGTFSSYA (SEQ ID NO: 330) CDR L1: SSNIGAGYD (서열번호: 334)CDR L1: SSNIGAGYD (SEQ ID NO: 334) CDR H2: IIPILGIA (서열번호: 331)CDR H2: IIPILGIA (SEQ ID NO: 331) CDR L2: GDI (서열번호: 335)CDR L2: GDI (SEQ ID NO: 335) CDR H3: AKPRDGYNLVAFDI (서열번호: 332)CDR H3: AKPRDGYNLVAFDI (SEQ ID NO: 332) CDR L3: QSYDSSLSGGV (서열번호: 336)CDR L3: QSYDSSLSGGV (SEQ ID NO: 336)

실시예 21.32. ACE-31의 제조Example 21.32. Preparation of ACE-31

ACE-31은 2개의 상이한 중쇄 유사 사슬 (ACE-31-VH 및 ACE-31-VL) 및 2개의 동일한 경쇄 (ACE-31-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다:ACE-31 contains two different heavy chain-like chains (ACE-31-VH and ACE-31-VL) and two identical light chains (ACE-31-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-31-VH amino acid sequence (서열번호: 344)ACE-31-VH amino acid sequence (SEQ ID NO: 344)

EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFDV WGQGTTLTVFS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPPCPAPELLGGPggggsggggsQMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFDV WGQGTTLTVFS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPPCPAPELLGGP ggggsggggs QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS

ACE-31-VL amino acid sequence (서열번호: 345)ACE-31-VL amino acid sequence (SEQ ID NO: 345)

EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFDV WGQGTTLTVFS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPPCPAPELLGGPggggsQLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVLR EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFDV WGQGTTLTVFS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPPCPAPELLGGP ggggs QLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVLR

ACE-31-LC amino acid sequence (서열번호: 324)ACE-31-LC amino acid sequence (SEQ ID NO: 324)

DIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR[TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] DIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR [ TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPYPREAKVQWKVDTLSKVQWKLSKDSKSKLSVT

CD3을 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 PD-L1을 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 36에 열거되어있다:The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting CD3 and the second antigen binding domain monovalent Fv region targeting PD-L1 are listed in Table 36 below. have:

Fab region
(Anti-CD3)
Fab region
(Anti-CD3)
VH: EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (서열번호: 325)VH: EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (SEQ ID NO: 325) VL:
DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (서열번호: 337)
VL:
DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (SEQ ID NO: 337)
CDR H1: GYSFTGYT (서열번호: 326)CDR H1: GYSFTGYT (SEQ ID NO: 326) CDR L1: QDIRNY (서열번호: 338)CDR L1: QDIRNY (SEQ ID NO: 338) CDR H2: INPYKGVS (서열번호: 327)CDR H2: INPYKGVS (SEQ ID NO: 327) CDR L2: YTS (서열번호: 339)CDR L2: YTS (SEQ ID NO: 339) CDR H3: ARSGYYGDSDWYFDV (서열번호: 328)CDR H3: ARSGYYGDSDWYFDV (SEQ ID NO: 328) CDR L3: QQGNTLPWT (서열번호: 340)CDR L3: QQGNTLPWT (SEQ ID NO: 340) Fv region
(Anti-PD-L1)
Fv region
(Anti-PD-L1)
VH: QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (서열번호: 329)VH: QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (SEQ ID NO: 329) VL:
QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLR (서열번호: 333)
VL:
QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLR (SEQ ID NO: 333)
CDR H1: GGTFSSYA (서열번호: 330)CDR H1: GGTFSSYA (SEQ ID NO: 330) CDR L1: SSNIGAGYD (서열번호: 334)CDR L1: SSNIGAGYD (SEQ ID NO: 334) CDR H2: IIPILGIA (서열번호: 331)CDR H2: IIPILGIA (SEQ ID NO: 331) CDR L2: GDI (서열번호: 335)CDR L2: GDI (SEQ ID NO: 335) CDR H3: AKPRDGYNLVAFDI (서열번호: 332)CDR H3: AKPRDGYNLVAFDI (SEQ ID NO: 332) CDR L3: QSYDSSLSGGV (서열번호: 336)CDR L3: QSYDSSLSGGV (SEQ ID NO: 336)

실시예 21.33. ACE-32의 제조Example 21.33. Preparation of ACE-32

ACE-32는 2개의 상이한 중쇄 유사 사슬 (ACE-32-VH 및 ACE-32-VL) 및 2개의 동일한 경쇄 (ACE-32-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다:ACE-32 contains two different heavy chain-like chains (ACE-32-VH and ACE-32-VL) and two identical light chains (ACE-32-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-32-VH amino acid sequence (서열번호: 342)ACE-32-VH amino acid sequence (SEQ ID NO: 342)

QVQLKQSGPGLVQPSQSLSITCTVS GFSLTNYG VHWVRQSPGKGLEWLGV IWSGGNT DYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYC ARALTYYDYEFAY WGQGTLVTVSA[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPPCPAPELLGGPggggsggggsEVKLLESGGGLVQPKGSLKLSCAAS GFTFNTYA MNWVRQAPGKGLEWVAR IRSKYNNYAT YYADSVKDRFTISRDDSQSILYLQMNNLKTEDTAMYYC VRHGNFGNSYVSWFAY WGQGTLVTVSA QVQLKQSGPGLVQPSQSLSITCTVS GFSLTNYG VHWVRQSPGKGLEWLGV IWSGGNT DYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYC ARALTYYDYEFAY WGQGTLVTVSA [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPPCPAPELLGGP ggggsggggs EVKLLESGGGLVQPKGSLKLSCAAS GFTFNTYA MNWVRQAPGKGLEWVAR IRSKYNNYAT YYADSVKDRFTISRDDSQSILYLQMNNLKTEDTAMYYC VRHGNFGNSYVSWFAY WGQGTLVTVSA

ACE-32-VL amino acid sequence) (서열번호: 293)ACE-32-VL amino acid sequence) (SEQ ID NO: 293)

QVQLKQSGPGLVQPSQSLSITCTVS GFSLTNYG VHWVRQSPGKGLEWLGV IWSGGNT DYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYC ARALTYYDYEFAY WGQGTLVTVSA[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPPCPAPELLGGPggggsQAVVTQESALTTSPGETVTLTCRSS TGAVTTSNY ANWVQEKPDHLFTGLIG GTN KRAPGVPARFSGSLIGDKAALTITGAQTEDEAIYFC ALWYSNLWV FGGGTKLTVL QVQLKQSGPGLVQPSQSLSITCTVS GFSLTNYG VHWVRQSPGKGLEWLGV IWSGGNT DYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYC ARALTYYDYEFAY WGQGTLVTVSA [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPPCPAPELLGGP ggggs QAVVTQESALTTSPGETVTLTCRSS TGAVTTSNY ANWVQEKPDHLFTGLIG GTN KRAPGVPARFSGSLIGDKAALTITGAQTEDEAIYFC ALWYSNLWV FGGGTKLTVL

ACE-32-LC amino acid sequence (서열번호: 232)ACE-32-LC amino acid sequence (SEQ ID NO: 232)

DILLTQSPVILSVSPGERVSFSCRAS QSIGTN IHWYQQRTNGSPRLLIK YAS ESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYC QQNNNWPTT FGAGTKLELK[RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] DILLTQSPVILSVSPGERVSFSCRAS QSIGTN IHWYQQRTNGSPRLLIK YAS ESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYC QQNNNWPTT FGAGTKLELK [ RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWHKVDNALKAQSGNSHKVDNALKLSQS

EGFR을 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 CD3를 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 37에 열거되어있다:The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting EGFR and the second antigen binding domain monovalent Fv region targeting CD3 are listed in Table 37 below:

Fab region
(EGFR)
Fab region
(EGFR)
VH: QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSA (서열번호: 233)VH: QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSA (SEQ ID NO: 233) VL: DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELK (서열번호: 237)VL: DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELK (SEQ ID NO: 237)
CDR H1: GFSLTNYG (서열번호: 234)CDR H1: GFSLTNYG (SEQ ID NO: 234) CDR L1: QSIGTN (서열번호: 238)CDR L1: QSIGTN (SEQ ID NO: 238) CDR H2: IWSGGNT (서열번호: 235)CDR H2: IWSGGNT (SEQ ID NO: 235) CDR L2: YAS (서열번호: 239)CDR L2: YAS (SEQ ID NO: 239) CDR H3: ARALTYYDYEFAY (서열번호: 236)CDR H3: ARALTYYDYEFAY (SEQ ID NO: 236) CDR L3: QQNNNWPTT (서열번호: 240)CDR L3: QQNNNWPTT (SEQ ID NO: 240) Fv region
(Anti-CD3)
Fv region
(Anti-CD3)
VH: EVKLLESGGGLVQPKGSLKLSCAASGFTFNTYAMNWVRQAPGKGLEWVARIRSKYNNYATYYADSVKDRFTISRDDSQSILYLQMNNLKTEDTAMYYCVRHGNFGNSYVSWFAYWGQGTLVTVSA (서열번호: 294)VH: EVKLLESGGGLVQPKGSLKLSCAASGFTFNTYAMNWVRQAPGKGLEWVARIRSKYNNYATYYADSVKDRFTISRDDSQSILYLQMNNLKTEDTAMYYCVRHGNFGNSYVSWFAYWGQGTLVTVSA (SEQ ID NO: 294) VL:
QAVVTQESALTTSPGETVTLTCRSSTGAVTTSNYANWVQEKPDHLFTGLIGGTNKRAPGVPARFSGSLIGDKAALTITGAQTEDEAIYFCALWYSNLWVFGGGTKLTVL (서열번호: 298)
VL:
QAVVTQESALTTSPGETVTLTCRSSTGAVTTSNYANWVQEKPDHLFTGLIGGTNKRAPGVPARFSGSLIGDKAALTITGAQTEDEAIYFCALWYSNLWVFGGGTKLTVL (SEQ ID NO: 298)
CDR H1: GFTFNTYA (서열번호: 295)CDR H1: GFTFNTYA (SEQ ID NO: 295) CDR L1: TGAVTTSNY (서열번호: 299)CDR L1: TGAVTTSNY (SEQ ID NO: 299) CDR H2: IRSKYNNYAT (서열번호: 296)CDR H2: IRSKYNNYAT (SEQ ID NO: 296) CDR L2: GTN (서열번호: 300)CDR L2: GTN (SEQ ID NO: 300) CDR H3: VRHGNFGNSYVSWFAY (서열번호: 297)CDR H3: VRHGNFGNSYVSWFAY (SEQ ID NO: 297) CDR L3: ALWYSNLWV (서열번호: 301)CDR L3: ALWYSNLWV (SEQ ID NO: 301)

실시예 21.34. ACE-33의 제조Example 21.34. Preparation of ACE-33

ACE-33은 2개의 상이한 중쇄 유사 사슬 (ACE-33-VH 및 ACE-33-VL) 및 2개의 동일한 경쇄 (ACE-33-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다:ACE-33 contains two different heavy chain-like chains (ACE-33-VH and ACE-33-VL) and two identical light chains (ACE-33-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-33-VH amino acid sequence (서열번호: 341)ACE-33-VH amino acid sequence (SEQ ID NO: 341)

EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFDV WGQGTTLTVFS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPAPELLGGPggggsggggsQMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFDV WGQGTTLTVFS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPAPELLGGP ggggsggggs QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS

ACE-33-VL amino acid sequence (서열번호: 323)ACE-33-VL amino acid sequence (SEQ ID NO: 323)

EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFDV WGQGTTLTVFS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPAPELLGGPggggsQLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVLR EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFDV WGQGTTLTVFS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPAPELLGGP ggggs QLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVLR

ACE-33-LC amino acid sequence (서열번호: 324)ACE-33-LC amino acid sequence (SEQ ID NO: 324)

DIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR[TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] DIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR [ TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPYPREAKVQWKVDTLSKVQWKLSKDSKSKLSVT

CD3을 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 PD-L1을 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 38에 열거되어있다:The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting CD3 and the second antigen binding domain monovalent Fv region targeting PD-L1 are listed in Table 38 below. have:

Fab region
(Anti-CD3)
Fab region
(Anti-CD3)
VH: EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (서열번호: 325)VH: EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (SEQ ID NO: 325) VL: DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (서열번호: 337)VL: DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (SEQ ID NO: 337)
CDR H1: GYSFTGYT (서열번호: 326)CDR H1: GYSFTGYT (SEQ ID NO: 326) CDR L1: QDIRNY (서열번호: 338)CDR L1: QDIRNY (SEQ ID NO: 338) CDR H2: INPYKGVS (서열번호: 327)CDR H2: INPYKGVS (SEQ ID NO: 327) CDR L2: YTS (서열번호: 339)CDR L2: YTS (SEQ ID NO: 339) CDR H3: ARSGYYGDSDWYFDV (서열번호: 328)CDR H3: ARSGYYGDSDWYFDV (SEQ ID NO: 328) CDR L3: QQGNTLPWT (서열번호: 340)CDR L3: QQGNTLPWT (SEQ ID NO: 340) Fv region
(Anti-PD-L1)
Fv region
(Anti-PD-L1)
VH:
QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (서열번호: 329)
VH:
QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (SEQ ID NO: 329)
VL: QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLR(서열번호: 333)VL: QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLR (SEQ ID NO: 333)
CDR H1: GGTFSSYA (서열번호: 330)CDR H1: GGTFSSYA (SEQ ID NO: 330) CDR L1: SSNIGAGYD (서열번호: 334CDR L1: SSNIGAGYD (SEQ ID NO: 334 CDR H2: IIPILGIA (서열번호: 331)CDR H2: IIPILGIA (SEQ ID NO: 331) CDR L2: GDI (서열번호: 335)CDR L2: GDI (SEQ ID NO: 335) CDR H3: AKPRDGYNLVAFDI (서열번호: 332)CDR H3: AKPRDGYNLVAFDI (SEQ ID NO: 332) CDR L3: QSYDSSLSGGV (서열번호: 336)CDR L3: QSYDSSLSGGV (SEQ ID NO: 336)

실시예 21.35. ACE-34의 제조Example 21.35. Preparation of ACE-34

ACE-34는 2개의 상이한 중쇄 유사 사슬 (ACE-34-VH 및 ACE-34-VL) 및 2개의 동일한 경쇄 (ACE-34-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다:ACE-34 contains two different heavy chain-like chains (ACE-34-VH and ACE-34-VL) and two identical light chains (ACE-34-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-34-VH amino acid sequence (서열번호: 346)ACE-34-VH amino acid sequence (SEQ ID NO: 346)

QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPPCPAPELLGGPggggsEVQLVESGGGLVQPGKSLKLSCEASGFTFS GYGMH WVRQAPGRGLESVA YITSSSINIKYADAVKG RFTVSRDNAKNLLFLQMNILKSEDTAMYYCAR FDWDKN YWGQGTMVTVSS QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPPCPAPELLGGP ggggs EVQLVESGGGLVQPGKSLKLSCEASGFTFS GYGMH WVRQAPGRGLESVA YITSSSINIKYADAVKG RFTVSRDNAKNLLFLQMNILKSEDTAMYYCAR FDWDKN YWGQGTMVTVSS

ACE-34-VL amino acid sequence (서열번호: 347)ACE-34-VL amino acid sequence (SEQ ID NO: 347)

QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPPCPAPELLGGPggggsDIQMTQSPSSLPASLGDRVTINC QASQDISNYLN WYQQKPGKAPKLLIY YTNKLAD GVPSRFSGSGSGRDSSFTISSLESEDIGSYYC QQYYNYPWT FGPGTKLEIK QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPPCPAPELLGGP ggggs DIQMTQSPSSLPASLGDRVTINC QASQDISNYLN WYQQKPGKAPKLLIY YTNKLAD GVPSRFSGSGSGRDSSFTISSLESEDIGSYYC QQYYNYPWT FGPGTKLEIK

ACE-34-LC amino acid sequence (서열번호: 157)ACE-34-LC amino acid sequence (SEQ ID NO: 157)

QLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVLR[SVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] QLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVLR [SVAAPSVFIFPPSDEQLKSGTASVVCSKSVLTQLKSGTASVVCSKNFQLKSGTASVVCSKNFREADS

PD-L1을 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 CD3를 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 39에 열거되어있다:The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting PD-L1 and the second antigen binding domain monovalent Fv region targeting CD3 are listed in Table 39 below. have:

Fab region
(Anti-PD-L1)
Fab region
(Anti-PD-L1)
VH: QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (서열번호: 158)VH: QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (SEQ ID NO: 158) VL: QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLR(서열번호: 170)
VL: QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLR (SEQ ID NO: 170)
CDR H1: GGTFSSYA (서열번호: 159)CDR H1: GGTFSSYA (SEQ ID NO: 159) CDR L1: SSNIGAGYD (서열번호: 171)CDR L1: SSNIGAGYD (SEQ ID NO: 171) CDR H2: IIPILGIA (서열번호: 160)CDR H2: IIPILGIA (SEQ ID NO: 160) CDR L2: GDI (서열번호: 172)CDR L2: GDI (SEQ ID NO: 172) CDR H3: AKPRDGYNLVAFDI (서열번호: 161)CDR H3: AKPRDGYNLVAFDI (SEQ ID NO: 161) CDR L3: QSYDSSLSGGV (서열번호: 173)CDR L3: QSYDSSLSGGV (SEQ ID NO: 173) Fv region
(Anti-CD3)
Fv region
(Anti-CD3)
VH: EVQLVESGGGLVQPGKSLKLSCEASGFTFSGYGMHWVRQAPGRGLESVAYITSSSINIKYADAVKGRFTVSRDNAKNLLFLQMNILKSEDTAMYYCARFDWDKNYWGQGTMVTVSS (서열번호: 348)VH: EVQLVESGGGLVQPGKSLKLSCEASGFTFSGYGMHWVRQAPGRGLESVAYITSSSINIKYADAVKGRFTVSRDNAKNLLFLQMNILKSEDTAMYYCARFDWDKNYWGQGTMVTVSS (SEQ ID NO: 348) VL: DIQMTQSPSSLPASLGDRVTINCQASQDISNYLNWYQQKPGKAPKLLIYYTNKLADGVPSRFSGSGSGRDSSFTISSLESEDIGSYYCQQYYNYPWTFGPGTKLEIK (서열번호: 352)VL: DIQMTQSPSSLPASLGDRVTINCQASQDISNYLNWYQQKPGKAPKLLIYYTNKLADGVPSRFSGSGSGRDSSFTISSLESEDIGSYYCQQYYNYPWTFGPGTKLEIK (SEQ ID NO: 352)
CDR H1: GYGMH (서열번호: 349)CDR H1: GYGMH (SEQ ID NO: 349) CDR L1: QASQDISNYLN (서열번호: 353)CDR L1: QASQDISNYLN (SEQ ID NO: 353) CDR H2: YITSSSINIKYADAVKG (서열번호: 350)CDR H2: YITSSSINIKYADAVKG (SEQ ID NO: 350) CDR L2: YTNKLAD(서열번호: 354)CDR L2: YTNKLAD (SEQ ID NO: 354) CDR H3: FDWDKN (서열번호: 351)CDR H3: FDWDKN (SEQ ID NO: 351) CDR L3: QQYYNYPWT (서열번호: 355)CDR L3: QQYYNYPWT (SEQ ID NO: 355)

실시예 21.36. ACE-35의 제조Example 21.36. Preparation of ACE-35

ACE-35는 2개의 상이한 중쇄 유사 사슬 (ACE-35-VH 및 ACE-35-VL) 및 2개의 동일한 경쇄 (ACE-35-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다:ACE-35 contains two different heavy chain-like chains (ACE-35-VH and ACE-35-VL) and two identical light chains (ACE-35-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-35-VH amino acid sequence (서열번호: 356)ACE-35-VH amino acid sequence (SEQ ID NO: 356)

QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPPCPAPELLGGPggggsQVKLQQSGSELGKPGASVKLSCKTSGYIFT DHYIS WVKQKPGESLQWIG NVYGGNGGTSYNQKFQG KATLTVDKISSTAYMELSSLTSEDSAIYYCAR RPVATGHAMDY WGQGIQVTVSS QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPPCPAPELLGGP ggggs QVKLQQSGSELGKPGASVKLSCKTSGYIFT DHYIS WVKQKPGESLQWIG NVYGGNGGTSYNQKFQG KATLTVDKISSTAYMELSSLTSEDSAIYYCAR RPVATGHAMDY WGQGIQVTVSS

ACE-35-VL amino acid sequence (서열번호: 357)ACE-35-VL amino acid sequence (SEQ ID NO: 357)

QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPPCPAPELLGGPggggsDIVLTQTPATLSLIPGERVTMTC KTSQNIGTILH WYHQKPKEAPRALIK YASQSIP GIPSRFSGSGSETDFTLSINNLEPDDIGIYYC QQSRSWPVT FGPGTKLEIK QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPPCPAPELLGGP ggggs DIVLTQTPATLSLIPGERVTMTC KTSQNIGTILH WYHQKPKEAPRALIK YASQSIP GIPSRFSGSGSETDFTLSINNLEPDDIGIYYC QQSRSWPVT FGPGTKLEIK

ACE-35-LC amino acid sequence (서열번호: 157)ACE-35-LC amino acid sequence (SEQ ID NO: 157)

QLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVLR[SVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] QLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVLR [SVAAPSVFIFPPSDEQLKSGTASVVCSKSVLTQLKSGTASVVCSKNFQLKSGTASVVCSKNFREADS

PD-L1을 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 CD3를 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 40에 열거되어있다:The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting PD-L1 and the second antigen binding domain monovalent Fv region targeting CD3 are listed in Table 40 below. have:

Fab region
(Anti-PD-L1)
Fab region
(Anti-PD-L1)
VH:
QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (서열번호: 158)
VH:
QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (SEQ ID NO: 158)
VL: QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLR(서열번호: 170)VL: QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLR (SEQ ID NO: 170)
CDR H1: GGTFSSYA (서열번호: 159)CDR H1: GGTFSSYA (SEQ ID NO: 159) CDR L1: SSNIGAGYD (서열번호: 171)CDR L1: SSNIGAGYD (SEQ ID NO: 171) CDR H2: IIPILGIA (서열번호: 160)CDR H2: IIPILGIA (SEQ ID NO: 160) CDR L2: GDI (서열번호: 172)CDR L2: GDI (SEQ ID NO: 172) CDR H3: AKPRDGYNLVAFDI (서열번호: 161)CDR H3: AKPRDGYNLVAFDI (SEQ ID NO: 161) CDR L3: QSYDSSLSGGV (서열번호: 173)CDR L3: QSYDSSLSGGV (SEQ ID NO: 173) Fv region
(Anti-CD3)
Fv region
(Anti-CD3)
VH: QVKLQQSGSELGKPGASVKLSCKTSGYIFTDHYISWVKQKPGESLQWIGNVYGGNGGTSYNQKFQGKATLTVDKISSTAYMELSSLTSEDSAIYYCARRPVATGHAMDYWGQGIQVTVSS (서열번호: 358)VH: QVKLQQSGSELGKPGASVKLSCKTSGYIFTDHYISWVKQKPGESLQWIGNVYGGNGGTSYNQKFQGKATLTVDKISSTAYMELSSLTSEDSAIYYCARRPVATGHAMDYWGQGIQVTVSS (SEQ ID NO: 358) VL:
DIVLTQTPATLSLIPGERVTMTCKTSQNIGTILHWYHQKPKEAPRALIKYASQSIPGIPSRFSGSGSETDFTLSINNLEPDDIGIYYCQQSRSWPVTFGPGTKLEIK (서열번호: 362)
VL:
DIVLTQTPATLSLIPGERVTMTCKTSQNIGTILHWYHQKPKEAPRALIKYASQSIPGIPSRFSGSGSETDFTLSINNLEPDDIGIYYCQQSRSWPVTFGPGTKLEIK (SEQ ID NO: 362)
CDR H1: DHYIS (서열번호: 359)CDR H1: DHYIS (SEQ ID NO: 359) CDR L1: KTSQNIGTILH (서열번호: 363)CDR L1: KTSQNIGTILH (SEQ ID NO: 363) CDR H2: NVYGGNGGTSYNQKFQG (서열번호: 360)CDR H2: NVYGGNGGTSYNQKFQG (SEQ ID NO: 360) CDR L2: YASQSIP (서열번호: 364)CDR L2: YASQSIP (SEQ ID NO: 364) CDR H3: RPVATGHAMDY (서열번호: 361)CDR H3: RPVATGHAMDY (SEQ ID NO: 361) CDR L3: QQSRSWPVT (서열번호: 365)CDR L3: QQSRSWPVT (SEQ ID NO: 365)

실시예 21.37. ACE-36의 제조Example 21.37. Preparation of ACE-36

ACE-36은 2개의 상이한 중쇄 유사 사슬 (ACE-36-VH 및 ACE-36-VL) 및 2개의 동일한 경쇄 (ACE-36-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다:ACE-36 contains two different heavy chain-like chains (ACE-36-VH and ACE-36-VL) and two identical light chains (ACE-36-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-36-VH amino acid sequence (서열번호: 366)ACE-36-VH amino acid sequence (SEQ ID NO: 366)

QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPPCPAPELLGGPggggsQVQLVESGGGVVQPGRSLRLSCAAS GFTFSSYT MHWVRQAPGKGLEWVTF ISYDGNNK YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAIYYC ARTGWLGPFDY WGQGTLVTVSS QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPPCPAPELLGGP ggggs QVQLVESGGGVVQPGRSLRLSCAAS GFTFSSYT MHWVRQAPGKGLEWVTF ISYDGNNK YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAIYYC ARTGWLGPFDY WGQGTLVTVSS

ACE-36-VL amino acid sequence (서열번호: 367)ACE-36-VL amino acid sequence (SEQ ID NO: 367)

QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPPCPAPELLG EIVLTQSPGTLSLSPGERATLSCRAS QSVGSSY LAWYQQKPGQAPRLLIY GAF SRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYC QQYGSSPWT FGQGTKVEIK QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPPCPAPELLG EIVLTQSPGTLSLSPGERATLSCRAS QSVGSSY LAWYQQKPGQAPRLLIY GAF SRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYC QQYGSSPWT FGQGTKVEIK

ACE-36-LC amino acid sequence (서열번호: 157)ACE-36-LC amino acid sequence (SEQ ID NO: 157)

QLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVL[RSVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] QLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVL [ RSVAAPSVFIFPPSDEQLKSGTASVVCSKSVLTQLKSGTASVVCSKNFQLKSGTASVVCSKNFREADS

PD-L1을 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 CTLA-4를 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 41에 열거되어있다:The VH and VL amino acid sequences and CDR sequences therein for the first antigen-binding domain bivalent Fab region targeting PD-L1 and the second antigen-binding domain monovalent Fv region targeting CTLA-4 are shown in Table 41 below. It is listed:

Fab region
(Anti-PD-L1)
Fab region
(Anti-PD-L1)
VH: QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (서열번호: 158)VH: QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (SEQ ID NO: 158) VL:
QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVL (서열번호: 376)
VL:
QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVL (SEQ ID NO: 376)
CDR H1: GGTFSSYA (서열번호: 159)CDR H1: GGTFSSYA (SEQ ID NO: 159) CDR L1: SSNIGAGYD (서열번호: 171)CDR L1: SSNIGAGYD (SEQ ID NO: 171) CDR H2: IIPILGIA (서열번호: 160)CDR H2: IIPILGIA (SEQ ID NO: 160) CDR L2: GDI (서열번호: 172)CDR L2: GDI (SEQ ID NO: 172) CDR H3: AKPRDGYNLVAFDI (서열번호: 161)CDR H3: AKPRDGYNLVAFDI (SEQ ID NO: 161) CDR L3: QSYDSSLSGGV (서열번호: 173)CDR L3: QSYDSSLSGGV (SEQ ID NO: 173) Fv region
(Anti-CTLA4)
Fv region
(Anti-CTLA4)
VH: QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYTMHWVRQAPGKGLEWVTFISYDGNNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAIYYCARTGWLGPFDYWGQGTLVTVSS (서열번호: 368)VH: QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYTMHWVRQAPGKGLEWVTFISYDGNNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAIYYCARTGWLGPFDYWGQGTLVTVSS (SEQ ID NO: 368) VL:
EIVLTQSPGTLSLSPGERATLSCRASQSVGSSYLAWYQQKPGQAPRLLIYGAFSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPWTFGQGTKVEIK (서열번호: 372)
VL:
EIVLTQSPGTLSLSPGERATLSCRASQSVGSSYLAWYQQKPGQAPRLLIYGAFSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPWTFGQGTKVEIK (SEQ ID NO: 372)
CDR H1: GFTFSSYT (서열번호: 369)CDR H1: GFTFSSYT (SEQ ID NO: 369) CDR L1: QSVGSSY (서열번호: 373)CDR L1: QSVGSSY (SEQ ID NO: 373) CDR H2: ISYDGNNK (서열번호: 370)CDR H2: ISYDGNNK (SEQ ID NO: 370) CDR L2: GAF (서열번호: 374)CDR L2: GAF (SEQ ID NO: 374) CDR H3: ARTGWLGPFDY (서열번호: 371)CDR H3: ARTGWLGPFDY (SEQ ID NO: 371) CDR L3: QQYGSSPWT (서열번호: 375)CDR L3: QQYGSSPWT (SEQ ID NO: 375)

실시예 21.38. ACE-37의 제조Example 21.38. Preparation of ACE-37

ACE-37은 2개의 상이한 중쇄 유사 사슬 (ACE-37-VH 및 ACE-37-VL) 및 2개의 동일한 경쇄 (ACE-37-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다:ACE-37 contains two different heavy chain-like chains (ACE-37-VH and ACE-37-VL) and two identical light chains (ACE-37-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-37-VH amino acid sequence (서열번호: 377)ACE-37-VH amino acid sequence (SEQ ID NO: 377)

QVQLQQPGAELVKPGASVKMSCKAS GYTFTSYN MHWVKQTPGRGLEWIGA IYPGNGDT SYNQKFKGKATLTADKSSSTAYMQLSSLTSEDSAVYYC ARSTYYGGDWYFNV WGAGTTVTVSA[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC]DKTHTCPPCPPCPAPELLGGPggggsQVQLVESGGGVVQPGRSLRLSCAAS GFTFSSYT MHWVRQAPGKGLEWVTF ISYDGNNK YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAIYYC ARTGWLGPFDY WGQGTLVTVSS QVQLQQPGAELVKPGASVKMSCKAS GYTFTSYN MHWVKQTPGRGLEWIGA IYPGNGDT SYNQKFKGKATLTADKSSSTAYMQLSSLTSEDSAVYYC ARSTYYGGDWYFNV WGAGTTVTVSA [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC] DKTHTCPPCPPCPAPELLGGP ggggs QVQLVESGGGVVQPGRSLRLSCAAS GFTFSSYT MHWVRQAPGKGLEWVTF ISYDGNNK YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAIYYC ARTGWLGPFDY WGQGTLVTVSS

ACE-37-VL amino acid sequence (서열번호: 378)ACE-37-VL amino acid sequence (SEQ ID NO: 378)

QVQLQQPGAELVKPGASVKMSCKASGYTFTSYNMHWVKQTPGRGLEWIGAIYPGNGDTSYNQKFKGKATLTADKSSSTAYMQLSSLTSEDSAVYYCARSTYYGGDWYFNVWGAGTTVTVSA[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC]DKTHTCPPCPPCPAPELLG EIVLTQSPGTLSLSPGERATLSCRAS QSVGSSY LAWYQQKPGQAPRLLIY GAF SRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYC QQYGSSPWT FGQGTKVEIK QVQLQQPGAELVKPGASVKMSCKASGYTFTSYNMHWVKQTPGRGLEWIGAIYPGNGDTSYNQKFKGKATLTADKSSSTAYMQLSSLTSEDSAVYYCARSTYYGGDWYFNVWGAGTTVTVSA [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC] DKTHTCPPCPPCPAPELLG EIVLTQSPGTLSLSPGERATLSCRAS QSVGSSY LAWYQQKPGQAPRLLIY GAF SRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYC QQYGSSPWT FGQGTKVEIK

ACE-37-LC amino acid sequence (서열번호: 221)ACE-37-LC amino acid sequence (SEQ ID NO: 221)

QIVLSQSPAILSASPGEKVTMTCRAS SSVSY IHWFQQKPGSSPKPWIY ATS NLASGVPVRFSGSGSGTSYSLTISRVEAEDAATYYC QQWTSNPPT FGGGTKLEIK[RSVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] QIVLSQSPAILSASPGEKVTMTCRAS SSVSY IHWFQQKPGSSPKPWIY ATS NLASGVPVRFSGSGSGTSYSLTISRVEAEDAATYYC QQWTSNPPT FGGGTKLEIK [ RSVAAPSVFIFPPSDEQLKSGTKLEIK [RSVAAPSVFIFPPSDEQLKSGTKLEIK [RSVAAPSVFIFPPSDEQLKSGTKLEIK [RSVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPYPREAKVQWKVSTLSKVQWKVDTLSKADSKWKVT

CD20을 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 CTLA-4를 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 42에 열거되어있다:The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting CD20 and the second antigen binding domain monovalent Fv region targeting CTLA-4 are listed in Table 42 below. have:

Fab region
(Anti-CD20)
Fab region
(Anti-CD20)
VH: QVQLQQPGAELVKPGASVKMSCKASGYTFTSYNMHWVKQTPGRGLEWIGAIYPGNGDTSYNQKFKGKATLTADKSSSTAYMQLSSLTSEDSAVYYCARSTYYGGDWYFNVWGAGTTVTVSA (서열번호: 222)VH: QVQLQQPGAELVKPGASVKMSCKASGYTFTSYNMHWVKQTPGRGLEWIGAIYPGNGDTSYNQKFKGKATLTADKSSSTAYMQLSSLTSEDSAVYYCARSTYYGGDWYFNVWGAGTTVTVSA (SEQ ID NO: 222) VL:
QIVLSQSPAILSASPGEKVTMTCRASSSVSYIHWFQQKPGSSPKPWIYATSNLASGVPVRFSGSGSGTSYSLTISRVEAEDAATYYCQQWTSNPPTFGGGTKLEIK (서열번호: 226)
VL:
QIVLSQSPAILSASPGEKVTMTCRASSSVSYIHWFQQKPGSSPKPWIYATSNLASGVPVRFSGSGSGTSYSLTISRVEAEDAATYYCQQWTSNPPTFGGGTKLEIK (SEQ ID NO: 226)
CDR H1: GYTFTSYN (서열번호: 223)CDR H1: GYTFTSYN (SEQ ID NO: 223) CDR L1: SSVSY (서열번호: 227)CDR L1: SSVSY (SEQ ID NO: 227) CDR H2: IYPGNGDT (서열번호: 224)CDR H2: IYPGNGDT (SEQ ID NO: 224) CDR L2: ATS (서열번호: 228)CDR L2: ATS (SEQ ID NO: 228) CDR H3: ARSTYYGGDWYFNV (서열번호: 225)CDR H3: ARSTYYGGDWYFNV (SEQ ID NO: 225) CDR L3: QQWTSNPPT (서열번호: 229)CDR L3: QQWTSNPPT (SEQ ID NO: 229) Fv region
(Anti-CTLA-4)
Fv region
(Anti-CTLA-4)
VH: QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYTMHWVRQAPGKGLEWVTFISYDGNNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAIYYCARTGWLGPFDYWGQGTLVTVSS (서열번호: 368)VH: QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYTMHWVRQAPGKGLEWVTFISYDGNNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAIYYCARTGWLGPFDYWGQGTLVTVSS (SEQ ID NO: 368) VL: EIVLTQSPGTLSLSPGERATLSCRASQSVGSSYLAWYQQKPGQAPRLLIYGAFSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPWTFGQGTKVEIK (서열번호: 372)VL: EIVLTQSPGTLSLSPGERATLSCRASQSVGSSYLAWYQQKPGQAPRLLIYGAFSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPWTFGQGTKVEIK (SEQ ID NO: 372)
CDR H1: GFTFSSYT (서열번호: 369)CDR H1: GFTFSSYT (SEQ ID NO: 369) CDR L1: QSVGSSY (서열번호: 373)CDR L1: QSVGSSY (SEQ ID NO: 373) CDR H2: ISYDGNNK (서열번호: 370)CDR H2: ISYDGNNK (SEQ ID NO: 370) CDR L2: GAF (서열번호: 374)CDR L2: GAF (SEQ ID NO: 374) CDR H3: ARTGWLGPFDY (서열번호: 371)CDR H3: ARTGWLGPFDY (SEQ ID NO: 371) CDR L3: QQYGSSPWT (서열번호: 375)CDR L3: QQYGSSPWT (SEQ ID NO: 375)

실시예 21.39. ACE-38의 제조Example 21.39. Preparation of ACE-38

ACE-38은 2개의 상이한 중쇄 유사 사슬 (ACE-38-VH 및 ACE-38-VL) 및 2개의 동일한 경쇄 (ACE-38-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다:ACE-38 contains two different heavy chain-like chains (ACE-38-VH and ACE-38-VL) and two identical light chains (ACE-38-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-38-VH amino acid sequence (서열번호: 381)ACE-38-VH amino acid sequence (SEQ ID NO: 381)

QVQLKQSGPGLVQPSQSLSITCTVS GFSLTNYG VHWVRQSPGKGLEWLGV IWSGGNT DYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYC ARALTYYDYEFAY WGQGTLVTVSA[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPPCPAPELLGGPggggsEVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFSGQPREPQVYTSPPSRDELTKNQVSLRCHVKGFYPSDIAVEWESNGQPENNYKTTKPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK QVQLKQSGPGLVQPSQSLSITCTVS GFSLTNYG VHWVRQSPGKGLEWLGV IWSGGNT DYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYC ARALTYYDYEFAY WGQGTLVTVSA [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPPCPAPELLGGP ggggs EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFS GQPREPQVYTSPPSRDELTKNQVSLRCHVKGFYPSDIAVEWESNGQPENNYKTTKPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

ACE-38-VL amino acid sequence (서열번호: 382)ACE-38-VL amino acid sequence (SEQ ID NO: 382)

QVQLKQSGPGLVQPSQSLSITCTVS GFSLTNYG VHWVRQSPGKGLEWLGV IWSGGNT DYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYC ARALTYYDYEFAY WGQGTLVTVSA[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPPCPAPELLGGPggggsDIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR QVQLKQSGPGLVQPSQSLSITCTVS GFSLTNYG VHWVRQSPGKGLEWLGV IWSGGNT DYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYC ARALTYYDYEFAY WGQGTLVTVSA [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPPCPAPELLGGP ggggs DIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR

ACE-38-LC amino acid sequence (서열번호: 232)ACE-38-LC amino acid sequence (SEQ ID NO: 232)

DILLTQSPVILSVSPGERVSFSCRAS QSIGTN IHWYQQRTNGSPRLLIK YAS ESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYC QQNNNWPTT FGAGTKLELK[RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] DILLTQSPVILSVSPGERVSFSCRAS QSIGTN IHWYQQRTNGSPRLLIK YAS ESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYC QQNNNWPTT FGAGTKLELK [ RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWHKVDNALKAQSGNSHKVDNALKLSQS

EGFR을 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 CD3를 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 43에 열거되어있다:The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting EGFR and the second antigen binding domain monovalent Fv region targeting CD3 are listed in Table 43 below:

Fab region
(Anti-EGFR)
Fab region
(Anti-EGFR)
VH: QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSA (서열번호: 233)VH: QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSA (SEQ ID NO: 233) VL:
DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELK (서열번호: 237)
VL:
DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELK (SEQ ID NO: 237)
CDR H1: GFSLTNYG (서열번호: 234)CDR H1: GFSLTNYG (SEQ ID NO: 234) CDR L1: QSIGTN (서열번호: 238)CDR L1: QSIGTN (SEQ ID NO: 238) CDR H2: IWSGGNT (서열번호: 235)CDR H2: IWSGGNT (SEQ ID NO: 235) CDR L2: YAS (서열번호: 239)CDR L2: YAS (SEQ ID NO: 239) CDR H3: ARALTYYDYEFAY (서열번호: 236)CDR H3: ARALTYYDYEFAY (SEQ ID NO: 236) CDR L3: QQNNNWPTT (서열번호: 240)CDR L3: QQNNNWPTT (SEQ ID NO: 240) Fv region
(Anti-CD3)
Fv region
(Anti-CD3)
VH: EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (서열번호: 215)VH: EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (SEQ ID NO: 215) VL:
DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (서열번호: 216)
VL:
DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (SEQ ID NO: 216)
CDR H1: GYSFTGYT (서열번호: 177)CDR H1: GYSFTGYT (SEQ ID NO: 177) CDR L1: QDIRNY (서열번호: 181)CDR L1: QDIRNY (SEQ ID NO: 181) CDR H2: INPYKGVS (서열번호: 178)CDR H2: INPYKGVS (SEQ ID NO: 178) CDR L2: YTS (서열번호: 182)CDR L2: YTS (SEQ ID NO: 182) CDR H3: ARSGYYGDSDWYFD (서열번호: 211)CDR H3: ARSGYYGDSDWYFD (SEQ ID NO: 211) CDR L3: QQGNTLPWT (서열번호: 207)CDR L3: QQGNTLPWT (SEQ ID NO: 207)

실시예 21.40. ACE-39의 제조Example 21.40. Preparation of ACE-39

ACE-39는 2개의 상이한 중쇄 유사 사슬 (ACE-39-VH 및 ACE-39-VL) 및 2개의 동일한 경쇄 (ACE-39-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다:ACE-39 contains two different heavy chain-like chains (ACE-39-VH and ACE-39-VL) and two identical light chains (ACE-39-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-39-VH amino acid sequence (서열번호: 383)ACE-39-VH amino acid sequence (SEQ ID NO: 383)

QVQLKQSGPGLVQPSQSLSITCTVS GFSLTNYG VHWVRQSPGKGLEWLGV IWSGGNT DYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYC ARALTYYDYEFAY WGQGTLVTVSA[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPPCPAPELLGGPggggsEVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFS QVQLKQSGPGLVQPSQSLSITCTVS GFSLTNYG VHWVRQSPGKGLEWLGV IWSGGNT DYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYC ARALTYYDYEFAY WGQGTLVTVSA [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPPCPAPELLGGP ggggs EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFS

ACE-39-VL amino acid sequence (서열번호: 384)ACE-39-VL amino acid sequence (SEQ ID NO: 384)

QVQLKQSGPGLVQPSQSLSITCTVS GFSLTNYG VHWVRQSPGKGLEWLGV IWSGGNT DYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYC ARALTYYDYEFAY WGQGTLVTVSA[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPPCPAPELLGGPggggsDIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKRGQPREPQVYTSPPSRDELTKNQVSLRCHVKGFYPSDIAVEWESNGQPENNYKTTKPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK QVQLKQSGPGLVQPSQSLSITCTVS GFSLTNYG VHWVRQSPGKGLEWLGV IWSGGNT DYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYC ARALTYYDYEFAY WGQGTLVTVSA [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPPCPAPELLGGP ggggs DIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR GQPREPQVYTSPPSRDELTKNQVSLRCHVKGFYPSDIAVEWESNGQPENNYKTTKPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

ACE-39-LC amino acid sequence (서열번호: 232)ACE-39-LC amino acid sequence (SEQ ID NO: 232)

DILLTQSPVILSVSPGERVSFSCRAS QSIGTN IHWYQQRTNGSPRLLIK YAS ESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYC QQNNNWPTT FGAGTKLELK[RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] DILLTQSPVILSVSPGERVSFSCRAS QSIGTN IHWYQQRTNGSPRLLIK YAS ESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYC QQNNNWPTT FGAGTKLELK [ RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWHKVDNALKAQSGNSHKVDNALKLSQS

EGFR을 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 CD3를 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 44에 열거되어있다:The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting EGFR and the second antigen binding domain monovalent Fv region targeting CD3 are listed in Table 44 below:

Fab region
(EGFR)
Fab region
(EGFR)
VH: QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSA (서열번호: 233)VH: QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSA (SEQ ID NO: 233) VL:
DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELK (서열번호: 237)
VL:
DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELK (SEQ ID NO: 237)
CDR H1: GFSLTNYG (서열번호: 234)CDR H1: GFSLTNYG (SEQ ID NO: 234) CDR L1: QSIGTN (서열번호: 238)CDR L1: QSIGTN (SEQ ID NO: 238) CDR H2: IWSGGNT (서열번호: 235)CDR H2: IWSGGNT (SEQ ID NO: 235) CDR L2: YAS (서열번호: 239)CDR L2: YAS (SEQ ID NO: 239) CDR H3: ARALTYYDYEFAY (서열번호: 236)CDR H3: ARALTYYDYEFAY (SEQ ID NO: 236) CDR L3: QQNNNWPTT (서열번호: 240)CDR L3: QQNNNWPTT (SEQ ID NO: 240) Fv region
(Anti-CD3)
Fv region
(Anti-CD3)
VH: EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (서열번호: 215)VH: EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (SEQ ID NO: 215) VL: DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (서열번호: 216)VL: DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (SEQ ID NO: 216)
CDR H1: GYSFTGYT (서열번호: 177)CDR H1: GYSFTGYT (SEQ ID NO: 177) CDR L1: QDIRNY (서열번호: 181)CDR L1: QDIRNY (SEQ ID NO: 181) CDR H2: INPYKGVS (서열번호: 178)CDR H2: INPYKGVS (SEQ ID NO: 178) CDR L2: YTS (서열번호: 182)CDR L2: YTS (SEQ ID NO: 182) CDR H3: ARSGYYGDSDWYFD (서열번호: 211)CDR H3: ARSGYYGDSDWYFD (SEQ ID NO: 211) CDR L3: QQGNTLPWT (서열번호: 207)CDR L3: QQGNTLPWT (SEQ ID NO: 207)

실시예 21.41. ACE-40의 제조Example 21.41. Preparation of ACE-40

ACE-40은 2개의 다른 중쇄 유사 사슬 (ACE-40-VH 및 ACE-40-VL) 및 2개의 동일한 경쇄 (ACE-40-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다:ACE-40 contains two different heavy chain-like chains (ACE-40-VH and ACE-40-VL) and two identical light chains (ACE-40-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-40-VH amino acid sequence (서열번호: 381)ACE-40-VH amino acid sequence (SEQ ID NO: 381)

QVQLKQSGPGLVQPSQSLSITCTVS GFSLTNYG VHWVRQSPGKGLEWLGV IWSGGNT DYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYC ARALTYYDYEFAY WGQGTLVTVSA[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPPCPAPELLGGPggggsEVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFSGQPREPQVYTSPPSRDELTKNQVSLRCHVKGFYPSDIAVEWESNGQPENNYKTTKPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK QVQLKQSGPGLVQPSQSLSITCTVS GFSLTNYG VHWVRQSPGKGLEWLGV IWSGGNT DYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYC ARALTYYDYEFAY WGQGTLVTVSA [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPPCPAPELLGGP ggggs EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFS GQPREPQVYTSPPSRDELTKNQVSLRCHVKGFYPSDIAVEWESNGQPENNYKTTKPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

ACE-40-VL amino acid sequence (서열번호: 384)ACE-40-VL amino acid sequence (SEQ ID NO: 384)

QVQLKQSGPGLVQPSQSLSITCTVS GFSLTNYG VHWVRQSPGKGLEWLGV IWSGGNT DYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYC ARALTYYDYEFAY WGQGTLVTVSA[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPPCPAPELLGGPggggsDIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKRGQPREPQVYTSPPSRDELTKNQVSLRCHVKGFYPSDIAVEWESNGQPENNYKTTKPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK QVQLKQSGPGLVQPSQSLSITCTVS GFSLTNYG VHWVRQSPGKGLEWLGV IWSGGNT DYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYC ARALTYYDYEFAY WGQGTLVTVSA [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPPCPAPELLGGP ggggs DIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR GQPREPQVYTSPPSRDELTKNQVSLRCHVKGFYPSDIAVEWESNGQPENNYKTTKPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

ACE-40-LC amino acid sequence (서열번호: 232)ACE-40-LC amino acid sequence (SEQ ID NO: 232)

DILLTQSPVILSVSPGERVSFSCRAS QSIGTN IHWYQQRTNGSPRLLIK YAS ESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYC QQNNNWPTT FGAGTKLELK[RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] DILLTQSPVILSVSPGERVSFSCRAS QSIGTN IHWYQQRTNGSPRLLIK YAS ESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYC QQNNNWPTT FGAGTKLELK [ RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWHKVDNALKAQSGNSHKVDNALKLSQS

EGFR을 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 CD3를 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 45에 열거되어있다:The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting EGFR and the second antigen binding domain monovalent Fv region targeting CD3 are listed in Table 45 below:

Fab region
(Anti-EGFR)
Fab region
(Anti-EGFR)
VH: QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSA (서열번호: 233)VH: QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSA (SEQ ID NO: 233) VL:
DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELK (서열번호: 237)
VL:
DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELK (SEQ ID NO: 237)
CDR H1: GFSLTNYG (서열번호: 234)CDR H1: GFSLTNYG (SEQ ID NO: 234) CDR L1: QSIGTN (서열번호: 238)CDR L1: QSIGTN (SEQ ID NO: 238) CDR H2: IWSGGNT (서열번호: 235)CDR H2: IWSGGNT (SEQ ID NO: 235) CDR L2: YAS (서열번호: 239)CDR L2: YAS (SEQ ID NO: 239) CDR H3: ARALTYYDYEFAY (서열번호: 236)CDR H3: ARALTYYDYEFAY (SEQ ID NO: 236) CDR L3: QQNNNWPTT (서열번호: 240)CDR L3: QQNNNWPTT (SEQ ID NO: 240) Fv region
(Anti-CD3)
Fv region
(Anti-CD3)
VH:
EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (서열번호: 215)
VH:
EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (SEQ ID NO: 215)
VL:
DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (서열번호: 216)
VL:
DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (SEQ ID NO: 216)
CDR H1: GYSFTGYT (서열번호: 177)CDR H1: GYSFTGYT (SEQ ID NO: 177) CDR L1: QDIRNY (서열번호: 181)CDR L1: QDIRNY (SEQ ID NO: 181) CDR H2: INPYKGVS (서열번호: 178)CDR H2: INPYKGVS (SEQ ID NO: 178) CDR L2: YTS (서열번호: 182)CDR L2: YTS (SEQ ID NO: 182) CDR H3: ARSGYYGDSDWYFD (서열번호: 211)CDR H3: ARSGYYGDSDWYFD (SEQ ID NO: 211) CDR L3: QQGNTLPWT (서열번호: 207)CDR L3: QQGNTLPWT (SEQ ID NO: 207)

실시예 21.42. ACE-00r의 제조Example 21.42. Preparation of ACE-00r

ACE-00r은 2개의 상이한 중쇄 유사 사슬 (ACE-00r-VH 및 ACE-00r-VL) 및 2개의 동일한 경쇄 (ACE-00r-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다:ACE-00r contains two different heavy chain-like chains (ACE-00r-VH and ACE-00r-VL) and two identical light chains (ACE-00r-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-00r-VH amino acid sequence: ACE-00r-VH amino acid sequence :

EVQLVESGGGLVQPGRSLRLSCAAS GFTFDDYA MHWVRQAPGKGLEWVSA ITWNSGHI DYADSVEGRFTISRDNAKNSLYLQMNSLRAEDTAVYYC AKVSYLSTASSLDY WGQGTLVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC]DKTHTCPPCPAPELLGGP EVQLVESGGGLVQPGGSLRLSCAAS GFNIKDTY IHWVRQAPGKGLEWVAR IYPTNGYT RYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYC SRWGGDGFYAMDY WGQGTLVTVSS (서열번호: 388) EVQLVESGGGLVQPGRSLRLSCAAS GFTFDDYA MHWVRQAPGKGLEWVSA ITWNSGHI DYADSVEGRFTISRDNAKNSLYLQMNSLRAEDTAVYYC AKVSYLSTASSLDY WGQGTLVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC] DKTHTCPPCPAPELLGGP EVQLVESGGGLVQPGGSLRLSCAAS GFNIKDTY IHWVRQAPGKGLEWVAR IYPTNGYT RYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYC SRWGGDGFYAMDY WGQGTLVTVSS (SEQ ID NO: 388)

ACE-00r-VL amino acid sequence: ACE-00r-VL amino acid sequence :

EVQLVESGGGLVQPGRSLRLSCAAS GFTFDDYA MHWVRQAPGKGLEWVSA ITWNSGHI DYADSVEGRFTISRDNAKNSLYLQMNSLRAEDTAVYYC AKVSYLSTASSLDY WGQGTLVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC]DKTHTCPPCPAPELLGGP DIQMTQSPSSLSASVGDRVTITCRAS QDVNTA VAWYQQKPGKAPKLLIY SAS FLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYC QQHYTTPPT FGQGTKVEIK (서열번호: 389) EVQLVESGGGLVQPGRSLRLSCAAS GFTFDDYA MHWVRQAPGKGLEWVSA ITWNSGHI DYADSVEGRFTISRDNAKNSLYLQMNSLRAEDTAVYYC AKVSYLSTASSLDY WGQGTLVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC] DKTHTCPPCPAPELLGGP DIQMTQSPSSLSASVGDRVTITCRAS QDVNTA VAWYQQKPGKAPKLLIY SAS FLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYC QQHYTTPPT FGQGTKVEIK (SEQ ID NO: 389)

ACE-00r-LC amino acid sequence: ACE-00r-LC amino acid sequence :

DIQMTQSPSSLSASVGDRVTITCRAS QGIRNY LAWYQQKPGKAPKLLIY AAS TLQSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYC QRYNRAPYT FGQGTKVEIKR[RSVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC](서열번호: 390) DIQMTQSPSSLSASVGDRVTITCRAS QGIRNY LAWYQQKPGKAPKLLIY AAS TLQSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYC QRYNRAPYT FGQGTKVEIKR [RSVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] (SEQ ID NO: 390)

TNF를 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 HER2를 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 46에 열거되어있다:The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting TNF and the second antigen binding domain monovalent Fv region targeting HER2 are listed in Table 46 below:

Fab region
(Anti-TNF alpha)
Fab region
(Anti-TNF alpha)
VH:
EVQLVESGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSAITWNSGHIDYADSVEGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAKVSYLSTASSLDYWGQGTLVTVSS (서열번호: 279)
VH:
EVQLVESGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSAITWNSGHIDYADSVEGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAKVSYLSTASSLDYWGQGTLVTVSS (SEQ ID NO: 279)
VL:
DIQMTQSPSSLSASVGDRVTITCRASQGIRNYLAWYQQKPGKAPKLLIYAASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQRYNRAPYTFGQGTKVEIKR (서열번호: 283)
VL:
DIQMTQSPSSLSASVGDRVTITCRASQGIRNYLAWYQQKPGKAPKLLIYAASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQRYNRAPYTFGQGTKVEIKR (SEQ ID NO: 283)
CDR H1: GFTFDDYA (서열번호: 280)CDR H1: GFTFDDYA (SEQ ID NO: 280) CDR L1: QGIRNY (서열번호: 284)CDR L1: QGIRNY (SEQ ID NO: 284) CDR H2: ITWNSGHI (서열번호: 281)CDR H2: ITWNSGHI (SEQ ID NO: 281) CDR L2: AAS (서열번호: 285)CDR L2: AAS (SEQ ID NO: 285) CDR H3: AKVSYLSTASSLDY (서열번호: 282)CDR H3: AKVSYLSTASSLDY (SEQ ID NO: 282) CDR L3: QRYNRAPYT (서열번호: 286)CDR L3: QRYNRAPYT (SEQ ID NO: 286) Fv region
(Anti-Her2)
Fv region
(Anti-Her2)
VH: EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS (SEQ ID 275)VH: EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS (SEQ ID 275) VL:
DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKR (서열번호: 389)
VL:
DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKR (SEQ ID NO: 389)
CDR H1:GFNIKDTY (서열번호: 276)CDR H1:GFNIKDTY (SEQ ID NO: 276) CDR L1: QDVNTA (서열번호: 288)CDR L1: QDVNTA (SEQ ID NO: 288) CDR H2: IYPTNGYT (서열번호: 277)CDR H2: IYPTNGYT (SEQ ID NO: 277) CDR L2: SAS (서열번호: 289)CDR L2: SAS (SEQ ID NO: 289) CDR H3: SRWGGDGFYAMDY (서열번호: 278)CDR H3: SRWGGDGFYAMDY (SEQ ID NO: 278) CDR L3: QQHYTTPPT (서열번호: 290)CDR L3: QQHYTTPPT (SEQ ID NO: 290)

실시예 21.43. ACE-01r의 제조Example 21.43. Preparation of ACE-01r

ACE-01r은 2개의 다른 중쇄 유사 사슬 (ACE-01r-VH 및 ACE-01r-VL) 및 2개의 동일한 경쇄 (ACE-01r-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다: ACE-01r contains two different heavy chain-like chains (ACE-01r-VH and ACE-01r-VL) and two identical light chains (ACE-01r-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-01r-VH amino acid sequence (서열번호: 391)ACE-01r-VH amino acid sequence (SEQ ID NO: 391)

QVQLQQSGAELARPGASVKMSCKAS GYTFTRYT MHWVKQRPGQGLEWIGY INPSRGYT NYNQKFKDKATLTTDKSSSTAYMQLSSLTSEDSAVYYC ARYYDDHYCLDY WGQGTTVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC]DKTHTCPPCPAPELLGGP QVQLQQSGAELVRPGSSVKISCKASGYAFS SYWMN WVKQRPGQGLEWIGQ IWPGDGDT NYNGKFKGKATLTADESSSTAYMQLSSLASEDSAVYFC ARRETTTVGRYYYAMDY WGQGTTVTVSS QVQLQQSGAELARPGASVKMSCKAS GYTFTRYT MHWVKQRPGQGLEWIGY INPSRGYT NYNQKFKDKATLTTDKSSSTAYMQLSSLTSEDSAVYYC ARYYDDHYCLDY WGQGTTVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC] DKTHTCPPCPAPELLGGP QVQLQQSGAELVRPGSSVKISCKASGYAFS SYWMN WVKQRPGQGLEWIGQ IWPGDGDT NYNGKFKGKATLTADESSSTAYMQLSSLASEDSAVYFC ARRETTTVGRYYYAMDY WGQGTTVTVSS

ACE-01r -VL amino acid sequence (서열번호: 392)ACE-01r -VL amino acid sequence (SEQ ID NO: 392)

QVQLQQSGAELARPGASVKMSCKAS GYTFTRYT MHWVKQRPGQGLEWIGY INPSRGYT NYNQKFKDKATLTTDKSSSTAYMQLSSLTSEDSAVYYC ARYYDDHYCLDY WGQGTTVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC]DKTHTCPPCPAPELLGGPDIQLTQSPASLAVSLGQRATISCKAS QSVDYDGDSY LNWYQQIPGQPPKLLIY DAS NLVSGIPPRFSGSGSGTDFTLNIHPVEKVDAATYHC QQSTEDPWT FGGGTKLEIK QVQLQQSGAELARPGASVKMSCKAS GYTFTRYT MHWVKQRPGQGLEWIGY INPSRGYT NYNQKFKDKATLTTDKSSSTAYMQLSSLTSEDSAVYYC ARYYDDHYCLDY WGQGTTVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC] DKTHTCPPCPAPELLGGP DIQLTQSPASLAVSLGQRATISCKAS QSVDYDGDSY LNWYQQIPGQPPKLLIY DAS NLVSGIPPRFSGSGSGTDFTLNIHPVEKVDAATYHC QQSTEDPWT FGGGTKLEIK

ACE-01r-LC amino acid sequence (서열번호: 393)ACE-01r-LC amino acid sequence (SEQ ID NO: 393)

QIVLTQSPAIMSASPGEKVTMTCSAS SSVSY MNWYQQKSGTSPKRWIY DTS KLASGVPAHFRGSGSGTSYSLTISGMEAEDAATYYC QQWSSNPFTF GSGTKLEINR[RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] QIVLTQSPAIMSASPGEKVTMTCSAS SSVSY MNWYQQKSGTSPKRWIY DTS KLASGVPAHFRGSGSGTSYSLTISGMEAEDAATYYC QQWSSNPFTF GSGTKLEINR [ RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVFISPPSDEQLKSGTASVVCLLNNFYPREAKVFIDSCHKVDLSQDSKSKVDLSQDS

제1 항원 결합 도메인 (CD3를 표적으로하는 2가 Fab 영역) 및 제2 항원 결합 도메인 (CD19를 표적으로하는 1가 Fv 영역)에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 47에 나열되어있다: The VH and VL amino acid sequences and CDR sequences therein for the first antigen-binding domain (divalent Fab region targeting CD3) and the second antigen-binding domain (monovalent Fv region targeting CD19) are shown in Table 47 below. Are listed:

Fv region
(Anti-CD19)
Fv region
(Anti-CD19)
VH: QVQLQQSGAELVRPGSSVKISCKASGYAFSSYWMNWVKQRPGQGLEWIGQIWPGDGDTNYNGKFKGKATLTADESSSTAYMQLSSLASEDSAVYFCARRETTTVGRYYYAMDYWGQGTTVTVSS (서열번호: 139)VH: QVQLQQSGAELVRPGSSVKISCKASGYAFSSYWMNWVKQRPGQGLEWIGQIWPGDGDTNYNGKFKGKATLTADESSSTAYMQLSSLASEDSAVYFCARRETTTVGRYYYAMDYWGQGTTVTVSS (SEQ ID NO: 139) VL:
DIQLTQSPASLAVSLGQRATISCKASQSVDYDGDSYLNWYQQIPGQPPKLLIYDASNLVSGIPPRFSGSGSGTDFTLNIHPVEKVDAATYHCQQSTEDPWTFGGGTKLEIK (서열번호: 151)
VL:
DIQLTQSPASLAVSLGQRATISCKASQSVDYDGDSYLNWYQQIPGQPPKLLIYDASNLVSGIPPRFSGSGSGTDFTLNIHPVEKVDAATYHCQQSTEDPWTFGGGTKLEIK (SEQ ID NO: 151)
CDR H1: SYWMN (서열번호: 140)CDR H1: SYWMN (SEQ ID NO: 140) CDR L1: QSVDYDGDSY (서열번호: 152)CDR L1: QSVDYDGDSY (SEQ ID NO: 152) CDR H2: IWPGDGDT (서열번호: 141)CDR H2: IWPGDGDT (SEQ ID NO: 141) CDR L2: DAS (서열번호: 153)CDR L2: DAS (SEQ ID NO: 153) CDR H3: ARRETTTVGRYYYAMDY (서열번호: 142)CDR H3: ARRETTTVGRYYYAMDY (SEQ ID NO: 142) CDR L3: QQSTEDPWT (서열번호: 154)CDR L3: QQSTEDPWT (SEQ ID NO: 154) Fab region
(Anti-CD3)
Fab region
(Anti-CD3)
VH:
QVQLQQSGAELARPGASVKMSCKASGYTFTRYTMHWVKQRPGQGLEWIGYINPSRGYTNYNQKFKDKATLTTDKSSSTAYMQLSSLTSEDSAVYYCARYYDDHYCLDYWGQGTTVTVSS (서열번호: 143)
VH:
QVQLQQSGAELARPGASVKMSCKASGYTFTRYTMHWVKQRPGQGLEWIGYINPSRGYTNYNQKFKDKATLTTDKSSSTAYMQLSSLTSEDSAVYYCARYYDDHYCLDYWGQGTTVTVSS (SEQ ID NO: 143)
VL:
QIVLTQSPAIMSASPGEKVTMTCSASSSVSYMNWYQQKSGTSPKRWIYDTSKLASGVPAHFRGSGSGTSYSLTISGMEAEDAATYYCQQWSSNPFTFGSGTKLEINR (서열번호: 147)
VL:
QIVLTQSPAIMSASPGEKVTMTCSASSSVSYMNWYQQKSGTSPKRWIYDTSKLASGVPAHFRGSGSGTSYSLTISGMEAEDAATYYCQQWSSNPFTFGSGTKLEINR (SEQ ID NO: 147)
CDR H1: GYTFTRYT (서열번호: 144)CDR H1: GYTFTRYT (SEQ ID NO: 144) CDR L1: SSVSY (서열번호: 148)CDR L1: SSVSY (SEQ ID NO: 148) CDR H2: INPSRGYT (서열번호: 145)CDR H2: INPSRGYT (SEQ ID NO: 145) CDR L2: DTS (서열번호: 149)CDR L2: DTS (SEQ ID NO: 149) CDR H3: ARYYDDHYCLDY (서열번호: 146)CDR H3: ARYYDDHYCLDY (SEQ ID NO: 146) CDR L3: QQWSSNPFTF (서열번호: 150)CDR L3: QQWSSNPFTF (SEQ ID NO: 150)

실시예 21.44. ACE-02r의 제조Example 21.44. Preparation of ACE-02r

ACE-02r은 2개의 상이한 중쇄 유사 사슬 (ACE-02r-VH 및 ACE-02r-VL) 및 2개의 동일한 경쇄 (ACE-02r-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다: ACE-02r contains two different heavy chain-like chains (ACE-02r-VH and ACE-02r-VL) and two identical light chains (ACE-02r-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-02r-VH amino acid sequence: ACE-02r-VH amino acid sequence :

QVQLVQSGGGVVQPGRSLRLSCKAS GYTFTSYT MHWVRQAPGKGLEWIGY INPSSGYT KYNQKFKDRFTISADKSKSTAFLQMDSLRPEDTGVYFC ARWQDYDVYFDY WGQGTPVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC]DKTHTCPPCPAPELLGGP QVQLQQSGAELVRPGSSVKISCKASGYAFS SYWMN WVKQRPGQGLEWIGQ IWPGDGDT NYNGKFKGKATLTADESSSTAYMQLSSLASEDSAVYFC ARRETTTVGRYYYAMDY WGQGTTVTVSS (서열번호: 394) QVQLVQSGGGVVQPGRSLRLSCKAS GYTFTSYT MHWVRQAPGKGLEWIGY INPSSGYT KYNQKFKDRFTISADKSKSTAFLQMDSLRPEDTGVYFC ARWQDYDVYFDY WGQGTPVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC] DKTHTCPPCPAPELLGGP QVQLQQSGAELVRPGSSVKISCKASGYAFS SYWMN WVKQRPGQGLEWIGQ IWPGDGDT NYNGKFKGKATLTADESSSTAYMQLSSLASEDSAVYFC ARRETTTVGRYYYAMDY WGQGTTVTVSS (SEQ ID NO: 394)

ACE-02r-VL amino acid sequence: ACE-02r-VL amino acid sequence :

QVQLVQSGGGVVQPGRSLRLSCKAS GYTFTSYT MHWVRQAPGKGLEWIGY INPSSGYT KYNQKFKDRFTISADKSKSTAFLQMDSLRPEDTGVYFC ARWQDYDVYFDY WGQGTPVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC]DKTHTCPPCPAPELLGGP DIQLTQSPASLAVSLGQRATISCKAS QSVDYDGDSY LNWYQQIPGQPPKLLIY DAS NLVSGIPPRFSGSGSGTDFTLNIHPVEKVDAATYHC QQSTEDPWT FGGGTKLEIK (서열번호: 399) QVQLVQSGGGVVQPGRSLRLSCKAS GYTFTSYT MHWVRQAPGKGLEWIGY INPSSGYT KYNQKFKDRFTISADKSKSTAFLQMDSLRPEDTGVYFC ARWQDYDVYFDY WGQGTPVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC] DKTHTCPPCPAPELLGGP DIQLTQSPASLAVSLGQRATISCKAS QSVDYDGDSY LNWYQQIPGQPPKLLIY DAS NLVSGIPPRFSGSGSGTDFTLNIHPVEKVDAATYHC QQSTEDPWT FGGGTKLEIK (SEQ ID NO: 399)

ACE-02r-LC amino acid sequence: ACE-02r-LC amino acid sequence :

DIQMTQSPSSLSASVGDRVTMTCRA SSSVSY MHWYQQTPGKAPKPWIY ATS NLASGVPSRFSGSGSGTDYTLTISSLQPEDIATYYC QQWSSNPPT FGQGTKLQITR[RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] (서열번호: 400) DIQMTQSPSSLSASVGDRVTMTCRA SSSVSY MHWYQQTPGKAPKPWIY ATS NLASGVPSRFSGSGSGTDYTLTISSLQPEDIATYYC QQWSSNPPT FGQGTKLQITR [ RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNVDYPREAKSQGNSVSTYPREAKVQWKTHKLSKDSQWKDS

CD3을 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 CD19를 표적으로하는 제2 항원 결합 도메인 1가 Fvr egion에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 48에 열거되어있다: The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting CD3 and the second antigen binding domain monovalent Fvr egion targeting CD19 are listed in Table 48 below:

Fv region
(Anti-CD19)
Fv region
(Anti-CD19)
VH: QVQLQQSGAELVRPGSSVKISCKASGYAFSSYWMNWVKQRPGQGLEWIGQIWPGDGDTNYNGKFKGKATLTADESSSTAYMQLSSLASEDSAVYFCARRETTTVGRYYYAMDYWGQGTTVTVSS (서열번호: 139)VH: QVQLQQSGAELVRPGSSVKISCKASGYAFSSYWMNWVKQRPGQGLEWIGQIWPGDGDTNYNGKFKGKATLTADESSSTAYMQLSSLASEDSAVYFCARRETTTVGRYYYAMDYWGQGTTVTVSS (SEQ ID NO: 139) VL:
DIQLTQSPASLAVSLGQRATISCKASQSVDYDGDSYLNWYQQIPGQPPKLLIYDASNLVSGIPPRFSGSGSGTDFTLNIHPVEKVDAATYHCQQSTEDPWTFGGGTKLEIK (서열번호: 151)
VL:
DIQLTQSPASLAVSLGQRATISCKASQSVDYDGDSYLNWYQQIPGQPPKLLIYDASNLVSGIPPRFSGSGSGTDFTLNIHPVEKVDAATYHCQQSTEDPWTFGGGTKLEIK (SEQ ID NO: 151)
CDR H1: SYWMN (서열번호: 140)CDR H1: SYWMN (SEQ ID NO: 140) CDR L1: QSVDYDGDSY (서열번호: 152)CDR L1: QSVDYDGDSY (SEQ ID NO: 152) CDR H2: QIWPGDGDTNYNGKFKG (서열번호: 141)CDR H2: QIWPGDGDTNYNGKFKG (SEQ ID NO: 141) CDR L2: DAS (서열번호: 153)CDR L2: DAS (SEQ ID NO: 153) CDR H3: RETTTVGRYYYAMDY (서열번호: 142)CDR H3: RETTTVGRYYYAMDY (SEQ ID NO: 142) CDR L3: QQSTEDPWT (서열번호: 154)CDR L3: QQSTEDPWT (SEQ ID NO: 154) Fab region
(Anti-CD3)
Fab region
(Anti-CD3)
VH:
QVQLVQSGGGVVQPGRSLRLSCKASGYTFTSYTMHWVRQAPGKGLEWIGYINPSSGYTKYNQKFKDRFTISADKSKSTAFLQMDSLRPEDTGVYFCARWQDYDVYFDYWGQGTPVTVSS (서열번호: 395)
VH:
QVQLVQSGGGVVQPGRSLRLSCKASGYTFTSYTMHWVRQAPGKGLEWIGYINPSSGYTKYNQKFKDRFTISADKSKSTAFLQMDSLRPEDTGVYFCARWQDYDVYFDYWGQGTPVTVSS (SEQ ID NO: 395)
VL:
DIQMTQSPSSLSASVGDRVTMTCRASSSVSYMHWYQQTPGKAPKPWIYATSNLASGVPSRFSGSGSGTDYTLTISSLQPEDIATYYCQQWSSNPPTFGQGTKLQITR (서열번호: 401)
VL:
DIQMTQSPSSLSASVGDRVTMTCRASSSVSYMHWYQQTPGKAPKPWIYATSNLASGVPSRFSGSGSGTDYTLTISSLQPEDIATYYCQQWSSNPPTFGQGTKLQITR (SEQ ID NO: 401)
CDR H1: GYTFTSYT (서열번호: 396)CDR H1: GYTFTSYT (SEQ ID NO: 396) CDR L1: SSSVSY (서열번호: 402)CDR L1: SSSVSY (SEQ ID NO: 402) CDR H2: INPSSGYT (서열번호: 397)CDR H2: INPSSGYT (SEQ ID NO: 397) CDR L2: ATS (서열번호: 403)CDR L2: ATS (SEQ ID NO: 403) CDR H3: ARWQDYDVYFDY (서열번호: 398)CDR H3: ARWQDYDVYFDY (SEQ ID NO: 398) CDR L3: QQWSSNPPT (서열번호: 404)CDR L3: QQWSSNPPT (SEQ ID NO: 404)

실시예 21.45. ACE-03r의 제조Example 21.45. Preparation of ACE-03r

ACE-03r은 2개의 상이한 중쇄 유사 사슬 (ACE-03r-VH 및 ACE-03r-VL) 및 2개의 동일한 경쇄 (ACE-03r-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다: ACE-03r contains two different heavy chain-like chains (ACE-03r-VH and ACE-03r-VL) and two identical light chains (ACE-03r-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-03r-VH amino acid sequence:ACE-03r-VH amino acid sequence:

VQLVQSGGGVVQPGRSLRLSCKAS GYTFTRYT MHWVRQAPGKGLEWIGY INPSRGYT NYNQKVKDRFTISTDKSKSTAFLQMDSLRPEDTAVYYC ARYYDDHYCLDY WGQGTPVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC]DKTHTCPPCPAPELLGGP QVQLQQSGAELVRPGSSVKISCKASGYAFS SYWMN WVKQRPGQGLEWIGQ IWPGDGDT NYNGKFKGKATLTADESSSTAYMQLSSLASEDSAVYFC ARRETTTVGRYYYAMDY WGQGTTVTVSS (서열번호: 405) VQLVQSGGGVVQPGRSLRLSCKAS GYTFTRYT MHWVRQAPGKGLEWIGY INPSRGYT NYNQKVKDRFTISTDKSKSTAFLQMDSLRPEDTAVYYC ARYYDDHYCLDY WGQGTPVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC] DKTHTCPPCPAPELLGGP QVQLQQSGAELVRPGSSVKISCKASGYAFS SYWMN WVKQRPGQGLEWIGQ IWPGDGDT NYNGKFKGKATLTADESSSTAYMQLSSLASEDSAVYFC ARRETTTVGRYYYAMDY WGQGTTVTVSS (SEQ ID NO: 405)

ACE-03r-VL amino acid sequence: ACE-03r-VL amino acid sequence :

VQLVQSGGGVVQPGRSLRLSCKAS GYTFTRYT MHWVRQAPGKGLEWIGY INPSRGYT NYNQKVKDRFTISTDKSKSTAFLQMDSLRPEDTAVYYC ARYYDDHYCLDY WGQGTPVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC]DKTHTCPPCPAPELLGGP DIQLTQSPASLAVSLGQRATISCKAS QSVDYDGDSY LNWYQQIPGQPPKLLIY DAS NLVSGIPPRFSGSGSGTDFTLNIHPVEKVDAATYHC QQSTEDPWT FGGGTKLEIK (서열번호: 407) VQLVQSGGGVVQPGRSLRLSCKAS GYTFTRYT MHWVRQAPGKGLEWIGY INPSRGYT NYNQKVKDRFTISTDKSKSTAFLQMDSLRPEDTAVYYC ARYYDDHYCLDY WGQGTPVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC] DKTHTCPPCPAPELLGGP DIQLTQSPASLAVSLGQRATISCKAS QSVDYDGDSY LNWYQQIPGQPPKLLIY DAS NLVSGIPPRFSGSGSGTDFTLNIHPVEKVDAATYHC QQSTEDPWT FGGGTKLEIK (SEQ ID NO: 407)

ACE-03r-LC amino acid sequence: ACE-03r-LC amino acid sequence :

DIQMTQSPSSLSASVGDRVTITCSAS SSVSY MNWYQQTPGKAPKRWIY DTS KLASGVPSRFSGSGSGTDYTFTISSLQPEDIATYYC QQWSSNPFT FGQGTKLQITR[RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] (서열번호: 408) DIQMTQSPSSLSASVGDRVTITCSAS SSVSY MNWYQQTPGKAPKRWIY DTS KLASGVPSRFSGSGSGTDYTFTISSLQPEDIATYYC QQWSSNPFT FGQGTKLQITR [ RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPYPREASKVQWKLSVTYPREAKVQWKLSVGDSKVQWKLSVGDSKVQWK

CD3을 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 CD19를 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 49에 열거되어있다: The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting CD3 and the second antigen binding domain monovalent Fv region targeting CD19 are listed in Table 49 below:

Fv region
(Anti-CD19)
Fv region
(Anti-CD19)
VH: QVQLQQSGAELVRPGSSVKISCKASGYAFSSYWMNWVKQRPGQGLEWIGQIWPGDGDTNYNGKFKGKATLTADESSSTAYMQLSSLASEDSAVYFCARRETTTVGRYYYAMDYWGQGTTVTVSS (서열번호: 139)VH: QVQLQQSGAELVRPGSSVKISCKASGYAFSSYWMNWVKQRPGQGLEWIGQIWPGDGDTNYNGKFKGKATLTADESSSTAYMQLSSLASEDSAVYFCARRETTTVGRYYYAMDYWGQGTTVTVSS (SEQ ID NO: 139) VL:
DIQLTQSPASLAVSLGQRATISCKASQSVDYDGDSYLNWYQQIPGQPPKLLIYDASNLVSGIPPRFSGSGSGTDFTLNIHPVEKVDAATYHCQQSTEDPWTFGGGTKLEIK (서열번호: 151)
VL:
DIQLTQSPASLAVSLGQRATISCKASQSVDYDGDSYLNWYQQIPGQPPKLLIYDASNLVSGIPPRFSGSGSGTDFTLNIHPVEKVDAATYHCQQSTEDPWTFGGGTKLEIK (SEQ ID NO: 151)
CDR H1: SYWMN (서열번호: 140)CDR H1: SYWMN (SEQ ID NO: 140) CDR L1: QSVDYDGDSY (서열번호: 152)CDR L1: QSVDYDGDSY (SEQ ID NO: 152) CDR H2: IWPGDGDT (서열번호: 141)CDR H2: IWPGDGDT (SEQ ID NO: 141) CDR L2: DAS (서열번호: 153)CDR L2: DAS (SEQ ID NO: 153) CDR H3: ARETTTVGRYYYAMDY (서열번호: 142)CDR H3: ARETTTVGRYYYAMDY (SEQ ID NO: 142) CDR L3: QQSTEDPWT (서열번호: 154)CDR L3: QQSTEDPWT (SEQ ID NO: 154) Fab region
(Anti-CD3)
Fab region
(Anti-CD3)
VH:
VQLVQSGGGVVQPGRSLRLSCKASGYTFTRYTMHWVRQAPGKGLEWIGYINPSRGYTNYNQKVKDRFTISTDKSKSTAFLQMDSLRPEDTAVYYCARYYDDHYCLDYWGQGTPVTVSS (서열번호: 406)
VH:
VQLVQSGGGVVQPGRSLRLSCKASGYTFTRYTMHWVRQAPGKGLEWIGYINPSRGYTNYNQKVKDRFTISTDKSKSTAFLQMDSLRPEDTAVYYCARYYDDHYCLDYWGQGTPVTVSS (SEQ ID NO: 406)
VL:
DIQMTQSPSSLSASVGDRVTITCSASSSVSYMNWYQQTPGKAPKRWIYDTSKLASGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQQWSSNPFTFGQGTKLQITR (서열번호: 409)
VL:
DIQMTQSPSSLSASVGDRVTITCSASSSVSYMNWYQQTPGKAPKRWIYDTSKLASGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQQWSSNPFTFGQGTKLQITR (SEQ ID NO: 409)
CDR H1: GYTFTRYT (서열번호: 144)CDR H1: GYTFTRYT (SEQ ID NO: 144) CDR L1: SSVSY (서열번호: 148)CDR L1: SSVSY (SEQ ID NO: 148) CDR H2: INPSRGYT (서열번호: 145)CDR H2: INPSRGYT (SEQ ID NO: 145) CDR L2: DTS (서열번호: 149)CDR L2: DTS (SEQ ID NO: 149) CDR H3: ARYYDDHYCLDY (서열번호: 146)CDR H3: ARYYDDHYCLDY (SEQ ID NO: 146) CDR L3: QQWSSNPFT (서열번호: 410)CDR L3: QQWSSNPFT (SEQ ID NO: 410)

실시예 21.46. ACE-04r의 제조Example 21.46. Preparation of ACE-04r

ACE-04r은 ACE-04r-VH (VL-CL-VH-CH1) 및 ACE-04r-VL (VH-CH1-VL-CL) 사슬과 같은 2개의 다른 중쇄 및 2개의 동일한 경쇄(ACE- 04r-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다: ACE-04r has two different heavy chains such as ACE-04r-VH (VL-CL-VH-CH1) and ACE-04r-VL (VH-CH1-VL-CL) chains and two identical light chains (ACE-04r- LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-04r-VH amino acid sequence: ACE-04r-VH amino acid sequence :

QVQLQQSGAELARPGASVKMSCKAS GYTFTRYT MHWVKQRPGQGLEWIGY INPSRGYT NYNQKFKDKATLTTDKSSSTAYMQLSSLTSEDSAVYYC ARYYDDHYCLDY WGQGTTVTVSA[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPAPELLGGPggggsQMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC] (서열번호: 411) QVQLQQSGAELARPGASVKMSCKAS GYTFTRYT MHWVKQRPGQGLEWIGY INPSRGYT NYNQKFKDKATLTTDKSSSTAYMQLSSLTSEDSAVYYC ARYYDDHYCLDY WGQGTTVTVSA [ ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPAPELLGGP ggggs QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC] ( SEQ ID NO: 411)

ACE-04r-VL amino acid sequence: ACE-04r-VL amino acid sequence :

QVQLQQSGAELARPGASVKMSCKAS GYTFTRYT MHWVKQRPGQGLEWIGY INPSRGYT NYNQKFKDKATLTTDKSSSTAYMQLSSLTSEDSAVYYC ARYYDDHYCLDY WGQGTTVTVSA[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPAPELLGGPggggsQLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVL[RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] (서열번호: 413) QVQLQQSGAELARPGASVKMSCKAS GYTFTRYT MHWVKQRPGQGLEWIGY INPSRGYT NYNQKFKDKATLTTDKSSSTAYMQLSSLTSEDSAVYYC ARYYDDHYCLDY WGQGTTVTVSA [ ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPAPELLGGP ggggs QLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVL [RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] ( SEQ ID NO: 413)

ACE-04r-LC amino acid sequence: ACE-04r-LC amino acid sequence :

QIVLTQSPAIMSASPGEKVTMTCSAS SSVSY MNWYQQKSGTSPKRWIY DTS KLASGVPAHFRGSGSGTSYSLTISGMEAEDAATYYC QQWSSNPF TFGSGTKLEIN[RSVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC](서열번호: 414) QIVLTQSPAIMSASPGEKVTMTCSAS SSVSY MNWYQQKSGTSPKRWIY DTS KLASGVPAHFRGSGSGTSYSLTISGMEAEDAATYYC QQWSSNPF TFGSGTKLEIN [ RSVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVFIPSDEQLKSGTASVVCLLNNFYPREAKVFIPSDEQLKSGTASVVCLLNNFYPREADSKVQWKVDLSQDS

CD3을 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 PD-L1을 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 50에 열거되어있다: The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting CD3 and the second antigen binding domain monovalent Fv region targeting PD-L1 are listed in Table 50 below. have:

Fv region
(Anti-PD-L1)
Fv region
(Anti-PD-L1)
VH: QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (서열번호: 329)VH: QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (SEQ ID NO: 329) VL:
QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVL (서열번호: 376)
VL:
QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVL (SEQ ID NO: 376)
CDR H1: GGTFSSYA (서열번호: 330)CDR H1: GGTFSSYA (SEQ ID NO: 330) CDR L1: SSNIGAGYD (서열번호: 334)CDR L1: SSNIGAGYD (SEQ ID NO: 334) CDR H2: IIPILGIA (서열번호: 331)CDR H2: IIPILGIA (SEQ ID NO: 331) CDR L2: GDI (서열번호: 335)CDR L2: GDI (SEQ ID NO: 335) CDR H3: AKPRDGYNLVAFDI (서열번호: 332)CDR H3: AKPRDGYNLVAFDI (SEQ ID NO: 332) CDR L3: QSYDSSLSGGV (서열번호: 336)CDR L3: QSYDSSLSGGV (SEQ ID NO: 336) Fab region
(Anti-CD3)
Fab region
(Anti-CD3)
VH:
QVQLQQSGAELARPGASVKMSCKASGYTFTRYTMHWVKQRPGQGLEWIGYINPSRGYTNYNQKFKDKATLTTDKSSSTAYMQLSSLTSEDSAVYYCARYYDDHYCLDYWGQGTTVTVSA (서열번호: 412)
VH:
QVQLQQSGAELARPGASVKMSCKASGYTFTRYTMHWVKQRPGQGLEWIGYINPSRGYTNYNQKFKDKATLTTDKSSSTAYMQLSSLTSEDSAVYYCARYYDDHYCLDYWGQGTTVTVSA (SEQ ID NO: 412)
VL:
QIVLTQSPAIMSASPGEKVTMTCSASSSVSYMNWYQQKSGTSPKRWIYDTSKLASGVPAHFRGSGSGTSYSLTISGMEAEDAATYYCQQWSSNPFTFGSGTKLEIN (서열번호: 415)
VL:
QIVLTQSPAIMSASPGEKVTMTCSASSSVSYMNWYQQKSGTSPKRWIYDTSKLASGVPAHFRGSGSGTSYSLTISGMEAEDAATYYCQQWSSNPFTFGSGTKLEIN (SEQ ID NO: 415)
CDR H1: GYTFTRYT (서열번호: 144)CDR H1: GYTFTRYT (SEQ ID NO: 144) CDR L1: SSVSY (서열번호: 148)CDR L1: SSVSY (SEQ ID NO: 148) CDR H2: INPSRGYT (서열번호: 145)CDR H2: INPSRGYT (SEQ ID NO: 145) CDR L2: DTS (서열번호: 149)CDR L2: DTS (SEQ ID NO: 149) CDR H3: ARYYDDHYCLDY (서열번호: 146)CDR H3: ARYYDDHYCLDY (SEQ ID NO: 146) CDR L3: QQWSSNPF (서열번호: 416)CDR L3: QQWSSNPF (SEQ ID NO: 416)

실시예 21.47. ACE-05r의 제조Example 21.47. Preparation of ACE-05r

ACE-05r은 2개의 상이한 중쇄 유사 사슬 (ACE-05r-VH 및 ACE-05r-VL) 및 2개의 동일한 경쇄 (ACE-05r-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다: ACE-05r contains two different heavy chain-like chains (ACE-05r-VH and ACE-05r-VL) and two identical light chains (ACE-05r-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-05r-VH amino acid sequence (서열번호: 417)ACE-05r-VH amino acid sequence (SEQ ID NO: 417)

EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFDV WGQGTTLTVFS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPAPELLGGPggggsQMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFDV WGQGTTLTVFS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPAPELLGGP ggggs QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS

ACE-05r-VL amino acid sequence (서열번호: 418)ACE-05r-VL amino acid sequence (SEQ ID NO: 418)

EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFDV WGQGTTLTVFS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPAPELLGGPggggsQLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVL EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFDV WGQGTTLTVFS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPAPELLGGP ggggs QLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVL

ACE-05r-LC amino acid sequence (서열번호: 419)ACE-05r-LC amino acid sequence (SEQ ID NO: 419)

DIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR[RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] DIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR [ RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPYPREAKVQWKLSVTYPREAKVQWKLSVDSKVQWKLSVT

CD3을 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 PD-L1을 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 51에 열거되어있다: The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting CD3 and the second antigen binding domain monovalent Fv region targeting PD-L1 are listed in Table 51 below. have:

Fv region
(Anti-PD-L1)
Fv region
(Anti-PD-L1)
VH: QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (서열번호: 329)VH: QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (SEQ ID NO: 329) VL:
QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVL (서열번호: 376)
VL:
QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVL (SEQ ID NO: 376)
CDR H1: GGTFSSYA (서열번호: 330)CDR H1: GGTFSSYA (SEQ ID NO: 330) CDR L1: SSNIGAGYD (서열번호: 334)CDR L1: SSNIGAGYD (SEQ ID NO: 334) CDR H2: IIPILGIA (서열번호: 331)CDR H2: IIPILGIA (SEQ ID NO: 331) CDR L2: GDI (서열번호: 335)CDR L2: GDI (SEQ ID NO: 335) CDR H3: AKPRDGYNLVAFDI (서열번호: 332)CDR H3: AKPRDGYNLVAFDI (SEQ ID NO: 332) CDR L3: QSYDSSLSGGV (서열번호: 336)CDR L3: QSYDSSLSGGV (SEQ ID NO: 336) Fab region
(Anti-CD3)
Fab region
(Anti-CD3)
VH:
EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (서열번호: 325)
VH:
EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (SEQ ID NO: 325)
VL:
DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (서열번호: 337)
VL:
DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (SEQ ID NO: 337)
CDR H1: GYSFTGYT (서열번호: 326)CDR H1: GYSFTGYT (SEQ ID NO: 326) CDR L1: QDIRNY (서열번호: 338)CDR L1: QDIRNY (SEQ ID NO: 338) CDR H2: INPYKGVS (서열번호: 327)CDR H2: INPYKGVS (SEQ ID NO: 327) CDR L2: YTS (서열번호: 339)CDR L2: YTS (SEQ ID NO: 339) CDR H3: ARSGYYGDSDWYFDV (서열번호: 328)CDR H3: ARSGYYGDSDWYFDV (SEQ ID NO: 328) CDR L3: QQGNTLPWT (서열번호: 340)CDR L3: QQGNTLPWT (SEQ ID NO: 340)

실시예 21.48. ACE-06r의 제조Example 21.48. Preparation of ACE-06r

ACE-06r은 2개의 상이한 중쇄 유사 사슬 (ACE-06r-VH 및 ACE-06r-VL) 및 2개의 동일한 경쇄 (ACE-06r-LC)를 포함합니다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다: ACE-06r contains two different heavy chain-like chains (ACE-06r-VH and ACE-06r-VL) and two identical light chains (ACE-06r-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-06r-VH amino acid sequence (서열번호: 420)ACE-06r-VH amino acid sequence (SEQ ID NO: 420)

QVQLVESGGGVVQPGRSLRLSCAAS GFKFSGYG MHWVRQAPGKGLEWVAVI WYDGSKK YYVDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC ARQMGYWHFDL WGRGTLVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPAPELLGGPggggsQMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS QVQLVESGGGVVQPGRSLRLSCAAS GFKFSGYG MHWVRQAPGKGLEWVAVI WYDGSKK YYVDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC ARQMGYWHFDL WGRGTLVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPAPELLGGP ggggs QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS

ACE-06r-VL amino acid sequence (서열번호: 421)ACE-06r-VL amino acid sequence (SEQ ID NO: 421)

QVQLVESGGGVVQPGRSLRLSCAAS GFKFSGYG MHWVRQAPGKGLEWVAVI WYDGSKK YYVDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC ARQMGYWHFDL WGRGTLVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPAPELLGGPggggsQLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVLR QVQLVESGGGVVQPGRSLRLSCAAS GFKFSGYG MHWVRQAPGKGLEWVAVI WYDGSKK YYVDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC ARQMGYWHFDL WGRGTLVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPAPELLGGP ggggs QLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVLR

ACE-06r-LC amino acid sequence(서열번호: 422)ACE-06r-LC amino acid sequence (SEQ ID NO: 422)

EIVLTQSPATLSLSPGERATLSCRAS QSVSSY LAWYQQKPGQAPRLLIY DAS NRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYC QQRSNWPPLT FGGGTKVEIKR[SVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] EIVLTQSPATLSLSPGERATLSCRAS QSVSSY LAWYQQKPGQAPRLLIY DAS NRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYC QQRSNWPPLT FGGGTKVEIKR [ SVAAPSVFIFPPSDEQLKSGTKVEIKR [SVAAPSVFIFPPSDEQLKSGTKVEIKR [SVAAPSVFIFPPSDEQLKSGTKVEIKR [SVAAPSVFIFPPSDEQLKSGTGNASVVCLLNNFYPREADSKVQSKVLTQYPREAKVQSKVDLSKDS

CD3을 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 PD-L1을 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 52에 열거되어있다: The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting CD3 and the second antigen binding domain monovalent Fv region targeting PD-L1 are listed in Table 52 below. have:

Fv region
(Anti-PD-L1)
Fv region
(Anti-PD-L1)
VH:
QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (서열번호: 158)
VH:
QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (SEQ ID NO: 158)
VL:
QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLR (서열번호: 170)
VL:
QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLR (SEQ ID NO: 170)
CDR H1: GGTFSSYA (서열번호: 159)CDR H1: GGTFSSYA (SEQ ID NO: 159) CDR L1: SSNIGAGYD (서열번호: 171)CDR L1: SSNIGAGYD (SEQ ID NO: 171) CDR H2: IIPILGIA (서열번호: 160)CDR H2: IIPILGIA (SEQ ID NO: 160) CDR L2:
GDI (서열번호: 172)
CDR L2:
GDI (SEQ ID NO: 172)
CDR H3: AKPRDGYNLVAFDI (서열번호: 161)CDR H3: AKPRDGYNLVAFDI (SEQ ID NO: 161) CDR L3: QSYDSSLSGGV (서열번호: 173)CDR L3: QSYDSSLSGGV (SEQ ID NO: 173) Fab region
(Anti-CD3)
Fab region
(Anti-CD3)
VH:
QVQLVESGGGVVQPGRSLRLSCAASGFKFSGYGMHWVRQAPGKGLEWVAVIWYDGSKKYYVDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARQMGYWHFDLWGRGTLVTVSS (서열번호: 162)
VH:
QVQLVESGGGVVQPGRSLRLSCAASGFKFSGYGMHWVRQAPGKGLEWVAVIWYDGSKKYYVDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARQMGYWHFDLWGRGTLVTVSS (SEQ ID NO: 162)
VL:
EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPPLTFGGGTKVEIKR (서열번호: 166)
VL:
EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPPLTFGGGTKVEIKR (SEQ ID NO: 166)
CDR H1: GFKFSGYG (서열번호: 163)CDR H1: GFKFSGYG (SEQ ID NO: 163) CDR L1:
QSVSSY (서열번호: 167)
CDR L1:
QSVSSY (SEQ ID NO: 167)
CDR H2: IWYDGSKK (서열번호: 271)CDR H2: IWYDGSKK (SEQ ID NO: 271) CDR L2: DAS (서열번호: 168)CDR L2: DAS (SEQ ID NO: 168) CDR H3: ARQMGYWHFDL (서열번호: 165)CDR H3: ARQMGYWHFDL (SEQ ID NO: 165) CDR L3: QQRSNWPPLT (서열번호: 169)CDR L3: QQRSNWPPLT (SEQ ID NO: 169)

실시예 21.49. ACE-07r의 제조Example 21.49. Preparation of ACE-07r

ACE-07r은 2개의 상이한 중쇄 유사 사슬 (ACE-07r-VH 및 ACE-07r-VL) 및 2개의 동일한 경쇄 (ACE-07r-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다:ACE-07r contains two different heavy chain-like chains (ACE-07r-VH and ACE-07r-VL) and two identical light chains (ACE-07r-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-07r-VH amino acid sequence(서열번호: 423)ACE-07r-VH amino acid sequence (SEQ ID NO: 423)

EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKCLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFDV WGQGTTLTVFSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPggggsQMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKCLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFDV WGQGTTLTVFS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC DKTHTCPPCPAPELLGGP ggggs QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS

ACE-07r-VL amino acid sequence(서열번호: 424)ACE-07r-VL amino acid sequence (SEQ ID NO: 424)

EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKCLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFDV WGQGTTLTVFSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPggggsQLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVLR EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKCLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFDV WGQGTTLTVFS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC DKTHTCPPCPAPELLGGP ggggs QLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVLR

ACE-07r-LC amino acid sequence(서열번호: 425)ACE-07r-LC amino acid sequence (SEQ ID NO: 425)

DIQMTQTTSSLSASLGDRVTISCRASDIQMTQTTSSLSASLGDRVTISCRAS QDIRNYQDIRNY LNWYQQKPDGTVKLLIYLNWYQQKPDGTVKLLIY YTSYTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWQQGNTLPW TFAGCTKLEIKRTFAGCTKLEIKR SVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECSVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

PD-L1을 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 CD3를 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 53에 열거되어있다: The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting PD-L1 and the second antigen binding domain monovalent Fv region targeting CD3 are listed in Table 53 below. have:

Fv region
(Anti-PD-L1)
Fv region
(Anti-PD-L1)
VH:
QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (서열번호: 158)
VH:
QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (SEQ ID NO: 158)
VL:
QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLR (서열번호: 170)
VL:
QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLR (SEQ ID NO: 170)
CDR H1: GGTFSSYA (서열번호: 159)
CDR H1: GGTFSSYA (SEQ ID NO: 159)
CDR L1: SSNIGAGYD (서열번호: 171)
CDR L1: SSNIGAGYD (SEQ ID NO: 171)
CDR H2: IIPILGIA (서열번호: 160)CDR H2: IIPILGIA (SEQ ID NO: 160) CDR L2: GDI (서열번호: 172)CDR L2: GDI (SEQ ID NO: 172) CDR H3: AKPRDGYNLVAFDI (서열번호: 161)CDR H3: AKPRDGYNLVAFDI (SEQ ID NO: 161) CDR L3: QSYDSSLSGGV (서열번호: 173)CDR L3: QSYDSSLSGGV (SEQ ID NO: 173) Fab region
(Anti-CD3)
Fab region
(Anti-CD3)
VH: EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKCLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (서열번호: 176)VH: EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKCLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (SEQ ID NO: 176) VL: DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGCTKLEIKR (서열번호: 180)VL: DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGCTKLEIKR (SEQ ID NO: 180)
CDR H1: GYSFTGYT (서열번호: 177)CDR H1: GYSFTGYT (SEQ ID NO: 177) CDR L1: QDIRNY (서열번호: 181)CDR L1: QDIRNY (SEQ ID NO: 181) CDR H2: INPYKGVS (서열번호: 178)CDR H2: INPYKGVS (SEQ ID NO: 178) CDR L2: YTS (서열번호: 182)CDR L2: YTS (SEQ ID NO: 182) CDR H3: ARSGYYGDSDWYFDV (서열번호: 179)CDR H3: ARSGYYGDSDWYFDV (SEQ ID NO: 179) CDR L3: QQGNTLPW (서열번호: 183)CDR L3: QQGNTLPW (SEQ ID NO: 183)

실시예 21.50. ACE-08r의 제조Example 21.50. Preparation of ACE-08r

ACE-08r은 2개의 상이한 중쇄 유사 사슬 (ACE-08r-VH 및 ACE-08r-VL) 및 2개의 동일한 경쇄 (ACE-08r-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다:ACE-08r contains two different heavy chain-like chains (ACE-08r-VH and ACE-08r-VL) and two identical light chains (ACE-08r-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-08r-HC-VH amino acid sequence(서열번호: 426)ACE-08r-HC-VH amino acid sequence (SEQ ID NO: 426)

EVQLVESGGGLVQPGKSLKLSCEAS GFTFSGYG MHWVRQAPGRCLESVAY ITSSSINI KYADAVKGRFTVSRDNAKNLLFLQMNILKSEDTAMYYC ARFDWDKNY WGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPggggsQMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS EVQLVESGGGLVQPGKSLKLSCEAS GFTFSGYG MHWVRQAPGRCLESVAY ITSSSINI KYADAVKGRFTVSRDNAKNLLFLQMNILKSEDTAMYYC ARFDWDKNY WGQGTMVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTC PPCPAPELLGGP ggggs QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS

ACE-08r-HC-VL amino acid sequence(서열번호: 427)ACE-08r-HC-VL amino acid sequence (SEQ ID NO: 427)

EVQLVESGGGLVQPGKSLKLSCEAS GFTFSGYG MHWVRQAPGRCLESVAY ITSSSINI KYADAVKGRFTVSRDNAKNLLFLQMNILKSEDTAMYYC ARFDWDKNY WGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPggggsQLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVLR EVQLVESGGGLVQPGKSLKLSCEAS GFTFSGYG MHWVRQAPGRCLESVAY ITSSSINI KYADAVKGRFTVSRDNAKNLLFLQMNILKSEDTAMYYC ARFDWDKNY WGQGTMVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTC PPCPAPELLGGP ggggs QLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVLR

ACE-08r-LC amino acid sequence(서열번호: 428)ACE-08r-LC amino acid sequence (SEQ ID NO: 428)

QMTQSPSSLPASLGDRVTINCQASQMTQSPSSLPASLGDRVTINCQAS QDISNYQDISNY LNWYQQKPGKAPKLLIYLNWYQQKPGKAPKLLIY YTNYTN KLADGVPSRFSGSGSGRDSSFTISSLESEDIGSYYCKLADGVPSRFSGSGSGRDSSFTISSLESEDIGSYYC QQYYNYPWTQQYYNYPWT FGPCTKLEIKRFGPCTKLEIKR SVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC*SVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC*

CD3을 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 PD-L1을 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 54에 열거되어있다: The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting CD3 and the second antigen binding domain monovalent Fv region targeting PD-L1 are listed in Table 54 below. have:

Fv region
(Anti-PD-L1)
Fv region
(Anti-PD-L1)
VH: QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (서열번호: 158)VH: QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (SEQ ID NO: 158) VL:
QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLR (서열번호: 170)
VL:
QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLR (SEQ ID NO: 170)
CDR H1: GGTFSSYA (서열번호: 159)CDR H1: GGTFSSYA (SEQ ID NO: 159) CDR L1: SSNIGAGYD (서열번호: 171)CDR L1: SSNIGAGYD (SEQ ID NO: 171) CDR H2: IIPILGIA (서열번호: 160)CDR H2: IIPILGIA (SEQ ID NO: 160) CDR L2: GDI (서열번호: 172)CDR L2: GDI (SEQ ID NO: 172) CDR H3: AKPRDGYNLVAFDI (서열번호: 161)CDR H3: AKPRDGYNLVAFDI (SEQ ID NO: 161) CDR L3: QSYDSSLSGGV (서열번호: 173)CDR L3: QSYDSSLSGGV (SEQ ID NO: 173) Fab region
(Anti-CD3)
Fab region
(Anti-CD3)
VH:
EVQLVESGGGLVQPGKSLKLSCEASGFTFSGYGMHWVRQAPGRCLESVAYITSSSINIKYADAVKGRFTVSRDNAKNLLFLQMNILKSEDTAMYYCARFDWDKNYWGQGTMVTVSS (서열번호: 186)
VH:
EVQLVESGGGLVQPGKSLKLSCEASGFTFSGYGMHWVRQAPGRCLESVAYITSSSINIKYADAVKGRFTVSRDNAKNLLFLQMNILKSEDTAMYYCARFDWDKNYWGQGTMVTVSS (SEQ ID NO: 186)
VL: QMTQSPSSLPASLGDRVTINCQASQDISNYLNWYQQKPGKAPKLLIYYTNKLADGVPSRFSGSGSGRDSSFTISSLESEDIGSYYCQQYYNYPWTFGPCTKLEIKR (서열번호: 190)VL: QMTQSPSSLPASLGDRVTINCQASQDISNYLNWYQQKPGKAPKLLIYYTNKLADGVPSRFSGSGSGRDSSFTISSLESEDIGSYYCQQYYNYPWTFGPCTKLEIKR (SEQ ID NO: 190)
CDR H1: GFTFSGYG (서열번호: 187)CDR H1: GFTFSGYG (SEQ ID NO: 187) CDR L1: QDISNY (서열번호: 191)
CDR L1: QDISNY (SEQ ID NO: 191)
CDR H2: ITSSSINI (서열번호: 188)CDR H2: ITSSSINI (SEQ ID NO: 188) CDR L2: YTN (서열번호: 192)CDR L2: YTN (SEQ ID NO: 192) CDR H3: ARFDWDKNY (서열번호: 189)CDR H3: ARFDWDKNY (SEQ ID NO: 189) CDR L3: QQYYNYPWT (서열번호: 193)CDR L3: QQYYNYPWT (SEQ ID NO: 193)

실시예 21.51. ACE-09r의 제조Example 21.51. Preparation of ACE-09r

ACE-09는 두 개의 다른 중쇄 유사 사슬 (ACE-09-VH 및 ACE-09-VL) 및 두 개의 동일한 경쇄 (ACE-09-LC)를 포함한다. ACE-05와 비교하여 ACE-09는 유연한 펩타이드 영역에 G4S 링커 (GGGS의 아미노산 서열)를 포함하지 않는다. 이 세 가지 유형의 폴리 펩타이드의 아미노산 서열은 다음과 같다: ACE-09 contains two different heavy chain-like chains (ACE-09-VH and ACE-09-VL) and two identical light chains (ACE-09-LC). Compared to ACE-05, ACE-09 does not contain a G4S linker (amino acid sequence of GGGS) in the flexible peptide region. The amino acid sequences of these three types of polypeptides are as follows:

ACE-09r-VH amino acid sequence (서열번호: 429)ACE-09r-VH amino acid sequence (SEQ ID NO: 429)

EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFDV WGQGTTLTVFS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPAPELLGGP QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFDV WGQGTTLTVFS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPAPELLGGP QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS

ACE-09r-VL amino acid sequence (서열번호: 430)ACE-09r-VL amino acid sequence (SEQ ID NO: 430)

EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFDV WGQGTTLTVFS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPAPELLGGP QLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVL EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFDV WGQGTTLTVFS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPAPELLGGP QLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVL

ACE-09r-LC amino acid sequence (서열번호: 431)ACE-09r-LC amino acid sequence (SEQ ID NO: 431)

DIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR[RSVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] DIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR [ RSVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPYPREAKVQWKLSVTYPREAKVQWKLSVDSKVQWKLSVT

CD3을 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 PD-L1을 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 55에 나열되어있다: The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting CD3 and the second antigen binding domain monovalent Fv region targeting PD-L1 are listed in Table 55 below. have:

Fv region
(Anti-PD-L1)
Fv region
(Anti-PD-L1)
VH: QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (서열번호: 329)VH: QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (SEQ ID NO: 329) VL:
QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVL(서열번호: 376)
VL:
QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVL (SEQ ID NO: 376)
CDR H1: GGTFSSYA (서열번호: 330)CDR H1: GGTFSSYA (SEQ ID NO: 330) CDR L1: SSNIGAGYD (서열번호: 171)CDR L1: SSNIGAGYD (SEQ ID NO: 171) CDR H2: IIPILGIA (서열번호: 331)CDR H2: IIPILGIA (SEQ ID NO: 331) CDR L2: GDI (서열번호: 172)CDR L2: GDI (SEQ ID NO: 172) CDR H3: AKPRDGYNLVAFDI (서열번호: 332)CDR H3: AKPRDGYNLVAFDI (SEQ ID NO: 332) CDR L3: QSYDSSLSGGV (서열번호: 173)CDR L3: QSYDSSLSGGV (SEQ ID NO: 173) Fab region
(Anti-CD3)
Fab region
(Anti-CD3)
VH:
EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (서열번호: 325)
VH:
EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (SEQ ID NO: 325)
VL:
DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (서열번호: 337)
VL:
DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (SEQ ID NO: 337)
CDR H1: GYSFTGYT (서열번호: 326)CDR H1: GYSFTGYT (SEQ ID NO: 326) CDR L1: QDIRNY (서열번호: 338)CDR L1: QDIRNY (SEQ ID NO: 338) CDR H2: INPYKGVS (서열번호: 327)CDR H2: INPYKGVS (SEQ ID NO: 327) CDR L2: YTS (서열번호: 339)CDR L2: YTS (SEQ ID NO: 339) CDR H3: ARSGYYGDSDWYFDV (서열번호: 328)CDR H3: ARSGYYGDSDWYFDV (SEQ ID NO: 328) CDR L3: QQGNTLPWT (서열번호: 340)CDR L3: QQGNTLPWT (SEQ ID NO: 340)

실시예 21.52. ACE-10r의 제조Example 21.52. Preparation of ACE-10r

ACE-10r은 2개의 다른 중쇄 유사 사슬 (ACE-10r-VH 및 ACE-10r-VL) 및 2개의 동일한 경쇄 (ACE-10r-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다: ACE-10r contains two different heavy chain-like chains (ACE-10r-VH and ACE-10r-VL) and two identical light chains (ACE-10r-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-10r-VH amino acid sequence: ACE-10r-VH amino acid sequence :

EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFDV WGQGTTLTVFS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPAPELLGGPggggsQVQLQQPGAELVKPGASVKMSCKAS GYTFTSYN MHWVKQTPGRGLEWIGA IYPGNGDT SYNQKFKGKATLTADKSSSTAYMQLSSLTSEDSAVYYC ARSTYYGGDWYFNV WGAGTTVTVSA (서열번호: 432) EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFDV WGQGTTLTVFS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPAPELLGGP ggggs QVQLQQPGAELVKPGASVKMSCKAS GYTFTSYN MHWVKQTPGRGLEWIGA IYPGNGDT SYNQKFKGKATLTADKSSSTAYMQLSSLTSEDSAVYYC ARSTYYGGDWYFNV WGAGTTVTVSA (SEQ ID NO: 432)

ACE-10r-VL amino acid sequence: ACE-10r-VL amino acid sequence :

EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFDV WGQGTTLTVFS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPAPELLGGPggggsQIVLSQSPAILSASPGEKVTMTCRAS SSVSY IHWFQQKPGSSPKPWIY ATS NLASGVPVRFSGSGSGTSYSLTISRVEAEDAATYYC QQWTSNPPT FGGGTKLEIK (서열번호: 433) EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFDV WGQGTTLTVFS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPAPELLGGP ggggs QIVLSQSPAILSASPGEKVTMTCRAS SSVSY IHWFQQKPGSSPKPWIY ATS NLASGVPVRFSGSGSGTSYSLTISRVEAEDAATYYC QQWTSNPPT FGGGTKLEIK (SEQ ID NO: 433)

ACE-10r-LC amino acid sequence: ACE-10r-LC amino acid sequence :

DIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR[RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] (서열번호: 419) DIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR [ RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPYPREAKVQWKLSTSPDSKVQWKLSVGDSKVQWKLTHV

CD3을 표적으로하는 2가 Fab 영역 및 CD20을 표적으로하는 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 아래 표 56에 나열되어있다: The VH and VL amino acid sequences and CDR sequences therein for the bivalent Fab region targeting CD3 and the monovalent Fv region targeting CD20 are listed in Table 56 below:

Fv region
(Anti-CD20)
Fv region
(Anti-CD20)
VH
QVQLQQPGAELVKPGASVKMSCKASGYTFTSYNMHWVKQTPGRGLEWIGAIYPGNGDTSYNQKFKGKATLTADKSSSTAYMQLSSLTSEDSAVYYCARSTYYGGDWYFNVWGAGTTVTVSA (서열번호: 222)
VH
QVQLQQPGAELVKPGASVKMSCKASGYTFTSYNMHWVKQTPGRGLEWIGAIYPGNGDTSYNQKFKGKATLTADKSSSTAYMQLSSLTSEDSAVYYCARSTYYGGDWYFNVWGAGTTVTVSA (SEQ ID NO: 222)
VL
QIVLSQSPAILSASPGEKVTMTCRASSSVSYIHWFQQKPGSSPKPWIYATSNLASGVPVRFSGSGSGTSYSLTISRVEAEDAATYYCQQWTSNPPTFGGGTKLEIK (서열번호: 226)
VL
QIVLSQSPAILSASPGEKVTMTCRASSSVSYIHWFQQKPGSSPKPWIYATSNLASGVPVRFSGSGSGTSYSLTISRVEAEDAATYYCQQWTSNPPTFGGGTKLEIK (SEQ ID NO: 226)
CDR H1: GYTFTSYN (서열번호: 223)CDR H1: GYTFTSYN (SEQ ID NO: 223) CDR L1: SSVSY (서열번호: 227)CDR L1: SSVSY (SEQ ID NO: 227) CDR H2: IYPGNGDT (서열번호: 224)CDR H2: IYPGNGDT (SEQ ID NO: 224) CDR L2: ATS (서열번호: 228)CDR L2: ATS (SEQ ID NO: 228) CDR H3: ARSTYYGGDWYFNV (서열번호: 225)CDR H3: ARSTYYGGDWYFNV (SEQ ID NO: 225) CDR L3: QQWTSNPPT (서열번호: 229)CDR L3: QQWTSNPPT (SEQ ID NO: 229) Fab region
(Anti-CD3)
Fab region
(Anti-CD3)
VH: EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (서열번호: 325)VH: EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (SEQ ID NO: 325) VL
DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (서열번호: 337)
VL
DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (SEQ ID NO: 337)
CDR H1: GYSFTGYT (서열번호: 326)CDR H1: GYSFTGYT (SEQ ID NO: 326) CDR L1: QDIRNY (서열번호: 338)CDR L1: QDIRNY (SEQ ID NO: 338) CDR H2: INPYKGVS (서열번호: 327)CDR H2: INPYKGVS (SEQ ID NO: 327) CDR L2: YTS (서열번호: 339)CDR L2: YTS (SEQ ID NO: 339) CDR H1 ARSGYYGDSDWYFDV (서열번호: 328)CDR H1 ARSGYYGDSDWYFDV (SEQ ID NO: 328) CDR L3: QQGNTLPWT (서열번호: 340)CDR L3: QQGNTLPWT (SEQ ID NO: 340)

실시예 21.53. ACE-11r의 제조Example 21.53. Preparation of ACE-11r

ACE-11r은 2개의 상이한 중쇄 유사 사슬 (ACE-11r-VH 및 ACE-11r-VL) 및 2개의 동일한 경쇄 (ACE-11r-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다: ACE-11r contains two different heavy chain-like chains (ACE-11r-VH and ACE-11r-VL) and two identical light chains (ACE-11r-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-11r-VH amino acid sequence (서열번호: 434)ACE-11r-VH amino acid sequence (SEQ ID NO: 434)

EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFDV WGQGTTLTVFS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPAPELLGGPggggsQVQLKQSGPGLVQPSQSLSITCTVS GFSLTNYG VHWVRQSPGKGLEWLGV IWSGGNT DYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYC ARALTYYDYEFAY WGQGTLVTVSA EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFDV WGQGTTLTVFS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPAPELLGGP ggggs QVQLKQSGPGLVQPSQSLSITCTVS GFSLTNYG VHWVRQSPGKGLEWLGV IWSGGNT DYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYC ARALTYYDYEFAY WGQGTLVTVSA

ACE-11r-VL amino acid sequence (서열번호: 439)ACE-11r-VL amino acid sequence (SEQ ID NO: 439)

EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFDV WGQGTTLTVFS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPAPELLGGPggggsDILLTQSPVILSVSPGERVSFSCRAS QSIGTN IHWYQQRTNGSPRLLIK YAS ESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYC QQNNNWPTT FGAGTKLELK EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFDV WGQGTTLTVFS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPAPELLGGP ggggs DILLTQSPVILSVSPGERVSFSCRAS QSIGTN IHWYQQRTNGSPRLLIK YAS ESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYC QQNNNWPTT FGAGTKLELK

ACE-11r-LC amino acid sequence (서열번호: 419)ACE-11r-LC amino acid sequence (SEQ ID NO: 419)

DIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR[RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] DIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR [ RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPYPREAKVQWKLSVTYPREAKVQWKLSVDSKVQWKLSVT

CD3을 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 EGFR을 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 57에 열거되어있다: The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting CD3 and the second antigen binding domain monovalent Fv region targeting EGFR are listed in Table 57 below:

Fab region
(Anti-CD3)
Fab region
(Anti-CD3)
VH: EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (서열번호: 325)VH: EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFDV WGQGTTLTVFS (SEQ ID NO: 325) VL:
DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (서열번호: 337)
VL:
DIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR (SEQ ID NO: 337)
CDR H1: GYSFTGYT(서열번호: 326)CDR H1: GYSFTGYT (SEQ ID NO: 326) CDR L1: QDIRNY (서열번호: 338)CDR L1: QDIRNY (SEQ ID NO: 338) CDR H2: INPYKGVS (서열번호: 327)CDR H2: INPYKGVS (SEQ ID NO: 327) CDR L2: YTS (서열번호: 339)CDR L2: YTS (SEQ ID NO: 339) CDR H3: ARSGYYGDSDWYFDV (서열번호: 328)CDR H3: ARSGYYGDSDWYFDV (SEQ ID NO: 328) CDR L3: QQGNTLPWT (서열번호: 340)CDR L3: QQGNTLPWT (SEQ ID NO: 340) Fv region
(Anti-EGFR)
Fv region
(Anti-EGFR)
VH: QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSA (서열번호: 435)VH: QVQLKQSGPGLVQPSQSLSITCTVS GFSLTNYG VHWVRQSPGKGLEWLGV IWSGGNT DYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYC ARALTYYDYEFAY WGQGTLVTVSA (SEQ ID NO: 435) VL:
DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELK (서열번호: 440)
VL:
DILLTQSPVILSVSPGERVSFSCRAS QSIGTN IHWYQQRTNGSPRLLIK YAS ESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYC QQNNNWPTT FGAGTKLELK (SEQ ID NO: 440)
CDR H1: GFSLTNYG (서열번호: 436)CDR H1: GFSLTNYG (SEQ ID NO: 436) CDR L1: QSIGTN (서열번호: 441)CDR L1: QSIGTN (SEQ ID NO: 441) CDR H2: IWSGGNT (서열번호: 437)CDR H2: IWSGGNT (SEQ ID NO: 437) CDR L2: YAS (서열번호: 442)CDR L2: YAS (SEQ ID NO: 442) CDR H3: ARALTYYDYEFAY (서열번호: 438)CDR H3: ARALTYYDYEFAY (SEQ ID NO: 438) CDR L3: QQNNNWPTT (서열번호: 443)CDR L3: QQNNNWPTT (SEQ ID NO: 443)

실시예 21.54. ACE-12r의 제조Example 21.54. Preparation of ACE-12r

ACE-12r은 2개의 상이한 중쇄 유사 사슬 (ACE-12r-VH 및 ACE-12r-VL) 및 2개의 동일한 경쇄 (ACE-12r-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다:ACE-12r contains two different heavy chain-like chains (ACE-12r-VH and ACE-12r-VL) and two identical light chains (ACE-12r-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-12r-VH amino acid sequence (서열번호: 444)ACE-12r-VH amino acid sequence (SEQ ID NO: 444)

EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFDV WGQGTTLTVFS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPAPELLGGPggggsggggsQMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFDV WGQGTTLTVFS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPAPELLGGP ggggsggggs QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS

ACE-12r-VL amino acid sequence (서열번호: 445)ACE-12r-VL amino acid sequence (SEQ ID NO: 445)

EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFDV WGQGTTLTVFS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPAPELLGGPggsggggsgQLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVL EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFDV WGQGTTLTVFS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPAPELLGGP ggsggggsg QLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVL

ACE-12r-LC amino acid sequence (서열번호: 431)ACE-12r-LC amino acid sequence (SEQ ID NO: 431)

DIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR[RSVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] DIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR [ RSVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPYPREAKVQWKLSVTYPREAKVQWKLSVDSKVQWKLSVT

CD3을 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 PD-L1을 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 58에 열거되어있다: The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting CD3 and the second antigen binding domain monovalent Fv region targeting PD-L1 are listed in Table 58 below. have:

Fv region
(Anti-PD-L1)
Fv region
(Anti-PD-L1)
VH: QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (서열번호: 329)VH: QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (SEQ ID NO: 329) VL:
QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVL(서열번호: 376)
VL:
QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVL (SEQ ID NO: 376)
CDR H1: GGTFSSYA (서열번호: 330)CDR H1: GGTFSSYA (SEQ ID NO: 330) CDR L1: SSNIGAGYD (서열번호: 171)CDR L1: SSNIGAGYD (SEQ ID NO: 171) CDR H2: IIPILGIA (서열번호: 331)CDR H2: IIPILGIA (SEQ ID NO: 331) CDR L2: GDI (서열번호: 172)CDR L2: GDI (SEQ ID NO: 172) CDR H3: AKPRDGYNLVAFDI (서열번호: 332)CDR H3: AKPRDGYNLVAFDI (SEQ ID NO: 332) CDR L3: QSYDSSLSGGV (서열번호: 173)CDR L3: QSYDSSLSGGV (SEQ ID NO: 173) Fab region
(Anti-CD3)
Fab region
(Anti-CD3)
VH:
EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (서열번호: 325)
VH:
EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (SEQ ID NO: 325)
VL: DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (서열번호: 337)VL: DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (SEQ ID NO: 337)
CDR H1: GYSFTGYT (서열번호: 326)CDR H1: GYSFTGYT (SEQ ID NO: 326) CDR L1: QDIRNY (서열번호: 338)CDR L1: QDIRNY (SEQ ID NO: 338) CDR H2: INPYKGVS (서열번호: 327)CDR H2: INPYKGVS (SEQ ID NO: 327) CDR L2: YTS (서열번호: 339)CDR L2: YTS (SEQ ID NO: 339) CDR H3: ARSGYYGDSDWYFDV (서열번호: 328)CDR H3: ARSGYYGDSDWYFDV (SEQ ID NO: 328) CDR L3: QQGNTLPWT (서열번호: 340)CDR L3: QQGNTLPWT (SEQ ID NO: 340)

실시예 21.55. ACE-13r의 제조Example 21.55. Preparation of ACE-13r

ACE-13r은 2개의 다른 중쇄 유사 사슬 (ACE-13r-VH 및 ACE-13r-VL) 및 2개의 동일한 경쇄 (ACE-13r-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다: ACE-13r contains two different heavy chain-like chains (ACE-13r-VH and ACE-13r-VL) and two identical light chains (ACE-13r-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-13r-VH amino acid sequence (서열번호: 446)ACE-13r-VH amino acid sequence (SEQ ID NO: 446)

QVQLVESGGGVVQPGRSLRLSCAAS GFTFLRYA MHWVRQAPGKGLEWVAV ISYDGRYK YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC TTTTFDS WGQGTLVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPAPELLGGPggggsQMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS QVQLVESGGGVVQPGRSLRLSCAAS GFTFLRYA MHWVRQAPGKGLEWVAV ISYDGRYK YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC TTTTFDS WGQGTLVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPAPELLGGP ggggs QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS

ACE-13r-VLamino acid sequence (서열번호: 447)ACE-13r-VLamino acid sequence (SEQ ID NO: 447)

QVQLVESGGGVVQPGRSLRLSCAAS GFTFLRYA MHWVRQAPGKGLEWVAV ISYDGRYK YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC TTTTFDS WGQGTLVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPAPELLGGPggggsQLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVLR QVQLVESGGGVVQPGRSLRLSCAAS GFTFLRYA MHWVRQAPGKGLEWVAV ISYDGRYK YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC TTTTFDS WGQGTLVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPAPELLGGP ggggs QLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVLR

ACE-13r-LC amino acid sequence (서열번호: 448)ACE-13r-LC amino acid sequence (SEQ ID NO: 448)

DIVMTQTPLSLPVTPGEAASISCRSS QSLLDSEDGNTY LDWYLQKPGQSPQLLIY TLS HRASGVPDRFSGSGSGTDFTLEISRVEAEDVGVYYC MQRRDFPFT FGQGTKVDIKR[SVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC]* DIVMTQTPLSLPVTPGEAASISCRSS QSLLDSEDGNTY LDWYLQKPGQSPQLLIY TLS HRASGVPDRFSGSGSGTDFTLEISRVEAEDVGVYYC MQRRDFPFT FGQGTKVDIKR [ SVAAPSVFIFPPSDEQLKSGTASVVCLLVNNFYPQDSGNQSVKDYPQKREADSQSV

PD-1을 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 PD-L1를 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 59에 열거되어있다: The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting PD-1 and the second antigen binding domain monovalent Fv region targeting PD-L1 are shown in Table 59 below. It is listed:

Fv region
(Anti-PD-L1)
Fv region
(Anti-PD-L1)
VH: QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (서열번호: 158)VH: QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (SEQ ID NO: 158) VL:
QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLR (서열번호: 170)
VL:
QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLR (SEQ ID NO: 170)
CDR H1: GGTFSSYA (서열번호: 159)CDR H1: GGTFSSYA (SEQ ID NO: 159) CDR L1: SSNIGAGYD (서열번호: 171)CDR L1: SSNIGAGYD (SEQ ID NO: 171) CDR H2: IIPILGIA (서열번호: 160)CDR H2: IIPILGIA (SEQ ID NO: 160) CDR L2: GDI (서열번호: 172)CDR L2: GDI (SEQ ID NO: 172) CDR H3: AKPRDGYNLVAFDI (서열번호: 161)CDR H3: AKPRDGYNLVAFDI (SEQ ID NO: 161) CDR L3: QSYDSSLSGGV (서열번호: 173)CDR L3: QSYDSSLSGGV (SEQ ID NO: 173) Fab region
(Anti-PD-1)
Fab region
(Anti-PD-1)
VH: QVQLVESGGGVVQPGRSLRLSCAASGFTFLRYAMHWVRQAPGKGLEWVAVISYDGRYKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCTTTTFDSWGQGTLVTVSS (서열번호: 196)VH: QVQLVESGGGVVQPGRSLRLSCAASGFTFLRYAMHWVRQAPGKGLEWVAVISYDGRYKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCTTTTFDSWGQGTLVTVSS (SEQ ID NO: 196) VL:
DIVMTQTPLSLPVTPGEAASISCRSSQSLLDSEDGNTYLDWYLQKPGQSPQLLIYTLSHRASGVPDRFSGSGSGTDFTLEISRVEAEDVGVYYCMQRRDFPFTFGQGTKVDIKR (서열번호: 200)
VL:
DIVMTQTPLSLPVTPGEAASISCRSSQSLLDSEDGNTYLDWYLQKPGQSPQLLIYTLSHRASGVPDRFSGSGSGTDFTLEISRVEAEDVGVYYCMQRRDFPFTFGQGTKVDIKR (SEQ ID NO: 200)
CDR H1: GFTFLRYA (서열번호: 197)CDR H1: GFTFLRYA (SEQ ID NO: 197) CDR L1: QSLLDSEDGNTY (서열번호: 201)CDR L1: QSLLDSEDGNTY (SEQ ID NO: 201) CDR H2: ISYDGRYK (서열번호: 198)CDR H2: ISYDGRYK (SEQ ID NO: 198) CDR L2: TLS (서열번호: 202)CDR L2: TLS (SEQ ID NO: 202) CDR H3: TTTTFDS (서열번호: 199)CDR H3: TTTTFDS (SEQ ID NO: 199) CDR L3: MQRRDFPFT (서열번호: 203)CDR L3: MQRRDFPFT (SEQ ID NO: 203)

실시예 21.56. ACE-14r의 제조Example 21.56. Preparation of ACE-14r

ACE-14r은 2개의 상이한 중쇄 유사 사슬 (ACE-14r-VH 및 ACE-14r-VL) 및 2개의 동일한 경쇄 (ACE-14r-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다: ACE-14r contains two different heavy chain-like chains (ACE-14r-VH and ACE-14r-VL) and two identical light chains (ACE-14r-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-14r-VH amino acid sequence (서열번호: 449)ACE-14r-VH amino acid sequence (SEQ ID NO: 449)

EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKCLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFDV WGQGTTLTVFS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPAPELLGGPggggsggggsQMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKCLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFDV WGQGTTLTVFS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPAPELLGGP ggggsggggs QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS

ACE-14r-VL amino acid sequence (서열번호: 450)ACE-14r-VL amino acid sequence (SEQ ID NO: 450)

EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKCLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFDV WGQGTTLTVFS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPAPELLGGPggggsggggsQLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVLR EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKCLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFDV WGQGTTLTVFS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPAPELLGGP ggggsggggs QLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVLR

ACE-14r-LC amino acid sequence (서열번호: 451)ACE-14r-LC amino acid sequence (SEQ ID NO: 451)

DIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FACGTKLEIKR[SVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] DIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FACGTKLEIKR [ SVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPYPREAKVQWKLSVTYPREAKVQWKLSVDSKVQWKLSVT

CD3을 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 PD-L1을 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 60에 열거되어있다: The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting CD3 and the second antigen binding domain monovalent Fv region targeting PD-L1 are listed in Table 60 below. have:

Fv region
(Anti-PD-L1)
Fv region
(Anti-PD-L1)
VH: QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (서열번호: 158)VH: QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (SEQ ID NO: 158) VL:
QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLR (서열번호: 170)
VL:
QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLR (SEQ ID NO: 170)
CDR H1: GGTFSSYA (서열번호: 159)CDR H1: GGTFSSYA (SEQ ID NO: 159) CDR L1: SSNIGAGYD (서열번호: 171)CDR L1: SSNIGAGYD (SEQ ID NO: 171) CDR H2: IIPILGIA (서열번호: 160)CDR H2: IIPILGIA (SEQ ID NO: 160) CDR L2: GDI (서열번호: 172)CDR L2: GDI (SEQ ID NO: 172) CDR H3: AKPRDGYNLVAFDI (서열번호: 161)CDR H3: AKPRDGYNLVAFDI (SEQ ID NO: 161) CDR L3: QSYDSSLSGGV (서열번호: 173)CDR L3: QSYDSSLSGGV (SEQ ID NO: 173) Fab region
(Anti-CD3)
Fab region
(Anti-CD3)
VH: EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKCLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (서열번호: 176)VH: EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKCLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (SEQ ID NO: 176) VL: DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFACGTKLEIKR (서열번호: 206)VL: DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFACGTKLEIKR (SEQ ID NO: 206)
CDR H1: GYSFTGYT (서열번호: 177)CDR H1: GYSFTGYT (SEQ ID NO: 177) CDR L1: QDIRNY (서열번호: 181)CDR L1: QDIRNY (SEQ ID NO: 181) CDR H2: INPYKGVS (서열번호: 178)CDR H2: INPYKGVS (SEQ ID NO: 178) CDR L2: YTS (서열번호: 182)CDR L2: YTS (SEQ ID NO: 182) CDR H3: ARSGYYGDSDWYFDV (서열번호: 179)CDR H3: ARSGYYGDSDWYFDV (SEQ ID NO: 179) CDR L3: QQGNTLPWT (서열번호: 207)CDR L3: QQGNTLPWT (SEQ ID NO: 207)

실시예 21.57. ACE-15r의 제조Example 21.57. Preparation of ACE-15r

ACE-15r은 2개의 상이한 중쇄 유사 사슬 (ACE-15r-VH 및 ACE-15r-VL) 및 2개의 동일한 경쇄 (ACE-15r-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다: ACE-15r contains two different heavy chain-like chains (ACE-15r-VH and ACE-15r-VL) and two identical light chains (ACE-15r-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-15r-VH amino acid sequence(서열번호: 452)ACE-15r-VH amino acid sequence (SEQ ID NO: 452)

EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGCGTTLTVFS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPAPELLGGPggggsQMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGCGTTLTVFS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPAPELLGGP ggggs QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS

ACE-15r-VL amino acid sequence(서열번호: 453)ACE-15r-VL amino acid sequence (SEQ ID NO: 453)

EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGCGTTLTVFS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPAPELLGGPggggsQLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVLR EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGCGTTLTVFS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPAPELLGGP ggggs QLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVLR

ACE-15r-LC amino acid sequence(서열번호: 454)ACE-15r-LC amino acid sequence (SEQ ID NO: 454)

DIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGCVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR[SVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] DIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGCVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR [ SVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPYPREAKVQWKLSVTYPREAKVQWKLSVDSKVQWKLSVT

CD3을 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 PD-L1을 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 61에 열거되어있다: The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting CD3 and the second antigen binding domain monovalent Fv region targeting PD-L1 are listed in Table 61 below. have:

Fv region
(Anti-PD-L1)
Fv region
(Anti-PD-L1)
VH: QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (서열번호: 158)VH: QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (SEQ ID NO: 158) VL:
QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLR (서열번호: 170)
VL:
QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLR (SEQ ID NO: 170)
CDR H1: GGTFSSYA (서열번호: 159)CDR H1: GGTFSSYA (SEQ ID NO: 159) CDR L1: SSNIGAGYD (서열번호: 171)CDR L1: SSNIGAGYD (SEQ ID NO: 171) CDR H2: IIPILGIA (서열번호: 160)CDR H2: IIPILGIA (SEQ ID NO: 160) CDR L2: GDI (서열번호: 172)CDR L2: GDI (SEQ ID NO: 172) CDR H3: AKPRDGYNLVAFDI (서열번호: 161)CDR H3: AKPRDGYNLVAFDI (SEQ ID NO: 161) CDR L3: QSYDSSLSGGV (서열번호: 173)CDR L3: QSYDSSLSGGV (SEQ ID NO: 173) Fab region
(Anti-CD3)
Fab region
(Anti-CD3)
VH:
EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGCGTTLTVFS (서열번호: 210)
VH:
EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGCGTTLTVFS (SEQ ID NO: 210)
VL:
DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGCVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (서열번호: 212)
VL:
DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGCVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (SEQ ID NO: 212)
CDR H1: GYSFTGYT (서열번호: 177)CDR H1: GYSFTGYT (SEQ ID NO: 177) CDR L1: QDIRNY (서열번호: 181)CDR L1: QDIRNY (SEQ ID NO: 181) CDR H2: INPYKGVS (서열번호: 178)CDR H2: INPYKGVS (SEQ ID NO: 178) CDR L2: YTS (서열번호: 182)CDR L2: YTS (SEQ ID NO: 182) CDR H3: ARSGYYGDSDWYFD (서열번호: 211)CDR H3: ARSGYYGDSDWYFD (SEQ ID NO: 211) CDR L3: QQGNTLPWT (서열번호: 207)CDR L3: QQGNTLPWT (SEQ ID NO: 207)

실시예 21.58. ACE-16r의 제조Example 21.58. Preparation of ACE-16r

ACE-16r은 2개의 상이한 중쇄 유사 사슬 (ACE-16r-VH 및 ACE-16r-VL) 및 2개의 동일한 경쇄 (ACE-16r-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다: ACE-16r contains two different heavy chain-like chains (ACE-16r-VH and ACE-16r-VL) and two identical light chains (ACE-16r-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-16r-VH amino acid sequence (서열번호: 455)ACE-16r-VH amino acid sequence (SEQ ID NO: 455)

EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPPCPAPELLGGPggggsQMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPPCPAPELLGGP ggggs QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS

ACE-16r-VL amino acid sequence (서열번호: 456)ACE-16r-VL amino acid sequence (SEQ ID NO: 456)

EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPPCPAPELLGGPggggsQLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVLR EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPPCPAPELLGGP ggggs QLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVLR

ACE-16r-LC amino acid sequence (서열번호: 457)ACE-16r-LC amino acid sequence (SEQ ID NO: 457)

DIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR[SVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] DIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR [ SVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPYPREAKVQWKLSVTYPREAKVQWKLSTSPDSKVQWKLSVT

CD3을 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 PD-L1을 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 62에 열거되어있다.The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting CD3 and the second antigen binding domain monovalent Fv region targeting PD-L1 are listed in Table 62 below. have.

Fv region
(Anti-PD-L1)
Fv region
(Anti-PD-L1)
VH: QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (서열번호: 158)VH: QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (SEQ ID NO: 158) VL:
QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLR (서열번호: 170)
VL:
QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLR (SEQ ID NO: 170)
CDR H1: GGTFSSYA (서열번호: 159)CDR H1: GGTFSSYA (SEQ ID NO: 159) CDR L1: SSNIGAGYD (서열번호: 171)CDR L1: SSNIGAGYD (SEQ ID NO: 171) CDR H2: IIPILGIA (서열번호: 160)CDR H2: IIPILGIA (SEQ ID NO: 160) CDR L2: GDI (서열번호: 172)CDR L2: GDI (SEQ ID NO: 172) CDR H3: AKPRDGYNLVAFDI (서열번호: 161)CDR H3: AKPRDGYNLVAFDI (SEQ ID NO: 161) CDR L3: QSYDSSLSGGV (서열번호: 173)CDR L3: QSYDSSLSGGV (SEQ ID NO: 173) Fab region
(Anti-CD3)
Fab region
(Anti-CD3)
VH: EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (서열번호: 215)VH: EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (SEQ ID NO: 215) VL: DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (서열번호: 216)VL: DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (SEQ ID NO: 216)
CDR H1: GYSFTGYT (서열번호: 177)CDR H1: GYSFTGYT (SEQ ID NO: 177) CDR L1: QDIRNY (서열번호: 181)CDR L1: QDIRNY (SEQ ID NO: 181) CDR H2: INPYKGVS (서열번호: 178)CDR H2: INPYKGVS (SEQ ID NO: 178) CDR L2: YTS (서열번호: 182)CDR L2: YTS (SEQ ID NO: 182) CDR H3: ARSGYYGDSDWYFD (서열번호: 211)CDR H3: ARSGYYGDSDWYFD (SEQ ID NO: 211) CDR L3: QQGNTLPWT (서열번호: 207)CDR L3: QQGNTLPWT (SEQ ID NO: 207)

실시예 21.59. ACE-17r의 제조Example 21.59. Preparation of ACE-17r

ACE-17r은 두 개의 다른 중쇄 유사 사슬 (ACE-17r-VH 및 ACE-17r-VL) 및 두 개의 동일한 경쇄 (ACE-17r-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다: ACE-17r contains two different heavy chain-like chains (ACE-17r-VH and ACE-17r-VL) and two identical light chains (ACE-17r-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-17r-VH amino acid sequence (서열번호: 458)ACE-17r-VH amino acid sequence (SEQ ID NO: 458)

EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPPCPAPELLGGP QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPPCPAPELLGGP QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS

ACE-17r-VL amino acid sequence (서열번호: 459)ACE-17r-VL amino acid sequence (SEQ ID NO: 459)

EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPPCPAPELLGGP QLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVLR EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPPCPAPELLGGP QLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVLR

ACE-17r-LC amino acid sequence (서열번호: 457)ACE-17r-LC amino acid sequence (SEQ ID NO: 457)

DIQMTQTTSSLSASLGDRVTISCRASDIQMTQTTSSLSASLGDRVTISCRAS QDIRNYQDIRNY LNWYQQKPDGTVKLLIYLNWYQQKPDGTVKLLIY YTSYTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWTQQGNTLPWT FAGGTKLEIKR[FAGGTKLEIKR[ SVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC]SVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC]

CD3을 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 PD-L1을 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 63에 열거되어있다.The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting CD3 and the second antigen binding domain monovalent Fv region targeting PD-L1 are listed in Table 63 below. have.

Fv region
(Anti-PD-L1)
Fv region
(Anti-PD-L1)
VH: QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (서열번호: 158)VH: QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (SEQ ID NO: 158) VL:
QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLR (서열번호: 170)
VL:
QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLR (SEQ ID NO: 170)
CDR H1: GGTFSSYA (서열번호: 159)CDR H1: GGTFSSYA (SEQ ID NO: 159) CDR L1: SSNIGAGYD (서열번호: 171)CDR L1: SSNIGAGYD (SEQ ID NO: 171) CDR H2: IIPILGIA (서열번호: 160)CDR H2: IIPILGIA (SEQ ID NO: 160) CDR L2: GDI (서열번호: 172)CDR L2: GDI (SEQ ID NO: 172) CDR H3: AKPRDGYNLVAFDI (서열번호: 161)CDR H3: AKPRDGYNLVAFDI (SEQ ID NO: 161) CDR L3: QSYDSSLSGGV (서열번호: 173)CDR L3: QSYDSSLSGGV (SEQ ID NO: 173) Fab region
(Anti-CD3)
Fab region
(Anti-CD3)
VH:
EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (서열번호: 215)
VH:
EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (SEQ ID NO: 215)
VL:
DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (서열번호: 216)
VL:
DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (SEQ ID NO: 216)
CDR H1: GYSFTGYT (서열번호: 177)CDR H1: GYSFTGYT (SEQ ID NO: 177) CDR L1: QDIRNY (서열번호: 181)CDR L1: QDIRNY (SEQ ID NO: 181) CDR H2: INPYKGVS (서열번호: 178)CDR H2: INPYKGVS (SEQ ID NO: 178) CDR L2: YTS (서열번호: 182)CDR L2: YTS (SEQ ID NO: 182) CDR H3: ARSGYYGDSDWYFD (서열번호: 211)CDR H3: ARSGYYGDSDWYFD (SEQ ID NO: 211) CDR L3: QQGNTLPWT (서열번호: 207)CDR L3: QQGNTLPWT (SEQ ID NO: 207)

실시예 21.60. ACE-18r의 제조Example 21.60. Preparation of ACE-18r

ACE-18r은 2개의 상이한 중쇄 유사 사슬 (ACE-18r-VH 및 ACE-18r-VL) 및 2개의 동일한 경쇄 (ACE-18r-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다: ACE-18r contains two different heavy chain-like chains (ACE-18r-VH and ACE-18r-VL) and two identical light chains (ACE-18r-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-18r-VH amino acid sequence (서열번호: 460)ACE-18r-VH amino acid sequence (SEQ ID NO: 460)

EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPPCPAPELLGGPGGGGSQVQLQQPGAELVKPGASVKMSCKAS GYTFTSYN MHWVKQTPGRGLEWIGA IYPGNGDT SYNQKFKGKATLTADKSSSTAYMQLSSLTSEDSAVYYC ARSTYYGGDWYFNV WGAGTTVTVSA EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC DKTHTCPPCPPCPAPELLGGP GGGGS QVQLQQPGAELVKPGASVKMSCKAS GYTFTSYN MHWVKQTPGRGLEWIGA IYPGNGDT SYNQKFKGKATLTADKSSSTAYMQLSSLTSEDSAVYYC ARSTYYGGDWYFNV WGAGTTVTVSA

ACE-18r-VL amino acid sequence (서열번호: 461)ACE-18r-VL amino acid sequence (SEQ ID NO: 461)

EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPPCPAPELLGGPGGGGSQIVLSQSPAILSASPGEKVTMTCRAS SSVSY IHWFQQKPGSSPKPWIY ATS NLASGVPVRFSGSGSGTSYSLTISRVEAEDAATYYC QQWTSNPPT FGGGTKLEIK EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC DKTHTCPPCPPCPAPELLGGP GGGGS QIVLSQSPAILSASPGEKVTMTCRAS SSVSY IHWFQQKPGSSPKPWIY ATS NLASGVPVRFSGSGSGTSYSLTISRVEAEDAATYYC QQWTSNPPT FGGGTKLEIK

ACE-18r-LC amino acid sequence (서열번호: 431)ACE-18r-LC amino acid sequence (SEQ ID NO: 431)

DIQMTQTTSSLSASLGDRVTISCRASDIQMTQTTSSLSASLGDRVTISCRAS QDIRNYQDIRNY LNWYQQKPDGTVKLLIYLNWYQQKPDGTVKLLIY YTSYTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWTQQGNTLPWT FAGGTKLEIKRFAGGTKLEIKR RSVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC*RSVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC*

CD3을 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 CD20을 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 64에 열거되어있다.The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting CD3 and the second antigen binding domain monovalent Fv region targeting CD20 are listed in Table 64 below.

Fv region
(Anti-CD20)
Fv region
(Anti-CD20)
VH: QVQLQQPGAELVKPGASVKMSCKASGYTFTSYNMHWVKQTPGRGLEWIGAIYPGNGDTSYNQKFKGKATLTADKSSSTAYMQLSSLTSEDSAVYYCARSTYYGGDWYFNVWGAGTTVTVSA (서열번호: 222)VH: QVQLQQPGAELVKPGASVKMSCKASGYTFTSYNMHWVKQTPGRGLEWIGAIYPGNGDTSYNQKFKGKATLTADKSSSTAYMQLSSLTSEDSAVYYCARSTYYGGDWYFNVWGAGTTVTVSA (SEQ ID NO: 222) VL:
QIVLSQSPAILSASPGEKVTMTCRASSSVSYIHWFQQKPGSSPKPWIYATSNLASGVPVRFSGSGSGTSYSLTISRVEAEDAATYYCQQWTSNPPTFGGGTKLEIK (서열번호: 226)
VL:
QIVLSQSPAILSASPGEKVTMTCRASSSVSYIHWFQQKPGSSPKPWIYATSNLASGVPVRFSGSGSGTSYSLTISRVEAEDAATYYCQQWTSNPPTFGGGTKLEIK (SEQ ID NO: 226)
CDR H1: GYTFTSYN (서열번호: 223)CDR H1: GYTFTSYN (SEQ ID NO: 223) CDR L1: SSVSY (서열번호: 227)CDR L1: SSVSY (SEQ ID NO: 227) CDR H2: IYPGNGDT (서열번호: 224)CDR H2: IYPGNGDT (SEQ ID NO: 224) CDR L2: ATS (서열번호: 228)CDR L2: ATS (SEQ ID NO: 228) CDR H3: ARSTYYGGDWYFNV (서열번호: 225)CDR H3: ARSTYYGGDWYFNV (SEQ ID NO: 225) CDR L3: QQWTSNPPT (서열번호: 229)CDR L3: QQWTSNPPT (SEQ ID NO: 229) Fab region
(Anti-CD3)
Fab region
(Anti-CD3)
VH: EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (서열번호: 215)VH: EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (SEQ ID NO: 215) VL:
DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (서열번호: 216)
VL:
DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (SEQ ID NO: 216)
CDR H1: GYSFTGYT (서열번호: 177)CDR H1: GYSFTGYT (SEQ ID NO: 177) CDR L1: QDIRNY (서열번호: 181)CDR L1: QDIRNY (SEQ ID NO: 181) CDR H2: INPYKGVS (서열번호: 178)CDR H2: INPYKGVS (SEQ ID NO: 178) CDR L2: YTS (서열번호: 182)CDR L2: YTS (SEQ ID NO: 182) CDR H3: ARSGYYGDSDWYFD (서열번호: 211)CDR H3: ARSGYYGDSDWYFD (SEQ ID NO: 211) CDR L3: QQGNTLPWT (서열번호: 207)CDR L3: QQGNTLPWT (SEQ ID NO: 207)

실시예 21.61. ACE-19r의 제조Example 21.61. Preparation of ACE-19r

ACE-19r은 2개의 상이한 중쇄 유사 사슬 (ACE-19r-VH 및 ACE-19r-VL) 및 2개의 동일한 경쇄 (ACE-19r-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다: ACE-19r contains two different heavy chain-like chains (ACE-19r-VH and ACE-19r-VL) and two identical light chains (ACE-19r-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-19r-VH amino acid sequence (서열번호: 462)ACE-19r-VH amino acid sequence (SEQ ID NO: 462)

EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC]DKTHTCPPCPPCPAPELLGGPGGGGSQVQLKQSGPGLVQPSQSLSITCTVS GFSLTNYG VHWVRQSPGKGLEWLGV IWSGGNT DYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYC ARALTYYDYEFAY WGQGTLVTVSA EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC] DKTHTCPPCPPCPAPELLGGP GGGGS QVQLKQSGPGLVQPSQSLSITCTVS GFSLTNYG VHWVRQSPGKGLEWLGV IWSGGNT DYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYC ARALTYYDYEFAY WGQGTLVTVSA

ACE-19r-VL amino acid sequence (서열번호: 463)ACE-19r-VL amino acid sequence (SEQ ID NO: 463)

EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC]DKTHTCPPCPPCPAPELLGGPGGGGSDILLTQSPVILSVSPGERVSFSCRAS QSIGTN IHWYQQRTNGSPRLLIK YAS ESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYC QQNNNWPTT FGAGTKLELK EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC] DKTHTCPPCPPCPAPELLGGP GGGGS DILLTQSPVILSVSPGERVSFSCRAS QSIGTN IHWYQQRTNGSPRLLIK YAS ESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYC QQNNNWPTT FGAGTKLELK

ACE-19r-LC amino acid sequence (서열번호: 419)ACE-19r-LC amino acid sequence (SEQ ID NO: 419)

DIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR[RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] DIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR [ RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPYPREAKVQWKLSVTYPREAKVQWKLSVDSKVQWKLSVT

CD3를 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 EGFR을 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 65에 나열되어있다.The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting CD3 and the second antigen binding domain monovalent Fv region targeting EGFR are listed in Table 65 below.

Fv region
(Anti-EGFR)
Fv region
(Anti-EGFR)
VH: QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSA (서열번호: 233)VH: QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSA (SEQ ID NO: 233) VL:
DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELK (서열번호: 237)
VL:
DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELK (SEQ ID NO: 237)
CDR H1: GFSLTNYG (서열번호: 234)CDR H1: GFSLTNYG (SEQ ID NO: 234) CDR L1: QSIGTN (서열번호: 238)CDR L1: QSIGTN (SEQ ID NO: 238) CDR H2: IWSGGNT (서열번호: 235)CDR H2: IWSGGNT (SEQ ID NO: 235) CDR L2: YAS (서열번호: 239)CDR L2: YAS (SEQ ID NO: 239) CDR H3: ARALTYYDYEFAY (서열번호: 236)CDR H3: ARALTYYDYEFAY (SEQ ID NO: 236) CDR L3: QQNNNWPTT (서열번호: 240)CDR L3: QQNNNWPTT (SEQ ID NO: 240) Fab region
(Anti-CD3)
Fab region
(Anti-CD3)
VH:
EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (서열번호: 215)
VH:
EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (SEQ ID NO: 215)
VL:
DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (서열번호: 216)
VL:
DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (SEQ ID NO: 216)
CDR H1: GYSFTGYT (서열번호: 177)CDR H1: GYSFTGYT (SEQ ID NO: 177) CDR L1: QDIRNY (서열번호: 181)CDR L1: QDIRNY (SEQ ID NO: 181) CDR H2: INPYKGVS (서열번호: 178)CDR H2: INPYKGVS (SEQ ID NO: 178) CDR L2: YTS (서열번호: 182)CDR L2: YTS (SEQ ID NO: 182) CDR H3: ARSGYYGDSDWYFD (서열번호: 211)CDR H3: ARSGYYGDSDWYFD (SEQ ID NO: 211) CDR L3: QQGNTLPWT (서열번호: 207)CDR L3: QQGNTLPWT (SEQ ID NO: 207)

실시예 21.62. ACE-20r의 제조Example 21.62. Preparation of ACE-20r

ACE-20r은 2개의 상이한 중쇄 유사 사슬 (ACE-20r-VH 및 ACE-20r-VL) 및 2개의 동일한 경쇄 (ACE-20r-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다: ACE-20r contains two different heavy chain-like chains (ACE-20r-VH and ACE-20r-VL) and two identical light chains (ACE-20r-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-20r-VH amino acid sequence(서열번호: 464)ACE-20r-VH amino acid sequence (SEQ ID NO: 464)

EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPPCPAPELLGGPggggsQVQLVQSGAEVKKPGASVKVSCKAS GYTFTSHW MHWVRQAPGQGLEWIGE FNPSNGRT NYNEKFKSKATMTVDTSTNTAYMELSSLRSEDTAVYYC ASRDYDYDCRYFDY WGQGTLVTVSS EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPPCPAPELLGGP ggggs QVQLVQSGAEVKKPGASVKVSCKAS GYTFTSHW MHWVRQAPGQGLEWIGE FNPSNGRT NYNEKFKSKATMTVDTSTNTAYMELSSLRSEDTAVYYC ASRDYDYDCRYFDY WGQGTLVTVSS

ACE-20r-VL amino acid sequence(서열번호: 465)ACE-20r-VL amino acid sequence (SEQ ID NO: 465)

EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPPCPAPELLGGPggggsDIQMTQSPSSLSASVGDRVTITCSAS SSVTY MYWYQQKPGKAPKLLIY DTS NLASGVPSRFSGSGSGTDYTFTISSLQPEDIATYYC QQWSSHIFT FGQGTKVEIKR EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPPCPAPELLGGP ggggs DIQMTQSPSSLSASVGDRVTITCSAS SSVTY MYWYQQKPGKAPKLLIY DTS NLASGVPSRFSGSGSGTDYTFTISSLQPEDIATYYC QQWSSHIFT FGQGTKVEIKR

ACE-20r-LC amino acid sequence(서열번호: 324)ACE-20r-LC amino acid sequence (SEQ ID NO: 324)

DIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR[TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] DIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR [ TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPYPREAKVQWKVDTLSKVQWKLSKDSKSKLSVT

CD3을 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 EGFR을 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 66에 열거되어있다.The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting CD3 and the second antigen binding domain monovalent Fv region targeting EGFR are listed in Table 66 below.

Fv region
(Anti-EGFR)
Fv region
(Anti-EGFR)
VH: QVQLVQSGAEVKKPGASVKVSCKASGYTFTSHWMHWVRQAPGQGLEWIGEFNPSNGRTNYNEKFKSKATMTVDTSTNTAYMELSSLRSEDTAVYYCASRDYDYDCRYFDYWGQGTLVTVSS (서열번호: 244)VH: QVQLVQSGAEVKKPGASVKVSCKASGYTFTSHWMHWVRQAPGQGLEWIGEFNPSNGRTNYNEKFKSKATMTVDTSTNTAYMELSSLRSEDTAVYYCASRDYDYDCRYFDYWGQGTLVTVSS (SEQ ID NO: 244) VL:
DIQMTQSPSSLSASVGDRVTITCSASSSVTYMYWYQQKPGKAPKLLIYDTSNLASGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQQWSSHIFTFGQGTKVEIKR (서열번호: 248)
VL:
DIQMTQSPSSLSASVGDRVTITCSASSSVTYMYWYQQKPGKAPKLLIYDTSNLASGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQQWSSHIFTFGQGTKVEIKR (SEQ ID NO: 248)
CDR H1: GYTFTSHW (서열번호: 245)CDR H1: GYTFTSHW (SEQ ID NO: 245) CDR L1: SSVTY (서열번호: 249)CDR L1: SSVTY (SEQ ID NO: 249) CDR H2: FNPSNGRT (서열번호: 246)CDR H2: FNPSNGRT (SEQ ID NO: 246) CDR L2: DTS (서열번호: 250)CDR L2: DTS (SEQ ID NO: 250) CDR H3: ASRDYDYDCRYFDY (서열번호: 247)CDR H3: ASRDYDYDCRYFDY (SEQ ID NO: 247) CDR L3: QQWSSHIFT (서열번호: 251)CDR L3: QQWSSHIFT (SEQ ID NO: 251) Fab region
(Anti-CD3)
Fab region
(Anti-CD3)
VH: EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (서열번호: 215)VH: EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (SEQ ID NO: 215) VL:
DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (서열번호: 216)
VL:
DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (SEQ ID NO: 216)
CDR H1: GYSFTGYT (서열번호: 177)CDR H1: GYSFTGYT (SEQ ID NO: 177) CDR L1: QDIRNY (서열번호: 181)CDR L1: QDIRNY (SEQ ID NO: 181) CDR H2: INPYKGVS (서열번호: 178)CDR H2: INPYKGVS (SEQ ID NO: 178) CDR L2: YTS (서열번호: 182)CDR L2: YTS (SEQ ID NO: 182) CDR H3: ARSGYYGDSDWYFD (서열번호: 211)CDR H3: ARSGYYGDSDWYFD (SEQ ID NO: 211) CDR L3: QQGNTLPWT (서열번호: 207)CDR L3: QQGNTLPWT (SEQ ID NO: 207)

실시예 21.63. ACE-21r의 제조Example 21.63. Preparation of ACE-21r

ACE-21r은 2개의 상이한 중쇄 유사 사슬 (ACE-21r-VH 및 ACE-21r-VL) 및 2개의 동일한 경쇄 (ACE-21r-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다: ACE-21r contains two different heavy chain-like chains (ACE-21r-VH and ACE-21r-VL) and two identical light chains (ACE-21r-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-21r-VH amino acid sequence (서열번호: 466)ACE-21r-VH amino acid sequence (SEQ ID NO: 466)

EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC]DKTHTCPPCPPCPAPELLGGPggggsQVQLVESGGGVVQPGRSLRLSCAAS GFTFSTYG MHWVRQAPGKGLEWVAV IWDDGSYK YYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC ARDGITMVRGVMKDYFDY WGQGTLVTVSS EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC] DKTHTCPPCPPCPAPELLGGP ggggs QVQLVESGGGVVQPGRSLRLSCAAS GFTFSTYG MHWVRQAPGKGLEWVAV IWDDGSYK YYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC ARDGITMVRGVMKDYFDY WGQGTLVTVSS

ACE-21r-VL amino acid sequence (서열번호: 467)ACE-21r-VL amino acid sequence (SEQ ID NO: 467)

EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC]DKTHTCPPCPPCPAPELLGGPggggsAIQLTQSPSSLSASVGDRVTITCRAS QDISSA LVWYQQKPGKAPKLLIY DAS SLESGVPSRFSGSESGTDFTLTISSLQPEDFATYYC QQFNSYPLT FGGGTKVEIKR EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC] DKTHTCPPCPPCPAPELLGGP ggggs AIQLTQSPSSLSASVGDRVTITCRAS QDISSA LVWYQQKPGKAPKLLIY DAS SLESGVPSRFSGSESGTDFTLTISSLQPEDFATYYC QQFNSYPLT FGGGTKVEIKR

ACE-21r-LC amino acid sequence (서열번호: 324)ACE-21r-LC amino acid sequence (SEQ ID NO: 324)

DIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR[TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] DIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR [ TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPYPREAKVQWKVDTLSKVQWKLSKDSKSKLSVT

CD3을 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 EGFR을 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 67에 열거되어있다.The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting CD3 and the second antigen binding domain monovalent Fv region targeting EGFR are listed in Table 67 below.

Fv region
(Anti-EGFR)
Fv region
(Anti-EGFR)
VH: QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWDDGSYKYYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGITMVRGVMKDYFDYWGQGTLVTVSS (서열번호: 255)VH: QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWDDGSYKYYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGITMVRGVMKDYFDYWGQGTLVTVSS (SEQ ID NO: 255) VL:
AIQLTQSPSSLSASVGDRVTITCRASQDISSALVWYQQKPGKAPKLLIYDASSLESGVPSRFSGSESGTDFTLTISSLQPEDFATYYCQQFNSYPLTFGGGTKVEIKR (서열번호: 259)
VL:
AIQLTQSPSSLSASVGDRVTITCRASQDISSALVWYQQKPGKAPKLLIYDASSLESGVPSRFSGSESGTDFTLTISSLQPEDFATYYCQQFNSYPLTFGGGTKVEIKR (SEQ ID NO: 259)
CDR H1: GFTFSTYG (서열번호: 256)CDR H1: GFTFSTYG (SEQ ID NO: 256) CDR L1: QDISSA (서열번호: 260)CDR L1: QDISSA (SEQ ID NO: 260) CDR H2: IWDDGSYK (서열번호: 257)CDR H2: IWDDGSYK (SEQ ID NO: 257) CDR L2: DAS (서열번호: 261)CDR L2: DAS (SEQ ID NO: 261) CDR H3: ARDGITMVRGVMKDYFDY (서열번호: 258)CDR H3: ARDGITMVRGVMKDYFDY (SEQ ID NO: 258) CDR L3: QQFNSYPLT (서열번호: 262)CDR L3: QQFNSYPLT (SEQ ID NO: 262) Fab region
(Anti-CD3)
Fab region
(Anti-CD3)
VH:
EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (서열번호: 215)
VH:
EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (SEQ ID NO: 215)
VL: DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (서열번호: 216)VL: DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (SEQ ID NO: 216)
CDR H1: GYSFTGYT (서열번호: 177)CDR H1: GYSFTGYT (SEQ ID NO: 177) CDR L1: QDIRNY (서열번호: 181)CDR L1: QDIRNY (SEQ ID NO: 181) CDR H2: INPYKGVS (서열번호: 178)CDR H2: INPYKGVS (SEQ ID NO: 178) CDR L2: YTS (서열번호: 182)CDR L2: YTS (SEQ ID NO: 182) CDR H3: ARSGYYGDSDWYFD (서열번호: 211)CDR H3: ARSGYYGDSDWYFD (SEQ ID NO: 211) CDR L3: QQGNTLPWT (서열번호: 207)CDR L3: QQGNTLPWT (SEQ ID NO: 207)

실시예 21.64. ACE-22r의 제조Example 21.64. Preparation of ACE-22r

ACE-22r은 2개의 상이한 중쇄 유사 사슬 (ACE-22r-VH 및 ACE-22r-VL) 및 2개의 동일한 경쇄 (ACE-22r-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다: ACE-22r contains two different heavy chain-like chains (ACE-22r-VH and ACE-22r-VL) and two identical light chains (ACE-22r-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-22r-VH amino acid sequence (서열번호: 468)ACE-22r-VH amino acid sequence (SEQ ID NO: 468)

EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC]DKTHTCPPCPPCPAPELLGGP QVQLQQPGAELVKPGASVKMSCKAS GYTFTSYN MHWVKQTPGRGLEWIGA IYPGNGDT SYNQKFKGKATLTADKSSSTAYMQLSSLTSEDSAVYYC ARSTYYGGDWYFNV WGAGTTVTVSA EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC] DKTHTCPPCPPCPAPELLGGP QVQLQQPGAELVKPGASVKMSCKAS GYTFTSYN MHWVKQTPGRGLEWIGA IYPGNGDT SYNQKFKGKATLTADKSSSTAYMQLSSLTSEDSAVYYC ARSTYYGGDWYFNV WGAGTTVTVSA

ACE-22r-VL amino acid sequence (서열번호: 469)ACE-22r-VL amino acid sequence (SEQ ID NO: 469)

EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC]DKTHTCPPCPPCPAPELLGGP QIVLSQSPAILSASPGEKVTMTCRAS SSVSY IHWFQQKPGSSPKPWIY ATS NLASGVPVRFSGSGSGTSYSLTISRVEAEDAATYYC QQWTSNPPT FGGGTKLEIK EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFS [ ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC] DKTHTCPPCPPCPAPELLGGP QIVLSQSPAILSASPGEKVTMTCRAS SSVSY IHWFQQKPGSSPKPWIY ATS NLASGVPVRFSGSGSGTSYSLTISRVEAEDAATYYC QQWTSNPPT FGGGTKLEIK

ACE-22r-LC amino acid sequence (서열번호: 431)ACE-22r-LC amino acid sequence (SEQ ID NO: 431)

DIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR[RSVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] DIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR [ RSVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPYPREAKVQWKLSVTYPREAKVQWKLSVDSKVQWKLSVT

CD3을 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 CD20을 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 68에 열거되어있다.The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting CD3 and the second antigen binding domain monovalent Fv region targeting CD20 are listed in Table 68 below.

Fv region
(Anti-CD20)
Fv region
(Anti-CD20)
VH: QVQLQQPGAELVKPGASVKMSCKASGYTFTSYNMHWVKQTPGRGLEWIGAIYPGNGDTSYNQKFKGKATLTADKSSSTAYMQLSSLTSEDSAVYYCARSTYYGGDWYFNVWGAGTTVTVSA (서열번호: 222)VH: QVQLQQPGAELVKPGASVKMSCKASGYTFTSYNMHWVKQTPGRGLEWIGAIYPGNGDTSYNQKFKGKATLTADKSSSTAYMQLSSLTSEDSAVYYCARSTYYGGDWYFNVWGAGTTVTVSA (SEQ ID NO: 222) VL:
QIVLSQSPAILSASPGEKVTMTCRASSSVSYIHWFQQKPGSSPKPWIYATSNLASGVPVRFSGSGSGTSYSLTISRVEAEDAATYYCQQWTSNPPTFGGGTKLEIK (서열번호: 226)
VL:
QIVLSQSPAILSASPGEKVTMTCRASSSVSYIHWFQQKPGSSPKPWIYATSNLASGVPVRFSGSGSGTSYSLTISRVEAEDAATYYCQQWTSNPPTFGGGTKLEIK (SEQ ID NO: 226)
CDR H1: GYTFTSYN (서열번호: 223)CDR H1: GYTFTSYN (SEQ ID NO: 223) CDR L1: SSVSY (서열번호: 227)CDR L1: SSVSY (SEQ ID NO: 227) CDR H2: IYPGNGDT (서열번호: 224)CDR H2: IYPGNGDT (SEQ ID NO: 224) CDR L2: ATS (서열번호: 228)CDR L2: ATS (SEQ ID NO: 228) CDR H3: ARSTYYGGDWYFNV (서열번호: 225)CDR H3: ARSTYYGGDWYFNV (SEQ ID NO: 225) CDR L3: QQWTSNPPT (서열번호: 229)CDR L3: QQWTSNPPT (SEQ ID NO: 229) Fab region
(Anti-CD3)
Fab region
(Anti-CD3)
VH: EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (서열번호: 215)VH: EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (SEQ ID NO: 215) VL: DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (서열번호: 216)VL: DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (SEQ ID NO: 216)
CDR H1: GYSFTGYT (서열번호: 177)CDR H1: GYSFTGYT (SEQ ID NO: 177) CDR L1: QDIRNY (서열번호: 181)CDR L1: QDIRNY (SEQ ID NO: 181) CDR H2: INPYKGVS (서열번호: 178)CDR H2: INPYKGVS (SEQ ID NO: 178) CDR L2: YTS (서열번호: 182)CDR L2: YTS (SEQ ID NO: 182) CDR H3: ARSGYYGDSDWYFD (서열번호: 211)CDR H3: ARSGYYGDSDWYFD (SEQ ID NO: 211) CDR L3: QQGNTLPWT (서열번호: 207)CDR L3: QQGNTLPWT (SEQ ID NO: 207)

실시예 21.65. ACE-23r의 제조Example 21.65. Preparation of ACE-23r

ACE-23r은 2개의 상이한 중쇄 유사 사슬 (ACE-23r-VH 및 ACE-23-VL) 및 2개의 동일한 경쇄 (ACE-23r-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다: ACE-23r contains two different heavy chain-like chains (ACE-23r-VH and ACE-23-VL) and two identical light chains (ACE-23r-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-23r-VH amino acid sequence (서열번호: 470)ACE-23r-VH amino acid sequence (SEQ ID NO: 470)

QVQLVESGGGVVQPGRSLRLSCAAS GFKFSGYG MHWVRQAPGKGLEWVAV IWYDGSKK YYVDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC ARQMGYWHFDL WGRGTLVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPPCPAPELLGGPggggsQMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS QVQLVESGGGVVQPGRSLRLSCAAS GFKFSGYG MHWVRQAPGKGLEWVAV IWYDGSKK YYVDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC ARQMGYWHFDL WGRGTLVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPPCPAPELLGGP ggggs QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS

ACE-23r-VL amino acid sequence (서열번호: 471)ACE-23r-VL amino acid sequence (SEQ ID NO: 471)

QVQLVESGGGVVQPGRSLRLSCAAS GFKFSGYG MHWVRQAPGKGLEWVAV IWYDGSKK YYVDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC ARQMGYWHFDL WGRGTLVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPPCPAPELLGGPggggsQLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVLR QVQLVESGGGVVQPGRSLRLSCAAS GFKFSGYG MHWVRQAPGKGLEWVAV IWYDGSKK YYVDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC ARQMGYWHFDL WGRGTLVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPPCPAPELLGGP ggggs QLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVLR

ACE-23r-LC amino acid sequence (서열번호: 422)ACE-23r-LC amino acid sequence (SEQ ID NO: 422)

EIVLTQSPATLSLSPGERATLSCRAS QSVSSY LAWYQQKPGQAPRLLIY DAS NRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYC QQRSNWPPLT FGGGTKVEIKR[SVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] EIVLTQSPATLSLSPGERATLSCRAS QSVSSY LAWYQQKPGQAPRLLIY DAS NRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYC QQRSNWPPLT FGGGTKVEIKR [ SVAAPSVFIFPPSDEQLKSGTKVEIKR [SVAAPSVFIFPPSDEQLKSGTKVEIKR [SVAAPSVFIFPPSDEQLKSGTKVEIKR [SVAAPSVFIFPPSDEQLKSGTGNASVVCLLNNFYPREADSKVQSKVLTQYPREAKVQSKVDLSKDS

CD3을 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 PD-L1을 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 69에 열거되어있다.The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting CD3 and the second antigen binding domain monovalent Fv region targeting PD-L1 are listed in Table 69 below. have.

Fv region
(Anti-PD-L1)
Fv region
(Anti-PD-L1)
VH: QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (서열번호: 158)VH: QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (SEQ ID NO: 158) VL:
QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLR (서열번호: 170)
VL:
QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLR (SEQ ID NO: 170)
CDR H1: GGTFSSYA (서열번호: 159)CDR H1: GGTFSSYA (SEQ ID NO: 159) CDR L1: SSNIGAGYD (서열번호: 171)CDR L1: SSNIGAGYD (SEQ ID NO: 171) CDR H2: IIPILGIA (서열번호: 160)CDR H2: IIPILGIA (SEQ ID NO: 160) CDR L2: GDI (서열번호: 172)CDR L2: GDI (SEQ ID NO: 172) CDR H3: AKPRDGYNLVAFDI (서열번호: 161)CDR H3: AKPRDGYNLVAFDI (SEQ ID NO: 161) CDR L3: QSYDSSLSGGV (서열번호: 173)CDR L3: QSYDSSLSGGV (SEQ ID NO: 173) Fab region
(Anti-CD3)
Fab region
(Anti-CD3)
VH: QVQLVESGGGVVQPGRSLRLSCAASGFKFSGYGMHWVRQAPGKGLEWVAVIWYDGSKKYYVDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARQMGYWHFDLWGRGTLVTVSS (서열번호: 162)VH: QVQLVESGGGVVQPGRSLRLSCAASGFKFSGYGMHWVRQAPGKGLEWVAVIWYDGSKKYYVDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARQMGYWHFDLWGRGTLVTVSS (SEQ ID NO: 162) VL:
EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPPLTFGGGTKVEIKR (서열번호: 166)
VL:
EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPPLTFGGGTKVEIKR (SEQ ID NO: 166)
CDR H1: GFKFSGYG (서열번호: 163)CDR H1: GFKFSGYG (SEQ ID NO: 163) CDR L1: QSVSSY (서열번호: 167)CDR L1: QSVSSY (SEQ ID NO: 167) CDR H2: IWYDGSKK (서열번호: 271)CDR H2: IWYDGSKK (SEQ ID NO: 271) CDR L2: DAS (서열번호: 168)CDR L2: DAS (SEQ ID NO: 168) CDR H3: ARQMGYWHFDL (서열번호: 165)CDR H3: ARQMGYWHFDL (SEQ ID NO: 165) CDR L3: QQRSNWPPLT (서열번호: 169)CDR L3: QQRSNWPPLT (SEQ ID NO: 169)

실시예 21.66. ACE-24r의 제조Example 21.66. Preparation of ACE-24r

ACE-24r은 2개의 상이한 중쇄 유사 사슬 (ACE-24r-VH 및 ACE-24r-VL) 및 2개의 동일한 경쇄 (ACE-24r-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다: ACE-24r contains two different heavy chain-like chains (ACE-24r-VH and ACE-24r-VL) and two identical light chains (ACE-24r-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-24r-VH amino acid sequence (서열번호: 472)ACE-24r-VH amino acid sequence (SEQ ID NO: 472)

EVQLVESGGGLVQPGRSLRLSCAAS GFTFDDYA MHWVRQAPGKGLEWVSA ITWNSGHI DYADSVEGRFTISRDNAKNSLYLQMNSLRAEDTAVYYC AKVSYLSTASSLDY WGQGTLVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPAPELLGGPggggsEVQLVESGGGLVQPGGSLRLSCAAS GFNIKDTY IHWVRQAPGKGLEWVAR IYPTNGYT RYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYC SRWGGDGFYAMDY WGQGTLVTVSS EVQLVESGGGLVQPGRSLRLSCAAS GFTFDDYA MHWVRQAPGKGLEWVSA ITWNSGHI DYADSVEGRFTISRDNAKNSLYLQMNSLRAEDTAVYYC AKVSYLSTASSLDY WGQGTLVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPAPELLGGP ggggs EVQLVESGGGLVQPGGSLRLSCAAS GFNIKDTY IHWVRQAPGKGLEWVAR IYPTNGYT RYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYC SRWGGDGFYAMDY WGQGTLVTVSS

ACE-24r-VL amino acid sequence (서열번호: 473)ACE-24r-VL amino acid sequence (SEQ ID NO: 473)

EVQLVESGGGLVQPGRSLRLSCAAS GFTFDDYA MHWVRQAPGKGLEWVSA ITWNSGHI DYADSVEGRFTISRDNAKNSLYLQMNSLRAEDTAVYYC AKVSYLSTASSLDY WGQGTLVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC]DKTHTCPPCPAPELLGGP DIQMTQSPSSLSASVGDRVTITCRAS QDVNTA VAWYQQKPGKAPKLLIY SAS FLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYC QQHYTTPPT FGQGTKVEIK EVQLVESGGGLVQPGRSLRLSCAAS GFTFDDYA MHWVRQAPGKGLEWVSA ITWNSGHI DYADSVEGRFTISRDNAKNSLYLQMNSLRAEDTAVYYC AKVSYLSTASSLDY WGQGTLVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC] DKTHTCPPCPAPELLGGP DIQMTQSPSSLSASVGDRVTITCRAS QDVNTA VAWYQQKPGKAPKLLIY SAS FLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYC QQHYTTPPT FGQGTKVEIK

ACE-24r-LC amino acid sequence (서열번호: 390)ACE-24r-LC amino acid sequence (SEQ ID NO: 390)

DIQMTQSPSSLSASVGDRVTITCRAS QGIRNY LAWYQQKPGKAPKLLIY AAS TLQSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYC QRYNRAPYT FGQGTKVEIKR[RSVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] DIQMTQSPSSLSASVGDRVTITCRAS QGIRNY LAWYQQKPGKAPKLLIY AAS TLQSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYC QRYNRAPYT FGQGTKVEIKR [ RSVAAPSVFIFPPSDEQLKSGTASVVCLLVNNFYPKDSGGNSSPYVDKDSQKV

TNF를 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 HER2를 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 70에 열거되어있다.The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting TNF and the second antigen binding domain monovalent Fv region targeting HER2 are listed in Table 70 below.

Fv region
(Anti-HER2)
Fv region
(Anti-HER2)
VH: EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS (서열번호: 275)VH: EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS (SEQ ID NO: 275) VL:
DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIK (서열번호: 287)
VL:
DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIK (SEQ ID NO: 287)
CDR H1: GFNIKDTY (서열번호: 276)CDR H1: GFNIKDTY (SEQ ID NO: 276) CDR L1: QDVNTA (서열번호: 288)CDR L1: QDVNTA (SEQ ID NO: 288) CDR H2: IYPTNGYT (서열번호: 277)CDR H2: IYPTNGYT (SEQ ID NO: 277) CDR L2: SAS (서열번호: 289)CDR L2: SAS (SEQ ID NO: 289) CDR H3: SRWGGDGFYAMDY (서열번호: 278)CDR H3: SRWGGDGFYAMDY (SEQ ID NO: 278) CDR L3: QQHYTTPPT (서열번호: 290)CDR L3: QQHYTTPPT (SEQ ID NO: 290) Fab region
(Anti-TNF)
Fab region
(Anti-TNF)
VH: EVQLVESGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSAITWNSGHIDYADSVEGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAKVSYLSTASSLDYWGQGTLVTVSS (서열번호: 279)VH: EVQLVESGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSAITWNSGHIDYADSVEGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAKVSYLSTASSLDYWGQGTLVTVSS (SEQ ID NO: 279) VL:
DIQMTQSPSSLSASVGDRVTITCRASQGIRNYLAWYQQKPGKAPKLLIYAASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQRYNRAPYTFGQGTKVEIKR (서열번호: 283)
VL:
DIQMTQSPSSLSASVGDRVTITCRASQGIRNYLAWYQQKPGKAPKLLIYAASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQRYNRAPYTFGQGTKVEIKR (SEQ ID NO: 283)
CDR H1: GFTFDDYA (서열번호: 280)CDR H1: GFTFDDYA (SEQ ID NO: 280) CDR L1: QGIRNY (서열번호: 284)
CDR L1: QGIRNY (SEQ ID NO: 284)
CDR H2: ITWNSGHI (서열번호: 281)CDR H2: ITWNSGHI (SEQ ID NO: 281) CDR L2: AAS (서열번호: 285)CDR L2: AAS (SEQ ID NO: 285) CDR H3: AKVSYLSTASSLDY (서열번호: 282)CDR H3: AKVSYLSTASSLDY (SEQ ID NO: 282) CDR L3: QRYNRAPYT (서열번호: 286)CDR L3: QRYNRAPYT (SEQ ID NO: 286)

실시예 21.67. ACE-25r의 제조Example 21.67. Preparation of ACE-25r

ACE-25r은 2개의 상이한 중쇄 유사 사슬 (ACE-25r-VH 및 ACE-25r-VL) 및 2개의 동일한 경쇄 (ACE-25r-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다: ACE-25r contains two different heavy chain-like chains (ACE-25r-VH and ACE-25r-VL) and two identical light chains (ACE-25r-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-25r-HC-VH amino acid sequence (서열번호: 474)ACE-25r-HC-VH amino acid sequence (SEQ ID NO: 474)

EVQLVESGGGLVQPGRSLRLSCAAS GFTFDDYA MHWVRQAPGKGLEWVSA ITWNSGHI DYADSVEGRFTISRDNAKNSLYLQMNSLRAEDTAVYYC AKVSYLSTASSLDY WGQGTLVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPAPELLGGPggggsggggs EVQLVESGGGLVQPGGSLRLSCAAS GFNIKDTY IHWVRQAPGKGLEWVAR IYPTNGYT RYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYC SRWGGDGFYAMDY WGQGTLVTVSS EVQLVESGGGLVQPGRSLRLSCAAS GFTFDDYA MHWVRQAPGKGLEWVSA ITWNSGHI DYADSVEGRFTISRDNAKNSLYLQMNSLRAEDTAVYYC AKVSYLSTASSLDY WGQGTLVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPAPELLGGPggggsggggs EVQLVESGGGLVQPGGSLRLSCAAS GFNIKDTY IHWVRQAPGKGLEWVAR IYPTNGYT RYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYC SRWGGDGFYAMDY WGQGTLVTVSS

ACE-25r-HC-VL amino acid sequence (서열번호: 475)ACE-25r-HC-VL amino acid sequence (SEQ ID NO: 475)

EVQLVESGGGLVQPGRSLRLSCAAS GFTFDDYA MHWVRQAPGKGLEWVSA ITWNSGHI DYADSVEGRFTISRDNAKNSLYLQMNSLRAEDTAVYYC AKVSYLSTASSLDY WGQGTLVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC]DKTHTCPPCPAPELLGGP DIQMTQSPSSLSASVGDRVTITCRAS QDVNTA VAWYQQKPGKAPKLLIY SAS FLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYC QQHYTTPPT FGQGTKVEIK EVQLVESGGGLVQPGRSLRLSCAAS GFTFDDYA MHWVRQAPGKGLEWVSA ITWNSGHI DYADSVEGRFTISRDNAKNSLYLQMNSLRAEDTAVYYC AKVSYLSTASSLDY WGQGTLVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC] DKTHTCPPCPAPELLGGP DIQMTQSPSSLSASVGDRVTITCRAS QDVNTA VAWYQQKPGKAPKLLIY SAS FLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYC QQHYTTPPT FGQGTKVEIK

ACE-25r-LC amino acid sequence (서열번호: 390)ACE-25r-LC amino acid sequence (SEQ ID NO: 390)

DIQMTQSPSSLSASVGDRVTITCRAS QGIRNY LAWYQQKPGKAPKLLIY AAS TLQSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYC QRYNRAPYT FGQGTKVEIKR[RSVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] DIQMTQSPSSLSASVGDRVTITCRAS QGIRNY LAWYQQKPGKAPKLLIY AAS TLQSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYC QRYNRAPYT FGQGTKVEIKR [ RSVAAPSVFIFPPSDEQLKSGTASVVCLLVNNFYPQDSGGNSVKDYPQKREADSQSV

TNF를 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 HER2를 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 71에 열거되어있다.The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting TNF and the second antigen binding domain monovalent Fv region targeting HER2 are listed in Table 71 below.

Fv region
(Anti-HER2)
Fv region
(Anti-HER2)
VH: EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS (서열번호: 275)VH: EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS (SEQ ID NO: 275) VL:
DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIK (서열번호: 287)
VL:
DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIK (SEQ ID NO: 287)
CDR H1: GFNIKDTY (서열번호: 276)CDR H1: GFNIKDTY (SEQ ID NO: 276) CDR L1: QDVNTA (서열번호: 288)CDR L1: QDVNTA (SEQ ID NO: 288) CDR H2: IYPTNGYT (서열번호: 277)CDR H2: IYPTNGYT (SEQ ID NO: 277) CDR L2: SAS (서열번호: 289)CDR L2: SAS (SEQ ID NO: 289) CDR H3: SRWGGDGFYAMDY (서열번호: 278)CDR H3: SRWGGDGFYAMDY (SEQ ID NO: 278) CDR L3: QQHYTTPPT (서열번호: 290)CDR L3: QQHYTTPPT (SEQ ID NO: 290) Fab region
(Anti-TNF)
Fab region
(Anti-TNF)
VH: EVQLVESGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSAITWNSGHIDYADSVEGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAKVSYLSTASSLDYWGQGTLVTVSS (서열번호: 279)VH: EVQLVESGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSAITWNSGHIDYADSVEGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAKVSYLSTASSLDYWGQGTLVTVSS (SEQ ID NO: 279) VL:
DIQMTQSPSSLSASVGDRVTITCRASQGIRNYLAWYQQKPGKAPKLLIYAASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQRYNRAPYTFGQGTKVEIKR (서열번호: 283)
VL:
DIQMTQSPSSLSASVGDRVTITCRASQGIRNYLAWYQQKPGKAPKLLIYAASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQRYNRAPYTFGQGTKVEIKR (SEQ ID NO: 283)
CDR H1: GFTFDDYA (서열번호: 280)CDR H1: GFTFDDYA (SEQ ID NO: 280) CDR L1: QGIRNY (서열번호: 284)CDR L1: QGIRNY (SEQ ID NO: 284) CDR H2: ITWNSGHI (서열번호: 281)CDR H2: ITWNSGHI (SEQ ID NO: 281) CDR L2: AAS (서열번호: 285)CDR L2: AAS (SEQ ID NO: 285) CDR H3: AKVSYLSTASSLDY (서열번호: 282)CDR H3: AKVSYLSTASSLDY (SEQ ID NO: 282) CDR L3: QRYNRAPYT (서열번호: 286)CDR L3: QRYNRAPYT (SEQ ID NO: 286)

실시예 21.68. ACE-26r의 제조Example 21.68. Preparation of ACE-26r

ACE-26r은 2개의 상이한 중쇄 유사 사슬 (ACE-26r-VH 및 ACE-26r-VL) 및 2개의 동일한 경쇄 (ACE-26r-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다: ACE-26r contains two different heavy chain-like chains (ACE-26r-VH and ACE-26r-VL) and two identical light chains (ACE-26r-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-26r-VH amino acid sequence (서열번호: 476)ACE-26r-VH amino acid sequence (SEQ ID NO: 476)

EVKLLESGGGLVQPKGSLKLSCAAS GFTFNTYA MNWVRQAPGKGLEWVAR IRSKYNNYAT YYADSVKDRFTISRDDSQSILYLQMNNLKTEDTAMYYC VRHGNFGNSYVSWFAY WGQGTLVTVSA[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPPCPAPELLGGPggggsQVQLKQSGPGLVQPSQSLSITCTVS GFSLTNYG VHWVRQSPGKGLEWLGV IWSGGNT DYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYC ARALTYYDYEFAY WGQGTLVTVSA* EVKLLESGGGLVQPKGSLKLSCAAS GFTFNTYA MNWVRQAPGKGLEWVAR IRSKYNNYAT YYADSVKDRFTISRDDSQSILYLQMNNLKTEDTAMYYC VRHGNFGNSYVSWFAY WGQGTLVTVSA [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPPCPAPELLGGP ggggs QVQLKQSGPGLVQPSQSLSITCTVS GFSLTNYG VHWVRQSPGKGLEWLGV IWSGGNT DYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYC ARALTYYDYEFAY WGQGTLVTVSA *

ACE-26r-VL amino acid sequence (서열번호: 477)ACE-26r-VL amino acid sequence (SEQ ID NO: 477)

EVKLLESGGGLVQPKGSLKLSCAAS GFTFNTYA MNWVRQAPGKGLEWVAR IRSKYNNYAT YYADSVKDRFTISRDDSQSILYLQMNNLKTEDTAMYYC VRHGNFGNSYVSWFAY WGQGTLVTVSA[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPPCPAPELLGGPggggsDILLTQSPVILSVSPGERVSFSCRAS QSIGTN IHWYQQRTNGSPRLLIK YAS ESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYC QQNNNWPTT FGAGTKLELK* EVKLLESGGGLVQPKGSLKLSCAAS GFTFNTYA MNWVRQAPGKGLEWVAR IRSKYNNYAT YYADSVKDRFTISRDDSQSILYLQMNNLKTEDTAMYYC VRHGNFGNSYVSWFAY WGQGTLVTVSA [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPPCPAPELLGGP ggggs DILLTQSPVILSVSPGERVSFSCRAS QSIGTN IHWYQQRTNGSPRLLIK YAS ESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYC QQNNNWPTT FGAGTKLELK *

ACE-26r-LC amino acid sequence (서열번호: 478)ACE-26r-LC amino acid sequence (SEQ ID NO: 478)

QAVVTQESALTTSPGETVTLTCRSS TGAVTTSNY ANWVQEKPDHLFTGLIG GTN KRAPGVPARFSGSLIGDKAALTITGAQTEDEAIYFC ALWYSNLWV FGGGTKLTVL[RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] QAVVTQESALTTSPGETVTLTCRSS TGAVTTSNY ANWVQEKPDHLFTGLIG GTN KRAPGVPARFSGSLIGDKAALTITGAQTEDEAIYFC ALWYSNLWV FGGGTKLTVL [ RTVAAPSVFIFPPSDEQLKSGTKLTVLNNFYPREADSKVQSKVLTQDSKVQSKVDSLGE

CD3를 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 EGFR을 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 72에 열거되어있다.The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting CD3 and the second antigen binding domain monovalent Fv region targeting EGFR are listed in Table 72 below.

Fv region
(Anti-EGFR)
Fv region
(Anti-EGFR)
VH: QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSA (서열번호: 233)VH: QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSA (SEQ ID NO: 233) VL:
DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELK (서열번호: 237)
VL:
DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELK (SEQ ID NO: 237)
CDR H1: GFSLTNYG (서열번호: 234)CDR H1: GFSLTNYG (SEQ ID NO: 234) CDR L1: QSIGTN (서열번호: 238)CDR L1: QSIGTN (SEQ ID NO: 238) CDR H2: IWSGGNT (서열번호: 235)CDR H2: IWSGGNT (SEQ ID NO: 235) CDR L2: YAS (서열번호: 239)CDR L2: YAS (SEQ ID NO: 239) CDR H3: ARALTYYDYEFAY (서열번호: 236)CDR H3: ARALTYYDYEFAY (SEQ ID NO: 236) CDR L3: QQNNNWPTT (서열번호: 240)CDR L3: QQNNNWPTT (SEQ ID NO: 240) Fab region
(Anti-CD3)
Fab region
(Anti-CD3)
VH: EVKLLESGGGLVQPKGSLKLSCAASGFTFNTYAMNWVRQAPGKGLEWVARIRSKYNNYATYYADSVKDRFTISRDDSQSILYLQMNNLKTEDTAMYYCVRHGNFGNSYVSWFAYWGQGTLVTVSA (서열번호: 294)VH: EVKLLESGGGLVQPKGSLKLSCAASGFTFNTYAMNWVRQAPGKGLEWVARIRSKYNNYATYYADSVKDRFTISRDDSQSILYLQMNNLKTEDTAMYYCVRHGNFGNSYVSWFAYWGQGTLVTVSA (SEQ ID NO: 294) VL:
QAVVTQESALTTSPGETVTLTCRSSTGAVTTSNYANWVQEKPDHLFTGLIGGTNKRAPGVPARFSGSLIGDKAALTITGAQTEDEAIYFCALWYSNLWVFGGGTKLTVL (서열번호: 298)
VL:
QAVVTQESALTTSPGETVTLTCRSSTGAVTTSNYANWVQEKPDHLFTGLIGGTNKRAPGVPARFSGSLIGDKAALTITGAQTEDEAIYFCALWYSNLWVFGGGTKLTVL (SEQ ID NO: 298)
CDR H1: GFTFNTYA (서열번호: 295)CDR H1: GFTFNTYA (SEQ ID NO: 295) CDR L1: TGAVTTSNY (서열번호: 299)CDR L1: TGAVTTSNY (SEQ ID NO: 299) CDR H2: IRSKYNNYAT (서열번호: 296)CDR H2: IRSKYNNYAT (SEQ ID NO: 296) CDR L2: GTN (서열번호: 300)CDR L2: GTN (SEQ ID NO: 300) CDR H3: VRHGNFGNSYVSWFAY (서열번호: 297)CDR H3: VRHGNFGNSYVSWFAY (SEQ ID NO: 297) CDR L3: ALWYSNLWV (서열번호: 301)CDR L3: ALWYSNLWV (SEQ ID NO: 301)

실시예 21.69. ACE-27r의 제조Example 21.69. Preparation of ACE-27r

ACE-27r은 2개의 상이한 중쇄 유사 사슬 (ACE-27r-VH 및 ACE-27r-VL) 및 2개의 동일한 경쇄 (ACE-27r-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다:ACE-27r contains two different heavy chain-like chains (ACE-27r-VH and ACE-27r-VL) and two identical light chains (ACE-27r-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-27r-VH amino acid sequence (서열번호: 479)ACE-27r-VH amino acid sequence (SEQ ID NO: 479)

EVKLLESGGGLVQPKGSLKLSCAAS GFTFNTYA MNWVRQAPGKGLEWVAR IRSKYNNYAT YYADSVKDRFTISRDDSQSILYLQMNNLKTEDTAMYYC VRHGNFGNSYVSWFAY WGQGTLVTVSA[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPPCPAPELLGGPggggs QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS EVKLLESGGGLVQPKGSLKLSCAAS GFTFNTYA MNWVRQAPGKGLEWVAR IRSKYNNYAT YYADSVKDRFTISRDDSQSILYLQMNNLKTEDTAMYYC VRHGNFGNSYVSWFAY WGQGTLVTVSA [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPPCPAPELLGGPggggs QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS

ACE-27r-VL amino acid sequence (서열번호: 480)ACE-27r-VL amino acid sequence (SEQ ID NO: 480)

EVKLLESGGGLVQPKGSLKLSCAAS GFTFNTYA MNWVRQAPGKGLEWVAR IRSKYNNYAT YYADSVKDRFTISRDDSQSILYLQMNNLKTEDTAMYYC VRHGNFGNSYVSWFAY WGQGTLVTVSA[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPPCPAPELLGGPggggsQAVVTQESALTTSPGETVTLTCRSS TGAVTTSNY ANWVQEKPDHLFTGLIG GTN KRAPGVPARFSGSLIGDKAALTITGAQTEDEAIYFC ALWYSNLWV FGGGTKLTVL EVKLLESGGGLVQPKGSLKLSCAAS GFTFNTYA MNWVRQAPGKGLEWVAR IRSKYNNYAT YYADSVKDRFTISRDDSQSILYLQMNNLKTEDTAMYYC VRHGNFGNSYVSWFAY WGQGTLVTVSA [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPPCPAPELLGGP ggggs QAVVTQESALTTSPGETVTLTCRSS TGAVTTSNY ANWVQEKPDHLFTGLIG GTN KRAPGVPARFSGSLIGDKAALTITGAQTEDEAIYFC ALWYSNLWV FGGGTKLTVL

ACE-27r-LC amino acid sequence (서열번호: 304)ACE-27r-LC amino acid sequence (SEQ ID NO: 304)

QAVVTQESALTTSPGETVTLTCRSS TGAVTTSNY ANWVQEKPDHLFTGLIG GTN KRAPGVPARFSGSLIGDKAALTITGAQTEDEAIYFC ALWYSNLWV FGGGTKLTVL[RSVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] QAVVTQESALTTSPGETVTLTCRSS TGAVTTSNY ANWVQEKPDHLFTGLIG GTN KRAPGVPARFSGSLIGDKAALTITGAQTEDEAIYFC ALWYSNLWV FGGGTKLTVL [ RSVAAPSVFIFPPSDEQLKSGTKLTVLNNFYPREADSKVQSKVLTQDSKVQSKVDSKDSK

CD3을 표적화하는 제1 항원 결합 도메인 2가 Fab 영역 및 PD-L1을 표적화하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 73에 열거되어있다:The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting CD3 and the second antigen binding domain monovalent Fv region targeting PD-L1 are listed in Table 73 below:

Fv region
(Anti-PD-L1)
Fv region
(Anti-PD-L1)
VH: QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (서열번호: 158)VH: QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (SEQ ID NO: 158) VL:
QAVVTQESALTTSPGETVTLTCRSSTGAVTTSNYANWVQEKPDHLFTGLIGGTNKRAPGVPARFSGSLIGDKAALTITGAQTEDEAIYFCALWYSNLWVFGGGTKLTVL (서열번호: 313)
VL:
QAVVTQESALTTSPGETVTLTCRSSTGAVTTSNYANWVQEKPDHLFTGLIGGTNKRAPGVPARFSGSLIGDKAALTITGAQTEDEAIYFCALWYSNLWVFGGGTKLTVL (SEQ ID NO: 313)
CDR H1: GGTFSSYA (서열번호: 159)CDR H1: GGTFSSYA (SEQ ID NO: 159) CD TGAVTTSNY (서열번호: 314)
R L1:
CD TGAVTTSNY (SEQ ID NO: 314)
R L1:
CDR H2: IIPILGIA (서열번호: 160)CDR H2: IIPILGIA (SEQ ID NO: 160) CDR L2: GTN (서열번호: 315)CDR L2: GTN (SEQ ID NO: 315) CDR H3: AKPRDGYNLVAFDI (서열번호: 161)CDR H3: AKPRDGYNLVAFDI (SEQ ID NO: 161) CDR L3: ALWYSNLWV (서열번호: 316)CDR L3: ALWYSNLWV (SEQ ID NO: 316) Fab region
(Anti-CD3)
Fab region
(Anti-CD3)
VH: EVKLLESGGGLVQPKGSLKLSCAASGFTFNTYAMNWVRQAPGKGLEWVARIRSKYNNYATYYADSVKDRFTISRDDSQSILYLQMNNLKTEDTAMYYCVRHGNFGNSYVSWFAYWGQGTLVTVSA (서열번호: 305)VH: EVKLLESGGGLVQPKGSLKLSCAASGFTFNTYAMNWVRQAPGKGLEWVARIRSKYNNYATYYADSVKDRFTISRDDSQSILYLQMNNLKTEDTAMYYCVRHGNFGNSYVSWFAYWGQGTLVTVSA (SEQ ID NO: 305) VL:
QAVVTQESALTTSPGETVTLTCRSSTGAVTTSNYANWVQEKPDHLFTGLIGGTNKRAPGVPARFSGSLIGDKAALTITGAQTEDEAIYFCALWYSNLWVFGGGTKLTVL (서열번호: 309)
VL:
QAVVTQESALTTSPGETVTLTCRSSTGAVTTSNYANWVQEKPDHLFTGLIGGTNKRAPGVPARFSGSLIGDKAALTITGAQTEDEAIYFCALWYSNLWVFGGGTKLTVL (SEQ ID NO: 309)
CDR H1: GFTFNTYA (서열번호: 306)CDR H1: GFTFNTYA (SEQ ID NO: 306) CDR L1: TGAVTTSNY (서열번호: 310)CDR L1: TGAVTTSNY (SEQ ID NO: 310) CDR H2: IRSKYNNYAT (서열번호: 307)CDR H2: IRSKYNNYAT (SEQ ID NO: 307) CDR L2: GTN (서열번호: 311)CDR L2: GTN (SEQ ID NO: 311) CDR H3: VRHGNFGNSYVSWFAY (서열번호: 308)CDR H3: VRHGNFGNSYVSWFAY (SEQ ID NO: 308) CDR L3: ALWYSNLWV (서열번호: 312)CDR L3: ALWYSNLWV (SEQ ID NO: 312)

실시예 21.70. ACE-28r의 제조Example 21.70. Preparation of ACE-28r

ACE-28r은 2개의 상이한 중쇄 유사 사슬 (ACE-28r-VH 및 ACE-28r-VL) 및 2개의 동일한 경쇄 (ACE-28r-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다:ACE-28r contains two different heavy chain-like chains (ACE-28r-VH and ACE-28r-VL) and two identical light chains (ACE-28r-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-28r-VH amino acid sequence (서열번호: 481)ACE-28r-VH amino acid sequence (SEQ ID NO: 481)

EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPPCPAPELLGGPggggsQVQLKQSGPGLVQPSQSLSITCTVS GFSLTNYG VHWVRQSPGKGLEWLGV IWSGGNT DYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYC ARALTYYDYEFAY WGQGTLVTVSAGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPPCPAPELLGGP ggggs QVQLKQSGPGLVQPSQSLSITCTVS GFSLTNYG VHWVRQSPGKGLEWLGV IWSGGNT DYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYC ARALTYYDYEFAY WGQGTLVTVSA GQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

ACE-28r-VL amino acid sequence (서열번호: 482)ACE-28r-VL amino acid sequence (SEQ ID NO: 482)

EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPPCPAPELLGGPggggsDILLTQSPVILSVSPGERVSFSCRAS QSIGTN IHWYQQRTNGSPRLLIK YAS ESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYC QQNNNWPTT FGAGTKLELKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPPCPAPELLGGP ggggs DILLTQSPVILSVSPGERVSFSCRAS QSIGTN IHWYQQRTNGSPRLLIK YAS ESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYC QQNNNWPTT FGAGTKLELK GQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

ACE-28r-LC amino acid sequence (서열번호: 419)ACE-28r-LC amino acid sequence (SEQ ID NO: 419)

DIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR[RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] DIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR [ RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPYPREAKVQWKLSVTYPREAKVQWKLSVDSKVQWKLSVT

CD3을 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 EGFR을 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 74에 열거되어있다.The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting CD3 and the second antigen binding domain monovalent Fv region targeting EGFR are listed in Table 74 below.

Fv region
(Anti-EGFR)
Fv region
(Anti-EGFR)
VH: QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSA (서열번호: 233)VH: QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSA (SEQ ID NO: 233) VL:
DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELK (서열번호: 237)
VL:
DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELK (SEQ ID NO: 237)
CDR H1: GFSLTNYG (서열번호: 234)CDR H1: GFSLTNYG (SEQ ID NO: 234) CDR L1: QSIGTN (서열번호: 238)CDR L1: QSIGTN (SEQ ID NO: 238) CDR H2: IWSGGNT (서열번호: 235)CDR H2: IWSGGNT (SEQ ID NO: 235) CDR L2: YAS (서열번호: 239)CDR L2: YAS (SEQ ID NO: 239) CDR H3: ARALTYYDYEFAY (서열번호: 236)CDR H3: ARALTYYDYEFAY (SEQ ID NO: 236) CDR L3: QQNNNWPTT (서열번호: 240)CDR L3: QQNNNWPTT (SEQ ID NO: 240) Fab region
(Anti-CD3)
Fab region
(Anti-CD3)
VH: EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (서열번호: 215)VH: EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (SEQ ID NO: 215) VL:
DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (서열번호: 216)
VL:
DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (SEQ ID NO: 216)
CDR H1: GYSFTGYT (서열번호: 177)CDR H1: GYSFTGYT (SEQ ID NO: 177) CDR L1: QDIRNY (서열번호: 181)CDR L1: QDIRNY (SEQ ID NO: 181) CDR H2: INPYKGVS (서열번호: 178)CDR H2: INPYKGVS (SEQ ID NO: 178) CDR L2: YTS (서열번호: 182)CDR L2: YTS (SEQ ID NO: 182) CDR H3: ARSGYYGDSDWYFD (서열번호: 211)CDR H3: ARSGYYGDSDWYFD (SEQ ID NO: 211) CDR L3: QQGNTLPWT (서열번호: 207)CDR L3: QQGNTLPWT (SEQ ID NO: 207)

실시예 21.71. ACE-29r의 제조Example 21.71. Preparation of ACE-29r

ACE-29r은 2개의 상이한 중쇄 유사 사슬 (ACE-29r-VH 및 ACE-29r-VL) 및 2개의 동일한 경쇄 (ACE-29r-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다:ACE-29r contains two different heavy chain-like chains (ACE-29r-VH and ACE-29r-VL) and two identical light chains (ACE-29r-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-29r-VH amino acid sequence(서열번호: 483)ACE-29r-VH amino acid sequence (SEQ ID NO: 483)

EVKLLESGGGLVQPKGSLKLSCAAS GFTFNTYA MNWVRQAPGKGLEWVAR IRSKYNNYAT YYADSVKDRFTISRDDSQSILYLQMNNLKTEDTAMYYC VRHGNFGNSYVSWFAY WGQGTLVTVSA[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPPCPAPELLGGP]ggggsQVQLKQSGPGLVQPSQSLSITCTVS GFSLTNYG VHWVRQSPGKGLEWLGV IWSGGNT DYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYC ARALTYYDYEFAY WGQGTLVTVSAGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK EVKLLESGGGLVQPKGSLKLSCAAS GFTFNTYA MNWVRQAPGKGLEWVAR IRSKYNNYAT YYADSVKDRFTISRDDSQSILYLQMNNLKTEDTAMYYC VRHGNFGNSYVSWFAY WGQGTLVTVSA [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPPCPAPELLGGP] ggggs QVQLKQSGPGLVQPSQSLSITCTVS GFSLTNYG VHWVRQSPGKGLEWLGV IWSGGNT DYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYC ARALTYYDYEFAY WGQGTLVTVSA GQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

ACE-29r-VL amino acid sequence(서열번호: 484)ACE-29r-VL amino acid sequence (SEQ ID NO: 484)

EVKLLESGGGLVQPKGSLKLSCAAS GFTFNTYA MNWVRQAPGKGLEWVAR IRSKYNNYAT YYADSVKDRFTISRDDSQSILYLQMNNLKTEDTAMYYC VRHGNFGNSYVSWFAY WGQGTLVTVSA[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPPCPAPELLGGP]ggggsDILLTQSPVILSVSPGERVSFSCRAS QSIGTN IHWYQQRTNGSPRLLIK YAS ESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYC QQNNNWPTT FGAGTKLELKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK EVKLLESGGGLVQPKGSLKLSCAAS GFTFNTYA MNWVRQAPGKGLEWVAR IRSKYNNYAT YYADSVKDRFTISRDDSQSILYLQMNNLKTEDTAMYYC VRHGNFGNSYVSWFAY WGQGTLVTVSA [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPPCPAPELLGGP] ggggs DILLTQSPVILSVSPGERVSFSCRAS QSIGTN IHWYQQRTNGSPRLLIK YAS ESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYC QQNNNWPTT FGAGTKLELK GQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

ACE-29r-LC amino acid sequence (서열번호: 478)ACE-29r-LC amino acid sequence (SEQ ID NO: 478)

QAVVTQESALTTSPGETVTLTCRSS TGAVTTSNY ANWVQEKPDHLFTGLIG GTN KRAPGVPARFSGSLIGDKAALTITGAQTEDEAIYFC ALWYSNLWV FGGGTKLTVL[RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] QAVVTQESALTTSPGETVTLTCRSS TGAVTTSNY ANWVQEKPDHLFTGLIG GTN KRAPGVPARFSGSLIGDKAALTITGAQTEDEAIYFC ALWYSNLWV FGGGTKLTVL [ RTVAAPSVFIFPPSDEQLKSGTKLTVLNNFYPREADSKVQSKVLTQDSKVQSKVDSLGE

CD3를 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 EGFR을 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 75에 열거되어있다.The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting CD3 and the second antigen binding domain monovalent Fv region targeting EGFR are listed in Table 75 below.

Fv region
(Anti-EGFR)
Fv region
(Anti-EGFR)
VH: QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSA (서열번호: 233)VH: QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSA (SEQ ID NO: 233) VL:
DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELK (서열번호: 237)
VL:
DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELK (SEQ ID NO: 237)
CDR H1: GFSLTNYG (서열번호: 234)CDR H1: GFSLTNYG (SEQ ID NO: 234) CDR L1: QSIGTN (서열번호: 238)CDR L1: QSIGTN (SEQ ID NO: 238) CDR H2: IWSGGNT (서열번호: 235)CDR H2: IWSGGNT (SEQ ID NO: 235) CDR L2: YAS (서열번호: 239)CDR L2: YAS (SEQ ID NO: 239) CDR H3: ARALTYYDYEFAY (서열번호: 236)CDR H3: ARALTYYDYEFAY (SEQ ID NO: 236) CDR L3: QQNNNWPTT (서열번호: 240)CDR L3: QQNNNWPTT (SEQ ID NO: 240) Fab region
(Anti-CD3)
Fab region
(Anti-CD3)
VH:
EVKLLESGGGLVQPKGSLKLSCAASGFTFNTYAMNWVRQAPGKGLEWVARIRSKYNNYATYYADSVKDRFTISRDDSQSILYLQMNNLKTEDTAMYYCVRHGNFGNSYVSWFAYWGQGTLVTVSA (서열번호: 294)
VH:
EVKLLESGGGLVQPKGSLKLSCAASGFTFNTYAMNWVRQAPGKGLEWVARIRSKYNNYATYYADSVKDRFTISRDDSQSILYLQMNNLKTEDTAMYYCVRHGNFGNSYVSWFAYWGQGTLVTVSA (SEQ ID NO: 294)
VL:
QAVVTQESALTTSPGETVTLTCRSSTGAVTTSNYANWVQEKPDHLFTGLIGGTNKRAPGVPARFSGSLIGDKAALTITGAQTEDEAIYFCALWYSNLWVFGGGTKLTVL (서열번호: 298)
VL:
QAVVTQESALTTSPGETVTLTCRSSTGAVTTSNYANWVQEKPDHLFTGLIGGTNKRAPGVPARFSGSLIGDKAALTITGAQTEDEAIYFCALWYSNLWVFGGGTKLTVL (SEQ ID NO: 298)
CDR H1: GFTFNTYA (서열번호: 295)CDR H1: GFTFNTYA (SEQ ID NO: 295) CDR L1: TGAVTTSNY (서열번호: 299)CDR L1: TGAVTTSNY (SEQ ID NO: 299) CDR H2: IRSKYNNYAT (서열번호: 296)CDR H2: IRSKYNNYAT (SEQ ID NO: 296) CDR L2: GTN (서열번호: 300)CDR L2: GTN (SEQ ID NO: 300) CDR H3: VRHGNFGNSYVSWFAY (서열번호: 297)CDR H3: VRHGNFGNSYVSWFAY (SEQ ID NO: 297) CDR L3: ALWYSNLWV (서열번호: 301)CDR L3: ALWYSNLWV (SEQ ID NO: 301)

실시예 21.72. ACE-30r의 제조Example 21.72. Preparation of ACE-30r

ACE-30r은 2개의 상이한 중쇄 유사 사슬 (ACE-30r-VH 및 ACE-30r-VL) 및 2개의 동일한 경쇄 (ACE-30r-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다:ACE-30r contains two different heavy chain-like chains (ACE-30r-VH and ACE-30r-VL) and two identical light chains (ACE-30r-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-30r-VH amino acid sequence (서열번호: 485)ACE-30r-VH amino acid sequence (SEQ ID NO: 485)

QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPAPELLGGPggggsEVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFDV WGQGTTLTVFS QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPAPELLGGP ggggs EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFDV WGQGTTLTVFS

ACE-30r-VL amino acid sequence (서열번호: 486)ACE-30r-VL amino acid sequence (SEQ ID NO: 486)

QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPAPELLGGPggggsDIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPAPELLGGP ggggs DIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR

ACE-30r-LC amino acid sequence (서열번호: 487)ACE-30r-LC amino acid sequence (SEQ ID NO: 487)

QLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVLR[TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] QLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVLR [ TVAAPSVFIFPPSDEQLKSGTASVVCSHKNFLTQSGNSVVCSKNFDSKLSKSKSKNFREADS

PD-L1을 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 CD3를 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 76에 열거되어있다.The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting PD-L1 and the second antigen binding domain monovalent Fv region targeting CD3 are listed in Table 76 below. have.

Fv region
(Anti-CD3)
Fv region
(Anti-CD3)
VH: EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (서열번호: 325)VH: EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (SEQ ID NO: 325) VL:
DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (서열번호: 337)
VL:
DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (SEQ ID NO: 337)
CDR H1: GYSFTGYT (서열번호: 326)CDR H1: GYSFTGYT (SEQ ID NO: 326) CDR L1: QDIRNY (서열번호: 338)CDR L1: QDIRNY (SEQ ID NO: 338) CDR H2: INPYKGVS (서열번호: 327)CDR H2: INPYKGVS (SEQ ID NO: 327) CDR L2: YTS (서열번호: 339)CDR L2: YTS (SEQ ID NO: 339) CDR H3: ARSGYYGDSDWYFDV (서열번호: 328)CDR H3: ARSGYYGDSDWYFDV (SEQ ID NO: 328) CDR L3: QQGNTLPWT (서열번호: 340)CDR L3: QQGNTLPWT (SEQ ID NO: 340) Fab region
(Anti-PD-L1)
Fab region
(Anti-PD-L1)
VH:
QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (서열번호: 329)
VH:
QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (SEQ ID NO: 329)
VL: QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLR (서열번호: 333)VL: QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLR (SEQ ID NO: 333)
CDR H1: GGTFSSYA (서열번호: 330)CDR H1: GGTFSSYA (SEQ ID NO: 330) CDR L1: SSNIGAGYD (서열번호: 334)CDR L1: SSNIGAGYD (SEQ ID NO: 334) CDR H2: IIPILGIA (서열번호: 331)CDR H2: IIPILGIA (SEQ ID NO: 331) CDR L2: GDI (서열번호: 335)CDR L2: GDI (SEQ ID NO: 335) CDR H3: AKPRDGYNLVAFDI (서열번호: 332)CDR H3: AKPRDGYNLVAFDI (SEQ ID NO: 332) CDR L3: QSYDSSLSGGV (서열번호: 336)CDR L3: QSYDSSLSGGV (SEQ ID NO: 336)

실시예 21.73. ACE-31r의 제조Example 21.73. Preparation of ACE-31r

ACE-31r은 2개의 상이한 중쇄 유사 사슬 (ACE-31r-VH 및 ACE-31r-VL) 및 2개의 동일한 경쇄 (ACE-31r-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다:ACE-31r contains two different heavy chain-like chains (ACE-31r-VH and ACE-31r-VL) and two identical light chains (ACE-31r-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-31r-VH amino acid sequence (서열번호: 488)ACE-31r-VH amino acid sequence (SEQ ID NO: 488)

QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPAPELLGGPggggsggggsEVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFDV WGQGTTLTVFS QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPAPELLGGP ggggsggggs EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFDV WGQGTTLTVFS

ACE-31r-VL amino acid sequence (서열번호: 489)ACE-31r-VL amino acid sequence (SEQ ID NO: 489)

QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPAPELLGGPggggsDIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPAPELLGGP ggggs DIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR

ACE-31r-LC amino acid sequence (서열번호: 487)ACE-31r-LC amino acid sequence (SEQ ID NO: 487)

QLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVLR[TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] QLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVLR [ TVAAPSVFIFPPSDEQLKSGTASVVCSHKNFLTQSGNSVVCSKNFDSKLSKSKSKNFREADS

CD3을 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 PD-L1을 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 77에 열거되어있다.The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting CD3 and the second antigen binding domain monovalent Fv region targeting PD-L1 are listed in Table 77 below. have.

Fv region
(Anti-CD3)
Fv region
(Anti-CD3)
VH: EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (서열번호: 325)VH: EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (SEQ ID NO: 325) VL:
DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (서열번호: 337)
VL:
DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (SEQ ID NO: 337)
CDR H1: GYSFTGYT (서열번호: 326)CDR H1: GYSFTGYT (SEQ ID NO: 326) CDR L1: QDIRNY (서열번호: 338)CDR L1: QDIRNY (SEQ ID NO: 338) CDR H2: INPYKGVS (서열번호: 327)CDR H2: INPYKGVS (SEQ ID NO: 327) CDR L2: YTS (서열번호: 339)CDR L2: YTS (SEQ ID NO: 339) CDR H3: ARSGYYGDSDWYFDV (서열번호: 328)CDR H3: ARSGYYGDSDWYFDV (SEQ ID NO: 328) CDR L3: QQGNTLPWT (서열번호: 340)CDR L3: QQGNTLPWT (SEQ ID NO: 340) Fab region
(Anti-PD-L1)
Fab region
(Anti-PD-L1)
VH: QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (서열번호: 329)VH: QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (SEQ ID NO: 329) VL:
QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLR (서열번호: 333)
VL:
QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLR (SEQ ID NO: 333)
CDR H1: GGTFSSYA (서열번호: 330)CDR H1: GGTFSSYA (SEQ ID NO: 330) CDR L1: SSNIGAGYD (서열번호: 334)CDR L1: SSNIGAGYD (SEQ ID NO: 334) CDR H2: IIPILGIA (서열번호: 331)CDR H2: IIPILGIA (SEQ ID NO: 331) CDR L2: GDI (서열번호: 335)CDR L2: GDI (SEQ ID NO: 335) CDR H3: AKPRDGYNLVAFDI (서열번호: 332)CDR H3: AKPRDGYNLVAFDI (SEQ ID NO: 332) CDR L3: QSYDSSLSGGV (서열번호: 336)CDR L3: QSYDSSLSGGV (SEQ ID NO: 336)

실시예 21.74. ACE-32r의 제조Example 21.74. Preparation of ACE-32r

ACE-32r은 2개의 상이한 중쇄 유사 사슬 (ACE-32r-VH 및 ACE-32r-VL) 및 2개의 동일한 경쇄 (ACE-32r-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다:ACE-32r contains two different heavy chain-like chains (ACE-32r-VH and ACE-32r-VL) and two identical light chains (ACE-32r-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-32r-VH amino acid sequence (서열번호: 490)ACE-32r-VH amino acid sequence (SEQ ID NO: 490)

EVKLLESGGGLVQPKGSLKLSCAAS GFTFNTYA MNWVRQAPGKGLEWVAR IRSKYNNYAT YYADSVKDRFTISRDDSQSILYLQMNNLKTEDTAMYYC VRHGNFGNSYVSWFAY WGQGTLVTVSA[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPPCPAPELLGGPggggsggggsQVQLKQSGPGLVQPSQSLSITCTVS GFSLTNYG VHWVRQSPGKGLEWLGV IWSGGNT DYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYC ARALTYYDYEFAY WGQGTLVTVSA* EVKLLESGGGLVQPKGSLKLSCAAS GFTFNTYA MNWVRQAPGKGLEWVAR IRSKYNNYAT YYADSVKDRFTISRDDSQSILYLQMNNLKTEDTAMYYC VRHGNFGNSYVSWFAY WGQGTLVTVSA [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPPCPAPELLGGP ggggsggggs QVQLKQSGPGLVQPSQSLSITCTVS GFSLTNYG VHWVRQSPGKGLEWLGV IWSGGNT DYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYC ARALTYYDYEFAY WGQGTLVTVSA *

ACE-32r-VL amino acid sequence (서열번호: 491)ACE-32r-VL amino acid sequence (SEQ ID NO: 491)

EVKLLESGGGLVQPKGSLKLSCAAS GFTFNTYA MNWVRQAPGKGLEWVAR IRSKYNNYAT YYADSVKDRFTISRDDSQSILYLQMNNLKTEDTAMYYC VRHGNFGNSYVSWFAY WGQGTLVTVSA[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPPCPAPELLGGPggggsDILLTQSPVILSVSPGERVSFSCRAS QSIGTN IHWYQQRTNGSPRLLIK YAS ESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYC QQNNNWPTT FGAGTKLELK* EVKLLESGGGLVQPKGSLKLSCAAS GFTFNTYA MNWVRQAPGKGLEWVAR IRSKYNNYAT YYADSVKDRFTISRDDSQSILYLQMNNLKTEDTAMYYC VRHGNFGNSYVSWFAY WGQGTLVTVSA [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPPCPAPELLGGP ggggs DILLTQSPVILSVSPGERVSFSCRAS QSIGTN IHWYQQRTNGSPRLLIK YAS ESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYC QQNNNWPTT FGAGTKLELK *

ACE-32r-LC amino acid sequence (서열번호: 478)ACE-32r-LC amino acid sequence (SEQ ID NO: 478)

QAVVTQESALTTSPGETVTLTCRSS TGAVTTSNY ANWVQEKPDHLFTGLIG GTN KRAPGVPARFSGSLIGDKAALTITGAQTEDEAIYFC ALWYSNLWV FGGGTKLTVL[RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] QAVVTQESALTTSPGETVTLTCRSS TGAVTTSNY ANWVQEKPDHLFTGLIG GTN KRAPGVPARFSGSLIGDKAALTITGAQTEDEAIYFC ALWYSNLWV FGGGTKLTVL [ RTVAAPSVFIFPPSDEQLKSGTKLTVLNNFYPREADSKSCHKVLTQDSKVQWKVDSLGE

CD3을 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 EGFR을 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 78에 나열되어있다.The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting CD3 and the second antigen binding domain monovalent Fv region targeting EGFR are listed in Table 78 below.

Fv region
(Anti-EGFR)
Fv region
(Anti-EGFR)
VH: QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSA (서열번호: 233)VH: QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSA (SEQ ID NO: 233) VL: DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELK (서열번호: 237)VL: DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELK (SEQ ID NO: 237)
CDR H1: GFSLTNYG (서열번호: 234)CDR H1: GFSLTNYG (SEQ ID NO: 234) CDR L1: QSIGTN (서열번호: 238)CDR L1: QSIGTN (SEQ ID NO: 238) CDR H2: IWSGGNT (서열번호: 235)CDR H2: IWSGGNT (SEQ ID NO: 235) CDR L2: YAS (서열번호: 239)CDR L2: YAS (SEQ ID NO: 239) CDR H3: ARALTYYDYEFAY (서열번호: 236)CDR H3: ARALTYYDYEFAY (SEQ ID NO: 236) CDR L3: QQNNNWPTT (서열번호: 240)CDR L3: QQNNNWPTT (SEQ ID NO: 240) Fab region
(Anti-CD3)
Fab region
(Anti-CD3)
VH: EVKLLESGGGLVQPKGSLKLSCAASGFTFNTYAMNWVRQAPGKGLEWVARIRSKYNNYATYYADSVKDRFTISRDDSQSILYLQMNNLKTEDTAMYYCVRHGNFGNSYVSWFAYWGQGTLVTVSA (서열번호: 294)VH: EVKLLESGGGLVQPKGSLKLSCAASGFTFNTYAMNWVRQAPGKGLEWVARIRSKYNNYATYYADSVKDRFTISRDDSQSILYLQMNNLKTEDTAMYYCVRHGNFGNSYVSWFAYWGQGTLVTVSA (SEQ ID NO: 294) VL:
QAVVTQESALTTSPGETVTLTCRSSTGAVTTSNYANWVQEKPDHLFTGLIGGTNKRAPGVPARFSGSLIGDKAALTITGAQTEDEAIYFCALWYSNLWVFGGGTKLTVL (서열번호: 298)
VL:
QAVVTQESALTTSPGETVTLTCRSSTGAVTTSNYANWVQEKPDHLFTGLIGGTNKRAPGVPARFSGSLIGDKAALTITGAQTEDEAIYFCALWYSNLWVFGGGTKLTVL (SEQ ID NO: 298)
CDR H1: GFTFNTYA (서열번호: 295)CDR H1: GFTFNTYA (SEQ ID NO: 295) CDR L1: TGAVTTSNY (서열번호: 299)CDR L1: TGAVTTSNY (SEQ ID NO: 299) CDR H2: IRSKYNNYAT (서열번호: 296)CDR H2: IRSKYNNYAT (SEQ ID NO: 296) CDR L2: GTN (서열번호: 300)CDR L2: GTN (SEQ ID NO: 300) CDR H3: VRHGNFGNSYVSWFAY (서열번호: 297)CDR H3: VRHGNFGNSYVSWFAY (SEQ ID NO: 297) CDR L3: ALWYSNLWV (서열번호: 301)CDR L3: ALWYSNLWV (SEQ ID NO: 301)

실시예 21.75. ACE-33r의 제조Example 21.75. Preparation of ACE-33r

ACE-33r은 2개의 상이한 중쇄 유사 사슬 (ACE-33r-VH 및 ACE-33r-VL) 및 2개의 동일한 경쇄 (ACE-33r-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다:ACE-33r contains two different heavy chain-like chains (ACE-33r-VH and ACE-33r-VL) and two identical light chains (ACE-33r-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-33r-VH amino acid sequence (서열번호: 492)ACE-33r-VH amino acid sequence (SEQ ID NO: 492)

QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPPCPAPELLGGPggggsggggsEVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFDV WGQGTTLTVFS QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPPCPAPELLGGP ggggsggggs EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFDV WGQGTTLTVFS

ACE-33r-VL amino acid sequence (서열번호: 493)ACE-33r-VL amino acid sequence (SEQ ID NO: 493)

QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPPCPAPELLGGPggggsDIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPPCPAPELLGGP ggggs DIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR

ACE-33r-LC amino acid sequence (서열번호: 487)ACE-33r-LC amino acid sequence (SEQ ID NO: 487)

QLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVLR[TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] QLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVLR [ TVAAPSVFIFPPSDEQLKSGTASVVCSHKNFLTQSGNSVVCSKNFDSKLSKSKSKNFREADS

PD-L1을 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 CD3를 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 79에 열거되어있다.The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting PD-L1 and the second antigen binding domain monovalent Fv region targeting CD3 are listed in Table 79 below. have.

Fv region
(Anti-CD3)
Fv region
(Anti-CD3)
VH: EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (서열번호: 325)VH: EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (SEQ ID NO: 325) VL: DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (서열번호: 337)VL: DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (SEQ ID NO: 337)
CDR H1: GYSFTGYT (서열번호: 326)CDR H1: GYSFTGYT (SEQ ID NO: 326) CDR L1: QDIRNY (서열번호: 338)CDR L1: QDIRNY (SEQ ID NO: 338) CDR H2: INPYKGVS (서열번호: 327)CDR H2: INPYKGVS (SEQ ID NO: 327) CDR L2: YTS (서열번호: 339)CDR L2: YTS (SEQ ID NO: 339) CDR H3: ARSGYYGDSDWYFDV (서열번호: 328)CDR H3: ARSGYYGDSDWYFDV (SEQ ID NO: 328) CDR L3: QQGNTLPWT (서열번호: 340)CDR L3: QQGNTLPWT (SEQ ID NO: 340) Fab region
(Anti-PD-L1)
Fab region
(Anti-PD-L1)
VH:
QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (서열번호: 329)
VH:
QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (SEQ ID NO: 329)
VL: QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLR(서열번호: 333)VL: QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLR (SEQ ID NO: 333)
CDR H1: GGTFSSYA (서열번호: 330)CDR H1: GGTFSSYA (SEQ ID NO: 330) CDR L1: SSNIGAGYD (서열번호: 334CDR L1: SSNIGAGYD (SEQ ID NO: 334 CDR H2: IIPILGIA (서열번호: 331)CDR H2: IIPILGIA (SEQ ID NO: 331) CDR L2: GDI (서열번호: 335)CDR L2: GDI (SEQ ID NO: 335) CDR H3: AKPRDGYNLVAFDI (서열번호: 332)CDR H3: AKPRDGYNLVAFDI (SEQ ID NO: 332) CDR L3: QSYDSSLSGGV (서열번호: 336)CDR L3: QSYDSSLSGGV (SEQ ID NO: 336)

실시예 21.76. ACE-34r의 제조Example 21.76. Preparation of ACE-34r

ACE-34r은 2개의 상이한 중쇄 유사 사슬 (ACE-34r-VH 및 ACE-34r-VL) 및 2개의 동일한 경쇄 (ACE-34r-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다:ACE-34r contains two different heavy chain-like chains (ACE-34r-VH and ACE-34r-VL) and two identical light chains (ACE-34r-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-34r-VH amino acid sequence (서열번호: 494)ACE-34r-VH amino acid sequence (SEQ ID NO: 494)

EVQLVESGGGLVQPGKSLKLSCEASGFTFS GYGMH WVRQAPGRGLESVA YITSSSINIKYADAVKG RFTVSRDNAKNLLFLQMNILKSEDTAMYYCAR FDWDKN YWGQGTMVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPPCPAPELLGGPggggsQMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS EVQLVESGGGLVQPGKSLKLSCEASGFTFS GYGMH WVRQAPGRGLESVA YITSSSINIKYADAVKG RFTVSRDNAKNLLFLQMNILKSEDTAMYYCAR FDWDKN YWGQGTMVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPPCPAPELLGGP ggggs QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS

ACE-34r-VL amino acid sequence(서열번호: 495)ACE-34r-VL amino acid sequence (SEQ ID NO: 495)

EVQLVESGGGLVQPGKSLKLSCEASGFTFS GYGMH WVRQAPGRGLESVA YITSSSINIKYADAVKG RFTVSRDNAKNLLFLQMNILKSEDTAMYYCAR FDWDKN YWGQGTMVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPPCPAPELLGGPggggsQLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVLR EVQLVESGGGLVQPGKSLKLSCEASGFTFS GYGMH WVRQAPGRGLESVA YITSSSINIKYADAVKG RFTVSRDNAKNLLFLQMNILKSEDTAMYYCAR FDWDKN YWGQGTMVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPPCPAPELLGGP ggggs QLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVLR

ACE-34r-LC amino acid sequence (서열번호: 496)ACE-34r-LC amino acid sequence (SEQ ID NO: 496)

DIQMTQSPSSLPASLGDRVTINC QASQDISNYLN WYQQKPGKAPKLLIY YTNKLAD GVPSRFSGSGSGRDSSFTISSLESEDIGSYYC QQYYNYPWT FGPGTKLEIK[SVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] DIQMTQSPSSLPASLGDRVTINC QASQDISNYLN WYQQKPGKAPKLLIY YTNKLAD GVPSRFSGSGSGRDSSFTISSLESEDIGSYYC QQYYNYPWT FGPGTKLEIK [SVAAPSVFIFPPSDEQLKSGTASVVCLLNNVDYPREAKSQGNSVSTYPREAKVQWQLSKDS

CD3을 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 PD-L1을 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 80에 나열되어있다.The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting CD3 and the second antigen binding domain monovalent Fv region targeting PD-L1 are listed in Table 80 below. have.

Fv region
(Anti-PD-L1)
Fv region
(Anti-PD-L1)
VH: QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (서열번호: 158)VH: QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (SEQ ID NO: 158) VL: QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLR(서열번호: 170)
VL: QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLR (SEQ ID NO: 170)
CDR H1: GGTFSSYA (서열번호: 159)CDR H1: GGTFSSYA (SEQ ID NO: 159) CDR L1: SSNIGAGYD (서열번호: 171)CDR L1: SSNIGAGYD (SEQ ID NO: 171) CDR H2: IIPILGIA (서열번호: 160)CDR H2: IIPILGIA (SEQ ID NO: 160) CDR L2: GDI (서열번호: 172)CDR L2: GDI (SEQ ID NO: 172) CDR H3: AKPRDGYNLVAFDI (서열번호: 161)CDR H3: AKPRDGYNLVAFDI (SEQ ID NO: 161) CDR L3: QSYDSSLSGGV (서열번호: 173)CDR L3: QSYDSSLSGGV (SEQ ID NO: 173) Fab region
(Anti-CD3)
Fab region
(Anti-CD3)
VH: EVQLVESGGGLVQPGKSLKLSCEASGFTFSGYGMHWVRQAPGRGLESVAYITSSSINIKYADAVKGRFTVSRDNAKNLLFLQMNILKSEDTAMYYCARFDWDKNYWGQGTMVTVSS (서열번호: 348)VH: EVQLVESGGGLVQPGKSLKLSCEASGFTFSGYGMHWVRQAPGRGLESVAYITSSSINIKYADAVKGRFTVSRDNAKNLLFLQMNILKSEDTAMYYCARFDWDKNYWGQGTMVTVSS (SEQ ID NO: 348) VL: DIQMTQSPSSLPASLGDRVTINCQASQDISNYLNWYQQKPGKAPKLLIYYTNKLADGVPSRFSGSGSGRDSSFTISSLESEDIGSYYCQQYYNYPWTFGPGTKLEIK (서열번호: 352)VL: DIQMTQSPSSLPASLGDRVTINCQASQDISNYLNWYQQKPGKAPKLLIYYTNKLADGVPSRFSGSGSGRDSSFTISSLESEDIGSYYCQQYYNYPWTFGPGTKLEIK (SEQ ID NO: 352)
CDR H1: GYGMH (서열번호: 349)CDR H1: GYGMH (SEQ ID NO: 349) CDR L1: QASQDISNYLN (서열번호: 353)CDR L1: QASQDISNYLN (SEQ ID NO: 353) CDR H2: YITSSSINIKYADAVKG (서열번호: 350)CDR H2: YITSSSINIKYADAVKG (SEQ ID NO: 350) CDR L2: YTNKLAD(서열번호: 354)CDR L2: YTNKLAD (SEQ ID NO: 354) CDR H3: FDWDKN (서열번호: 351)CDR H3: FDWDKN (SEQ ID NO: 351) CDR L3: QQYYNYPWT (서열번호: 355)CDR L3: QQYYNYPWT (SEQ ID NO: 355)

실시예 21.77. ACE-35r의 제조Example 21.77. Preparation of ACE-35r

ACE-35r은 2개의 상이한 중쇄 유사 사슬 (ACE-35r-VH 및 ACE-35r-VL) 및 2개의 동일한 경쇄 (ACE-35r-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다:ACE-35r contains two different heavy chain-like chains (ACE-35r-VH and ACE-35r-VL) and two identical light chains (ACE-35r-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-35r-VH amino acid sequence (서열번호: 497)ACE-35r-VH amino acid sequence (SEQ ID NO: 497)

QVKLQQSGSELGKPGASVKLSCKTSGYIFT DHYIS WVKQKPGESLQWIG NVYGGNGGTSYNQKFQG KATLTVDKISSTAYMELSSLTSEDSAIYYCAR RPVATGHAMDY WGQGIQVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPPCPAPELLGGPggggsQMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS QVKLQQSGSELGKPGASVKLSCKTSGYIFT DHYIS WVKQKPGESLQWIG NVYGGNGGTSYNQKFQG KATLTVDKISSTAYMELSSLTSEDSAIYYCAR RPVATGHAMDY WGQGIQVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPPCPAPELLGGP ggggs QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS

ACE-35r-VL amino acid sequence (서열번호: 498)ACE-35r-VL amino acid sequence (SEQ ID NO: 498)

QVKLQQSGSELGKPGASVKLSCKTSGYIFT DHYIS WVKQKPGESLQWIG NVYGGNGGTSYNQKFQG KATLTVDKISSTAYMELSSLTSEDSAIYYCAR RPVATGHAMDY WGQGIQVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPPCPAPELLGGPggggsQLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVLR QVKLQQSGSELGKPGASVKLSCKTSGYIFT DHYIS WVKQKPGESLQWIG NVYGGNGGTSYNQKFQG KATLTVDKISSTAYMELSSLTSEDSAIYYCAR RPVATGHAMDY WGQGIQVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPPCPAPELLGGP ggggs QLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVLR

ACE-35r-LC amino acid sequence) (서열번호: 499)ACE-35r-LC amino acid sequence) (SEQ ID NO: 499)

DIVLTQTPATLSLIPGERVTMTC KTSQNIGTILH WYHQKPKEAPRALIK YASQSIP GIPSRFSGSGSETDFTLSINNLEPDDIGIYYC QQSRSWPVT FGPGTKLEIK[SVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] DIVLTQTPATLSLIPGERVTMTC KTSQNIGTILH WYHQKPKEAPRALIK YASQSIP GIPSRFSGSGSETDFTLSINNLEPDDIGIYYC QQSRSWPVT FGPGTKLEIK [SVAAPSVFIFPPSDEQLKSGTKLEIK [SVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREADSGLSQSKVLTQYPREAKVQSKVDLSKADS

CD3을 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 PD-L1을 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 81에 열거되어있다.The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting CD3 and the second antigen binding domain monovalent Fv region targeting PD-L1 are listed in Table 81 below. have.

Fv region
(Anti-PD-L1)
Fv region
(Anti-PD-L1)
VH:
QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (서열번호: 158)
VH:
QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (SEQ ID NO: 158)
VL: QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLR(서열번호: 170)VL: QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLR (SEQ ID NO: 170)
CDR H1: GGTFSSYA (서열번호: 159)CDR H1: GGTFSSYA (SEQ ID NO: 159) CDR L1: SSNIGAGYD (서열번호: 171)CDR L1: SSNIGAGYD (SEQ ID NO: 171) CDR H2: IIPILGIA (서열번호: 160)CDR H2: IIPILGIA (SEQ ID NO: 160) CDR L2: GDI (서열번호: 172)CDR L2: GDI (SEQ ID NO: 172) CDR H3: AKPRDGYNLVAFDI (서열번호: 161)CDR H3: AKPRDGYNLVAFDI (SEQ ID NO: 161) CDR L3: QSYDSSLSGGV (서열번호: 173)CDR L3: QSYDSSLSGGV (SEQ ID NO: 173) Fab region
(Anti-CD3)
Fab region
(Anti-CD3)
VH: QVKLQQSGSELGKPGASVKLSCKTSGYIFTDHYISWVKQKPGESLQWIGNVYGGNGGTSYNQKFQGKATLTVDKISSTAYMELSSLTSEDSAIYYCARRPVATGHAMDYWGQGIQVTVSS (서열번호: 358)VH: QVKLQQSGSELGKPGASVKLSCKTSGYIFTDHYISWVKQKPGESLQWIGNVYGGNGGTSYNQKFQGKATLTVDKISSTAYMELSSLTSEDSAIYYCARRPVATGHAMDYWGQGIQVTVSS (SEQ ID NO: 358) VL:
DIVLTQTPATLSLIPGERVTMTCKTSQNIGTILHWYHQKPKEAPRALIKYASQSIPGIPSRFSGSGSETDFTLSINNLEPDDIGIYYCQQSRSWPVTFGPGTKLEIK (서열번호: 362)
VL:
DIVLTQTPATLSLIPGERVTMTCKTSQNIGTILHWYHQKPKEAPRALIKYASQSIPGIPSRFSGSGSETDFTLSINNLEPDDIGIYYCQQSRSWPVTFGPGTKLEIK (SEQ ID NO: 362)
CDR H1: DHYIS (서열번호: 359)CDR H1: DHYIS (SEQ ID NO: 359) CDR L1: KTSQNIGTILH (서열번호: 363)CDR L1: KTSQNIGTILH (SEQ ID NO: 363) CDR H2: NVYGGNGGTSYNQKFQG (서열번호: 360)CDR H2: NVYGGNGGTSYNQKFQG (SEQ ID NO: 360) CDR L2: YASQSIP (서열번호: 364)CDR L2: YASQSIP (SEQ ID NO: 364) CDR H3: RPVATGHAMDY (서열번호: 361)CDR H3: RPVATGHAMDY (SEQ ID NO: 361) CDR L3: QQSRSWPVT (서열번호: 365)CDR L3: QQSRSWPVT (SEQ ID NO: 365)

실시예 21.78. ACE-36r의 제조Example 21.78. Preparation of ACE-36r

ACE-36r은 2개의 상이한 중쇄 유사 사슬 (ACE-36r-VH 및 ACE-36r-VL) 및 2개의 동일한 경쇄 (ACE-36r-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다:ACE-36r contains two different heavy chain-like chains (ACE-36r-VH and ACE-36r-VL) and two identical light chains (ACE-36r-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-36r-VH amino acid sequence (서열번호: 500)ACE-36r-VH amino acid sequence (SEQ ID NO: 500)

QVQLVESGGGVVQPGRSLRLSCAAS GFTFSSYT MHWVRQAPGKGLEWVTF ISYDGNNK YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAIYYC ARTGWLGPFDY WGQGTLVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPPCPAPELLGGPggggsQMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS QVQLVESGGGVVQPGRSLRLSCAAS GFTFSSYT MHWVRQAPGKGLEWVTF ISYDGNNK YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAIYYC ARTGWLGPFDY WGQGTLVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPPCPAPELLGGP ggggs QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC AKPRDGYNLVAFDI WGQGTMVTVSS

ACE-36r-VL amino acid sequence (서열번호: 501)ACE-36r-VL amino acid sequence (SEQ ID NO: 501)

QVQLVESGGGVVQPGRSLRLSCAAS GFTFSSYT MHWVRQAPGKGLEWVTF ISYDGNNK YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAIYYC ARTGWLGPFDY WGQGTLVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPPCPAPELLG QLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVL QVQLVESGGGVVQPGRSLRLSCAAS GFTFSSYT MHWVRQAPGKGLEWVTF ISYDGNNK YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAIYYC ARTGWLGPFDY WGQGTLVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPPCPAPELLG QLVLTQPPSVSGAPGQRVTISCTGS SSNIGAGYD VHWYQQLPGAAPKLLIY GDI NRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYC QSYDSSLSGGV FGGGTKLTVL

ACE-36r-LC amino acid sequence (서열번호: 502)ACE-36r-LC amino acid sequence (SEQ ID NO: 502)

EIVLTQSPGTLSLSPGERATLSCRAS QSVGSSY LAWYQQKPGQAPRLLIY GAF SRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYC QQYGSSPWT FGQGTKVEIK[RSVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] EIVLTQSPGTLSLSPGERATLSCRAS QSVGSSY LAWYQQKPGQAPRLLIY GAF SRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYC QQYGSSPWT FGQGTKVEIK [ RSVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPYPREASKVQWKVSTLSKVQWKLSKDSPWT

CTLA-4를 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 PD-L1을 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 82에 열거되어있다.The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting CTLA-4 and the second antigen binding domain monovalent Fv region targeting PD-L1 are shown in Table 82 below. Are listed.

Fv region
(Anti-PD-L1)
Fv region
(Anti-PD-L1)
VH: QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (서열번호: 158)VH: QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTMVTVSS (SEQ ID NO: 158) VL:
QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVL (서열번호: 376)
VL:
QLVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAITGLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVL (SEQ ID NO: 376)
CDR H1: GGTFSSYA (서열번호: 159)CDR H1: GGTFSSYA (SEQ ID NO: 159) CDR L1: SSNIGAGYD (서열번호: 171)CDR L1: SSNIGAGYD (SEQ ID NO: 171) CDR H2: IIPILGIA (서열번호: 160)CDR H2: IIPILGIA (SEQ ID NO: 160) CDR L2: GDI (서열번호: 172)CDR L2: GDI (SEQ ID NO: 172) CDR H3: AKPRDGYNLVAFDI (서열번호: 161)CDR H3: AKPRDGYNLVAFDI (SEQ ID NO: 161) CDR L3: QSYDSSLSGGV (서열번호: 173)CDR L3: QSYDSSLSGGV (SEQ ID NO: 173) Fab region
(Anti-CTLA4)
Fab region
(Anti-CTLA4)
VH: QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYTMHWVRQAPGKGLEWVTFISYDGNNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAIYYCARTGWLGPFDYWGQGTLVTVSS (서열번호: 368)VH: QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYTMHWVRQAPGKGLEWVTFISYDGNNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAIYYCARTGWLGPFDYWGQGTLVTVSS (SEQ ID NO: 368) VL:
EIVLTQSPGTLSLSPGERATLSCRASQSVGSSYLAWYQQKPGQAPRLLIYGAFSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPWTFGQGTKVEIK (서열번호: 372)
VL:
EIVLTQSPGTLSLSPGERATLSCRASQSVGSSYLAWYQQKPGQAPRLLIYGAFSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPWTFGQGTKVEIK (SEQ ID NO: 372)
CDR H1: GFTFSSYT (서열번호: 369)CDR H1: GFTFSSYT (SEQ ID NO: 369) CDR L1: QSVGSSY (서열번호: 373)CDR L1: QSVGSSY (SEQ ID NO: 373) CDR H2: ISYDGNNK (서열번호: 370)CDR H2: ISYDGNNK (SEQ ID NO: 370) CDR L2: GAF (서열번호: 374)CDR L2: GAF (SEQ ID NO: 374) CDR H3: ARTGWLGPFDY (서열번호: 371)CDR H3: ARTGWLGPFDY (SEQ ID NO: 371) CDR L3: QQYGSSPWT (서열번호: 375)CDR L3: QQYGSSPWT (SEQ ID NO: 375)

실시예 21.79. ACE-37r의 제조Example 21.79. Preparation of ACE-37r

ACE-37r은 2개의 상이한 중쇄 유사 사슬 (ACE-37r-VH 및 ACE-37r-VL) 및 2개의 동일한 경쇄 (ACE-37r-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다:ACE-37r contains two different heavy chain-like chains (ACE-37r-VH and ACE-37r-VL) and two identical light chains (ACE-37r-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-37r-VH amino acid sequence (서열번호: 503)ACE-37r-VH amino acid sequence (SEQ ID NO: 503)

QVQLVESGGGVVQPGRSLRLSCAAS GFTFSSYT MHWVRQAPGKGLEWVTF ISYDGNNK YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAIYYC ARTGWLGPFDY WGQGTLVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC]DKTHTCPPCPPCPAPELLGGPggggsQVQLQQPGAELVKPGASVKMSCKAS GYTFTSYN MHWVKQTPGRGLEWIGA IYPGNGDT SYNQKFKGKATLTADKSSSTAYMQLSSLTSEDSAVYYC ARSTYYGGDWYFNV WGAGTTVTVSA QVQLVESGGGVVQPGRSLRLSCAAS GFTFSSYT MHWVRQAPGKGLEWVTF ISYDGNNK YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAIYYC ARTGWLGPFDY WGQGTLVTVSS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC] DKTHTCPPCPPCPAPELLGGP ggggs QVQLQQPGAELVKPGASVKMSCKAS GYTFTSYN MHWVKQTPGRGLEWIGA IYPGNGDT SYNQKFKGKATLTADKSSSTAYMQLSSLTSEDSAVYYC ARSTYYGGDWYFNV WGAGTTVTVSA

ACE-37r-VL amino acid sequence (서열번호: 504)ACE-37r-VL amino acid sequence (SEQ ID NO: 504)

QVQLVESGGGVVQPGRSLRLSCAAS GFTFSSYT MHWVRQAPGKGLEWVTF ISYDGNNK YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAIYYC ARTGWLGPFDY WGQGTLVTVSS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC]DKTHTCPPCPPCPAPELLG QIVLSQSPAILSASPGEKVTMTCRAS SSVSY IHWFQQKPGSSPKPWIY ATS NLASGVPVRFSGSGSGTSYSLTISRVEAEDAATYYC QQWTSNPPT FGGGTKLEIK QVQLVESGGGVVQPGRSLRLSCAAS GFTFSSYT MHWVRQAPGKGLEWVTF ISYDGNNK YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAIYYC ARTGWLGPFDY WGQGTLVTVSS [ ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC] DKTHTCPPCPPCPAPELLG QIVLSQSPAILSASPGEKVTMTCRAS SSVSY IHWFQQKPGSSPKPWIY ATS NLASGVPVRFSGSGSGTSYSLTISRVEAEDAATYYC QQWTSNPPT FGGGTKLEIK

ACE-37r-LC amino acid sequence (서열번호: 502)ACE-37r-LC amino acid sequence (SEQ ID NO: 502)

EIVLTQSPGTLSLSPGERATLSCRAS QSVGSSY LAWYQQKPGQAPRLLIY GAF SRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYC QQYGSSPWT FGQGTKVEIK[RSVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] EIVLTQSPGTLSLSPGERATLSCRAS QSVGSSY LAWYQQKPGQAPRLLIY GAF SRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYC QQYGSSPWT FGQGTKVEIK [ RSVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPYPREASKVQWKVSTLSKVQWKLSKDSPWT

CTLA-4를 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 CD20을 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 83에 열거되어있다.The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting CTLA-4 and the second antigen binding domain monovalent Fv region targeting CD20 are listed in Table 83 below. have.

Fv region
(Anti-CD20)
Fv region
(Anti-CD20)
VH: QVQLQQPGAELVKPGASVKMSCKASGYTFTSYNMHWVKQTPGRGLEWIGAIYPGNGDTSYNQKFKGKATLTADKSSSTAYMQLSSLTSEDSAVYYCARSTYYGGDWYFNVWGAGTTVTVSA (서열번호: 222)VH: QVQLQQPGAELVKPGASVKMSCKASGYTFTSYNMHWVKQTPGRGLEWIGAIYPGNGDTSYNQKFKGKATLTADKSSSTAYMQLSSLTSEDSAVYYCARSTYYGGDWYFNVWGAGTTVTVSA (SEQ ID NO: 222) VL:
QIVLSQSPAILSASPGEKVTMTCRASSSVSYIHWFQQKPGSSPKPWIYATSNLASGVPVRFSGSGSGTSYSLTISRVEAEDAATYYCQQWTSNPPTFGGGTKLEIK (서열번호: 226)
VL:
QIVLSQSPAILSASPGEKVTMTCRASSSVSYIHWFQQKPGSSPKPWIYATSNLASGVPVRFSGSGSGTSYSLTISRVEAEDAATYYCQQWTSNPPTFGGGTKLEIK (SEQ ID NO: 226)
CDR H1: GYTFTSYN (서열번호: 223)CDR H1: GYTFTSYN (SEQ ID NO: 223) CDR L1: SSVSY (서열번호: 227)CDR L1: SSVSY (SEQ ID NO: 227) CDR H2: IYPGNGDT (서열번호: 224)CDR H2: IYPGNGDT (SEQ ID NO: 224) CDR L2: ATS (서열번호: 228)CDR L2: ATS (SEQ ID NO: 228) CDR H3: ARSTYYGGDWYFNV (서열번호: 225)CDR H3: ARSTYYGGDWYFNV (SEQ ID NO: 225) CDR L3: QQWTSNPPT (서열번호: 229)CDR L3: QQWTSNPPT (SEQ ID NO: 229) Fab region
(Anti-CTLA-4)
Fab region
(Anti-CTLA-4)
VH: QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYTMHWVRQAPGKGLEWVTFISYDGNNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAIYYCARTGWLGPFDYWGQGTLVTVSS (서열번호: 368)VH: QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYTMHWVRQAPGKGLEWVTFISYDGNNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAIYYCARTGWLGPFDYWGQGTLVTVSS (SEQ ID NO: 368) VL: EIVLTQSPGTLSLSPGERATLSCRASQSVGSSYLAWYQQKPGQAPRLLIYGAFSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPWTFGQGTKVEIK (서열번호: 372)VL: EIVLTQSPGTLSLSPGERATLSCRASQSVGSSYLAWYQQKPGQAPRLLIYGAFSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPWTFGQGTKVEIK (SEQ ID NO: 372)
CDR H1: GFTFSSYT (서열번호: 369)CDR H1: GFTFSSYT (SEQ ID NO: 369) CDR L1: QSVGSSY (서열번호: 373)CDR L1: QSVGSSY (SEQ ID NO: 373) CDR H2: ISYDGNNK (서열번호: 370)CDR H2: ISYDGNNK (SEQ ID NO: 370) CDR L2: GAF (서열번호: 374)CDR L2: GAF (SEQ ID NO: 374) CDR H3: ARTGWLGPFDY (서열번호: 371)CDR H3: ARTGWLGPFDY (SEQ ID NO: 371) CDR L3: QQYGSSPWT (서열번호: 375)CDR L3: QQYGSSPWT (SEQ ID NO: 375)

실시예 21.80. ACE-38r의 제조Example 21.80. Preparation of ACE-38r

ACE-38은 2개의 상이한 중쇄 유사 사슬 (ACE-38r-VH 및 ACE-38r-VL) 및 2개의 동일한 경쇄 (ACE-38r-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다:ACE-38 contains two different heavy chain-like chains (ACE-38r-VH and ACE-38r-VL) and two identical light chains (ACE-38r-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-38r-VH amino acid sequence (서열번호: 505)ACE-38r-VH amino acid sequence (SEQ ID NO: 505)

EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPPCPAPELLGGPggggsQVQLKQSGPGLVQPSQSLSITCTVS GFSLTNYG VHWVRQSPGKGLEWLGV IWSGGNT DYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYC ARALTYYDYEFAY WGQGTLVTVSAGQPREPQVYTSPPSRDELTKNQVSLRCHVKGFYPSDIAVEWESNGQPENNYKTTKPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPPCPAPELLGGP ggggs QVQLKQSGPGLVQPSQSLSITCTVS GFSLTNYG VHWVRQSPGKGLEWLGV IWSGGNT DYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYC ARALTYYDYEFAY WGQGTLVTVSA GQPREPQVYTSPPSRDELTKNQVSLRCHVKGFYPSDIAVEWESNGQPENNYKTTKPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

ACE-38r-VL amino acid sequence (서열번호: 506)ACE-38r-VL amino acid sequence (SEQ ID NO: 506)

EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPPCPAPELLGGPggggsDILLTQSPVILSVSPGERVSFSCRAS QSIGTN IHWYQQRTNGSPRLLIK YAS ESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYC QQNNNWPTT FGAGTKLELK EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPPCPAPELLGGP ggggs DILLTQSPVILSVSPGERVSFSCRAS QSIGTN IHWYQQRTNGSPRLLIK YAS ESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYC QQNNNWPTT FGAGTKLELK

ACE-38r-LC amino acid sequence (서열번호: 419)ACE-38r-LC amino acid sequence (SEQ ID NO: 419)

DIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR[RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] DIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR [ RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPYPREAKVQWKLSVTYPREAKVQWKLSVDSKVQWKLSVT

CD3을 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 EGFR을 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 84에 열거되어있다.The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting CD3 and the second antigen binding domain monovalent Fv region targeting EGFR are listed in Table 84 below.

Fv region
(Anti-EGFR)
Fv region
(Anti-EGFR)
VH: QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSA (서열번호: 233)VH: QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSA (SEQ ID NO: 233) VL:
DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELK (서열번호: 237)
VL:
DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELK (SEQ ID NO: 237)
CDR H1: GFSLTNYG (서열번호: 234)CDR H1: GFSLTNYG (SEQ ID NO: 234) CDR L1: QSIGTN (서열번호: 238)CDR L1: QSIGTN (SEQ ID NO: 238) CDR H2: IWSGGNT (서열번호: 235)CDR H2: IWSGGNT (SEQ ID NO: 235) CDR L2: YAS (서열번호: 239)CDR L2: YAS (SEQ ID NO: 239) CDR H3: ARALTYYDYEFAY (서열번호: 236)CDR H3: ARALTYYDYEFAY (SEQ ID NO: 236) CDR L3: QQNNNWPTT (서열번호: 240)CDR L3: QQNNNWPTT (SEQ ID NO: 240) Fab region
(Anti-CD3)
Fab region
(Anti-CD3)
VH: EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (서열번호: 215)VH: EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (SEQ ID NO: 215) VL:
DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (서열번호: 216)
VL:
DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (SEQ ID NO: 216)
CDR H1: GYSFTGYT (서열번호: 177)CDR H1: GYSFTGYT (SEQ ID NO: 177) CDR L1: QDIRNY (서열번호: 181)CDR L1: QDIRNY (SEQ ID NO: 181) CDR H2: INPYKGVS (서열번호: 178)CDR H2: INPYKGVS (SEQ ID NO: 178) CDR L2: YTS (서열번호: 182)CDR L2: YTS (SEQ ID NO: 182) CDR H3: ARSGYYGDSDWYFD (서열번호: 211)CDR H3: ARSGYYGDSDWYFD (SEQ ID NO: 211) CDR L3: QQGNTLPWT (서열번호: 207)CDR L3: QQGNTLPWT (SEQ ID NO: 207)

실시예 21.81. ACE-39r의 제조Example 21.81. Preparation of ACE-39r

ACE-39r은 2개의 상이한 중쇄 유사 사슬 (ACE-39r-VH 및 ACE-39r-VL) 및 2개의 동일한 경쇄 (ACE-39r-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다:ACE-39r contains two different heavy chain-like chains (ACE-39r-VH and ACE-39r-VL) and two identical light chains (ACE-39r-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-39r-VH amino acid sequence (서열번호: 507)ACE-39r-VH amino acid sequence (SEQ ID NO: 507)

EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPPCPAPELLGGPggggsQVQLKQSGPGLVQPSQSLSITCTVS GFSLTNYG VHWVRQSPGKGLEWLGV IWSGGNT DYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYC ARALTYYDYEFAY WGQGTLVTVSA EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPPCPAPELLGGP ggggs QVQLKQSGPGLVQPSQSLSITCTVS GFSLTNYG VHWVRQSPGKGLEWLGV IWSGGNT DYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYC ARALTYYDYEFAY WGQGTLVTVSA

ACE-39r-VL amino acid sequence (서열번호: 508)ACE-39r-VL amino acid sequence (SEQ ID NO: 508)

EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPPCPAPELLGGPggggsDILLTQSPVILSVSPGERVSFSCRAS QSIGTN IHWYQQRTNGSPRLLIK YAS ESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYC QQNNNWPTT FGAGTKLELKGQPREPQVYTSPPSRDELTKNQVSLRCHVKGFYPSDIAVEWESNGQPENNYKTTKPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPPCPAPELLGGP ggggs DILLTQSPVILSVSPGERVSFSCRAS QSIGTN IHWYQQRTNGSPRLLIK YAS ESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYC QQNNNWPTT FGAGTKLELK GQPREPQVYTSPPSRDELTKNQVSLRCHVKGFYPSDIAVEWESNGQPENNYKTTKPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

ACE-39r-LC amino acid sequence (서열번호: 419)ACE-39r-LC amino acid sequence (SEQ ID NO: 419)

DIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR[RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] DIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR [ RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPYPREAKVQWKLSVTYPREAKVQWKLSVDSKVQWKLSVT

CD3를 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 EGFR을 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 85에 열거되어있다.The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting CD3 and the second antigen binding domain monovalent Fv region targeting EGFR are listed in Table 85 below.

Fv region
(Anti-EGFR)
Fv region
(Anti-EGFR)
VH: QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSA (서열번호: 233)VH: QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSA (SEQ ID NO: 233) VL:
DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELK (서열번호: 237)
VL:
DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELK (SEQ ID NO: 237)
CDR H1: GFSLTNYG (서열번호: 234)CDR H1: GFSLTNYG (SEQ ID NO: 234) CDR L1: QSIGTN (서열번호: 238)CDR L1: QSIGTN (SEQ ID NO: 238) CDR H2: IWSGGNT (서열번호: 235)CDR H2: IWSGGNT (SEQ ID NO: 235) CDR L2: YAS (서열번호: 239)CDR L2: YAS (SEQ ID NO: 239) CDR H3: ARALTYYDYEFAY (서열번호: 236)CDR H3: ARALTYYDYEFAY (SEQ ID NO: 236) CDR L3: QQNNNWPTT (서열번호: 240)CDR L3: QQNNNWPTT (SEQ ID NO: 240) Fab region
(Anti-CD3)
Fab region
(Anti-CD3)
VH: EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (서열번호: 215)VH: EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (SEQ ID NO: 215) VL: DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (서열번호: 216)VL: DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (SEQ ID NO: 216)
CDR H1: GYSFTGYT (서열번호: 177)CDR H1: GYSFTGYT (SEQ ID NO: 177) CDR L1: QDIRNY (서열번호: 181)CDR L1: QDIRNY (SEQ ID NO: 181) CDR H2: INPYKGVS (서열번호: 178)CDR H2: INPYKGVS (SEQ ID NO: 178) CDR L2: YTS (서열번호: 182)CDR L2: YTS (SEQ ID NO: 182) CDR H3: ARSGYYGDSDWYFD (서열번호: 211)CDR H3: ARSGYYGDSDWYFD (SEQ ID NO: 211) CDR L3: QQGNTLPWT (서열번호: 207)CDR L3: QQGNTLPWT (SEQ ID NO: 207)

실시예 21.82. ACE-40r의 제조Example 21.82. Preparation of ACE-40r

ACE-40r은 2개의 상이한 중쇄 유사 사슬 (ACE-40r-VH 및 ACE-40r-VL) 및 2개의 동일한 경쇄 (ACE-40r-LC)를 포함한다. 이 세 가지 유형의 폴리펩티드의 아미노산 서열은 다음과 같다:ACE-40r contains two different heavy chain-like chains (ACE-40r-VH and ACE-40r-VL) and two identical light chains (ACE-40r-LC). The amino acid sequences of these three types of polypeptides are as follows:

ACE-40r-VH amino acid sequence (서열번호: 509)ACE-40r-VH amino acid sequence (SEQ ID NO: 509)

EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPPCPAPELLGGPggggsQVQLKQSGPGLVQPSQSLSITCTVS GFSLTNYG VHWVRQSPGKGLEWLGV IWSGGNT DYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYC ARALTYYDYEFAY WGQGTLVTVSAGQPREPQVYTSPPSRDELTKNQVSLRCHVKGFYPSDIAVEWESNGQPENNYKTTKPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPPCPAPELLGGP ggggs QVQLKQSGPGLVQPSQSLSITCTVS GFSLTNYG VHWVRQSPGKGLEWLGV IWSGGNT DYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYC ARALTYYDYEFAY WGQGTLVTVSA GQPREPQVYTSPPSRDELTKNQVSLRCHVKGFYPSDIAVEWESNGQPENNYKTTKPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

ACE-40r-VL amino acid sequence (서열번호: 510)ACE-40r-VL amino acid sequence (SEQ ID NO: 510)

EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFS[ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC]DKTHTCPPCPPCPAPELLGGPggggsDILLTQSPVILSVSPGERVSFSCRAS QSIGTN IHWYQQRTNGSPRLLIK YAS ESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYC QQNNNWPTT FGAGTKLELKGQPREPQVYTSPPSRDELTKNQVSLRCHVKGFYPSDIAVEWESNGQPENNYKTTKPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK EVQLQQSGPELVKPGPSMKISCKAS GYSFTGYT MNWVKQSHGKNLEWMGL INPYKGVS TYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYC ARSGYYGDSDWYFD VWGQGTTLTVFS [ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC] DKTHTCPPCPPCPAPELLGGP ggggs DILLTQSPVILSVSPGERVSFSCRAS QSIGTN IHWYQQRTNGSPRLLIK YAS ESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYC QQNNNWPTT FGAGTKLELK GQPREPQVYTSPPSRDELTKNQVSLRCHVKGFYPSDIAVEWESNGQPENNYKTTKPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

ACE-40r-LC amino acid sequence (서열번호: 419)ACE-40r-LC amino acid sequence (SEQ ID NO: 419)

DIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR[RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC] DIQMTQTTSSLSASLGDRVTISCRAS QDIRNY LNWYQQKPDGTVKLLIY YTS RLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFC QQGNTLPWT FAGGTKLEIKR [ RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPYPREAKVQWKLSVTYPREAKVQWKLSVDSKVQWKLSVT

CD3을 표적으로하는 제1 항원 결합 도메인 2가 Fab 영역 및 EGFR을 표적으로하는 제2 항원 결합 도메인 1가 Fv 영역에 대한 VH 및 VL 아미노산 서열 및 그 안의 CDR 서열은 하기 표 86에 열거되어있다.The VH and VL amino acid sequences and CDR sequences therein for the first antigen binding domain bivalent Fab region targeting CD3 and the second antigen binding domain monovalent Fv region targeting EGFR are listed in Table 86 below.

Fv region
(Anti-EGFR)
Fv region
(Anti-EGFR)
VH: QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSA (서열번호: 233)VH: QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSA (SEQ ID NO: 233) VL:
DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELK (서열번호: 237)
VL:
DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELK (SEQ ID NO: 237)
CDR H1: GFSLTNYG (서열번호: 234)CDR H1: GFSLTNYG (SEQ ID NO: 234) CDR L1: QSIGTN (서열번호: 238)CDR L1: QSIGTN (SEQ ID NO: 238) CDR H2: IWSGGNT (서열번호: 235)CDR H2: IWSGGNT (SEQ ID NO: 235) CDR L2: YAS (서열번호: 239)CDR L2: YAS (SEQ ID NO: 239) CDR H3: ARALTYYDYEFAY (서열번호: 236)CDR H3: ARALTYYDYEFAY (SEQ ID NO: 236) CDR L3: QQNNNWPTT (서열번호: 240)CDR L3: QQNNNWPTT (SEQ ID NO: 240) Fab region
(Anti-CD3)
Fab region
(Anti-CD3)
VH:
EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (서열번호: 215)
VH:
EVQLQQSGPELVKPGPSMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS (SEQ ID NO: 215)
VL:
DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (서열번호: 216)
VL:
DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKR (SEQ ID NO: 216)
CDR H1: GYSFTGYT (서열번호: 177)CDR H1: GYSFTGYT (SEQ ID NO: 177) CDR L1: QDIRNY (서열번호: 181)CDR L1: QDIRNY (SEQ ID NO: 181) CDR H2: INPYKGVS (서열번호: 178)CDR H2: INPYKGVS (SEQ ID NO: 178) CDR L2: YTS (서열번호: 182)CDR L2: YTS (SEQ ID NO: 182) CDR H3: ARSGYYGDSDWYFD (서열번호: 211)CDR H3: ARSGYYGDSDWYFD (SEQ ID NO: 211) CDR L3: QQGNTLPWT (서열번호: 207)CDR L3: QQGNTLPWT (SEQ ID NO: 207)

전술한 내용으로부터, 특정 실시예가 예시의 목적으로 여기에 설명되었지만, 여기에 제공된 것의 정신 및 범위를 벗어나지 않고 다양한 수정이 이루어질 수 있음을 이해할 것이다. 위에서 언급한 모든 참고 문헌은 그 전체가 참고로 여기에 포함된다.From the foregoing, while specific embodiments have been described herein for purposes of illustration, it will be understood that various modifications may be made without departing from the spirit and scope of what is provided herein. All references mentioned above are incorporated herein by reference in their entirety.

<110> Y-BIOLOGICS, INC. <120> MULTI SPECIFIC FUSION PROTEIN AND USE THEREOF <130> SPD20-121-YBL <150> US 62/913,165 <151> 2019-10-10 <160> 510 <170> PatentIn version 3.5 <210> 1 <211> 369 <212> PRT <213> Artificial Sequence <220> <223> ACE-16-VH amino acid sequence <400> 1 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Gly Gly Gly Gly Ser Glu Val Gln Leu Gln Gln Ser Gly Pro 245 250 255 Glu Leu Val Lys Pro Gly Pro Ser Met Lys Ile Ser Cys Lys Ala Ser 260 265 270 Gly Tyr Ser Phe Thr Gly Tyr Thr Met Asn Trp Val Lys Gln Ser His 275 280 285 Gly Lys Asn Leu Glu Trp Met Gly Leu Ile Asn Pro Tyr Lys Gly Val 290 295 300 Ser Thr Tyr Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Val Asp 305 310 315 320 Lys Ser Ser Ser Thr Ala Tyr Met Glu Leu Leu Ser Leu Thr Ser Glu 325 330 335 Asp Ser Ala Val Tyr Tyr Cys Ala Arg Ser Gly Tyr Tyr Gly Asp Ser 340 345 350 Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly Thr Thr Leu Thr Val Phe 355 360 365 Ser <210> 2 <211> 355 <212> PRT <213> Artificial Sequence <220> <223> ACE-16-VL amino acid sequence <400> 2 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Thr Thr Ser 245 250 255 Ser Leu Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Arg Ala 260 265 270 Ser Gln Asp Ile Arg Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp 275 280 285 Gly Thr Val Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu His Ser Gly 290 295 300 Val Pro Ser Lys Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu 305 310 315 320 Thr Ile Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys Gln 325 330 335 Gln Gly Asn Thr Leu Pro Trp Thr Phe Ala Gly Gly Thr Lys Leu Glu 340 345 350 Ile Lys Arg 355 <210> 3 <211> 218 <212> PRT <213> Artificial Sequence <220> <223> ACE-16-LC amino acid sequence <400> 3 Gln Leu Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly 20 25 30 Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Ala Ala Pro Lys Leu 35 40 45 Leu Ile Tyr Gly Asp Ile Asn Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Ile Ser Ala Ser Leu Ala Ile Thr Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser 85 90 95 Leu Ser Gly Gly Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Arg 100 105 110 Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln 115 120 125 Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr 130 135 140 Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser 145 150 155 160 Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr 165 170 175 Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys 180 185 190 His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro 195 200 205 Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 4 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> Fab region (PD-L1) in VH of ACE-04, ACE-16, ACE-09, and ACE-12 <400> 4 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser 115 120 <210> 5 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fab region (PD-L1) in CDR H1 of ACE-04, ACE-16, ACE-09, and ACE-12 <400> 5 Gly Gly Thr Phe Ser Ser Tyr Ala 1 5 <210> 6 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fab region (PD-L1) in CDR H2 of ACE-04, ACE-16, ACE-09, and ACE-12 <400> 6 Ile Ile Pro Ile Leu Gly Ile Ala 1 5 <210> 7 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> Fab region (PD-L1) CDR H3 of ACE-04, ACE-16, ACE-09, and ACE-12 <400> 7 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile 1 5 10 <210> 8 <211> 112 <212> PRT <213> Artificial Sequence <220> <223> Fab region (PD-L1) in VL of ACE-04, ACE-16, ACE-09, and ACE-12 <400> 8 Gln Leu Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly 20 25 30 Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Ala Ala Pro Lys Leu 35 40 45 Leu Ile Tyr Gly Asp Ile Asn Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Ile Ser Ala Ser Leu Ala Ile Thr Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser 85 90 95 Leu Ser Gly Gly Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Arg 100 105 110 <210> 9 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fab region (PD-L1) in CDR L1 of ACE-04, ACE-16, ACE-09, and ACE-12 <400> 9 Ser Ser Asn Ile Gly Ala Gly Tyr Asp 1 5 <210> 10 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Fab region (PD-L1) in CDR L2 of ACE-04, ACE-16, ACE-09, and ACE-12 <400> 10 Gly Asp Ile 1 <210> 11 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Fab region (PD-L1) in CDR L3 of ACE-04, ACE-16, ACE-09, and ACE-12 <400> 11 Gln Ser Tyr Asp Ser Ser Leu Ser Gly Gly Val 1 5 10 <210> 12 <211> 122 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in VH of ACE-16, ACE-09, ACE-10, ACE-11, and ACE-12 <400> 12 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser 115 120 <210> 13 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR H1 of ACE-16, ACE-09, ACE-10, ACE-11, and ACE-12 <400> 13 Gly Tyr Ser Phe Thr Gly Tyr Thr Met Asn 1 5 10 <210> 14 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR H2 of ACE-16, ACE-09, ACE-10, ACE-11, and ACE-12 <400> 14 Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr 1 5 10 <210> 15 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR H3 of ACE-16, ACE-09, ACE-10, ACE-11, and ACE-12 <400> 15 Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val 1 5 10 <210> 16 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in VL of ACE-16, ACE-09, ACE-10, ACE-11, and ACE-12 <400> 16 Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly 1 5 10 15 Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Arg Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile 35 40 45 Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Lys Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln 65 70 75 80 Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Trp 85 90 95 Thr Phe Ala Gly Gly Thr Lys Leu Glu Ile Lys Arg 100 105 <210> 17 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR L1 of ACE-16, ACE-09, ACE-10, ACE-11, and ACE-12 <400> 17 Arg Ala Ser Gln Asp Ile Arg Asn Tyr Leu Asn 1 5 10 <210> 18 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR L2 of ACE-16, ACE-09, ACE-10, ACE-11, and ACE-12 <400> 18 Tyr Thr Ser Arg Leu His Ser 1 5 <210> 19 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR L3 of ACE-16, ACE-09, ACE-10, ACE-11, and ACE-12 <400> 19 Gln Gln Gly Asn Thr Leu Pro Trp Thr 1 5 <210> 20 <211> 1110 <212> DNA <213> Artificial Sequence <220> <223> ACE-16-VH nucleotide sequence <400> 20 cagatgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60 tcctgcaagg cttctggagg caccttcagc agctatgcta tcagctgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggaagg atcatcccta tccttggtat agcaaactac 180 gcacagaagt tccagggcag agtcacgatt accgcggaca aatccacgag cacagcctac 240 atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gaaaccgaga 300 gatggctaca atttggttgc ttttgatatc tggggccaag ggacgatggt caccgtctcc 360 tcagctagca ccaagggccc atcggtcttc cccctggcac cctcctccaa gagcacctct 420 gggggcacag cggccctggg ctgcctggtc aaggactact tccccgaacc ggtgacggtg 480 tcgtggaact caggcgccct gaccagcggc gtgcacacct tcccggctgt cctacagtcc 540 tcaggactct actccctcag cagcgtggtg accgtgccct ccagcagcct gggcacccag 600 acctacatct gcaacgtgaa tcacaagccc agcaacacca aggtggacaa gaaagttgag 660 cccaaatctt gtgacaaaac tcacacatgc ccaccgtgcc cagcacctga actcctgggg 720 ggaccgggcg gaggtgggag tgaggtgcag ctccagcagt ctggacctga gctggtgaag 780 cctggacctt caatgaagat atcctgcaag gcttctggtt actcattcac tggctacacc 840 atgaactggg tgaagcagag tcatggaaag aaccttgagt ggatgggact tattaatcct 900 tacaaaggtg ttagtaccta caaccagaag ttcaaggaca aggccacact gactgtagac 960 aagtcatcca gcacagccta catggaactc ctcagtctga catctgagga ctctgcagtc 1020 tattactgtg caagatcggg gtactacggt gatagtgact ggtacttcga tgtctggggc 1080 caggggacca cgctgaccgt cttctcataa 1110 <210> 21 <211> 1068 <212> DNA <213> Artificial Sequence <220> <223> ACE-16-VL nucleotide sequence <400> 21 cagatgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60 tcctgcaagg cttctggagg caccttcagc agctatgcta tcagctgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggaagg atcatcccta tccttggtat agcaaactac 180 gcacagaagt tccagggcag agtcacgatt accgcggaca aatccacgag cacagcctac 240 atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gaaaccgaga 300 gatggctaca atttggttgc ttttgatatc tggggccaag ggacgatggt caccgtctcc 360 tcagctagca ccaagggccc atcggtcttc cccctggcac cctcctccaa gagcacctct 420 gggggcacag cggccctggg ctgcctggtc aaggactact tccccgaacc ggtgacggtg 480 tcgtggaact caggcgccct gaccagcggc gtgcacacct tcccggctgt cctacagtcc 540 tcaggactct actccctcag cagcgtggtg accgtgccct ccagcagcct gggcacccag 600 acctacatct gcaacgtgaa tcacaagccc agcaacacca aggtggacaa gaaagttgag 660 cccaaatctt gtgacaaaac tcacacatgc ccaccgtgcc cagcacctga actcctgggg 720 ggaccgggcg gaggtgggag tgacatccag atgacccaga ccacctcctc cctgtctgcc 780 tccctgggcg acagagtcac catcagttgc agggcaagtc aggacattag aaattattta 840 aactggtatc aacagaaacc agatggaact gttaaactcc tgatctacta cacatcaaga 900 ttacactcag gagtcccatc aaagttcagt ggcagtgggt ctggaacaga ttattctctc 960 accattagca acctggagca agaggatatt gccacttact tttgccaaca gggtaatacg 1020 cttccgtgga cgttcgctgg aggcaccaag ctggaaatca aacggtaa 1068 <210> 22 <211> 657 <212> DNA <213> Artificial Sequence <220> <223> ACE-16-LC nucleotide sequence <400> 22 cagctcgtgc tgactcagcc gccctcagtg tctggggccc cagggcagag ggtcaccatc 60 tcctgcactg ggagcagctc caacatcggg gcaggttatg atgtacactg gtatcagcaa 120 cttccaggag cagcccccaa actcctcatc tatggcgaca tcaatcggcc ctcaggggtc 180 cctgaccgat tctctggctc caagtctggc atctcagcct ccctggctat cactgggctc 240 caggctgagg acgaggctga ttattactgc cagtcctatg acagcagcct gagtgggggg 300 gtgttcggcg gagggaccaa gctgaccgtc ctaagaaccg tggctgcacc atctgtcttc 360 atcttcccgc catctgatga gcagttgaaa tctggaactg cctctgttgt gtgcctgctg 420 aataacttct atcccagaga ggccaaagta cagtggaagg tggataacgc cctccaatcg 480 ggtaactccc aggagagtgt cacagagcag gacagcaagg acagcaccta cagcctcagc 540 agcaccctga cgctgagcaa agcagactac gagaaacaca aagtctacgc ctgcgaagtc 600 acccatcagg gcctgagctc gcccgtcaca aagagcttca acaggggaga gtgttaa 657 <210> 23 <211> 369 <212> PRT <213> Artificial Sequence <220> <223> ACE-10-VH amino acid sequence <400> 23 Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asn Met His Trp Val Lys Gln Thr Pro Gly Arg Gly Leu Glu Trp Ile 35 40 45 Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val Trp Gly 100 105 110 Ala Gly Thr Thr Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Gly Gly Gly Gly Ser Glu Val Gln Leu Gln Gln Ser Gly Pro 245 250 255 Glu Leu Val Lys Pro Gly Pro Ser Met Lys Ile Ser Cys Lys Ala Ser 260 265 270 Gly Tyr Ser Phe Thr Gly Tyr Thr Met Asn Trp Val Lys Gln Ser His 275 280 285 Gly Lys Asn Leu Glu Trp Met Gly Leu Ile Asn Pro Tyr Lys Gly Val 290 295 300 Ser Thr Tyr Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Val Asp 305 310 315 320 Lys Ser Ser Ser Thr Ala Tyr Met Glu Leu Leu Ser Leu Thr Ser Glu 325 330 335 Asp Ser Ala Val Tyr Tyr Cys Ala Arg Ser Gly Tyr Tyr Gly Asp Ser 340 345 350 Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly Thr Thr Leu Thr Val Phe 355 360 365 Ser <210> 24 <211> 355 <212> PRT <213> Artificial Sequence <220> <223> ACE-10-VL amino acid sequence <400> 24 Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asn Met His Trp Val Lys Gln Thr Pro Gly Arg Gly Leu Glu Trp Ile 35 40 45 Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val Trp Gly 100 105 110 Ala Gly Thr Thr Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Thr Thr Ser 245 250 255 Ser Leu Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Arg Ala 260 265 270 Ser Gln Asp Ile Arg Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp 275 280 285 Gly Thr Val Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu His Ser Gly 290 295 300 Val Pro Ser Lys Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu 305 310 315 320 Thr Ile Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys Gln 325 330 335 Gln Gly Asn Thr Leu Pro Trp Thr Phe Ala Gly Gly Thr Lys Leu Glu 340 345 350 Ile Lys Arg 355 <210> 25 <211> 213 <212> PRT <213> Artificial Sequence <220> <223> ACE-10-LC amino acid sequence <400> 25 Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Ile 20 25 30 His Trp Phe Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr 35 40 45 Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Val Glu Ala Glu 65 70 75 80 Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Thr Ser Asn Pro Pro Thr 85 90 95 Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala Pro 100 105 110 Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 115 120 125 Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135 140 Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu 145 150 155 160 Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175 Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190 Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200 205 Asn Arg Gly Glu Cys 210 <210> 26 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD20) in VH of ACE-10 <400> 26 Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asn Met His Trp Val Lys Gln Thr Pro Gly Arg Gly Leu Glu Trp Ile 35 40 45 Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val Trp Gly 100 105 110 Ala Gly Thr Thr Val Thr Val Ser Ala 115 120 <210> 27 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD20) in CDR H1 of ACE-10 <400> 27 Gly Tyr Thr Phe Thr Ser Tyr Asn 1 5 <210> 28 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD20) in CDR H2 of ACE-10 <400> 28 Ile Tyr Pro Gly Asn Gly Asp Thr 1 5 <210> 29 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD20) in CDR H3 of ACE-10 <400> 29 Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val 1 5 10 <210> 30 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD20) in VL of ACE-10 <400> 30 Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Ile 20 25 30 His Trp Phe Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr 35 40 45 Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Val Glu Ala Glu 65 70 75 80 Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Thr Ser Asn Pro Pro Thr 85 90 95 Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg 100 105 <210> 31 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD20) in CDR L1 of ACE-10 <400> 31 Ser Ser Val Ser Tyr 1 5 <210> 32 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD20) in CDR L2 of ACE-10 <400> 32 Ala Thr Ser 1 <210> 33 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD20) in CDR L3 of ACE-10 <400> 33 Gln Gln Trp Thr Ser Asn Pro Pro Thr 1 5 <210> 34 <211> 1110 <212> DNA <213> Artificial Sequence <220> <223> ACE-10-VH nucleotide sequence <400> 34 caggtgcagc tgcagcagcc tggagccgag ctggtgaagc ccggcgccag cgtgaagatg 60 agctgcaagg ccagcggcta caccttcacc agctacaaca tgcactgggt gaagcagacc 120 cctggaagag gactggagtg gatcggcgcc atctaccccg gcaacggcga caccagctac 180 aaccagaagt tcaagggcaa ggccaccctg accgccgaca agagcagcag caccgcctac 240 atgcagctga gcagcctgac cagcgaggac agcgccgtgt actactgcgc ccgcagcacc 300 tactacggcg gcgactggta cttcaacgtg tggggagctg gaaccaccgt gaccgtgagc 360 gccgctagca ccaagggccc atcggtcttc cccctggcac cctcctccaa gagcacctct 420 gggggcacag cggccctggg ctgcctggtc aaggactact tccccgaacc ggtgacggtg 480 tcgtggaact caggcgccct gaccagcggc gtgcacacct tcccggctgt cctacagtcc 540 tcaggactct actccctcag cagcgtggtg accgtgccct ccagcagcct gggcacccag 600 acctacatct gcaacgtgaa tcacaagccc agcaacacca aggtggacaa gaaggttgag 660 cccaaatctt gtgacaaaac tcacacatgc ccaccgtgcc cagcacctga actcctgggg 720 ggaccgggcg gaggtgggag tgaggtgcag ctccagcagt ctggacctga gctggtgaag 780 cctggacctt caatgaagat atcctgcaag gcttctggtt actcattcac tggctacacc 840 atgaactggg tgaagcagag tcatggaaag aaccttgagt ggatgggact tattaatcct 900 tacaaaggtg ttagtaccta caaccagaag ttcaaggaca aggccacact gactgtagac 960 aagtcatcca gcacagccta catggaactc ctcagtctga catctgagga ctctgcagtc 1020 tattactgtg caagatcggg gtactacggt gatagtgact ggtacttcga tgtctggggc 1080 caggggacca cgctgaccgt cttctcataa 1110 <210> 35 <211> 1068 <212> DNA <213> Artificial Sequence <220> <223> ACE-10-VL nucleotide sequence <400> 35 caggtgcagc tgcagcagcc tggagccgag ctggtgaagc ccggcgccag cgtgaagatg 60 agctgcaagg ccagcggcta caccttcacc agctacaaca tgcactgggt gaagcagacc 120 cctggaagag gactggagtg gatcggcgcc atctaccccg gcaacggcga caccagctac 180 aaccagaagt tcaagggcaa ggccaccctg accgccgaca agagcagcag caccgcctac 240 atgcagctga gcagcctgac cagcgaggac agcgccgtgt actactgcgc ccgcagcacc 300 tactacggcg gcgactggta cttcaacgtg tggggagctg gaaccaccgt gaccgtgagc 360 gccgctagca ccaagggccc atcggtcttc cccctggcac cctcctccaa gagcacctct 420 gggggcacag cggccctggg ctgcctggtc aaggactact tccccgaacc ggtgacggtg 480 tcgtggaact caggcgccct gaccagcggc gtgcacacct tcccggctgt cctacagtcc 540 tcaggactct actccctcag cagcgtggtg accgtgccct ccagcagcct gggcacccag 600 acctacatct gcaacgtgaa tcacaagccc agcaacacca aggtggacaa gaaggttgag 660 cccaaatctt gtgacaaaac tcacacatgc ccaccgtgcc cagcacctga actcctgggg 720 ggaccgggcg gaggtgggag tgacatccag atgacccaga ccacctcctc cctgtctgcc 780 tccctgggcg acagagtcac catcagttgc agggcaagtc aggacattag aaattattta 840 aactggtatc aacagaaacc agatggaact gttaaactcc tgatctacta cacatcaaga 900 ttacactcag gagtcccatc aaagttcagt ggcagtgggt ctggaacaga ttattctctc 960 accattagca acctggagca agaggatatt gccacttact tttgccaaca gggtaatacg 1020 cttccgtgga cgttcgctgg aggcaccaag ctggaaatca aacggtaa 1068 <210> 36 <211> 642 <212> DNA <213> Artificial Sequence <220> <223> ACE-10-LC nucleotide sequence <400> 36 cagatcgtgc tgagccagag ccctgctatc ctgagcgcca gccctggcga gaaggtgacc 60 atgacctgcc gcgccagcag cagcgtgagc tacatccact ggttccagca gaagcccggc 120 agcagcccca agccctggat ctacgccacc agcaacctgg ccagcggagt gcctgtgcgc 180 ttcagcggca gcggcagcgg caccagctac agcctgacca tcagcagagt ggaggctgag 240 gacgccgcta cctactactg ccagcagtgg accagcaacc cccccacctt cggcggcggc 300 accaagctgg agatcaagag aaccgtggct gcaccatctg tcttcatctt cccgccatct 360 gatgagcagt tgaaatctgg aactgcctct gttgtgtgcc tgctgaataa cttctatccc 420 agagaggcca aagtacagtg gaaggtggat aacgccctcc aatcgggtaa ctcccaggag 480 agtgtcacag agcaggacag caaggacagc acctacagcc tcagcagcac cctgacgctg 540 agcaaagcag actacgagaa acacaaagtc tacgcctgcg aagtcaccca tcagggcctg 600 agctcgcccg tcacaaagag cttcaacagg ggagagtgtt ag 642 <210> 37 <211> 367 <212> PRT <213> Artificial Sequence <220> <223> ACE-11-VH amino acid sequence <400> 37 Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30 Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60 Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe 65 70 75 80 Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala 85 90 95 Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230 235 240 Gly Gly Gly Gly Ser Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu 245 250 255 Val Lys Pro Gly Pro Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr 260 265 270 Ser Phe Thr Gly Tyr Thr Met Asn Trp Val Lys Gln Ser His Gly Lys 275 280 285 Asn Leu Glu Trp Met Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr 290 295 300 Tyr Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser 305 310 315 320 Ser Ser Thr Ala Tyr Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser 325 330 335 Ala Val Tyr Tyr Cys Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp 340 345 350 Tyr Phe Asp Val Trp Gly Gln Gly Thr Thr Leu Thr Val Phe Ser 355 360 365 <210> 38 <211> 353 <212> PRT <213> Artificial Sequence <220> <223> ACE-11-VL amino acid sequence <400> 38 Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30 Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60 Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe 65 70 75 80 Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala 85 90 95 Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230 235 240 Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu 245 250 255 Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln 260 265 270 Asp Ile Arg Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr 275 280 285 Val Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro 290 295 300 Ser Lys Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile 305 310 315 320 Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly 325 330 335 Asn Thr Leu Pro Trp Thr Phe Ala Gly Gly Thr Lys Leu Glu Ile Lys 340 345 350 Arg <210> 39 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> ACE-11-LC amino acid sequence <400> 39 Asp Ile Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn 20 25 30 Ile His Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile 35 40 45 Lys Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser 65 70 75 80 Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr 85 90 95 Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 40 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD20) in VH of ACE-11 <400> 40 Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30 Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60 Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe 65 70 75 80 Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala 85 90 95 Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ala 115 <210> 41 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD20) in CDR H1 of ACE-11 <400> 41 Gly Phe Ser Leu Thr Asn Tyr Gly 1 5 <210> 42 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD20) in CDR H2 of ACE-11 <400> 42 Ile Trp Ser Gly Gly Asn Thr 1 5 <210> 43 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD20) in CDR H3 of ACE-11 <400> 43 Ala Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr 1 5 10 <210> 44 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD20) in VL of ACE-11 <400> 44 Asp Ile Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn 20 25 30 Ile His Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile 35 40 45 Lys Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser 65 70 75 80 Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr 85 90 95 Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg 100 105 <210> 45 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD20) in CDR L1 of ACE-11 <400> 45 Gln Ser Ile Gly Thr Asn 1 5 <210> 46 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD20) in CDR L2 of ACE-11 <400> 46 Tyr Ala Ser 1 <210> 47 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD20) in CDR L3 of ACE-11 <400> 47 Gln Gln Asn Asn Asn Trp Pro Thr Thr 1 5 <210> 48 <211> 1104 <212> DNA <213> Artificial Sequence <220> <223> ACE-11-VH nucleotide sequence <400> 48 caagtccaac tgaaacaatc gggtccgggt ctggtccaac cgtcccaatc actgagcatc 60 acctgtaccg tgtcgggctt ctcgctgacc aattatggtg tgcattgggt tcgtcagagt 120 ccgggcaaag gtctggaatg gctgggcgtt atttggtccg gcggtaatac cgattacaac 180 accccgttta cgagtcgcct gtccatcaat aaagacaact cgaaaagcca ggtgtttttc 240 aaaatgaatt cactgcaatc gaacgatacc gcgatttatt actgcgcacg tgctctgacg 300 tattacgact atgaatttgc ctactggggc cagggtaccc tggtgacggt tagcgcggct 360 agcaccaagg gcccatcggt cttccccctg gcaccctcct ccaagagcac ctctgggggc 420 acagcggccc tgggctgcct ggtcaaggac tacttccccg aaccggtgac ggtgtcgtgg 480 aactcaggcg ccctgaccag cggcgtgcac accttcccgg ctgtcctaca gtcctcagga 540 ctctactccc tcagcagcgt ggtgaccgtg ccctccagca gcctgggcac ccagacctac 600 atctgcaacg tgaatcacaa gcccagcaac accaaggtgg acaagaaggt tgagcccaaa 660 tcttgtgaca aaactcacac atgcccaccg tgcccagcac ctgaactcct ggggggaccg 720 ggcggaggtg ggagtgaggt gcagctccag cagtctggac ctgagctggt gaagcctgga 780 ccttcaatga agatatcctg caaggcttct ggttactcat tcactggcta caccatgaac 840 tgggtgaagc agagtcatgg aaagaacctt gagtggatgg gacttattaa tccttacaaa 900 ggtgttagta cctacaacca gaagttcaag gacaaggcca cactgactgt agacaagtca 960 tccagcacag cctacatgga actcctcagt ctgacatctg aggactctgc agtctattac 1020 tgtgcaagat cggggtacta cggtgatagt gactggtact tcgatgtctg gggccagggg 1080 accacgctga ccgtcttctc ataa 1104 <210> 49 <211> 1062 <212> DNA <213> Artificial Sequence <220> <223> ACE-11-VL nucleotide sequence <400> 49 caagtccaac tgaaacaatc gggtccgggt ctggtccaac cgtcccaatc actgagcatc 60 acctgtaccg tgtcgggctt ctcgctgacc aattatggtg tgcattgggt tcgtcagagt 120 ccgggcaaag gtctggaatg gctgggcgtt atttggtccg gcggtaatac cgattacaac 180 accccgttta cgagtcgcct gtccatcaat aaagacaact cgaaaagcca ggtgtttttc 240 aaaatgaatt cactgcaatc gaacgatacc gcgatttatt actgcgcacg tgctctgacg 300 tattacgact atgaatttgc ctactggggc cagggtaccc tggtgacggt tagcgcggct 360 agcaccaagg gcccatcggt cttccccctg gcaccctcct ccaagagcac ctctgggggc 420 acagcggccc tgggctgcct ggtcaaggac tacttccccg aaccggtgac ggtgtcgtgg 480 aactcaggcg ccctgaccag cggcgtgcac accttcccgg ctgtcctaca gtcctcagga 540 ctctactccc tcagcagcgt ggtgaccgtg ccctccagca gcctgggcac ccagacctac 600 atctgcaacg tgaatcacaa gcccagcaac accaaggtgg acaagaaggt tgagcccaaa 660 tcttgtgaca aaactcacac atgcccaccg tgcccagcac ctgaactcct ggggggaccg 720 ggcggaggtg ggagtgacat ccagatgacc cagaccacct cctccctgtc tgcctccctg 780 ggcgacagag tcaccatcag ttgcagggca agtcaggaca ttagaaatta tttaaactgg 840 tatcaacaga aaccagatgg aactgttaaa ctcctgatct actacacatc aagattacac 900 tcaggagtcc catcaaagtt cagtggcagt gggtctggaa cagattattc tctcaccatt 960 agcaacctgg agcaagagga tattgccact tacttttgcc aacagggtaa tacgcttccg 1020 tggacgttcg ctggaggcac caagctggaa atcaaacggt aa 1062 <210> 50 <211> 645 <212> DNA <213> Artificial Sequence <220> <223> ACE-11-LC nucleotide sequence <400> 50 gatattctgc tgacccagag cccggtgatc ctgagtgttt ccccgggcga acgtgtgtca 60 ttttcgtgtc gcgcgagcca gtctattggt accaatatcc actggtatca gcaacgtacg 120 aacggctctc cgcgcctgct gattaaatac gccagtgaat ccatttcagg catcccgagc 180 cgcttttcgg gcagcggttc tggcaccgat ttcacgctga gtattaactc cgtggaatca 240 gaagatatcg cagactatta ctgccagcaa aacaataact ggccgaccac gtttggtgct 300 ggcaccaaac tggaactgaa aagaaccgtg gctgcaccat ctgtcttcat cttcccgcca 360 tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420 cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480 gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540 ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600 ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gttaa 645 <210> 51 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> Fab region (Her2) in VH of ACE-00 <400> 51 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 52 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> Fab region (Her2) in VL of ACE-00 <400> 52 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105 <210> 53 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> Fv region (TNF alpha) in VH of ACE-00 <400> 53 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Thr Trp Asn Ser Gly His Ile Asp Tyr Ala Asp Ser Val 50 55 60 Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Val Ser Tyr Leu Ser Thr Ala Ser Ser Leu Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 54 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> Fv region (TNF alpha) in VL of ACE-00 <400> 54 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Val Ala Thr Tyr Tyr Cys Gln Arg Tyr Asn Arg Ala Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105 <210> 55 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> Core hinge region sequence of IgG1 <400> 55 Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro 1 5 10 15 <210> 56 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Core hinge region sequence of IgG2 <400> 56 Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro 1 5 10 <210> 57 <211> 61 <212> PRT <213> Artificial Sequence <220> <223> Core hinge region sequence of IgG3 <400> 57 Glu Leu Lys Thr Pro Leu Asp Thr Thr His Thr Cys Pro Arg Cys Pro 1 5 10 15 Glu Pro Lys Ser Cys Asp Thr Pro Pro Pro Cys Pro Arg Cys Pro Glu 20 25 30 Pro Lys Ser Cys Asp Thr Pro Pro Pro Cys Pro Arg Cys Pro Glu Pro 35 40 45 Lys Ser Cys Asp Thr Pro Pro Pro Cys Pro Arg Cys Pro 50 55 60 <210> 58 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Core hinge region sequence of IgG4 <400> 58 Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro 1 5 10 <210> 59 <211> 106 <212> PRT <213> Artificial Sequence <220> <223> A representative CL region of the Fab region <400> 59 Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln 1 5 10 15 Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr 20 25 30 Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser 35 40 45 Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr 50 55 60 Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys 65 70 75 80 His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro 85 90 95 Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 100 105 <210> 60 <211> 98 <212> PRT <213> Artificial Sequence <220> <223> A representative CH1 region of the Fab region <400> 60 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95 Lys Val <210> 61 <211> 124 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD19) in VH of ACE-02, and ACE-03 <400> 61 Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ser 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Ser Tyr 20 25 30 Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Gln Ile Trp Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gly Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Glu Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95 Ala Arg Arg Glu Thr Thr Thr Val Gly Arg Tyr Tyr Tyr Ala Met Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 62 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD19) in CDR H1 of ACE-02, and ACE-03 <400> 62 Ser Tyr Trp Met Asn 1 5 <210> 63 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD19) in CDR H2 of ACE-02, and ACE-03 <400> 63 Gln Ile Trp Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gly Lys Phe Lys 1 5 10 15 Gly <210> 64 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD19) in CDR H3 of ACE-02, and ACE-03 <400> 64 Arg Glu Thr Thr Thr Val Gly Arg Tyr Tyr Tyr Ala Met Asp Tyr 1 5 10 15 <210> 65 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD19) in VL of ACE-02, and ACE-03 <400> 65 Asp Ile Gln Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Gln Arg Ala Thr Ile Ser Cys Lys Ala Ser Gln Ser Val Asp Tyr Asp 20 25 30 Gly Asp Ser Tyr Leu Asn Trp Tyr Gln Gln Ile Pro Gly Gln Pro Pro 35 40 45 Lys Leu Leu Ile Tyr Asp Ala Ser Asn Leu Val Ser Gly Ile Pro Pro 50 55 60 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile His 65 70 75 80 Pro Val Glu Lys Val Asp Ala Ala Thr Tyr His Cys Gln Gln Ser Thr 85 90 95 Glu Asp Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 <210> 66 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD19) in CDR L1 of ACE-02, and ACE-03 <400> 66 Gln Ser Val Asp Tyr Asp Gly Asp Ser Tyr 1 5 10 <210> 67 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD19) in CDR L2 of ACE-02, and ACE-03 <400> 67 Asp Ala Ser 1 <210> 68 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD19) in CDR L3 of ACE-02, and ACE-03 <400> 68 Gln Gln Ser Thr Glu Asp Pro Trp Thr 1 5 <210> 69 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in VH of ACE-02 <400> 69 Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Asn Pro Ser Ser Gly Tyr Thr Lys Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Arg Phe Thr Ile Ser Ala Asp Lys Ser Lys Ser Thr Ala Phe 65 70 75 80 Leu Gln Met Asp Ser Leu Arg Pro Glu Asp Thr Gly Val Tyr Phe Cys 85 90 95 Ala Arg Trp Gln Asp Tyr Asp Val Tyr Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Pro Val Thr Val Ser Ser 115 <210> 70 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR H1 of ACE-02 <400> 70 Gly Tyr Thr Phe Thr Ser Tyr Thr 1 5 <210> 71 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR H2 of ACE-02 <400> 71 Ile Asn Pro Ser Ser Gly Tyr Thr 1 5 <210> 72 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR H3 of ACE-02 <400> 72 Ala Arg Trp Gln Asp Tyr Asp Val Tyr Phe Asp Tyr 1 5 10 <210> 73 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in VL of ACE-02 <400> 73 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Met 20 25 30 His Trp Tyr Gln Gln Thr Pro Gly Lys Ala Pro Lys Pro Trp Ile Tyr 35 40 45 Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu 65 70 75 80 Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Pro Thr 85 90 95 Phe Gly Gln Gly Thr Lys Leu Gln Ile Thr Arg 100 105 <210> 74 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR L1 of ACE-02 <400> 74 Ser Ser Ser Val Ser Tyr 1 5 <210> 75 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR L2 of ACE-02 <400> 75 Ala Thr Ser 1 <210> 76 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR L3 of ACE-02 <400> 76 Gln Gln Trp Ser Ser Asn Pro Pro Thr 1 5 <210> 77 <211> 118 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in VH of ACE-03 <400> 77 Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser 1 5 10 15 Leu Arg Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr Thr 20 25 30 Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly 35 40 45 Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Val Lys 50 55 60 Asp Arg Phe Thr Ile Ser Thr Asp Lys Ser Lys Ser Thr Ala Phe Leu 65 70 75 80 Gln Met Asp Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Pro Val Thr Val Ser Ser 115 <210> 78 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR H1 of ACE-03, and ACE-04 <400> 78 Gly Tyr Thr Phe Thr Arg Tyr Thr 1 5 <210> 79 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR H2 of ACE-03, and ACE-04 <400> 79 Ile Asn Pro Ser Arg Gly Tyr Thr 1 5 <210> 80 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR H3 of ACE-03, and ACE-04 <400> 80 Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr 1 5 10 <210> 81 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in VL of ACE-03 <400> 81 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met 20 25 30 Asn Trp Tyr Gln Gln Thr Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr 35 40 45 Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu 65 70 75 80 Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Phe Thr 85 90 95 Phe Gly Gln Gly Thr Lys Leu Gln Ile Thr Arg 100 105 <210> 82 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR L1 of ACE-03, and ACE-04 <400> 82 Ser Ser Val Ser Tyr 1 5 <210> 83 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR L2 of ACE-03, and ACE-04 <400> 83 Asp Thr Ser 1 <210> 84 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR L3 of ACE-03 <400> 84 Gln Gln Trp Ser Ser Asn Pro Phe Thr 1 5 <210> 85 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in VH of ACE-04 <400> 85 Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr 20 25 30 Thr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Thr Val Thr Val Ser Ala 115 <210> 86 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in VL of ACE-04 <400> 86 Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met 20 25 30 Asn Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr 35 40 45 Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala His Phe Arg Gly Ser 50 55 60 Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Gly Met Glu Ala Glu 65 70 75 80 Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Phe Thr 85 90 95 Phe Gly Ser Gly Thr Lys Leu Glu Ile Asn Arg 100 105 <210> 87 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR L3 of ACE-04 <400> 87 Gln Gln Trp Ser Ser Asn Pro Phe 1 5 <210> 88 <211> 364 <212> PRT <213> Artificial Sequence <220> <223> ACE-02-VH amino acid sequence <400> 88 Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ser 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Ser Tyr 20 25 30 Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Gln Ile Trp Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gly Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Glu Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95 Ala Arg Arg Glu Thr Thr Thr Val Gly Arg Tyr Tyr Tyr Ala Met Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys 115 120 125 Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 130 135 140 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 145 150 155 160 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 165 170 175 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 180 185 190 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn 195 200 205 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro 210 215 220 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val 245 250 255 Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Lys Ala Ser Gly Tyr 260 265 270 Thr Phe Thr Ser Tyr Thr Met His Trp Val Arg Gln Ala Pro Gly Lys 275 280 285 Gly Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Ser Gly Tyr Thr Lys 290 295 300 Tyr Asn Gln Lys Phe Lys Asp Arg Phe Thr Ile Ser Ala Asp Lys Ser 305 310 315 320 Lys Ser Thr Ala Phe Leu Gln Met Asp Ser Leu Arg Pro Glu Asp Thr 325 330 335 Gly Val Tyr Phe Cys Ala Arg Trp Gln Asp Tyr Asp Val Tyr Phe Asp 340 345 350 Tyr Trp Gly Gln Gly Thr Pro Val Thr Val Ser Ser 355 360 <210> 89 <211> 352 <212> PRT <213> Artificial Sequence <220> <223> ACE-02-VL amino acid sequence <400> 89 Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ser 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Ser Tyr 20 25 30 Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Gln Ile Trp Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gly Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Glu Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95 Ala Arg Arg Glu Thr Thr Thr Val Gly Arg Tyr Tyr Tyr Ala Met Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys 115 120 125 Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 130 135 140 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 145 150 155 160 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 165 170 175 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 180 185 190 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn 195 200 205 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro 210 215 220 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu 245 250 255 Ser Ala Ser Val Gly Asp Arg Val Thr Met Thr Cys Arg Ala Ser Ser 260 265 270 Ser Val Ser Tyr Met His Trp Tyr Gln Gln Thr Pro Gly Lys Ala Pro 275 280 285 Lys Pro Trp Ile Tyr Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Ser 290 295 300 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser 305 310 315 320 Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Trp Ser 325 330 335 Ser Asn Pro Pro Thr Phe Gly Gln Gly Thr Lys Leu Gln Ile Thr Arg 340 345 350 <210> 90 <211> 218 <212> PRT <213> Artificial Sequence <220> <223> ACE-02-LC, ACE-03-LC (anti-CD19 antibody light chain) <400> 90 Asp Ile Gln Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Gln Arg Ala Thr Ile Ser Cys Lys Ala Ser Gln Ser Val Asp Tyr Asp 20 25 30 Gly Asp Ser Tyr Leu Asn Trp Tyr Gln Gln Ile Pro Gly Gln Pro Pro 35 40 45 Lys Leu Leu Ile Tyr Asp Ala Ser Asn Leu Val Ser Gly Ile Pro Pro 50 55 60 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile His 65 70 75 80 Pro Val Glu Lys Val Asp Ala Ala Thr Tyr His Cys Gln Gln Ser Thr 85 90 95 Glu Asp Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg 100 105 110 Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln 115 120 125 Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr 130 135 140 Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser 145 150 155 160 Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr 165 170 175 Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys 180 185 190 His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro 195 200 205 Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 91 <211> 363 <212> PRT <213> Artificial Sequence <220> <223> ACE-03-VH amino acid sequence <400> 91 Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ser 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Ser Tyr 20 25 30 Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Gln Ile Trp Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gly Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Glu Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95 Ala Arg Arg Glu Thr Thr Thr Val Gly Arg Tyr Tyr Tyr Ala Met Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys 115 120 125 Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 130 135 140 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 145 150 155 160 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 165 170 175 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 180 185 190 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn 195 200 205 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro 210 215 220 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Val Gln Leu Val Gln Ser Gly Gly Gly Val Val 245 250 255 Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Lys Ala Ser Gly Tyr Thr 260 265 270 Phe Thr Arg Tyr Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly 275 280 285 Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr 290 295 300 Asn Gln Lys Val Lys Asp Arg Phe Thr Ile Ser Thr Asp Lys Ser Lys 305 310 315 320 Ser Thr Ala Phe Leu Gln Met Asp Ser Leu Arg Pro Glu Asp Thr Ala 325 330 335 Val Tyr Tyr Cys Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr 340 345 350 Trp Gly Gln Gly Thr Pro Val Thr Val Ser Ser 355 360 <210> 92 <211> 352 <212> PRT <213> Artificial Sequence <220> <223> ACE-03-VL amino acid sequence <400> 92 Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ser 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Ser Tyr 20 25 30 Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Gln Ile Trp Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gly Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Glu Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95 Ala Arg Arg Glu Thr Thr Thr Val Gly Arg Tyr Tyr Tyr Ala Met Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys 115 120 125 Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 130 135 140 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 145 150 155 160 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 165 170 175 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 180 185 190 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn 195 200 205 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro 210 215 220 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu 245 250 255 Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Ser 260 265 270 Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Thr Pro Gly Lys Ala Pro 275 280 285 Lys Arg Trp Ile Tyr Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser 290 295 300 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser 305 310 315 320 Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Trp Ser 325 330 335 Ser Asn Pro Phe Thr Phe Gly Gln Gly Thr Lys Leu Gln Ile Thr Arg 340 345 350 <210> 93 <211> 469 <212> PRT <213> Artificial Sequence <220> <223> ACE-04-VH amino acid seqeunce <400> 93 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Gln Ser Gly Ala 245 250 255 Glu Leu Ala Arg Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser 260 265 270 Gly Tyr Thr Phe Thr Arg Tyr Thr Met His Trp Val Lys Gln Arg Pro 275 280 285 Gly Gln Gly Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Arg Gly Tyr 290 295 300 Thr Asn Tyr Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Thr Asp 305 310 315 320 Lys Ser Ser Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu 325 330 335 Asp Ser Ala Val Tyr Tyr Cys Ala Arg Tyr Tyr Asp Asp His Tyr Cys 340 345 350 Leu Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ala Ala Ser 355 360 365 Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr 370 375 380 Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro 385 390 395 400 Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val 405 410 415 His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser 420 425 430 Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile 435 440 445 Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val 450 455 460 Glu Pro Lys Ser Cys 465 <210> 94 <211> 460 <212> PRT <213> Artificial Sequence <220> <223> ACE-04-VL amino acid sequence <400> 94 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Gly Gly Gly Gly Ser Gln Ile Val Leu Thr Gln Ser Pro Ala 245 250 255 Ile Met Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Ser Ala 260 265 270 Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Ser Gly Thr 275 280 285 Ser Pro Lys Arg Trp Ile Tyr Asp Thr Ser Lys Leu Ala Ser Gly Val 290 295 300 Pro Ala His Phe Arg Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr 305 310 315 320 Ile Ser Gly Met Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln 325 330 335 Trp Ser Ser Asn Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile 340 345 350 Asn Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 355 360 365 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 370 375 380 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 385 390 395 400 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 405 410 415 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 420 425 430 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 435 440 445 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 450 455 460 <210> 95 <211> 218 <212> PRT <213> Artificial Sequence <220> <223> ACE-04-LC, ACE-09-LC, and ACE-12-LC (anti-PD-L1 antibody light chain) <400> 95 Gln Leu Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly 20 25 30 Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Ala Ala Pro Lys Leu 35 40 45 Leu Ile Tyr Gly Asp Ile Asn Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Ile Ser Ala Ser Leu Ala Ile Thr Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser 85 90 95 Leu Ser Gly Gly Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Arg 100 105 110 Ser Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln 115 120 125 Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr 130 135 140 Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser 145 150 155 160 Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr 165 170 175 Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys 180 185 190 His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro 195 200 205 Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 96 <211> 364 <212> PRT <213> Artificial Sequence <220> <223> ACE-09-VH amino acid sequence (without G4S linker) <400> 96 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro 245 250 255 Gly Pro Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr 260 265 270 Gly Tyr Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu 275 280 285 Trp Met Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln 290 295 300 Lys Phe Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr 305 310 315 320 Ala Tyr Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr 325 330 335 Tyr Cys Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp 340 345 350 Val Trp Gly Gln Gly Thr Thr Leu Thr Val Phe Ser 355 360 <210> 97 <211> 350 <212> PRT <213> Artificial Sequence <220> <223> ACE-09-VL amino acid sequence (without G4S linker) <400> 97 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser 245 250 255 Leu Gly Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Arg 260 265 270 Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu 275 280 285 Leu Ile Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Lys Phe 290 295 300 Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu 305 310 315 320 Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu 325 330 335 Pro Trp Thr Phe Ala Gly Gly Thr Lys Leu Glu Ile Lys Arg 340 345 350 <210> 98 <211> 374 <212> PRT <213> Artificial Sequence <220> <223> ACE-12-VH amino acid sequence (with 10 residues) <400> 98 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu 245 250 255 Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro Ser Met Lys Ile 260 265 270 Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr Thr Met Asn Trp 275 280 285 Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met Gly Leu Ile Asn 290 295 300 Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe Lys Asp Lys Ala 305 310 315 320 Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr Met Glu Leu Leu 325 330 335 Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg Ser Gly 340 345 350 Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly Thr 355 360 365 Thr Leu Thr Val Phe Ser 370 <210> 99 <211> 359 <212> PRT <213> Artificial Sequence <220> <223> ACE-12-VL amino acid sequence (with 9 residues) <400> 99 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Gly Gly Ser Gly Gly Gly Gly Ser Gly Asp Ile Gln Met Thr 245 250 255 Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly Asp Arg Val Thr Ile 260 265 270 Ser Cys Arg Ala Ser Gln Asp Ile Arg Asn Tyr Leu Asn Trp Tyr Gln 275 280 285 Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile Tyr Tyr Thr Ser Arg 290 295 300 Leu His Ser Gly Val Pro Ser Lys Phe Ser Gly Ser Gly Ser Gly Thr 305 310 315 320 Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr 325 330 335 Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Trp Thr Phe Ala Gly Gly 340 345 350 Thr Lys Leu Glu Ile Lys Arg 355 <210> 100 <211> 1095 <212> DNA <213> Artificial Sequence <220> <223> ACE-02-VH nucleotide sequence <400> 100 caggttcaat tgcagcaaag cggggctgag ttggtacggc ctgggtccag cgtgaagata 60 tcatgtaagg cttctggata tgccttctcc tcttactgga tgaactgggt caagcaacgg 120 ccaggacaag gcctggagtg gattgggcaa atatggcccg gggacggaga tactaattat 180 aatggcaagt ttaaggggaa agctacactg accgcagacg aaagctcctc tacggcctat 240 atgcagctct catctcttgc gtccgaagat agtgcagtat atttttgtgc gcgccgcgag 300 accaccacgg ttgggaggta ctattacgcg atggattact ggggccaggg gactacagtt 360 acggtttcat cagctagcac caagggccca tcggtcttcc ccctggcacc ctcctccaag 420 agcacctctg ggggcacagc ggccctgggc tgcctggtca aggactactt ccccgaaccg 480 gtgacggtgt cgtggaactc aggcgccctg accagcggcg tgcacacctt cccggctgtc 540 ctacagtcct caggactcta ctccctcagc agcgtggtga ccgtgccctc cagcagcctg 600 ggcacccaga cctacatctg caacgtgaat cacaagccca gcaacaccaa ggtggacaag 660 agagttgagc ccaaatcttg tgacaaaact cacacatgcc caccgtgccc agcacctgaa 720 ctcctggggg gaccgcaggt gcagctggtg cagagcggcg gcggcgtggt gcagcccggc 780 cgcagcctgc gcctgagctg caaggccagc ggctacacct tcaccagcta caccatgcac 840 tgggtgcgcc aggcccccgg caagggcctg gagtggatcg gctacatcaa ccccagcagc 900 ggctacacca agtacaacca gaagttcaag gaccgcttca ccatcagcgc cgacaagagc 960 aagagcaccg ccttcctgca gatggacagc ctgcgccccg aggacaccgg cgtgtacttc 1020 tgcgcccgct ggcaggacta cgacgtgtac ttcgactact ggggccaggg cacccccgtg 1080 accgtgagca gctaa 1095 <210> 101 <211> 1059 <212> DNA <213> Artificial Sequence <220> <223> ACE-02-VL nucleotide sequence <400> 101 caggttcaat tgcagcaaag cggggctgag ttggtacggc ctgggtccag cgtgaagata 60 tcatgtaagg cttctggata tgccttctcc tcttactgga tgaactgggt caagcaacgg 120 ccaggacaag gcctggagtg gattgggcaa atatggcccg gggacggaga tactaattat 180 aatggcaagt ttaaggggaa agctacactg accgcagacg aaagctcctc tacggcctat 240 atgcagctct catctcttgc gtccgaagat agtgcagtat atttttgtgc gcgccgcgag 300 accaccacgg ttgggaggta ctattacgcg atggattact ggggccaggg gactacagtt 360 acggtttcat cagctagcac caagggccca tcggtcttcc ccctggcacc ctcctccaag 420 agcacctctg ggggcacagc ggccctgggc tgcctggtca aggactactt ccccgaaccg 480 gtgacggtgt cgtggaactc aggcgccctg accagcggcg tgcacacctt cccggctgtc 540 ctacagtcct caggactcta ctccctcagc agcgtggtga ccgtgccctc cagcagcctg 600 ggcacccaga cctacatctg caacgtgaat cacaagccca gcaacaccaa ggtggacaag 660 agagttgagc ccaaatcttg tgacaaaact cacacatgcc caccgtgccc agcacctgaa 720 ctcctggggg gaccggacat ccagatgacc cagagcccca gcagcctgag cgccagcgtg 780 ggcgaccgcg tgaccatgac ctgccgcgcc agcagcagcg tgagctacat gcactggtac 840 cagcagaccc ccggcaaggc ccccaagccc tggatctacg ccaccagcaa cctggccagc 900 ggcgtgccca gccgcttcag cggcagcggc agcggcaccg actacaccct gaccatcagc 960 agcctgcagc ccgaggacat cgccacctac tactgccagc agtggagcag caaccccccc 1020 accttcggcc agggcaccaa gctgcagatc acccgctaa 1059 <210> 102 <211> 657 <212> DNA <213> Artificial Sequence <220> <223> ACE-02-LC, and ACE-03-LC (anti-CD19 antibody light chain nucleotide sequence) <400> 102 gatattcaac tcacgcaatc tccagcaagt ctcgcagtta gtttggggca gcgagctaca 60 ataagttgca aggcgagcca atccgtggat tatgatggag acagctatct taactggtat 120 cagcaaattc caggccagcc acccaagttg ctgatctacg acgcgtcaaa cctggtctca 180 gggatccctc caagatttag cggctcaggt tcaggtacgg attttacgct caatatccat 240 cctgtagaga aggttgatgc agctacatac cactgtcaac agagtaccga ggatccttgg 300 accttcggag gcggtacaaa gctggagatc aagagaaccg tggctgcacc atctgtcttc 360 atcttcccgc catctgatga gcagttgaaa tctggaactg cctctgttgt gtgcctgctg 420 aataacttct atcccagaga ggccaaagta cagtggaagg tggataacgc cctccaatcg 480 ggtaactccc aggagagtgt cacagagcag gacagcaagg acagcaccta cagcctcagc 540 agcaccctga cgctgagcaa agcagactac gagaaacaca aagtctacgc ctgcgaagtc 600 acccatcagg gcctgagctc gcccgtcaca aagagcttca acaggggaga gtgttaa 657 <210> 103 <211> 1092 <212> DNA <213> Artificial Sequence <220> <223> ACE-03-VH nucleotide sequence <400> 103 caggttcaat tgcagcaaag cggggctgag ttggtacggc ctgggtccag cgtgaagata 60 tcatgtaagg cttctggata tgccttctcc tcttactgga tgaactgggt caagcaacgg 120 ccaggacaag gcctggagtg gattgggcaa atatggcccg gggacggaga tactaattat 180 aatggcaagt ttaaggggaa agctacactg accgcagacg aaagctcctc tacggcctat 240 atgcagctct catctcttgc gtccgaagat agtgcagtat atttttgtgc gcgccgcgag 300 accaccacgg ttgggaggta ctattacgcg atggattact ggggccaggg gactacagtt 360 acggtttcat cagctagcac caagggccca tcggtcttcc ccctggcacc ctcctccaag 420 agcacctctg ggggcacagc ggccctgggc tgcctggtca aggactactt ccccgaaccg 480 gtgacggtgt cgtggaactc aggcgccctg accagcggcg tgcacacctt cccggctgtc 540 ctacagtcct caggactcta ctccctcagc agcgtggtga ccgtgccctc cagcagcctg 600 ggcacccaga cctacatctg caacgtgaat cacaagccca gcaacaccaa ggtggacaag 660 agagttgagc ccaaatcttg tgacaaaact cacacatgcc caccgtgccc agcacctgaa 720 ctcctggggg gaccggtgca gctggtgcag agcggcggcg gcgtggtgca gcccggccgc 780 agcctgcgcc tgagctgcaa ggccagcggc tacaccttca cccgctacac catgcactgg 840 gtgcgccagg cccccggcaa gggcctggag tggatcggct acatcaaccc cagccgcggc 900 tacaccaact acaaccagaa ggtgaaggac cgcttcacca tcagcaccga caagagcaag 960 agcaccgcct tcctgcagat ggacagcctg cgccccgagg acaccgccgt gtactactgc 1020 gcccgctact acgacgacca ctactgcctg gactactggg gccagggcac ccccgtgacc 1080 gtgagcagct aa 1092 <210> 104 <211> 1059 <212> DNA <213> Artificial Sequence <220> <223> ACE-03-VL nucleotide sequence <400> 104 caggttcaat tgcagcaaag cggggctgag ttggtacggc ctgggtccag cgtgaagata 60 tcatgtaagg cttctggata tgccttctcc tcttactgga tgaactgggt caagcaacgg 120 ccaggacaag gcctggagtg gattgggcaa atatggcccg gggacggaga tactaattat 180 aatggcaagt ttaaggggaa agctacactg accgcagacg aaagctcctc tacggcctat 240 atgcagctct catctcttgc gtccgaagat agtgcagtat atttttgtgc gcgccgcgag 300 accaccacgg ttgggaggta ctattacgcg atggattact ggggccaggg gactacagtt 360 acggtttcat cagctagcac caagggccca tcggtcttcc ccctggcacc ctcctccaag 420 agcacctctg ggggcacagc ggccctgggc tgcctggtca aggactactt ccccgaaccg 480 gtgacggtgt cgtggaactc aggcgccctg accagcggcg tgcacacctt cccggctgtc 540 ctacagtcct caggactcta ctccctcagc agcgtggtga ccgtgccctc cagcagcctg 600 ggcacccaga cctacatctg caacgtgaat cacaagccca gcaacaccaa ggtggacaag 660 agagttgagc ccaaatcttg tgacaaaact cacacatgcc caccgtgccc agcacctgaa 720 ctcctggggg gaccggacat ccagatgacc cagagcccca gcagcctgag cgccagcgtg 780 ggcgaccgcg tgaccatcac ctgcagcgcc agcagcagcg tgagctacat gaactggtac 840 cagcagaccc ccggcaaggc ccccaagcgc tggatctacg acaccagcaa gctggccagc 900 ggcgtgccca gccgcttcag cggcagcggc agcggcaccg actacacctt caccatcagc 960 agcctgcagc ccgaggacat cgccacctac tactgccagc agtggagcag caaccccttc 1020 accttcggcc agggcaccaa gctgcagatc acccgctaa 1059 <210> 105 <211> 1410 <212> DNA <213> Artificial Sequence <220> <223> ACE-04-VH nucleotide seqeunce <400> 105 cagatgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60 tcctgcaagg cttctggagg caccttcagc agctatgcta tcagctgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggaagg atcatcccta tccttggtat agcaaactac 180 gcacagaagt tccagggcag agtcacgatt accgcggaca aatccacgag cacagcctac 240 atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gaaaccgaga 300 gatggctaca atttggttgc ttttgatatc tggggccaag ggacgatggt caccgtctcc 360 tcagctagca ccaagggccc atcggtcttc cccctggcac cctcctccaa gagcacctct 420 gggggcacag cggccctggg ctgcctggtc aaggactact tccccgaacc ggtgacggtg 480 tcgtggaact caggcgccct gaccagcggc gtgcacacct tcccggctgt cctacagtcc 540 tcaggactct actccctcag cagcgtggtg accgtgccct ccagcagcct gggcacccag 600 acctacatct gcaacgtgaa tcacaagccc agcaacacca aggtggacaa gaaagttgag 660 cccaaatctt gtgacaaaac tcacacatgc ccaccgtgcc cagcacctga actcctgggg 720 ggaccgggcg gaggtgggag tcaggtccag ttgcaacagt ctggagccga gctcgccagg 780 ccaggagcct ccgtcaaaat gtcatgcaag gcctcagggt acacatttac gcgatatacc 840 atgcactggg tgaaacaaag accaggtcag ggacttgaat ggatcggtta cattaacccc 900 tctagaggct atacgaatta caaccagaaa ttcaaagaca aagcaacact tacgactgac 960 aaatccagta gtacggctta catgcagctc tcatctttga cttcagaaga ctctgctgta 1020 tattattgtg cccgctatta cgatgaccat tactgccttg attactgggg ccagggcact 1080 actgttaccg taagtgcggc tagcaccaag ggcccatcgg tcttccccct ggcaccctcc 1140 tccaagagca cctctggggg cacagcggcc ctgggctgcc tggtcaagga ctacttcccc 1200 gaaccggtga cggtgtcgtg gaactcaggc gccctgacca gcggcgtgca caccttcccg 1260 gctgtcctac agtcctcagg actctactcc ctcagcagcg tggtgaccgt gccctccagc 1320 agcctgggca cccagaccta catctgcaac gtgaatcaca agcccagcaa caccaaggtg 1380 gacaagagag ttgagcccaa atcttgttga 1410 <210> 106 <211> 1383 <212> DNA <213> Artificial Sequence <220> <223> ACE-04-VL nucleotide sequence <400> 106 cagatgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60 tcctgcaagg cttctggagg caccttcagc agctatgcta tcagctgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggaagg atcatcccta tccttggtat agcaaactac 180 gcacagaagt tccagggcag agtcacgatt accgcggaca aatccacgag cacagcctac 240 atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gaaaccgaga 300 gatggctaca atttggttgc ttttgatatc tggggccaag ggacgatggt caccgtctcc 360 tcagctagca ccaagggccc atcggtcttc cccctggcac cctcctccaa gagcacctct 420 gggggcacag cggccctggg ctgcctggtc aaggactact tccccgaacc ggtgacggtg 480 tcgtggaact caggcgccct gaccagcggc gtgcacacct tcccggctgt cctacagtcc 540 tcaggactct actccctcag cagcgtggtg accgtgccct ccagcagcct gggcacccag 600 acctacatct gcaacgtgaa tcacaagccc agcaacacca aggtggacaa gaaagttgag 660 cccaaatctt gtgacaaaac tcacacatgc ccaccgtgcc cagcacctga actcctgggg 720 ggaccgggcg gaggtgggag tcagatcgtc ctcactcaaa gtcctgctat tatgtccgca 780 agccctggtg aaaaggttac catgacttgc tccgcatcta gttctgtctc ttacatgaac 840 tggtaccagc aaaagtctgg aacgtccccg aaaaggtgga tatatgatac gagcaaattg 900 gcaagcggag tacccgcgca ttttaggggt tcaggcagcg gtacgtcata tagcctgact 960 attagcggaa tggaggcgga ggatgctgca acatattatt gccaacaatg gtcatcaaat 1020 ccttttactt tcggctcagg cacaaaactt gaaataaata gaaccgtggc tgcaccatct 1080 gtcttcatct tcccgccatc tgatgagcag ttgaaatctg gaactgcctc tgttgtgtgc 1140 ctgctgaata acttctatcc cagagaggcc aaagtacagt ggaaggtgga taacgccctc 1200 caatcgggta actcccagga gagtgtcaca gagcaggaca gcaaggacag cacctacagc 1260 ctcagcagca ccctgacgct gagcaaagca gactacgaga aacacaaagt ctacgcctgc 1320 gaagtcaccc atcagggcct gagctcgccc gtcacaaaga gcttcaacag gggagagtgt 1380 taa 1383 <210> 107 <211> 657 <212> DNA <213> Artificial Sequence <220> <223> ACE-04-LC, ACE-09-LC, ACE-12-LC (anti-PD-L1 antibody light chain nucleotide sequence) <400> 107 cagctcgtgc tgactcagcc gccctcagtg tctggggccc cagggcagag ggtcaccatc 60 tcctgcactg ggagcagctc caacatcggg gcaggttatg atgtacactg gtatcagcaa 120 cttccaggag cagcccccaa actcctcatc tatggcgaca tcaatcggcc ctcaggggtc 180 cctgaccgat tctctggctc caagtctggc atctcagcct ccctggctat cactgggctc 240 caggctgagg acgaggctga ttattactgc cagtcctatg acagcagcct gagtgggggg 300 gtgttcggcg gagggaccaa gctgaccgtc ctaagatctg tggctgcacc atctgtcttc 360 atcttcccgc catctgatga gcagttgaaa tctggaactg cctctgttgt gtgcctgctg 420 aataacttct atcccagaga ggccaaagta cagtggaagg tggataacgc cctccaatcg 480 ggtaactccc aggagagtgt cacagagcag gacagcaagg acagcaccta cagcctcagc 540 agcaccctga cgctgagcaa agcagactac gagaaacaca aagtctacgc ctgcgaagtc 600 acccatcagg gcctgagctc gcccgtcaca aagagcttca acaggggaga gtgttag 657 <210> 108 <211> 1095 <212> DNA <213> Artificial Sequence <220> <223> ACE-09-VH nucleotide sequence (without G4S linker) <400> 108 cagatgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60 tcctgcaagg cttctggagg caccttcagc agctatgcta tcagctgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggaagg atcatcccta tccttggtat agcaaactac 180 gcacagaagt tccagggcag agtcacgatt accgcggaca aatccacgag cacagcctac 240 atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gaaaccgaga 300 gatggctaca atttggttgc ttttgatatc tggggccaag ggacgatggt caccgtctcc 360 tcagctagca ccaagggccc atcggtcttc cccctggcac cctcctccaa gagcacctct 420 gggggcacag cggccctggg ctgcctggtc aaggactact tccccgaacc ggtgacggtg 480 tcgtggaact caggcgccct gaccagcggc gtgcacacct tcccggctgt cctacagtcc 540 tcaggactct actccctcag cagcgtggtg accgtgccct ccagcagcct gggcacccag 600 acctacatct gcaacgtgaa tcacaagccc agcaacacca aggtggacaa gaaagttgag 660 cccaaatctt gtgacaaaac tcacacatgc ccaccgtgcc cagcacctga actcctgggg 720 ggaccggagg tgcagctcca gcagtctgga cctgagctgg tgaagcctgg accttcaatg 780 aagatatcct gcaaggcttc tggttactca ttcactggct acaccatgaa ctgggtgaag 840 cagagtcatg gaaagaacct tgagtggatg ggacttatta atccttacaa aggtgttagt 900 acctacaacc agaagttcaa ggacaaggcc acactgactg tagacaagtc atccagcaca 960 gcctacatgg aactcctcag tctgacatct gaggactctg cagtctatta ctgtgcaaga 1020 tcggggtact acggtgatag tgactggtac ttcgatgtct ggggccaggg gaccacgctg 1080 accgtcttct cataa 1095 <210> 109 <211> 1053 <212> DNA <213> Artificial Sequence <220> <223> ACE-09-VL nucleotide sequence (without G4S linker) <400> 109 cagatgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60 tcctgcaagg cttctggagg caccttcagc agctatgcta tcagctgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggaagg atcatcccta tccttggtat agcaaactac 180 gcacagaagt tccagggcag agtcacgatt accgcggaca aatccacgag cacagcctac 240 atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gaaaccgaga 300 gatggctaca atttggttgc ttttgatatc tggggccaag ggacgatggt caccgtctcc 360 tcagctagca ccaagggccc atcggtcttc cccctggcac cctcctccaa gagcacctct 420 gggggcacag cggccctggg ctgcctggtc aaggactact tccccgaacc ggtgacggtg 480 tcgtggaact caggcgccct gaccagcggc gtgcacacct tcccggctgt cctacagtcc 540 tcaggactct actccctcag cagcgtggtg accgtgccct ccagcagcct gggcacccag 600 acctacatct gcaacgtgaa tcacaagccc agcaacacca aggtggacaa gaaagttgag 660 cccaaatctt gtgacaaaac tcacacatgc ccaccgtgcc cagcacctga actcctgggg 720 ggaccggaca tccagatgac ccagaccacc tcctccctgt ctgcctccct gggcgacaga 780 gtcaccatca gttgcagggc aagtcaggac attagaaatt atttaaactg gtatcaacag 840 aaaccagatg gaactgttaa actcctgatc tactacacat caagattaca ctcaggagtc 900 ccatcaaagt tcagtggcag tgggtctgga acagattatt ctctcaccat tagcaacctg 960 gagcaagagg atattgccac ttacttttgc caacagggta atacgcttcc gtggacgttc 1020 gctggaggca ccaagctgga aatcaaacgg taa 1053 <210> 110 <211> 1125 <212> DNA <213> Artificial Sequence <220> <223> ACE-12-VH nucleotide sequence (with 10 residues) <400> 110 cagatgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60 tcctgcaagg cttctggagg caccttcagc agctatgcta tcagctgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggaagg atcatcccta tccttggtat agcaaactac 180 gcacagaagt tccagggcag agtcacgatt accgcggaca aatccacgag cacagcctac 240 atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gaaaccgaga 300 gatggctaca atttggttgc ttttgatatc tggggccaag ggacgatggt caccgtctcc 360 tcagctagca ccaagggccc atcggtcttc cccctggcac cctcctccaa gagcacctct 420 gggggcacag cggccctggg ctgcctggtc aaggactact tccccgaacc ggtgacggtg 480 tcgtggaact caggcgccct gaccagcggc gtgcacacct tcccggctgt cctacagtcc 540 tcaggactct actccctcag cagcgtggtg accgtgccct ccagcagcct gggcacccag 600 acctacatct gcaacgtgaa tcacaagccc agcaacacca aggtggacaa gaaagttgag 660 cccaaatctt gtgacaaaac tcacacatgc ccaccgtgcc cagcacctga actcctgggg 720 ggaccgggcg gaggtgggag tggaggcgga ggatctgagg tgcagctcca gcagtctgga 780 cctgagctgg tgaagcctgg accttcaatg aagatatcct gcaaggcttc tggttactca 840 ttcactggct acaccatgaa ctgggtgaag cagagtcatg gaaagaacct tgagtggatg 900 ggacttatta atccttacaa aggtgttagt acctacaacc agaagttcaa ggacaaggcc 960 acactgactg tagacaagtc atccagcaca gcctacatgg aactcctcag tctgacatct 1020 gaggactctg cagtctatta ctgtgcaaga tcggggtact acggtgatag tgactggtac 1080 ttcgatgtct ggggccaggg gaccacgctg accgtcttct cataa 1125 <210> 111 <211> 1080 <212> DNA <213> Artificial Sequence <220> <223> ACE-12-VL nucleotide sequence (with 9 residues) <400> 111 cagatgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60 tcctgcaagg cttctggagg caccttcagc agctatgcta tcagctgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggaagg atcatcccta tccttggtat agcaaactac 180 gcacagaagt tccagggcag agtcacgatt accgcggaca aatccacgag cacagcctac 240 atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gaaaccgaga 300 gatggctaca atttggttgc ttttgatatc tggggccaag ggacgatggt caccgtctcc 360 tcagctagca ccaagggccc atcggtcttc cccctggcac cctcctccaa gagcacctct 420 gggggcacag cggccctggg ctgcctggtc aaggactact tccccgaacc ggtgacggtg 480 tcgtggaact caggcgccct gaccagcggc gtgcacacct tcccggctgt cctacagtcc 540 tcaggactct actccctcag cagcgtggtg accgtgccct ccagcagcct gggcacccag 600 acctacatct gcaacgtgaa tcacaagccc agcaacacca aggtggacaa gaaagttgag 660 cccaaatctt gtgacaaaac tcacacatgc ccaccgtgcc cagcacctga actcctgggg 720 ggaccgggcg gatccggcgg aggcggcagc ggagacatcc agatgaccca gaccacctcc 780 tccctgtctg cctccctggg cgacagagtc accatcagtt gcagggcaag tcaggacatt 840 agaaattatt taaactggta tcaacagaaa ccagatggaa ctgttaaact cctgatctac 900 tacacatcaa gattacactc aggagtccca tcaaagttca gtggcagtgg gtctggaaca 960 gattattctc tcaccattag caacctggag caagaggata ttgccactta cttttgccaa 1020 cagggtaata cgcttccgtg gacgttcgct ggaggcacca agctggaaat caaacggtaa 1080 1080 <210> 112 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Linker in ACE-16-VH and ACE-16-VL <400> 112 Gly Gly Gly Gly Ser 1 5 <210> 113 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Linker in ACE-12-VH <400> 113 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 1 5 10 <210> 114 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Linker in ACE-12-VL <400> 114 Gly Gly Ser Gly Gly Gly Gly Ser Gly 1 5 <210> 115 <211> 362 <212> PRT <213> Artificial Sequence <220> <223> ACE-00-VH amino acid sequence <400> 115 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp 210 215 220 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 225 230 235 240 Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly 245 250 255 Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp 260 265 270 Tyr Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp 275 280 285 Val Ser Ala Ile Thr Trp Asn Ser Gly His Ile Asp Tyr Ala Asp Ser 290 295 300 Val Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu 305 310 315 320 Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr 325 330 335 Cys Ala Lys Val Ser Tyr Leu Ser Thr Ala Ser Ser Leu Asp Tyr Trp 340 345 350 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 355 360 <210> 116 <211> 349 <212> PRT <213> Artificial Sequence <220> <223> ACE-00-VL amino acid sequence <400> 116 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp 210 215 220 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 225 230 235 240 Pro Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val 245 250 255 Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn 260 265 270 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu 275 280 285 Ile Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser 290 295 300 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln 305 310 315 320 Pro Glu Asp Val Ala Thr Tyr Tyr Cys Gln Arg Tyr Asn Arg Ala Pro 325 330 335 Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 340 345 <210> 117 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> ACE-00-LC amino acid sequence (anti-CD19 antibody light chain) <400> 117 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Ser Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 118 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fab region (Anti-Her2) in CDR H1 of ACE-00 <400> 118 Gly Phe Asn Ile Lys Asp Thr Tyr 1 5 <210> 119 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fab region (Anti-Her2) in CDR H2 of ACE-00 <400> 119 Ile Tyr Pro Thr Asn Gly Tyr Thr 1 5 <210> 120 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Fab region (Anti-Her2) in CDR H3 of ACE-00 <400> 120 Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr 1 5 10 <210> 121 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Fab region (Anti-Her2) in CDR L1 of ACE-00 <400> 121 Gln Asp Val Asn Thr Ala 1 5 <210> 122 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Fab region (Anti-Her2) in CDR L2 of ACE-00 <400> 122 Ser Ala Ser 1 <210> 123 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fab region (Anti-Her2) in CDR L3 of ACE-00 <400> 123 Gln Gln His Tyr Thr Thr Pro Pro Thr 1 5 <210> 124 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fv region (Anti-TNF alpha) in CDR H1 of ACE-00 <400> 124 Gly Phe Thr Phe Asp Asp Tyr Ala 1 5 <210> 125 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fv region (Anti-TNF alpha) in CDR H2 of ACE-00 <400> 125 Ile Thr Trp Asn Ser Gly His Ile 1 5 <210> 126 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> Fv region (Anti-TNF alpha) in CDR H3 of ACE-00 <400> 126 Ala Lys Val Ser Tyr Leu Ser Thr Ala Ser Ser Leu Asp Tyr 1 5 10 <210> 127 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Fv region (Anti-TNF alpha) in CDR L1 of ACE-00 <400> 127 Gln Gly Ile Arg Asn Tyr 1 5 <210> 128 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Fv region (Anti-TNF alpha) in CDR L2 of ACE-00 <400> 128 Ala Ala Ser 1 <210> 129 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fv region (Anti-TNF alpha) in CDR L3 of ACE-00 <400> 129 Gln Arg Tyr Asn Arg Ala Pro Tyr Thr 1 5 <210> 130 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> linker <400> 130 Gly Gly Gly Gly Ser 1 5 <210> 131 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> linker <400> 131 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 1 5 10 <210> 132 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> linker <400> 132 Gly Gly Ser Gly Gly Gly Gly Ser Gly 1 5 <210> 133 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> linker <220> <221> REPEAT <222> (1)..(5) <223> The sequence can be repeated one, two, three, four or more times <400> 133 Gly Gly Gly Gly Ser 1 5 <210> 134 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> linker <400> 134 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 1 5 10 15 <210> 135 <211> 20 <212> PRT <213> Artificial Sequence <220> <223> linker <400> 135 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 1 5 10 15 Gly Gly Gly Ser 20 <210> 136 <211> 364 <212> PRT <213> Artificial Sequence <220> <223> ACE-01-VH amino acid sequence <400> 136 Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ser 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Ser Tyr 20 25 30 Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Gln Ile Trp Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gly Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Glu Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95 Ala Arg Arg Glu Thr Thr Thr Val Gly Arg Tyr Tyr Tyr Ala Met Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys 115 120 125 Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 130 135 140 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 145 150 155 160 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 165 170 175 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 180 185 190 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn 195 200 205 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro 210 215 220 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu 245 250 255 Ala Arg Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr 260 265 270 Thr Phe Thr Arg Tyr Thr Met His Trp Val Lys Gln Arg Pro Gly Gln 275 280 285 Gly Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn 290 295 300 Tyr Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser 305 310 315 320 Ser Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser 325 330 335 Ala Val Tyr Tyr Cys Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp 340 345 350 Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 355 360 <210> 137 <211> 352 <212> PRT <213> Artificial Sequence <220> <223> ACE-01-VL amino acid sequence <400> 137 Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ser 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Ser Tyr 20 25 30 Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Gln Ile Trp Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gly Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Glu Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95 Ala Arg Arg Glu Thr Thr Thr Val Gly Arg Tyr Tyr Tyr Ala Met Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys 115 120 125 Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 130 135 140 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 145 150 155 160 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 165 170 175 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 180 185 190 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn 195 200 205 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro 210 215 220 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met 245 250 255 Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser 260 265 270 Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro 275 280 285 Lys Arg Trp Ile Tyr Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala 290 295 300 His Phe Arg Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser 305 310 315 320 Gly Met Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser 325 330 335 Ser Asn Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Asn Arg 340 345 350 <210> 138 <211> 218 <212> PRT <213> Artificial Sequence <220> <223> ACE-01-LC amino acid sequence <400> 138 Asp Ile Gln Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Gln Arg Ala Thr Ile Ser Cys Lys Ala Ser Gln Ser Val Asp Tyr Asp 20 25 30 Gly Asp Ser Tyr Leu Asn Trp Tyr Gln Gln Ile Pro Gly Gln Pro Pro 35 40 45 Lys Leu Leu Ile Tyr Asp Ala Ser Asn Leu Val Ser Gly Ile Pro Pro 50 55 60 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile His 65 70 75 80 Pro Val Glu Lys Val Asp Ala Ala Thr Tyr His Cys Gln Gln Ser Thr 85 90 95 Glu Asp Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg 100 105 110 Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln 115 120 125 Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr 130 135 140 Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser 145 150 155 160 Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr 165 170 175 Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys 180 185 190 His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro 195 200 205 Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 139 <211> 124 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD19) in VH of ACE-01; Fv region (CD19) in VH of ACE-01r-03r <400> 139 Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ser 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Ser Tyr 20 25 30 Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Gln Ile Trp Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gly Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Glu Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95 Ala Arg Arg Glu Thr Thr Thr Val Gly Arg Tyr Tyr Tyr Ala Met Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 140 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD19) in CDR H1 of ACE-01; Fv region (CD19) in CDR H1 of ACE-01r-03r <400> 140 Ser Tyr Trp Met Asn 1 5 <210> 141 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD19) in CDR H2 of ACE-01; Fv region (CD19) in CDR H2 of ACE-01r, 02r <400> 141 Ile Trp Pro Gly Asp Gly Asp Thr 1 5 <210> 142 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD19) in CDR H3 of ACE-01; Fv region (CD19) in CDR H3 of ACE-01r, 02r <400> 142 Ala Arg Arg Glu Thr Thr Thr Val Gly Arg Tyr Tyr Tyr Ala Met Asp 1 5 10 15 Tyr <210> 143 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in VH of ACE-01; Fab region (CD3) in VH of ACE-01r <400> 143 Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr 20 25 30 Thr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Thr Val Thr Val Ser Ser 115 <210> 144 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR H1 of ACE-01; Fab region (CD3) in CDR H1 of ACE-01r, 03r, 04r, <400> 144 Gly Tyr Thr Phe Thr Arg Tyr Thr 1 5 <210> 145 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR H2 of ACE-01; Fab region (CD3) in CDR H2 of ACE-01r, 03r, 04r <400> 145 Ile Asn Pro Ser Arg Gly Tyr Thr 1 5 <210> 146 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR H3 of ACE-01; Fab region (CD3) in CDR H3 of ACE-01r, 03r, 04r <400> 146 Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr 1 5 10 <210> 147 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in VL of ACE-01; Fab region (CD3) in VL of ACE-01r <400> 147 Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met 20 25 30 Asn Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr 35 40 45 Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala His Phe Arg Gly Ser 50 55 60 Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Gly Met Glu Ala Glu 65 70 75 80 Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Phe Thr 85 90 95 Phe Gly Ser Gly Thr Lys Leu Glu Ile Asn Arg 100 105 <210> 148 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR L1 of ACE-01; Fab region (CD3) in CDR L1 of ACE-01r, 03r, 04r <400> 148 Ser Ser Val Ser Tyr 1 5 <210> 149 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR L2 of ACE-01; Fab region (CD3) in CDR L2 of ACE-01r, 03r, 04r <400> 149 Asp Thr Ser 1 <210> 150 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR L3 of ACE-01; Fab region (CD3) in CDR L3 of ACE-01r <400> 150 Gln Gln Trp Ser Ser Asn Pro Phe Thr Phe 1 5 10 <210> 151 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD19) in VL of ACE-01; Fv region (CD19) in VL of ACE-01r-03r <400> 151 Asp Ile Gln Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Gln Arg Ala Thr Ile Ser Cys Lys Ala Ser Gln Ser Val Asp Tyr Asp 20 25 30 Gly Asp Ser Tyr Leu Asn Trp Tyr Gln Gln Ile Pro Gly Gln Pro Pro 35 40 45 Lys Leu Leu Ile Tyr Asp Ala Ser Asn Leu Val Ser Gly Ile Pro Pro 50 55 60 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile His 65 70 75 80 Pro Val Glu Lys Val Asp Ala Ala Thr Tyr His Cys Gln Gln Ser Thr 85 90 95 Glu Asp Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 <210> 152 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD19) in CDR L1 of ACE-01; Fv region (CD19) in CDR L1 of ACE-01r-03r <400> 152 Gln Ser Val Asp Tyr Asp Gly Asp Ser Tyr 1 5 10 <210> 153 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD19) in CDR L2 of ACE-01; Fv region (CD19) in CDR L2 of ACE-01r-03r <400> 153 Asp Ala Ser 1 <210> 154 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD19) in CDR L3 of ACE-01; Fv region (CD19) in CDR L3 of ACE-01r-03r <400> 154 Gln Gln Ser Thr Glu Asp Pro Trp Thr 1 5 <210> 155 <211> 365 <212> PRT <213> Artificial Sequence <220> <223> ACE-06-VH amino acid sequence <400> 155 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Gly Gly Gly Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly 245 250 255 Gly Val Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser 260 265 270 Gly Phe Lys Phe Ser Gly Tyr Gly Met His Trp Val Arg Gln Ala Pro 275 280 285 Gly Lys Gly Leu Glu Trp Val Ala Val Ile Trp Tyr Asp Gly Ser Lys 290 295 300 Lys Tyr Tyr Val Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp 305 310 315 320 Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu 325 330 335 Asp Thr Ala Val Tyr Tyr Cys Ala Arg Gln Met Gly Tyr Trp His Phe 340 345 350 Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser 355 360 365 <210> 156 <211> 356 <212> PRT <213> Artificial Sequence <220> <223> ACE-06-VL amino acid sequence <400> 156 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Ala 245 250 255 Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala 260 265 270 Ser Gln Ser Val Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly 275 280 285 Gln Ala Pro Arg Leu Leu Ile Tyr Asp Ala Ser Asn Arg Ala Thr Gly 290 295 300 Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 305 310 315 320 Thr Ile Ser Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln 325 330 335 Gln Arg Ser Asn Trp Pro Pro Leu Thr Phe Gly Gly Gly Thr Lys Val 340 345 350 Glu Ile Lys Arg 355 <210> 157 <211> 218 <212> PRT <213> Artificial Sequence <220> <223> ACE-06-LC, ACE-07-LC, ACE-08-LC, ACE-13-LC, ACE-14-LC, ACE-15-LC, ACE-05-LC, ACE-17-LC, ACE-23-LC, ACE-34-LC, ACE-35-LC, ACE-36-LC amino acid sequence <400> 157 Gln Leu Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly 20 25 30 Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Ala Ala Pro Lys Leu 35 40 45 Leu Ile Tyr Gly Asp Ile Asn Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Ile Ser Ala Ser Leu Ala Ile Thr Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser 85 90 95 Leu Ser Gly Gly Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Arg 100 105 110 Ser Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln 115 120 125 Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr 130 135 140 Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser 145 150 155 160 Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr 165 170 175 Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys 180 185 190 His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro 195 200 205 Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 158 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> Fab region (PD-L1) in VH of ACE-06-08, 13-17, 23, 27, 34-36; Fv region (PD-L1) in VH of ACE-06r-08r, 13r-17r, 23r, 27r, 34r-36r <400> 158 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser 115 120 <210> 159 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fab region (PD-L1) in CDR H1 of ACE-06-08, 13-17, 23, 27, 34-36; Fv region (PD-L1) in CDR H1 of ACE-06r <400> 159 Gly Gly Thr Phe Ser Ser Tyr Ala 1 5 <210> 160 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fab region (PD-L1) in CDR H2 of ACE-06-08, 13-17, 23, 27, 34-36; Fv region (PD-L1) in CDR H2 of ACE-06r <400> 160 Ile Ile Pro Ile Leu Gly Ile Ala 1 5 <210> 161 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> Fab region (PD-L1) in CDR H3 of ACE-06-08, 13-17, 23, 27, 34-36; Fv region (PD-L1) in CDR H3 of ACE-06r <400> 161 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile 1 5 10 <210> 162 <211> 118 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in VH of ACE-06, 23; Fab region (CD3) in VH of ACE-06r, 23r <400> 162 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Lys Phe Ser Gly Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp Tyr Asp Gly Ser Lys Lys Tyr Tyr Val Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gln Met Gly Tyr Trp His Phe Asp Leu Trp Gly Arg Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 163 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR H1 of ACE-06, 23; Fab region (CD3) in CDR H1 of ACE-06r, 23r <400> 163 Gly Phe Lys Phe Ser Gly Tyr Gly 1 5 <210> 164 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic sequence <400> 164 Trp Tyr Asp Gly Ser Lys Lys 1 5 <210> 165 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR H3 of ACE-06, 23; Fab region (CD3) in CDR H3 of ACE-06r, 23r <400> 165 Ala Arg Gln Met Gly Tyr Trp His Phe Asp Leu 1 5 10 <210> 166 <211> 109 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in VL of ACE-06, 23; Fab region (CD3) in VL of ACE-06r, 23r <400> 166 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Pro 85 90 95 Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 100 105 <210> 167 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR L1 of ACE-06, 23; Fab region (CD3) in CDR L1 of ACE-06r, 23r <400> 167 Gln Ser Val Ser Ser Tyr 1 5 <210> 168 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR L2 of ACE-06, 23; Fab region (CD3) in CDR L2 of ACE-06r, 23r <400> 168 Asp Ala Ser 1 <210> 169 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR L3 of ACE-06, 23; Fab region (CD3) in CDR L3 of ACE-06r, 23r <400> 169 Gln Gln Arg Ser Asn Trp Pro Pro Leu Thr 1 5 10 <210> 170 <211> 112 <212> PRT <213> Artificial Sequence <220> <223> Fab region (PD-L1) in VL of ACE-06-08,13-17, 23, 34, 35; Fv region (PD-L1) in VL of ACE-06r-08r,13r-17r, 23r, 34r, 35r <400> 170 Gln Leu Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly 20 25 30 Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Ala Ala Pro Lys Leu 35 40 45 Leu Ile Tyr Gly Asp Ile Asn Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Ile Ser Ala Ser Leu Ala Ile Thr Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser 85 90 95 Leu Ser Gly Gly Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Arg 100 105 110 <210> 171 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fab region (PD-L1) in CDR L1 of ACE-06-08,13-17, 23, 34-36; Fv region (PD-L1) in CDR L1 of ACE-06r-10r,13r-17r, 23r, 34-36r <400> 171 Ser Ser Asn Ile Gly Ala Gly Tyr Asp 1 5 <210> 172 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Fab region (PD-L1) in CDR L2 of ACE-06-08,13-17, 23, 34-36; Fv region (PD-L1) in CDR L2 of ACE-06r-10r,13r-17r, 23r, 34-36r <400> 172 Gly Asp Ile 1 <210> 173 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Fab region (PD-L1) in CDR L3 of ACE-06-08,13-17, 23, 34-36; Fv region (PD-L1) in CDR L3 of ACE-06r-10r,13r-17r, 23r, 34-36r <400> 173 Gln Ser Tyr Asp Ser Ser Leu Ser Gly Gly Val 1 5 10 <210> 174 <211> 369 <212> PRT <213> Artificial Sequence <220> <223> ACE-07-VH amino acid sequence <400> 174 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Gly Gly Gly Gly Ser Glu Val Gln Leu Gln Gln Ser Gly Pro 245 250 255 Glu Leu Val Lys Pro Gly Pro Ser Met Lys Ile Ser Cys Lys Ala Ser 260 265 270 Gly Tyr Ser Phe Thr Gly Tyr Thr Met Asn Trp Val Lys Gln Ser His 275 280 285 Gly Lys Cys Leu Glu Trp Met Gly Leu Ile Asn Pro Tyr Lys Gly Val 290 295 300 Ser Thr Tyr Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Val Asp 305 310 315 320 Lys Ser Ser Ser Thr Ala Tyr Met Glu Leu Leu Ser Leu Thr Ser Glu 325 330 335 Asp Ser Ala Val Tyr Tyr Cys Ala Arg Ser Gly Tyr Tyr Gly Asp Ser 340 345 350 Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly Thr Thr Leu Thr Val Phe 355 360 365 Ser <210> 175 <211> 355 <212> PRT <213> Artificial Sequence <220> <223> ACE-07-VL amino acid sequence <400> 175 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Thr Thr Ser 245 250 255 Ser Leu Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Arg Ala 260 265 270 Ser Gln Asp Ile Arg Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp 275 280 285 Gly Thr Val Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu His Ser Gly 290 295 300 Val Pro Ser Lys Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu 305 310 315 320 Thr Ile Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys Gln 325 330 335 Gln Gly Asn Thr Leu Pro Trp Thr Phe Ala Gly Cys Thr Lys Leu Glu 340 345 350 Ile Lys Arg 355 <210> 176 <211> 122 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in VH of ACE-07, 14; Fab region (CD3) in VH of ACE-07r, 14r <400> 176 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Cys Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser 115 120 <210> 177 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR H1 of ACE-07, 14-22, 28, 38-40; Fab region (CD3) in CDR H1 of ACE-07r, 14r-22r, 28r, 38r-40r <400> 177 Gly Tyr Ser Phe Thr Gly Tyr Thr 1 5 <210> 178 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR H2 of ACE-07, 14-22, 28, 38-40; Fab region (CD3) in CDR H2 of ACE-07r, 14r-22r, 28r, 38r-40r <400> 178 Ile Asn Pro Tyr Lys Gly Val Ser 1 5 <210> 179 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR H3 of ACE-07, 14; Fab region (CD3) in CDR H3 of ACE-07r, 14r <400> 179 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val 1 5 10 15 <210> 180 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in VL of ACE-07 <400> 180 Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly 1 5 10 15 Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Arg Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile 35 40 45 Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Lys Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln 65 70 75 80 Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Trp 85 90 95 Thr Phe Ala Gly Cys Thr Lys Leu Glu Ile Lys Arg 100 105 <210> 181 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR L1 of ACE-07, 14-22, 28, 38-40; Fab region (CD3) in CDR L1 of ACE-07r, 14r-22r, 28r, 38r-40r <400> 181 Gln Asp Ile Arg Asn Tyr 1 5 <210> 182 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR L2 of ACE-07, 14-22, 28, 38-40; Fab region (CD3) in CDR L2 of ACE-07r, 14r-22r, 28r, 38r-40r <400> 182 Tyr Thr Ser 1 <210> 183 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR L3 of ACE-07; Fab region (CD3) in CDR L3 of ACE-07r <400> 183 Gln Gln Gly Asn Thr Leu Pro Trp 1 5 <210> 184 <211> 363 <212> PRT <213> Artificial Sequence <220> <223> ACE-08-VH amino acid sequence <400> 184 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly 245 250 255 Gly Leu Val Gln Pro Gly Lys Ser Leu Lys Leu Ser Cys Glu Ala Ser 260 265 270 Gly Phe Thr Phe Ser Gly Tyr Gly Met His Trp Val Arg Gln Ala Pro 275 280 285 Gly Arg Cys Leu Glu Ser Val Ala Tyr Ile Thr Ser Ser Ser Ile Asn 290 295 300 Ile Lys Tyr Ala Asp Ala Val Lys Gly Arg Phe Thr Val Ser Arg Asp 305 310 315 320 Asn Ala Lys Asn Leu Leu Phe Leu Gln Met Asn Ile Leu Lys Ser Glu 325 330 335 Asp Thr Ala Met Tyr Tyr Cys Ala Arg Phe Asp Trp Asp Lys Asn Tyr 340 345 350 Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser 355 360 <210> 185 <211> 353 <212> PRT <213> Artificial Sequence <220> <223> ACE-08-VL amino acid sequence <400> 185 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Gly Gly Gly Gly Ser Gln Met Thr Gln Ser Pro Ser Ser Leu 245 250 255 Pro Ala Ser Leu Gly Asp Arg Val Thr Ile Asn Cys Gln Ala Ser Gln 260 265 270 Asp Ile Ser Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala 275 280 285 Pro Lys Leu Leu Ile Tyr Tyr Thr Asn Lys Leu Ala Asp Gly Val Pro 290 295 300 Ser Arg Phe Ser Gly Ser Gly Ser Gly Arg Asp Ser Ser Phe Thr Ile 305 310 315 320 Ser Ser Leu Glu Ser Glu Asp Ile Gly Ser Tyr Tyr Cys Gln Gln Tyr 325 330 335 Tyr Asn Tyr Pro Trp Thr Phe Gly Pro Cys Thr Lys Leu Glu Ile Lys 340 345 350 Arg <210> 186 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in VH of ACE-08; Fab region (CD3) in VH of ACE-08r <400> 186 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Lys 1 5 10 15 Ser Leu Lys Leu Ser Cys Glu Ala Ser Gly Phe Thr Phe Ser Gly Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Arg Cys Leu Glu Ser Val 35 40 45 Ala Tyr Ile Thr Ser Ser Ser Ile Asn Ile Lys Tyr Ala Asp Ala Val 50 55 60 Lys Gly Arg Phe Thr Val Ser Arg Asp Asn Ala Lys Asn Leu Leu Phe 65 70 75 80 Leu Gln Met Asn Ile Leu Lys Ser Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Arg Phe Asp Trp Asp Lys Asn Tyr Trp Gly Gln Gly Thr Met Val 100 105 110 Thr Val Ser Ser 115 <210> 187 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR H1 of ACE-08; Fab region (CD3) in CDR H1 of ACE-08r <400> 187 Gly Phe Thr Phe Ser Gly Tyr Gly 1 5 <210> 188 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR H2 of ACE-08; Fab region (CD3) in CDR H2 of ACE-08r <400> 188 Ile Thr Ser Ser Ser Ile Asn Ile 1 5 <210> 189 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR H3 of ACE-08; Fab region (CD3) in CDR H3 of ACE-08r <400> 189 Ala Arg Phe Asp Trp Asp Lys Asn Tyr 1 5 <210> 190 <211> 106 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in VL of ACE-08; Fab region (CD3) in VL of ACE-08r <400> 190 Gln Met Thr Gln Ser Pro Ser Ser Leu Pro Ala Ser Leu Gly Asp Arg 1 5 10 15 Val Thr Ile Asn Cys Gln Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn 20 25 30 Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr 35 40 45 Thr Asn Lys Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly Ser Gly 50 55 60 Ser Gly Arg Asp Ser Ser Phe Thr Ile Ser Ser Leu Glu Ser Glu Asp 65 70 75 80 Ile Gly Ser Tyr Tyr Cys Gln Gln Tyr Tyr Asn Tyr Pro Trp Thr Phe 85 90 95 Gly Pro Cys Thr Lys Leu Glu Ile Lys Arg 100 105 <210> 191 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR L1 of ACE-08; Fab region (CD3) in CDR L1 of ACE-08r <400> 191 Gln Asp Ile Ser Asn Tyr 1 5 <210> 192 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR L2 of ACE-08; Fab region (CD3) in CDR L2 of ACE-08r <400> 192 Tyr Thr Asn 1 <210> 193 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR L3 of ACE-08; Fab region (CD3) in CDR L3 of ACE-08r <400> 193 Gln Gln Tyr Tyr Asn Tyr Pro Trp Thr 1 5 <210> 194 <211> 361 <212> PRT <213> Artificial Sequence <220> <223> ACE-13-VH amino acid sequence <400> 194 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Gly Gly Gly Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly 245 250 255 Gly Val Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser 260 265 270 Gly Phe Thr Phe Leu Arg Tyr Ala Met His Trp Val Arg Gln Ala Pro 275 280 285 Gly Lys Gly Leu Glu Trp Val Ala Val Ile Ser Tyr Asp Gly Arg Tyr 290 295 300 Lys Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp 305 310 315 320 Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu 325 330 335 Asp Thr Ala Val Tyr Tyr Cys Thr Thr Thr Thr Phe Asp Ser Trp Gly 340 345 350 Gln Gly Thr Leu Val Thr Val Ser Ser 355 360 <210> 195 <211> 361 <212> PRT <213> Artificial Sequence <220> <223> ACE-13-VL amino acid sequence <400> 195 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln Thr Pro Leu 245 250 255 Ser Leu Pro Val Thr Pro Gly Glu Ala Ala Ser Ile Ser Cys Arg Ser 260 265 270 Ser Gln Ser Leu Leu Asp Ser Glu Asp Gly Asn Thr Tyr Leu Asp Trp 275 280 285 Tyr Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Thr Leu 290 295 300 Ser His Arg Ala Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser 305 310 315 320 Gly Thr Asp Phe Thr Leu Glu Ile Ser Arg Val Glu Ala Glu Asp Val 325 330 335 Gly Val Tyr Tyr Cys Met Gln Arg Arg Asp Phe Pro Phe Thr Phe Gly 340 345 350 Gln Gly Thr Lys Val Asp Ile Lys Arg 355 360 <210> 196 <211> 114 <212> PRT <213> Artificial Sequence <220> <223> Fv region (PD-1) in VH of ACE-13; Fab region (CD3) in VH of ACE-13r <400> 196 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Leu Arg Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Arg Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Thr Thr Thr Thr Phe Asp Ser Trp Gly Gln Gly Thr Leu Val Thr Val 100 105 110 Ser Ser <210> 197 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fv region (PD-1) in CDR H1 of ACE-13; Fab region (CD3) in CDR H1 of ACE-13r <400> 197 Gly Phe Thr Phe Leu Arg Tyr Ala 1 5 <210> 198 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fv region (PD-1) in CDR H2 of ACE-13; Fab region (CD3) in CDR H2 of ACE-13r <400> 198 Ile Ser Tyr Asp Gly Arg Tyr Lys 1 5 <210> 199 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Fv region (PD-1) in CDR H3 of ACE-13; Fab region (CD3) in CDR H3 of ACE-13r <400> 199 Thr Thr Thr Thr Phe Asp Ser 1 5 <210> 200 <211> 114 <212> PRT <213> Artificial Sequence <220> <223> Fv region (PD-1) in VL of ACE-13; Fab region (CD3) in VL of ACE-13r <400> 200 Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly 1 5 10 15 Glu Ala Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu Asp Ser 20 25 30 Glu Asp Gly Asn Thr Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln 35 40 45 Ser Pro Gln Leu Leu Ile Tyr Thr Leu Ser His Arg Ala Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Glu 65 70 75 80 Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln 85 90 95 Arg Arg Asp Phe Pro Phe Thr Phe Gly Gln Gly Thr Lys Val Asp Ile 100 105 110 Lys Arg <210> 201 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Fv region (PD-1) in CDR L1 of ACE-13; Fab region (CD3) in CDR L1 of ACE-13r <400> 201 Gln Ser Leu Leu Asp Ser Glu Asp Gly Asn Thr Tyr 1 5 10 <210> 202 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Fv region (PD-1) in CDR L2 of ACE-13; Fab region (CD3) in CDR L2 of ACE-13r <400> 202 Thr Leu Ser 1 <210> 203 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fv region (PD-1) in CDR L3 of ACE-13; Fab region (CD3) in CDR L3 of ACE-13r <400> 203 Met Gln Arg Arg Asp Phe Pro Phe Thr 1 5 <210> 204 <211> 374 <212> PRT <213> Artificial Sequence <220> <223> ACE-14-VH amino acid sequence <400> 204 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu 245 250 255 Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro Ser Met Lys Ile 260 265 270 Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr Thr Met Asn Trp 275 280 285 Val Lys Gln Ser His Gly Lys Cys Leu Glu Trp Met Gly Leu Ile Asn 290 295 300 Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe Lys Asp Lys Ala 305 310 315 320 Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr Met Glu Leu Leu 325 330 335 Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg Ser Gly 340 345 350 Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly Thr 355 360 365 Thr Leu Thr Val Phe Ser 370 <210> 205 <211> 360 <212> PRT <213> Artificial Sequence <220> <223> ACE-14-VL amino acid sequence <400> 205 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met 245 250 255 Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly Asp Arg Val Thr 260 265 270 Ile Ser Cys Arg Ala Ser Gln Asp Ile Arg Asn Tyr Leu Asn Trp Tyr 275 280 285 Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile Tyr Tyr Thr Ser 290 295 300 Arg Leu His Ser Gly Val Pro Ser Lys Phe Ser Gly Ser Gly Ser Gly 305 310 315 320 Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln Glu Asp Ile Ala 325 330 335 Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Trp Thr Phe Ala Cys 340 345 350 Gly Thr Lys Leu Glu Ile Lys Arg 355 360 <210> 206 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in VL of ACE-14; Fab region (CD3) in VL of ACE-14r <400> 206 Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly 1 5 10 15 Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Arg Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile 35 40 45 Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Lys Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln 65 70 75 80 Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Trp 85 90 95 Thr Phe Ala Cys Gly Thr Lys Leu Glu Ile Lys Arg 100 105 <210> 207 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR L3 of ACE-14-22, 28, 38-40; Fab region (CD3) in CDR L3 of ACE-14r-22r, 28r, 38r-40r <400> 207 Gln Gln Gly Asn Thr Leu Pro Trp Thr 1 5 <210> 208 <211> 369 <212> PRT <213> Artificial Sequence <220> <223> ACE-15-VH amino acid sequence <400> 208 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Gly Gly Gly Gly Ser Glu Val Gln Leu Gln Gln Ser Gly Pro 245 250 255 Glu Leu Val Lys Pro Gly Pro Ser Met Lys Ile Ser Cys Lys Ala Ser 260 265 270 Gly Tyr Ser Phe Thr Gly Tyr Thr Met Asn Trp Val Lys Gln Ser His 275 280 285 Gly Lys Asn Leu Glu Trp Met Gly Leu Ile Asn Pro Tyr Lys Gly Val 290 295 300 Ser Thr Tyr Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Val Asp 305 310 315 320 Lys Ser Ser Ser Thr Ala Tyr Met Glu Leu Leu Ser Leu Thr Ser Glu 325 330 335 Asp Ser Ala Val Tyr Tyr Cys Ala Arg Ser Gly Tyr Tyr Gly Asp Ser 340 345 350 Asp Trp Tyr Phe Asp Val Trp Gly Cys Gly Thr Thr Leu Thr Val Phe 355 360 365 Ser <210> 209 <211> 355 <212> PRT <213> Artificial Sequence <220> <223> ACE-15-VL amino acid sequence <400> 209 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Thr Thr Ser 245 250 255 Ser Leu Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Arg Ala 260 265 270 Ser Gln Asp Ile Arg Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp 275 280 285 Gly Cys Val Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu His Ser Gly 290 295 300 Val Pro Ser Lys Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu 305 310 315 320 Thr Ile Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys Gln 325 330 335 Gln Gly Asn Thr Leu Pro Trp Thr Phe Ala Gly Gly Thr Lys Leu Glu 340 345 350 Ile Lys Arg 355 <210> 210 <211> 122 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in VH of ACE-15; Fab region (CD3) in VH of ACE-15r <400> 210 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Cys Gly Thr Thr Leu Thr Val Phe Ser 115 120 <210> 211 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR H3 of ACE-15-22, 28, 38-40; Fab region (CD3) in CDR H3 of ACE-15r-22r, 28r, 38r-40r <400> 211 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp 1 5 10 <210> 212 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in VL of ACE-15; Fab region (CD3) in VL of ACE-15r <400> 212 Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly 1 5 10 15 Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Arg Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Cys Val Lys Leu Leu Ile 35 40 45 Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Lys Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln 65 70 75 80 Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Trp 85 90 95 Thr Phe Ala Gly Gly Thr Lys Leu Glu Ile Lys Arg 100 105 <210> 213 <211> 372 <212> PRT <213> Artificial Sequence <220> <223> ACE-05-VH amino acid sequence <400> 213 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Glu Val Gln Leu Gln Gln 245 250 255 Ser Gly Pro Glu Leu Val Lys Pro Gly Pro Ser Met Lys Ile Ser Cys 260 265 270 Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr Thr Met Asn Trp Val Lys 275 280 285 Gln Ser His Gly Lys Asn Leu Glu Trp Met Gly Leu Ile Asn Pro Tyr 290 295 300 Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu 305 310 315 320 Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr Met Glu Leu Leu Ser Leu 325 330 335 Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg Ser Gly Tyr Tyr 340 345 350 Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly Thr Thr Leu 355 360 365 Thr Val Phe Ser 370 <210> 214 <211> 358 <212> PRT <213> Artificial Sequence <220> <223> ACE-05-VL amino acid sequence <400> 214 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln 245 250 255 Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser 260 265 270 Cys Arg Ala Ser Gln Asp Ile Arg Asn Tyr Leu Asn Trp Tyr Gln Gln 275 280 285 Lys Pro Asp Gly Thr Val Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu 290 295 300 His Ser Gly Val Pro Ser Lys Phe Ser Gly Ser Gly Ser Gly Thr Asp 305 310 315 320 Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr 325 330 335 Phe Cys Gln Gln Gly Asn Thr Leu Pro Trp Thr Phe Ala Gly Gly Thr 340 345 350 Lys Leu Glu Ile Lys Arg 355 <210> 215 <211> 122 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in VH of ACE-05, 17-22, 28, 38-40; Fab region (CD3) in VH of ACE-16r-22r, 28r, 38r-40r <400> 215 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser 115 120 <210> 216 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in VL of ACE-05,17-22, 28, 38-40; Fab region (CD3) in VL of ACE-16r-22r, 28r, 38r-40r <400> 216 Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly 1 5 10 15 Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Arg Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile 35 40 45 Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Lys Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln 65 70 75 80 Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Trp 85 90 95 Thr Phe Ala Gly Gly Thr Lys Leu Glu Ile Lys Arg 100 105 <210> 217 <211> 367 <212> PRT <213> Artificial Sequence <220> <223> ACE-17-VH amino acid sequence <400> 217 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu 245 250 255 Val Lys Pro Gly Pro Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr 260 265 270 Ser Phe Thr Gly Tyr Thr Met Asn Trp Val Lys Gln Ser His Gly Lys 275 280 285 Asn Leu Glu Trp Met Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr 290 295 300 Tyr Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser 305 310 315 320 Ser Ser Thr Ala Tyr Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser 325 330 335 Ala Val Tyr Tyr Cys Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp 340 345 350 Tyr Phe Asp Val Trp Gly Gln Gly Thr Thr Leu Thr Val Phe Ser 355 360 365 <210> 218 <211> 353 <212> PRT <213> Artificial Sequence <220> <223> ACE-17-VL amino acid sequence <400> 218 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu 245 250 255 Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln 260 265 270 Asp Ile Arg Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr 275 280 285 Val Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro 290 295 300 Ser Lys Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile 305 310 315 320 Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly 325 330 335 Asn Thr Leu Pro Trp Thr Phe Ala Gly Gly Thr Lys Leu Glu Ile Lys 340 345 350 Arg <210> 219 <211> 372 <212> PRT <213> Artificial Sequence <220> <223> ACE-18-VH amino acid sequence <400> 219 Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asn Met His Trp Val Lys Gln Thr Pro Gly Arg Gly Leu Glu Trp Ile 35 40 45 Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val Trp Gly 100 105 110 Ala Gly Thr Thr Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Glu Val Gln Leu Gln Gln 245 250 255 Ser Gly Pro Glu Leu Val Lys Pro Gly Pro Ser Met Lys Ile Ser Cys 260 265 270 Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr Thr Met Asn Trp Val Lys 275 280 285 Gln Ser His Gly Lys Asn Leu Glu Trp Met Gly Leu Ile Asn Pro Tyr 290 295 300 Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu 305 310 315 320 Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr Met Glu Leu Leu Ser Leu 325 330 335 Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg Ser Gly Tyr Tyr 340 345 350 Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly Thr Thr Leu 355 360 365 Thr Val Phe Ser 370 <210> 220 <211> 358 <212> PRT <213> Artificial Sequence <220> <223> ACE-18-VL amino acid sequence <400> 220 Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asn Met His Trp Val Lys Gln Thr Pro Gly Arg Gly Leu Glu Trp Ile 35 40 45 Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val Trp Gly 100 105 110 Ala Gly Thr Thr Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln 245 250 255 Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser 260 265 270 Cys Arg Ala Ser Gln Asp Ile Arg Asn Tyr Leu Asn Trp Tyr Gln Gln 275 280 285 Lys Pro Asp Gly Thr Val Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu 290 295 300 His Ser Gly Val Pro Ser Lys Phe Ser Gly Ser Gly Ser Gly Thr Asp 305 310 315 320 Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr 325 330 335 Phe Cys Gln Gln Gly Asn Thr Leu Pro Trp Thr Phe Ala Gly Gly Thr 340 345 350 Lys Leu Glu Ile Lys Arg 355 <210> 221 <211> 213 <212> PRT <213> Artificial Sequence <220> <223> ACE-18-LC, ACE-22-LC, ACE-37-LC amino acid sequence <400> 221 Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Ile 20 25 30 His Trp Phe Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr 35 40 45 Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Val Glu Ala Glu 65 70 75 80 Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Thr Ser Asn Pro Pro Thr 85 90 95 Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Ser Val Ala Ala Pro 100 105 110 Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 115 120 125 Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135 140 Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu 145 150 155 160 Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175 Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190 Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200 205 Asn Arg Gly Glu Cys 210 <210> 222 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD20) in VH of ACE-18, 22, 37; Fv region (CD20) in VH of ACE-10r, 18r, 22r, 37r <400> 222 Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asn Met His Trp Val Lys Gln Thr Pro Gly Arg Gly Leu Glu Trp Ile 35 40 45 Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val Trp Gly 100 105 110 Ala Gly Thr Thr Val Thr Val Ser Ala 115 120 <210> 223 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD20) in CDR H1 of ACE-18, 22, 37; Fv region (CD20) in CDR H1 of ACE-10r, 18r, 22r, 37r <400> 223 Gly Tyr Thr Phe Thr Ser Tyr Asn 1 5 <210> 224 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD20) in CDR H2 of ACE-18, 22, 37; Fv region (CD20) in CDR H2 of ACE-10r, 18r, 22r, 37r <400> 224 Ile Tyr Pro Gly Asn Gly Asp Thr 1 5 <210> 225 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD20) in CDR H3 of ACE-18, 22, 37; Fv region (CD20) in CDR H3 of ACE-10r, 18r, 22r, 37r <400> 225 Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val 1 5 10 <210> 226 <211> 106 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD20) in VL of ACE-18, 22, 37; Fv region (CD20) in VL of ACE-10r, 18r, 22r, 37r <400> 226 Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Ile 20 25 30 His Trp Phe Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr 35 40 45 Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Val Glu Ala Glu 65 70 75 80 Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Thr Ser Asn Pro Pro Thr 85 90 95 Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 227 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD20) in CDR L1 of ACE-18, 22, 37; Fv region (CD20) in CDR L1 of ACE-10r, 18r, 22r, 37r <400> 227 Ser Ser Val Ser Tyr 1 5 <210> 228 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD20) in CDR L2 of ACE-18, 22, 37; Fv region (CD20) in CDR L2 of ACE-10r, 18r, 22r, 37r <400> 228 Ala Thr Ser 1 <210> 229 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD20) in CDR L3 of ACE-18, 22, 37; Fv region (CD20) in CDR L3 of ACE-10r, 18r, 22r, 37r <400> 229 Gln Gln Trp Thr Ser Asn Pro Pro Thr 1 5 <210> 230 <211> 370 <212> PRT <213> Artificial Sequence <220> <223> ACE-19-VH amino acid sequence <400> 230 Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30 Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60 Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe 65 70 75 80 Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala 85 90 95 Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Gly Gly Gly Gly Ser Glu Val Gln Leu Gln Gln Ser Gly 245 250 255 Pro Glu Leu Val Lys Pro Gly Pro Ser Met Lys Ile Ser Cys Lys Ala 260 265 270 Ser Gly Tyr Ser Phe Thr Gly Tyr Thr Met Asn Trp Val Lys Gln Ser 275 280 285 His Gly Lys Asn Leu Glu Trp Met Gly Leu Ile Asn Pro Tyr Lys Gly 290 295 300 Val Ser Thr Tyr Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Val 305 310 315 320 Asp Lys Ser Ser Ser Thr Ala Tyr Met Glu Leu Leu Ser Leu Thr Ser 325 330 335 Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg Ser Gly Tyr Tyr Gly Asp 340 345 350 Ser Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly Thr Thr Leu Thr Val 355 360 365 Phe Ser 370 <210> 231 <211> 356 <212> PRT <213> Artificial Sequence <220> <223> ACE-19-VL amino acid sequence <400> 231 Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30 Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60 Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe 65 70 75 80 Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala 85 90 95 Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Thr Thr 245 250 255 Ser Ser Leu Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Arg 260 265 270 Ala Ser Gln Asp Ile Arg Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro 275 280 285 Asp Gly Thr Val Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu His Ser 290 295 300 Gly Val Pro Ser Lys Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser 305 310 315 320 Leu Thr Ile Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys 325 330 335 Gln Gln Gly Asn Thr Leu Pro Trp Thr Phe Ala Gly Gly Thr Lys Leu 340 345 350 Glu Ile Lys Arg 355 <210> 232 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> ACE-19-LC, ACE-26-LC, ACE-28-LC, ACE-29-LC, ACE-32-LC, ACE-38-LC, ACE-39-LC, ACE-40-LC amino acid sequence <400> 232 Asp Ile Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn 20 25 30 Ile His Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile 35 40 45 Lys Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser 65 70 75 80 Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr 85 90 95 Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 233 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> Fab region (EGFR) in VH of ACE-19, 26, 28, 29, 32, 38-40; Fv region (EGFR) in VH of ACE-19r, 26r, 28r, 29r, 32r, 38r-40r <400> 233 Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30 Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60 Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe 65 70 75 80 Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala 85 90 95 Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ala 115 <210> 234 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fab region (EGFR) in CDR H1 of ACE-19, 26, 28, 29, 32, 38-40; Fv region (EGFR) in CDR H1 of ACE-19r, 26r, 28r, 29r, 32r, 38r-40r <400> 234 Gly Phe Ser Leu Thr Asn Tyr Gly 1 5 <210> 235 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Fab region (EGFR) in CDR H2 of ACE-19, 26, 28, 29, 32, 38-40; Fv region (EGFR) in CDR H2 of ACE-19r, 26r, 28r, 29r, 32r, 38r-40r <400> 235 Ile Trp Ser Gly Gly Asn Thr 1 5 <210> 236 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Fab region (EGFR) in CDR H3 of ACE-19, 26, 28, 29, 32, 38-40; Fv region (EGFR) in CDR H3 of ACE-19r, 26r, 28r, 29r, 32r, 38r-40r <400> 236 Ala Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr 1 5 10 <210> 237 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Fab region (EGFR) in VL of ACE-19, 26, 28, 29, 32, 38-40; Fv region (EGFR) in VL of ACE-19r, 26r, 28r, 29r, 32r, 38r-40r <400> 237 Asp Ile Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn 20 25 30 Ile His Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile 35 40 45 Lys Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser 65 70 75 80 Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr 85 90 95 Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys 100 105 <210> 238 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Fab region (EGFR) in CDR L1 of ACE-19, 26, 28, 29, 32, 38-40; Fv region (EGFR) in CDR L1 of ACE-19r, 26r, 28r, 29r, 32r, 38r-40r <400> 238 Gln Ser Ile Gly Thr Asn 1 5 <210> 239 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Fab region (EGFR) in CDR L2 of ACE-19, 26, 28, 29, 32, 38-40; Fv region (EGFR) in CDR L2 of ACE-19r, 26r, 28r, 29r, 32r, 38r-40r <400> 239 Tyr Ala Ser 1 <210> 240 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fab region (EGFR) in CDR L3 of ACE-19, 26, 28, 29, 32, 38-40; Fv region (EGFR) in CDR L3 of ACE-19r, 26r, 28r, 29r, 32r, 38r-40r <400> 240 Gln Gln Asn Asn Asn Trp Pro Thr Thr 1 5 <210> 241 <211> 372 <212> PRT <213> Artificial Sequence <220> <223> ACE-20-VH amino acid sequence <400> 241 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser His 20 25 30 Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Glu Phe Asn Pro Ser Asn Gly Arg Thr Asn Tyr Asn Glu Lys Phe 50 55 60 Lys Ser Lys Ala Thr Met Thr Val Asp Thr Ser Thr Asn Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ser Arg Asp Tyr Asp Tyr Asp Cys Arg Tyr Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Glu Val Gln Leu Gln Gln 245 250 255 Ser Gly Pro Glu Leu Val Lys Pro Gly Pro Ser Met Lys Ile Ser Cys 260 265 270 Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr Thr Met Asn Trp Val Lys 275 280 285 Gln Ser His Gly Lys Asn Leu Glu Trp Met Gly Leu Ile Asn Pro Tyr 290 295 300 Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu 305 310 315 320 Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr Met Glu Leu Leu Ser Leu 325 330 335 Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg Ser Gly Tyr Tyr 340 345 350 Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly Thr Thr Leu 355 360 365 Thr Val Phe Ser 370 <210> 242 <211> 358 <212> PRT <213> Artificial Sequence <220> <223> ACE-20-VL amino acid sequence <400> 242 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser His 20 25 30 Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Glu Phe Asn Pro Ser Asn Gly Arg Thr Asn Tyr Asn Glu Lys Phe 50 55 60 Lys Ser Lys Ala Thr Met Thr Val Asp Thr Ser Thr Asn Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ser Arg Asp Tyr Asp Tyr Asp Cys Arg Tyr Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln 245 250 255 Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser 260 265 270 Cys Arg Ala Ser Gln Asp Ile Arg Asn Tyr Leu Asn Trp Tyr Gln Gln 275 280 285 Lys Pro Asp Gly Thr Val Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu 290 295 300 His Ser Gly Val Pro Ser Lys Phe Ser Gly Ser Gly Ser Gly Thr Asp 305 310 315 320 Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr 325 330 335 Phe Cys Gln Gln Gly Asn Thr Leu Pro Trp Thr Phe Ala Gly Gly Thr 340 345 350 Lys Leu Glu Ile Lys Arg 355 <210> 243 <211> 213 <212> PRT <213> Artificial Sequence <220> <223> ACE-20-LC amino acid sequence <400> 243 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Ser Ser Val Thr Tyr Met 20 25 30 Tyr Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr 35 40 45 Asp Thr Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu 65 70 75 80 Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser His Ile Phe Thr 85 90 95 Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro 100 105 110 Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 115 120 125 Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135 140 Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu 145 150 155 160 Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175 Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190 Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200 205 Asn Arg Gly Glu Cys 210 <210> 244 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> Fab region (EGFR) in VH of ACE-20; Fv region (EGFR) in VH of ACE-20r <400> 244 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser His 20 25 30 Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Glu Phe Asn Pro Ser Asn Gly Arg Thr Asn Tyr Asn Glu Lys Phe 50 55 60 Lys Ser Lys Ala Thr Met Thr Val Asp Thr Ser Thr Asn Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ser Arg Asp Tyr Asp Tyr Asp Cys Arg Tyr Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 245 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fab region (EGFR) in CDR H1 of ACE-20; Fv region (EGFR) in CDR H1 of ACE-20r <400> 245 Gly Tyr Thr Phe Thr Ser His Trp 1 5 <210> 246 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fab region (EGFR) in CDR H2 of ACE-20; Fv region (EGFR) in CDR H2 of ACE-20r <400> 246 Phe Asn Pro Ser Asn Gly Arg Thr 1 5 <210> 247 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> Fab region (EGFR) in CDR H3 of ACE-20; Fv region (EGFR) in CDR H3 of ACE-20r <400> 247 Ala Ser Arg Asp Tyr Asp Tyr Asp Cys Arg Tyr Phe Asp Tyr 1 5 10 <210> 248 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Fab region (EGFR) in VL of ACE-20; Fv region (EGFR) in VL of ACE-20r <400> 248 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Ser Ser Val Thr Tyr Met 20 25 30 Tyr Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr 35 40 45 Asp Thr Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu 65 70 75 80 Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser His Ile Phe Thr 85 90 95 Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105 <210> 249 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Fab region (EGFR) in CDR L1 of ACE-20; Fv region (EGFR) in CDR L1 of ACE-20r <400> 249 Ser Ser Val Thr Tyr 1 5 <210> 250 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Fab region (EGFR) in CDR L2 of ACE-20; Fv region (EGFR) in CDR L2 of ACE-20r <400> 250 Asp Thr Ser 1 <210> 251 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fab region (EGFR) in CDR L3 of ACE-20; Fv region (EGFR) in CDR L3 of ACE-20r <400> 251 Gln Gln Trp Ser Ser His Ile Phe Thr 1 5 <210> 252 <211> 376 <212> PRT <213> Artificial Sequence <220> <223> ACE-21-VH amino acid sequence <400> 252 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp Asp Asp Gly Ser Tyr Lys Tyr Tyr Gly Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Gly Ile Thr Met Val Arg Gly Val Met Lys Asp Tyr Phe 100 105 110 Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 115 120 125 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140 Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175 Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190 Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys 195 200 205 Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu 210 215 220 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys 225 230 235 240 Pro Ala Pro Glu Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Glu Val 245 250 255 Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro Ser Met 260 265 270 Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr Thr Met 275 280 285 Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met Gly Leu 290 295 300 Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe Lys Asp 305 310 315 320 Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr Met Glu 325 330 335 Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg 340 345 350 Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp Gly Gln 355 360 365 Gly Thr Thr Leu Thr Val Phe Ser 370 375 <210> 253 <211> 362 <212> PRT <213> Artificial Sequence <220> <223> ACE-21-VL amino acid sequence <400> 253 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp Asp Asp Gly Ser Tyr Lys Tyr Tyr Gly Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Gly Ile Thr Met Val Arg Gly Val Met Lys Asp Tyr Phe 100 105 110 Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 115 120 125 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140 Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175 Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190 Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys 195 200 205 Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu 210 215 220 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys 225 230 235 240 Pro Ala Pro Glu Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Asp Ile 245 250 255 Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly Asp Arg 260 265 270 Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Arg Asn Tyr Leu Asn 275 280 285 Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile Tyr Tyr 290 295 300 Thr Ser Arg Leu His Ser Gly Val Pro Ser Lys Phe Ser Gly Ser Gly 305 310 315 320 Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln Glu Asp 325 330 335 Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Trp Thr Phe 340 345 350 Ala Gly Gly Thr Lys Leu Glu Ile Lys Arg 355 360 <210> 254 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> ACE-21-LC amino acid sequence <400> 254 Ala Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Ala 20 25 30 Leu Val Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Glu Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 255 <211> 125 <212> PRT <213> Artificial Sequence <220> <223> Fab region (EGFR) in VH of ACE-21; Fv region (EGFR) in VH of ACE-21r <400> 255 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp Asp Asp Gly Ser Tyr Lys Tyr Tyr Gly Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Gly Ile Thr Met Val Arg Gly Val Met Lys Asp Tyr Phe 100 105 110 Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 125 <210> 256 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fab region (EGFR) in CDR H1 of ACE-21; Fv region (EGFR) in CDR H1 of ACE-21r <400> 256 Gly Phe Thr Phe Ser Thr Tyr Gly 1 5 <210> 257 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fab region (EGFR) in CDR H2 of ACE-21; Fv region (EGFR) in CDR H2 of ACE-21r <400> 257 Ile Trp Asp Asp Gly Ser Tyr Lys 1 5 <210> 258 <211> 18 <212> PRT <213> Artificial Sequence <220> <223> Fab region (EGFR) in CDR H3 of ACE-21; Fv region (EGFR) in CDR H3 of ACE-21r <400> 258 Ala Arg Asp Gly Ile Thr Met Val Arg Gly Val Met Lys Asp Tyr Phe 1 5 10 15 Asp Tyr <210> 259 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> Fab region (EGFR) in VL of ACE-21; Fv region (EGFR) in VL of ACE-21r <400> 259 Ala Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Ala 20 25 30 Leu Val Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Glu Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 100 105 <210> 260 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Fab region (EGFR) in CDR L1 of ACE-21; Fv region (EGFR) in CDR L1 of ACE-21r <400> 260 Gln Asp Ile Ser Ser Ala 1 5 <210> 261 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Fab region (EGFR) in CDR L2 of ACE-21; Fv region (EGFR) in CDR L2 of ACE-21r <400> 261 Asp Ala Ser 1 <210> 262 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fab region (EGFR) in CDR L3 of ACE-21; Fv region (EGFR) in CDR L3 of ACE-21r <400> 262 Gln Gln Phe Asn Ser Tyr Pro Leu Thr 1 5 <210> 263 <211> 367 <212> PRT <213> Artificial Sequence <220> <223> ACE-22-VH amino acid sequence <400> 263 Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asn Met His Trp Val Lys Gln Thr Pro Gly Arg Gly Leu Glu Trp Ile 35 40 45 Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val Trp Gly 100 105 110 Ala Gly Thr Thr Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu 245 250 255 Val Lys Pro Gly Pro Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr 260 265 270 Ser Phe Thr Gly Tyr Thr Met Asn Trp Val Lys Gln Ser His Gly Lys 275 280 285 Asn Leu Glu Trp Met Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr 290 295 300 Tyr Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser 305 310 315 320 Ser Ser Thr Ala Tyr Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser 325 330 335 Ala Val Tyr Tyr Cys Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp 340 345 350 Tyr Phe Asp Val Trp Gly Gln Gly Thr Thr Leu Thr Val Phe Ser 355 360 365 <210> 264 <211> 353 <212> PRT <213> Artificial Sequence <220> <223> ACE-22-VL amino acid sequence <400> 264 Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asn Met His Trp Val Lys Gln Thr Pro Gly Arg Gly Leu Glu Trp Ile 35 40 45 Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val Trp Gly 100 105 110 Ala Gly Thr Thr Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu 245 250 255 Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln 260 265 270 Asp Ile Arg Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr 275 280 285 Val Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro 290 295 300 Ser Lys Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile 305 310 315 320 Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly 325 330 335 Asn Thr Leu Pro Trp Thr Phe Ala Gly Gly Thr Lys Leu Glu Ile Lys 340 345 350 Arg <210> 265 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Synthetic sequence <400> 265 Gly Tyr Thr Phe Thr Ser Tyr Asn Met 1 5 <210> 266 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Synthetic sequence <400> 266 Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe 1 5 10 <210> 267 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Synthetic sequence <400> 267 Arg Ala Ser Gln Asp Ile Arg Asn Tyr Leu Asn 1 5 10 <210> 268 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic sequence <400> 268 Tyr Thr Ser Arg Leu His Ser 1 5 <210> 269 <211> 368 <212> PRT <213> Artificial Sequence <220> <223> ACE-23-VH amino acid sequence <400> 269 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Gln Val Gln Leu Val Glu 245 250 255 Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys 260 265 270 Ala Ala Ser Gly Phe Lys Phe Ser Gly Tyr Gly Met His Trp Val Arg 275 280 285 Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Val Ile Trp Tyr Asp 290 295 300 Gly Ser Lys Lys Tyr Tyr Val Asp Ser Val Lys Gly Arg Phe Thr Ile 305 310 315 320 Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu 325 330 335 Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Gln Met Gly Tyr 340 345 350 Trp His Phe Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser 355 360 365 <210> 270 <211> 359 <212> PRT <213> Artificial Sequence <220> <223> ACE-23-HC-VL amino acid sequence <400> 270 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln 245 250 255 Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser 260 265 270 Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu Ala Trp Tyr Gln Gln 275 280 285 Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Asp Ala Ser Asn Arg 290 295 300 Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp 305 310 315 320 Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr 325 330 335 Tyr Cys Gln Gln Arg Ser Asn Trp Pro Pro Leu Thr Phe Gly Gly Gly 340 345 350 Thr Lys Val Glu Ile Lys Arg 355 <210> 271 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR H2 of ACE-06, 23; Fab region (CD3) in CDR H2 of ACE-06r, 23r <400> 271 Ile Trp Tyr Asp Gly Ser Lys Lys 1 5 <210> 272 <211> 367 <212> PRT <213> Artificial Sequence <220> <223> ACE-24-VH amino acid sequence <400> 272 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp 210 215 220 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 225 230 235 240 Pro Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly 245 250 255 Leu Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly 260 265 270 Phe Thr Phe Asp Asp Tyr Ala Met His Trp Val Arg Gln Ala Pro Gly 275 280 285 Lys Gly Leu Glu Trp Val Ser Ala Ile Thr Trp Asn Ser Gly His Ile 290 295 300 Asp Tyr Ala Asp Ser Val Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn 305 310 315 320 Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp 325 330 335 Thr Ala Val Tyr Tyr Cys Ala Lys Val Ser Tyr Leu Ser Thr Ala Ser 340 345 350 Ser Leu Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 355 360 365 <210> 273 <211> 349 <212> PRT <213> Artificial Sequence <220> <223> ACE-24-VL, ACE-25-VL amino acid sequence <400> 273 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp 210 215 220 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 225 230 235 240 Pro Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val 245 250 255 Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn 260 265 270 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu 275 280 285 Ile Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser 290 295 300 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln 305 310 315 320 Pro Glu Asp Val Ala Thr Tyr Tyr Cys Gln Arg Tyr Asn Arg Ala Pro 325 330 335 Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 340 345 <210> 274 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> ACE-24-LC, ACE-25-LC amino acid sequence <400> 274 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Ser Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 275 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> Fab region (HER2) in VH of ACE-24, 25; Fv region (HER2) in VH of ACE-00r, 24r, 25r <400> 275 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 276 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fab region (HER2) in CDR H1 of ACE-24, 25; Fv region (HER2) in CDR H1 of ACE-00r, 24r, 25r <400> 276 Gly Phe Asn Ile Lys Asp Thr Tyr 1 5 <210> 277 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fab region (HER2) in CDR H2 of ACE-24, 25; Fv region (HER2) in CDR H2 of ACE-00r, 24r, 25r <400> 277 Ile Tyr Pro Thr Asn Gly Tyr Thr 1 5 <210> 278 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Fab region (HER2) in CDR H3 of ACE-24, 25; Fv region (HER2) in CDR H3 of ACE-00r, 24r, 25r <400> 278 Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr 1 5 10 <210> 279 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> Fv region (TNF) in VH of ACE-24, 25; Fab region (TNF) in VH of ACE-00r, 24r, 25r <400> 279 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Thr Trp Asn Ser Gly His Ile Asp Tyr Ala Asp Ser Val 50 55 60 Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Val Ser Tyr Leu Ser Thr Ala Ser Ser Leu Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 280 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fv region (TNF) in CDR H1 of ACE-24, 25; Fab region (TNF) in CDR H1 of ACE-00r, 24r, 25r <400> 280 Gly Phe Thr Phe Asp Asp Tyr Ala 1 5 <210> 281 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fv region (TNF) in CDR H2 of ACE-24, 25; Fab region (TNF) in CDR H2 of ACE-00r, 24r, 25r <400> 281 Ile Thr Trp Asn Ser Gly His Ile 1 5 <210> 282 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> Fv region (TNF) in CDR H3 of ACE-24, 25; Fab region (TNF) in CDR H3 of ACE00r, 24r, 25r <400> 282 Ala Lys Val Ser Tyr Leu Ser Thr Ala Ser Ser Leu Asp Tyr 1 5 10 <210> 283 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> Fv region (TNF) in VL of ACE-24, 25; Fab region (TNF) in VL of ACE-00r, 24r, 25r <400> 283 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Val Ala Thr Tyr Tyr Cys Gln Arg Tyr Asn Arg Ala Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105 <210> 284 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Fv region (TNF) in CDR L1 of ACE-24, 25; Fab region (TNF) in CDR L1 of ACE-00r, 24r, 25r <400> 284 Gln Gly Ile Arg Asn Tyr 1 5 <210> 285 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Fv region (TNF) in CDR L2 of ACE-24, 25; Fab region (TNF) in CDR L2 of ACE-00r, 24r, 25r <400> 285 Ala Ala Ser 1 <210> 286 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fv region (TNF) in CDR L3 of ACE-24, 25; Fab region (TNF) in CDR L3 of ACE-00r, 24r, 25r <400> 286 Gln Arg Tyr Asn Arg Ala Pro Tyr Thr 1 5 <210> 287 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Fab region (HER2) in VL of ACE-24, 25; Fv region (HER2) in VL of ACE-00r, 24r, 25r <400> 287 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 288 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Fab region (HER2) in CDR L1 of ACE-24, 25; Fv region (HER2) in CDR L1 of ACE-00r, 24r, 25r <400> 288 Gln Asp Val Asn Thr Ala 1 5 <210> 289 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Fab region (HER2) in CDR L2 of ACE-24, 25; Fv region (HER2) in CDR L2 of ACE-00r, 24r, 25r <400> 289 Ser Ala Ser 1 <210> 290 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fab region (HER2) in CDR L3 of ACE-24, 25; Fv region (HER2) in CDR L3 of ACE-00r, 24r, 25r <400> 290 Gln Gln His Tyr Thr Thr Pro Pro Thr 1 5 <210> 291 <211> 372 <212> PRT <213> Artificial Sequence <220> <223> ACE-25-VH amino acid sequence <400> 291 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp 210 215 220 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 225 230 235 240 Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val 245 250 255 Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg Ser Leu Arg Leu Ser 260 265 270 Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr Ala Met His Trp Val 275 280 285 Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ala Ile Thr Trp 290 295 300 Asn Ser Gly His Ile Asp Tyr Ala Asp Ser Val Glu Gly Arg Phe Thr 305 310 315 320 Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser 325 330 335 Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Val Ser Tyr 340 345 350 Leu Ser Thr Ala Ser Ser Leu Asp Tyr Trp Gly Gln Gly Thr Leu Val 355 360 365 Thr Val Ser Ser 370 <210> 292 <211> 373 <212> PRT <213> Artificial Sequence <220> <223> ACE-26-VH amino acid sequence <400> 292 Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30 Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60 Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe 65 70 75 80 Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala 85 90 95 Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Gly Gly Gly Gly Ser Glu Val Lys Leu Leu Glu Ser Gly 245 250 255 Gly Gly Leu Val Gln Pro Lys Gly Ser Leu Lys Leu Ser Cys Ala Ala 260 265 270 Ser Gly Phe Thr Phe Asn Thr Tyr Ala Met Asn Trp Val Arg Gln Ala 275 280 285 Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn 290 295 300 Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile 305 310 315 320 Ser Arg Asp Asp Ser Gln Ser Ile Leu Tyr Leu Gln Met Asn Asn Leu 325 330 335 Lys Thr Glu Asp Thr Ala Met Tyr Tyr Cys Val Arg His Gly Asn Phe 340 345 350 Gly Asn Ser Tyr Val Ser Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu 355 360 365 Val Thr Val Ser Ala 370 <210> 293 <211> 357 <212> PRT <213> Artificial Sequence <220> <223> ACE-26-VL, ACE-32-VL amino acid sequence <400> 293 Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30 Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60 Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe 65 70 75 80 Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala 85 90 95 Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Gly Gly Gly Gly Ser Gln Ala Val Val Thr Gln Glu Ser 245 250 255 Ala Leu Thr Thr Ser Pro Gly Glu Thr Val Thr Leu Thr Cys Arg Ser 260 265 270 Ser Thr Gly Ala Val Thr Thr Ser Asn Tyr Ala Asn Trp Val Gln Glu 275 280 285 Lys Pro Asp His Leu Phe Thr Gly Leu Ile Gly Gly Thr Asn Lys Arg 290 295 300 Ala Pro Gly Val Pro Ala Arg Phe Ser Gly Ser Leu Ile Gly Asp Lys 305 310 315 320 Ala Ala Leu Thr Ile Thr Gly Ala Gln Thr Glu Asp Glu Ala Ile Tyr 325 330 335 Phe Cys Ala Leu Trp Tyr Ser Asn Leu Trp Val Phe Gly Gly Gly Thr 340 345 350 Lys Leu Thr Val Leu 355 <210> 294 <211> 125 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in VH of ACE-26, 29, 32; Fab region (CD3) in VH of ACE-26r, 29r, 32r <400> 294 Glu Val Lys Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Lys Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp 50 55 60 Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Ser Ile 65 70 75 80 Leu Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr 85 90 95 Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe 100 105 110 Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala 115 120 125 <210> 295 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR H1 of ACE-26, 29, 32; Fab region (CD3) in CDR H1 of ACE-26r, 29r, 32r <400> 295 Gly Phe Thr Phe Asn Thr Tyr Ala 1 5 <210> 296 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR H2 of ACE-26, 29, 32; Fab region (CD3) in CDR H2 of ACE-26r, 29r, 32r <400> 296 Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr 1 5 10 <210> 297 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR H3 of ACE-26, 29, 32; Fab region (CD3) in CDR H3 of ACE-26r, 29r, 32r <400> 297 Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe Ala Tyr 1 5 10 15 <210> 298 <211> 109 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in VL of ACE-26, 29, 32; Fab region (CD3) in VL of ACE-26r, 29r, 32r <400> 298 Gln Ala Val Val Thr Gln Glu Ser Ala Leu Thr Thr Ser Pro Gly Glu 1 5 10 15 Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser 20 25 30 Asn Tyr Ala Asn Trp Val Gln Glu Lys Pro Asp His Leu Phe Thr Gly 35 40 45 Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ala Arg Phe 50 55 60 Ser Gly Ser Leu Ile Gly Asp Lys Ala Ala Leu Thr Ile Thr Gly Ala 65 70 75 80 Gln Thr Glu Asp Glu Ala Ile Tyr Phe Cys Ala Leu Trp Tyr Ser Asn 85 90 95 Leu Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 299 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR L1 of ACE-26, 29, 32; Fab region (CD3) in CDR L1 of ACE-26r, 29r, 32r <400> 299 Thr Gly Ala Val Thr Thr Ser Asn Tyr 1 5 <210> 300 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR L2 of ACE-26, 29, 32; Fab region (CD3) in CDR L2 of ACE-26r, 29r, 32r <400> 300 Gly Thr Asn 1 <210> 301 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR L3 of ACE-26, 29, 32; Fab region (CD3) in CDR L3 of ACE-26r, 29r, 32r <400> 301 Ala Leu Trp Tyr Ser Asn Leu Trp Val 1 5 <210> 302 <211> 375 <212> PRT <213> Artificial Sequence <220> <223> ACE-27-VH amino acid sequence <400> 302 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Glu Val Lys Leu Leu Glu 245 250 255 Ser Gly Gly Gly Leu Val Gln Pro Lys Gly Ser Leu Lys Leu Ser Cys 260 265 270 Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr Ala Met Asn Trp Val Arg 275 280 285 Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys 290 295 300 Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe 305 310 315 320 Thr Ile Ser Arg Asp Asp Ser Gln Ser Ile Leu Tyr Leu Gln Met Asn 325 330 335 Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr Tyr Cys Val Arg His Gly 340 345 350 Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe Ala Tyr Trp Gly Gln Gly 355 360 365 Thr Leu Val Thr Val Ser Ala 370 375 <210> 303 <211> 359 <212> PRT <213> Artificial Sequence <220> <223> ACE-27-VL amino acid sequence <400> 303 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Gln Ala Val Val Thr Gln 245 250 255 Glu Ser Ala Leu Thr Thr Ser Pro Gly Glu Thr Val Thr Leu Thr Cys 260 265 270 Arg Ser Ser Thr Gly Ala Val Thr Thr Ser Asn Tyr Ala Asn Trp Val 275 280 285 Gln Glu Lys Pro Asp His Leu Phe Thr Gly Leu Ile Gly Gly Thr Asn 290 295 300 Lys Arg Ala Pro Gly Val Pro Ala Arg Phe Ser Gly Ser Leu Ile Gly 305 310 315 320 Asp Lys Ala Ala Leu Thr Ile Thr Gly Ala Gln Thr Glu Asp Glu Ala 325 330 335 Ile Tyr Phe Cys Ala Leu Trp Tyr Ser Asn Leu Trp Val Phe Gly Gly 340 345 350 Gly Thr Lys Leu Thr Val Leu 355 <210> 304 <211> 216 <212> PRT <213> Artificial Sequence <220> <223> ACE-27-LC, ACE-27r-LC amino acid sequence <400> 304 Gln Ala Val Val Thr Gln Glu Ser Ala Leu Thr Thr Ser Pro Gly Glu 1 5 10 15 Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser 20 25 30 Asn Tyr Ala Asn Trp Val Gln Glu Lys Pro Asp His Leu Phe Thr Gly 35 40 45 Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ala Arg Phe 50 55 60 Ser Gly Ser Leu Ile Gly Asp Lys Ala Ala Leu Thr Ile Thr Gly Ala 65 70 75 80 Gln Thr Glu Asp Glu Ala Ile Tyr Phe Cys Ala Leu Trp Tyr Ser Asn 85 90 95 Leu Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Arg Ser Val 100 105 110 Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys 115 120 125 Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg 130 135 140 Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn 145 150 155 160 Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser 165 170 175 Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys 180 185 190 Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr 195 200 205 Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 305 <211> 125 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in VH of ACE-27; Fab region (CD3) in VH of ACE-27r <400> 305 Glu Val Lys Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Lys Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp 50 55 60 Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Ser Ile 65 70 75 80 Leu Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr 85 90 95 Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe 100 105 110 Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala 115 120 125 <210> 306 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR H1 of ACE-27; Fab region (CD3) in CDR H1 of ACE-27r <400> 306 Gly Phe Thr Phe Asn Thr Tyr Ala 1 5 <210> 307 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR H2 of ACE-27; Fab region (CD3) in CDR H2 of ACE-27r <400> 307 Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr 1 5 10 <210> 308 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR H3 of ACE-27; Fab region (CD3) in CDR H3 of ACE-27r <400> 308 Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe Ala Tyr 1 5 10 15 <210> 309 <211> 109 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in VL of ACE-27; Fab region (CD3) in VL of ACE-27r <400> 309 Gln Ala Val Val Thr Gln Glu Ser Ala Leu Thr Thr Ser Pro Gly Glu 1 5 10 15 Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser 20 25 30 Asn Tyr Ala Asn Trp Val Gln Glu Lys Pro Asp His Leu Phe Thr Gly 35 40 45 Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ala Arg Phe 50 55 60 Ser Gly Ser Leu Ile Gly Asp Lys Ala Ala Leu Thr Ile Thr Gly Ala 65 70 75 80 Gln Thr Glu Asp Glu Ala Ile Tyr Phe Cys Ala Leu Trp Tyr Ser Asn 85 90 95 Leu Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 310 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR L1 of ACE-27; Fab region (CD3) in CDR L1 of ACE-27r <400> 310 Thr Gly Ala Val Thr Thr Ser Asn Tyr 1 5 <210> 311 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR L2 of ACE-27; Fab region (CD3) in CDR L2 of ACE-27r <400> 311 Gly Thr Asn 1 <210> 312 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR L3 of ACE-27; Fab region (CD3) in CDR L3 of ACE-27r <400> 312 Ala Leu Trp Tyr Ser Asn Leu Trp Val 1 5 <210> 313 <211> 109 <212> PRT <213> Artificial Sequence <220> <223> Fab region (PD-L1) in VL of ACE-27; Fv region (PD-L1) in VL of ACE-27r <400> 313 Gln Ala Val Val Thr Gln Glu Ser Ala Leu Thr Thr Ser Pro Gly Glu 1 5 10 15 Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser 20 25 30 Asn Tyr Ala Asn Trp Val Gln Glu Lys Pro Asp His Leu Phe Thr Gly 35 40 45 Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ala Arg Phe 50 55 60 Ser Gly Ser Leu Ile Gly Asp Lys Ala Ala Leu Thr Ile Thr Gly Ala 65 70 75 80 Gln Thr Glu Asp Glu Ala Ile Tyr Phe Cys Ala Leu Trp Tyr Ser Asn 85 90 95 Leu Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 314 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fab region (PD-L1) in CDR L1 of ACE-27; Fv region (PD-L1) in CDR L1 of ACE-27r <400> 314 Thr Gly Ala Val Thr Thr Ser Asn Tyr 1 5 <210> 315 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Fab region (PD-L1) in CDR L2 of ACE-27; Fv region (PD-L1) in CDR L2 of ACE-27r <400> 315 Gly Thr Asn 1 <210> 316 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fab region (PD-L1) in CDR L3 of ACE-27; Fv region (PD-L1) in CDR L3 of ACE-27r <400> 316 Ala Leu Trp Tyr Ser Asn Leu Trp Val 1 5 <210> 317 <211> 477 <212> PRT <213> Artificial Sequence <220> <223> ACE-28-VH amino acid sequence <400> 317 Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30 Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60 Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe 65 70 75 80 Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala 85 90 95 Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Gly Gly Gly Gly Ser Glu Val Gln Leu Gln Gln Ser Gly 245 250 255 Pro Glu Leu Val Lys Pro Gly Pro Ser Met Lys Ile Ser Cys Lys Ala 260 265 270 Ser Gly Tyr Ser Phe Thr Gly Tyr Thr Met Asn Trp Val Lys Gln Ser 275 280 285 His Gly Lys Asn Leu Glu Trp Met Gly Leu Ile Asn Pro Tyr Lys Gly 290 295 300 Val Ser Thr Tyr Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Val 305 310 315 320 Asp Lys Ser Ser Ser Thr Ala Tyr Met Glu Leu Leu Ser Leu Thr Ser 325 330 335 Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg Ser Gly Tyr Tyr Gly Asp 340 345 350 Ser Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly Thr Thr Leu Thr Val 355 360 365 Phe Ser Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser 370 375 380 Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys 385 390 395 400 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 405 410 415 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 420 425 430 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln 435 440 445 Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 450 455 460 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 465 470 475 <210> 318 <211> 463 <212> PRT <213> Artificial Sequence <220> <223> ACE-28-VL amino acid sequence <400> 318 Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30 Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60 Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe 65 70 75 80 Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala 85 90 95 Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Thr Thr 245 250 255 Ser Ser Leu Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Arg 260 265 270 Ala Ser Gln Asp Ile Arg Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro 275 280 285 Asp Gly Thr Val Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu His Ser 290 295 300 Gly Val Pro Ser Lys Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser 305 310 315 320 Leu Thr Ile Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys 325 330 335 Gln Gln Gly Asn Thr Leu Pro Trp Thr Phe Ala Gly Gly Thr Lys Leu 340 345 350 Glu Ile Lys Arg Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 355 360 365 Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 370 375 380 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 385 390 395 400 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 405 410 415 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 420 425 430 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 435 440 445 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 450 455 460 <210> 319 <211> 480 <212> PRT <213> Artificial Sequence <220> <223> ACE-29-VH amino acid sequence <400> 319 Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30 Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60 Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe 65 70 75 80 Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala 85 90 95 Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Gly Gly Gly Gly Ser Glu Val Lys Leu Leu Glu Ser Gly 245 250 255 Gly Gly Leu Val Gln Pro Lys Gly Ser Leu Lys Leu Ser Cys Ala Ala 260 265 270 Ser Gly Phe Thr Phe Asn Thr Tyr Ala Met Asn Trp Val Arg Gln Ala 275 280 285 Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn 290 295 300 Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile 305 310 315 320 Ser Arg Asp Asp Ser Gln Ser Ile Leu Tyr Leu Gln Met Asn Asn Leu 325 330 335 Lys Thr Glu Asp Thr Ala Met Tyr Tyr Cys Val Arg His Gly Asn Phe 340 345 350 Gly Asn Ser Tyr Val Ser Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu 355 360 365 Val Thr Val Ser Ala Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 370 375 380 Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys 385 390 395 400 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 405 410 415 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 420 425 430 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 435 440 445 Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 450 455 460 Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 465 470 475 480 <210> 320 <211> 464 <212> PRT <213> Artificial Sequence <220> <223> ACE-29-VL amino acid sequence <400> 320 Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30 Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60 Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe 65 70 75 80 Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala 85 90 95 Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Gly Gly Gly Gly Ser Gln Ala Val Val Thr Gln Glu Ser 245 250 255 Ala Leu Thr Thr Ser Pro Gly Glu Thr Val Thr Leu Thr Cys Arg Ser 260 265 270 Ser Thr Gly Ala Val Thr Thr Ser Asn Tyr Ala Asn Trp Val Gln Glu 275 280 285 Lys Pro Asp His Leu Phe Thr Gly Leu Ile Gly Gly Thr Asn Lys Arg 290 295 300 Ala Pro Gly Val Pro Ala Arg Phe Ser Gly Ser Leu Ile Gly Asp Lys 305 310 315 320 Ala Ala Leu Thr Ile Thr Gly Ala Gln Thr Glu Asp Glu Ala Ile Tyr 325 330 335 Phe Cys Ala Leu Trp Tyr Ser Asn Leu Trp Val Phe Gly Gly Gly Thr 340 345 350 Lys Leu Thr Val Leu Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 355 360 365 Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys 370 375 380 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 385 390 395 400 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 405 410 415 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 420 425 430 Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 435 440 445 Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 450 455 460 <210> 321 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Synthetic sequence <400> 321 Ile Arg Ser Lys Tyr Asn Asn Tyr Ala 1 5 <210> 322 <211> 369 <212> PRT <213> Artificial Sequence <220> <223> ACE-30-VH amino acid sequence <400> 322 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Gly Gly Gly Gly Ser Gln Met Gln Leu Val Gln Ser Gly 245 250 255 Ala Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala 260 265 270 Ser Gly Gly Thr Phe Ser Ser Tyr Ala Ile Ser Trp Val Arg Gln Ala 275 280 285 Pro Gly Gln Gly Leu Glu Trp Met Gly Arg Ile Ile Pro Ile Leu Gly 290 295 300 Ile Ala Asn Tyr Ala Gln Lys Phe Gln Gly Arg Val Thr Ile Thr Ala 305 310 315 320 Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser 325 330 335 Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Pro Arg Asp Gly Tyr Asn 340 345 350 Leu Val Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser 355 360 365 Ser <210> 323 <211> 360 <212> PRT <213> Artificial Sequence <220> <223> ACE-30-VL, ACE-33-VL amino acid sequence <400> 323 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Gly Gly Gly Gly Ser Gln Leu Val Leu Thr Gln Pro Pro 245 250 255 Ser Val Ser Gly Ala Pro Gly Gln Arg Val Thr Ile Ser Cys Thr Gly 260 265 270 Ser Ser Ser Asn Ile Gly Ala Gly Tyr Asp Val His Trp Tyr Gln Gln 275 280 285 Leu Pro Gly Ala Ala Pro Lys Leu Leu Ile Tyr Gly Asp Ile Asn Arg 290 295 300 Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Ile Ser 305 310 315 320 Ala Ser Leu Ala Ile Thr Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr 325 330 335 Tyr Cys Gln Ser Tyr Asp Ser Ser Leu Ser Gly Gly Val Phe Gly Gly 340 345 350 Gly Thr Lys Leu Thr Val Leu Arg 355 360 <210> 324 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> ACE-30-LC, ACE-31-LC, ACE-33-LC, ACE-20r-LC, ACE-21r-LC amino acid sequence <400> 324 Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly 1 5 10 15 Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Arg Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile 35 40 45 Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Lys Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln 65 70 75 80 Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Trp 85 90 95 Thr Phe Ala Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 325 <211> 122 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD3) in VH of ACE-30, 31, 33, 05r, 09r-12r; Fv region (CD3) in VH of ACE-30r, 31r, 33r <400> 325 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser 115 120 <210> 326 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD3) in CDR H1 of ACE-30, 31, 33; Fv region (CD3) in CDR H1 of ACE-05r, 09r-12r, 30r, 31r, 33r <400> 326 Gly Tyr Ser Phe Thr Gly Tyr Thr 1 5 <210> 327 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD3) in CDR H2 of ACE-30, 31, 33; Fv region (CD3) in CDR H2 of ACE-05r, 09r-12r, 30r, 31r, 33r <400> 327 Ile Asn Pro Tyr Lys Gly Val Ser 1 5 <210> 328 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD3) in CDR H3 of ACE-30, 31, 33; Fv region (CD3) in CDR H3 of ACE-05r, 09r-12r, 30r, 31r, 33r <400> 328 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val 1 5 10 15 <210> 329 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> Fv region (PD-L1) in VH of ACE-30, 31, 33, 04r, 05r, 09r, 12r; Fab region (PD-L1) in VH of ACE-30r, 31r, 33r <400> 329 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser 115 120 <210> 330 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fv region (PD-L1) in CDR H1 of ACE-30, 31, 33, 04r, 05r, 09r, 12r; Fab region (PD-L1) in CDR H1 of ACE-30r, 31r, 33r <400> 330 Gly Gly Thr Phe Ser Ser Tyr Ala 1 5 <210> 331 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fv region (PD-L1) in CDR H2 of ACE-30, 31, 33, 04r, 05r, 09r, 12r; Fab region (PD-L1) in CDR H2 of ACE-30r, 31r, 33r <400> 331 Ile Ile Pro Ile Leu Gly Ile Ala 1 5 <210> 332 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> Fv region (PD-L1) in CDR H3 of ACE-30, 31, 33, 04r, 05r, 09r, 12r; Fab region (PD-L1) in CDR H3 of ACE-30r, 31r, 33r <400> 332 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile 1 5 10 <210> 333 <211> 112 <212> PRT <213> Artificial Sequence <220> <223> Fv region (PD-L1) in VL of ACE-30, 31, 33; Fab region (PD-L1) in VL of ACE-30r, 31r, 33r <400> 333 Gln Leu Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly 20 25 30 Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Ala Ala Pro Lys Leu 35 40 45 Leu Ile Tyr Gly Asp Ile Asn Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Ile Ser Ala Ser Leu Ala Ile Thr Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser 85 90 95 Leu Ser Gly Gly Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Arg 100 105 110 <210> 334 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fv region (PD-L1) in CDR L1 of ACE-30, 31, 33, 04r, 05r; Fab region (PD-L1) in CDR L1 of ACE-30r, 31r, 33r <400> 334 Ser Ser Asn Ile Gly Ala Gly Tyr Asp 1 5 <210> 335 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Fv region (PD-L1) in CDR L2 of ACE-30, 31, 33, 04r, 05r; Fab region (PD-L1) in CDR L2 of ACE-30r, 31r, 33r <400> 335 Gly Asp Ile 1 <210> 336 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Fv region (PD-L1) in CDR L3 of ACE-30, 31, 33, 04r, 05r; Fab region (PD-L1) in CDR L3 of ACE-30r, 31r, 33r <400> 336 Gln Ser Tyr Asp Ser Ser Leu Ser Gly Gly Val 1 5 10 <210> 337 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD3) in VL of ACE-30, 31, 33, 05r, 09r, 10r, 11r, 12r; Fv region (CD3) in VL of ACE-30r, 31r, 33r <400> 337 Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly 1 5 10 15 Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Arg Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile 35 40 45 Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Lys Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln 65 70 75 80 Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Trp 85 90 95 Thr Phe Ala Gly Gly Thr Lys Leu Glu Ile Lys Arg 100 105 <210> 338 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD3) in CDR L1 of ACE-30, 31, 33, 05r, 09r, 10r, 11r, 12r; Fv region (CD3) in CDR L1 of ACE-30r, 31r, 33r <400> 338 Gln Asp Ile Arg Asn Tyr 1 5 <210> 339 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD3) in CDR L2 of ACE-30, 31, 33, 05r, 09r, 10r, 11r, 12r; Fv region (CD3) in CDR L2 of ACE-30r, 31r, 33r <400> 339 Tyr Thr Ser 1 <210> 340 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD3) in CDR L3 of ACE-30, 31, 33, 05r, 09r, 10r, 11r, 12r; Fv region (CD3) in CDR L3 of ACE-30r, 31r, 33r <400> 340 Gln Gln Gly Asn Thr Leu Pro Trp Thr 1 5 <210> 341 <211> 374 <212> PRT <213> Artificial Sequence <220> <223> ACE-33-VH amino acid sequence <400> 341 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Met Gln 245 250 255 Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser Ser Val Lys 260 265 270 Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr Ala Ile Ser 275 280 285 Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Arg Ile 290 295 300 Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe Gln Gly Arg 305 310 315 320 Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu 325 330 335 Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Pro 340 345 350 Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly Gln Gly Thr 355 360 365 Met Val Thr Val Ser Ser 370 <210> 342 <211> 378 <212> PRT <213> Artificial Sequence <220> <223> ACE-32-VH amino acid sequence <400> 342 Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30 Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60 Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe 65 70 75 80 Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala 85 90 95 Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Lys 245 250 255 Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Lys Gly Ser Leu Lys 260 265 270 Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr Ala Met Asn 275 280 285 Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile 290 295 300 Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys 305 310 315 320 Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Ser Ile Leu Tyr Leu 325 330 335 Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr Tyr Cys Val 340 345 350 Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe Ala Tyr Trp 355 360 365 Gly Gln Gly Thr Leu Val Thr Val Ser Ala 370 375 <210> 343 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Synthetic sequence <400> 343 Val Ile Trp Ser Gly Gly Asn Thr 1 5 <210> 344 <211> 377 <212> PRT <213> Artificial Sequence <220> <223> ACE-31-VH amino acid sequence <400> 344 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro 225 230 235 240 Glu Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 245 250 255 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 260 265 270 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 275 280 285 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 290 295 300 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 305 310 315 320 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 325 330 335 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 340 345 350 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 355 360 365 Gln Gly Thr Met Val Thr Val Ser Ser 370 375 <210> 345 <211> 363 <212> PRT <213> Artificial Sequence <220> <223> ACE-31-VL amino acid sequence <400> 345 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro 225 230 235 240 Glu Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Gln Leu Val Leu Thr 245 250 255 Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln Arg Val Thr Ile Ser 260 265 270 Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly Tyr Asp Val His Trp 275 280 285 Tyr Gln Gln Leu Pro Gly Ala Ala Pro Lys Leu Leu Ile Tyr Gly Asp 290 295 300 Ile Asn Arg Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser 305 310 315 320 Gly Ile Ser Ala Ser Leu Ala Ile Thr Gly Leu Gln Ala Glu Asp Glu 325 330 335 Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser Leu Ser Gly Gly Val 340 345 350 Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Arg 355 360 <210> 346 <211> 366 <212> PRT <213> Artificial Sequence <220> <223> ACE-34-VH amino acid sequence <400> 346 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu 245 250 255 Ser Gly Gly Gly Leu Val Gln Pro Gly Lys Ser Leu Lys Leu Ser Cys 260 265 270 Glu Ala Ser Gly Phe Thr Phe Ser Gly Tyr Gly Met His Trp Val Arg 275 280 285 Gln Ala Pro Gly Arg Gly Leu Glu Ser Val Ala Tyr Ile Thr Ser Ser 290 295 300 Ser Ile Asn Ile Lys Tyr Ala Asp Ala Val Lys Gly Arg Phe Thr Val 305 310 315 320 Ser Arg Asp Asn Ala Lys Asn Leu Leu Phe Leu Gln Met Asn Ile Leu 325 330 335 Lys Ser Glu Asp Thr Ala Met Tyr Tyr Cys Ala Arg Phe Asp Trp Asp 340 345 350 Lys Asn Tyr Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser 355 360 365 <210> 347 <211> 357 <212> PRT <213> Artificial Sequence <220> <223> ACE-34-VL amino acid sequence <400> 347 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln 245 250 255 Ser Pro Ser Ser Leu Pro Ala Ser Leu Gly Asp Arg Val Thr Ile Asn 260 265 270 Cys Gln Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn Trp Tyr Gln Gln 275 280 285 Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Asn Lys Leu 290 295 300 Ala Asp Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Arg Asp 305 310 315 320 Ser Ser Phe Thr Ile Ser Ser Leu Glu Ser Glu Asp Ile Gly Ser Tyr 325 330 335 Tyr Cys Gln Gln Tyr Tyr Asn Tyr Pro Trp Thr Phe Gly Pro Gly Thr 340 345 350 Lys Leu Glu Ile Lys 355 <210> 348 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> Fv region (mouse CD3) in VH of ACE-34; Fab region (mouse CD3) in VH of ACE-34r <400> 348 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Lys 1 5 10 15 Ser Leu Lys Leu Ser Cys Glu Ala Ser Gly Phe Thr Phe Ser Gly Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Arg Gly Leu Glu Ser Val 35 40 45 Ala Tyr Ile Thr Ser Ser Ser Ile Asn Ile Lys Tyr Ala Asp Ala Val 50 55 60 Lys Gly Arg Phe Thr Val Ser Arg Asp Asn Ala Lys Asn Leu Leu Phe 65 70 75 80 Leu Gln Met Asn Ile Leu Lys Ser Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Arg Phe Asp Trp Asp Lys Asn Tyr Trp Gly Gln Gly Thr Met Val 100 105 110 Thr Val Ser Ser 115 <210> 349 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Fv region (mouse CD3) in CDR H1 of ACE-34; Fab region (mouse CD3) in CDR H1 of ACE-34r <400> 349 Gly Tyr Gly Met His 1 5 <210> 350 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Fv region (mouse CD3) in CDR H2 of ACE-34; Fab region (mouse CD3) in CDR H2 of ACE-34r <400> 350 Tyr Ile Thr Ser Ser Ser Ile Asn Ile Lys Tyr Ala Asp Ala Val Lys 1 5 10 15 Gly <210> 351 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Fv region (mouse CD3) in CDR H3 of ACE-34; Fab region (mouse CD3) in CDR H3 of ACE-34r <400> 351 Phe Asp Trp Asp Lys Asn 1 5 <210> 352 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Fv region (mouse CD3) in VL of ACE-34; Fab region (mouse CD3) in VL of ACE-34r <400> 352 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Pro Ala Ser Leu Gly 1 5 10 15 Asp Arg Val Thr Ile Asn Cys Gln Ala Ser Gln Asp Ile Ser Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Tyr Thr Asn Lys Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Arg Asp Ser Ser Phe Thr Ile Ser Ser Leu Glu Ser 65 70 75 80 Glu Asp Ile Gly Ser Tyr Tyr Cys Gln Gln Tyr Tyr Asn Tyr Pro Trp 85 90 95 Thr Phe Gly Pro Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 353 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Fv region (mouse CD3) in CDR L1 of ACE-34; Fab region (mouse CD3) in CDR L1 of ACE-34r <400> 353 Gln Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn 1 5 10 <210> 354 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Fv region (mouse CD3) in CDR L2 of ACE-34; Fab region (mouse CD3) in CDR L2 of ACE-34r <400> 354 Tyr Thr Asn Lys Leu Ala Asp 1 5 <210> 355 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fv region (mouse CD3) in CDR L3 of ACE-34; Fab region (mouse CD3) in CDR L3 of ACE-34r <400> 355 Gln Gln Tyr Tyr Asn Tyr Pro Trp Thr 1 5 <210> 356 <211> 370 <212> PRT <213> Artificial Sequence <220> <223> ACE-35-VH amino acid sequence <400> 356 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Gln Val Lys Leu Gln Gln 245 250 255 Ser Gly Ser Glu Leu Gly Lys Pro Gly Ala Ser Val Lys Leu Ser Cys 260 265 270 Lys Thr Ser Gly Tyr Ile Phe Thr Asp His Tyr Ile Ser Trp Val Lys 275 280 285 Gln Lys Pro Gly Glu Ser Leu Gln Trp Ile Gly Asn Val Tyr Gly Gly 290 295 300 Asn Gly Gly Thr Ser Tyr Asn Gln Lys Phe Gln Gly Lys Ala Thr Leu 305 310 315 320 Thr Val Asp Lys Ile Ser Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu 325 330 335 Thr Ser Glu Asp Ser Ala Ile Tyr Tyr Cys Ala Arg Arg Pro Val Ala 340 345 350 Thr Gly His Ala Met Asp Tyr Trp Gly Gln Gly Ile Gln Val Thr Val 355 360 365 Ser Ser 370 <210> 357 <211> 357 <212> PRT <213> Artificial Sequence <220> <223> ACE-35-VL amino acid sequence <400> 357 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Asp Ile Val Leu Thr Gln 245 250 255 Thr Pro Ala Thr Leu Ser Leu Ile Pro Gly Glu Arg Val Thr Met Thr 260 265 270 Cys Lys Thr Ser Gln Asn Ile Gly Thr Ile Leu His Trp Tyr His Gln 275 280 285 Lys Pro Lys Glu Ala Pro Arg Ala Leu Ile Lys Tyr Ala Ser Gln Ser 290 295 300 Ile Pro Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly Ser Glu Thr Asp 305 310 315 320 Phe Thr Leu Ser Ile Asn Asn Leu Glu Pro Asp Asp Ile Gly Ile Tyr 325 330 335 Tyr Cys Gln Gln Ser Arg Ser Trp Pro Val Thr Phe Gly Pro Gly Thr 340 345 350 Lys Leu Glu Ile Lys 355 <210> 358 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> Fv region (mouse CD3) in VH of ACE-35; Fab region (mouse CD3) in VH of ACE-35r <400> 358 Gln Val Lys Leu Gln Gln Ser Gly Ser Glu Leu Gly Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Thr Ser Gly Tyr Ile Phe Thr Asp His 20 25 30 Tyr Ile Ser Trp Val Lys Gln Lys Pro Gly Glu Ser Leu Gln Trp Ile 35 40 45 Gly Asn Val Tyr Gly Gly Asn Gly Gly Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Gln Gly Lys Ala Thr Leu Thr Val Asp Lys Ile Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Ile Tyr Tyr Cys 85 90 95 Ala Arg Arg Pro Val Ala Thr Gly His Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Ile Gln Val Thr Val Ser Ser 115 120 <210> 359 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Fv region (mouse CD3) in CDR H1 of ACE-35; Fab region (mouse CD3) in CDR H1 of ACE-35r <400> 359 Asp His Tyr Ile Ser 1 5 <210> 360 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Fv region (mouse CD3) in CDR H2 of ACE-35; Fab region (mouse CD3) in CDR H2 of ACE-35r <400> 360 Asn Val Tyr Gly Gly Asn Gly Gly Thr Ser Tyr Asn Gln Lys Phe Gln 1 5 10 15 Gly <210> 361 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Fv region (mouse CD3) in CDR H3 of ACE-35; Fab region (mouse CD3) in CDR H3 of ACE-35r <400> 361 Arg Pro Val Ala Thr Gly His Ala Met Asp Tyr 1 5 10 <210> 362 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Fv region (mouse CD3) in VL of ACE-35; Fab region (mouse CD3) in VL of ACE-35r <400> 362 Asp Ile Val Leu Thr Gln Thr Pro Ala Thr Leu Ser Leu Ile Pro Gly 1 5 10 15 Glu Arg Val Thr Met Thr Cys Lys Thr Ser Gln Asn Ile Gly Thr Ile 20 25 30 Leu His Trp Tyr His Gln Lys Pro Lys Glu Ala Pro Arg Ala Leu Ile 35 40 45 Lys Tyr Ala Ser Gln Ser Ile Pro Gly Ile Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Glu Thr Asp Phe Thr Leu Ser Ile Asn Asn Leu Glu Pro 65 70 75 80 Asp Asp Ile Gly Ile Tyr Tyr Cys Gln Gln Ser Arg Ser Trp Pro Val 85 90 95 Thr Phe Gly Pro Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 363 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Fv region (mouse CD3) in CDR L1 of ACE-35; Fab region (mouse CD3) in CDR L1 of ACE-35r <400> 363 Lys Thr Ser Gln Asn Ile Gly Thr Ile Leu His 1 5 10 <210> 364 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Fv region (mouse CD3) in CDR L2 of ACE-35; Fab region (mouse CD3) in CDR L2 of ACE-35r <400> 364 Tyr Ala Ser Gln Ser Ile Pro 1 5 <210> 365 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fv region (mouse CD3) in CDR L3 of ACE-35; Fab region (mouse CD3) in CDR L3 of ACE-35r <400> 365 Gln Gln Ser Arg Ser Trp Pro Val Thr 1 5 <210> 366 <211> 368 <212> PRT <213> Artificial Sequence <220> <223> ACE-36-VH amino acid sequence <400> 366 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Gln Val Gln Leu Val Glu 245 250 255 Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys 260 265 270 Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Thr Met His Trp Val Arg 275 280 285 Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Thr Phe Ile Ser Tyr Asp 290 295 300 Gly Asn Asn Lys Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile 305 310 315 320 Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu 325 330 335 Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys Ala Arg Thr Gly Trp Leu 340 345 350 Gly Pro Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 355 360 365 <210> 367 <211> 351 <212> PRT <213> Artificial Sequence <220> <223> ACE-36-VL amino acid sequence <400> 367 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu 245 250 255 Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val 260 265 270 Gly Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro 275 280 285 Arg Leu Leu Ile Tyr Gly Ala Phe Ser Arg Ala Thr Gly Ile Pro Asp 290 295 300 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser 305 310 315 320 Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly 325 330 335 Ser Ser Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 340 345 350 <210> 368 <211> 118 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CTLA4) in VH of ACE-36, 37; Fab region (CTLA4) in VH of ACE-36r, 37r <400> 368 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Thr Phe Ile Ser Tyr Asp Gly Asn Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys 85 90 95 Ala Arg Thr Gly Trp Leu Gly Pro Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 369 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CTLA4) in CDR H1 of ACE-36, 37; Fab region (CTLA4) in CDR H1 of ACE-36r, 37r <400> 369 Gly Phe Thr Phe Ser Ser Tyr Thr 1 5 <210> 370 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CTLA4) in CDR H2 of ACE-36, ACE-37; Fab region (CTLA4) in CDR H2 of ACE-36r, 37r <400> 370 Ile Ser Tyr Asp Gly Asn Asn Lys 1 5 <210> 371 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CTLA4) in CDR H3 of ACE-36, ACE-37; Fab region (CTLA4) in CDR H3 of ACE-36r, 37r <400> 371 Ala Arg Thr Gly Trp Leu Gly Pro Phe Asp Tyr 1 5 10 <210> 372 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CTLA4) in VL of ACE-36, 37; Fab region (CTLA4) in VL of ACE-36r, 37r <400> 372 Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Gly Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Phe Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro 85 90 95 Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 373 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CTLA4) in CDR L1 of ACE-36, 37; Fab region (CTLA4) in CDR L1 of ACE-36r, 37r <400> 373 Gln Ser Val Gly Ser Ser Tyr 1 5 <210> 374 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CTLA4) in CDR L2 of ACE-36, 37; Fab region (CTLA4) in CDR L2 of ACE-36r, 37r <400> 374 Gly Ala Phe 1 <210> 375 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CTLA4) in CDR L3 of ACE-36, 37; Fab region (CTLA4) in CDR L3 of ACE-36r, 37r <400> 375 Gln Gln Tyr Gly Ser Ser Pro Trp Thr 1 5 <210> 376 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> Fab region (PD-L1) in VL of ACE-36; Fv region (PD-L1) in VL of ACE-04r, 05r, 09r, 12r, 36r <400> 376 Gln Leu Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly 20 25 30 Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Ala Ala Pro Lys Leu 35 40 45 Leu Ile Tyr Gly Asp Ile Asn Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Ile Ser Ala Ser Leu Ala Ile Thr Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser 85 90 95 Leu Ser Gly Gly Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 377 <211> 368 <212> PRT <213> Artificial Sequence <220> <223> ACE-37-VH amino acid sequence <400> 377 Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asn Met His Trp Val Lys Gln Thr Pro Gly Arg Gly Leu Glu Trp Ile 35 40 45 Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val Trp Gly 100 105 110 Ala Gly Thr Thr Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Gln Val Gln Leu Val Glu 245 250 255 Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys 260 265 270 Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Thr Met His Trp Val Arg 275 280 285 Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Thr Phe Ile Ser Tyr Asp 290 295 300 Gly Asn Asn Lys Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile 305 310 315 320 Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu 325 330 335 Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys Ala Arg Thr Gly Trp Leu 340 345 350 Gly Pro Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 355 360 365 <210> 378 <211> 351 <212> PRT <213> Artificial Sequence <220> <223> ACE-37-VL amino acid sequence <400> 378 Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asn Met His Trp Val Lys Gln Thr Pro Gly Arg Gly Leu Glu Trp Ile 35 40 45 Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val Trp Gly 100 105 110 Ala Gly Thr Thr Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu 245 250 255 Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val 260 265 270 Gly Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro 275 280 285 Arg Leu Leu Ile Tyr Gly Ala Phe Ser Arg Ala Thr Gly Ile Pro Asp 290 295 300 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser 305 310 315 320 Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly 325 330 335 Ser Ser Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 340 345 350 <210> 379 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic sequence <400> 379 Gly Phe Thr Phe Ser Ser Tyr 1 5 <210> 380 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Synthetic sequence <400> 380 Gln Trp Thr Ser Asn Pro Pro Thr 1 5 <210> 381 <211> 477 <212> PRT <213> Artificial Sequence <220> <223> ACE-38-VH, ACE-40-VH amino acid sequence <400> 381 Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30 Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60 Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe 65 70 75 80 Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala 85 90 95 Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Gly Gly Gly Gly Ser Glu Val Gln Leu Gln Gln Ser Gly 245 250 255 Pro Glu Leu Val Lys Pro Gly Pro Ser Met Lys Ile Ser Cys Lys Ala 260 265 270 Ser Gly Tyr Ser Phe Thr Gly Tyr Thr Met Asn Trp Val Lys Gln Ser 275 280 285 His Gly Lys Asn Leu Glu Trp Met Gly Leu Ile Asn Pro Tyr Lys Gly 290 295 300 Val Ser Thr Tyr Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Val 305 310 315 320 Asp Lys Ser Ser Ser Thr Ala Tyr Met Glu Leu Leu Ser Leu Thr Ser 325 330 335 Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg Ser Gly Tyr Tyr Gly Asp 340 345 350 Ser Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly Thr Thr Leu Thr Val 355 360 365 Phe Ser Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Ser Pro Pro Ser 370 375 380 Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Arg Cys His Val Lys 385 390 395 400 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 405 410 415 Pro Glu Asn Asn Tyr Lys Thr Thr Lys Pro Val Leu Asp Ser Asp Gly 420 425 430 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln 435 440 445 Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 450 455 460 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 465 470 475 <210> 382 <211> 356 <212> PRT <213> Artificial Sequence <220> <223> ACE-38-VL amino acid sequence <400> 382 Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30 Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60 Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe 65 70 75 80 Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala 85 90 95 Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Thr Thr 245 250 255 Ser Ser Leu Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Arg 260 265 270 Ala Ser Gln Asp Ile Arg Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro 275 280 285 Asp Gly Thr Val Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu His Ser 290 295 300 Gly Val Pro Ser Lys Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser 305 310 315 320 Leu Thr Ile Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys 325 330 335 Gln Gln Gly Asn Thr Leu Pro Trp Thr Phe Ala Gly Gly Thr Lys Leu 340 345 350 Glu Ile Lys Arg 355 <210> 383 <211> 370 <212> PRT <213> Artificial Sequence <220> <223> ACE-39-VH amino acid sequence <400> 383 Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30 Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60 Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe 65 70 75 80 Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala 85 90 95 Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Gly Gly Gly Gly Ser Glu Val Gln Leu Gln Gln Ser Gly 245 250 255 Pro Glu Leu Val Lys Pro Gly Pro Ser Met Lys Ile Ser Cys Lys Ala 260 265 270 Ser Gly Tyr Ser Phe Thr Gly Tyr Thr Met Asn Trp Val Lys Gln Ser 275 280 285 His Gly Lys Asn Leu Glu Trp Met Gly Leu Ile Asn Pro Tyr Lys Gly 290 295 300 Val Ser Thr Tyr Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Val 305 310 315 320 Asp Lys Ser Ser Ser Thr Ala Tyr Met Glu Leu Leu Ser Leu Thr Ser 325 330 335 Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg Ser Gly Tyr Tyr Gly Asp 340 345 350 Ser Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly Thr Thr Leu Thr Val 355 360 365 Phe Ser 370 <210> 384 <211> 463 <212> PRT <213> Artificial Sequence <220> <223> ACE-39-VL, ACE-40-VL amino acid sequence <400> 384 Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30 Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60 Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe 65 70 75 80 Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala 85 90 95 Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Thr Thr 245 250 255 Ser Ser Leu Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Arg 260 265 270 Ala Ser Gln Asp Ile Arg Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro 275 280 285 Asp Gly Thr Val Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu His Ser 290 295 300 Gly Val Pro Ser Lys Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser 305 310 315 320 Leu Thr Ile Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys 325 330 335 Gln Gln Gly Asn Thr Leu Pro Trp Thr Phe Ala Gly Gly Thr Lys Leu 340 345 350 Glu Ile Lys Arg Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Ser Pro 355 360 365 Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Arg Cys His 370 375 380 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 385 390 395 400 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Lys Pro Val Leu Asp Ser 405 410 415 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 420 425 430 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 435 440 445 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 450 455 460 <210> 385 <211> 21 <212> PRT <213> Artificial Sequence <220> <223> Hinge 1 <400> 385 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu 1 5 10 15 Leu Leu Gly Gly Pro 20 <210> 386 <211> 18 <212> PRT <213> Artificial Sequence <220> <223> Hinge 2 <400> 386 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro <210> 387 <211> 19 <212> PRT <213> Artificial Sequence <220> <223> Hinge 3 <400> 387 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu 1 5 10 15 Leu Leu Gly <210> 388 <211> 362 <212> PRT <213> Artificial Sequence <220> <223> ACE-00r-VH amino acid sequence <400> 388 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Thr Trp Asn Ser Gly His Ile Asp Tyr Ala Asp Ser Val 50 55 60 Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Val Ser Tyr Leu Ser Thr Ala Ser Ser Leu Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro 245 250 255 Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys 260 265 270 Asp Thr Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu 275 280 285 Trp Val Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp 290 295 300 Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr 305 310 315 320 Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr 325 330 335 Tyr Cys Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp 340 345 350 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 355 360 <210> 389 <211> 349 <212> PRT <213> Artificial Sequence <220> <223> ACE-00r-VL amino acid sequence <400> 389 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Thr Trp Asn Ser Gly His Ile Asp Tyr Ala Asp Ser Val 50 55 60 Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Val Ser Tyr Leu Ser Thr Ala Ser Ser Leu Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser 245 250 255 Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn 260 265 270 Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu 275 280 285 Leu Ile Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe 290 295 300 Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu 305 310 315 320 Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr 325 330 335 Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 340 345 <210> 390 <211> 215 <212> PRT <213> Artificial Sequence <220> <223> ACE-00r-LC, ACE-24r-LC, ACE-25r-LC amino acid sequence <400> 390 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Val Ala Thr Tyr Tyr Cys Gln Arg Tyr Asn Arg Ala Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Arg Ser Val Ala 100 105 110 Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser 115 120 125 Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu 130 135 140 Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser 145 150 155 160 Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu 165 170 175 Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 180 185 190 Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys 195 200 205 Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 391 <211> 364 <212> PRT <213> Artificial Sequence <220> <223> ACE-01r-VH amino acid sequence <400> 391 Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr 20 25 30 Thr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230 235 240 Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ser 245 250 255 Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Ser Tyr 260 265 270 Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 275 280 285 Gly Gln Ile Trp Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gly Lys Phe 290 295 300 Lys Gly Lys Ala Thr Leu Thr Ala Asp Glu Ser Ser Ser Thr Ala Tyr 305 310 315 320 Met Gln Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Phe Cys 325 330 335 Ala Arg Arg Glu Thr Thr Thr Val Gly Arg Tyr Tyr Tyr Ala Met Asp 340 345 350 Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 355 360 <210> 392 <211> 351 <212> PRT <213> Artificial Sequence <220> <223> ACE-01r-VL amino acid sequence <400> 392 Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr 20 25 30 Thr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230 235 240 Asp Ile Gln Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly 245 250 255 Gln Arg Ala Thr Ile Ser Cys Lys Ala Ser Gln Ser Val Asp Tyr Asp 260 265 270 Gly Asp Ser Tyr Leu Asn Trp Tyr Gln Gln Ile Pro Gly Gln Pro Pro 275 280 285 Lys Leu Leu Ile Tyr Asp Ala Ser Asn Leu Val Ser Gly Ile Pro Pro 290 295 300 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile His 305 310 315 320 Pro Val Glu Lys Val Asp Ala Ala Thr Tyr His Cys Gln Gln Ser Thr 325 330 335 Glu Asp Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 340 345 350 <210> 393 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> ACE-01r-LC amino acid sequence <400> 393 Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met 20 25 30 Asn Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr 35 40 45 Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala His Phe Arg Gly Ser 50 55 60 Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Gly Met Glu Ala Glu 65 70 75 80 Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Phe Thr 85 90 95 Phe Gly Ser Gly Thr Lys Leu Glu Ile Asn Arg Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 394 <211> 364 <212> PRT <213> Artificial Sequence <220> <223> ACE-02r-VH amino acid sequence <400> 394 Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Asn Pro Ser Ser Gly Tyr Thr Lys Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Arg Phe Thr Ile Ser Ala Asp Lys Ser Lys Ser Thr Ala Phe 65 70 75 80 Leu Gln Met Asp Ser Leu Arg Pro Glu Asp Thr Gly Val Tyr Phe Cys 85 90 95 Ala Arg Trp Gln Asp Tyr Asp Val Tyr Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Pro Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230 235 240 Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ser 245 250 255 Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Ser Tyr 260 265 270 Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 275 280 285 Gly Gln Ile Trp Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gly Lys Phe 290 295 300 Lys Gly Lys Ala Thr Leu Thr Ala Asp Glu Ser Ser Ser Thr Ala Tyr 305 310 315 320 Met Gln Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Phe Cys 325 330 335 Ala Arg Arg Glu Thr Thr Thr Val Gly Arg Tyr Tyr Tyr Ala Met Asp 340 345 350 Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 355 360 <210> 395 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD3) in VH of ACE-02r <400> 395 Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Asn Pro Ser Ser Gly Tyr Thr Lys Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Arg Phe Thr Ile Ser Ala Asp Lys Ser Lys Ser Thr Ala Phe 65 70 75 80 Leu Gln Met Asp Ser Leu Arg Pro Glu Asp Thr Gly Val Tyr Phe Cys 85 90 95 Ala Arg Trp Gln Asp Tyr Asp Val Tyr Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Pro Val Thr Val Ser Ser 115 <210> 396 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD3) in CDR H1 of ACE-02r <400> 396 Gly Tyr Thr Phe Thr Ser Tyr Thr 1 5 <210> 397 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD3) in CDR H2 of ACE-02r <400> 397 Ile Asn Pro Ser Ser Gly Tyr Thr 1 5 <210> 398 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD3) in CDR H3 of ACE-02r <400> 398 Ala Arg Trp Gln Asp Tyr Asp Val Tyr Phe Asp Tyr 1 5 10 <210> 399 <211> 351 <212> PRT <213> Artificial Sequence <220> <223> ACE-02r-VL amino acid sequence <400> 399 Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Asn Pro Ser Ser Gly Tyr Thr Lys Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Arg Phe Thr Ile Ser Ala Asp Lys Ser Lys Ser Thr Ala Phe 65 70 75 80 Leu Gln Met Asp Ser Leu Arg Pro Glu Asp Thr Gly Val Tyr Phe Cys 85 90 95 Ala Arg Trp Gln Asp Tyr Asp Val Tyr Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Pro Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230 235 240 Asp Ile Gln Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly 245 250 255 Gln Arg Ala Thr Ile Ser Cys Lys Ala Ser Gln Ser Val Asp Tyr Asp 260 265 270 Gly Asp Ser Tyr Leu Asn Trp Tyr Gln Gln Ile Pro Gly Gln Pro Pro 275 280 285 Lys Leu Leu Ile Tyr Asp Ala Ser Asn Leu Val Ser Gly Ile Pro Pro 290 295 300 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile His 305 310 315 320 Pro Val Glu Lys Val Asp Ala Ala Thr Tyr His Cys Gln Gln Ser Thr 325 330 335 Glu Asp Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 340 345 350 <210> 400 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> ACE-02r-LC amino acid sequence <400> 400 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Met 20 25 30 His Trp Tyr Gln Gln Thr Pro Gly Lys Ala Pro Lys Pro Trp Ile Tyr 35 40 45 Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu 65 70 75 80 Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Pro Thr 85 90 95 Phe Gly Gln Gly Thr Lys Leu Gln Ile Thr Arg Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 401 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD3) in VL of ACE-02r <400> 401 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Met 20 25 30 His Trp Tyr Gln Gln Thr Pro Gly Lys Ala Pro Lys Pro Trp Ile Tyr 35 40 45 Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu 65 70 75 80 Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Pro Thr 85 90 95 Phe Gly Gln Gly Thr Lys Leu Gln Ile Thr Arg 100 105 <210> 402 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD3) in CDR L1 of ACE-02r <400> 402 Ser Ser Ser Val Ser Tyr 1 5 <210> 403 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD3) in CDR L2 of ACE-02r <400> 403 Ala Thr Ser 1 <210> 404 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD3) in CDR L3 of ACE-02r <400> 404 Gln Gln Trp Ser Ser Asn Pro Pro Thr 1 5 <210> 405 <211> 363 <212> PRT <213> Artificial Sequence <220> <223> ACE-03r-VH amino acid sequence <400> 405 Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser 1 5 10 15 Leu Arg Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr Thr 20 25 30 Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly 35 40 45 Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Val Lys 50 55 60 Asp Arg Phe Thr Ile Ser Thr Asp Lys Ser Lys Ser Thr Ala Phe Leu 65 70 75 80 Gln Met Asp Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Pro Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205 Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215 220 His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Gln 225 230 235 240 Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ser Ser 245 250 255 Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Ser Tyr Trp 260 265 270 Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly 275 280 285 Gln Ile Trp Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gly Lys Phe Lys 290 295 300 Gly Lys Ala Thr Leu Thr Ala Asp Glu Ser Ser Ser Thr Ala Tyr Met 305 310 315 320 Gln Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Phe Cys Ala 325 330 335 Arg Arg Glu Thr Thr Thr Val Gly Arg Tyr Tyr Tyr Ala Met Asp Tyr 340 345 350 Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 355 360 <210> 406 <211> 118 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD3) in VH of ACE-03r <400> 406 Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser 1 5 10 15 Leu Arg Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr Thr 20 25 30 Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly 35 40 45 Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Val Lys 50 55 60 Asp Arg Phe Thr Ile Ser Thr Asp Lys Ser Lys Ser Thr Ala Phe Leu 65 70 75 80 Gln Met Asp Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Pro Val Thr Val Ser Ser 115 <210> 407 <211> 350 <212> PRT <213> Artificial Sequence <220> <223> ACE-03r-VL amino acid sequence <400> 407 Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser 1 5 10 15 Leu Arg Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr Thr 20 25 30 Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly 35 40 45 Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Val Lys 50 55 60 Asp Arg Phe Thr Ile Ser Thr Asp Lys Ser Lys Ser Thr Ala Phe Leu 65 70 75 80 Gln Met Asp Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Pro Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205 Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215 220 His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Asp 225 230 235 240 Ile Gln Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly Gln 245 250 255 Arg Ala Thr Ile Ser Cys Lys Ala Ser Gln Ser Val Asp Tyr Asp Gly 260 265 270 Asp Ser Tyr Leu Asn Trp Tyr Gln Gln Ile Pro Gly Gln Pro Pro Lys 275 280 285 Leu Leu Ile Tyr Asp Ala Ser Asn Leu Val Ser Gly Ile Pro Pro Arg 290 295 300 Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile His Pro 305 310 315 320 Val Glu Lys Val Asp Ala Ala Thr Tyr His Cys Gln Gln Ser Thr Glu 325 330 335 Asp Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 340 345 350 <210> 408 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> ACE-03r-LC amino acid sequence <400> 408 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met 20 25 30 Asn Trp Tyr Gln Gln Thr Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr 35 40 45 Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu 65 70 75 80 Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Phe Thr 85 90 95 Phe Gly Gln Gly Thr Lys Leu Gln Ile Thr Arg Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 409 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD3) in VL of ACE-03r <400> 409 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met 20 25 30 Asn Trp Tyr Gln Gln Thr Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr 35 40 45 Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu 65 70 75 80 Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Phe Thr 85 90 95 Phe Gly Gln Gly Thr Lys Leu Gln Ile Thr Arg 100 105 <210> 410 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD3) in CDR L3 of ACE-03r <400> 410 Gln Gln Trp Ser Ser Asn Pro Phe Thr 1 5 <210> 411 <211> 469 <212> PRT <213> Artificial Sequence <220> <223> ACE-04r-VH amino acid sequence <400> 411 Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr 20 25 30 Thr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Thr Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230 235 240 Gly Gly Gly Gly Ser Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val 245 250 255 Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly 260 265 270 Thr Phe Ser Ser Tyr Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln 275 280 285 Gly Leu Glu Trp Met Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn 290 295 300 Tyr Ala Gln Lys Phe Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser 305 310 315 320 Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr 325 330 335 Ala Val Tyr Tyr Cys Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala 340 345 350 Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser 355 360 365 Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr 370 375 380 Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro 385 390 395 400 Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val 405 410 415 His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser 420 425 430 Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile 435 440 445 Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val 450 455 460 Glu Pro Lys Ser Cys 465 <210> 412 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD3) in VH of ACE-04r <400> 412 Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr 20 25 30 Thr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Thr Val Thr Val Ser Ala 115 <210> 413 <211> 463 <212> PRT <213> Artificial Sequence <220> <223> ACE-04r-VL amino acid sequence <400> 413 Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr 20 25 30 Thr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Thr Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230 235 240 Gly Gly Gly Gly Ser Gln Leu Val Leu Thr Gln Pro Pro Ser Val Ser 245 250 255 Gly Ala Pro Gly Gln Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser 260 265 270 Asn Ile Gly Ala Gly Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly 275 280 285 Ala Ala Pro Lys Leu Leu Ile Tyr Gly Asp Ile Asn Arg Pro Ser Gly 290 295 300 Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Ile Ser Ala Ser Leu 305 310 315 320 Ala Ile Thr Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln 325 330 335 Ser Tyr Asp Ser Ser Leu Ser Gly Gly Val Phe Gly Gly Gly Thr Lys 340 345 350 Leu Thr Val Leu Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro 355 360 365 Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu 370 375 380 Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp 385 390 395 400 Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp 405 410 415 Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys 420 425 430 Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln 435 440 445 Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 450 455 460 <210> 414 <211> 213 <212> PRT <213> Artificial Sequence <220> <223> ACE-04r-LC amino acid sequence <400> 414 Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met 20 25 30 Asn Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr 35 40 45 Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala His Phe Arg Gly Ser 50 55 60 Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Gly Met Glu Ala Glu 65 70 75 80 Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Phe Thr 85 90 95 Phe Gly Ser Gly Thr Lys Leu Glu Ile Asn Arg Ser Val Ala Ala Pro 100 105 110 Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 115 120 125 Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135 140 Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu 145 150 155 160 Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175 Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190 Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200 205 Asn Arg Gly Glu Cys 210 <210> 415 <211> 106 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD3) in VL of ACE-04r <400> 415 Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met 20 25 30 Asn Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr 35 40 45 Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala His Phe Arg Gly Ser 50 55 60 Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Gly Met Glu Ala Glu 65 70 75 80 Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Phe Thr 85 90 95 Phe Gly Ser Gly Thr Lys Leu Glu Ile Asn 100 105 <210> 416 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD3) in CDR L3 of ACE-04r <400> 416 Gln Gln Trp Ser Ser Asn Pro Phe 1 5 <210> 417 <211> 369 <212> PRT <213> Artificial Sequence <220> <223> ACE-05r-VH amino acid sequence <400> 417 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Gly Gly Gly Gly Ser Gln Met Gln Leu Val Gln Ser Gly 245 250 255 Ala Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala 260 265 270 Ser Gly Gly Thr Phe Ser Ser Tyr Ala Ile Ser Trp Val Arg Gln Ala 275 280 285 Pro Gly Gln Gly Leu Glu Trp Met Gly Arg Ile Ile Pro Ile Leu Gly 290 295 300 Ile Ala Asn Tyr Ala Gln Lys Phe Gln Gly Arg Val Thr Ile Thr Ala 305 310 315 320 Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser 325 330 335 Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Pro Arg Asp Gly Tyr Asn 340 345 350 Leu Val Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser 355 360 365 Ser <210> 418 <211> 359 <212> PRT <213> Artificial Sequence <220> <223> ACE-05r-VL amino acid sequence <400> 418 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Gly Gly Gly Gly Ser Gln Leu Val Leu Thr Gln Pro Pro 245 250 255 Ser Val Ser Gly Ala Pro Gly Gln Arg Val Thr Ile Ser Cys Thr Gly 260 265 270 Ser Ser Ser Asn Ile Gly Ala Gly Tyr Asp Val His Trp Tyr Gln Gln 275 280 285 Leu Pro Gly Ala Ala Pro Lys Leu Leu Ile Tyr Gly Asp Ile Asn Arg 290 295 300 Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Ile Ser 305 310 315 320 Ala Ser Leu Ala Ile Thr Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr 325 330 335 Tyr Cys Gln Ser Tyr Asp Ser Ser Leu Ser Gly Gly Val Phe Gly Gly 340 345 350 Gly Thr Lys Leu Thr Val Leu 355 <210> 419 <211> 215 <212> PRT <213> Artificial Sequence <220> <223> ACE-05r-LC, ACE-10r-LC, ACE-11r-LC, ACE-19r-LC, ACE-28r-LC, ACE-38r-LC, ACE-39r-LC, ACE-40r-LC amino acid sequence <400> 419 Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly 1 5 10 15 Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Arg Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile 35 40 45 Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Lys Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln 65 70 75 80 Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Trp 85 90 95 Thr Phe Ala Gly Gly Thr Lys Leu Glu Ile Lys Arg Arg Thr Val Ala 100 105 110 Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser 115 120 125 Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu 130 135 140 Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser 145 150 155 160 Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu 165 170 175 Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 180 185 190 Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys 195 200 205 Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 420 <211> 365 <212> PRT <213> Artificial Sequence <220> <223> ACE-06r-VH amino acid sequence <400> 420 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Lys Phe Ser Gly Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp Tyr Asp Gly Ser Lys Lys Tyr Tyr Val Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gln Met Gly Tyr Trp His Phe Asp Leu Trp Gly Arg Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205 Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215 220 His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Gly 225 230 235 240 Gly Gly Gly Ser Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys 245 250 255 Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr 260 265 270 Phe Ser Ser Tyr Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly 275 280 285 Leu Glu Trp Met Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr 290 295 300 Ala Gln Lys Phe Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr 305 310 315 320 Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala 325 330 335 Val Tyr Tyr Cys Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe 340 345 350 Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser 355 360 365 <210> 421 <211> 356 <212> PRT <213> Artificial Sequence <220> <223> ACE-06r-VL amino acid sequence <400> 421 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Lys Phe Ser Gly Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp Tyr Asp Gly Ser Lys Lys Tyr Tyr Val Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gln Met Gly Tyr Trp His Phe Asp Leu Trp Gly Arg Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205 Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215 220 His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Gly 225 230 235 240 Gly Gly Gly Ser Gln Leu Val Leu Thr Gln Pro Pro Ser Val Ser Gly 245 250 255 Ala Pro Gly Gln Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn 260 265 270 Ile Gly Ala Gly Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Ala 275 280 285 Ala Pro Lys Leu Leu Ile Tyr Gly Asp Ile Asn Arg Pro Ser Gly Val 290 295 300 Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Ile Ser Ala Ser Leu Ala 305 310 315 320 Ile Thr Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser 325 330 335 Tyr Asp Ser Ser Leu Ser Gly Gly Val Phe Gly Gly Gly Thr Lys Leu 340 345 350 Thr Val Leu Arg 355 <210> 422 <211> 215 <212> PRT <213> Artificial Sequence <220> <223> ACE-06r-LC, ACE-23r-LC amino acid sequence <400> 422 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Pro 85 90 95 Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Ser Val Ala 100 105 110 Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser 115 120 125 Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu 130 135 140 Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser 145 150 155 160 Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu 165 170 175 Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 180 185 190 Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys 195 200 205 Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 423 <211> 369 <212> PRT <213> Artificial Sequence <220> <223> ACE-07r-VH amino acid sequence <400> 423 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Cys Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Gly Gly Gly Gly Ser Gln Met Gln Leu Val Gln Ser Gly 245 250 255 Ala Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala 260 265 270 Ser Gly Gly Thr Phe Ser Ser Tyr Ala Ile Ser Trp Val Arg Gln Ala 275 280 285 Pro Gly Gln Gly Leu Glu Trp Met Gly Arg Ile Ile Pro Ile Leu Gly 290 295 300 Ile Ala Asn Tyr Ala Gln Lys Phe Gln Gly Arg Val Thr Ile Thr Ala 305 310 315 320 Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser 325 330 335 Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Pro Arg Asp Gly Tyr Asn 340 345 350 Leu Val Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser 355 360 365 Ser <210> 424 <211> 360 <212> PRT <213> Artificial Sequence <220> <223> ACE-07r-VL amino acid sequence <400> 424 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Cys Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Gly Gly Gly Gly Ser Gln Leu Val Leu Thr Gln Pro Pro 245 250 255 Ser Val Ser Gly Ala Pro Gly Gln Arg Val Thr Ile Ser Cys Thr Gly 260 265 270 Ser Ser Ser Asn Ile Gly Ala Gly Tyr Asp Val His Trp Tyr Gln Gln 275 280 285 Leu Pro Gly Ala Ala Pro Lys Leu Leu Ile Tyr Gly Asp Ile Asn Arg 290 295 300 Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Ile Ser 305 310 315 320 Ala Ser Leu Ala Ile Thr Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr 325 330 335 Tyr Cys Gln Ser Tyr Asp Ser Ser Leu Ser Gly Gly Val Phe Gly Gly 340 345 350 Gly Thr Lys Leu Thr Val Leu Arg 355 360 <210> 425 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> ACE-07r-LC amino acid sequence <400> 425 Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly 1 5 10 15 Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Arg Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile 35 40 45 Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Lys Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln 65 70 75 80 Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Trp 85 90 95 Thr Phe Ala Gly Cys Thr Lys Leu Glu Ile Lys Arg Ser Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 426 <211> 363 <212> PRT <213> Artificial Sequence <220> <223> ACE-08r-VH amino acid sequence <400> 426 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Lys 1 5 10 15 Ser Leu Lys Leu Ser Cys Glu Ala Ser Gly Phe Thr Phe Ser Gly Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Arg Cys Leu Glu Ser Val 35 40 45 Ala Tyr Ile Thr Ser Ser Ser Ile Asn Ile Lys Tyr Ala Asp Ala Val 50 55 60 Lys Gly Arg Phe Thr Val Ser Arg Asp Asn Ala Lys Asn Leu Leu Phe 65 70 75 80 Leu Gln Met Asn Ile Leu Lys Ser Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Arg Phe Asp Trp Asp Lys Asn Tyr Trp Gly Gln Gly Thr Met Val 100 105 110 Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala 115 120 125 Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu 130 135 140 Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly 145 150 155 160 Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser 165 170 175 Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu 180 185 190 Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr 195 200 205 Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr 210 215 220 Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Gly Gly Gly 225 230 235 240 Gly Ser Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro 245 250 255 Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser 260 265 270 Ser Tyr Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu 275 280 285 Trp Met Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln 290 295 300 Lys Phe Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr 305 310 315 320 Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr 325 330 335 Tyr Cys Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile 340 345 350 Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser 355 360 <210> 427 <211> 354 <212> PRT <213> Artificial Sequence <220> <223> ACE-08r-VL amino acid sequence <400> 427 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Lys 1 5 10 15 Ser Leu Lys Leu Ser Cys Glu Ala Ser Gly Phe Thr Phe Ser Gly Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Arg Cys Leu Glu Ser Val 35 40 45 Ala Tyr Ile Thr Ser Ser Ser Ile Asn Ile Lys Tyr Ala Asp Ala Val 50 55 60 Lys Gly Arg Phe Thr Val Ser Arg Asp Asn Ala Lys Asn Leu Leu Phe 65 70 75 80 Leu Gln Met Asn Ile Leu Lys Ser Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Arg Phe Asp Trp Asp Lys Asn Tyr Trp Gly Gln Gly Thr Met Val 100 105 110 Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala 115 120 125 Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu 130 135 140 Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly 145 150 155 160 Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser 165 170 175 Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu 180 185 190 Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr 195 200 205 Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr 210 215 220 Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Gly Gly Gly 225 230 235 240 Gly Ser Gln Leu Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro 245 250 255 Gly Gln Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly 260 265 270 Ala Gly Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Ala Ala Pro 275 280 285 Lys Leu Leu Ile Tyr Gly Asp Ile Asn Arg Pro Ser Gly Val Pro Asp 290 295 300 Arg Phe Ser Gly Ser Lys Ser Gly Ile Ser Ala Ser Leu Ala Ile Thr 305 310 315 320 Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp 325 330 335 Ser Ser Leu Ser Gly Gly Val Phe Gly Gly Gly Thr Lys Leu Thr Val 340 345 350 Leu Arg <210> 428 <211> 212 <212> PRT <213> Artificial Sequence <220> <223> ACE-08r-LC amino acid sequence <400> 428 Gln Met Thr Gln Ser Pro Ser Ser Leu Pro Ala Ser Leu Gly Asp Arg 1 5 10 15 Val Thr Ile Asn Cys Gln Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn 20 25 30 Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr 35 40 45 Thr Asn Lys Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly Ser Gly 50 55 60 Ser Gly Arg Asp Ser Ser Phe Thr Ile Ser Ser Leu Glu Ser Glu Asp 65 70 75 80 Ile Gly Ser Tyr Tyr Cys Gln Gln Tyr Tyr Asn Tyr Pro Trp Thr Phe 85 90 95 Gly Pro Cys Thr Lys Leu Glu Ile Lys Arg Ser Val Ala Ala Pro Ser 100 105 110 Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala 115 120 125 Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val 130 135 140 Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser 145 150 155 160 Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr 165 170 175 Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys 180 185 190 Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn 195 200 205 Arg Gly Glu Cys 210 <210> 429 <211> 364 <212> PRT <213> Artificial Sequence <220> <223> ACE-09r-VH amino acid sequence <400> 429 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys 245 250 255 Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe 260 265 270 Ser Ser Tyr Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu 275 280 285 Glu Trp Met Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala 290 295 300 Gln Lys Phe Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser 305 310 315 320 Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val 325 330 335 Tyr Tyr Cys Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp 340 345 350 Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser 355 360 <210> 430 <211> 354 <212> PRT <213> Artificial Sequence <220> <223> ACE-09r-VL amino acid sequence <400> 430 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Gln Leu Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala 245 250 255 Pro Gly Gln Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile 260 265 270 Gly Ala Gly Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Ala Ala 275 280 285 Pro Lys Leu Leu Ile Tyr Gly Asp Ile Asn Arg Pro Ser Gly Val Pro 290 295 300 Asp Arg Phe Ser Gly Ser Lys Ser Gly Ile Ser Ala Ser Leu Ala Ile 305 310 315 320 Thr Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr 325 330 335 Asp Ser Ser Leu Ser Gly Gly Val Phe Gly Gly Gly Thr Lys Leu Thr 340 345 350 Val Leu <210> 431 <211> 215 <212> PRT <213> Artificial Sequence <220> <223> ACE-09r-LC, ACE-12r-LC, ACE-18r-LC, ACE-22r-LC amino acid sequence <400> 431 Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly 1 5 10 15 Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Arg Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile 35 40 45 Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Lys Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln 65 70 75 80 Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Trp 85 90 95 Thr Phe Ala Gly Gly Thr Lys Leu Glu Ile Lys Arg Arg Ser Val Ala 100 105 110 Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser 115 120 125 Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu 130 135 140 Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser 145 150 155 160 Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu 165 170 175 Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 180 185 190 Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys 195 200 205 Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 432 <211> 369 <212> PRT <213> Artificial Sequence <220> <223> ACE-10r-VH amino acid sequence <400> 432 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Gln Pro Gly 245 250 255 Ala Glu Leu Val Lys Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala 260 265 270 Ser Gly Tyr Thr Phe Thr Ser Tyr Asn Met His Trp Val Lys Gln Thr 275 280 285 Pro Gly Arg Gly Leu Glu Trp Ile Gly Ala Ile Tyr Pro Gly Asn Gly 290 295 300 Asp Thr Ser Tyr Asn Gln Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala 305 310 315 320 Asp Lys Ser Ser Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser 325 330 335 Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg Ser Thr Tyr Tyr Gly Gly 340 345 350 Asp Trp Tyr Phe Asn Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser 355 360 365 Ala <210> 433 <211> 354 <212> PRT <213> Artificial Sequence <220> <223> ACE-10r-VL amino acid sequence <400> 433 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Gly Gly Gly Gly Ser Gln Ile Val Leu Ser Gln Ser Pro 245 250 255 Ala Ile Leu Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Arg 260 265 270 Ala Ser Ser Ser Val Ser Tyr Ile His Trp Phe Gln Gln Lys Pro Gly 275 280 285 Ser Ser Pro Lys Pro Trp Ile Tyr Ala Thr Ser Asn Leu Ala Ser Gly 290 295 300 Val Pro Val Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu 305 310 315 320 Thr Ile Ser Arg Val Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln 325 330 335 Gln Trp Thr Ser Asn Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu Glu 340 345 350 Ile Lys <210> 434 <211> 367 <212> PRT <213> Artificial Sequence <220> <223> ACE-11r-VH amino acid sequence <400> 434 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Gly Gly Gly Gly Ser Gln Val Gln Leu Lys Gln Ser Gly 245 250 255 Pro Gly Leu Val Gln Pro Ser Gln Ser Leu Ser Ile Thr Cys Thr Val 260 265 270 Ser Gly Phe Ser Leu Thr Asn Tyr Gly Val His Trp Val Arg Gln Ser 275 280 285 Pro Gly Lys Gly Leu Glu Trp Leu Gly Val Ile Trp Ser Gly Gly Asn 290 295 300 Thr Asp Tyr Asn Thr Pro Phe Thr Ser Arg Leu Ser Ile Asn Lys Asp 305 310 315 320 Asn Ser Lys Ser Gln Val Phe Phe Lys Met Asn Ser Leu Gln Ser Asn 325 330 335 Asp Thr Ala Ile Tyr Tyr Cys Ala Arg Ala Leu Thr Tyr Tyr Asp Tyr 340 345 350 Glu Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala 355 360 365 <210> 435 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> Fv region (EGFR) in VH of ACE-11r <400> 435 Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30 Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60 Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe 65 70 75 80 Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala 85 90 95 Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ala 115 <210> 436 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD20) in CDR H1 of ACE-11r <400> 436 Gly Phe Ser Leu Thr Asn Tyr Gly 1 5 <210> 437 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD20) in CDR H2 of ACE-11r <400> 437 Ile Trp Ser Gly Gly Asn Thr 1 5 <210> 438 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD20) in CDR H3 of ACE-11r <400> 438 Ala Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr 1 5 10 <210> 439 <211> 355 <212> PRT <213> Artificial Sequence <220> <223> ACE-11r-VL amino acid sequence <400> 439 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Gly Gly Gly Gly Ser Asp Ile Leu Leu Thr Gln Ser Pro 245 250 255 Val Ile Leu Ser Val Ser Pro Gly Glu Arg Val Ser Phe Ser Cys Arg 260 265 270 Ala Ser Gln Ser Ile Gly Thr Asn Ile His Trp Tyr Gln Gln Arg Thr 275 280 285 Asn Gly Ser Pro Arg Leu Leu Ile Lys Tyr Ala Ser Glu Ser Ile Ser 290 295 300 Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 305 310 315 320 Leu Ser Ile Asn Ser Val Glu Ser Glu Asp Ile Ala Asp Tyr Tyr Cys 325 330 335 Gln Gln Asn Asn Asn Trp Pro Thr Thr Phe Gly Ala Gly Thr Lys Leu 340 345 350 Glu Leu Lys 355 <210> 440 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD20) in VL of ACE-11r <400> 440 Asp Ile Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn 20 25 30 Ile His Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile 35 40 45 Lys Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser 65 70 75 80 Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr 85 90 95 Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys 100 105 <210> 441 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD20) in CDR L1 of ACE-11r <400> 441 Gln Ser Ile Gly Thr Asn 1 5 <210> 442 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD20) in CDR L2 of ACE-11r <400> 442 Tyr Ala Ser 1 <210> 443 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD20) in CDR L3 of ACE-11r <400> 443 Gln Gln Asn Asn Asn Trp Pro Thr Thr 1 5 <210> 444 <211> 374 <212> PRT <213> Artificial Sequence <220> <223> ACE-12r-VH amino acid sequence <400> 444 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Met Gln 245 250 255 Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser Ser Val Lys 260 265 270 Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr Ala Ile Ser 275 280 285 Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Arg Ile 290 295 300 Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe Gln Gly Arg 305 310 315 320 Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu 325 330 335 Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Pro 340 345 350 Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly Gln Gly Thr 355 360 365 Met Val Thr Val Ser Ser 370 <210> 445 <211> 363 <212> PRT <213> Artificial Sequence <220> <223> ACE-12r-VL amino acid sequence <400> 445 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Gly Gly Ser Gly Gly Gly Gly Ser Gly Gln Leu Val Leu 245 250 255 Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln Arg Val Thr Ile 260 265 270 Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly Tyr Asp Val His 275 280 285 Trp Tyr Gln Gln Leu Pro Gly Ala Ala Pro Lys Leu Leu Ile Tyr Gly 290 295 300 Asp Ile Asn Arg Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys 305 310 315 320 Ser Gly Ile Ser Ala Ser Leu Ala Ile Thr Gly Leu Gln Ala Glu Asp 325 330 335 Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser Leu Ser Gly Gly 340 345 350 Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 355 360 <210> 446 <211> 361 <212> PRT <213> Artificial Sequence <220> <223> ACE-13r-VH amino acid sequence <400> 446 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Leu Arg Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Arg Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Thr Thr Thr Thr Phe Asp Ser Trp Gly Gln Gly Thr Leu Val Thr Val 100 105 110 Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser 115 120 125 Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys 130 135 140 Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu 145 150 155 160 Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu 165 170 175 Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr 180 185 190 Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val 195 200 205 Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro 210 215 220 Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser 225 230 235 240 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 245 250 255 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 260 265 270 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 275 280 285 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 290 295 300 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 305 310 315 320 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 325 330 335 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 340 345 350 Gln Gly Thr Met Val Thr Val Ser Ser 355 360 <210> 447 <211> 352 <212> PRT <213> Artificial Sequence <220> <223> ACE-13r-VL amino acid sequence <400> 447 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Leu Arg Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Arg Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Thr Thr Thr Thr Phe Asp Ser Trp Gly Gln Gly Thr Leu Val Thr Val 100 105 110 Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser 115 120 125 Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys 130 135 140 Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu 145 150 155 160 Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu 165 170 175 Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr 180 185 190 Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val 195 200 205 Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro 210 215 220 Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser 225 230 235 240 Gln Leu Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln 245 250 255 Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly 260 265 270 Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Ala Ala Pro Lys Leu 275 280 285 Leu Ile Tyr Gly Asp Ile Asn Arg Pro Ser Gly Val Pro Asp Arg Phe 290 295 300 Ser Gly Ser Lys Ser Gly Ile Ser Ala Ser Leu Ala Ile Thr Gly Leu 305 310 315 320 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser 325 330 335 Leu Ser Gly Gly Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Arg 340 345 350 <210> 448 <211> 220 <212> PRT <213> Artificial Sequence <220> <223> ACE-13r-LC amino acid sequence <400> 448 Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly 1 5 10 15 Glu Ala Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu Asp Ser 20 25 30 Glu Asp Gly Asn Thr Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln 35 40 45 Ser Pro Gln Leu Leu Ile Tyr Thr Leu Ser His Arg Ala Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Glu 65 70 75 80 Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln 85 90 95 Arg Arg Asp Phe Pro Phe Thr Phe Gly Gln Gly Thr Lys Val Asp Ile 100 105 110 Lys Arg Ser Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 115 120 125 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 130 135 140 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 145 150 155 160 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 165 170 175 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 180 185 190 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 195 200 205 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 220 <210> 449 <211> 374 <212> PRT <213> Artificial Sequence <220> <223> ACE-14r-VH amino acid sequence <400> 449 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Cys Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Met Gln 245 250 255 Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser Ser Val Lys 260 265 270 Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr Ala Ile Ser 275 280 285 Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Arg Ile 290 295 300 Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe Gln Gly Arg 305 310 315 320 Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu 325 330 335 Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Pro 340 345 350 Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly Gln Gly Thr 355 360 365 Met Val Thr Val Ser Ser 370 <210> 450 <211> 365 <212> PRT <213> Artificial Sequence <220> <223> ACE-14r-VL amino acid sequence <400> 450 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Cys Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Leu Val 245 250 255 Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln Arg Val Thr 260 265 270 Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly Tyr Asp Val 275 280 285 His Trp Tyr Gln Gln Leu Pro Gly Ala Ala Pro Lys Leu Leu Ile Tyr 290 295 300 Gly Asp Ile Asn Arg Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser 305 310 315 320 Lys Ser Gly Ile Ser Ala Ser Leu Ala Ile Thr Gly Leu Gln Ala Glu 325 330 335 Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser Leu Ser Gly 340 345 350 Gly Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Arg 355 360 365 <210> 451 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> ACE-14r-LC amino acid sequence <400> 451 Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly 1 5 10 15 Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Arg Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile 35 40 45 Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Lys Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln 65 70 75 80 Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Trp 85 90 95 Thr Phe Ala Cys Gly Thr Lys Leu Glu Ile Lys Arg Ser Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 452 <211> 369 <212> PRT <213> Artificial Sequence <220> <223> ACE-15r-VH amino acid sequence <400> 452 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Cys Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Gly Gly Gly Gly Ser Gln Met Gln Leu Val Gln Ser Gly 245 250 255 Ala Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala 260 265 270 Ser Gly Gly Thr Phe Ser Ser Tyr Ala Ile Ser Trp Val Arg Gln Ala 275 280 285 Pro Gly Gln Gly Leu Glu Trp Met Gly Arg Ile Ile Pro Ile Leu Gly 290 295 300 Ile Ala Asn Tyr Ala Gln Lys Phe Gln Gly Arg Val Thr Ile Thr Ala 305 310 315 320 Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser 325 330 335 Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Pro Arg Asp Gly Tyr Asn 340 345 350 Leu Val Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser 355 360 365 Ser <210> 453 <211> 360 <212> PRT <213> Artificial Sequence <220> <223> ACE-15r-VL amino acid sequence <400> 453 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Cys Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Gly Gly Gly Gly Ser Gln Leu Val Leu Thr Gln Pro Pro 245 250 255 Ser Val Ser Gly Ala Pro Gly Gln Arg Val Thr Ile Ser Cys Thr Gly 260 265 270 Ser Ser Ser Asn Ile Gly Ala Gly Tyr Asp Val His Trp Tyr Gln Gln 275 280 285 Leu Pro Gly Ala Ala Pro Lys Leu Leu Ile Tyr Gly Asp Ile Asn Arg 290 295 300 Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Ile Ser 305 310 315 320 Ala Ser Leu Ala Ile Thr Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr 325 330 335 Tyr Cys Gln Ser Tyr Asp Ser Ser Leu Ser Gly Gly Val Phe Gly Gly 340 345 350 Gly Thr Lys Leu Thr Val Leu Arg 355 360 <210> 454 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> ACE-15r-LC amino acid sequence <400> 454 Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly 1 5 10 15 Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Arg Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Cys Val Lys Leu Leu Ile 35 40 45 Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Lys Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln 65 70 75 80 Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Trp 85 90 95 Thr Phe Ala Gly Gly Thr Lys Leu Glu Ile Lys Arg Ser Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 455 <211> 372 <212> PRT <213> Artificial Sequence <220> <223> ACE-16r-VH amino acid sequence <400> 455 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro 225 230 235 240 Glu Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Gln Met Gln Leu Val 245 250 255 Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val Ser 260 265 270 Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr Ala Ile Ser Trp Val 275 280 285 Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Arg Ile Ile Pro 290 295 300 Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe Gln Gly Arg Val Thr 305 310 315 320 Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser 325 330 335 Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Pro Arg Asp 340 345 350 Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Val 355 360 365 Thr Val Ser Ser 370 <210> 456 <211> 363 <212> PRT <213> Artificial Sequence <220> <223> ACE-16r-VL amino acid sequence <400> 456 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro 225 230 235 240 Glu Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Gln Leu Val Leu Thr 245 250 255 Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln Arg Val Thr Ile Ser 260 265 270 Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly Tyr Asp Val His Trp 275 280 285 Tyr Gln Gln Leu Pro Gly Ala Ala Pro Lys Leu Leu Ile Tyr Gly Asp 290 295 300 Ile Asn Arg Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser 305 310 315 320 Gly Ile Ser Ala Ser Leu Ala Ile Thr Gly Leu Gln Ala Glu Asp Glu 325 330 335 Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser Leu Ser Gly Gly Val 340 345 350 Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Arg 355 360 <210> 457 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> ACE-16r-LC, ACE-17r-LC amino acid sequence <400> 457 Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly 1 5 10 15 Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Arg Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile 35 40 45 Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Lys Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln 65 70 75 80 Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Trp 85 90 95 Thr Phe Ala Gly Gly Thr Lys Leu Glu Ile Lys Arg Ser Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 458 <211> 367 <212> PRT <213> Artificial Sequence <220> <223> ACE-17r-VH amino acid sequence <400> 458 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro 225 230 235 240 Glu Leu Leu Gly Gly Pro Gln Met Gln Leu Val Gln Ser Gly Ala Glu 245 250 255 Val Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly 260 265 270 Gly Thr Phe Ser Ser Tyr Ala Ile Ser Trp Val Arg Gln Ala Pro Gly 275 280 285 Gln Gly Leu Glu Trp Met Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala 290 295 300 Asn Tyr Ala Gln Lys Phe Gln Gly Arg Val Thr Ile Thr Ala Asp Lys 305 310 315 320 Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp 325 330 335 Thr Ala Val Tyr Tyr Cys Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val 340 345 350 Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser 355 360 365 <210> 459 <211> 358 <212> PRT <213> Artificial Sequence <220> <223> ACE-17r-VL amino acid sequence <400> 459 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro 225 230 235 240 Glu Leu Leu Gly Gly Pro Gln Leu Val Leu Thr Gln Pro Pro Ser Val 245 250 255 Ser Gly Ala Pro Gly Gln Arg Val Thr Ile Ser Cys Thr Gly Ser Ser 260 265 270 Ser Asn Ile Gly Ala Gly Tyr Asp Val His Trp Tyr Gln Gln Leu Pro 275 280 285 Gly Ala Ala Pro Lys Leu Leu Ile Tyr Gly Asp Ile Asn Arg Pro Ser 290 295 300 Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Ile Ser Ala Ser 305 310 315 320 Leu Ala Ile Thr Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys 325 330 335 Gln Ser Tyr Asp Ser Ser Leu Ser Gly Gly Val Phe Gly Gly Gly Thr 340 345 350 Lys Leu Thr Val Leu Arg 355 <210> 460 <211> 372 <212> PRT <213> Artificial Sequence <220> <223> ACE-18r-VH amino acid sequence <400> 460 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro 225 230 235 240 Glu Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Gln Val Gln Leu Gln 245 250 255 Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala Ser Val Lys Met Ser 260 265 270 Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr Asn Met His Trp Val 275 280 285 Lys Gln Thr Pro Gly Arg Gly Leu Glu Trp Ile Gly Ala Ile Tyr Pro 290 295 300 Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe Lys Gly Lys Ala Thr 305 310 315 320 Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr Met Gln Leu Ser Ser 325 330 335 Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg Ser Thr Tyr 340 345 350 Tyr Gly Gly Asp Trp Tyr Phe Asn Val Trp Gly Ala Gly Thr Thr Val 355 360 365 Thr Val Ser Ala 370 <210> 461 <211> 357 <212> PRT <213> Artificial Sequence <220> <223> ACE-18r-VL amino acid sequence <400> 461 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro 225 230 235 240 Glu Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Gln Ile Val Leu Ser 245 250 255 Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly Glu Lys Val Thr Met 260 265 270 Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Ile His Trp Phe Gln Gln 275 280 285 Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr Ala Thr Ser Asn Leu 290 295 300 Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser 305 310 315 320 Tyr Ser Leu Thr Ile Ser Arg Val Glu Ala Glu Asp Ala Ala Thr Tyr 325 330 335 Tyr Cys Gln Gln Trp Thr Ser Asn Pro Pro Thr Phe Gly Gly Gly Thr 340 345 350 Lys Leu Glu Ile Lys 355 <210> 462 <211> 370 <212> PRT <213> Artificial Sequence <220> <223> ACE-19r-VH amino acid sequence <400> 462 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro 225 230 235 240 Glu Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Gln Val Gln Leu Lys 245 250 255 Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln Ser Leu Ser Ile Thr 260 265 270 Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr Gly Val His Trp Val 275 280 285 Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu Gly Val Ile Trp Ser 290 295 300 Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr Ser Arg Leu Ser Ile 305 310 315 320 Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe Lys Met Asn Ser Leu 325 330 335 Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala Arg Ala Leu Thr Tyr 340 345 350 Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val 355 360 365 Ser Ala 370 <210> 463 <211> 358 <212> PRT <213> Artificial Sequence <220> <223> ACE-19r-VL amino acid sequence <400> 463 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro 225 230 235 240 Glu Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Asp Ile Leu Leu Thr 245 250 255 Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly Glu Arg Val Ser Phe 260 265 270 Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile His Trp Tyr Gln 275 280 285 Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile Lys Tyr Ala Ser Glu 290 295 300 Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr 305 310 315 320 Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser Glu Asp Ile Ala Asp 325 330 335 Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr Thr Phe Gly Ala Gly 340 345 350 Thr Lys Leu Glu Leu Lys 355 <210> 464 <211> 372 <212> PRT <213> Artificial Sequence <220> <223> ACE-20r-VH amino acid sequence <400> 464 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro 225 230 235 240 Glu Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Gln Val Gln Leu Val 245 250 255 Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser 260 265 270 Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser His Trp Met His Trp Val 275 280 285 Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile Gly Glu Phe Asn Pro 290 295 300 Ser Asn Gly Arg Thr Asn Tyr Asn Glu Lys Phe Lys Ser Lys Ala Thr 305 310 315 320 Met Thr Val Asp Thr Ser Thr Asn Thr Ala Tyr Met Glu Leu Ser Ser 325 330 335 Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ser Arg Asp Tyr 340 345 350 Asp Tyr Asp Cys Arg Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 355 360 365 Thr Val Ser Ser 370 <210> 465 <211> 358 <212> PRT <213> Artificial Sequence <220> <223> ACE-20r-VL amino acid sequence <400> 465 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro 225 230 235 240 Glu Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Asp Ile Gln Met Thr 245 250 255 Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile 260 265 270 Thr Cys Ser Ala Ser Ser Ser Val Thr Tyr Met Tyr Trp Tyr Gln Gln 275 280 285 Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Asp Thr Ser Asn Leu 290 295 300 Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp 305 310 315 320 Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr 325 330 335 Tyr Cys Gln Gln Trp Ser Ser His Ile Phe Thr Phe Gly Gln Gly Thr 340 345 350 Lys Val Glu Ile Lys Arg 355 <210> 466 <211> 376 <212> PRT <213> Artificial Sequence <220> <223> ACE-21r-VH amino acid sequence <400> 466 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro 225 230 235 240 Glu Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Gln Val Gln Leu Val 245 250 255 Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser Leu Arg Leu Ser 260 265 270 Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr Gly Met His Trp Val 275 280 285 Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Val Ile Trp Asp 290 295 300 Asp Gly Ser Tyr Lys Tyr Tyr Gly Asp Ser Val Lys Gly Arg Phe Thr 305 310 315 320 Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser 325 330 335 Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Gly Ile 340 345 350 Thr Met Val Arg Gly Val Met Lys Asp Tyr Phe Asp Tyr Trp Gly Gln 355 360 365 Gly Thr Leu Val Thr Val Ser Ser 370 375 <210> 467 <211> 359 <212> PRT <213> Artificial Sequence <220> <223> ACE-21r-VL amino acid sequence <400> 467 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro 225 230 235 240 Glu Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Ala Ile Gln Leu Thr 245 250 255 Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile 260 265 270 Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Ala Leu Val Trp Tyr Gln 275 280 285 Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Asp Ala Ser Ser 290 295 300 Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Glu Ser Gly Thr 305 310 315 320 Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr 325 330 335 Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Leu Thr Phe Gly Gly Gly 340 345 350 Thr Lys Val Glu Ile Lys Arg 355 <210> 468 <211> 367 <212> PRT <213> Artificial Sequence <220> <223> ACE-22r-VH amino acid sequence <400> 468 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro 225 230 235 240 Glu Leu Leu Gly Gly Pro Gln Val Gln Leu Gln Gln Pro Gly Ala Glu 245 250 255 Leu Val Lys Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly 260 265 270 Tyr Thr Phe Thr Ser Tyr Asn Met His Trp Val Lys Gln Thr Pro Gly 275 280 285 Arg Gly Leu Glu Trp Ile Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr 290 295 300 Ser Tyr Asn Gln Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys 305 310 315 320 Ser Ser Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp 325 330 335 Ser Ala Val Tyr Tyr Cys Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp 340 345 350 Tyr Phe Asn Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ala 355 360 365 <210> 469 <211> 352 <212> PRT <213> Artificial Sequence <220> <223> ACE-22r-VL amino acid sequence <400> 469 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro 225 230 235 240 Glu Leu Leu Gly Gly Pro Gln Ile Val Leu Ser Gln Ser Pro Ala Ile 245 250 255 Leu Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Arg Ala Ser 260 265 270 Ser Ser Val Ser Tyr Ile His Trp Phe Gln Gln Lys Pro Gly Ser Ser 275 280 285 Pro Lys Pro Trp Ile Tyr Ala Thr Ser Asn Leu Ala Ser Gly Val Pro 290 295 300 Val Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile 305 310 315 320 Ser Arg Val Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp 325 330 335 Thr Ser Asn Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 340 345 350 <210> 470 <211> 368 <212> PRT <213> Artificial Sequence <220> <223> ACE-23r-VH amino acid sequence <400> 470 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Lys Phe Ser Gly Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp Tyr Asp Gly Ser Lys Lys Tyr Tyr Val Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gln Met Gly Tyr Trp His Phe Asp Leu Trp Gly Arg Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205 Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215 220 His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Gly Gly Gly Gly Ser Gln Met Gln Leu Val Gln Ser Gly Ala 245 250 255 Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser 260 265 270 Gly Gly Thr Phe Ser Ser Tyr Ala Ile Ser Trp Val Arg Gln Ala Pro 275 280 285 Gly Gln Gly Leu Glu Trp Met Gly Arg Ile Ile Pro Ile Leu Gly Ile 290 295 300 Ala Asn Tyr Ala Gln Lys Phe Gln Gly Arg Val Thr Ile Thr Ala Asp 305 310 315 320 Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu 325 330 335 Asp Thr Ala Val Tyr Tyr Cys Ala Lys Pro Arg Asp Gly Tyr Asn Leu 340 345 350 Val Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser 355 360 365 <210> 471 <211> 359 <212> PRT <213> Artificial Sequence <220> <223> ACE-23r-VL amino acid sequence <400> 471 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Lys Phe Ser Gly Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp Tyr Asp Gly Ser Lys Lys Tyr Tyr Val Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gln Met Gly Tyr Trp His Phe Asp Leu Trp Gly Arg Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205 Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215 220 His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Gly Gly Gly Gly Ser Gln Leu Val Leu Thr Gln Pro Pro Ser 245 250 255 Val Ser Gly Ala Pro Gly Gln Arg Val Thr Ile Ser Cys Thr Gly Ser 260 265 270 Ser Ser Asn Ile Gly Ala Gly Tyr Asp Val His Trp Tyr Gln Gln Leu 275 280 285 Pro Gly Ala Ala Pro Lys Leu Leu Ile Tyr Gly Asp Ile Asn Arg Pro 290 295 300 Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Ile Ser Ala 305 310 315 320 Ser Leu Ala Ile Thr Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Tyr 325 330 335 Cys Gln Ser Tyr Asp Ser Ser Leu Ser Gly Gly Val Phe Gly Gly Gly 340 345 350 Thr Lys Leu Thr Val Leu Arg 355 <210> 472 <211> 367 <212> PRT <213> Artificial Sequence <220> <223> ACE-24r-VH amino acid sequence <400> 472 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Thr Trp Asn Ser Gly His Ile Asp Tyr Ala Asp Ser Val 50 55 60 Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Val Ser Tyr Leu Ser Thr Ala Ser Ser Leu Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly 245 250 255 Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser 260 265 270 Gly Phe Asn Ile Lys Asp Thr Tyr Ile His Trp Val Arg Gln Ala Pro 275 280 285 Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Tyr Pro Thr Asn Gly Tyr 290 295 300 Thr Arg Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp 305 310 315 320 Thr Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu 325 330 335 Asp Thr Ala Val Tyr Tyr Cys Ser Arg Trp Gly Gly Asp Gly Phe Tyr 340 345 350 Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 355 360 365 <210> 473 <211> 349 <212> PRT <213> Artificial Sequence <220> <223> ACE-24r-VL amino acid sequence <400> 473 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Thr Trp Asn Ser Gly His Ile Asp Tyr Ala Asp Ser Val 50 55 60 Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Val Ser Tyr Leu Ser Thr Ala Ser Ser Leu Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser 245 250 255 Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn 260 265 270 Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu 275 280 285 Leu Ile Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe 290 295 300 Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu 305 310 315 320 Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr 325 330 335 Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 340 345 <210> 474 <211> 372 <212> PRT <213> Artificial Sequence <220> <223> ACE-25r-VH amino acid sequence <400> 474 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Thr Trp Asn Ser Gly His Ile Asp Tyr Ala Asp Ser Val 50 55 60 Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Val Ser Tyr Leu Ser Thr Ala Ser Ser Leu Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu 245 250 255 Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu 260 265 270 Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr Tyr Ile His Trp 275 280 285 Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Tyr 290 295 300 Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val Lys Gly Arg Phe 305 310 315 320 Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn 325 330 335 Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ser Arg Trp Gly 340 345 350 Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val 355 360 365 Thr Val Ser Ser 370 <210> 475 <211> 349 <212> PRT <213> Artificial Sequence <220> <223> ACE-25r-VL amino acid sequence <400> 475 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Thr Trp Asn Ser Gly His Ile Asp Tyr Ala Asp Ser Val 50 55 60 Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Val Ser Tyr Leu Ser Thr Ala Ser Ser Leu Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser 245 250 255 Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn 260 265 270 Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu 275 280 285 Leu Ile Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe 290 295 300 Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu 305 310 315 320 Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr 325 330 335 Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 340 345 <210> 476 <211> 373 <212> PRT <213> Artificial Sequence <220> <223> ACE-26r-VH amino acid sequence <400> 476 Glu Val Lys Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Lys Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp 50 55 60 Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Ser Ile 65 70 75 80 Leu Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr 85 90 95 Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe 100 105 110 Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala Ala Ser Thr 115 120 125 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140 Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175 Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190 Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys 195 200 205 Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys 225 230 235 240 Pro Ala Pro Glu Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Gln Val 245 250 255 Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln Ser Leu 260 265 270 Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr Gly Val 275 280 285 His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu Gly Val 290 295 300 Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr Ser Arg 305 310 315 320 Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe Lys Met 325 330 335 Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala Arg Ala 340 345 350 Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly Thr Leu 355 360 365 Val Thr Val Ser Ala 370 <210> 477 <211> 361 <212> PRT <213> Artificial Sequence <220> <223> ACE-26r-VL amino acid sequence <400> 477 Glu Val Lys Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Lys Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp 50 55 60 Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Ser Ile 65 70 75 80 Leu Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr 85 90 95 Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe 100 105 110 Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala Ala Ser Thr 115 120 125 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140 Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175 Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190 Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys 195 200 205 Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys 225 230 235 240 Pro Ala Pro Glu Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Asp Ile 245 250 255 Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly Glu Arg 260 265 270 Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile His 275 280 285 Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile Lys Tyr 290 295 300 Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly 305 310 315 320 Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser Glu Asp 325 330 335 Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr Thr Phe 340 345 350 Gly Ala Gly Thr Lys Leu Glu Leu Lys 355 360 <210> 478 <211> 216 <212> PRT <213> Artificial Sequence <220> <223> ACE-26r-LC, ACE-29r-LC, ACE-32r-LC amino acid sequence <400> 478 Gln Ala Val Val Thr Gln Glu Ser Ala Leu Thr Thr Ser Pro Gly Glu 1 5 10 15 Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser 20 25 30 Asn Tyr Ala Asn Trp Val Gln Glu Lys Pro Asp His Leu Phe Thr Gly 35 40 45 Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ala Arg Phe 50 55 60 Ser Gly Ser Leu Ile Gly Asp Lys Ala Ala Leu Thr Ile Thr Gly Ala 65 70 75 80 Gln Thr Glu Asp Glu Ala Ile Tyr Phe Cys Ala Leu Trp Tyr Ser Asn 85 90 95 Leu Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Arg Thr Val 100 105 110 Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys 115 120 125 Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg 130 135 140 Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn 145 150 155 160 Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser 165 170 175 Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys 180 185 190 Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr 195 200 205 Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 479 <211> 375 <212> PRT <213> Artificial Sequence <220> <223> ACE-27r-VH amino acid sequence <400> 479 Glu Val Lys Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Lys Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp 50 55 60 Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Ser Ile 65 70 75 80 Leu Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr 85 90 95 Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe 100 105 110 Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala Ala Ser Thr 115 120 125 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140 Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175 Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190 Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys 195 200 205 Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys 225 230 235 240 Pro Ala Pro Glu Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Gln Met 245 250 255 Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser Ser Val 260 265 270 Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr Ala Ile 275 280 285 Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Arg 290 295 300 Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe Gln Gly 305 310 315 320 Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu 325 330 335 Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys 340 345 350 Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly Gln Gly 355 360 365 Thr Met Val Thr Val Ser Ser 370 375 <210> 480 <211> 363 <212> PRT <213> Artificial Sequence <220> <223> ACE-27r-VL amino acid sequence <400> 480 Glu Val Lys Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Lys Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp 50 55 60 Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Ser Ile 65 70 75 80 Leu Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr 85 90 95 Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe 100 105 110 Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala Ala Ser Thr 115 120 125 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140 Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175 Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190 Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys 195 200 205 Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys 225 230 235 240 Pro Ala Pro Glu Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Gln Ala 245 250 255 Val Val Thr Gln Glu Ser Ala Leu Thr Thr Ser Pro Gly Glu Thr Val 260 265 270 Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser Asn Tyr 275 280 285 Ala Asn Trp Val Gln Glu Lys Pro Asp His Leu Phe Thr Gly Leu Ile 290 295 300 Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ala Arg Phe Ser Gly 305 310 315 320 Ser Leu Ile Gly Asp Lys Ala Ala Leu Thr Ile Thr Gly Ala Gln Thr 325 330 335 Glu Asp Glu Ala Ile Tyr Phe Cys Ala Leu Trp Tyr Ser Asn Leu Trp 340 345 350 Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 355 360 <210> 481 <211> 477 <212> PRT <213> Artificial Sequence <220> <223> ACE-28r-VH amino acid sequence <400> 481 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro 225 230 235 240 Glu Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Gln Val Gln Leu Lys 245 250 255 Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln Ser Leu Ser Ile Thr 260 265 270 Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr Gly Val His Trp Val 275 280 285 Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu Gly Val Ile Trp Ser 290 295 300 Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr Ser Arg Leu Ser Ile 305 310 315 320 Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe Lys Met Asn Ser Leu 325 330 335 Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala Arg Ala Leu Thr Tyr 340 345 350 Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val 355 360 365 Ser Ala Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser 370 375 380 Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys 385 390 395 400 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 405 410 415 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 420 425 430 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln 435 440 445 Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 450 455 460 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 465 470 475 <210> 482 <211> 465 <212> PRT <213> Artificial Sequence <220> <223> ACE-28r-VL amino acid sequence <400> 482 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro 225 230 235 240 Glu Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Asp Ile Leu Leu Thr 245 250 255 Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly Glu Arg Val Ser Phe 260 265 270 Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile His Trp Tyr Gln 275 280 285 Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile Lys Tyr Ala Ser Glu 290 295 300 Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr 305 310 315 320 Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser Glu Asp Ile Ala Asp 325 330 335 Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr Thr Phe Gly Ala Gly 340 345 350 Thr Lys Leu Glu Leu Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 355 360 365 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 370 375 380 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 385 390 395 400 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 405 410 415 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 420 425 430 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 435 440 445 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 450 455 460 Lys 465 <210> 483 <211> 480 <212> PRT <213> Artificial Sequence <220> <223> ACE-29r-VH amino acid sequence <400> 483 Glu Val Lys Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Lys Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp 50 55 60 Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Ser Ile 65 70 75 80 Leu Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr 85 90 95 Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe 100 105 110 Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala Ala Ser Thr 115 120 125 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140 Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175 Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190 Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys 195 200 205 Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys 225 230 235 240 Pro Ala Pro Glu Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Gln Val 245 250 255 Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln Ser Leu 260 265 270 Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr Gly Val 275 280 285 His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu Gly Val 290 295 300 Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr Ser Arg 305 310 315 320 Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe Lys Met 325 330 335 Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala Arg Ala 340 345 350 Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly Thr Leu 355 360 365 Val Thr Val Ser Ala Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 370 375 380 Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys 385 390 395 400 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 405 410 415 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 420 425 430 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 435 440 445 Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 450 455 460 Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 465 470 475 480 <210> 484 <211> 468 <212> PRT <213> Artificial Sequence <220> <223> ACE-29r-VL amino acid sequence <400> 484 Glu Val Lys Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Lys Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp 50 55 60 Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Ser Ile 65 70 75 80 Leu Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr 85 90 95 Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe 100 105 110 Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala Ala Ser Thr 115 120 125 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140 Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175 Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190 Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys 195 200 205 Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys 225 230 235 240 Pro Ala Pro Glu Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Asp Ile 245 250 255 Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly Glu Arg 260 265 270 Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile His 275 280 285 Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile Lys Tyr 290 295 300 Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly 305 310 315 320 Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser Glu Asp 325 330 335 Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr Thr Phe 340 345 350 Gly Ala Gly Thr Lys Leu Glu Leu Lys Gly Gln Pro Arg Glu Pro Gln 355 360 365 Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val 370 375 380 Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 385 390 395 400 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 405 410 415 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 420 425 430 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 435 440 445 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 450 455 460 Ser Pro Gly Lys 465 <210> 485 <211> 369 <212> PRT <213> Artificial Sequence <220> <223> ACE-30r-VH amino acid sequence <400> 485 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Gly Gly Gly Gly Ser Glu Val Gln Leu Gln Gln Ser Gly Pro 245 250 255 Glu Leu Val Lys Pro Gly Pro Ser Met Lys Ile Ser Cys Lys Ala Ser 260 265 270 Gly Tyr Ser Phe Thr Gly Tyr Thr Met Asn Trp Val Lys Gln Ser His 275 280 285 Gly Lys Asn Leu Glu Trp Met Gly Leu Ile Asn Pro Tyr Lys Gly Val 290 295 300 Ser Thr Tyr Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Val Asp 305 310 315 320 Lys Ser Ser Ser Thr Ala Tyr Met Glu Leu Leu Ser Leu Thr Ser Glu 325 330 335 Asp Ser Ala Val Tyr Tyr Cys Ala Arg Ser Gly Tyr Tyr Gly Asp Ser 340 345 350 Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly Thr Thr Leu Thr Val Phe 355 360 365 Ser <210> 486 <211> 355 <212> PRT <213> Artificial Sequence <220> <223> ACE-30r-VL amino acid sequence <400> 486 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Thr Thr Ser 245 250 255 Ser Leu Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Arg Ala 260 265 270 Ser Gln Asp Ile Arg Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp 275 280 285 Gly Thr Val Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu His Ser Gly 290 295 300 Val Pro Ser Lys Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu 305 310 315 320 Thr Ile Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys Gln 325 330 335 Gln Gly Asn Thr Leu Pro Trp Thr Phe Ala Gly Gly Thr Lys Leu Glu 340 345 350 Ile Lys Arg 355 <210> 487 <211> 218 <212> PRT <213> Artificial Sequence <220> <223> ACE-30r-LC, ACE-31r-LC, ACE-33r-LC amino acid sequence <400> 487 Gln Leu Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly 20 25 30 Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Ala Ala Pro Lys Leu 35 40 45 Leu Ile Tyr Gly Asp Ile Asn Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Ile Ser Ala Ser Leu Ala Ile Thr Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser 85 90 95 Leu Ser Gly Gly Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Arg 100 105 110 Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln 115 120 125 Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr 130 135 140 Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser 145 150 155 160 Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr 165 170 175 Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys 180 185 190 His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro 195 200 205 Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 488 <211> 374 <212> PRT <213> Artificial Sequence <220> <223> ACE-31r-VH amino acid sequence <400> 488 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu 245 250 255 Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro Ser Met Lys Ile 260 265 270 Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr Thr Met Asn Trp 275 280 285 Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met Gly Leu Ile Asn 290 295 300 Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe Lys Asp Lys Ala 305 310 315 320 Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr Met Glu Leu Leu 325 330 335 Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg Ser Gly 340 345 350 Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly Thr 355 360 365 Thr Leu Thr Val Phe Ser 370 <210> 489 <211> 355 <212> PRT <213> Artificial Sequence <220> <223> ACE-31r-VL amino acid sequence <400> 489 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Thr Thr Ser 245 250 255 Ser Leu Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Arg Ala 260 265 270 Ser Gln Asp Ile Arg Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp 275 280 285 Gly Thr Val Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu His Ser Gly 290 295 300 Val Pro Ser Lys Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu 305 310 315 320 Thr Ile Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys Gln 325 330 335 Gln Gly Asn Thr Leu Pro Trp Thr Phe Ala Gly Gly Thr Lys Leu Glu 340 345 350 Ile Lys Arg 355 <210> 490 <211> 378 <212> PRT <213> Artificial Sequence <220> <223> ACE-32r-VH amino acid sequence <400> 490 Glu Val Lys Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Lys Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp 50 55 60 Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Ser Ile 65 70 75 80 Leu Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr 85 90 95 Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe 100 105 110 Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala Ala Ser Thr 115 120 125 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140 Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175 Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190 Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys 195 200 205 Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys 225 230 235 240 Pro Ala Pro Glu Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Gly Gly 245 250 255 Gly Gly Ser Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln 260 265 270 Pro Ser Gln Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu 275 280 285 Thr Asn Tyr Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu 290 295 300 Glu Trp Leu Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr 305 310 315 320 Pro Phe Thr Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln 325 330 335 Val Phe Phe Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr 340 345 350 Tyr Cys Ala Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp 355 360 365 Gly Gln Gly Thr Leu Val Thr Val Ser Ala 370 375 <210> 491 <211> 361 <212> PRT <213> Artificial Sequence <220> <223> ACE-32r-VL amino acid sequence <400> 491 Glu Val Lys Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Lys Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp 50 55 60 Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Ser Ile 65 70 75 80 Leu Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr 85 90 95 Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe 100 105 110 Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala Ala Ser Thr 115 120 125 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140 Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175 Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190 Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys 195 200 205 Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys 225 230 235 240 Pro Ala Pro Glu Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Asp Ile 245 250 255 Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly Glu Arg 260 265 270 Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile His 275 280 285 Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile Lys Tyr 290 295 300 Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly 305 310 315 320 Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser Glu Asp 325 330 335 Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr Thr Phe 340 345 350 Gly Ala Gly Thr Lys Leu Glu Leu Lys 355 360 <210> 492 <211> 377 <212> PRT <213> Artificial Sequence <220> <223> ACE-33r-VH amino acid sequence <400> 492 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu 245 250 255 Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro Ser 260 265 270 Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr Thr 275 280 285 Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met Gly 290 295 300 Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe Lys 305 310 315 320 Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr Met 325 330 335 Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala 340 345 350 Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp Gly 355 360 365 Gln Gly Thr Thr Leu Thr Val Phe Ser 370 375 <210> 493 <211> 358 <212> PRT <213> Artificial Sequence <220> <223> ACE-33r-VL amino acid sequence <400> 493 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln 245 250 255 Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser 260 265 270 Cys Arg Ala Ser Gln Asp Ile Arg Asn Tyr Leu Asn Trp Tyr Gln Gln 275 280 285 Lys Pro Asp Gly Thr Val Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu 290 295 300 His Ser Gly Val Pro Ser Lys Phe Ser Gly Ser Gly Ser Gly Thr Asp 305 310 315 320 Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr 325 330 335 Phe Cys Gln Gln Gly Asn Thr Leu Pro Trp Thr Phe Ala Gly Gly Thr 340 345 350 Lys Leu Glu Ile Lys Arg 355 <210> 494 <211> 366 <212> PRT <213> Artificial Sequence <220> <223> ACE-34r-VH amino acid sequence <400> 494 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Lys 1 5 10 15 Ser Leu Lys Leu Ser Cys Glu Ala Ser Gly Phe Thr Phe Ser Gly Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Arg Gly Leu Glu Ser Val 35 40 45 Ala Tyr Ile Thr Ser Ser Ser Ile Asn Ile Lys Tyr Ala Asp Ala Val 50 55 60 Lys Gly Arg Phe Thr Val Ser Arg Asp Asn Ala Lys Asn Leu Leu Phe 65 70 75 80 Leu Gln Met Asn Ile Leu Lys Ser Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Arg Phe Asp Trp Asp Lys Asn Tyr Trp Gly Gln Gly Thr Met Val 100 105 110 Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala 115 120 125 Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu 130 135 140 Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly 145 150 155 160 Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser 165 170 175 Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu 180 185 190 Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr 195 200 205 Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr 210 215 220 Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230 235 240 Gly Gly Gly Gly Ser Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val 245 250 255 Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly 260 265 270 Thr Phe Ser Ser Tyr Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln 275 280 285 Gly Leu Glu Trp Met Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn 290 295 300 Tyr Ala Gln Lys Phe Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser 305 310 315 320 Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr 325 330 335 Ala Val Tyr Tyr Cys Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala 340 345 350 Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser 355 360 365 <210> 495 <211> 357 <212> PRT <213> Artificial Sequence <220> <223> ACE-34r-VL amino acid sequence <400> 495 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Lys 1 5 10 15 Ser Leu Lys Leu Ser Cys Glu Ala Ser Gly Phe Thr Phe Ser Gly Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Arg Gly Leu Glu Ser Val 35 40 45 Ala Tyr Ile Thr Ser Ser Ser Ile Asn Ile Lys Tyr Ala Asp Ala Val 50 55 60 Lys Gly Arg Phe Thr Val Ser Arg Asp Asn Ala Lys Asn Leu Leu Phe 65 70 75 80 Leu Gln Met Asn Ile Leu Lys Ser Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Arg Phe Asp Trp Asp Lys Asn Tyr Trp Gly Gln Gly Thr Met Val 100 105 110 Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala 115 120 125 Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu 130 135 140 Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly 145 150 155 160 Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser 165 170 175 Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu 180 185 190 Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr 195 200 205 Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr 210 215 220 Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230 235 240 Gly Gly Gly Gly Ser Gln Leu Val Leu Thr Gln Pro Pro Ser Val Ser 245 250 255 Gly Ala Pro Gly Gln Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser 260 265 270 Asn Ile Gly Ala Gly Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly 275 280 285 Ala Ala Pro Lys Leu Leu Ile Tyr Gly Asp Ile Asn Arg Pro Ser Gly 290 295 300 Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Ile Ser Ala Ser Leu 305 310 315 320 Ala Ile Thr Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln 325 330 335 Ser Tyr Asp Ser Ser Leu Ser Gly Gly Val Phe Gly Gly Gly Thr Lys 340 345 350 Leu Thr Val Leu Arg 355 <210> 496 <211> 213 <212> PRT <213> Artificial Sequence <220> <223> ACE-34r-LC amino acid sequence <400> 496 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Pro Ala Ser Leu Gly 1 5 10 15 Asp Arg Val Thr Ile Asn Cys Gln Ala Ser Gln Asp Ile Ser Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Tyr Thr Asn Lys Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Arg Asp Ser Ser Phe Thr Ile Ser Ser Leu Glu Ser 65 70 75 80 Glu Asp Ile Gly Ser Tyr Tyr Cys Gln Gln Tyr Tyr Asn Tyr Pro Trp 85 90 95 Thr Phe Gly Pro Gly Thr Lys Leu Glu Ile Lys Ser Val Ala Ala Pro 100 105 110 Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 115 120 125 Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135 140 Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu 145 150 155 160 Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175 Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190 Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200 205 Asn Arg Gly Glu Cys 210 <210> 497 <211> 370 <212> PRT <213> Artificial Sequence <220> <223> ACE-35r-VH amino acid sequence <400> 497 Gln Val Lys Leu Gln Gln Ser Gly Ser Glu Leu Gly Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Thr Ser Gly Tyr Ile Phe Thr Asp His 20 25 30 Tyr Ile Ser Trp Val Lys Gln Lys Pro Gly Glu Ser Leu Gln Trp Ile 35 40 45 Gly Asn Val Tyr Gly Gly Asn Gly Gly Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Gln Gly Lys Ala Thr Leu Thr Val Asp Lys Ile Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Ile Tyr Tyr Cys 85 90 95 Ala Arg Arg Pro Val Ala Thr Gly His Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Ile Gln Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp 210 215 220 Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Leu 225 230 235 240 Leu Gly Gly Pro Gly Gly Gly Gly Ser Gln Met Gln Leu Val Gln Ser 245 250 255 Gly Ala Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys 260 265 270 Ala Ser Gly Gly Thr Phe Ser Ser Tyr Ala Ile Ser Trp Val Arg Gln 275 280 285 Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Arg Ile Ile Pro Ile Leu 290 295 300 Gly Ile Ala Asn Tyr Ala Gln Lys Phe Gln Gly Arg Val Thr Ile Thr 305 310 315 320 Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg 325 330 335 Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Pro Arg Asp Gly Tyr 340 345 350 Asn Leu Val Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val 355 360 365 Ser Ser 370 <210> 498 <211> 361 <212> PRT <213> Artificial Sequence <220> <223> ACE-35r-VL amino acid sequence <400> 498 Gln Val Lys Leu Gln Gln Ser Gly Ser Glu Leu Gly Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Thr Ser Gly Tyr Ile Phe Thr Asp His 20 25 30 Tyr Ile Ser Trp Val Lys Gln Lys Pro Gly Glu Ser Leu Gln Trp Ile 35 40 45 Gly Asn Val Tyr Gly Gly Asn Gly Gly Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Gln Gly Lys Ala Thr Leu Thr Val Asp Lys Ile Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Ile Tyr Tyr Cys 85 90 95 Ala Arg Arg Pro Val Ala Thr Gly His Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Ile Gln Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp 210 215 220 Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Leu 225 230 235 240 Leu Gly Gly Pro Gly Gly Gly Gly Ser Gln Leu Val Leu Thr Gln Pro 245 250 255 Pro Ser Val Ser Gly Ala Pro Gly Gln Arg Val Thr Ile Ser Cys Thr 260 265 270 Gly Ser Ser Ser Asn Ile Gly Ala Gly Tyr Asp Val His Trp Tyr Gln 275 280 285 Gln Leu Pro Gly Ala Ala Pro Lys Leu Leu Ile Tyr Gly Asp Ile Asn 290 295 300 Arg Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Ile 305 310 315 320 Ser Ala Ser Leu Ala Ile Thr Gly Leu Gln Ala Glu Asp Glu Ala Asp 325 330 335 Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser Leu Ser Gly Gly Val Phe Gly 340 345 350 Gly Gly Thr Lys Leu Thr Val Leu Arg 355 360 <210> 499 <211> 213 <212> PRT <213> Artificial Sequence <220> <223> ACE-35r-LC amino acid sequence <400> 499 Asp Ile Val Leu Thr Gln Thr Pro Ala Thr Leu Ser Leu Ile Pro Gly 1 5 10 15 Glu Arg Val Thr Met Thr Cys Lys Thr Ser Gln Asn Ile Gly Thr Ile 20 25 30 Leu His Trp Tyr His Gln Lys Pro Lys Glu Ala Pro Arg Ala Leu Ile 35 40 45 Lys Tyr Ala Ser Gln Ser Ile Pro Gly Ile Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Glu Thr Asp Phe Thr Leu Ser Ile Asn Asn Leu Glu Pro 65 70 75 80 Asp Asp Ile Gly Ile Tyr Tyr Cys Gln Gln Ser Arg Ser Trp Pro Val 85 90 95 Thr Phe Gly Pro Gly Thr Lys Leu Glu Ile Lys Ser Val Ala Ala Pro 100 105 110 Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 115 120 125 Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135 140 Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu 145 150 155 160 Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175 Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190 Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200 205 Asn Arg Gly Glu Cys 210 <210> 500 <211> 368 <212> PRT <213> Artificial Sequence <220> <223> ACE-36r-VH amino acid sequence <400> 500 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Thr Phe Ile Ser Tyr Asp Gly Asn Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys 85 90 95 Ala Arg Thr Gly Trp Leu Gly Pro Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205 Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215 220 His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Gly Gly Gly Gly Ser Gln Met Gln Leu Val Gln Ser Gly Ala 245 250 255 Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser 260 265 270 Gly Gly Thr Phe Ser Ser Tyr Ala Ile Ser Trp Val Arg Gln Ala Pro 275 280 285 Gly Gln Gly Leu Glu Trp Met Gly Arg Ile Ile Pro Ile Leu Gly Ile 290 295 300 Ala Asn Tyr Ala Gln Lys Phe Gln Gly Arg Val Thr Ile Thr Ala Asp 305 310 315 320 Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu 325 330 335 Asp Thr Ala Val Tyr Tyr Cys Ala Lys Pro Arg Asp Gly Tyr Asn Leu 340 345 350 Val Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser 355 360 365 <210> 501 <211> 351 <212> PRT <213> Artificial Sequence <220> <223> ACE-36r-VL amino acid sequence <400> 501 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Thr Phe Ile Ser Tyr Asp Gly Asn Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys 85 90 95 Ala Arg Thr Gly Trp Leu Gly Pro Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205 Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215 220 His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gln Leu Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln 245 250 255 Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly 260 265 270 Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Ala Ala Pro Lys Leu 275 280 285 Leu Ile Tyr Gly Asp Ile Asn Arg Pro Ser Gly Val Pro Asp Arg Phe 290 295 300 Ser Gly Ser Lys Ser Gly Ile Ser Ala Ser Leu Ala Ile Thr Gly Leu 305 310 315 320 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser 325 330 335 Leu Ser Gly Gly Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 340 345 350 <210> 502 <211> 215 <212> PRT <213> Artificial Sequence <220> <223> ACE-36r-LC, ACE-37r-LC amino acid sequence <400> 502 Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Gly Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Phe Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro 85 90 95 Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Ser Val Ala 100 105 110 Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser 115 120 125 Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu 130 135 140 Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser 145 150 155 160 Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu 165 170 175 Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 180 185 190 Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys 195 200 205 Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 503 <211> 368 <212> PRT <213> Artificial Sequence <220> <223> ACE-37r-VH amino acid sequence <400> 503 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Thr Phe Ile Ser Tyr Asp Gly Asn Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys 85 90 95 Ala Arg Thr Gly Trp Leu Gly Pro Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205 Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215 220 His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Gln Pro Gly Ala 245 250 255 Glu Leu Val Lys Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser 260 265 270 Gly Tyr Thr Phe Thr Ser Tyr Asn Met His Trp Val Lys Gln Thr Pro 275 280 285 Gly Arg Gly Leu Glu Trp Ile Gly Ala Ile Tyr Pro Gly Asn Gly Asp 290 295 300 Thr Ser Tyr Asn Gln Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp 305 310 315 320 Lys Ser Ser Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu 325 330 335 Asp Ser Ala Val Tyr Tyr Cys Ala Arg Ser Thr Tyr Tyr Gly Gly Asp 340 345 350 Trp Tyr Phe Asn Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ala 355 360 365 <210> 504 <211> 346 <212> PRT <213> Artificial Sequence <220> <223> ACE-37r-VL amino acid sequence <400> 504 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Thr Phe Ile Ser Tyr Asp Gly Asn Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys 85 90 95 Ala Arg Thr Gly Trp Leu Gly Pro Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205 Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215 220 His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly 245 250 255 Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Ile 260 265 270 His Trp Phe Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr 275 280 285 Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser 290 295 300 Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Val Glu Ala Glu 305 310 315 320 Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Thr Ser Asn Pro Pro Thr 325 330 335 Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 340 345 <210> 505 <211> 477 <212> PRT <213> Artificial Sequence <220> <223> ACE-38r-VH amino acid sequence <400> 505 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro 225 230 235 240 Glu Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Gln Val Gln Leu Lys 245 250 255 Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln Ser Leu Ser Ile Thr 260 265 270 Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr Gly Val His Trp Val 275 280 285 Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu Gly Val Ile Trp Ser 290 295 300 Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr Ser Arg Leu Ser Ile 305 310 315 320 Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe Lys Met Asn Ser Leu 325 330 335 Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala Arg Ala Leu Thr Tyr 340 345 350 Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val 355 360 365 Ser Ala Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Ser Pro Pro Ser 370 375 380 Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Arg Cys His Val Lys 385 390 395 400 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 405 410 415 Pro Glu Asn Asn Tyr Lys Thr Thr Lys Pro Val Leu Asp Ser Asp Gly 420 425 430 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln 435 440 445 Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 450 455 460 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 465 470 475 <210> 506 <211> 358 <212> PRT <213> Artificial Sequence <220> <223> ACE-38r-VL amino acid sequence <400> 506 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro 225 230 235 240 Glu Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Asp Ile Leu Leu Thr 245 250 255 Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly Glu Arg Val Ser Phe 260 265 270 Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile His Trp Tyr Gln 275 280 285 Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile Lys Tyr Ala Ser Glu 290 295 300 Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr 305 310 315 320 Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser Glu Asp Ile Ala Asp 325 330 335 Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr Thr Phe Gly Ala Gly 340 345 350 Thr Lys Leu Glu Leu Lys 355 <210> 507 <211> 370 <212> PRT <213> Artificial Sequence <220> <223> ACE-39r-VH amino acid sequence <400> 507 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro 225 230 235 240 Glu Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Gln Val Gln Leu Lys 245 250 255 Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln Ser Leu Ser Ile Thr 260 265 270 Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr Gly Val His Trp Val 275 280 285 Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu Gly Val Ile Trp Ser 290 295 300 Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr Ser Arg Leu Ser Ile 305 310 315 320 Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe Lys Met Asn Ser Leu 325 330 335 Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala Arg Ala Leu Thr Tyr 340 345 350 Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val 355 360 365 Ser Ala 370 <210> 508 <211> 465 <212> PRT <213> Artificial Sequence <220> <223> ACE-39r-VL amino acid sequence <400> 508 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro 225 230 235 240 Glu Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Asp Ile Leu Leu Thr 245 250 255 Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly Glu Arg Val Ser Phe 260 265 270 Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile His Trp Tyr Gln 275 280 285 Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile Lys Tyr Ala Ser Glu 290 295 300 Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr 305 310 315 320 Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser Glu Asp Ile Ala Asp 325 330 335 Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr Thr Phe Gly Ala Gly 340 345 350 Thr Lys Leu Glu Leu Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 355 360 365 Ser Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Arg 370 375 380 Cys His Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 385 390 395 400 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Lys Pro Val Leu 405 410 415 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 420 425 430 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 435 440 445 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 450 455 460 Lys 465 <210> 509 <211> 477 <212> PRT <213> Artificial Sequence <220> <223> ACE-40r-VH amino acid sequence <400> 509 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro 225 230 235 240 Glu Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Gln Val Gln Leu Lys 245 250 255 Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln Ser Leu Ser Ile Thr 260 265 270 Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr Gly Val His Trp Val 275 280 285 Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu Gly Val Ile Trp Ser 290 295 300 Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr Ser Arg Leu Ser Ile 305 310 315 320 Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe Lys Met Asn Ser Leu 325 330 335 Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala Arg Ala Leu Thr Tyr 340 345 350 Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val 355 360 365 Ser Ala Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Ser Pro Pro Ser 370 375 380 Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Arg Cys His Val Lys 385 390 395 400 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 405 410 415 Pro Glu Asn Asn Tyr Lys Thr Thr Lys Pro Val Leu Asp Ser Asp Gly 420 425 430 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln 435 440 445 Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 450 455 460 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 465 470 475 <210> 510 <211> 465 <212> PRT <213> Artificial Sequence <220> <223> ACE-40r-VL amino acid sequence <400> 510 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro 225 230 235 240 Glu Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Asp Ile Leu Leu Thr 245 250 255 Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly Glu Arg Val Ser Phe 260 265 270 Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile His Trp Tyr Gln 275 280 285 Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile Lys Tyr Ala Ser Glu 290 295 300 Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr 305 310 315 320 Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser Glu Asp Ile Ala Asp 325 330 335 Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr Thr Phe Gly Ala Gly 340 345 350 Thr Lys Leu Glu Leu Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 355 360 365 Ser Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Arg 370 375 380 Cys His Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 385 390 395 400 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Lys Pro Val Leu 405 410 415 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 420 425 430 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 435 440 445 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 450 455 460 Lys 465 <110> Y-BIOLOGICS, INC. <120> MULTI SPECIFIC FUSION PROTEIN AND USE THEREOF <130> SPD20-121-YBL <150> US 62/913,165 <151> 2019-10-10 <160> 510 <170> PatentIn version 3.5 <210> 1 <211> 369 <212> PRT <213> Artificial Sequence <220> <223> ACE-16-VH amino acid sequence <400> 1 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Gly Gly Gly Gly Ser Glu Val Gln Leu Gln Gln Ser Gly Pro 245 250 255 Glu Leu Val Lys Pro Gly Pro Ser Met Lys Ile Ser Cys Lys Ala Ser 260 265 270 Gly Tyr Ser Phe Thr Gly Tyr Thr Met Asn Trp Val Lys Gln Ser His 275 280 285 Gly Lys Asn Leu Glu Trp Met Gly Leu Ile Asn Pro Tyr Lys Gly Val 290 295 300 Ser Thr Tyr Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Val Asp 305 310 315 320 Lys Ser Ser Ser Thr Ala Tyr Met Glu Leu Leu Ser Leu Thr Ser Glu 325 330 335 Asp Ser Ala Val Tyr Tyr Cys Ala Arg Ser Gly Tyr Tyr Gly Asp Ser 340 345 350 Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly Thr Thr Leu Thr Val Phe 355 360 365 Ser <210> 2 <211> 355 <212> PRT <213> Artificial Sequence <220> <223> ACE-16-VL amino acid sequence <400> 2 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Thr Thr Ser 245 250 255 Ser Leu Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Arg Ala 260 265 270 Ser Gln Asp Ile Arg Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp 275 280 285 Gly Thr Val Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu His Ser Gly 290 295 300 Val Pro Ser Lys Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu 305 310 315 320 Thr Ile Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys Gln 325 330 335 Gln Gly Asn Thr Leu Pro Trp Thr Phe Ala Gly Gly Thr Lys Leu Glu 340 345 350 Ile Lys Arg 355 <210> 3 <211> 218 <212> PRT <213> Artificial Sequence <220> <223> ACE-16-LC amino acid sequence <400> 3 Gln Leu Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly 20 25 30 Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Ala Ala Pro Lys Leu 35 40 45 Leu Ile Tyr Gly Asp Ile Asn Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Ile Ser Ala Ser Leu Ala Ile Thr Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser 85 90 95 Leu Ser Gly Gly Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Arg 100 105 110 Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln 115 120 125 Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr 130 135 140 Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser 145 150 155 160 Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr 165 170 175 Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys 180 185 190 His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro 195 200 205 Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 4 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> Fab region (PD-L1) in VH of ACE-04, ACE-16, ACE-09, and ACE-12 <400> 4 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser 115 120 <210> 5 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fab region (PD-L1) in CDR H1 of ACE-04, ACE-16, ACE-09, and ACE-12 <400> 5 Gly Gly Thr Phe Ser Ser Tyr Ala 1 5 <210> 6 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fab region (PD-L1) in CDR H2 of ACE-04, ACE-16, ACE-09, and ACE-12 <400> 6 Ile Ile Pro Ile Leu Gly Ile Ala 1 5 <210> 7 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> Fab region (PD-L1) CDR H3 of ACE-04, ACE-16, ACE-09, and ACE-12 <400> 7 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile 1 5 10 <210> 8 <211> 112 <212> PRT <213> Artificial Sequence <220> <223> Fab region (PD-L1) in VL of ACE-04, ACE-16, ACE-09, and ACE-12 <400> 8 Gln Leu Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly 20 25 30 Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Ala Ala Pro Lys Leu 35 40 45 Leu Ile Tyr Gly Asp Ile Asn Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Ile Ser Ala Ser Leu Ala Ile Thr Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser 85 90 95 Leu Ser Gly Gly Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Arg 100 105 110 <210> 9 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fab region (PD-L1) in CDR L1 of ACE-04, ACE-16, ACE-09, and ACE-12 <400> 9 Ser Ser Asn Ile Gly Ala Gly Tyr Asp 1 5 <210> 10 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Fab region (PD-L1) in CDR L2 of ACE-04, ACE-16, ACE-09, and ACE-12 <400> 10 Gly Asp Ile One <210> 11 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Fab region (PD-L1) in CDR L3 of ACE-04, ACE-16, ACE-09, and ACE-12 <400> 11 Gln Ser Tyr Asp Ser Ser Leu Ser Gly Gly Val 1 5 10 <210> 12 <211> 122 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in VH of ACE-16, ACE-09, ACE-10, ACE-11, and ACE-12 <400> 12 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser 115 120 <210> 13 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR H1 of ACE-16, ACE-09, ACE-10, ACE-11, and ACE-12 <400> 13 Gly Tyr Ser Phe Thr Gly Tyr Thr Met Asn 1 5 10 <210> 14 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR H2 of ACE-16, ACE-09, ACE-10, ACE-11, and ACE-12 <400> 14 Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr 1 5 10 <210> 15 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR H3 of ACE-16, ACE-09, ACE-10, ACE-11, and ACE-12 <400> 15 Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val 1 5 10 <210> 16 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in VL of ACE-16, ACE-09, ACE-10, ACE-11, and ACE-12 <400> 16 Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly 1 5 10 15 Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Arg Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile 35 40 45 Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Lys Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln 65 70 75 80 Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Trp 85 90 95 Thr Phe Ala Gly Gly Thr Lys Leu Glu Ile Lys Arg 100 105 <210> 17 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR L1 of ACE-16, ACE-09, ACE-10, ACE-11, and ACE-12 <400> 17 Arg Ala Ser Gln Asp Ile Arg Asn Tyr Leu Asn 1 5 10 <210> 18 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR L2 of ACE-16, ACE-09, ACE-10, ACE-11, and ACE-12 <400> 18 Tyr Thr Ser Arg Leu His Ser 1 5 <210> 19 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR L3 of ACE-16, ACE-09, ACE-10, ACE-11, and ACE-12 <400> 19 Gln Gln Gly Asn Thr Leu Pro Trp Thr 1 5 <210> 20 <211> 1110 <212> DNA <213> Artificial Sequence <220> <223> ACE-16-VH nucleotide sequence <400> 20 cagatgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60 tcctgcaagg cttctggagg caccttcagc agctatgcta tcagctgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggaagg atcatcccta tccttggtat agcaaactac 180 gcacagaagt tccagggcag agtcacgatt accgcggaca aatccacgag cacagcctac 240 atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gaaaccgaga 300 gatggctaca atttggttgc ttttgatatc tggggccaag ggacgatggt caccgtctcc 360 tcagctagca ccaagggccc atcggtcttc cccctggcac cctcctccaa gagcacctct 420 gggggcacag cggccctggg ctgcctggtc aaggactact tccccgaacc ggtgacggtg 480 tcgtggaact caggcgccct gaccagcggc gtgcacacct tcccggctgt cctacagtcc 540 tcaggactct actccctcag cagcgtggtg accgtgccct ccagcagcct gggcacccag 600 acctacatct gcaacgtgaa tcacaagccc agcaacacca aggtggacaa gaaagttgag 660 cccaaatctt gtgacaaaac tcacacatgc ccaccgtgcc cagcacctga actcctgggg 720 ggaccgggcg gaggtgggag tgaggtgcag ctccagcagt ctggacctga gctggtgaag 780 cctggacctt caatgaagat atcctgcaag gcttctggtt actcattcac tggctacacc 840 atgaactggg tgaagcagag tcatggaaag aaccttgagt ggatgggact tattaatcct 900 tacaaaggtg ttagtaccta caaccagaag ttcaaggaca aggccacact gactgtagac 960 aagtcatcca gcacagccta catggaactc ctcagtctga catctgagga ctctgcagtc 1020 tattactgtg caagatcggg gtactacggt gatagtgact ggtacttcga tgtctggggc 1080 caggggacca cgctgaccgt cttctcataa 1110 <210> 21 <211> 1068 <212> DNA <213> Artificial Sequence <220> <223> ACE-16-VL nucleotide sequence <400> 21 cagatgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60 tcctgcaagg cttctggagg caccttcagc agctatgcta tcagctgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggaagg atcatcccta tccttggtat agcaaactac 180 gcacagaagt tccagggcag agtcacgatt accgcggaca aatccacgag cacagcctac 240 atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gaaaccgaga 300 gatggctaca atttggttgc ttttgatatc tggggccaag ggacgatggt caccgtctcc 360 tcagctagca ccaagggccc atcggtcttc cccctggcac cctcctccaa gagcacctct 420 gggggcacag cggccctggg ctgcctggtc aaggactact tccccgaacc ggtgacggtg 480 tcgtggaact caggcgccct gaccagcggc gtgcacacct tcccggctgt cctacagtcc 540 tcaggactct actccctcag cagcgtggtg accgtgccct ccagcagcct gggcacccag 600 acctacatct gcaacgtgaa tcacaagccc agcaacacca aggtggacaa gaaagttgag 660 cccaaatctt gtgacaaaac tcacacatgc ccaccgtgcc cagcacctga actcctgggg 720 ggaccgggcg gaggtgggag tgacatccag atgacccaga ccacctcctc cctgtctgcc 780 tccctgggcg acagagtcac catcagttgc agggcaagtc aggacattag aaattattta 840 aactggtatc aacagaaacc agatggaact gttaaactcc tgatctacta cacatcaaga 900 ttacactcag gagtcccatc aaagttcagt ggcagtgggt ctggaacaga ttattctctc 960 accattagca acctggagca agaggatatt gccacttact tttgccaaca gggtaatacg 1020 cttccgtgga cgttcgctgg aggcaccaag ctggaaatca aacggtaa 1068 <210> 22 <211> 657 <212> DNA <213> Artificial Sequence <220> <223> ACE-16-LC nucleotide sequence <400> 22 cagctcgtgc tgactcagcc gccctcagtg tctggggccc cagggcagag ggtcaccatc 60 tcctgcactg ggagcagctc caacatcggg gcaggttatg atgtacactg gtatcagcaa 120 cttccaggag cagcccccaa actcctcatc tatggcgaca tcaatcggcc ctcaggggtc 180 cctgaccgat tctctggctc caagtctggc atctcagcct ccctggctat cactgggctc 240 caggctgagg acgaggctga ttattactgc cagtcctatg acagcagcct gagtgggggg 300 gtgttcggcg gagggaccaa gctgaccgtc ctaagaaccg tggctgcacc atctgtcttc 360 atcttcccgc catctgatga gcagttgaaa tctggaactg cctctgttgt gtgcctgctg 420 aataacttct atcccagaga ggccaaagta cagtggaagg tggataacgc cctccaatcg 480 ggtaactccc aggagagtgt cacagagcag gacagcaagg acagcaccta cagcctcagc 540 agcaccctga cgctgagcaa agcagactac gagaaacaca aagtctacgc ctgcgaagtc 600 acccatcagg gcctgagctc gcccgtcaca aagagcttca acaggggaga gtgttaa 657 <210> 23 <211> 369 <212> PRT <213> Artificial Sequence <220> <223> ACE-10-VH amino acid sequence <400> 23 Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asn Met His Trp Val Lys Gln Thr Pro Gly Arg Gly Leu Glu Trp Ile 35 40 45 Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val Trp Gly 100 105 110 Ala Gly Thr Thr Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Gly Gly Gly Gly Ser Glu Val Gln Leu Gln Gln Ser Gly Pro 245 250 255 Glu Leu Val Lys Pro Gly Pro Ser Met Lys Ile Ser Cys Lys Ala Ser 260 265 270 Gly Tyr Ser Phe Thr Gly Tyr Thr Met Asn Trp Val Lys Gln Ser His 275 280 285 Gly Lys Asn Leu Glu Trp Met Gly Leu Ile Asn Pro Tyr Lys Gly Val 290 295 300 Ser Thr Tyr Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Val Asp 305 310 315 320 Lys Ser Ser Ser Thr Ala Tyr Met Glu Leu Leu Ser Leu Thr Ser Glu 325 330 335 Asp Ser Ala Val Tyr Tyr Cys Ala Arg Ser Gly Tyr Tyr Gly Asp Ser 340 345 350 Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly Thr Thr Leu Thr Val Phe 355 360 365 Ser <210> 24 <211> 355 <212> PRT <213> Artificial Sequence <220> <223> ACE-10-VL amino acid sequence <400> 24 Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asn Met His Trp Val Lys Gln Thr Pro Gly Arg Gly Leu Glu Trp Ile 35 40 45 Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val Trp Gly 100 105 110 Ala Gly Thr Thr Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Thr Thr Ser 245 250 255 Ser Leu Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Arg Ala 260 265 270 Ser Gln Asp Ile Arg Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp 275 280 285 Gly Thr Val Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu His Ser Gly 290 295 300 Val Pro Ser Lys Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu 305 310 315 320 Thr Ile Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys Gln 325 330 335 Gln Gly Asn Thr Leu Pro Trp Thr Phe Ala Gly Gly Thr Lys Leu Glu 340 345 350 Ile Lys Arg 355 <210> 25 <211> 213 <212> PRT <213> Artificial Sequence <220> <223> ACE-10-LC amino acid sequence <400> 25 Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Ile 20 25 30 His Trp Phe Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr 35 40 45 Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Val Glu Ala Glu 65 70 75 80 Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Thr Ser Asn Pro Pro Thr 85 90 95 Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala Pro 100 105 110 Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 115 120 125 Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135 140 Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu 145 150 155 160 Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175 Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190 Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200 205 Asn Arg Gly Glu Cys 210 <210> 26 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD20) in VH of ACE-10 <400> 26 Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asn Met His Trp Val Lys Gln Thr Pro Gly Arg Gly Leu Glu Trp Ile 35 40 45 Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val Trp Gly 100 105 110 Ala Gly Thr Thr Val Thr Val Ser Ala 115 120 <210> 27 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD20) in CDR H1 of ACE-10 <400> 27 Gly Tyr Thr Phe Thr Ser Tyr Asn 1 5 <210> 28 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD20) in CDR H2 of ACE-10 <400> 28 Ile Tyr Pro Gly Asn Gly Asp Thr 1 5 <210> 29 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD20) in CDR H3 of ACE-10 <400> 29 Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val 1 5 10 <210> 30 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD20) in VL of ACE-10 <400> 30 Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Ile 20 25 30 His Trp Phe Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr 35 40 45 Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Val Glu Ala Glu 65 70 75 80 Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Thr Ser Asn Pro Pro Thr 85 90 95 Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg 100 105 <210> 31 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD20) in CDR L1 of ACE-10 <400> 31 Ser Ser Val Ser Tyr 1 5 <210> 32 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD20) in CDR L2 of ACE-10 <400> 32 Ala Thr Ser One <210> 33 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD20) in CDR L3 of ACE-10 <400> 33 Gln Gln Trp Thr Ser Asn Pro Pro Thr 1 5 <210> 34 <211> 1110 <212> DNA <213> Artificial Sequence <220> <223> ACE-10-VH nucleotide sequence <400> 34 caggtgcagc tgcagcagcc tggagccgag ctggtgaagc ccggcgccag cgtgaagatg 60 agctgcaagg ccagcggcta caccttcacc agctacaaca tgcactgggt gaagcagacc 120 cctggaagag gactggagtg gatcggcgcc atctaccccg gcaacggcga caccagctac 180 aaccagaagt tcaagggcaa ggccaccctg accgccgaca agagcagcag caccgcctac 240 atgcagctga gcagcctgac cagcgaggac agcgccgtgt actactgcgc ccgcagcacc 300 tactacggcg gcgactggta cttcaacgtg tggggagctg gaaccaccgt gaccgtgagc 360 gccgctagca ccaagggccc atcggtcttc cccctggcac cctcctccaa gagcacctct 420 gggggcacag cggccctggg ctgcctggtc aaggactact tccccgaacc ggtgacggtg 480 tcgtggaact caggcgccct gaccagcggc gtgcacacct tcccggctgt cctacagtcc 540 tcaggactct actccctcag cagcgtggtg accgtgccct ccagcagcct gggcacccag 600 acctacatct gcaacgtgaa tcacaagccc agcaacacca aggtggacaa gaaggttgag 660 cccaaatctt gtgacaaaac tcacacatgc ccaccgtgcc cagcacctga actcctgggg 720 ggaccgggcg gaggtgggag tgaggtgcag ctccagcagt ctggacctga gctggtgaag 780 cctggacctt caatgaagat atcctgcaag gcttctggtt actcattcac tggctacacc 840 atgaactggg tgaagcagag tcatggaaag aaccttgagt ggatgggact tattaatcct 900 tacaaaggtg ttagtaccta caaccagaag ttcaaggaca aggccacact gactgtagac 960 aagtcatcca gcacagccta catggaactc ctcagtctga catctgagga ctctgcagtc 1020 tattactgtg caagatcggg gtactacggt gatagtgact ggtacttcga tgtctggggc 1080 caggggacca cgctgaccgt cttctcataa 1110 <210> 35 <211> 1068 <212> DNA <213> Artificial Sequence <220> <223> ACE-10-VL nucleotide sequence <400> 35 caggtgcagc tgcagcagcc tggagccgag ctggtgaagc ccggcgccag cgtgaagatg 60 agctgcaagg ccagcggcta caccttcacc agctacaaca tgcactgggt gaagcagacc 120 cctggaagag gactggagtg gatcggcgcc atctaccccg gcaacggcga caccagctac 180 aaccagaagt tcaagggcaa ggccaccctg accgccgaca agagcagcag caccgcctac 240 atgcagctga gcagcctgac cagcgaggac agcgccgtgt actactgcgc ccgcagcacc 300 tactacggcg gcgactggta cttcaacgtg tggggagctg gaaccaccgt gaccgtgagc 360 gccgctagca ccaagggccc atcggtcttc cccctggcac cctcctccaa gagcacctct 420 gggggcacag cggccctggg ctgcctggtc aaggactact tccccgaacc ggtgacggtg 480 tcgtggaact caggcgccct gaccagcggc gtgcacacct tcccggctgt cctacagtcc 540 tcaggactct actccctcag cagcgtggtg accgtgccct ccagcagcct gggcacccag 600 acctacatct gcaacgtgaa tcacaagccc agcaacacca aggtggacaa gaaggttgag 660 cccaaatctt gtgacaaaac tcacacatgc ccaccgtgcc cagcacctga actcctgggg 720 ggaccgggcg gaggtgggag tgacatccag atgacccaga ccacctcctc cctgtctgcc 780 tccctgggcg acagagtcac catcagttgc agggcaagtc aggacattag aaattattta 840 aactggtatc aacagaaacc agatggaact gttaaactcc tgatctacta cacatcaaga 900 ttacactcag gagtcccatc aaagttcagt ggcagtgggt ctggaacaga ttattctctc 960 accattagca acctggagca agaggatatt gccacttact tttgccaaca gggtaatacg 1020 cttccgtgga cgttcgctgg aggcaccaag ctggaaatca aacggtaa 1068 <210> 36 <211> 642 <212> DNA <213> Artificial Sequence <220> <223> ACE-10-LC nucleotide sequence <400> 36 cagatcgtgc tgagccagag ccctgctatc ctgagcgcca gccctggcga gaaggtgacc 60 atgacctgcc gcgccagcag cagcgtgagc tacatccact ggttccagca gaagcccggc 120 agcagcccca agccctggat ctacgccacc agcaacctgg ccagcggagt gcctgtgcgc 180 ttcagcggca gcggcagcgg caccagctac agcctgacca tcagcagagt ggaggctgag 240 gacgccgcta cctactactg ccagcagtgg accagcaacc cccccacctt cggcggcggc 300 accaagctgg agatcaagag aaccgtggct gcaccatctg tcttcatctt cccgccatct 360 gatgagcagt tgaaatctgg aactgcctct gttgtgtgcc tgctgaataa cttctatccc 420 agagaggcca aagtacagtg gaaggtggat aacgccctcc aatcgggtaa ctcccaggag 480 agtgtcacag agcaggacag caaggacagc acctacagcc tcagcagcac cctgacgctg 540 agcaaagcag actacgagaa acacaaagtc tacgcctgcg aagtcaccca tcagggcctg 600 agctcgcccg tcacaaagag cttcaacagg ggagagtgtt ag 642 <210> 37 <211> 367 <212> PRT <213> Artificial Sequence <220> <223> ACE-11-VH amino acid sequence <400> 37 Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30 Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60 Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe 65 70 75 80 Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala 85 90 95 Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230 235 240 Gly Gly Gly Gly Ser Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu 245 250 255 Val Lys Pro Gly Pro Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr 260 265 270 Ser Phe Thr Gly Tyr Thr Met Asn Trp Val Lys Gln Ser His Gly Lys 275 280 285 Asn Leu Glu Trp Met Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr 290 295 300 Tyr Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser 305 310 315 320 Ser Ser Thr Ala Tyr Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser 325 330 335 Ala Val Tyr Tyr Cys Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp 340 345 350 Tyr Phe Asp Val Trp Gly Gln Gly Thr Thr Leu Thr Val Phe Ser 355 360 365 <210> 38 <211> 353 <212> PRT <213> Artificial Sequence <220> <223> ACE-11-VL amino acid sequence <400> 38 Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30 Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60 Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe 65 70 75 80 Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala 85 90 95 Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230 235 240 Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu 245 250 255 Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln 260 265 270 Asp Ile Arg Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr 275 280 285 Val Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro 290 295 300 Ser Lys Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile 305 310 315 320 Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly 325 330 335 Asn Thr Leu Pro Trp Thr Phe Ala Gly Gly Thr Lys Leu Glu Ile Lys 340 345 350 Arg <210> 39 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> ACE-11-LC amino acid sequence <400> 39 Asp Ile Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn 20 25 30 Ile His Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile 35 40 45 Lys Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser 65 70 75 80 Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr 85 90 95 Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 40 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD20) in VH of ACE-11 <400> 40 Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30 Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60 Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe 65 70 75 80 Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala 85 90 95 Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ala 115 <210> 41 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD20) in CDR H1 of ACE-11 <400> 41 Gly Phe Ser Leu Thr Asn Tyr Gly 1 5 <210> 42 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD20) in CDR H2 of ACE-11 <400> 42 Ile Trp Ser Gly Gly Asn Thr 1 5 <210> 43 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD20) in CDR H3 of ACE-11 <400> 43 Ala Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr 1 5 10 <210> 44 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD20) in VL of ACE-11 <400> 44 Asp Ile Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn 20 25 30 Ile His Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile 35 40 45 Lys Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser 65 70 75 80 Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr 85 90 95 Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg 100 105 <210> 45 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD20) in CDR L1 of ACE-11 <400> 45 Gln Ser Ile Gly Thr Asn 1 5 <210> 46 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD20) in CDR L2 of ACE-11 <400> 46 Tyr Ala Ser One <210> 47 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD20) in CDR L3 of ACE-11 <400> 47 Gln Gln Asn Asn Asn Trp Pro Thr Thr 1 5 <210> 48 <211> 1104 <212> DNA <213> Artificial Sequence <220> <223> ACE-11-VH nucleotide sequence <400> 48 caagtccaac tgaaacaatc gggtccgggt ctggtccaac cgtcccaatc actgagcatc 60 acctgtaccg tgtcgggctt ctcgctgacc aattatggtg tgcattgggt tcgtcagagt 120 ccgggcaaag gtctggaatg gctgggcgtt atttggtccg gcggtaatac cgattacaac 180 accccgttta cgagtcgcct gtccatcaat aaagacaact cgaaaagcca ggtgtttttc 240 aaaatgaatt cactgcaatc gaacgatacc gcgatttatt actgcgcacg tgctctgacg 300 tattacgact atgaatttgc ctactggggc cagggtaccc tggtgacggt tagcgcggct 360 agcaccaagg gcccatcggt cttccccctg gcaccctcct ccaagagcac ctctgggggc 420 acagcggccc tgggctgcct ggtcaaggac tacttccccg aaccggtgac ggtgtcgtgg 480 aactcaggcg ccctgaccag cggcgtgcac accttcccgg ctgtcctaca gtcctcagga 540 ctctactccc tcagcagcgt ggtgaccgtg ccctccagca gcctgggcac ccagacctac 600 atctgcaacg tgaatcacaa gcccagcaac accaaggtgg acaagaaggt tgagcccaaa 660 tcttgtgaca aaactcacac atgcccaccg tgcccagcac ctgaactcct ggggggaccg 720 ggcggaggtg ggagtgaggt gcagctccag cagtctggac ctgagctggt gaagcctgga 780 ccttcaatga agatatcctg caaggcttct ggttactcat tcactggcta caccatgaac 840 tgggtgaagc agagtcatgg aaagaacctt gagtggatgg gacttattaa tccttacaaa 900 ggtgttagta cctacaacca gaagttcaag gacaaggcca cactgactgt agacaagtca 960 tccagcacag cctacatgga actcctcagt ctgacatctg aggactctgc agtctattac 1020 tgtgcaagat cggggtacta cggtgatagt gactggtact tcgatgtctg gggccagggg 1080 accacgctga ccgtcttctc ataa 1104 <210> 49 <211> 1062 <212> DNA <213> Artificial Sequence <220> <223> ACE-11-VL nucleotide sequence <400> 49 caagtccaac tgaaacaatc gggtccgggt ctggtccaac cgtcccaatc actgagcatc 60 acctgtaccg tgtcgggctt ctcgctgacc aattatggtg tgcattgggt tcgtcagagt 120 ccgggcaaag gtctggaatg gctgggcgtt atttggtccg gcggtaatac cgattacaac 180 accccgttta cgagtcgcct gtccatcaat aaagacaact cgaaaagcca ggtgtttttc 240 aaaatgaatt cactgcaatc gaacgatacc gcgatttatt actgcgcacg tgctctgacg 300 tattacgact atgaatttgc ctactggggc cagggtaccc tggtgacggt tagcgcggct 360 agcaccaagg gcccatcggt cttccccctg gcaccctcct ccaagagcac ctctgggggc 420 acagcggccc tgggctgcct ggtcaaggac tacttccccg aaccggtgac ggtgtcgtgg 480 aactcaggcg ccctgaccag cggcgtgcac accttcccgg ctgtcctaca gtcctcagga 540 ctctactccc tcagcagcgt ggtgaccgtg ccctccagca gcctgggcac ccagacctac 600 atctgcaacg tgaatcacaa gcccagcaac accaaggtgg acaagaaggt tgagcccaaa 660 tcttgtgaca aaactcacac atgcccaccg tgcccagcac ctgaactcct ggggggaccg 720 ggcggaggtg ggagtgacat ccagatgacc cagaccacct cctccctgtc tgcctccctg 780 ggcgacagag tcaccatcag ttgcagggca agtcaggaca ttagaaatta tttaaactgg 840 tatcaacaga aaccagatgg aactgttaaa ctcctgatct actacacatc aagattacac 900 tcaggagtcc catcaaagtt cagtggcagt gggtctggaa cagattattc tctcaccatt 960 agcaacctgg agcaagagga tattgccact tacttttgcc aacagggtaa tacgcttccg 1020 tggacgttcg ctggaggcac caagctggaa atcaaacggt aa 1062 <210> 50 <211> 645 <212> DNA <213> Artificial Sequence <220> <223> ACE-11-LC nucleotide sequence <400> 50 gatattctgc tgacccagag cccggtgatc ctgagtgttt ccccgggcga acgtgtgtca 60 ttttcgtgtc gcgcgagcca gtctattggt accaatatcc actggtatca gcaacgtacg 120 aacggctctc cgcgcctgct gattaaatac gccagtgaat ccatttcagg catcccgagc 180 cgcttttcgg gcagcggttc tggcaccgat ttcacgctga gtattaactc cgtggaatca 240 gaagatatcg cagactatta ctgccagcaa aacaataact ggccgaccac gtttggtgct 300 ggcaccaaac tggaactgaa aagaaccgtg gctgcaccat ctgtcttcat cttcccgcca 360 tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420 cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480 gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540 ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600 ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gttaa 645 <210> 51 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> Fab region (Her2) in VH of ACE-00 <400> 51 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 52 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> Fab region (Her2) in VL of ACE-00 <400> 52 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105 <210> 53 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> Fv region (TNF alpha) in VH of ACE-00 <400> 53 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Thr Trp Asn Ser Gly His Ile Asp Tyr Ala Asp Ser Val 50 55 60 Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Val Ser Tyr Leu Ser Thr Ala Ser Ser Leu Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 54 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> Fv region (TNF alpha) in VL of ACE-00 <400> 54 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Val Ala Thr Tyr Tyr Cys Gln Arg Tyr Asn Arg Ala Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105 <210> 55 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> Core hinge region sequence of IgG1 <400> 55 Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro 1 5 10 15 <210> 56 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Core hinge region sequence of IgG2 <400> 56 Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro 1 5 10 <210> 57 <211> 61 <212> PRT <213> Artificial Sequence <220> <223> Core hinge region sequence of IgG3 <400> 57 Glu Leu Lys Thr Pro Leu Asp Thr Thr His Thr Cys Pro Arg Cys Pro 1 5 10 15 Glu Pro Lys Ser Cys Asp Thr Pro Pro Pro Cys Pro Arg Cys Pro Glu 20 25 30 Pro Lys Ser Cys Asp Thr Pro Pro Pro Cys Pro Arg Cys Pro Glu Pro 35 40 45 Lys Ser Cys Asp Thr Pro Pro Pro Cys Pro Arg Cys Pro 50 55 60 <210> 58 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Core hinge region sequence of IgG4 <400> 58 Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro 1 5 10 <210> 59 <211> 106 <212> PRT <213> Artificial Sequence <220> <223> A representative CL region of the Fab region <400> 59 Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln 1 5 10 15 Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr 20 25 30 Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser 35 40 45 Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr 50 55 60 Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys 65 70 75 80 His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro 85 90 95 Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 100 105 <210> 60 <211> 98 <212> PRT <213> Artificial Sequence <220> <223> A representative CH1 region of the Fab region <400> 60 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95 Lys Val <210> 61 <211> 124 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD19) in VH of ACE-02, and ACE-03 <400> 61 Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ser 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Ser Tyr 20 25 30 Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Gln Ile Trp Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gly Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Glu Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95 Ala Arg Arg Glu Thr Thr Thr Val Gly Arg Tyr Tyr Tyr Ala Met Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 62 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD19) in CDR H1 of ACE-02, and ACE-03 <400> 62 Ser Tyr Trp Met Asn 1 5 <210> 63 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD19) in CDR H2 of ACE-02, and ACE-03 <400> 63 Gln Ile Trp Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gly Lys Phe Lys 1 5 10 15 Gly <210> 64 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD19) in CDR H3 of ACE-02, and ACE-03 <400> 64 Arg Glu Thr Thr Thr Val Gly Arg Tyr Tyr Tyr Ala Met Asp Tyr 1 5 10 15 <210> 65 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD19) in VL of ACE-02, and ACE-03 <400> 65 Asp Ile Gln Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Gln Arg Ala Thr Ile Ser Cys Lys Ala Ser Gln Ser Val Asp Tyr Asp 20 25 30 Gly Asp Ser Tyr Leu Asn Trp Tyr Gln Gln Ile Pro Gly Gln Pro Pro 35 40 45 Lys Leu Leu Ile Tyr Asp Ala Ser Asn Leu Val Ser Gly Ile Pro Pro 50 55 60 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile His 65 70 75 80 Pro Val Glu Lys Val Asp Ala Ala Thr Tyr His Cys Gln Gln Ser Thr 85 90 95 Glu Asp Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 <210> 66 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD19) in CDR L1 of ACE-02, and ACE-03 <400> 66 Gln Ser Val Asp Tyr Asp Gly Asp Ser Tyr 1 5 10 <210> 67 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD19) in CDR L2 of ACE-02, and ACE-03 <400> 67 Asp Ala Ser One <210> 68 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD19) in CDR L3 of ACE-02, and ACE-03 <400> 68 Gln Gln Ser Thr Glu Asp Pro Trp Thr 1 5 <210> 69 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in VH of ACE-02 <400> 69 Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Asn Pro Ser Ser Gly Tyr Thr Lys Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Arg Phe Thr Ile Ser Ala Asp Lys Ser Lys Ser Thr Ala Phe 65 70 75 80 Leu Gln Met Asp Ser Leu Arg Pro Glu Asp Thr Gly Val Tyr Phe Cys 85 90 95 Ala Arg Trp Gln Asp Tyr Asp Val Tyr Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Pro Val Thr Val Ser Ser 115 <210> 70 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR H1 of ACE-02 <400> 70 Gly Tyr Thr Phe Thr Ser Tyr Thr 1 5 <210> 71 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR H2 of ACE-02 <400> 71 Ile Asn Pro Ser Ser Gly Tyr Thr 1 5 <210> 72 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR H3 of ACE-02 <400> 72 Ala Arg Trp Gln Asp Tyr Asp Val Tyr Phe Asp Tyr 1 5 10 <210> 73 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in VL of ACE-02 <400> 73 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Met 20 25 30 His Trp Tyr Gln Gln Thr Pro Gly Lys Ala Pro Lys Pro Trp Ile Tyr 35 40 45 Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu 65 70 75 80 Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Pro Thr 85 90 95 Phe Gly Gln Gly Thr Lys Leu Gln Ile Thr Arg 100 105 <210> 74 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR L1 of ACE-02 <400> 74 Ser Ser Ser Val Ser Tyr 1 5 <210> 75 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR L2 of ACE-02 <400> 75 Ala Thr Ser One <210> 76 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR L3 of ACE-02 <400> 76 Gln Gln Trp Ser Ser Asn Pro Pro Thr 1 5 <210> 77 <211> 118 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in VH of ACE-03 <400> 77 Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser 1 5 10 15 Leu Arg Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr Thr 20 25 30 Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly 35 40 45 Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Val Lys 50 55 60 Asp Arg Phe Thr Ile Ser Thr Asp Lys Ser Lys Ser Thr Ala Phe Leu 65 70 75 80 Gln Met Asp Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Pro Val Thr Val Ser Ser 115 <210> 78 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR H1 of ACE-03, and ACE-04 <400> 78 Gly Tyr Thr Phe Thr Arg Tyr Thr 1 5 <210> 79 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR H2 of ACE-03, and ACE-04 <400> 79 Ile Asn Pro Ser Arg Gly Tyr Thr 1 5 <210> 80 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR H3 of ACE-03, and ACE-04 <400> 80 Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr 1 5 10 <210> 81 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in VL of ACE-03 <400> 81 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met 20 25 30 Asn Trp Tyr Gln Gln Thr Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr 35 40 45 Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu 65 70 75 80 Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Phe Thr 85 90 95 Phe Gly Gln Gly Thr Lys Leu Gln Ile Thr Arg 100 105 <210> 82 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR L1 of ACE-03, and ACE-04 <400> 82 Ser Ser Val Ser Tyr 1 5 <210> 83 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR L2 of ACE-03, and ACE-04 <400> 83 Asp Thr Ser One <210> 84 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR L3 of ACE-03 <400> 84 Gln Gln Trp Ser Ser Asn Pro Phe Thr 1 5 <210> 85 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in VH of ACE-04 <400> 85 Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr 20 25 30 Thr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Thr Val Thr Val Ser Ala 115 <210> 86 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in VL of ACE-04 <400> 86 Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met 20 25 30 Asn Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr 35 40 45 Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala His Phe Arg Gly Ser 50 55 60 Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Gly Met Glu Ala Glu 65 70 75 80 Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Phe Thr 85 90 95 Phe Gly Ser Gly Thr Lys Leu Glu Ile Asn Arg 100 105 <210> 87 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR L3 of ACE-04 <400> 87 Gln Gln Trp Ser Ser Asn Pro Phe 1 5 <210> 88 <211> 364 <212> PRT <213> Artificial Sequence <220> <223> ACE-02-VH amino acid sequence <400> 88 Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ser 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Ser Tyr 20 25 30 Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Gln Ile Trp Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gly Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Glu Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95 Ala Arg Arg Glu Thr Thr Thr Val Gly Arg Tyr Tyr Tyr Ala Met Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys 115 120 125 Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 130 135 140 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 145 150 155 160 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 165 170 175 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 180 185 190 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn 195 200 205 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro 210 215 220 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val 245 250 255 Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Lys Ala Ser Gly Tyr 260 265 270 Thr Phe Thr Ser Tyr Thr Met His Trp Val Arg Gln Ala Pro Gly Lys 275 280 285 Gly Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Ser Gly Tyr Thr Lys 290 295 300 Tyr Asn Gln Lys Phe Lys Asp Arg Phe Thr Ile Ser Ala Asp Lys Ser 305 310 315 320 Lys Ser Thr Ala Phe Leu Gln Met Asp Ser Leu Arg Pro Glu Asp Thr 325 330 335 Gly Val Tyr Phe Cys Ala Arg Trp Gln Asp Tyr Asp Val Tyr Phe Asp 340 345 350 Tyr Trp Gly Gln Gly Thr Pro Val Thr Val Ser Ser 355 360 <210> 89 <211> 352 <212> PRT <213> Artificial Sequence <220> <223> ACE-02-VL amino acid sequence <400> 89 Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ser 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Ser Tyr 20 25 30 Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Gln Ile Trp Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gly Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Glu Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95 Ala Arg Arg Glu Thr Thr Thr Val Gly Arg Tyr Tyr Tyr Ala Met Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys 115 120 125 Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 130 135 140 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 145 150 155 160 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 165 170 175 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 180 185 190 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn 195 200 205 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro 210 215 220 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu 245 250 255 Ser Ala Ser Val Gly Asp Arg Val Thr Met Thr Cys Arg Ala Ser Ser 260 265 270 Ser Val Ser Tyr Met His Trp Tyr Gln Gln Thr Pro Gly Lys Ala Pro 275 280 285 Lys Pro Trp Ile Tyr Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Ser 290 295 300 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser 305 310 315 320 Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Trp Ser 325 330 335 Ser Asn Pro Pro Thr Phe Gly Gln Gly Thr Lys Leu Gln Ile Thr Arg 340 345 350 <210> 90 <211> 218 <212> PRT <213> Artificial Sequence <220> <223> ACE-02-LC, ACE-03-LC (anti-CD19 antibody light chain) <400> 90 Asp Ile Gln Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Gln Arg Ala Thr Ile Ser Cys Lys Ala Ser Gln Ser Val Asp Tyr Asp 20 25 30 Gly Asp Ser Tyr Leu Asn Trp Tyr Gln Gln Ile Pro Gly Gln Pro Pro 35 40 45 Lys Leu Leu Ile Tyr Asp Ala Ser Asn Leu Val Ser Gly Ile Pro Pro 50 55 60 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile His 65 70 75 80 Pro Val Glu Lys Val Asp Ala Ala Thr Tyr His Cys Gln Gln Ser Thr 85 90 95 Glu Asp Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg 100 105 110 Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln 115 120 125 Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr 130 135 140 Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser 145 150 155 160 Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr 165 170 175 Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys 180 185 190 His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro 195 200 205 Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 91 <211> 363 <212> PRT <213> Artificial Sequence <220> <223> ACE-03-VH amino acid sequence <400> 91 Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ser 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Ser Tyr 20 25 30 Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Gln Ile Trp Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gly Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Glu Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95 Ala Arg Arg Glu Thr Thr Thr Val Gly Arg Tyr Tyr Tyr Ala Met Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys 115 120 125 Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 130 135 140 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 145 150 155 160 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 165 170 175 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 180 185 190 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn 195 200 205 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro 210 215 220 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Val Gln Leu Val Gln Ser Gly Gly Gly Val Val 245 250 255 Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Lys Ala Ser Gly Tyr Thr 260 265 270 Phe Thr Arg Tyr Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly 275 280 285 Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr 290 295 300 Asn Gln Lys Val Lys Asp Arg Phe Thr Ile Ser Thr Asp Lys Ser Lys 305 310 315 320 Ser Thr Ala Phe Leu Gln Met Asp Ser Leu Arg Pro Glu Asp Thr Ala 325 330 335 Val Tyr Tyr Cys Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr 340 345 350 Trp Gly Gln Gly Thr Pro Val Thr Val Ser Ser 355 360 <210> 92 <211> 352 <212> PRT <213> Artificial Sequence <220> <223> ACE-03-VL amino acid sequence <400> 92 Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ser 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Ser Tyr 20 25 30 Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Gln Ile Trp Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gly Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Glu Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95 Ala Arg Arg Glu Thr Thr Thr Val Gly Arg Tyr Tyr Tyr Ala Met Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys 115 120 125 Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 130 135 140 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 145 150 155 160 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 165 170 175 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 180 185 190 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn 195 200 205 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro 210 215 220 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu 245 250 255 Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Ser 260 265 270 Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Thr Pro Gly Lys Ala Pro 275 280 285 Lys Arg Trp Ile Tyr Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser 290 295 300 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser 305 310 315 320 Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Trp Ser 325 330 335 Ser Asn Pro Phe Thr Phe Gly Gln Gly Thr Lys Leu Gln Ile Thr Arg 340 345 350 <210> 93 <211> 469 <212> PRT <213> Artificial Sequence <220> <223> ACE-04-VH amino acid seqeunce <400> 93 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Gln Ser Gly Ala 245 250 255 Glu Leu Ala Arg Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser 260 265 270 Gly Tyr Thr Phe Thr Arg Tyr Thr Met His Trp Val Lys Gln Arg Pro 275 280 285 Gly Gln Gly Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Arg Gly Tyr 290 295 300 Thr Asn Tyr Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Thr Asp 305 310 315 320 Lys Ser Ser Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu 325 330 335 Asp Ser Ala Val Tyr Tyr Cys Ala Arg Tyr Tyr Asp Asp His Tyr Cys 340 345 350 Leu Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ala Ala Ser 355 360 365 Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr 370 375 380 Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro 385 390 395 400 Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val 405 410 415 His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser 420 425 430 Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile 435 440 445 Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val 450 455 460 Glu Pro Lys Ser Cys 465 <210> 94 <211> 460 <212> PRT <213> Artificial Sequence <220> <223> ACE-04-VL amino acid sequence <400> 94 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Gly Gly Gly Gly Ser Gln Ile Val Leu Thr Gln Ser Pro Ala 245 250 255 Ile Met Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Ser Ala 260 265 270 Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Ser Gly Thr 275 280 285 Ser Pro Lys Arg Trp Ile Tyr Asp Thr Ser Lys Leu Ala Ser Gly Val 290 295 300 Pro Ala His Phe Arg Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr 305 310 315 320 Ile Ser Gly Met Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln 325 330 335 Trp Ser Ser Asn Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile 340 345 350 Asn Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 355 360 365 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 370 375 380 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 385 390 395 400 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 405 410 415 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 420 425 430 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 435 440 445 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 450 455 460 <210> 95 <211> 218 <212> PRT <213> Artificial Sequence <220> <223> ACE-04-LC, ACE-09-LC, and ACE-12-LC (anti-PD-L1 antibody light chain) <400> 95 Gln Leu Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly 20 25 30 Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Ala Ala Pro Lys Leu 35 40 45 Leu Ile Tyr Gly Asp Ile Asn Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Ile Ser Ala Ser Leu Ala Ile Thr Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser 85 90 95 Leu Ser Gly Gly Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Arg 100 105 110 Ser Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln 115 120 125 Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr 130 135 140 Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser 145 150 155 160 Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr 165 170 175 Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys 180 185 190 His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro 195 200 205 Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 96 <211> 364 <212> PRT <213> Artificial Sequence <220> <223> ACE-09-VH amino acid sequence (without G4S linker) <400> 96 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro 245 250 255 Gly Pro Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr 260 265 270 Gly Tyr Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu 275 280 285 Trp Met Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln 290 295 300 Lys Phe Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr 305 310 315 320 Ala Tyr Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr 325 330 335 Tyr Cys Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp 340 345 350 Val Trp Gly Gln Gly Thr Thr Leu Thr Val Phe Ser 355 360 <210> 97 <211> 350 <212> PRT <213> Artificial Sequence <220> <223> ACE-09-VL amino acid sequence (without G4S linker) <400> 97 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser 245 250 255 Leu Gly Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Arg 260 265 270 Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu 275 280 285 Leu Ile Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Lys Phe 290 295 300 Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu 305 310 315 320 Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu 325 330 335 Pro Trp Thr Phe Ala Gly Gly Thr Lys Leu Glu Ile Lys Arg 340 345 350 <210> 98 <211> 374 <212> PRT <213> Artificial Sequence <220> <223> ACE-12-VH amino acid sequence (with 10 residues) <400> 98 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu 245 250 255 Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro Ser Met Lys Ile 260 265 270 Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr Thr Met Asn Trp 275 280 285 Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met Gly Leu Ile Asn 290 295 300 Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe Lys Asp Lys Ala 305 310 315 320 Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr Met Glu Leu Leu 325 330 335 Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg Ser Gly 340 345 350 Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly Thr 355 360 365 Thr Leu Thr Val Phe Ser 370 <210> 99 <211> 359 <212> PRT <213> Artificial Sequence <220> <223> ACE-12-VL amino acid sequence (with 9 residues) <400> 99 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Gly Gly Ser Gly Gly Gly Gly Ser Gly Asp Ile Gln Met Thr 245 250 255 Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly Asp Arg Val Thr Ile 260 265 270 Ser Cys Arg Ala Ser Gln Asp Ile Arg Asn Tyr Leu Asn Trp Tyr Gln 275 280 285 Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile Tyr Tyr Thr Ser Arg 290 295 300 Leu His Ser Gly Val Pro Ser Lys Phe Ser Gly Ser Gly Ser Gly Thr 305 310 315 320 Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr 325 330 335 Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Trp Thr Phe Ala Gly Gly 340 345 350 Thr Lys Leu Glu Ile Lys Arg 355 <210> 100 <211> 1095 <212> DNA <213> Artificial Sequence <220> <223> ACE-02-VH nucleotide sequence <400> 100 caggttcaat tgcagcaaag cggggctgag ttggtacggc ctgggtccag cgtgaagata 60 tcatgtaagg cttctggata tgccttctcc tcttactgga tgaactgggt caagcaacgg 120 ccaggacaag gcctggagtg gattgggcaa atatggcccg gggacggaga tactaattat 180 aatggcaagt ttaaggggaa agctacactg accgcagacg aaagctcctc tacggcctat 240 atgcagctct catctcttgc gtccgaagat agtgcagtat atttttgtgc gcgccgcgag 300 accaccacgg ttgggaggta ctattacgcg atggattact ggggccaggg gactacagtt 360 acggtttcat cagctagcac caagggccca tcggtcttcc ccctggcacc ctcctccaag 420 agcacctctg ggggcacagc ggccctgggc tgcctggtca aggactactt ccccgaaccg 480 gtgacggtgt cgtggaactc aggcgccctg accagcggcg tgcacacctt cccggctgtc 540 ctacagtcct caggactcta ctccctcagc agcgtggtga ccgtgccctc cagcagcctg 600 ggcacccaga cctacatctg caacgtgaat cacaagccca gcaacaccaa ggtggacaag 660 agagttgagc ccaaatcttg tgacaaaact cacacatgcc caccgtgccc agcacctgaa 720 ctcctggggg gaccgcaggt gcagctggtg cagagcggcg gcggcgtggt gcagcccggc 780 cgcagcctgc gcctgagctg caaggccagc ggctacacct tcaccagcta caccatgcac 840 tgggtgcgcc aggcccccgg caagggcctg gagtggatcg gctacatcaa ccccagcagc 900 ggctacacca agtacaacca gaagttcaag gaccgcttca ccatcagcgc cgacaagagc 960 aagagcaccg ccttcctgca gatggacagc ctgcgccccg aggacaccgg cgtgtacttc 1020 tgcgcccgct ggcaggacta cgacgtgtac ttcgactact ggggccaggg cacccccgtg 1080 accgtgagca gctaa 1095 <210> 101 <211> 1059 <212> DNA <213> Artificial Sequence <220> <223> ACE-02-VL nucleotide sequence <400> 101 caggttcaat tgcagcaaag cggggctgag ttggtacggc ctgggtccag cgtgaagata 60 tcatgtaagg cttctggata tgccttctcc tcttactgga tgaactgggt caagcaacgg 120 ccaggacaag gcctggagtg gattgggcaa atatggcccg gggacggaga tactaattat 180 aatggcaagt ttaaggggaa agctacactg accgcagacg aaagctcctc tacggcctat 240 atgcagctct catctcttgc gtccgaagat agtgcagtat atttttgtgc gcgccgcgag 300 accaccacgg ttgggaggta ctattacgcg atggattact ggggccaggg gactacagtt 360 acggtttcat cagctagcac caagggccca tcggtcttcc ccctggcacc ctcctccaag 420 agcacctctg ggggcacagc ggccctgggc tgcctggtca aggactactt ccccgaaccg 480 gtgacggtgt cgtggaactc aggcgccctg accagcggcg tgcacacctt cccggctgtc 540 ctacagtcct caggactcta ctccctcagc agcgtggtga ccgtgccctc cagcagcctg 600 ggcacccaga cctacatctg caacgtgaat cacaagccca gcaacaccaa ggtggacaag 660 agagttgagc ccaaatcttg tgacaaaact cacacatgcc caccgtgccc agcacctgaa 720 ctcctggggg gaccggacat ccagatgacc cagagcccca gcagcctgag cgccagcgtg 780 ggcgaccgcg tgaccatgac ctgccgcgcc agcagcagcg tgagctacat gcactggtac 840 cagcagaccc ccggcaaggc ccccaagccc tggatctacg ccaccagcaa cctggccagc 900 ggcgtgccca gccgcttcag cggcagcggc agcggcaccg actacaccct gaccatcagc 960 agcctgcagc ccgaggacat cgccacctac tactgccagc agtggagcag caaccccccc 1020 accttcggcc agggcaccaa gctgcagatc acccgctaa 1059 <210> 102 <211> 657 <212> DNA <213> Artificial Sequence <220> <223> ACE-02-LC, and ACE-03-LC (anti-CD19 antibody light chain nucleotide sequence) <400> 102 gatattcaac tcacgcaatc tccagcaagt ctcgcagtta gtttggggca gcgagctaca 60 ataagttgca aggcgagcca atccgtggat tatgatggag acagctatct taactggtat 120 cagcaaattc caggccagcc acccaagttg ctgatctacg acgcgtcaaa cctggtctca 180 gggatccctc caagatttag cggctcaggt tcaggtacgg attttacgct caatatccat 240 cctgtagaga aggttgatgc agctacatac cactgtcaac agagtaccga ggatccttgg 300 accttcggag gcggtacaaa gctggagatc aagagaaccg tggctgcacc atctgtcttc 360 atcttcccgc catctgatga gcagttgaaa tctggaactg cctctgttgt gtgcctgctg 420 aataacttct atcccagaga ggccaaagta cagtggaagg tggataacgc cctccaatcg 480 ggtaactccc aggagagtgt cacagagcag gacagcaagg acagcaccta cagcctcagc 540 agcaccctga cgctgagcaa agcagactac gagaaacaca aagtctacgc ctgcgaagtc 600 acccatcagg gcctgagctc gcccgtcaca aagagcttca acaggggaga gtgttaa 657 <210> 103 <211> 1092 <212> DNA <213> Artificial Sequence <220> <223> ACE-03-VH nucleotide sequence <400> 103 caggttcaat tgcagcaaag cggggctgag ttggtacggc ctgggtccag cgtgaagata 60 tcatgtaagg cttctggata tgccttctcc tcttactgga tgaactgggt caagcaacgg 120 ccaggacaag gcctggagtg gattgggcaa atatggcccg gggacggaga tactaattat 180 aatggcaagt ttaaggggaa agctacactg accgcagacg aaagctcctc tacggcctat 240 atgcagctct catctcttgc gtccgaagat agtgcagtat atttttgtgc gcgccgcgag 300 accaccacgg ttgggaggta ctattacgcg atggattact ggggccaggg gactacagtt 360 acggtttcat cagctagcac caagggccca tcggtcttcc ccctggcacc ctcctccaag 420 agcacctctg ggggcacagc ggccctgggc tgcctggtca aggactactt ccccgaaccg 480 gtgacggtgt cgtggaactc aggcgccctg accagcggcg tgcacacctt cccggctgtc 540 ctacagtcct caggactcta ctccctcagc agcgtggtga ccgtgccctc cagcagcctg 600 ggcacccaga cctacatctg caacgtgaat cacaagccca gcaacaccaa ggtggacaag 660 agagttgagc ccaaatcttg tgacaaaact cacacatgcc caccgtgccc agcacctgaa 720 ctcctggggg gaccggtgca gctggtgcag agcggcggcg gcgtggtgca gcccggccgc 780 agcctgcgcc tgagctgcaa ggccagcggc tacaccttca cccgctacac catgcactgg 840 gtgcgccagg cccccggcaa gggcctggag tggatcggct acatcaaccc cagccgcggc 900 tacaccaact acaaccagaa ggtgaaggac cgcttcacca tcagcaccga caagagcaag 960 agcaccgcct tcctgcagat ggacagcctg cgccccgagg acaccgccgt gtactactgc 1020 gcccgctact acgacgacca ctactgcctg gactactggg gccagggcac ccccgtgacc 1080 gtgagcagct aa 1092 <210> 104 <211> 1059 <212> DNA <213> Artificial Sequence <220> <223> ACE-03-VL nucleotide sequence <400> 104 caggttcaat tgcagcaaag cggggctgag ttggtacggc ctgggtccag cgtgaagata 60 tcatgtaagg cttctggata tgccttctcc tcttactgga tgaactgggt caagcaacgg 120 ccaggacaag gcctggagtg gattgggcaa atatggcccg gggacggaga tactaattat 180 aatggcaagt ttaaggggaa agctacactg accgcagacg aaagctcctc tacggcctat 240 atgcagctct catctcttgc gtccgaagat agtgcagtat atttttgtgc gcgccgcgag 300 accaccacgg ttgggaggta ctattacgcg atggattact ggggccaggg gactacagtt 360 acggtttcat cagctagcac caagggccca tcggtcttcc ccctggcacc ctcctccaag 420 agcacctctg ggggcacagc ggccctgggc tgcctggtca aggactactt ccccgaaccg 480 gtgacggtgt cgtggaactc aggcgccctg accagcggcg tgcacacctt cccggctgtc 540 ctacagtcct caggactcta ctccctcagc agcgtggtga ccgtgccctc cagcagcctg 600 ggcacccaga cctacatctg caacgtgaat cacaagccca gcaacaccaa ggtggacaag 660 agagttgagc ccaaatcttg tgacaaaact cacacatgcc caccgtgccc agcacctgaa 720 ctcctggggg gaccggacat ccagatgacc cagagcccca gcagcctgag cgccagcgtg 780 ggcgaccgcg tgaccatcac ctgcagcgcc agcagcagcg tgagctacat gaactggtac 840 cagcagaccc ccggcaaggc ccccaagcgc tggatctacg acaccagcaa gctggccagc 900 ggcgtgccca gccgcttcag cggcagcggc agcggcaccg actacacctt caccatcagc 960 agcctgcagc ccgaggacat cgccacctac tactgccagc agtggagcag caaccccttc 1020 accttcggcc agggcaccaa gctgcagatc acccgctaa 1059 <210> 105 <211> 1410 <212> DNA <213> Artificial Sequence <220> <223> ACE-04-VH nucleotide seqeunce <400> 105 cagatgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60 tcctgcaagg cttctggagg caccttcagc agctatgcta tcagctgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggaagg atcatcccta tccttggtat agcaaactac 180 gcacagaagt tccagggcag agtcacgatt accgcggaca aatccacgag cacagcctac 240 atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gaaaccgaga 300 gatggctaca atttggttgc ttttgatatc tggggccaag ggacgatggt caccgtctcc 360 tcagctagca ccaagggccc atcggtcttc cccctggcac cctcctccaa gagcacctct 420 gggggcacag cggccctggg ctgcctggtc aaggactact tccccgaacc ggtgacggtg 480 tcgtggaact caggcgccct gaccagcggc gtgcacacct tcccggctgt cctacagtcc 540 tcaggactct actccctcag cagcgtggtg accgtgccct ccagcagcct gggcacccag 600 acctacatct gcaacgtgaa tcacaagccc agcaacacca aggtggacaa gaaagttgag 660 cccaaatctt gtgacaaaac tcacacatgc ccaccgtgcc cagcacctga actcctgggg 720 ggaccgggcg gaggtgggag tcaggtccag ttgcaacagt ctggagccga gctcgccagg 780 ccaggagcct ccgtcaaaat gtcatgcaag gcctcagggt acacatttac gcgatatacc 840 atgcactggg tgaaacaaag accaggtcag ggacttgaat ggatcggtta cattaacccc 900 tctagaggct atacgaatta caaccagaaa ttcaaagaca aagcaacact tacgactgac 960 aaatccagta gtacggctta catgcagctc tcatctttga cttcagaaga ctctgctgta 1020 tattattgtg cccgctatta cgatgaccat tactgccttg attactgggg ccagggcact 1080 actgttaccg taagtgcggc tagcaccaag ggcccatcgg tcttccccct ggcaccctcc 1140 tccaagagca cctctggggg cacagcggcc ctgggctgcc tggtcaagga ctacttcccc 1200 gaaccggtga cggtgtcgtg gaactcaggc gccctgacca gcggcgtgca caccttcccg 1260 gctgtcctac agtcctcagg actctactcc ctcagcagcg tggtgaccgt gccctccagc 1320 agcctgggca cccagaccta catctgcaac gtgaatcaca agcccagcaa caccaaggtg 1380 gacaagagag ttgagcccaa atcttgttga 1410 <210> 106 <211> 1383 <212> DNA <213> Artificial Sequence <220> <223> ACE-04-VL nucleotide sequence <400> 106 cagatgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60 tcctgcaagg cttctggagg caccttcagc agctatgcta tcagctgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggaagg atcatcccta tccttggtat agcaaactac 180 gcacagaagt tccagggcag agtcacgatt accgcggaca aatccacgag cacagcctac 240 atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gaaaccgaga 300 gatggctaca atttggttgc ttttgatatc tggggccaag ggacgatggt caccgtctcc 360 tcagctagca ccaagggccc atcggtcttc cccctggcac cctcctccaa gagcacctct 420 gggggcacag cggccctggg ctgcctggtc aaggactact tccccgaacc ggtgacggtg 480 tcgtggaact caggcgccct gaccagcggc gtgcacacct tcccggctgt cctacagtcc 540 tcaggactct actccctcag cagcgtggtg accgtgccct ccagcagcct gggcacccag 600 acctacatct gcaacgtgaa tcacaagccc agcaacacca aggtggacaa gaaagttgag 660 cccaaatctt gtgacaaaac tcacacatgc ccaccgtgcc cagcacctga actcctgggg 720 ggaccgggcg gaggtgggag tcagatcgtc ctcactcaaa gtcctgctat tatgtccgca 780 agccctggtg aaaaggttac catgacttgc tccgcatcta gttctgtctc ttacatgaac 840 tggtaccagc aaaagtctgg aacgtccccg aaaaggtgga tatatgatac gagcaaattg 900 gcaagcggag tacccgcgca ttttaggggt tcaggcagcg gtacgtcata tagcctgact 960 attagcggaa tggaggcgga ggatgctgca acatattatt gccaacaatg gtcatcaaat 1020 ccttttactt tcggctcagg cacaaaactt gaaataaata gaaccgtggc tgcaccatct 1080 gtcttcatct tcccgccatc tgatgagcag ttgaaatctg gaactgcctc tgttgtgtgc 1140 ctgctgaata acttctatcc cagagaggcc aaagtacagt ggaaggtgga taacgccctc 1200 caatcgggta actcccagga gagtgtcaca gagcaggaca gcaaggacag cacctacagc 1260 ctcagcagca ccctgacgct gagcaaagca gactacgaga aacacaaagt ctacgcctgc 1320 gaagtcaccc atcagggcct gagctcgccc gtcacaaaga gcttcaacag gggagagtgt 1380 taa 1383 <210> 107 <211> 657 <212> DNA <213> Artificial Sequence <220> <223> ACE-04-LC, ACE-09-LC, ACE-12-LC (anti-PD-L1 antibody light chain nucleotide sequence) <400> 107 cagctcgtgc tgactcagcc gccctcagtg tctggggccc cagggcagag ggtcaccatc 60 tcctgcactg ggagcagctc caacatcggg gcaggttatg atgtacactg gtatcagcaa 120 cttccaggag cagcccccaa actcctcatc tatggcgaca tcaatcggcc ctcaggggtc 180 cctgaccgat tctctggctc caagtctggc atctcagcct ccctggctat cactgggctc 240 caggctgagg acgaggctga ttattactgc cagtcctatg acagcagcct gagtgggggg 300 gtgttcggcg gagggaccaa gctgaccgtc ctaagatctg tggctgcacc atctgtcttc 360 atcttcccgc catctgatga gcagttgaaa tctggaactg cctctgttgt gtgcctgctg 420 aataacttct atcccagaga ggccaaagta cagtggaagg tggataacgc cctccaatcg 480 ggtaactccc aggagagtgt cacagagcag gacagcaagg acagcaccta cagcctcagc 540 agcaccctga cgctgagcaa agcagactac gagaaacaca aagtctacgc ctgcgaagtc 600 acccatcagg gcctgagctc gcccgtcaca aagagcttca acaggggaga gtgttag 657 <210> 108 <211> 1095 <212> DNA <213> Artificial Sequence <220> <223> ACE-09-VH nucleotide sequence (without G4S linker) <400> 108 cagatgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60 tcctgcaagg cttctggagg caccttcagc agctatgcta tcagctgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggaagg atcatcccta tccttggtat agcaaactac 180 gcacagaagt tccagggcag agtcacgatt accgcggaca aatccacgag cacagcctac 240 atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gaaaccgaga 300 gatggctaca atttggttgc ttttgatatc tggggccaag ggacgatggt caccgtctcc 360 tcagctagca ccaagggccc atcggtcttc cccctggcac cctcctccaa gagcacctct 420 gggggcacag cggccctggg ctgcctggtc aaggactact tccccgaacc ggtgacggtg 480 tcgtggaact caggcgccct gaccagcggc gtgcacacct tcccggctgt cctacagtcc 540 tcaggactct actccctcag cagcgtggtg accgtgccct ccagcagcct gggcacccag 600 acctacatct gcaacgtgaa tcacaagccc agcaacacca aggtggacaa gaaagttgag 660 cccaaatctt gtgacaaaac tcacacatgc ccaccgtgcc cagcacctga actcctgggg 720 ggaccggagg tgcagctcca gcagtctgga cctgagctgg tgaagcctgg accttcaatg 780 aagatatcct gcaaggcttc tggttactca ttcactggct acaccatgaa ctgggtgaag 840 cagagtcatg gaaagaacct tgagtggatg ggacttatta atccttacaa aggtgttagt 900 acctacaacc agaagttcaa ggacaaggcc acactgactg tagacaagtc atccagcaca 960 gcctacatgg aactcctcag tctgacatct gaggactctg cagtctatta ctgtgcaaga 1020 tcggggtact acggtgatag tgactggtac ttcgatgtct ggggccaggg gaccacgctg 1080 accgtcttct cataa 1095 <210> 109 <211> 1053 <212> DNA <213> Artificial Sequence <220> <223> ACE-09-VL nucleotide sequence (without G4S linker) <400> 109 cagatgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60 tcctgcaagg cttctggagg caccttcagc agctatgcta tcagctgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggaagg atcatcccta tccttggtat agcaaactac 180 gcacagaagt tccagggcag agtcacgatt accgcggaca aatccacgag cacagcctac 240 atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gaaaccgaga 300 gatggctaca atttggttgc ttttgatatc tggggccaag ggacgatggt caccgtctcc 360 tcagctagca ccaagggccc atcggtcttc cccctggcac cctcctccaa gagcacctct 420 gggggcacag cggccctggg ctgcctggtc aaggactact tccccgaacc ggtgacggtg 480 tcgtggaact caggcgccct gaccagcggc gtgcacacct tcccggctgt cctacagtcc 540 tcaggactct actccctcag cagcgtggtg accgtgccct ccagcagcct gggcacccag 600 acctacatct gcaacgtgaa tcacaagccc agcaacacca aggtggacaa gaaagttgag 660 cccaaatctt gtgacaaaac tcacacatgc ccaccgtgcc cagcacctga actcctgggg 720 ggaccggaca tccagatgac ccagaccacc tcctccctgt ctgcctccct gggcgacaga 780 gtcaccatca gttgcagggc aagtcaggac attagaaatt atttaaactg gtatcaacag 840 aaaccagatg gaactgttaa actcctgatc tactacacat caagattaca ctcaggagtc 900 ccatcaaagt tcagtggcag tgggtctgga acagattatt ctctcaccat tagcaacctg 960 gagcaagagg atattgccac ttacttttgc caacagggta atacgcttcc gtggacgttc 1020 gctggaggca ccaagctgga aatcaaacgg taa 1053 <210> 110 <211> 1125 <212> DNA <213> Artificial Sequence <220> <223> ACE-12-VH nucleotide sequence (with 10 residues) <400> 110 cagatgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60 tcctgcaagg cttctggagg caccttcagc agctatgcta tcagctgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggaagg atcatcccta tccttggtat agcaaactac 180 gcacagaagt tccagggcag agtcacgatt accgcggaca aatccacgag cacagcctac 240 atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gaaaccgaga 300 gatggctaca atttggttgc ttttgatatc tggggccaag ggacgatggt caccgtctcc 360 tcagctagca ccaagggccc atcggtcttc cccctggcac cctcctccaa gagcacctct 420 gggggcacag cggccctggg ctgcctggtc aaggactact tccccgaacc ggtgacggtg 480 tcgtggaact caggcgccct gaccagcggc gtgcacacct tcccggctgt cctacagtcc 540 tcaggactct actccctcag cagcgtggtg accgtgccct ccagcagcct gggcacccag 600 acctacatct gcaacgtgaa tcacaagccc agcaacacca aggtggacaa gaaagttgag 660 cccaaatctt gtgacaaaac tcacacatgc ccaccgtgcc cagcacctga actcctgggg 720 ggaccgggcg gaggtgggag tggaggcgga ggatctgagg tgcagctcca gcagtctgga 780 cctgagctgg tgaagcctgg accttcaatg aagatatcct gcaaggcttc tggttactca 840 ttcactggct acaccatgaa ctgggtgaag cagagtcatg gaaagaacct tgagtggatg 900 ggacttatta atccttacaa aggtgttagt acctacaacc agaagttcaa ggacaaggcc 960 acactgactg tagacaagtc atccagcaca gcctacatgg aactcctcag tctgacatct 1020 gaggactctg cagtctatta ctgtgcaaga tcggggtact acggtgatag tgactggtac 1080 ttcgatgtct ggggccaggg gaccacgctg accgtcttct cataa 1125 <210> 111 <211> 1080 <212> DNA <213> Artificial Sequence <220> <223> ACE-12-VL nucleotide sequence (with 9 residues) <400> 111 cagatgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60 tcctgcaagg cttctggagg caccttcagc agctatgcta tcagctgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggaagg atcatcccta tccttggtat agcaaactac 180 gcacagaagt tccagggcag agtcacgatt accgcggaca aatccacgag cacagcctac 240 atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gaaaccgaga 300 gatggctaca atttggttgc ttttgatatc tggggccaag ggacgatggt caccgtctcc 360 tcagctagca ccaagggccc atcggtcttc cccctggcac cctcctccaa gagcacctct 420 gggggcacag cggccctggg ctgcctggtc aaggactact tccccgaacc ggtgacggtg 480 tcgtggaact caggcgccct gaccagcggc gtgcacacct tcccggctgt cctacagtcc 540 tcaggactct actccctcag cagcgtggtg accgtgccct ccagcagcct gggcacccag 600 acctacatct gcaacgtgaa tcacaagccc agcaacacca aggtggacaa gaaagttgag 660 cccaaatctt gtgacaaaac tcacacatgc ccaccgtgcc cagcacctga actcctgggg 720 ggaccgggcg gatccggcgg aggcggcagc ggagacatcc agatgaccca gaccacctcc 780 tccctgtctg cctccctggg cgacagagtc accatcagtt gcagggcaag tcaggacatt 840 agaaattatt taaactggta tcaacagaaa ccagatggaa ctgttaaact cctgatctac 900 tacacatcaa gattacactc aggagtccca tcaaagttca gtggcagtgg gtctggaaca 960 gattattctc tcaccattag caacctggag caagaggata ttgccactta cttttgccaa 1020 cagggtaata cgcttccgtg gacgttcgct ggaggcacca agctggaaat caaacggtaa 1080 1080 <210> 112 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Linker in ACE-16-VH and ACE-16-VL <400> 112 Gly Gly Gly Gly Ser 1 5 <210> 113 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Linker in ACE-12-VH <400> 113 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 1 5 10 <210> 114 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Linker in ACE-12-VL <400> 114 Gly Gly Ser Gly Gly Gly Gly Ser Gly 1 5 <210> 115 <211> 362 <212> PRT <213> Artificial Sequence <220> <223> ACE-00-VH amino acid sequence <400> 115 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp 210 215 220 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 225 230 235 240 Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly 245 250 255 Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp 260 265 270 Tyr Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp 275 280 285 Val Ser Ala Ile Thr Trp Asn Ser Gly His Ile Asp Tyr Ala Asp Ser 290 295 300 Val Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu 305 310 315 320 Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr 325 330 335 Cys Ala Lys Val Ser Tyr Leu Ser Thr Ala Ser Ser Leu Asp Tyr Trp 340 345 350 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 355 360 <210> 116 <211> 349 <212> PRT <213> Artificial Sequence <220> <223> ACE-00-VL amino acid sequence <400> 116 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp 210 215 220 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 225 230 235 240 Pro Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val 245 250 255 Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn 260 265 270 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu 275 280 285 Ile Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser 290 295 300 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln 305 310 315 320 Pro Glu Asp Val Ala Thr Tyr Tyr Cys Gln Arg Tyr Asn Arg Ala Pro 325 330 335 Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 340 345 <210> 117 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> ACE-00-LC amino acid sequence (anti-CD19 antibody light chain) <400> 117 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Ser Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 118 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fab region (Anti-Her2) in CDR H1 of ACE-00 <400> 118 Gly Phe Asn Ile Lys Asp Thr Tyr 1 5 <210> 119 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fab region (Anti-Her2) in CDR H2 of ACE-00 <400> 119 Ile Tyr Pro Thr Asn Gly Tyr Thr 1 5 <210> 120 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Fab region (Anti-Her2) in CDR H3 of ACE-00 <400> 120 Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr 1 5 10 <210> 121 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Fab region (Anti-Her2) in CDR L1 of ACE-00 <400> 121 Gln Asp Val Asn Thr Ala 1 5 <210> 122 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Fab region (Anti-Her2) in CDR L2 of ACE-00 <400> 122 Ser Ala Ser One <210> 123 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fab region (Anti-Her2) in CDR L3 of ACE-00 <400> 123 Gln Gln His Tyr Thr Thr Pro Pro Thr 1 5 <210> 124 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fv region (Anti-TNF alpha) in CDR H1 of ACE-00 <400> 124 Gly Phe Thr Phe Asp Asp Tyr Ala 1 5 <210> 125 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fv region (Anti-TNF alpha) in CDR H2 of ACE-00 <400> 125 Ile Thr Trp Asn Ser Gly His Ile 1 5 <210> 126 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> Fv region (Anti-TNF alpha) in CDR H3 of ACE-00 <400> 126 Ala Lys Val Ser Tyr Leu Ser Thr Ala Ser Ser Leu Asp Tyr 1 5 10 <210> 127 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Fv region (Anti-TNF alpha) in CDR L1 of ACE-00 <400> 127 Gln Gly Ile Arg Asn Tyr 1 5 <210> 128 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Fv region (Anti-TNF alpha) in CDR L2 of ACE-00 <400> 128 Ala Ala Ser One <210> 129 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fv region (Anti-TNF alpha) in CDR L3 of ACE-00 <400> 129 Gln Arg Tyr Asn Arg Ala Pro Tyr Thr 1 5 <210> 130 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> linker <400> 130 Gly Gly Gly Gly Ser 1 5 <210> 131 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> linker <400> 131 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 1 5 10 <210> 132 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> linker <400> 132 Gly Gly Ser Gly Gly Gly Gly Ser Gly 1 5 <210> 133 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> linker <220> <221> REPEAT <222> (1)..(5) <223> The sequence can be repeated one, two, three, four or more times <400> 133 Gly Gly Gly Gly Ser 1 5 <210> 134 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> linker <400> 134 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 1 5 10 15 <210> 135 <211> 20 <212> PRT <213> Artificial Sequence <220> <223> linker <400> 135 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 1 5 10 15 Gly Gly Gly Ser 20 <210> 136 <211> 364 <212> PRT <213> Artificial Sequence <220> <223> ACE-01-VH amino acid sequence <400> 136 Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ser 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Ser Tyr 20 25 30 Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Gln Ile Trp Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gly Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Glu Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95 Ala Arg Arg Glu Thr Thr Thr Val Gly Arg Tyr Tyr Tyr Ala Met Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys 115 120 125 Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 130 135 140 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 145 150 155 160 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 165 170 175 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 180 185 190 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn 195 200 205 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro 210 215 220 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu 245 250 255 Ala Arg Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr 260 265 270 Thr Phe Thr Arg Tyr Thr Met His Trp Val Lys Gln Arg Pro Gly Gln 275 280 285 Gly Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn 290 295 300 Tyr Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser 305 310 315 320 Ser Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser 325 330 335 Ala Val Tyr Tyr Cys Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp 340 345 350 Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 355 360 <210> 137 <211> 352 <212> PRT <213> Artificial Sequence <220> <223> ACE-01-VL amino acid sequence <400> 137 Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ser 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Ser Tyr 20 25 30 Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Gln Ile Trp Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gly Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Glu Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95 Ala Arg Arg Glu Thr Thr Thr Val Gly Arg Tyr Tyr Tyr Ala Met Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys 115 120 125 Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 130 135 140 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 145 150 155 160 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 165 170 175 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 180 185 190 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn 195 200 205 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro 210 215 220 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met 245 250 255 Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser 260 265 270 Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro 275 280 285 Lys Arg Trp Ile Tyr Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala 290 295 300 His Phe Arg Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser 305 310 315 320 Gly Met Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser 325 330 335 Ser Asn Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Asn Arg 340 345 350 <210> 138 <211> 218 <212> PRT <213> Artificial Sequence <220> <223> ACE-01-LC amino acid sequence <400> 138 Asp Ile Gln Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Gln Arg Ala Thr Ile Ser Cys Lys Ala Ser Gln Ser Val Asp Tyr Asp 20 25 30 Gly Asp Ser Tyr Leu Asn Trp Tyr Gln Gln Ile Pro Gly Gln Pro Pro 35 40 45 Lys Leu Leu Ile Tyr Asp Ala Ser Asn Leu Val Ser Gly Ile Pro Pro 50 55 60 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile His 65 70 75 80 Pro Val Glu Lys Val Asp Ala Ala Thr Tyr His Cys Gln Gln Ser Thr 85 90 95 Glu Asp Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg 100 105 110 Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln 115 120 125 Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr 130 135 140 Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser 145 150 155 160 Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr 165 170 175 Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys 180 185 190 His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro 195 200 205 Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 139 <211> 124 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD19) in VH of ACE-01; Fv region (CD19) in VH of ACE-01r-03r <400> 139 Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ser 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Ser Tyr 20 25 30 Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Gln Ile Trp Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gly Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Glu Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95 Ala Arg Arg Glu Thr Thr Thr Val Gly Arg Tyr Tyr Tyr Ala Met Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 140 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD19) in CDR H1 of ACE-01; Fv region (CD19) in CDR H1 of ACE-01r-03r <400> 140 Ser Tyr Trp Met Asn 1 5 <210> 141 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD19) in CDR H2 of ACE-01; Fv region (CD19) in CDR H2 of ACE-01r, 02r <400> 141 Ile Trp Pro Gly Asp Gly Asp Thr 1 5 <210> 142 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD19) in CDR H3 of ACE-01; Fv region (CD19) in CDR H3 of ACE-01r, 02r <400> 142 Ala Arg Arg Glu Thr Thr Thr Val Gly Arg Tyr Tyr Tyr Ala Met Asp 1 5 10 15 Tyr <210> 143 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in VH of ACE-01; Fab region (CD3) in VH of ACE-01r <400> 143 Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr 20 25 30 Thr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Thr Val Thr Val Ser Ser 115 <210> 144 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR H1 of ACE-01; Fab region (CD3) in CDR H1 of ACE-01r, 03r, 04r, <400> 144 Gly Tyr Thr Phe Thr Arg Tyr Thr 1 5 <210> 145 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR H2 of ACE-01; Fab region (CD3) in CDR H2 of ACE-01r, 03r, 04r <400> 145 Ile Asn Pro Ser Arg Gly Tyr Thr 1 5 <210> 146 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR H3 of ACE-01; Fab region (CD3) in CDR H3 of ACE-01r, 03r, 04r <400> 146 Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr 1 5 10 <210> 147 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in VL of ACE-01; Fab region (CD3) in VL of ACE-01r <400> 147 Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met 20 25 30 Asn Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr 35 40 45 Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala His Phe Arg Gly Ser 50 55 60 Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Gly Met Glu Ala Glu 65 70 75 80 Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Phe Thr 85 90 95 Phe Gly Ser Gly Thr Lys Leu Glu Ile Asn Arg 100 105 <210> 148 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR LI of ACE-01; Fab region (CD3) in CDR L1 of ACE-01r, 03r, 04r <400> 148 Ser Ser Val Ser Tyr 1 5 <210> 149 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR L2 of ACE-01; Fab region (CD3) in CDR L2 of ACE-01r, 03r, 04r <400> 149 Asp Thr Ser One <210> 150 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR L3 of ACE-01; Fab region (CD3) in CDR L3 of ACE-01r <400> 150 Gln Gln Trp Ser Ser Asn Pro Phe Thr Phe 1 5 10 <210> 151 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD19) in VL of ACE-01; Fv region (CD19) in VL of ACE-01r-03r <400> 151 Asp Ile Gln Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Gln Arg Ala Thr Ile Ser Cys Lys Ala Ser Gln Ser Val Asp Tyr Asp 20 25 30 Gly Asp Ser Tyr Leu Asn Trp Tyr Gln Gln Ile Pro Gly Gln Pro Pro 35 40 45 Lys Leu Leu Ile Tyr Asp Ala Ser Asn Leu Val Ser Gly Ile Pro Pro 50 55 60 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile His 65 70 75 80 Pro Val Glu Lys Val Asp Ala Ala Thr Tyr His Cys Gln Gln Ser Thr 85 90 95 Glu Asp Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 <210> 152 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD19) in CDR LI of ACE-01; Fv region (CD19) in CDR L1 of ACE-01r-03r <400> 152 Gln Ser Val Asp Tyr Asp Gly Asp Ser Tyr 1 5 10 <210> 153 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD19) in CDR L2 of ACE-01; Fv region (CD19) in CDR L2 of ACE-01r-03r <400> 153 Asp Ala Ser One <210> 154 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD19) in CDR L3 of ACE-01; Fv region (CD19) in CDR L3 of ACE-01r-03r <400> 154 Gln Gln Ser Thr Glu Asp Pro Trp Thr 1 5 <210> 155 <211> 365 <212> PRT <213> Artificial Sequence <220> <223> ACE-06-VH amino acid sequence <400> 155 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Gly Gly Gly Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly 245 250 255 Gly Val Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser 260 265 270 Gly Phe Lys Phe Ser Gly Tyr Gly Met His Trp Val Arg Gln Ala Pro 275 280 285 Gly Lys Gly Leu Glu Trp Val Ala Val Ile Trp Tyr Asp Gly Ser Lys 290 295 300 Lys Tyr Tyr Val Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp 305 310 315 320 Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu 325 330 335 Asp Thr Ala Val Tyr Tyr Cys Ala Arg Gln Met Gly Tyr Trp His Phe 340 345 350 Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser 355 360 365 <210> 156 <211> 356 <212> PRT <213> Artificial Sequence <220> <223> ACE-06-VL amino acid sequence <400> 156 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Ala 245 250 255 Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala 260 265 270 Ser Gln Ser Val Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly 275 280 285 Gln Ala Pro Arg Leu Leu Ile Tyr Asp Ala Ser Asn Arg Ala Thr Gly 290 295 300 Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 305 310 315 320 Thr Ile Ser Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln 325 330 335 Gln Arg Ser Asn Trp Pro Pro Leu Thr Phe Gly Gly Gly Thr Lys Val 340 345 350 Glu Ile Lys Arg 355 <210> 157 <211> 218 <212> PRT <213> Artificial Sequence <220> <223> ACE-06-LC, ACE-07-LC, ACE-08-LC, ACE-13-LC, ACE-14-LC, ACE-15-LC, ACE-05-LC, ACE-17-LC, ACE-23-LC, ACE-34-LC, ACE-35-LC, ACE-36-LC amino acid sequence <400> 157 Gln Leu Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly 20 25 30 Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Ala Ala Pro Lys Leu 35 40 45 Leu Ile Tyr Gly Asp Ile Asn Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Ile Ser Ala Ser Leu Ala Ile Thr Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser 85 90 95 Leu Ser Gly Gly Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Arg 100 105 110 Ser Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln 115 120 125 Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr 130 135 140 Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser 145 150 155 160 Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr 165 170 175 Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys 180 185 190 His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro 195 200 205 Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 158 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> Fab region (PD-L1) in VH of ACE-06-08, 13-17, 23, 27, 34-36; Fv region (PD-L1) in VH of ACE-06r-08r, 13r-17r, 23r, 27r, 34r-36r <400> 158 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser 115 120 <210> 159 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fab region (PD-L1) in CDR HI of ACE-06-08, 13-17, 23, 27, 34-36; Fv region (PD-L1) in CDR H1 of ACE-06r <400> 159 Gly Gly Thr Phe Ser Ser Tyr Ala 1 5 <210> 160 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fab region (PD-L1) in CDR H2 of ACE-06-08, 13-17, 23, 27, 34-36; Fv region (PD-L1) in CDR H2 of ACE-06r <400> 160 Ile Ile Pro Ile Leu Gly Ile Ala 1 5 <210> 161 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> Fab region (PD-L1) in CDR H3 of ACE-06-08, 13-17, 23, 27, 34-36; Fv region (PD-L1) in CDR H3 of ACE-06r <400> 161 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile 1 5 10 <210> 162 <211> 118 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in VH of ACE-06, 23; Fab region (CD3) in VH of ACE-06r, 23r <400> 162 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Lys Phe Ser Gly Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp Tyr Asp Gly Ser Lys Lys Tyr Tyr Val Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gln Met Gly Tyr Trp His Phe Asp Leu Trp Gly Arg Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 163 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR H1 of ACE-06, 23; Fab region (CD3) in CDR H1 of ACE-06r, 23r <400> 163 Gly Phe Lys Phe Ser Gly Tyr Gly 1 5 <210> 164 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic sequence <400> 164 Trp Tyr Asp Gly Ser Lys Lys 1 5 <210> 165 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR H3 of ACE-06, 23; Fab region (CD3) in CDR H3 of ACE-06r, 23r <400> 165 Ala Arg Gln Met Gly Tyr Trp His Phe Asp Leu 1 5 10 <210> 166 <211> 109 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in VL of ACE-06, 23; Fab region (CD3) in VL of ACE-06r, 23r <400> 166 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Pro 85 90 95 Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 100 105 <210> 167 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR LI of ACE-06, 23; Fab region (CD3) in CDR L1 of ACE-06r, 23r <400> 167 Gln Ser Val Ser Ser Tyr 1 5 <210> 168 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR L2 of ACE-06, 23; Fab region (CD3) in CDR L2 of ACE-06r, 23r <400> 168 Asp Ala Ser One <210> 169 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR L3 of ACE-06, 23; Fab region (CD3) in CDR L3 of ACE-06r, 23r <400> 169 Gln Gln Arg Ser Asn Trp Pro Pro Leu Thr 1 5 10 <210> 170 <211> 112 <212> PRT <213> Artificial Sequence <220> <223> Fab region (PD-L1) in VL of ACE-06-08, 13-17, 23, 34, 35; Fv region (PD-L1) in VL of ACE-06r-08r,13r-17r, 23r, 34r, 35r <400> 170 Gln Leu Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly 20 25 30 Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Ala Ala Pro Lys Leu 35 40 45 Leu Ile Tyr Gly Asp Ile Asn Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Ile Ser Ala Ser Leu Ala Ile Thr Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser 85 90 95 Leu Ser Gly Gly Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Arg 100 105 110 <210> 171 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fab region (PD-L1) in CDR LI of ACE-06-08, 13-17, 23, 34-36; Fv region (PD-L1) in CDR L1 of ACE-06r-10r,13r-17r, 23r, 34-36r <400> 171 Ser Ser Asn Ile Gly Ala Gly Tyr Asp 1 5 <210> 172 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Fab region (PD-L1) in CDR L2 of ACE-06-08, 13-17, 23, 34-36; Fv region (PD-L1) in CDR L2 of ACE-06r-10r,13r-17r, 23r, 34-36r <400> 172 Gly Asp Ile One <210> 173 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Fab region (PD-L1) in CDR L3 of ACE-06-08, 13-17, 23, 34-36; Fv region (PD-L1) in CDR L3 of ACE-06r-10r,13r-17r, 23r, 34-36r <400> 173 Gln Ser Tyr Asp Ser Ser Leu Ser Gly Gly Val 1 5 10 <210> 174 <211> 369 <212> PRT <213> Artificial Sequence <220> <223> ACE-07-VH amino acid sequence <400> 174 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Gly Gly Gly Gly Ser Glu Val Gln Leu Gln Gln Ser Gly Pro 245 250 255 Glu Leu Val Lys Pro Gly Pro Ser Met Lys Ile Ser Cys Lys Ala Ser 260 265 270 Gly Tyr Ser Phe Thr Gly Tyr Thr Met Asn Trp Val Lys Gln Ser His 275 280 285 Gly Lys Cys Leu Glu Trp Met Gly Leu Ile Asn Pro Tyr Lys Gly Val 290 295 300 Ser Thr Tyr Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Val Asp 305 310 315 320 Lys Ser Ser Ser Thr Ala Tyr Met Glu Leu Leu Ser Leu Thr Ser Glu 325 330 335 Asp Ser Ala Val Tyr Tyr Cys Ala Arg Ser Gly Tyr Tyr Gly Asp Ser 340 345 350 Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly Thr Thr Leu Thr Val Phe 355 360 365 Ser <210> 175 <211> 355 <212> PRT <213> Artificial Sequence <220> <223> ACE-07-VL amino acid sequence <400> 175 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Thr Thr Ser 245 250 255 Ser Leu Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Arg Ala 260 265 270 Ser Gln Asp Ile Arg Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp 275 280 285 Gly Thr Val Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu His Ser Gly 290 295 300 Val Pro Ser Lys Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu 305 310 315 320 Thr Ile Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys Gln 325 330 335 Gln Gly Asn Thr Leu Pro Trp Thr Phe Ala Gly Cys Thr Lys Leu Glu 340 345 350 Ile Lys Arg 355 <210> 176 <211> 122 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in VH of ACE-07, 14; Fab region (CD3) in VH of ACE-07r, 14r <400> 176 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Cys Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser 115 120 <210> 177 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR HI of ACE-07, 14-22, 28, 38-40; Fab region (CD3) in CDR H1 of ACE-07r, 14r-22r, 28r, 38r-40r <400> 177 Gly Tyr Ser Phe Thr Gly Tyr Thr 1 5 <210> 178 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR H2 of ACE-07, 14-22, 28, 38-40; Fab region (CD3) in CDR H2 of ACE-07r, 14r-22r, 28r, 38r-40r <400> 178 Ile Asn Pro Tyr Lys Gly Val Ser 1 5 <210> 179 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR H3 of ACE-07, 14; Fab region (CD3) in CDR H3 of ACE-07r, 14r <400> 179 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val 1 5 10 15 <210> 180 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in VL of ACE-07 <400> 180 Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly 1 5 10 15 Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Arg Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile 35 40 45 Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Lys Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln 65 70 75 80 Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Trp 85 90 95 Thr Phe Ala Gly Cys Thr Lys Leu Glu Ile Lys Arg 100 105 <210> 181 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR LI of ACE-07, 14-22, 28, 38-40; Fab region (CD3) in CDR L1 of ACE-07r, 14r-22r, 28r, 38r-40r <400> 181 Gln Asp Ile Arg Asn Tyr 1 5 <210> 182 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR L2 of ACE-07, 14-22, 28, 38-40; Fab region (CD3) in CDR L2 of ACE-07r, 14r-22r, 28r, 38r-40r <400> 182 Tyr Thr Ser One <210> 183 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR L3 of ACE-07; Fab region (CD3) in CDR L3 of ACE-07r <400> 183 Gln Gln Gly Asn Thr Leu Pro Trp 1 5 <210> 184 <211> 363 <212> PRT <213> Artificial Sequence <220> <223> ACE-08-VH amino acid sequence <400> 184 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly 245 250 255 Gly Leu Val Gln Pro Gly Lys Ser Leu Lys Leu Ser Cys Glu Ala Ser 260 265 270 Gly Phe Thr Phe Ser Gly Tyr Gly Met His Trp Val Arg Gln Ala Pro 275 280 285 Gly Arg Cys Leu Glu Ser Val Ala Tyr Ile Thr Ser Ser Ser Ile Asn 290 295 300 Ile Lys Tyr Ala Asp Ala Val Lys Gly Arg Phe Thr Val Ser Arg Asp 305 310 315 320 Asn Ala Lys Asn Leu Leu Phe Leu Gln Met Asn Ile Leu Lys Ser Glu 325 330 335 Asp Thr Ala Met Tyr Tyr Cys Ala Arg Phe Asp Trp Asp Lys Asn Tyr 340 345 350 Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser 355 360 <210> 185 <211> 353 <212> PRT <213> Artificial Sequence <220> <223> ACE-08-VL amino acid sequence <400> 185 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Gly Gly Gly Gly Ser Gln Met Thr Gln Ser Pro Ser Ser Leu 245 250 255 Pro Ala Ser Leu Gly Asp Arg Val Thr Ile Asn Cys Gln Ala Ser Gln 260 265 270 Asp Ile Ser Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala 275 280 285 Pro Lys Leu Leu Ile Tyr Tyr Thr Asn Lys Leu Ala Asp Gly Val Pro 290 295 300 Ser Arg Phe Ser Gly Ser Gly Ser Gly Arg Asp Ser Ser Phe Thr Ile 305 310 315 320 Ser Ser Leu Glu Ser Glu Asp Ile Gly Ser Tyr Tyr Cys Gln Gln Tyr 325 330 335 Tyr Asn Tyr Pro Trp Thr Phe Gly Pro Cys Thr Lys Leu Glu Ile Lys 340 345 350 Arg <210> 186 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in VH of ACE-08; Fab region (CD3) in VH of ACE-08r <400> 186 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Lys 1 5 10 15 Ser Leu Lys Leu Ser Cys Glu Ala Ser Gly Phe Thr Phe Ser Gly Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Arg Cys Leu Glu Ser Val 35 40 45 Ala Tyr Ile Thr Ser Ser Ser Ile Asn Ile Lys Tyr Ala Asp Ala Val 50 55 60 Lys Gly Arg Phe Thr Val Ser Arg Asp Asn Ala Lys Asn Leu Leu Phe 65 70 75 80 Leu Gln Met Asn Ile Leu Lys Ser Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Arg Phe Asp Trp Asp Lys Asn Tyr Trp Gly Gln Gly Thr Met Val 100 105 110 Thr Val Ser Ser 115 <210> 187 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR H1 of ACE-08; Fab region (CD3) in CDR H1 of ACE-08r <400> 187 Gly Phe Thr Phe Ser Gly Tyr Gly 1 5 <210> 188 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR H2 of ACE-08; Fab region (CD3) in CDR H2 of ACE-08r <400> 188 Ile Thr Ser Ser Ser Ile Asn Ile 1 5 <210> 189 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR H3 of ACE-08; Fab region (CD3) in CDR H3 of ACE-08r <400> 189 Ala Arg Phe Asp Trp Asp Lys Asn Tyr 1 5 <210> 190 <211> 106 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in VL of ACE-08; Fab region (CD3) in VL of ACE-08r <400> 190 Gln Met Thr Gln Ser Pro Ser Ser Leu Pro Ala Ser Leu Gly Asp Arg 1 5 10 15 Val Thr Ile Asn Cys Gln Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn 20 25 30 Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr 35 40 45 Thr Asn Lys Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly Ser Gly 50 55 60 Ser Gly Arg Asp Ser Ser Phe Thr Ile Ser Ser Leu Glu Ser Glu Asp 65 70 75 80 Ile Gly Ser Tyr Tyr Cys Gln Gln Tyr Tyr Asn Tyr Pro Trp Thr Phe 85 90 95 Gly Pro Cys Thr Lys Leu Glu Ile Lys Arg 100 105 <210> 191 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR LI of ACE-08; Fab region (CD3) in CDR L1 of ACE-08r <400> 191 Gln Asp Ile Ser Asn Tyr 1 5 <210> 192 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR L2 of ACE-08; Fab region (CD3) in CDR L2 of ACE-08r <400> 192 Tyr Thr Asn One <210> 193 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR L3 of ACE-08; Fab region (CD3) in CDR L3 of ACE-08r <400> 193 Gln Gln Tyr Tyr Asn Tyr Pro Trp Thr 1 5 <210> 194 <211> 361 <212> PRT <213> Artificial Sequence <220> <223> ACE-13-VH amino acid sequence <400> 194 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Gly Gly Gly Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly 245 250 255 Gly Val Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser 260 265 270 Gly Phe Thr Phe Leu Arg Tyr Ala Met His Trp Val Arg Gln Ala Pro 275 280 285 Gly Lys Gly Leu Glu Trp Val Ala Val Ile Ser Tyr Asp Gly Arg Tyr 290 295 300 Lys Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp 305 310 315 320 Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu 325 330 335 Asp Thr Ala Val Tyr Tyr Cys Thr Thr Thr Thr Phe Asp Ser Trp Gly 340 345 350 Gln Gly Thr Leu Val Thr Val Ser Ser 355 360 <210> 195 <211> 361 <212> PRT <213> Artificial Sequence <220> <223> ACE-13-VL amino acid sequence <400> 195 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln Thr Pro Leu 245 250 255 Ser Leu Pro Val Thr Pro Gly Glu Ala Ala Ser Ile Ser Cys Arg Ser 260 265 270 Ser Gln Ser Leu Leu Asp Ser Glu Asp Gly Asn Thr Tyr Leu Asp Trp 275 280 285 Tyr Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Thr Leu 290 295 300 Ser His Arg Ala Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser 305 310 315 320 Gly Thr Asp Phe Thr Leu Glu Ile Ser Arg Val Glu Ala Glu Asp Val 325 330 335 Gly Val Tyr Tyr Cys Met Gln Arg Arg Asp Phe Pro Phe Thr Phe Gly 340 345 350 Gln Gly Thr Lys Val Asp Ile Lys Arg 355 360 <210> 196 <211> 114 <212> PRT <213> Artificial Sequence <220> <223> Fv region (PD-1) in VH of ACE-13; Fab region (CD3) in VH of ACE-13r <400> 196 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Leu Arg Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Arg Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Thr Thr Thr Thr Phe Asp Ser Trp Gly Gln Gly Thr Leu Val Thr Val 100 105 110 Ser Ser <210> 197 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fv region (PD-1) in CDR H1 of ACE-13; Fab region (CD3) in CDR H1 of ACE-13r <400> 197 Gly Phe Thr Phe Leu Arg Tyr Ala 1 5 <210> 198 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fv region (PD-1) in CDR H2 of ACE-13; Fab region (CD3) in CDR H2 of ACE-13r <400> 198 Ile Ser Tyr Asp Gly Arg Tyr Lys 1 5 <210> 199 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Fv region (PD-1) in CDR H3 of ACE-13; Fab region (CD3) in CDR H3 of ACE-13r <400> 199 Thr Thr Thr Thr Phe Asp Ser 1 5 <210> 200 <211> 114 <212> PRT <213> Artificial Sequence <220> <223> Fv region (PD-1) in VL of ACE-13; Fab region (CD3) in VL of ACE-13r <400> 200 Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly 1 5 10 15 Glu Ala Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu Asp Ser 20 25 30 Glu Asp Gly Asn Thr Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln 35 40 45 Ser Pro Gln Leu Leu Ile Tyr Thr Leu Ser His Arg Ala Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Glu 65 70 75 80 Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln 85 90 95 Arg Arg Asp Phe Pro Phe Thr Phe Gly Gln Gly Thr Lys Val Asp Ile 100 105 110 Lys Arg <210> 201 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Fv region (PD-1) in CDR LI of ACE-13; Fab region (CD3) in CDR L1 of ACE-13r <400> 201 Gln Ser Leu Leu Asp Ser Glu Asp Gly Asn Thr Tyr 1 5 10 <210> 202 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Fv region (PD-1) in CDR L2 of ACE-13; Fab region (CD3) in CDR L2 of ACE-13r <400> 202 Thr Leu Ser One <210> 203 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fv region (PD-1) in CDR L3 of ACE-13; Fab region (CD3) in CDR L3 of ACE-13r <400> 203 Met Gln Arg Arg Asp Phe Pro Phe Thr 1 5 <210> 204 <211> 374 <212> PRT <213> Artificial Sequence <220> <223> ACE-14-VH amino acid sequence <400> 204 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu 245 250 255 Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro Ser Met Lys Ile 260 265 270 Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr Thr Met Asn Trp 275 280 285 Val Lys Gln Ser His Gly Lys Cys Leu Glu Trp Met Gly Leu Ile Asn 290 295 300 Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe Lys Asp Lys Ala 305 310 315 320 Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr Met Glu Leu Leu 325 330 335 Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg Ser Gly 340 345 350 Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly Thr 355 360 365 Thr Leu Thr Val Phe Ser 370 <210> 205 <211> 360 <212> PRT <213> Artificial Sequence <220> <223> ACE-14-VL amino acid sequence <400> 205 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met 245 250 255 Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly Asp Arg Val Thr 260 265 270 Ile Ser Cys Arg Ala Ser Gln Asp Ile Arg Asn Tyr Leu Asn Trp Tyr 275 280 285 Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile Tyr Tyr Thr Ser 290 295 300 Arg Leu His Ser Gly Val Pro Ser Lys Phe Ser Gly Ser Gly Ser Gly 305 310 315 320 Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln Glu Asp Ile Ala 325 330 335 Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Trp Thr Phe Ala Cys 340 345 350 Gly Thr Lys Leu Glu Ile Lys Arg 355 360 <210> 206 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in VL of ACE-14; Fab region (CD3) in VL of ACE-14r <400> 206 Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly 1 5 10 15 Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Arg Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile 35 40 45 Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Lys Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln 65 70 75 80 Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Trp 85 90 95 Thr Phe Ala Cys Gly Thr Lys Leu Glu Ile Lys Arg 100 105 <210> 207 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR L3 of ACE-14-22, 28, 38-40; Fab region (CD3) in CDR L3 of ACE-14r-22r, 28r, 38r-40r <400> 207 Gln Gln Gly Asn Thr Leu Pro Trp Thr 1 5 <210> 208 <211> 369 <212> PRT <213> Artificial Sequence <220> <223> ACE-15-VH amino acid sequence <400> 208 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Gly Gly Gly Gly Ser Glu Val Gln Leu Gln Gln Ser Gly Pro 245 250 255 Glu Leu Val Lys Pro Gly Pro Ser Met Lys Ile Ser Cys Lys Ala Ser 260 265 270 Gly Tyr Ser Phe Thr Gly Tyr Thr Met Asn Trp Val Lys Gln Ser His 275 280 285 Gly Lys Asn Leu Glu Trp Met Gly Leu Ile Asn Pro Tyr Lys Gly Val 290 295 300 Ser Thr Tyr Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Val Asp 305 310 315 320 Lys Ser Ser Ser Thr Ala Tyr Met Glu Leu Leu Ser Leu Thr Ser Glu 325 330 335 Asp Ser Ala Val Tyr Tyr Cys Ala Arg Ser Gly Tyr Tyr Gly Asp Ser 340 345 350 Asp Trp Tyr Phe Asp Val Trp Gly Cys Gly Thr Thr Leu Thr Val Phe 355 360 365 Ser <210> 209 <211> 355 <212> PRT <213> Artificial Sequence <220> <223> ACE-15-VL amino acid sequence <400> 209 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Thr Thr Ser 245 250 255 Ser Leu Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Arg Ala 260 265 270 Ser Gln Asp Ile Arg Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp 275 280 285 Gly Cys Val Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu His Ser Gly 290 295 300 Val Pro Ser Lys Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu 305 310 315 320 Thr Ile Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys Gln 325 330 335 Gln Gly Asn Thr Leu Pro Trp Thr Phe Ala Gly Gly Thr Lys Leu Glu 340 345 350 Ile Lys Arg 355 <210> 210 <211> 122 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in VH of ACE-15; Fab region (CD3) in VH of ACE-15r <400> 210 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Cys Gly Thr Thr Leu Thr Val Phe Ser 115 120 <210> 211 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR H3 of ACE-15-22, 28, 38-40; Fab region (CD3) in CDR H3 of ACE-15r-22r, 28r, 38r-40r <400> 211 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp 1 5 10 <210> 212 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in VL of ACE-15; Fab region (CD3) in VL of ACE-15r <400> 212 Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly 1 5 10 15 Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Arg Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Cys Val Lys Leu Leu Ile 35 40 45 Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Lys Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln 65 70 75 80 Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Trp 85 90 95 Thr Phe Ala Gly Gly Thr Lys Leu Glu Ile Lys Arg 100 105 <210> 213 <211> 372 <212> PRT <213> Artificial Sequence <220> <223> ACE-05-VH amino acid sequence <400> 213 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Glu Val Gln Leu Gln Gln 245 250 255 Ser Gly Pro Glu Leu Val Lys Pro Gly Pro Ser Met Lys Ile Ser Cys 260 265 270 Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr Thr Met Asn Trp Val Lys 275 280 285 Gln Ser His Gly Lys Asn Leu Glu Trp Met Gly Leu Ile Asn Pro Tyr 290 295 300 Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu 305 310 315 320 Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr Met Glu Leu Leu Ser Leu 325 330 335 Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg Ser Gly Tyr Tyr 340 345 350 Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly Thr Thr Leu 355 360 365 Thr Val Phe Ser 370 <210> 214 <211> 358 <212> PRT <213> Artificial Sequence <220> <223> ACE-05-VL amino acid sequence <400> 214 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln 245 250 255 Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser 260 265 270 Cys Arg Ala Ser Gln Asp Ile Arg Asn Tyr Leu Asn Trp Tyr Gln Gln 275 280 285 Lys Pro Asp Gly Thr Val Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu 290 295 300 His Ser Gly Val Pro Ser Lys Phe Ser Gly Ser Gly Ser Gly Thr Asp 305 310 315 320 Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr 325 330 335 Phe Cys Gln Gln Gly Asn Thr Leu Pro Trp Thr Phe Ala Gly Gly Thr 340 345 350 Lys Leu Glu Ile Lys Arg 355 <210> 215 <211> 122 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in VH of ACE-05, 17-22, 28, 38-40; Fab region (CD3) in VH of ACE-16r-22r, 28r, 38r-40r <400> 215 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser 115 120 <210> 216 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in VL of ACE-05, 17-22, 28, 38-40; Fab region (CD3) in VL of ACE-16r-22r, 28r, 38r-40r <400> 216 Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly 1 5 10 15 Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Arg Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile 35 40 45 Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Lys Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln 65 70 75 80 Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Trp 85 90 95 Thr Phe Ala Gly Gly Thr Lys Leu Glu Ile Lys Arg 100 105 <210> 217 <211> 367 <212> PRT <213> Artificial Sequence <220> <223> ACE-17-VH amino acid sequence <400> 217 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu 245 250 255 Val Lys Pro Gly Pro Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr 260 265 270 Ser Phe Thr Gly Tyr Thr Met Asn Trp Val Lys Gln Ser His Gly Lys 275 280 285 Asn Leu Glu Trp Met Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr 290 295 300 Tyr Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser 305 310 315 320 Ser Ser Thr Ala Tyr Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser 325 330 335 Ala Val Tyr Tyr Cys Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp 340 345 350 Tyr Phe Asp Val Trp Gly Gln Gly Thr Thr Leu Thr Val Phe Ser 355 360 365 <210> 218 <211> 353 <212> PRT <213> Artificial Sequence <220> <223> ACE-17-VL amino acid sequence <400> 218 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu 245 250 255 Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln 260 265 270 Asp Ile Arg Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr 275 280 285 Val Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro 290 295 300 Ser Lys Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile 305 310 315 320 Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly 325 330 335 Asn Thr Leu Pro Trp Thr Phe Ala Gly Gly Thr Lys Leu Glu Ile Lys 340 345 350 Arg <210> 219 <211> 372 <212> PRT <213> Artificial Sequence <220> <223> ACE-18-VH amino acid sequence <400> 219 Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asn Met His Trp Val Lys Gln Thr Pro Gly Arg Gly Leu Glu Trp Ile 35 40 45 Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val Trp Gly 100 105 110 Ala Gly Thr Thr Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Glu Val Gln Leu Gln Gln 245 250 255 Ser Gly Pro Glu Leu Val Lys Pro Gly Pro Ser Met Lys Ile Ser Cys 260 265 270 Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr Thr Met Asn Trp Val Lys 275 280 285 Gln Ser His Gly Lys Asn Leu Glu Trp Met Gly Leu Ile Asn Pro Tyr 290 295 300 Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu 305 310 315 320 Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr Met Glu Leu Leu Ser Leu 325 330 335 Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg Ser Gly Tyr Tyr 340 345 350 Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly Thr Thr Leu 355 360 365 Thr Val Phe Ser 370 <210> 220 <211> 358 <212> PRT <213> Artificial Sequence <220> <223> ACE-18-VL amino acid sequence <400> 220 Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asn Met His Trp Val Lys Gln Thr Pro Gly Arg Gly Leu Glu Trp Ile 35 40 45 Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val Trp Gly 100 105 110 Ala Gly Thr Thr Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln 245 250 255 Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser 260 265 270 Cys Arg Ala Ser Gln Asp Ile Arg Asn Tyr Leu Asn Trp Tyr Gln Gln 275 280 285 Lys Pro Asp Gly Thr Val Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu 290 295 300 His Ser Gly Val Pro Ser Lys Phe Ser Gly Ser Gly Ser Gly Thr Asp 305 310 315 320 Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr 325 330 335 Phe Cys Gln Gln Gly Asn Thr Leu Pro Trp Thr Phe Ala Gly Gly Thr 340 345 350 Lys Leu Glu Ile Lys Arg 355 <210> 221 <211> 213 <212> PRT <213> Artificial Sequence <220> <223> ACE-18-LC, ACE-22-LC, ACE-37-LC amino acid sequence <400> 221 Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Ile 20 25 30 His Trp Phe Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr 35 40 45 Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Val Glu Ala Glu 65 70 75 80 Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Thr Ser Asn Pro Pro Thr 85 90 95 Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Ser Val Ala Ala Pro 100 105 110 Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 115 120 125 Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135 140 Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu 145 150 155 160 Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175 Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190 Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200 205 Asn Arg Gly Glu Cys 210 <210> 222 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD20) in VH of ACE-18, 22, 37; Fv region (CD20) in VH of ACE-10r, 18r, 22r, 37r <400> 222 Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asn Met His Trp Val Lys Gln Thr Pro Gly Arg Gly Leu Glu Trp Ile 35 40 45 Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val Trp Gly 100 105 110 Ala Gly Thr Thr Val Thr Val Ser Ala 115 120 <210> 223 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD20) in CDR HI of ACE-18, 22, 37; Fv region (CD20) in CDR H1 of ACE-10r, 18r, 22r, 37r <400> 223 Gly Tyr Thr Phe Thr Ser Tyr Asn 1 5 <210> 224 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD20) in CDR H2 of ACE-18, 22, 37; Fv region (CD20) in CDR H2 of ACE-10r, 18r, 22r, 37r <400> 224 Ile Tyr Pro Gly Asn Gly Asp Thr 1 5 <210> 225 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD20) in CDR H3 of ACE-18, 22, 37; Fv region (CD20) in CDR H3 of ACE-10r, 18r, 22r, 37r <400> 225 Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val 1 5 10 <210> 226 <211> 106 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD20) in VL of ACE-18, 22, 37; Fv region (CD20) in VL of ACE-10r, 18r, 22r, 37r <400> 226 Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Ile 20 25 30 His Trp Phe Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr 35 40 45 Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Val Glu Ala Glu 65 70 75 80 Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Thr Ser Asn Pro Pro Thr 85 90 95 Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 227 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD20) in CDR LI of ACE-18, 22, 37; Fv region (CD20) in CDR L1 of ACE-10r, 18r, 22r, 37r <400> 227 Ser Ser Val Ser Tyr 1 5 <210> 228 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD20) in CDR L2 of ACE-18, 22, 37; Fv region (CD20) in CDR L2 of ACE-10r, 18r, 22r, 37r <400> 228 Ala Thr Ser One <210> 229 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD20) in CDR L3 of ACE-18, 22, 37; Fv region (CD20) in CDR L3 of ACE-10r, 18r, 22r, 37r <400> 229 Gln Gln Trp Thr Ser Asn Pro Pro Thr 1 5 <210> 230 <211> 370 <212> PRT <213> Artificial Sequence <220> <223> ACE-19-VH amino acid sequence <400> 230 Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30 Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60 Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe 65 70 75 80 Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala 85 90 95 Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Gly Gly Gly Gly Ser Glu Val Gln Leu Gln Gln Ser Gly 245 250 255 Pro Glu Leu Val Lys Pro Gly Pro Ser Met Lys Ile Ser Cys Lys Ala 260 265 270 Ser Gly Tyr Ser Phe Thr Gly Tyr Thr Met Asn Trp Val Lys Gln Ser 275 280 285 His Gly Lys Asn Leu Glu Trp Met Gly Leu Ile Asn Pro Tyr Lys Gly 290 295 300 Val Ser Thr Tyr Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Val 305 310 315 320 Asp Lys Ser Ser Ser Thr Ala Tyr Met Glu Leu Leu Ser Leu Thr Ser 325 330 335 Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg Ser Gly Tyr Tyr Gly Asp 340 345 350 Ser Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly Thr Thr Leu Thr Val 355 360 365 Phe Ser 370 <210> 231 <211> 356 <212> PRT <213> Artificial Sequence <220> <223> ACE-19-VL amino acid sequence <400> 231 Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30 Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60 Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe 65 70 75 80 Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala 85 90 95 Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Thr Thr 245 250 255 Ser Ser Leu Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Arg 260 265 270 Ala Ser Gln Asp Ile Arg Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro 275 280 285 Asp Gly Thr Val Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu His Ser 290 295 300 Gly Val Pro Ser Lys Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser 305 310 315 320 Leu Thr Ile Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys 325 330 335 Gln Gln Gly Asn Thr Leu Pro Trp Thr Phe Ala Gly Gly Thr Lys Leu 340 345 350 Glu Ile Lys Arg 355 <210> 232 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> ACE-19-LC, ACE-26-LC, ACE-28-LC, ACE-29-LC, ACE-32-LC, ACE-38-LC, ACE-39-LC, ACE-40-LC amino acid sequence <400> 232 Asp Ile Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn 20 25 30 Ile His Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile 35 40 45 Lys Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser 65 70 75 80 Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr 85 90 95 Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 233 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> Fab region (EGFR) in VH of ACE-19, 26, 28, 29, 32, 38-40; Fv region (EGFR) in VH of ACE-19r, 26r, 28r, 29r, 32r, 38r-40r <400> 233 Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30 Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60 Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe 65 70 75 80 Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala 85 90 95 Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ala 115 <210> 234 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fab region (EGFR) in CDR HI of ACE-19, 26, 28, 29, 32, 38-40; Fv region (EGFR) in CDR H1 of ACE-19r, 26r, 28r, 29r, 32r, 38r-40r <400> 234 Gly Phe Ser Leu Thr Asn Tyr Gly 1 5 <210> 235 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Fab region (EGFR) in CDR H2 of ACE-19, 26, 28, 29, 32, 38-40; Fv region (EGFR) in CDR H2 of ACE-19r, 26r, 28r, 29r, 32r, 38r-40r <400> 235 Ile Trp Ser Gly Gly Asn Thr 1 5 <210> 236 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Fab region (EGFR) in CDR H3 of ACE-19, 26, 28, 29, 32, 38-40; Fv region (EGFR) in CDR H3 of ACE-19r, 26r, 28r, 29r, 32r, 38r-40r <400> 236 Ala Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr 1 5 10 <210> 237 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Fab region (EGFR) in VL of ACE-19, 26, 28, 29, 32, 38-40; Fv region (EGFR) in VL of ACE-19r, 26r, 28r, 29r, 32r, 38r-40r <400> 237 Asp Ile Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn 20 25 30 Ile His Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile 35 40 45 Lys Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser 65 70 75 80 Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr 85 90 95 Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys 100 105 <210> 238 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Fab region (EGFR) in CDR LI of ACE-19, 26, 28, 29, 32, 38-40; Fv region (EGFR) in CDR L1 of ACE-19r, 26r, 28r, 29r, 32r, 38r-40r <400> 238 Gln Ser Ile Gly Thr Asn 1 5 <210> 239 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Fab region (EGFR) in CDR L2 of ACE-19, 26, 28, 29, 32, 38-40; Fv region (EGFR) in CDR L2 of ACE-19r, 26r, 28r, 29r, 32r, 38r-40r <400> 239 Tyr Ala Ser One <210> 240 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fab region (EGFR) in CDR L3 of ACE-19, 26, 28, 29, 32, 38-40; Fv region (EGFR) in CDR L3 of ACE-19r, 26r, 28r, 29r, 32r, 38r-40r <400> 240 Gln Gln Asn Asn Asn Trp Pro Thr Thr 1 5 <210> 241 <211> 372 <212> PRT <213> Artificial Sequence <220> <223> ACE-20-VH amino acid sequence <400> 241 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser His 20 25 30 Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Glu Phe Asn Pro Ser Asn Gly Arg Thr Asn Tyr Asn Glu Lys Phe 50 55 60 Lys Ser Lys Ala Thr Met Thr Val Asp Thr Ser Thr Asn Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ser Arg Asp Tyr Asp Tyr Asp Cys Arg Tyr Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Glu Val Gln Leu Gln Gln 245 250 255 Ser Gly Pro Glu Leu Val Lys Pro Gly Pro Ser Met Lys Ile Ser Cys 260 265 270 Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr Thr Met Asn Trp Val Lys 275 280 285 Gln Ser His Gly Lys Asn Leu Glu Trp Met Gly Leu Ile Asn Pro Tyr 290 295 300 Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu 305 310 315 320 Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr Met Glu Leu Leu Ser Leu 325 330 335 Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg Ser Gly Tyr Tyr 340 345 350 Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly Thr Thr Leu 355 360 365 Thr Val Phe Ser 370 <210> 242 <211> 358 <212> PRT <213> Artificial Sequence <220> <223> ACE-20-VL amino acid sequence <400> 242 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser His 20 25 30 Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Glu Phe Asn Pro Ser Asn Gly Arg Thr Asn Tyr Asn Glu Lys Phe 50 55 60 Lys Ser Lys Ala Thr Met Thr Val Asp Thr Ser Thr Asn Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ser Arg Asp Tyr Asp Tyr Asp Cys Arg Tyr Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln 245 250 255 Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser 260 265 270 Cys Arg Ala Ser Gln Asp Ile Arg Asn Tyr Leu Asn Trp Tyr Gln Gln 275 280 285 Lys Pro Asp Gly Thr Val Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu 290 295 300 His Ser Gly Val Pro Ser Lys Phe Ser Gly Ser Gly Ser Gly Thr Asp 305 310 315 320 Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr 325 330 335 Phe Cys Gln Gln Gly Asn Thr Leu Pro Trp Thr Phe Ala Gly Gly Thr 340 345 350 Lys Leu Glu Ile Lys Arg 355 <210> 243 <211> 213 <212> PRT <213> Artificial Sequence <220> <223> ACE-20-LC amino acid sequence <400> 243 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Ser Ser Val Thr Tyr Met 20 25 30 Tyr Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr 35 40 45 Asp Thr Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu 65 70 75 80 Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser His Ile Phe Thr 85 90 95 Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro 100 105 110 Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 115 120 125 Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135 140 Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu 145 150 155 160 Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175 Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190 Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200 205 Asn Arg Gly Glu Cys 210 <210> 244 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> Fab region (EGFR) in VH of ACE-20; Fv region (EGFR) in VH of ACE-20r <400> 244 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser His 20 25 30 Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Glu Phe Asn Pro Ser Asn Gly Arg Thr Asn Tyr Asn Glu Lys Phe 50 55 60 Lys Ser Lys Ala Thr Met Thr Val Asp Thr Ser Thr Asn Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ser Arg Asp Tyr Asp Tyr Asp Cys Arg Tyr Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 245 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fab region (EGFR) in CDR H1 of ACE-20; Fv region (EGFR) in CDR H1 of ACE-20r <400> 245 Gly Tyr Thr Phe Thr Ser His Trp 1 5 <210> 246 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fab region (EGFR) in CDR H2 of ACE-20; Fv region (EGFR) in CDR H2 of ACE-20r <400> 246 Phe Asn Pro Ser Asn Gly Arg Thr 1 5 <210> 247 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> Fab region (EGFR) in CDR H3 of ACE-20; Fv region (EGFR) in CDR H3 of ACE-20r <400> 247 Ala Ser Arg Asp Tyr Asp Tyr Asp Cys Arg Tyr Phe Asp Tyr 1 5 10 <210> 248 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Fab region (EGFR) in VL of ACE-20; Fv region (EGFR) in VL of ACE-20r <400> 248 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Ser Ser Val Thr Tyr Met 20 25 30 Tyr Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr 35 40 45 Asp Thr Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu 65 70 75 80 Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser His Ile Phe Thr 85 90 95 Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105 <210> 249 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Fab region (EGFR) in CDR LI of ACE-20; Fv region (EGFR) in CDR L1 of ACE-20r <400> 249 Ser Ser Val Thr Tyr 1 5 <210> 250 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Fab region (EGFR) in CDR L2 of ACE-20; Fv region (EGFR) in CDR L2 of ACE-20r <400> 250 Asp Thr Ser One <210> 251 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fab region (EGFR) in CDR L3 of ACE-20; Fv region (EGFR) in CDR L3 of ACE-20r <400> 251 Gln Gln Trp Ser Ser His Ile Phe Thr 1 5 <210> 252 <211> 376 <212> PRT <213> Artificial Sequence <220> <223> ACE-21-VH amino acid sequence <400> 252 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp Asp Asp Gly Ser Tyr Lys Tyr Tyr Gly Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Gly Ile Thr Met Val Arg Gly Val Met Lys Asp Tyr Phe 100 105 110 Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 115 120 125 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140 Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175 Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190 Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys 195 200 205 Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu 210 215 220 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys 225 230 235 240 Pro Ala Pro Glu Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Glu Val 245 250 255 Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro Ser Met 260 265 270 Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr Thr Met 275 280 285 Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met Gly Leu 290 295 300 Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe Lys Asp 305 310 315 320 Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr Met Glu 325 330 335 Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg 340 345 350 Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp Gly Gln 355 360 365 Gly Thr Thr Leu Thr Val Phe Ser 370 375 <210> 253 <211> 362 <212> PRT <213> Artificial Sequence <220> <223> ACE-21-VL amino acid sequence <400> 253 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp Asp Asp Gly Ser Tyr Lys Tyr Tyr Gly Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Gly Ile Thr Met Val Arg Gly Val Met Lys Asp Tyr Phe 100 105 110 Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 115 120 125 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140 Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175 Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190 Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys 195 200 205 Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu 210 215 220 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys 225 230 235 240 Pro Ala Pro Glu Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Asp Ile 245 250 255 Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly Asp Arg 260 265 270 Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Arg Asn Tyr Leu Asn 275 280 285 Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile Tyr Tyr 290 295 300 Thr Ser Arg Leu His Ser Gly Val Pro Ser Lys Phe Ser Gly Ser Gly 305 310 315 320 Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln Glu Asp 325 330 335 Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Trp Thr Phe 340 345 350 Ala Gly Gly Thr Lys Leu Glu Ile Lys Arg 355 360 <210> 254 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> ACE-21-LC amino acid sequence <400> 254 Ala Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Ala 20 25 30 Leu Val Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Glu Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 255 <211> 125 <212> PRT <213> Artificial Sequence <220> <223> Fab region (EGFR) in VH of ACE-21; Fv region (EGFR) in VH of ACE-21r <400> 255 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp Asp Asp Gly Ser Tyr Lys Tyr Tyr Gly Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Gly Ile Thr Met Val Arg Gly Val Met Lys Asp Tyr Phe 100 105 110 Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 125 <210> 256 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fab region (EGFR) in CDR H1 of ACE-21; Fv region (EGFR) in CDR H1 of ACE-21r <400> 256 Gly Phe Thr Phe Ser Thr Tyr Gly 1 5 <210> 257 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fab region (EGFR) in CDR H2 of ACE-21; Fv region (EGFR) in CDR H2 of ACE-21r <400> 257 Ile Trp Asp Asp Gly Ser Tyr Lys 1 5 <210> 258 <211> 18 <212> PRT <213> Artificial Sequence <220> <223> Fab region (EGFR) in CDR H3 of ACE-21; Fv region (EGFR) in CDR H3 of ACE-21r <400> 258 Ala Arg Asp Gly Ile Thr Met Val Arg Gly Val Met Lys Asp Tyr Phe 1 5 10 15 Asp Tyr <210> 259 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> Fab region (EGFR) in VL of ACE-21; Fv region (EGFR) in VL of ACE-21r <400> 259 Ala Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Ala 20 25 30 Leu Val Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Glu Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 100 105 <210> 260 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Fab region (EGFR) in CDR LI of ACE-21; Fv region (EGFR) in CDR L1 of ACE-21r <400> 260 Gln Asp Ile Ser Ser Ala 1 5 <210> 261 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Fab region (EGFR) in CDR L2 of ACE-21; Fv region (EGFR) in CDR L2 of ACE-21r <400> 261 Asp Ala Ser One <210> 262 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fab region (EGFR) in CDR L3 of ACE-21; Fv region (EGFR) in CDR L3 of ACE-21r <400> 262 Gln Gln Phe Asn Ser Tyr Pro Leu Thr 1 5 <210> 263 <211> 367 <212> PRT <213> Artificial Sequence <220> <223> ACE-22-VH amino acid sequence <400> 263 Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asn Met His Trp Val Lys Gln Thr Pro Gly Arg Gly Leu Glu Trp Ile 35 40 45 Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val Trp Gly 100 105 110 Ala Gly Thr Thr Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu 245 250 255 Val Lys Pro Gly Pro Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr 260 265 270 Ser Phe Thr Gly Tyr Thr Met Asn Trp Val Lys Gln Ser His Gly Lys 275 280 285 Asn Leu Glu Trp Met Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr 290 295 300 Tyr Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser 305 310 315 320 Ser Ser Thr Ala Tyr Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser 325 330 335 Ala Val Tyr Tyr Cys Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp 340 345 350 Tyr Phe Asp Val Trp Gly Gln Gly Thr Thr Leu Thr Val Phe Ser 355 360 365 <210> 264 <211> 353 <212> PRT <213> Artificial Sequence <220> <223> ACE-22-VL amino acid sequence <400> 264 Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asn Met His Trp Val Lys Gln Thr Pro Gly Arg Gly Leu Glu Trp Ile 35 40 45 Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val Trp Gly 100 105 110 Ala Gly Thr Thr Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu 245 250 255 Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln 260 265 270 Asp Ile Arg Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr 275 280 285 Val Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro 290 295 300 Ser Lys Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile 305 310 315 320 Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly 325 330 335 Asn Thr Leu Pro Trp Thr Phe Ala Gly Gly Thr Lys Leu Glu Ile Lys 340 345 350 Arg <210> 265 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Synthetic sequence <400> 265 Gly Tyr Thr Phe Thr Ser Tyr Asn Met 1 5 <210> 266 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Synthetic sequence <400> 266 Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe 1 5 10 <210> 267 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Synthetic sequence <400> 267 Arg Ala Ser Gln Asp Ile Arg Asn Tyr Leu Asn 1 5 10 <210> 268 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic sequence <400> 268 Tyr Thr Ser Arg Leu His Ser 1 5 <210> 269 <211> 368 <212> PRT <213> Artificial Sequence <220> <223> ACE-23-VH amino acid sequence <400> 269 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Gln Val Gln Leu Val Glu 245 250 255 Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys 260 265 270 Ala Ala Ser Gly Phe Lys Phe Ser Gly Tyr Gly Met His Trp Val Arg 275 280 285 Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Val Ile Trp Tyr Asp 290 295 300 Gly Ser Lys Lys Tyr Tyr Val Asp Ser Val Lys Gly Arg Phe Thr Ile 305 310 315 320 Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu 325 330 335 Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Gln Met Gly Tyr 340 345 350 Trp His Phe Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser 355 360 365 <210> 270 <211> 359 <212> PRT <213> Artificial Sequence <220> <223> ACE-23-HC-VL amino acid sequence <400> 270 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln 245 250 255 Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser 260 265 270 Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu Ala Trp Tyr Gln Gln 275 280 285 Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Asp Ala Ser Asn Arg 290 295 300 Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp 305 310 315 320 Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr 325 330 335 Tyr Cys Gln Gln Arg Ser Asn Trp Pro Pro Leu Thr Phe Gly Gly Gly 340 345 350 Thr Lys Val Glu Ile Lys Arg 355 <210> 271 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR H2 of ACE-06, 23; Fab region (CD3) in CDR H2 of ACE-06r, 23r <400> 271 Ile Trp Tyr Asp Gly Ser Lys Lys 1 5 <210> 272 <211> 367 <212> PRT <213> Artificial Sequence <220> <223> ACE-24-VH amino acid sequence <400> 272 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp 210 215 220 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 225 230 235 240 Pro Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly 245 250 255 Leu Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly 260 265 270 Phe Thr Phe Asp Asp Tyr Ala Met His Trp Val Arg Gln Ala Pro Gly 275 280 285 Lys Gly Leu Glu Trp Val Ser Ala Ile Thr Trp Asn Ser Gly His Ile 290 295 300 Asp Tyr Ala Asp Ser Val Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn 305 310 315 320 Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp 325 330 335 Thr Ala Val Tyr Tyr Cys Ala Lys Val Ser Tyr Leu Ser Thr Ala Ser 340 345 350 Ser Leu Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 355 360 365 <210> 273 <211> 349 <212> PRT <213> Artificial Sequence <220> <223> ACE-24-VL, ACE-25-VL amino acid sequence <400> 273 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp 210 215 220 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 225 230 235 240 Pro Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val 245 250 255 Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn 260 265 270 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu 275 280 285 Ile Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser 290 295 300 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln 305 310 315 320 Pro Glu Asp Val Ala Thr Tyr Tyr Cys Gln Arg Tyr Asn Arg Ala Pro 325 330 335 Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 340 345 <210> 274 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> ACE-24-LC, ACE-25-LC amino acid sequence <400> 274 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Ser Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 275 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> Fab region (HER2) in VH of ACE-24, 25; Fv region (HER2) in VH of ACE-00r, 24r, 25r <400> 275 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 276 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fab region (HER2) in CDR H1 of ACE-24, 25; Fv region (HER2) in CDR H1 of ACE-00r, 24r, 25r <400> 276 Gly Phe Asn Ile Lys Asp Thr Tyr 1 5 <210> 277 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fab region (HER2) in CDR H2 of ACE-24, 25; Fv region (HER2) in CDR H2 of ACE-00r, 24r, 25r <400> 277 Ile Tyr Pro Thr Asn Gly Tyr Thr 1 5 <210> 278 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Fab region (HER2) in CDR H3 of ACE-24, 25; Fv region (HER2) in CDR H3 of ACE-00r, 24r, 25r <400> 278 Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr 1 5 10 <210> 279 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> Fv region (TNF) in VH of ACE-24, 25; Fab region (TNF) in VH of ACE-00r, 24r, 25r <400> 279 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Thr Trp Asn Ser Gly His Ile Asp Tyr Ala Asp Ser Val 50 55 60 Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Val Ser Tyr Leu Ser Thr Ala Ser Ser Leu Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 280 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fv region (TNF) in CDR H1 of ACE-24, 25; Fab region (TNF) in CDR H1 of ACE-00r, 24r, 25r <400> 280 Gly Phe Thr Phe Asp Asp Tyr Ala 1 5 <210> 281 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fv region (TNF) in CDR H2 of ACE-24, 25; Fab region (TNF) in CDR H2 of ACE-00r, 24r, 25r <400> 281 Ile Thr Trp Asn Ser Gly His Ile 1 5 <210> 282 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> Fv region (TNF) in CDR H3 of ACE-24, 25; Fab region (TNF) in CDR H3 of ACE00r, 24r, 25r <400> 282 Ala Lys Val Ser Tyr Leu Ser Thr Ala Ser Ser Leu Asp Tyr 1 5 10 <210> 283 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> Fv region (TNF) in VL of ACE-24, 25; Fab region (TNF) in VL of ACE-00r, 24r, 25r <400> 283 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Val Ala Thr Tyr Tyr Cys Gln Arg Tyr Asn Arg Ala Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105 <210> 284 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Fv region (TNF) in CDR LI of ACE-24, 25; Fab region (TNF) in CDR L1 of ACE-00r, 24r, 25r <400> 284 Gln Gly Ile Arg Asn Tyr 1 5 <210> 285 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Fv region (TNF) in CDR L2 of ACE-24, 25; Fab region (TNF) in CDR L2 of ACE-00r, 24r, 25r <400> 285 Ala Ala Ser One <210> 286 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fv region (TNF) in CDR L3 of ACE-24, 25; Fab region (TNF) in CDR L3 of ACE-00r, 24r, 25r <400> 286 Gln Arg Tyr Asn Arg Ala Pro Tyr Thr 1 5 <210> 287 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Fab region (HER2) in VL of ACE-24, 25; Fv region (HER2) in VL of ACE-00r, 24r, 25r <400> 287 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 288 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Fab region (HER2) in CDR LI of ACE-24, 25; Fv region (HER2) in CDR L1 of ACE-00r, 24r, 25r <400> 288 Gln Asp Val Asn Thr Ala 1 5 <210> 289 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Fab region (HER2) in CDR L2 of ACE-24, 25; Fv region (HER2) in CDR L2 of ACE-00r, 24r, 25r <400> 289 Ser Ala Ser One <210> 290 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fab region (HER2) in CDR L3 of ACE-24, 25; Fv region (HER2) in CDR L3 of ACE-00r, 24r, 25r <400> 290 Gln Gln His Tyr Thr Thr Pro Pro Thr 1 5 <210> 291 <211> 372 <212> PRT <213> Artificial Sequence <220> <223> ACE-25-VH amino acid sequence <400> 291 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp 210 215 220 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 225 230 235 240 Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val 245 250 255 Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg Ser Leu Arg Leu Ser 260 265 270 Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr Ala Met His Trp Val 275 280 285 Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ala Ile Thr Trp 290 295 300 Asn Ser Gly His Ile Asp Tyr Ala Asp Ser Val Glu Gly Arg Phe Thr 305 310 315 320 Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser 325 330 335 Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Val Ser Tyr 340 345 350 Leu Ser Thr Ala Ser Ser Leu Asp Tyr Trp Gly Gln Gly Thr Leu Val 355 360 365 Thr Val Ser Ser 370 <210> 292 <211> 373 <212> PRT <213> Artificial Sequence <220> <223> ACE-26-VH amino acid sequence <400> 292 Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30 Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60 Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe 65 70 75 80 Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala 85 90 95 Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Gly Gly Gly Gly Ser Glu Val Lys Leu Leu Glu Ser Gly 245 250 255 Gly Gly Leu Val Gln Pro Lys Gly Ser Leu Lys Leu Ser Cys Ala Ala 260 265 270 Ser Gly Phe Thr Phe Asn Thr Tyr Ala Met Asn Trp Val Arg Gln Ala 275 280 285 Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn 290 295 300 Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile 305 310 315 320 Ser Arg Asp Asp Ser Gln Ser Ile Leu Tyr Leu Gln Met Asn Asn Leu 325 330 335 Lys Thr Glu Asp Thr Ala Met Tyr Tyr Cys Val Arg His Gly Asn Phe 340 345 350 Gly Asn Ser Tyr Val Ser Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu 355 360 365 Val Thr Val Ser Ala 370 <210> 293 <211> 357 <212> PRT <213> Artificial Sequence <220> <223> ACE-26-VL, ACE-32-VL amino acid sequence <400> 293 Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30 Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60 Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe 65 70 75 80 Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala 85 90 95 Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Gly Gly Gly Gly Ser Gln Ala Val Val Thr Gln Glu Ser 245 250 255 Ala Leu Thr Thr Ser Pro Gly Glu Thr Val Thr Leu Thr Cys Arg Ser 260 265 270 Ser Thr Gly Ala Val Thr Thr Ser Asn Tyr Ala Asn Trp Val Gln Glu 275 280 285 Lys Pro Asp His Leu Phe Thr Gly Leu Ile Gly Gly Thr Asn Lys Arg 290 295 300 Ala Pro Gly Val Pro Ala Arg Phe Ser Gly Ser Leu Ile Gly Asp Lys 305 310 315 320 Ala Ala Leu Thr Ile Thr Gly Ala Gln Thr Glu Asp Glu Ala Ile Tyr 325 330 335 Phe Cys Ala Leu Trp Tyr Ser Asn Leu Trp Val Phe Gly Gly Gly Thr 340 345 350 Lys Leu Thr Val Leu 355 <210> 294 <211> 125 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in VH of ACE-26, 29, 32; Fab region (CD3) in VH of ACE-26r, 29r, 32r <400> 294 Glu Val Lys Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Lys Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp 50 55 60 Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Ser Ile 65 70 75 80 Leu Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr 85 90 95 Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe 100 105 110 Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala 115 120 125 <210> 295 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR HI of ACE-26, 29, 32; Fab region (CD3) in CDR H1 of ACE-26r, 29r, 32r <400> 295 Gly Phe Thr Phe Asn Thr Tyr Ala 1 5 <210> 296 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR H2 of ACE-26, 29, 32; Fab region (CD3) in CDR H2 of ACE-26r, 29r, 32r <400> 296 Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr 1 5 10 <210> 297 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR H3 of ACE-26, 29, 32; Fab region (CD3) in CDR H3 of ACE-26r, 29r, 32r <400> 297 Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe Ala Tyr 1 5 10 15 <210> 298 <211> 109 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in VL of ACE-26, 29, 32; Fab region (CD3) in VL of ACE-26r, 29r, 32r <400> 298 Gln Ala Val Val Thr Gln Glu Ser Ala Leu Thr Thr Ser Pro Gly Glu 1 5 10 15 Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser 20 25 30 Asn Tyr Ala Asn Trp Val Gln Glu Lys Pro Asp His Leu Phe Thr Gly 35 40 45 Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ala Arg Phe 50 55 60 Ser Gly Ser Leu Ile Gly Asp Lys Ala Ala Leu Thr Ile Thr Gly Ala 65 70 75 80 Gln Thr Glu Asp Glu Ala Ile Tyr Phe Cys Ala Leu Trp Tyr Ser Asn 85 90 95 Leu Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 299 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR LI of ACE-26, 29, 32; Fab region (CD3) in CDR L1 of ACE-26r, 29r, 32r <400> 299 Thr Gly Ala Val Thr Thr Ser Asn Tyr 1 5 <210> 300 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR L2 of ACE-26, 29, 32; Fab region (CD3) in CDR L2 of ACE-26r, 29r, 32r <400> 300 Gly Thr Asn One <210> 301 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR L3 of ACE-26, 29, 32; Fab region (CD3) in CDR L3 of ACE-26r, 29r, 32r <400> 301 Ala Leu Trp Tyr Ser Asn Leu Trp Val 1 5 <210> 302 <211> 375 <212> PRT <213> Artificial Sequence <220> <223> ACE-27-VH amino acid sequence <400> 302 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Glu Val Lys Leu Leu Glu 245 250 255 Ser Gly Gly Gly Leu Val Gln Pro Lys Gly Ser Leu Lys Leu Ser Cys 260 265 270 Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr Ala Met Asn Trp Val Arg 275 280 285 Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys 290 295 300 Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe 305 310 315 320 Thr Ile Ser Arg Asp Asp Ser Gln Ser Ile Leu Tyr Leu Gln Met Asn 325 330 335 Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr Tyr Cys Val Arg His Gly 340 345 350 Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe Ala Tyr Trp Gly Gln Gly 355 360 365 Thr Leu Val Thr Val Ser Ala 370 375 <210> 303 <211> 359 <212> PRT <213> Artificial Sequence <220> <223> ACE-27-VL amino acid sequence <400> 303 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Gln Ala Val Val Thr Gln 245 250 255 Glu Ser Ala Leu Thr Thr Ser Pro Gly Glu Thr Val Thr Leu Thr Cys 260 265 270 Arg Ser Ser Thr Gly Ala Val Thr Thr Ser Asn Tyr Ala Asn Trp Val 275 280 285 Gln Glu Lys Pro Asp His Leu Phe Thr Gly Leu Ile Gly Gly Thr Asn 290 295 300 Lys Arg Ala Pro Gly Val Pro Ala Arg Phe Ser Gly Ser Leu Ile Gly 305 310 315 320 Asp Lys Ala Ala Leu Thr Ile Thr Gly Ala Gln Thr Glu Asp Glu Ala 325 330 335 Ile Tyr Phe Cys Ala Leu Trp Tyr Ser Asn Leu Trp Val Phe Gly Gly 340 345 350 Gly Thr Lys Leu Thr Val Leu 355 <210> 304 <211> 216 <212> PRT <213> Artificial Sequence <220> <223> ACE-27-LC, ACE-27r-LC amino acid sequence <400> 304 Gln Ala Val Val Thr Gln Glu Ser Ala Leu Thr Thr Ser Pro Gly Glu 1 5 10 15 Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser 20 25 30 Asn Tyr Ala Asn Trp Val Gln Glu Lys Pro Asp His Leu Phe Thr Gly 35 40 45 Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ala Arg Phe 50 55 60 Ser Gly Ser Leu Ile Gly Asp Lys Ala Ala Leu Thr Ile Thr Gly Ala 65 70 75 80 Gln Thr Glu Asp Glu Ala Ile Tyr Phe Cys Ala Leu Trp Tyr Ser Asn 85 90 95 Leu Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Arg Ser Val 100 105 110 Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys 115 120 125 Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg 130 135 140 Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn 145 150 155 160 Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser 165 170 175 Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys 180 185 190 Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr 195 200 205 Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 305 <211> 125 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in VH of ACE-27; Fab region (CD3) in VH of ACE-27r <400> 305 Glu Val Lys Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Lys Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp 50 55 60 Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Ser Ile 65 70 75 80 Leu Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr 85 90 95 Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe 100 105 110 Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala 115 120 125 <210> 306 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR H1 of ACE-27; Fab region (CD3) in CDR H1 of ACE-27r <400> 306 Gly Phe Thr Phe Asn Thr Tyr Ala 1 5 <210> 307 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR H2 of ACE-27; Fab region (CD3) in CDR H2 of ACE-27r <400> 307 Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr 1 5 10 <210> 308 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR H3 of ACE-27; Fab region (CD3) in CDR H3 of ACE-27r <400> 308 Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe Ala Tyr 1 5 10 15 <210> 309 <211> 109 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in VL of ACE-27; Fab region (CD3) in VL of ACE-27r <400> 309 Gln Ala Val Val Thr Gln Glu Ser Ala Leu Thr Thr Ser Pro Gly Glu 1 5 10 15 Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser 20 25 30 Asn Tyr Ala Asn Trp Val Gln Glu Lys Pro Asp His Leu Phe Thr Gly 35 40 45 Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ala Arg Phe 50 55 60 Ser Gly Ser Leu Ile Gly Asp Lys Ala Ala Leu Thr Ile Thr Gly Ala 65 70 75 80 Gln Thr Glu Asp Glu Ala Ile Tyr Phe Cys Ala Leu Trp Tyr Ser Asn 85 90 95 Leu Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 310 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR LI of ACE-27; Fab region (CD3) in CDR L1 of ACE-27r <400> 310 Thr Gly Ala Val Thr Thr Ser Asn Tyr 1 5 <210> 311 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR L2 of ACE-27; Fab region (CD3) in CDR L2 of ACE-27r <400> 311 Gly Thr Asn One <210> 312 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD3) in CDR L3 of ACE-27; Fab region (CD3) in CDR L3 of ACE-27r <400> 312 Ala Leu Trp Tyr Ser Asn Leu Trp Val 1 5 <210> 313 <211> 109 <212> PRT <213> Artificial Sequence <220> <223> Fab region (PD-L1) in VL of ACE-27; Fv region (PD-L1) in VL of ACE-27r <400> 313 Gln Ala Val Val Thr Gln Glu Ser Ala Leu Thr Thr Ser Pro Gly Glu 1 5 10 15 Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser 20 25 30 Asn Tyr Ala Asn Trp Val Gln Glu Lys Pro Asp His Leu Phe Thr Gly 35 40 45 Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ala Arg Phe 50 55 60 Ser Gly Ser Leu Ile Gly Asp Lys Ala Ala Leu Thr Ile Thr Gly Ala 65 70 75 80 Gln Thr Glu Asp Glu Ala Ile Tyr Phe Cys Ala Leu Trp Tyr Ser Asn 85 90 95 Leu Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 314 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fab region (PD-L1) in CDR LI of ACE-27; Fv region (PD-L1) in CDR L1 of ACE-27r <400> 314 Thr Gly Ala Val Thr Thr Ser Asn Tyr 1 5 <210> 315 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Fab region (PD-L1) in CDR L2 of ACE-27; Fv region (PD-L1) in CDR L2 of ACE-27r <400> 315 Gly Thr Asn One <210> 316 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fab region (PD-L1) in CDR L3 of ACE-27; Fv region (PD-L1) in CDR L3 of ACE-27r <400> 316 Ala Leu Trp Tyr Ser Asn Leu Trp Val 1 5 <210> 317 <211> 477 <212> PRT <213> Artificial Sequence <220> <223> ACE-28-VH amino acid sequence <400> 317 Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30 Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60 Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe 65 70 75 80 Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala 85 90 95 Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Gly Gly Gly Gly Ser Glu Val Gln Leu Gln Gln Ser Gly 245 250 255 Pro Glu Leu Val Lys Pro Gly Pro Ser Met Lys Ile Ser Cys Lys Ala 260 265 270 Ser Gly Tyr Ser Phe Thr Gly Tyr Thr Met Asn Trp Val Lys Gln Ser 275 280 285 His Gly Lys Asn Leu Glu Trp Met Gly Leu Ile Asn Pro Tyr Lys Gly 290 295 300 Val Ser Thr Tyr Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Val 305 310 315 320 Asp Lys Ser Ser Ser Thr Ala Tyr Met Glu Leu Leu Ser Leu Thr Ser 325 330 335 Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg Ser Gly Tyr Tyr Gly Asp 340 345 350 Ser Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly Thr Thr Leu Thr Val 355 360 365 Phe Ser Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser 370 375 380 Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys 385 390 395 400 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 405 410 415 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 420 425 430 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln 435 440 445 Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 450 455 460 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 465 470 475 <210> 318 <211> 463 <212> PRT <213> Artificial Sequence <220> <223> ACE-28-VL amino acid sequence <400> 318 Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30 Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60 Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe 65 70 75 80 Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala 85 90 95 Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Thr Thr 245 250 255 Ser Ser Leu Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Arg 260 265 270 Ala Ser Gln Asp Ile Arg Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro 275 280 285 Asp Gly Thr Val Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu His Ser 290 295 300 Gly Val Pro Ser Lys Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser 305 310 315 320 Leu Thr Ile Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys 325 330 335 Gln Gln Gly Asn Thr Leu Pro Trp Thr Phe Ala Gly Gly Thr Lys Leu 340 345 350 Glu Ile Lys Arg Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 355 360 365 Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 370 375 380 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 385 390 395 400 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 405 410 415 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 420 425 430 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 435 440 445 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 450 455 460 <210> 319 <211> 480 <212> PRT <213> Artificial Sequence <220> <223> ACE-29-VH amino acid sequence <400> 319 Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30 Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60 Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe 65 70 75 80 Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala 85 90 95 Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Gly Gly Gly Gly Ser Glu Val Lys Leu Leu Glu Ser Gly 245 250 255 Gly Gly Leu Val Gln Pro Lys Gly Ser Leu Lys Leu Ser Cys Ala Ala 260 265 270 Ser Gly Phe Thr Phe Asn Thr Tyr Ala Met Asn Trp Val Arg Gln Ala 275 280 285 Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn 290 295 300 Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile 305 310 315 320 Ser Arg Asp Asp Ser Gln Ser Ile Leu Tyr Leu Gln Met Asn Asn Leu 325 330 335 Lys Thr Glu Asp Thr Ala Met Tyr Tyr Cys Val Arg His Gly Asn Phe 340 345 350 Gly Asn Ser Tyr Val Ser Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu 355 360 365 Val Thr Val Ser Ala Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 370 375 380 Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys 385 390 395 400 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 405 410 415 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 420 425 430 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 435 440 445 Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 450 455 460 Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 465 470 475 480 <210> 320 <211> 464 <212> PRT <213> Artificial Sequence <220> <223> ACE-29-VL amino acid sequence <400> 320 Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30 Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60 Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe 65 70 75 80 Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala 85 90 95 Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Gly Gly Gly Gly Ser Gln Ala Val Val Thr Gln Glu Ser 245 250 255 Ala Leu Thr Thr Ser Pro Gly Glu Thr Val Thr Leu Thr Cys Arg Ser 260 265 270 Ser Thr Gly Ala Val Thr Thr Ser Asn Tyr Ala Asn Trp Val Gln Glu 275 280 285 Lys Pro Asp His Leu Phe Thr Gly Leu Ile Gly Gly Thr Asn Lys Arg 290 295 300 Ala Pro Gly Val Pro Ala Arg Phe Ser Gly Ser Leu Ile Gly Asp Lys 305 310 315 320 Ala Ala Leu Thr Ile Thr Gly Ala Gln Thr Glu Asp Glu Ala Ile Tyr 325 330 335 Phe Cys Ala Leu Trp Tyr Ser Asn Leu Trp Val Phe Gly Gly Gly Thr 340 345 350 Lys Leu Thr Val Leu Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 355 360 365 Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys 370 375 380 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 385 390 395 400 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 405 410 415 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 420 425 430 Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 435 440 445 Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 450 455 460 <210> 321 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Synthetic sequence <400> 321 Ile Arg Ser Lys Tyr Asn Asn Tyr Ala 1 5 <210> 322 <211> 369 <212> PRT <213> Artificial Sequence <220> <223> ACE-30-VH amino acid sequence <400> 322 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Gly Gly Gly Gly Ser Gln Met Gln Leu Val Gln Ser Gly 245 250 255 Ala Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala 260 265 270 Ser Gly Gly Thr Phe Ser Ser Tyr Ala Ile Ser Trp Val Arg Gln Ala 275 280 285 Pro Gly Gln Gly Leu Glu Trp Met Gly Arg Ile Ile Pro Ile Leu Gly 290 295 300 Ile Ala Asn Tyr Ala Gln Lys Phe Gln Gly Arg Val Thr Ile Thr Ala 305 310 315 320 Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser 325 330 335 Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Pro Arg Asp Gly Tyr Asn 340 345 350 Leu Val Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser 355 360 365 Ser <210> 323 <211> 360 <212> PRT <213> Artificial Sequence <220> <223> ACE-30-VL, ACE-33-VL amino acid sequence <400> 323 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Gly Gly Gly Gly Ser Gln Leu Val Leu Thr Gln Pro Pro 245 250 255 Ser Val Ser Gly Ala Pro Gly Gln Arg Val Thr Ile Ser Cys Thr Gly 260 265 270 Ser Ser Ser Asn Ile Gly Ala Gly Tyr Asp Val His Trp Tyr Gln Gln 275 280 285 Leu Pro Gly Ala Ala Pro Lys Leu Leu Ile Tyr Gly Asp Ile Asn Arg 290 295 300 Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Ile Ser 305 310 315 320 Ala Ser Leu Ala Ile Thr Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr 325 330 335 Tyr Cys Gln Ser Tyr Asp Ser Ser Leu Ser Gly Gly Val Phe Gly Gly 340 345 350 Gly Thr Lys Leu Thr Val Leu Arg 355 360 <210> 324 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> ACE-30-LC, ACE-31-LC, ACE-33-LC, ACE-20r-LC, ACE-21r-LC amino acid sequence <400> 324 Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly 1 5 10 15 Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Arg Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile 35 40 45 Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Lys Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln 65 70 75 80 Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Trp 85 90 95 Thr Phe Ala Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 325 <211> 122 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD3) in VH of ACE-30, 31, 33, 05r, 09r-12r; Fv region (CD3) in VH of ACE-30r, 31r, 33r <400> 325 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser 115 120 <210> 326 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD3) in CDR HI of ACE-30, 31, 33; Fv region (CD3) in CDR H1 of ACE-05r, 09r-12r, 30r, 31r, 33r <400> 326 Gly Tyr Ser Phe Thr Gly Tyr Thr 1 5 <210> 327 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD3) in CDR H2 of ACE-30, 31, 33; Fv region (CD3) in CDR H2 of ACE-05r, 09r-12r, 30r, 31r, 33r <400> 327 Ile Asn Pro Tyr Lys Gly Val Ser 1 5 <210> 328 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD3) in CDR H3 of ACE-30, 31, 33; Fv region (CD3) in CDR H3 of ACE-05r, 09r-12r, 30r, 31r, 33r <400> 328 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val 1 5 10 15 <210> 329 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> Fv region (PD-L1) in VH of ACE-30, 31, 33, 04r, 05r, 09r, 12r; Fab region (PD-L1) in VH of ACE-30r, 31r, 33r <400> 329 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser 115 120 <210> 330 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fv region (PD-L1) in CDR H1 of ACE-30, 31, 33, 04r, 05r, 09r, 12r; Fab region (PD-L1) in CDR H1 of ACE-30r, 31r, 33r <400> 330 Gly Gly Thr Phe Ser Ser Tyr Ala 1 5 <210> 331 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fv region (PD-L1) in CDR H2 of ACE-30, 31, 33, 04r, 05r, 09r, 12r; Fab region (PD-L1) in CDR H2 of ACE-30r, 31r, 33r <400> 331 Ile Ile Pro Ile Leu Gly Ile Ala 1 5 <210> 332 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> Fv region (PD-L1) in CDR H3 of ACE-30, 31, 33, 04r, 05r, 09r, 12r; Fab region (PD-L1) in CDR H3 of ACE-30r, 31r, 33r <400> 332 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile 1 5 10 <210> 333 <211> 112 <212> PRT <213> Artificial Sequence <220> <223> Fv region (PD-L1) in VL of ACE-30, 31, 33; Fab region (PD-L1) in VL of ACE-30r, 31r, 33r <400> 333 Gln Leu Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly 20 25 30 Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Ala Ala Pro Lys Leu 35 40 45 Leu Ile Tyr Gly Asp Ile Asn Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Ile Ser Ala Ser Leu Ala Ile Thr Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser 85 90 95 Leu Ser Gly Gly Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Arg 100 105 110 <210> 334 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fv region (PD-L1) in CDR LI of ACE-30, 31, 33, 04r, 05r; Fab region (PD-L1) in CDR L1 of ACE-30r, 31r, 33r <400> 334 Ser Ser Asn Ile Gly Ala Gly Tyr Asp 1 5 <210> 335 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Fv region (PD-L1) in CDR L2 of ACE-30, 31, 33, 04r, 05r; Fab region (PD-L1) in CDR L2 of ACE-30r, 31r, 33r <400> 335 Gly Asp Ile One <210> 336 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Fv region (PD-L1) in CDR L3 of ACE-30, 31, 33, 04r, 05r; Fab region (PD-L1) in CDR L3 of ACE-30r, 31r, 33r <400> 336 Gln Ser Tyr Asp Ser Ser Leu Ser Gly Gly Val 1 5 10 <210> 337 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD3) in VL of ACE-30, 31, 33, 05r, 09r, 10r, 11r, 12r; Fv region (CD3) in VL of ACE-30r, 31r, 33r <400> 337 Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly 1 5 10 15 Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Arg Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile 35 40 45 Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Lys Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln 65 70 75 80 Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Trp 85 90 95 Thr Phe Ala Gly Gly Thr Lys Leu Glu Ile Lys Arg 100 105 <210> 338 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD3) in CDR L1 of ACE-30, 31, 33, 05r, 09r, 10r, 11r, 12r; Fv region (CD3) in CDR L1 of ACE-30r, 31r, 33r <400> 338 Gln Asp Ile Arg Asn Tyr 1 5 <210> 339 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD3) in CDR L2 of ACE-30, 31, 33, 05r, 09r, 10r, 11r, 12r; Fv region (CD3) in CDR L2 of ACE-30r, 31r, 33r <400> 339 Tyr Thr Ser One <210> 340 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD3) in CDR L3 of ACE-30, 31, 33, 05r, 09r, 10r, 11r, 12r; Fv region (CD3) in CDR L3 of ACE-30r, 31r, 33r <400> 340 Gln Gln Gly Asn Thr Leu Pro Trp Thr 1 5 <210> 341 <211> 374 <212> PRT <213> Artificial Sequence <220> <223> ACE-33-VH amino acid sequence <400> 341 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Met Gln 245 250 255 Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser Ser Val Lys 260 265 270 Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr Ala Ile Ser 275 280 285 Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Arg Ile 290 295 300 Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe Gln Gly Arg 305 310 315 320 Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu 325 330 335 Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Pro 340 345 350 Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly Gln Gly Thr 355 360 365 Met Val Thr Val Ser Ser 370 <210> 342 <211> 378 <212> PRT <213> Artificial Sequence <220> <223> ACE-32-VH amino acid sequence <400> 342 Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30 Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60 Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe 65 70 75 80 Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala 85 90 95 Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Lys 245 250 255 Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Lys Gly Ser Leu Lys 260 265 270 Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr Ala Met Asn 275 280 285 Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile 290 295 300 Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys 305 310 315 320 Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Ser Ile Leu Tyr Leu 325 330 335 Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr Tyr Cys Val 340 345 350 Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe Ala Tyr Trp 355 360 365 Gly Gln Gly Thr Leu Val Thr Val Ser Ala 370 375 <210> 343 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Synthetic sequence <400> 343 Val Ile Trp Ser Gly Gly Asn Thr 1 5 <210> 344 <211> 377 <212> PRT <213> Artificial Sequence <220> <223> ACE-31-VH amino acid sequence <400> 344 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro 225 230 235 240 Glu Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 245 250 255 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 260 265 270 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 275 280 285 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 290 295 300 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 305 310 315 320 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 325 330 335 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 340 345 350 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 355 360 365 Gln Gly Thr Met Val Thr Val Ser Ser 370 375 <210> 345 <211> 363 <212> PRT <213> Artificial Sequence <220> <223> ACE-31-VL amino acid sequence <400> 345 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro 225 230 235 240 Glu Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Gln Leu Val Leu Thr 245 250 255 Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln Arg Val Thr Ile Ser 260 265 270 Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly Tyr Asp Val His Trp 275 280 285 Tyr Gln Gln Leu Pro Gly Ala Ala Pro Lys Leu Leu Ile Tyr Gly Asp 290 295 300 Ile Asn Arg Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser 305 310 315 320 Gly Ile Ser Ala Ser Leu Ala Ile Thr Gly Leu Gln Ala Glu Asp Glu 325 330 335 Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser Leu Ser Gly Gly Val 340 345 350 Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Arg 355 360 <210> 346 <211> 366 <212> PRT <213> Artificial Sequence <220> <223> ACE-34-VH amino acid sequence <400> 346 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu 245 250 255 Ser Gly Gly Gly Leu Val Gln Pro Gly Lys Ser Leu Lys Leu Ser Cys 260 265 270 Glu Ala Ser Gly Phe Thr Phe Ser Gly Tyr Gly Met His Trp Val Arg 275 280 285 Gln Ala Pro Gly Arg Gly Leu Glu Ser Val Ala Tyr Ile Thr Ser Ser 290 295 300 Ser Ile Asn Ile Lys Tyr Ala Asp Ala Val Lys Gly Arg Phe Thr Val 305 310 315 320 Ser Arg Asp Asn Ala Lys Asn Leu Leu Phe Leu Gln Met Asn Ile Leu 325 330 335 Lys Ser Glu Asp Thr Ala Met Tyr Tyr Cys Ala Arg Phe Asp Trp Asp 340 345 350 Lys Asn Tyr Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser 355 360 365 <210> 347 <211> 357 <212> PRT <213> Artificial Sequence <220> <223> ACE-34-VL amino acid sequence <400> 347 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln 245 250 255 Ser Pro Ser Ser Leu Pro Ala Ser Leu Gly Asp Arg Val Thr Ile Asn 260 265 270 Cys Gln Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn Trp Tyr Gln Gln 275 280 285 Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Asn Lys Leu 290 295 300 Ala Asp Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Arg Asp 305 310 315 320 Ser Ser Phe Thr Ile Ser Ser Leu Glu Ser Glu Asp Ile Gly Ser Tyr 325 330 335 Tyr Cys Gln Gln Tyr Tyr Asn Tyr Pro Trp Thr Phe Gly Pro Gly Thr 340 345 350 Lys Leu Glu Ile Lys 355 <210> 348 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> Fv region (mouse CD3) in VH of ACE-34; Fab region (mouse CD3) in VH of ACE-34r <400> 348 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Lys 1 5 10 15 Ser Leu Lys Leu Ser Cys Glu Ala Ser Gly Phe Thr Phe Ser Gly Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Arg Gly Leu Glu Ser Val 35 40 45 Ala Tyr Ile Thr Ser Ser Ser Ile Asn Ile Lys Tyr Ala Asp Ala Val 50 55 60 Lys Gly Arg Phe Thr Val Ser Arg Asp Asn Ala Lys Asn Leu Leu Phe 65 70 75 80 Leu Gln Met Asn Ile Leu Lys Ser Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Arg Phe Asp Trp Asp Lys Asn Tyr Trp Gly Gln Gly Thr Met Val 100 105 110 Thr Val Ser Ser 115 <210> 349 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Fv region (mouse CD3) in CDR H1 of ACE-34; Fab region (mouse CD3) in CDR H1 of ACE-34r <400> 349 Gly Tyr Gly Met His 1 5 <210> 350 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Fv region (mouse CD3) in CDR H2 of ACE-34; Fab region (mouse CD3) in CDR H2 of ACE-34r <400> 350 Tyr Ile Thr Ser Ser Ser Ile Asn Ile Lys Tyr Ala Asp Ala Val Lys 1 5 10 15 Gly <210> 351 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Fv region (mouse CD3) in CDR H3 of ACE-34; Fab region (mouse CD3) in CDR H3 of ACE-34r <400> 351 Phe Asp Trp Asp Lys Asn 1 5 <210> 352 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Fv region (mouse CD3) in VL of ACE-34; Fab region (mouse CD3) in VL of ACE-34r <400> 352 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Pro Ala Ser Leu Gly 1 5 10 15 Asp Arg Val Thr Ile Asn Cys Gln Ala Ser Gln Asp Ile Ser Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Tyr Thr Asn Lys Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Arg Asp Ser Ser Phe Thr Ile Ser Ser Leu Glu Ser 65 70 75 80 Glu Asp Ile Gly Ser Tyr Tyr Cys Gln Gln Tyr Tyr Asn Tyr Pro Trp 85 90 95 Thr Phe Gly Pro Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 353 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Fv region (mouse CD3) in CDR LI of ACE-34; Fab region (mouse CD3) in CDR L1 of ACE-34r <400> 353 Gln Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn 1 5 10 <210> 354 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Fv region (mouse CD3) in CDR L2 of ACE-34; Fab region (mouse CD3) in CDR L2 of ACE-34r <400> 354 Tyr Thr Asn Lys Leu Ala Asp 1 5 <210> 355 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fv region (mouse CD3) in CDR L3 of ACE-34; Fab region (mouse CD3) in CDR L3 of ACE-34r <400> 355 Gln Gln Tyr Tyr Asn Tyr Pro Trp Thr 1 5 <210> 356 <211> 370 <212> PRT <213> Artificial Sequence <220> <223> ACE-35-VH amino acid sequence <400> 356 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Gln Val Lys Leu Gln Gln 245 250 255 Ser Gly Ser Glu Leu Gly Lys Pro Gly Ala Ser Val Lys Leu Ser Cys 260 265 270 Lys Thr Ser Gly Tyr Ile Phe Thr Asp His Tyr Ile Ser Trp Val Lys 275 280 285 Gln Lys Pro Gly Glu Ser Leu Gln Trp Ile Gly Asn Val Tyr Gly Gly 290 295 300 Asn Gly Gly Thr Ser Tyr Asn Gln Lys Phe Gln Gly Lys Ala Thr Leu 305 310 315 320 Thr Val Asp Lys Ile Ser Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu 325 330 335 Thr Ser Glu Asp Ser Ala Ile Tyr Tyr Cys Ala Arg Arg Pro Val Ala 340 345 350 Thr Gly His Ala Met Asp Tyr Trp Gly Gln Gly Ile Gln Val Thr Val 355 360 365 Ser Ser 370 <210> 357 <211> 357 <212> PRT <213> Artificial Sequence <220> <223> ACE-35-VL amino acid sequence <400> 357 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Asp Ile Val Leu Thr Gln 245 250 255 Thr Pro Ala Thr Leu Ser Leu Ile Pro Gly Glu Arg Val Thr Met Thr 260 265 270 Cys Lys Thr Ser Gln Asn Ile Gly Thr Ile Leu His Trp Tyr His Gln 275 280 285 Lys Pro Lys Glu Ala Pro Arg Ala Leu Ile Lys Tyr Ala Ser Gln Ser 290 295 300 Ile Pro Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly Ser Glu Thr Asp 305 310 315 320 Phe Thr Leu Ser Ile Asn Asn Leu Glu Pro Asp Asp Ile Gly Ile Tyr 325 330 335 Tyr Cys Gln Gln Ser Arg Ser Trp Pro Val Thr Phe Gly Pro Gly Thr 340 345 350 Lys Leu Glu Ile Lys 355 <210> 358 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> Fv region (mouse CD3) in VH of ACE-35; Fab region (mouse CD3) in VH of ACE-35r <400> 358 Gln Val Lys Leu Gln Gln Ser Gly Ser Glu Leu Gly Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Thr Ser Gly Tyr Ile Phe Thr Asp His 20 25 30 Tyr Ile Ser Trp Val Lys Gln Lys Pro Gly Glu Ser Leu Gln Trp Ile 35 40 45 Gly Asn Val Tyr Gly Gly Asn Gly Gly Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Gln Gly Lys Ala Thr Leu Thr Val Asp Lys Ile Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Ile Tyr Tyr Cys 85 90 95 Ala Arg Arg Pro Val Ala Thr Gly His Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Ile Gln Val Thr Val Ser Ser 115 120 <210> 359 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Fv region (mouse CD3) in CDR H1 of ACE-35; Fab region (mouse CD3) in CDR H1 of ACE-35r <400> 359 Asp His Tyr Ile Ser 1 5 <210> 360 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Fv region (mouse CD3) in CDR H2 of ACE-35; Fab region (mouse CD3) in CDR H2 of ACE-35r <400> 360 Asn Val Tyr Gly Gly Asn Gly Gly Thr Ser Tyr Asn Gln Lys Phe Gln 1 5 10 15 Gly <210> 361 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Fv region (mouse CD3) in CDR H3 of ACE-35; Fab region (mouse CD3) in CDR H3 of ACE-35r <400> 361 Arg Pro Val Ala Thr Gly His Ala Met Asp Tyr 1 5 10 <210> 362 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Fv region (mouse CD3) in VL of ACE-35; Fab region (mouse CD3) in VL of ACE-35r <400> 362 Asp Ile Val Leu Thr Gln Thr Pro Ala Thr Leu Ser Leu Ile Pro Gly 1 5 10 15 Glu Arg Val Thr Met Thr Cys Lys Thr Ser Gln Asn Ile Gly Thr Ile 20 25 30 Leu His Trp Tyr His Gln Lys Pro Lys Glu Ala Pro Arg Ala Leu Ile 35 40 45 Lys Tyr Ala Ser Gln Ser Ile Pro Gly Ile Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Glu Thr Asp Phe Thr Leu Ser Ile Asn Asn Leu Glu Pro 65 70 75 80 Asp Asp Ile Gly Ile Tyr Tyr Cys Gln Gln Ser Arg Ser Trp Pro Val 85 90 95 Thr Phe Gly Pro Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 363 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Fv region (mouse CD3) in CDR LI of ACE-35; Fab region (mouse CD3) in CDR L1 of ACE-35r <400> 363 Lys Thr Ser Gln Asn Ile Gly Thr Ile Leu His 1 5 10 <210> 364 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Fv region (mouse CD3) in CDR L2 of ACE-35; Fab region (mouse CD3) in CDR L2 of ACE-35r <400> 364 Tyr Ala Ser Gln Ser Ile Pro 1 5 <210> 365 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fv region (mouse CD3) in CDR L3 of ACE-35; Fab region (mouse CD3) in CDR L3 of ACE-35r <400> 365 Gln Gln Ser Arg Ser Trp Pro Val Thr 1 5 <210> 366 <211> 368 <212> PRT <213> Artificial Sequence <220> <223> ACE-36-VH amino acid sequence <400> 366 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Gln Val Gln Leu Val Glu 245 250 255 Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys 260 265 270 Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Thr Met His Trp Val Arg 275 280 285 Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Thr Phe Ile Ser Tyr Asp 290 295 300 Gly Asn Asn Lys Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile 305 310 315 320 Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu 325 330 335 Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys Ala Arg Thr Gly Trp Leu 340 345 350 Gly Pro Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 355 360 365 <210> 367 <211> 351 <212> PRT <213> Artificial Sequence <220> <223> ACE-36-VL amino acid sequence <400> 367 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu 245 250 255 Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val 260 265 270 Gly Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro 275 280 285 Arg Leu Leu Ile Tyr Gly Ala Phe Ser Arg Ala Thr Gly Ile Pro Asp 290 295 300 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser 305 310 315 320 Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly 325 330 335 Ser Ser Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 340 345 350 <210> 368 <211> 118 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CTLA4) in VH of ACE-36, 37; Fab region (CTLA4) in VH of ACE-36r, 37r <400> 368 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Thr Phe Ile Ser Tyr Asp Gly Asn Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys 85 90 95 Ala Arg Thr Gly Trp Leu Gly Pro Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 369 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CTLA4) in CDR H1 of ACE-36, 37; Fab region (CTLA4) in CDR H1 of ACE-36r, 37r <400> 369 Gly Phe Thr Phe Ser Ser Tyr Thr 1 5 <210> 370 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CTLA4) in CDR H2 of ACE-36, ACE-37; Fab region (CTLA4) in CDR H2 of ACE-36r, 37r <400> 370 Ile Ser Tyr Asp Gly Asn Asn Lys 1 5 <210> 371 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CTLA4) in CDR H3 of ACE-36, ACE-37; Fab region (CTLA4) in CDR H3 of ACE-36r, 37r <400> 371 Ala Arg Thr Gly Trp Leu Gly Pro Phe Asp Tyr 1 5 10 <210> 372 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CTLA4) in VL of ACE-36, 37; Fab region (CTLA4) in VL of ACE-36r, 37r <400> 372 Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Gly Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Phe Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro 85 90 95 Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 373 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CTLA4) in CDR LI of ACE-36, 37; Fab region (CTLA4) in CDR L1 of ACE-36r, 37r <400> 373 Gln Ser Val Gly Ser Ser Tyr 1 5 <210> 374 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CTLA4) in CDR L2 of ACE-36, 37; Fab region (CTLA4) in CDR L2 of ACE-36r, 37r <400> 374 Gly Ala Phe One <210> 375 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CTLA4) in CDR L3 of ACE-36, 37; Fab region (CTLA4) in CDR L3 of ACE-36r, 37r <400> 375 Gln Gln Tyr Gly Ser Ser Pro Trp Thr 1 5 <210> 376 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> Fab region (PD-L1) in VL of ACE-36; Fv region (PD-L1) in VL of ACE-04r, 05r, 09r, 12r, 36r <400> 376 Gln Leu Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly 20 25 30 Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Ala Ala Pro Lys Leu 35 40 45 Leu Ile Tyr Gly Asp Ile Asn Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Ile Ser Ala Ser Leu Ala Ile Thr Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser 85 90 95 Leu Ser Gly Gly Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 377 <211> 368 <212> PRT <213> Artificial Sequence <220> <223> ACE-37-VH amino acid sequence <400> 377 Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asn Met His Trp Val Lys Gln Thr Pro Gly Arg Gly Leu Glu Trp Ile 35 40 45 Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val Trp Gly 100 105 110 Ala Gly Thr Thr Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Gln Val Gln Leu Val Glu 245 250 255 Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys 260 265 270 Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Thr Met His Trp Val Arg 275 280 285 Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Thr Phe Ile Ser Tyr Asp 290 295 300 Gly Asn Asn Lys Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile 305 310 315 320 Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu 325 330 335 Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys Ala Arg Thr Gly Trp Leu 340 345 350 Gly Pro Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 355 360 365 <210> 378 <211> 351 <212> PRT <213> Artificial Sequence <220> <223> ACE-37-VL amino acid sequence <400> 378 Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asn Met His Trp Val Lys Gln Thr Pro Gly Arg Gly Leu Glu Trp Ile 35 40 45 Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val Trp Gly 100 105 110 Ala Gly Thr Thr Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu 245 250 255 Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val 260 265 270 Gly Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro 275 280 285 Arg Leu Leu Ile Tyr Gly Ala Phe Ser Arg Ala Thr Gly Ile Pro Asp 290 295 300 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser 305 310 315 320 Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly 325 330 335 Ser Ser Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 340 345 350 <210> 379 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic sequence <400> 379 Gly Phe Thr Phe Ser Ser Tyr 1 5 <210> 380 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Synthetic sequence <400> 380 Gln Trp Thr Ser Asn Pro Pro Thr 1 5 <210> 381 <211> 477 <212> PRT <213> Artificial Sequence <220> <223> ACE-38-VH, ACE-40-VH amino acid sequence <400> 381 Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30 Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60 Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe 65 70 75 80 Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala 85 90 95 Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Gly Gly Gly Gly Ser Glu Val Gln Leu Gln Gln Ser Gly 245 250 255 Pro Glu Leu Val Lys Pro Gly Pro Ser Met Lys Ile Ser Cys Lys Ala 260 265 270 Ser Gly Tyr Ser Phe Thr Gly Tyr Thr Met Asn Trp Val Lys Gln Ser 275 280 285 His Gly Lys Asn Leu Glu Trp Met Gly Leu Ile Asn Pro Tyr Lys Gly 290 295 300 Val Ser Thr Tyr Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Val 305 310 315 320 Asp Lys Ser Ser Ser Thr Ala Tyr Met Glu Leu Leu Ser Leu Thr Ser 325 330 335 Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg Ser Gly Tyr Tyr Gly Asp 340 345 350 Ser Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly Thr Thr Leu Thr Val 355 360 365 Phe Ser Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Ser Pro Pro Ser 370 375 380 Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Arg Cys His Val Lys 385 390 395 400 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 405 410 415 Pro Glu Asn Asn Tyr Lys Thr Thr Lys Pro Val Leu Asp Ser Asp Gly 420 425 430 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln 435 440 445 Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 450 455 460 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 465 470 475 <210> 382 <211> 356 <212> PRT <213> Artificial Sequence <220> <223> ACE-38-VL amino acid sequence <400> 382 Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30 Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60 Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe 65 70 75 80 Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala 85 90 95 Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Thr Thr 245 250 255 Ser Ser Leu Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Arg 260 265 270 Ala Ser Gln Asp Ile Arg Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro 275 280 285 Asp Gly Thr Val Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu His Ser 290 295 300 Gly Val Pro Ser Lys Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser 305 310 315 320 Leu Thr Ile Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys 325 330 335 Gln Gln Gly Asn Thr Leu Pro Trp Thr Phe Ala Gly Gly Thr Lys Leu 340 345 350 Glu Ile Lys Arg 355 <210> 383 <211> 370 <212> PRT <213> Artificial Sequence <220> <223> ACE-39-VH amino acid sequence <400> 383 Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30 Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60 Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe 65 70 75 80 Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala 85 90 95 Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Gly Gly Gly Gly Ser Glu Val Gln Leu Gln Gln Ser Gly 245 250 255 Pro Glu Leu Val Lys Pro Gly Pro Ser Met Lys Ile Ser Cys Lys Ala 260 265 270 Ser Gly Tyr Ser Phe Thr Gly Tyr Thr Met Asn Trp Val Lys Gln Ser 275 280 285 His Gly Lys Asn Leu Glu Trp Met Gly Leu Ile Asn Pro Tyr Lys Gly 290 295 300 Val Ser Thr Tyr Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Val 305 310 315 320 Asp Lys Ser Ser Ser Thr Ala Tyr Met Glu Leu Leu Ser Leu Thr Ser 325 330 335 Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg Ser Gly Tyr Tyr Gly Asp 340 345 350 Ser Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly Thr Thr Leu Thr Val 355 360 365 Phe Ser 370 <210> 384 <211> 463 <212> PRT <213> Artificial Sequence <220> <223> ACE-39-VL, ACE-40-VL amino acid sequence <400> 384 Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30 Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60 Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe 65 70 75 80 Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala 85 90 95 Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Thr Thr 245 250 255 Ser Ser Leu Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Arg 260 265 270 Ala Ser Gln Asp Ile Arg Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro 275 280 285 Asp Gly Thr Val Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu His Ser 290 295 300 Gly Val Pro Ser Lys Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser 305 310 315 320 Leu Thr Ile Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys 325 330 335 Gln Gln Gly Asn Thr Leu Pro Trp Thr Phe Ala Gly Gly Thr Lys Leu 340 345 350 Glu Ile Lys Arg Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Ser Pro 355 360 365 Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Arg Cys His 370 375 380 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 385 390 395 400 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Lys Pro Val Leu Asp Ser 405 410 415 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 420 425 430 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 435 440 445 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 450 455 460 <210> 385 <211> 21 <212> PRT <213> Artificial Sequence <220> <223> Hinge 1 <400> 385 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu 1 5 10 15 Leu Leu Gly Gly Pro 20 <210> 386 <211> 18 <212> PRT <213> Artificial Sequence <220> <223> Hinge 2 <400> 386 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro <210> 387 <211> 19 <212> PRT <213> Artificial Sequence <220> <223> Hinge 3 <400> 387 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu 1 5 10 15 Leu Leu Gly <210> 388 <211> 362 <212> PRT <213> Artificial Sequence <220> <223> ACE-00r-VH amino acid sequence <400> 388 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Thr Trp Asn Ser Gly His Ile Asp Tyr Ala Asp Ser Val 50 55 60 Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Val Ser Tyr Leu Ser Thr Ala Ser Ser Leu Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro 245 250 255 Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys 260 265 270 Asp Thr Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu 275 280 285 Trp Val Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp 290 295 300 Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr 305 310 315 320 Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr 325 330 335 Tyr Cys Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp 340 345 350 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 355 360 <210> 389 <211> 349 <212> PRT <213> Artificial Sequence <220> <223> ACE-00r-VL amino acid sequence <400> 389 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Thr Trp Asn Ser Gly His Ile Asp Tyr Ala Asp Ser Val 50 55 60 Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Val Ser Tyr Leu Ser Thr Ala Ser Ser Leu Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser 245 250 255 Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn 260 265 270 Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu 275 280 285 Leu Ile Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe 290 295 300 Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu 305 310 315 320 Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr 325 330 335 Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 340 345 <210> 390 <211> 215 <212> PRT <213> Artificial Sequence <220> <223> ACE-00r-LC, ACE-24r-LC, ACE-25r-LC amino acid sequence <400> 390 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Val Ala Thr Tyr Tyr Cys Gln Arg Tyr Asn Arg Ala Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Arg Ser Val Ala 100 105 110 Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser 115 120 125 Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu 130 135 140 Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser 145 150 155 160 Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu 165 170 175 Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 180 185 190 Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys 195 200 205 Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 391 <211> 364 <212> PRT <213> Artificial Sequence <220> <223> ACE-01r-VH amino acid sequence <400> 391 Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr 20 25 30 Thr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230 235 240 Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ser 245 250 255 Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Ser Tyr 260 265 270 Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 275 280 285 Gly Gln Ile Trp Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gly Lys Phe 290 295 300 Lys Gly Lys Ala Thr Leu Thr Ala Asp Glu Ser Ser Ser Thr Ala Tyr 305 310 315 320 Met Gln Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Phe Cys 325 330 335 Ala Arg Arg Glu Thr Thr Thr Val Gly Arg Tyr Tyr Tyr Ala Met Asp 340 345 350 Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 355 360 <210> 392 <211> 351 <212> PRT <213> Artificial Sequence <220> <223> ACE-01r-VL amino acid sequence <400> 392 Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr 20 25 30 Thr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230 235 240 Asp Ile Gln Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly 245 250 255 Gln Arg Ala Thr Ile Ser Cys Lys Ala Ser Gln Ser Val Asp Tyr Asp 260 265 270 Gly Asp Ser Tyr Leu Asn Trp Tyr Gln Gln Ile Pro Gly Gln Pro Pro 275 280 285 Lys Leu Leu Ile Tyr Asp Ala Ser Asn Leu Val Ser Gly Ile Pro Pro 290 295 300 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile His 305 310 315 320 Pro Val Glu Lys Val Asp Ala Ala Thr Tyr His Cys Gln Gln Ser Thr 325 330 335 Glu Asp Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 340 345 350 <210> 393 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> ACE-01r-LC amino acid sequence <400> 393 Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met 20 25 30 Asn Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr 35 40 45 Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala His Phe Arg Gly Ser 50 55 60 Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Gly Met Glu Ala Glu 65 70 75 80 Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Phe Thr 85 90 95 Phe Gly Ser Gly Thr Lys Leu Glu Ile Asn Arg Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 394 <211> 364 <212> PRT <213> Artificial Sequence <220> <223> ACE-02r-VH amino acid sequence <400> 394 Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Asn Pro Ser Ser Gly Tyr Thr Lys Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Arg Phe Thr Ile Ser Ala Asp Lys Ser Lys Ser Thr Ala Phe 65 70 75 80 Leu Gln Met Asp Ser Leu Arg Pro Glu Asp Thr Gly Val Tyr Phe Cys 85 90 95 Ala Arg Trp Gln Asp Tyr Asp Val Tyr Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Pro Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230 235 240 Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ser 245 250 255 Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Ser Tyr 260 265 270 Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 275 280 285 Gly Gln Ile Trp Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gly Lys Phe 290 295 300 Lys Gly Lys Ala Thr Leu Thr Ala Asp Glu Ser Ser Ser Thr Ala Tyr 305 310 315 320 Met Gln Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Phe Cys 325 330 335 Ala Arg Arg Glu Thr Thr Thr Val Gly Arg Tyr Tyr Tyr Ala Met Asp 340 345 350 Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 355 360 <210> 395 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD3) in VH of ACE-02r <400> 395 Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Asn Pro Ser Ser Gly Tyr Thr Lys Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Arg Phe Thr Ile Ser Ala Asp Lys Ser Lys Ser Thr Ala Phe 65 70 75 80 Leu Gln Met Asp Ser Leu Arg Pro Glu Asp Thr Gly Val Tyr Phe Cys 85 90 95 Ala Arg Trp Gln Asp Tyr Asp Val Tyr Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Pro Val Thr Val Ser Ser 115 <210> 396 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD3) in CDR H1 of ACE-02r <400> 396 Gly Tyr Thr Phe Thr Ser Tyr Thr 1 5 <210> 397 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD3) in CDR H2 of ACE-02r <400> 397 Ile Asn Pro Ser Ser Gly Tyr Thr 1 5 <210> 398 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD3) in CDR H3 of ACE-02r <400> 398 Ala Arg Trp Gln Asp Tyr Asp Val Tyr Phe Asp Tyr 1 5 10 <210> 399 <211> 351 <212> PRT <213> Artificial Sequence <220> <223> ACE-02r-VL amino acid sequence <400> 399 Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Asn Pro Ser Ser Gly Tyr Thr Lys Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Arg Phe Thr Ile Ser Ala Asp Lys Ser Lys Ser Thr Ala Phe 65 70 75 80 Leu Gln Met Asp Ser Leu Arg Pro Glu Asp Thr Gly Val Tyr Phe Cys 85 90 95 Ala Arg Trp Gln Asp Tyr Asp Val Tyr Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Pro Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230 235 240 Asp Ile Gln Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly 245 250 255 Gln Arg Ala Thr Ile Ser Cys Lys Ala Ser Gln Ser Val Asp Tyr Asp 260 265 270 Gly Asp Ser Tyr Leu Asn Trp Tyr Gln Gln Ile Pro Gly Gln Pro Pro 275 280 285 Lys Leu Leu Ile Tyr Asp Ala Ser Asn Leu Val Ser Gly Ile Pro Pro 290 295 300 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile His 305 310 315 320 Pro Val Glu Lys Val Asp Ala Ala Thr Tyr His Cys Gln Gln Ser Thr 325 330 335 Glu Asp Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 340 345 350 <210> 400 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> ACE-02r-LC amino acid sequence <400> 400 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Met 20 25 30 His Trp Tyr Gln Gln Thr Pro Gly Lys Ala Pro Lys Pro Trp Ile Tyr 35 40 45 Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu 65 70 75 80 Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Pro Thr 85 90 95 Phe Gly Gln Gly Thr Lys Leu Gln Ile Thr Arg Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 401 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD3) in VL of ACE-02r <400> 401 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Met 20 25 30 His Trp Tyr Gln Gln Thr Pro Gly Lys Ala Pro Lys Pro Trp Ile Tyr 35 40 45 Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu 65 70 75 80 Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Pro Thr 85 90 95 Phe Gly Gln Gly Thr Lys Leu Gln Ile Thr Arg 100 105 <210> 402 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD3) in CDR L1 of ACE-02r <400> 402 Ser Ser Ser Val Ser Tyr 1 5 <210> 403 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD3) in CDR L2 of ACE-02r <400> 403 Ala Thr Ser One <210> 404 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD3) in CDR L3 of ACE-02r <400> 404 Gln Gln Trp Ser Ser Asn Pro Pro Thr 1 5 <210> 405 <211> 363 <212> PRT <213> Artificial Sequence <220> <223> ACE-03r-VH amino acid sequence <400> 405 Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser 1 5 10 15 Leu Arg Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr Thr 20 25 30 Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly 35 40 45 Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Val Lys 50 55 60 Asp Arg Phe Thr Ile Ser Thr Asp Lys Ser Lys Ser Thr Ala Phe Leu 65 70 75 80 Gln Met Asp Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Pro Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205 Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215 220 His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Gln 225 230 235 240 Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ser Ser 245 250 255 Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Ser Tyr Trp 260 265 270 Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly 275 280 285 Gln Ile Trp Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gly Lys Phe Lys 290 295 300 Gly Lys Ala Thr Leu Thr Ala Asp Glu Ser Ser Ser Thr Ala Tyr Met 305 310 315 320 Gln Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Phe Cys Ala 325 330 335 Arg Arg Glu Thr Thr Thr Val Gly Arg Tyr Tyr Tyr Ala Met Asp Tyr 340 345 350 Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 355 360 <210> 406 <211> 118 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD3) in VH of ACE-03r <400> 406 Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser 1 5 10 15 Leu Arg Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr Thr 20 25 30 Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly 35 40 45 Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Val Lys 50 55 60 Asp Arg Phe Thr Ile Ser Thr Asp Lys Ser Lys Ser Thr Ala Phe Leu 65 70 75 80 Gln Met Asp Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Pro Val Thr Val Ser Ser 115 <210> 407 <211> 350 <212> PRT <213> Artificial Sequence <220> <223> ACE-03r-VL amino acid sequence <400> 407 Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser 1 5 10 15 Leu Arg Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr Thr 20 25 30 Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly 35 40 45 Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Val Lys 50 55 60 Asp Arg Phe Thr Ile Ser Thr Asp Lys Ser Lys Ser Thr Ala Phe Leu 65 70 75 80 Gln Met Asp Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Pro Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205 Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215 220 His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Asp 225 230 235 240 Ile Gln Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly Gln 245 250 255 Arg Ala Thr Ile Ser Cys Lys Ala Ser Gln Ser Val Asp Tyr Asp Gly 260 265 270 Asp Ser Tyr Leu Asn Trp Tyr Gln Gln Ile Pro Gly Gln Pro Pro Lys 275 280 285 Leu Leu Ile Tyr Asp Ala Ser Asn Leu Val Ser Gly Ile Pro Pro Arg 290 295 300 Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile His Pro 305 310 315 320 Val Glu Lys Val Asp Ala Ala Thr Tyr His Cys Gln Gln Ser Thr Glu 325 330 335 Asp Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 340 345 350 <210> 408 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> ACE-03r-LC amino acid sequence <400> 408 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met 20 25 30 Asn Trp Tyr Gln Gln Thr Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr 35 40 45 Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu 65 70 75 80 Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Phe Thr 85 90 95 Phe Gly Gln Gly Thr Lys Leu Gln Ile Thr Arg Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 409 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD3) in VL of ACE-03r <400> 409 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met 20 25 30 Asn Trp Tyr Gln Gln Thr Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr 35 40 45 Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu 65 70 75 80 Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Phe Thr 85 90 95 Phe Gly Gln Gly Thr Lys Leu Gln Ile Thr Arg 100 105 <210> 410 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD3) in CDR L3 of ACE-03r <400> 410 Gln Gln Trp Ser Ser Asn Pro Phe Thr 1 5 <210> 411 <211> 469 <212> PRT <213> Artificial Sequence <220> <223> ACE-04r-VH amino acid sequence <400> 411 Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr 20 25 30 Thr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Thr Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230 235 240 Gly Gly Gly Gly Ser Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val 245 250 255 Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly 260 265 270 Thr Phe Ser Ser Tyr Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln 275 280 285 Gly Leu Glu Trp Met Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn 290 295 300 Tyr Ala Gln Lys Phe Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser 305 310 315 320 Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr 325 330 335 Ala Val Tyr Tyr Cys Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala 340 345 350 Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser 355 360 365 Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr 370 375 380 Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro 385 390 395 400 Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val 405 410 415 His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser 420 425 430 Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile 435 440 445 Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val 450 455 460 Glu Pro Lys Ser Cys 465 <210> 412 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD3) in VH of ACE-04r <400> 412 Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr 20 25 30 Thr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Thr Val Thr Val Ser Ala 115 <210> 413 <211> 463 <212> PRT <213> Artificial Sequence <220> <223> ACE-04r-VL amino acid sequence <400> 413 Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr 20 25 30 Thr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Thr Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230 235 240 Gly Gly Gly Gly Ser Gln Leu Val Leu Thr Gln Pro Pro Ser Val Ser 245 250 255 Gly Ala Pro Gly Gln Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser 260 265 270 Asn Ile Gly Ala Gly Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly 275 280 285 Ala Ala Pro Lys Leu Leu Ile Tyr Gly Asp Ile Asn Arg Pro Ser Gly 290 295 300 Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Ile Ser Ala Ser Leu 305 310 315 320 Ala Ile Thr Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln 325 330 335 Ser Tyr Asp Ser Ser Leu Ser Gly Gly Val Phe Gly Gly Gly Thr Lys 340 345 350 Leu Thr Val Leu Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro 355 360 365 Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu 370 375 380 Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp 385 390 395 400 Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp 405 410 415 Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys 420 425 430 Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln 435 440 445 Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 450 455 460 <210> 414 <211> 213 <212> PRT <213> Artificial Sequence <220> <223> ACE-04r-LC amino acid sequence <400> 414 Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met 20 25 30 Asn Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr 35 40 45 Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala His Phe Arg Gly Ser 50 55 60 Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Gly Met Glu Ala Glu 65 70 75 80 Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Phe Thr 85 90 95 Phe Gly Ser Gly Thr Lys Leu Glu Ile Asn Arg Ser Val Ala Ala Pro 100 105 110 Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 115 120 125 Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135 140 Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu 145 150 155 160 Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175 Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190 Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200 205 Asn Arg Gly Glu Cys 210 <210> 415 <211> 106 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD3) in VL of ACE-04r <400> 415 Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met 20 25 30 Asn Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr 35 40 45 Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala His Phe Arg Gly Ser 50 55 60 Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Gly Met Glu Ala Glu 65 70 75 80 Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Phe Thr 85 90 95 Phe Gly Ser Gly Thr Lys Leu Glu Ile Asn 100 105 <210> 416 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fab region (CD3) in CDR L3 of ACE-04r <400> 416 Gln Gln Trp Ser Ser Asn Pro Phe 1 5 <210> 417 <211> 369 <212> PRT <213> Artificial Sequence <220> <223> ACE-05r-VH amino acid sequence <400> 417 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Gly Gly Gly Gly Ser Gln Met Gln Leu Val Gln Ser Gly 245 250 255 Ala Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala 260 265 270 Ser Gly Gly Thr Phe Ser Ser Tyr Ala Ile Ser Trp Val Arg Gln Ala 275 280 285 Pro Gly Gln Gly Leu Glu Trp Met Gly Arg Ile Ile Pro Ile Leu Gly 290 295 300 Ile Ala Asn Tyr Ala Gln Lys Phe Gln Gly Arg Val Thr Ile Thr Ala 305 310 315 320 Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser 325 330 335 Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Pro Arg Asp Gly Tyr Asn 340 345 350 Leu Val Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser 355 360 365 Ser <210> 418 <211> 359 <212> PRT <213> Artificial Sequence <220> <223> ACE-05r-VL amino acid sequence <400> 418 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Gly Gly Gly Gly Ser Gln Leu Val Leu Thr Gln Pro Pro 245 250 255 Ser Val Ser Gly Ala Pro Gly Gln Arg Val Thr Ile Ser Cys Thr Gly 260 265 270 Ser Ser Ser Asn Ile Gly Ala Gly Tyr Asp Val His Trp Tyr Gln Gln 275 280 285 Leu Pro Gly Ala Ala Pro Lys Leu Leu Ile Tyr Gly Asp Ile Asn Arg 290 295 300 Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Ile Ser 305 310 315 320 Ala Ser Leu Ala Ile Thr Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr 325 330 335 Tyr Cys Gln Ser Tyr Asp Ser Ser Leu Ser Gly Gly Val Phe Gly Gly 340 345 350 Gly Thr Lys Leu Thr Val Leu 355 <210> 419 <211> 215 <212> PRT <213> Artificial Sequence <220> <223> ACE-05r-LC, ACE-10r-LC, ACE-11r-LC, ACE-19r-LC, ACE-28r-LC, ACE-38r-LC, ACE-39r-LC, ACE-40r-LC amino acid sequence <400> 419 Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly 1 5 10 15 Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Arg Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile 35 40 45 Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Lys Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln 65 70 75 80 Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Trp 85 90 95 Thr Phe Ala Gly Gly Thr Lys Leu Glu Ile Lys Arg Arg Thr Val Ala 100 105 110 Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser 115 120 125 Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu 130 135 140 Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser 145 150 155 160 Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu 165 170 175 Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 180 185 190 Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys 195 200 205 Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 420 <211> 365 <212> PRT <213> Artificial Sequence <220> <223> ACE-06r-VH amino acid sequence <400> 420 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Lys Phe Ser Gly Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp Tyr Asp Gly Ser Lys Lys Tyr Tyr Val Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gln Met Gly Tyr Trp His Phe Asp Leu Trp Gly Arg Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205 Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215 220 His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Gly 225 230 235 240 Gly Gly Gly Ser Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys 245 250 255 Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr 260 265 270 Phe Ser Ser Tyr Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly 275 280 285 Leu Glu Trp Met Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr 290 295 300 Ala Gln Lys Phe Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr 305 310 315 320 Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala 325 330 335 Val Tyr Tyr Cys Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe 340 345 350 Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser 355 360 365 <210> 421 <211> 356 <212> PRT <213> Artificial Sequence <220> <223> ACE-06r-VL amino acid sequence <400> 421 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Lys Phe Ser Gly Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp Tyr Asp Gly Ser Lys Lys Tyr Tyr Val Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gln Met Gly Tyr Trp His Phe Asp Leu Trp Gly Arg Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205 Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215 220 His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Gly 225 230 235 240 Gly Gly Gly Ser Gln Leu Val Leu Thr Gln Pro Pro Ser Val Ser Gly 245 250 255 Ala Pro Gly Gln Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn 260 265 270 Ile Gly Ala Gly Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Ala 275 280 285 Ala Pro Lys Leu Leu Ile Tyr Gly Asp Ile Asn Arg Pro Ser Gly Val 290 295 300 Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Ile Ser Ala Ser Leu Ala 305 310 315 320 Ile Thr Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser 325 330 335 Tyr Asp Ser Ser Leu Ser Gly Gly Val Phe Gly Gly Gly Thr Lys Leu 340 345 350 Thr Val Leu Arg 355 <210> 422 <211> 215 <212> PRT <213> Artificial Sequence <220> <223> ACE-06r-LC, ACE-23r-LC amino acid sequence <400> 422 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Pro 85 90 95 Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Ser Val Ala 100 105 110 Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser 115 120 125 Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu 130 135 140 Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser 145 150 155 160 Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu 165 170 175 Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 180 185 190 Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys 195 200 205 Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 423 <211> 369 <212> PRT <213> Artificial Sequence <220> <223> ACE-07r-VH amino acid sequence <400> 423 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Cys Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Gly Gly Gly Gly Ser Gln Met Gln Leu Val Gln Ser Gly 245 250 255 Ala Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala 260 265 270 Ser Gly Gly Thr Phe Ser Ser Tyr Ala Ile Ser Trp Val Arg Gln Ala 275 280 285 Pro Gly Gln Gly Leu Glu Trp Met Gly Arg Ile Ile Pro Ile Leu Gly 290 295 300 Ile Ala Asn Tyr Ala Gln Lys Phe Gln Gly Arg Val Thr Ile Thr Ala 305 310 315 320 Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser 325 330 335 Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Pro Arg Asp Gly Tyr Asn 340 345 350 Leu Val Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser 355 360 365 Ser <210> 424 <211> 360 <212> PRT <213> Artificial Sequence <220> <223> ACE-07r-VL amino acid sequence <400> 424 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Cys Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Gly Gly Gly Gly Ser Gln Leu Val Leu Thr Gln Pro Pro 245 250 255 Ser Val Ser Gly Ala Pro Gly Gln Arg Val Thr Ile Ser Cys Thr Gly 260 265 270 Ser Ser Ser Asn Ile Gly Ala Gly Tyr Asp Val His Trp Tyr Gln Gln 275 280 285 Leu Pro Gly Ala Ala Pro Lys Leu Leu Ile Tyr Gly Asp Ile Asn Arg 290 295 300 Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Ile Ser 305 310 315 320 Ala Ser Leu Ala Ile Thr Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr 325 330 335 Tyr Cys Gln Ser Tyr Asp Ser Ser Leu Ser Gly Gly Val Phe Gly Gly 340 345 350 Gly Thr Lys Leu Thr Val Leu Arg 355 360 <210> 425 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> ACE-07r-LC amino acid sequence <400> 425 Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly 1 5 10 15 Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Arg Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile 35 40 45 Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Lys Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln 65 70 75 80 Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Trp 85 90 95 Thr Phe Ala Gly Cys Thr Lys Leu Glu Ile Lys Arg Ser Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 426 <211> 363 <212> PRT <213> Artificial Sequence <220> <223> ACE-08r-VH amino acid sequence <400> 426 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Lys 1 5 10 15 Ser Leu Lys Leu Ser Cys Glu Ala Ser Gly Phe Thr Phe Ser Gly Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Arg Cys Leu Glu Ser Val 35 40 45 Ala Tyr Ile Thr Ser Ser Ser Ile Asn Ile Lys Tyr Ala Asp Ala Val 50 55 60 Lys Gly Arg Phe Thr Val Ser Arg Asp Asn Ala Lys Asn Leu Leu Phe 65 70 75 80 Leu Gln Met Asn Ile Leu Lys Ser Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Arg Phe Asp Trp Asp Lys Asn Tyr Trp Gly Gln Gly Thr Met Val 100 105 110 Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala 115 120 125 Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu 130 135 140 Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly 145 150 155 160 Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser 165 170 175 Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu 180 185 190 Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr 195 200 205 Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr 210 215 220 Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Gly Gly Gly 225 230 235 240 Gly Ser Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro 245 250 255 Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser 260 265 270 Ser Tyr Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu 275 280 285 Trp Met Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln 290 295 300 Lys Phe Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr 305 310 315 320 Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr 325 330 335 Tyr Cys Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile 340 345 350 Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser 355 360 <210> 427 <211> 354 <212> PRT <213> Artificial Sequence <220> <223> ACE-08r-VL amino acid sequence <400> 427 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Lys 1 5 10 15 Ser Leu Lys Leu Ser Cys Glu Ala Ser Gly Phe Thr Phe Ser Gly Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Arg Cys Leu Glu Ser Val 35 40 45 Ala Tyr Ile Thr Ser Ser Ser Ile Asn Ile Lys Tyr Ala Asp Ala Val 50 55 60 Lys Gly Arg Phe Thr Val Ser Arg Asp Asn Ala Lys Asn Leu Leu Phe 65 70 75 80 Leu Gln Met Asn Ile Leu Lys Ser Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Arg Phe Asp Trp Asp Lys Asn Tyr Trp Gly Gln Gly Thr Met Val 100 105 110 Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala 115 120 125 Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu 130 135 140 Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly 145 150 155 160 Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser 165 170 175 Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu 180 185 190 Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr 195 200 205 Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr 210 215 220 Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Gly Gly Gly 225 230 235 240 Gly Ser Gln Leu Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro 245 250 255 Gly Gln Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly 260 265 270 Ala Gly Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Ala Ala Pro 275 280 285 Lys Leu Leu Ile Tyr Gly Asp Ile Asn Arg Pro Ser Gly Val Pro Asp 290 295 300 Arg Phe Ser Gly Ser Lys Ser Gly Ile Ser Ala Ser Leu Ala Ile Thr 305 310 315 320 Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp 325 330 335 Ser Ser Leu Ser Gly Gly Val Phe Gly Gly Gly Thr Lys Leu Thr Val 340 345 350 Leu Arg <210> 428 <211> 212 <212> PRT <213> Artificial Sequence <220> <223> ACE-08r-LC amino acid sequence <400> 428 Gln Met Thr Gln Ser Pro Ser Ser Leu Pro Ala Ser Leu Gly Asp Arg 1 5 10 15 Val Thr Ile Asn Cys Gln Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn 20 25 30 Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr 35 40 45 Thr Asn Lys Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly Ser Gly 50 55 60 Ser Gly Arg Asp Ser Ser Phe Thr Ile Ser Ser Leu Glu Ser Glu Asp 65 70 75 80 Ile Gly Ser Tyr Tyr Cys Gln Gln Tyr Tyr Asn Tyr Pro Trp Thr Phe 85 90 95 Gly Pro Cys Thr Lys Leu Glu Ile Lys Arg Ser Val Ala Ala Pro Ser 100 105 110 Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala 115 120 125 Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val 130 135 140 Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser 145 150 155 160 Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr 165 170 175 Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys 180 185 190 Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn 195 200 205 Arg Gly Glu Cys 210 <210> 429 <211> 364 <212> PRT <213> Artificial Sequence <220> <223> ACE-09r-VH amino acid sequence <400> 429 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys 245 250 255 Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe 260 265 270 Ser Ser Tyr Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu 275 280 285 Glu Trp Met Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala 290 295 300 Gln Lys Phe Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser 305 310 315 320 Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val 325 330 335 Tyr Tyr Cys Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp 340 345 350 Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser 355 360 <210> 430 <211> 354 <212> PRT <213> Artificial Sequence <220> <223> ACE-09r-VL amino acid sequence <400> 430 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Gln Leu Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala 245 250 255 Pro Gly Gln Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile 260 265 270 Gly Ala Gly Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Ala Ala 275 280 285 Pro Lys Leu Leu Ile Tyr Gly Asp Ile Asn Arg Pro Ser Gly Val Pro 290 295 300 Asp Arg Phe Ser Gly Ser Lys Ser Gly Ile Ser Ala Ser Leu Ala Ile 305 310 315 320 Thr Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr 325 330 335 Asp Ser Ser Leu Ser Gly Gly Val Phe Gly Gly Gly Thr Lys Leu Thr 340 345 350 Val Leu <210> 431 <211> 215 <212> PRT <213> Artificial Sequence <220> <223> ACE-09r-LC, ACE-12r-LC, ACE-18r-LC, ACE-22r-LC amino acid sequence <400> 431 Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly 1 5 10 15 Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Arg Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile 35 40 45 Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Lys Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln 65 70 75 80 Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Trp 85 90 95 Thr Phe Ala Gly Gly Thr Lys Leu Glu Ile Lys Arg Arg Ser Val Ala 100 105 110 Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser 115 120 125 Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu 130 135 140 Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser 145 150 155 160 Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu 165 170 175 Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 180 185 190 Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys 195 200 205 Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 432 <211> 369 <212> PRT <213> Artificial Sequence <220> <223> ACE-10r-VH amino acid sequence <400> 432 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Gln Pro Gly 245 250 255 Ala Glu Leu Val Lys Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala 260 265 270 Ser Gly Tyr Thr Phe Thr Ser Tyr Asn Met His Trp Val Lys Gln Thr 275 280 285 Pro Gly Arg Gly Leu Glu Trp Ile Gly Ala Ile Tyr Pro Gly Asn Gly 290 295 300 Asp Thr Ser Tyr Asn Gln Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala 305 310 315 320 Asp Lys Ser Ser Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser 325 330 335 Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg Ser Thr Tyr Tyr Gly Gly 340 345 350 Asp Trp Tyr Phe Asn Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser 355 360 365 Ala <210> 433 <211> 354 <212> PRT <213> Artificial Sequence <220> <223> ACE-10r-VL amino acid sequence <400> 433 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Gly Gly Gly Gly Ser Gln Ile Val Leu Ser Gln Ser Pro 245 250 255 Ala Ile Leu Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Arg 260 265 270 Ala Ser Ser Ser Val Ser Tyr Ile His Trp Phe Gln Gln Lys Pro Gly 275 280 285 Ser Ser Pro Lys Pro Trp Ile Tyr Ala Thr Ser Asn Leu Ala Ser Gly 290 295 300 Val Pro Val Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu 305 310 315 320 Thr Ile Ser Arg Val Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln 325 330 335 Gln Trp Thr Ser Asn Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu Glu 340 345 350 Ile Lys <210> 434 <211> 367 <212> PRT <213> Artificial Sequence <220> <223> ACE-11r-VH amino acid sequence <400> 434 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Gly Gly Gly Gly Ser Gln Val Gln Leu Lys Gln Ser Gly 245 250 255 Pro Gly Leu Val Gln Pro Ser Gln Ser Leu Ser Ile Thr Cys Thr Val 260 265 270 Ser Gly Phe Ser Leu Thr Asn Tyr Gly Val His Trp Val Arg Gln Ser 275 280 285 Pro Gly Lys Gly Leu Glu Trp Leu Gly Val Ile Trp Ser Gly Gly Asn 290 295 300 Thr Asp Tyr Asn Thr Pro Phe Thr Ser Arg Leu Ser Ile Asn Lys Asp 305 310 315 320 Asn Ser Lys Ser Gln Val Phe Phe Lys Met Asn Ser Leu Gln Ser Asn 325 330 335 Asp Thr Ala Ile Tyr Tyr Cys Ala Arg Ala Leu Thr Tyr Tyr Asp Tyr 340 345 350 Glu Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala 355 360 365 <210> 435 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> Fv region (EGFR) in VH of ACE-11r <400> 435 Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30 Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60 Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe 65 70 75 80 Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala 85 90 95 Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ala 115 <210> 436 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD20) in CDR H1 of ACE-11r <400> 436 Gly Phe Ser Leu Thr Asn Tyr Gly 1 5 <210> 437 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD20) in CDR H2 of ACE-11r <400> 437 Ile Trp Ser Gly Gly Asn Thr 1 5 <210> 438 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD20) in CDR H3 of ACE-11r <400> 438 Ala Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr 1 5 10 <210> 439 <211> 355 <212> PRT <213> Artificial Sequence <220> <223> ACE-11r-VL amino acid sequence <400> 439 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Gly Gly Gly Gly Ser Asp Ile Leu Leu Thr Gln Ser Pro 245 250 255 Val Ile Leu Ser Val Ser Pro Gly Glu Arg Val Ser Phe Ser Cys Arg 260 265 270 Ala Ser Gln Ser Ile Gly Thr Asn Ile His Trp Tyr Gln Gln Arg Thr 275 280 285 Asn Gly Ser Pro Arg Leu Leu Ile Lys Tyr Ala Ser Glu Ser Ile Ser 290 295 300 Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 305 310 315 320 Leu Ser Ile Asn Ser Val Glu Ser Glu Asp Ile Ala Asp Tyr Tyr Cys 325 330 335 Gln Gln Asn Asn Asn Trp Pro Thr Thr Phe Gly Ala Gly Thr Lys Leu 340 345 350 Glu Leu Lys 355 <210> 440 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD20) in VL of ACE-11r <400> 440 Asp Ile Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn 20 25 30 Ile His Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile 35 40 45 Lys Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser 65 70 75 80 Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr 85 90 95 Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys 100 105 <210> 441 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD20) in CDR L1 of ACE-11r <400> 441 Gln Ser Ile Gly Thr Asn 1 5 <210> 442 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD20) in CDR L2 of ACE-11r <400> 442 Tyr Ala Ser One <210> 443 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Fv region (CD20) in CDR L3 of ACE-11r <400> 443 Gln Gln Asn Asn Asn Trp Pro Thr Thr 1 5 <210> 444 <211> 374 <212> PRT <213> Artificial Sequence <220> <223> ACE-12r-VH amino acid sequence <400> 444 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Met Gln 245 250 255 Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser Ser Val Lys 260 265 270 Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr Ala Ile Ser 275 280 285 Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Arg Ile 290 295 300 Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe Gln Gly Arg 305 310 315 320 Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu 325 330 335 Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Pro 340 345 350 Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly Gln Gly Thr 355 360 365 Met Val Thr Val Ser Ser 370 <210> 445 <211> 363 <212> PRT <213> Artificial Sequence <220> <223> ACE-12r-VL amino acid sequence <400> 445 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Gly Gly Ser Gly Gly Gly Gly Ser Gly Gln Leu Val Leu 245 250 255 Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln Arg Val Thr Ile 260 265 270 Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly Tyr Asp Val His 275 280 285 Trp Tyr Gln Gln Leu Pro Gly Ala Ala Pro Lys Leu Leu Ile Tyr Gly 290 295 300 Asp Ile Asn Arg Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys 305 310 315 320 Ser Gly Ile Ser Ala Ser Leu Ala Ile Thr Gly Leu Gln Ala Glu Asp 325 330 335 Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser Leu Ser Gly Gly 340 345 350 Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 355 360 <210> 446 <211> 361 <212> PRT <213> Artificial Sequence <220> <223> ACE-13r-VH amino acid sequence <400> 446 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Leu Arg Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Arg Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Thr Thr Thr Thr Phe Asp Ser Trp Gly Gln Gly Thr Leu Val Thr Val 100 105 110 Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser 115 120 125 Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys 130 135 140 Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu 145 150 155 160 Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu 165 170 175 Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr 180 185 190 Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val 195 200 205 Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro 210 215 220 Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser 225 230 235 240 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 245 250 255 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 260 265 270 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 275 280 285 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 290 295 300 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 305 310 315 320 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 325 330 335 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 340 345 350 Gln Gly Thr Met Val Thr Val Ser Ser 355 360 <210> 447 <211> 352 <212> PRT <213> Artificial Sequence <220> <223> ACE-13r-VL amino acid sequence <400> 447 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Leu Arg Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Arg Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Thr Thr Thr Thr Phe Asp Ser Trp Gly Gln Gly Thr Leu Val Thr Val 100 105 110 Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser 115 120 125 Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys 130 135 140 Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu 145 150 155 160 Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu 165 170 175 Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr 180 185 190 Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val 195 200 205 Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro 210 215 220 Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser 225 230 235 240 Gln Leu Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln 245 250 255 Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly 260 265 270 Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Ala Ala Pro Lys Leu 275 280 285 Leu Ile Tyr Gly Asp Ile Asn Arg Pro Ser Gly Val Pro Asp Arg Phe 290 295 300 Ser Gly Ser Lys Ser Gly Ile Ser Ala Ser Leu Ala Ile Thr Gly Leu 305 310 315 320 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser 325 330 335 Leu Ser Gly Gly Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Arg 340 345 350 <210> 448 <211> 220 <212> PRT <213> Artificial Sequence <220> <223> ACE-13r-LC amino acid sequence <400> 448 Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly 1 5 10 15 Glu Ala Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu Asp Ser 20 25 30 Glu Asp Gly Asn Thr Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln 35 40 45 Ser Pro Gln Leu Leu Ile Tyr Thr Leu Ser His Arg Ala Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Glu 65 70 75 80 Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln 85 90 95 Arg Arg Asp Phe Pro Phe Thr Phe Gly Gln Gly Thr Lys Val Asp Ile 100 105 110 Lys Arg Ser Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 115 120 125 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 130 135 140 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 145 150 155 160 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 165 170 175 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 180 185 190 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 195 200 205 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 220 <210> 449 <211> 374 <212> PRT <213> Artificial Sequence <220> <223> ACE-14r-VH amino acid sequence <400> 449 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Cys Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Met Gln 245 250 255 Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser Ser Val Lys 260 265 270 Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr Ala Ile Ser 275 280 285 Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Arg Ile 290 295 300 Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe Gln Gly Arg 305 310 315 320 Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu 325 330 335 Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Pro 340 345 350 Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly Gln Gly Thr 355 360 365 Met Val Thr Val Ser Ser 370 <210> 450 <211> 365 <212> PRT <213> Artificial Sequence <220> <223> ACE-14r-VL amino acid sequence <400> 450 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Cys Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Leu Val 245 250 255 Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln Arg Val Thr 260 265 270 Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly Tyr Asp Val 275 280 285 His Trp Tyr Gln Gln Leu Pro Gly Ala Ala Pro Lys Leu Leu Ile Tyr 290 295 300 Gly Asp Ile Asn Arg Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser 305 310 315 320 Lys Ser Gly Ile Ser Ala Ser Leu Ala Ile Thr Gly Leu Gln Ala Glu 325 330 335 Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser Leu Ser Gly 340 345 350 Gly Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Arg 355 360 365 <210> 451 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> ACE-14r-LC amino acid sequence <400> 451 Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly 1 5 10 15 Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Arg Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile 35 40 45 Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Lys Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln 65 70 75 80 Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Trp 85 90 95 Thr Phe Ala Cys Gly Thr Lys Leu Glu Ile Lys Arg Ser Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 452 <211> 369 <212> PRT <213> Artificial Sequence <220> <223> ACE-15r-VH amino acid sequence <400> 452 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Cys Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Gly Gly Gly Gly Ser Gln Met Gln Leu Val Gln Ser Gly 245 250 255 Ala Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala 260 265 270 Ser Gly Gly Thr Phe Ser Ser Tyr Ala Ile Ser Trp Val Arg Gln Ala 275 280 285 Pro Gly Gln Gly Leu Glu Trp Met Gly Arg Ile Ile Pro Ile Leu Gly 290 295 300 Ile Ala Asn Tyr Ala Gln Lys Phe Gln Gly Arg Val Thr Ile Thr Ala 305 310 315 320 Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser 325 330 335 Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Pro Arg Asp Gly Tyr Asn 340 345 350 Leu Val Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser 355 360 365 Ser <210> 453 <211> 360 <212> PRT <213> Artificial Sequence <220> <223> ACE-15r-VL amino acid sequence <400> 453 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Cys Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Gly Gly Gly Gly Ser Gln Leu Val Leu Thr Gln Pro Pro 245 250 255 Ser Val Ser Gly Ala Pro Gly Gln Arg Val Thr Ile Ser Cys Thr Gly 260 265 270 Ser Ser Ser Asn Ile Gly Ala Gly Tyr Asp Val His Trp Tyr Gln Gln 275 280 285 Leu Pro Gly Ala Ala Pro Lys Leu Leu Ile Tyr Gly Asp Ile Asn Arg 290 295 300 Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Ile Ser 305 310 315 320 Ala Ser Leu Ala Ile Thr Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr 325 330 335 Tyr Cys Gln Ser Tyr Asp Ser Ser Leu Ser Gly Gly Val Phe Gly Gly 340 345 350 Gly Thr Lys Leu Thr Val Leu Arg 355 360 <210> 454 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> ACE-15r-LC amino acid sequence <400> 454 Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly 1 5 10 15 Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Arg Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Cys Val Lys Leu Leu Ile 35 40 45 Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Lys Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln 65 70 75 80 Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Trp 85 90 95 Thr Phe Ala Gly Gly Thr Lys Leu Glu Ile Lys Arg Ser Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 455 <211> 372 <212> PRT <213> Artificial Sequence <220> <223> ACE-16r-VH amino acid sequence <400> 455 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro 225 230 235 240 Glu Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Gln Met Gln Leu Val 245 250 255 Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val Ser 260 265 270 Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr Ala Ile Ser Trp Val 275 280 285 Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Arg Ile Ile Pro 290 295 300 Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe Gln Gly Arg Val Thr 305 310 315 320 Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser 325 330 335 Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Pro Arg Asp 340 345 350 Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Val 355 360 365 Thr Val Ser Ser 370 <210> 456 <211> 363 <212> PRT <213> Artificial Sequence <220> <223> ACE-16r-VL amino acid sequence <400> 456 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro 225 230 235 240 Glu Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Gln Leu Val Leu Thr 245 250 255 Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln Arg Val Thr Ile Ser 260 265 270 Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly Tyr Asp Val His Trp 275 280 285 Tyr Gln Gln Leu Pro Gly Ala Ala Pro Lys Leu Leu Ile Tyr Gly Asp 290 295 300 Ile Asn Arg Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser 305 310 315 320 Gly Ile Ser Ala Ser Leu Ala Ile Thr Gly Leu Gln Ala Glu Asp Glu 325 330 335 Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser Leu Ser Gly Gly Val 340 345 350 Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Arg 355 360 <210> 457 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> ACE-16r-LC, ACE-17r-LC amino acid sequence <400> 457 Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly 1 5 10 15 Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Arg Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile 35 40 45 Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Lys Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln 65 70 75 80 Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Trp 85 90 95 Thr Phe Ala Gly Gly Thr Lys Leu Glu Ile Lys Arg Ser Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 458 <211> 367 <212> PRT <213> Artificial Sequence <220> <223> ACE-17r-VH amino acid sequence <400> 458 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro 225 230 235 240 Glu Leu Leu Gly Gly Pro Gln Met Gln Leu Val Gln Ser Gly Ala Glu 245 250 255 Val Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly 260 265 270 Gly Thr Phe Ser Ser Tyr Ala Ile Ser Trp Val Arg Gln Ala Pro Gly 275 280 285 Gln Gly Leu Glu Trp Met Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala 290 295 300 Asn Tyr Ala Gln Lys Phe Gln Gly Arg Val Thr Ile Thr Ala Asp Lys 305 310 315 320 Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp 325 330 335 Thr Ala Val Tyr Tyr Cys Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val 340 345 350 Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser 355 360 365 <210> 459 <211> 358 <212> PRT <213> Artificial Sequence <220> <223> ACE-17r-VL amino acid sequence <400> 459 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro 225 230 235 240 Glu Leu Leu Gly Gly Pro Gln Leu Val Leu Thr Gln Pro Pro Ser Val 245 250 255 Ser Gly Ala Pro Gly Gln Arg Val Thr Ile Ser Cys Thr Gly Ser Ser 260 265 270 Ser Asn Ile Gly Ala Gly Tyr Asp Val His Trp Tyr Gln Gln Leu Pro 275 280 285 Gly Ala Ala Pro Lys Leu Leu Ile Tyr Gly Asp Ile Asn Arg Pro Ser 290 295 300 Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Ile Ser Ala Ser 305 310 315 320 Leu Ala Ile Thr Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys 325 330 335 Gln Ser Tyr Asp Ser Ser Leu Ser Gly Gly Val Phe Gly Gly Gly Thr 340 345 350 Lys Leu Thr Val Leu Arg 355 <210> 460 <211> 372 <212> PRT <213> Artificial Sequence <220> <223> ACE-18r-VH amino acid sequence <400> 460 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro 225 230 235 240 Glu Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Gln Val Gln Leu Gln 245 250 255 Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala Ser Val Lys Met Ser 260 265 270 Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr Asn Met His Trp Val 275 280 285 Lys Gln Thr Pro Gly Arg Gly Leu Glu Trp Ile Gly Ala Ile Tyr Pro 290 295 300 Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe Lys Gly Lys Ala Thr 305 310 315 320 Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr Met Gln Leu Ser Ser 325 330 335 Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg Ser Thr Tyr 340 345 350 Tyr Gly Gly Asp Trp Tyr Phe Asn Val Trp Gly Ala Gly Thr Thr Val 355 360 365 Thr Val Ser Ala 370 <210> 461 <211> 357 <212> PRT <213> Artificial Sequence <220> <223> ACE-18r-VL amino acid sequence <400> 461 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro 225 230 235 240 Glu Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Gln Ile Val Leu Ser 245 250 255 Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly Glu Lys Val Thr Met 260 265 270 Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Ile His Trp Phe Gln Gln 275 280 285 Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr Ala Thr Ser Asn Leu 290 295 300 Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser 305 310 315 320 Tyr Ser Leu Thr Ile Ser Arg Val Glu Ala Glu Asp Ala Ala Thr Tyr 325 330 335 Tyr Cys Gln Gln Trp Thr Ser Asn Pro Pro Thr Phe Gly Gly Gly Thr 340 345 350 Lys Leu Glu Ile Lys 355 <210> 462 <211> 370 <212> PRT <213> Artificial Sequence <220> <223> ACE-19r-VH amino acid sequence <400> 462 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro 225 230 235 240 Glu Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Gln Val Gln Leu Lys 245 250 255 Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln Ser Leu Ser Ile Thr 260 265 270 Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr Gly Val His Trp Val 275 280 285 Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu Gly Val Ile Trp Ser 290 295 300 Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr Ser Arg Leu Ser Ile 305 310 315 320 Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe Lys Met Asn Ser Leu 325 330 335 Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala Arg Ala Leu Thr Tyr 340 345 350 Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val 355 360 365 Ser Ala 370 <210> 463 <211> 358 <212> PRT <213> Artificial Sequence <220> <223> ACE-19r-VL amino acid sequence <400> 463 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro 225 230 235 240 Glu Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Asp Ile Leu Leu Thr 245 250 255 Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly Glu Arg Val Ser Phe 260 265 270 Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile His Trp Tyr Gln 275 280 285 Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile Lys Tyr Ala Ser Glu 290 295 300 Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr 305 310 315 320 Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser Glu Asp Ile Ala Asp 325 330 335 Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr Thr Phe Gly Ala Gly 340 345 350 Thr Lys Leu Glu Leu Lys 355 <210> 464 <211> 372 <212> PRT <213> Artificial Sequence <220> <223> ACE-20r-VH amino acid sequence <400> 464 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro 225 230 235 240 Glu Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Gln Val Gln Leu Val 245 250 255 Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser 260 265 270 Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser His Trp Met His Trp Val 275 280 285 Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile Gly Glu Phe Asn Pro 290 295 300 Ser Asn Gly Arg Thr Asn Tyr Asn Glu Lys Phe Lys Ser Lys Ala Thr 305 310 315 320 Met Thr Val Asp Thr Ser Thr Asn Thr Ala Tyr Met Glu Leu Ser Ser 325 330 335 Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ser Arg Asp Tyr 340 345 350 Asp Tyr Asp Cys Arg Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 355 360 365 Thr Val Ser Ser 370 <210> 465 <211> 358 <212> PRT <213> Artificial Sequence <220> <223> ACE-20r-VL amino acid sequence <400> 465 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro 225 230 235 240 Glu Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Asp Ile Gln Met Thr 245 250 255 Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile 260 265 270 Thr Cys Ser Ala Ser Ser Ser Val Thr Tyr Met Tyr Trp Tyr Gln Gln 275 280 285 Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Asp Thr Ser Asn Leu 290 295 300 Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp 305 310 315 320 Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr 325 330 335 Tyr Cys Gln Gln Trp Ser Ser His Ile Phe Thr Phe Gly Gln Gly Thr 340 345 350 Lys Val Glu Ile Lys Arg 355 <210> 466 <211> 376 <212> PRT <213> Artificial Sequence <220> <223> ACE-21r-VH amino acid sequence <400> 466 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro 225 230 235 240 Glu Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Gln Val Gln Leu Val 245 250 255 Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser Leu Arg Leu Ser 260 265 270 Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr Gly Met His Trp Val 275 280 285 Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Val Ile Trp Asp 290 295 300 Asp Gly Ser Tyr Lys Tyr Tyr Gly Asp Ser Val Lys Gly Arg Phe Thr 305 310 315 320 Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser 325 330 335 Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Gly Ile 340 345 350 Thr Met Val Arg Gly Val Met Lys Asp Tyr Phe Asp Tyr Trp Gly Gln 355 360 365 Gly Thr Leu Val Thr Val Ser Ser 370 375 <210> 467 <211> 359 <212> PRT <213> Artificial Sequence <220> <223> ACE-21r-VL amino acid sequence <400> 467 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro 225 230 235 240 Glu Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Ala Ile Gln Leu Thr 245 250 255 Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile 260 265 270 Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Ala Leu Val Trp Tyr Gln 275 280 285 Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Asp Ala Ser Ser 290 295 300 Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Glu Ser Gly Thr 305 310 315 320 Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr 325 330 335 Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Leu Thr Phe Gly Gly Gly 340 345 350 Thr Lys Val Glu Ile Lys Arg 355 <210> 468 <211> 367 <212> PRT <213> Artificial Sequence <220> <223> ACE-22r-VH amino acid sequence <400> 468 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro 225 230 235 240 Glu Leu Leu Gly Gly Pro Gln Val Gln Leu Gln Gln Pro Gly Ala Glu 245 250 255 Leu Val Lys Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly 260 265 270 Tyr Thr Phe Thr Ser Tyr Asn Met His Trp Val Lys Gln Thr Pro Gly 275 280 285 Arg Gly Leu Glu Trp Ile Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr 290 295 300 Ser Tyr Asn Gln Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys 305 310 315 320 Ser Ser Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp 325 330 335 Ser Ala Val Tyr Tyr Cys Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp 340 345 350 Tyr Phe Asn Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ala 355 360 365 <210> 469 <211> 352 <212> PRT <213> Artificial Sequence <220> <223> ACE-22r-VL amino acid sequence <400> 469 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro 225 230 235 240 Glu Leu Leu Gly Gly Pro Gln Ile Val Leu Ser Gln Ser Pro Ala Ile 245 250 255 Leu Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Arg Ala Ser 260 265 270 Ser Ser Val Ser Tyr Ile His Trp Phe Gln Gln Lys Pro Gly Ser Ser 275 280 285 Pro Lys Pro Trp Ile Tyr Ala Thr Ser Asn Leu Ala Ser Gly Val Pro 290 295 300 Val Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile 305 310 315 320 Ser Arg Val Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp 325 330 335 Thr Ser Asn Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 340 345 350 <210> 470 <211> 368 <212> PRT <213> Artificial Sequence <220> <223> ACE-23r-VH amino acid sequence <400> 470 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Lys Phe Ser Gly Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp Tyr Asp Gly Ser Lys Lys Tyr Tyr Val Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gln Met Gly Tyr Trp His Phe Asp Leu Trp Gly Arg Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205 Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215 220 His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Gly Gly Gly Gly Ser Gln Met Gln Leu Val Gln Ser Gly Ala 245 250 255 Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser 260 265 270 Gly Gly Thr Phe Ser Ser Tyr Ala Ile Ser Trp Val Arg Gln Ala Pro 275 280 285 Gly Gln Gly Leu Glu Trp Met Gly Arg Ile Ile Pro Ile Leu Gly Ile 290 295 300 Ala Asn Tyr Ala Gln Lys Phe Gln Gly Arg Val Thr Ile Thr Ala Asp 305 310 315 320 Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu 325 330 335 Asp Thr Ala Val Tyr Tyr Cys Ala Lys Pro Arg Asp Gly Tyr Asn Leu 340 345 350 Val Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser 355 360 365 <210> 471 <211> 359 <212> PRT <213> Artificial Sequence <220> <223> ACE-23r-VL amino acid sequence <400> 471 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Lys Phe Ser Gly Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp Tyr Asp Gly Ser Lys Lys Tyr Tyr Val Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gln Met Gly Tyr Trp His Phe Asp Leu Trp Gly Arg Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205 Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215 220 His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Gly Gly Gly Gly Ser Gln Leu Val Leu Thr Gln Pro Pro Ser 245 250 255 Val Ser Gly Ala Pro Gly Gln Arg Val Thr Ile Ser Cys Thr Gly Ser 260 265 270 Ser Ser Asn Ile Gly Ala Gly Tyr Asp Val His Trp Tyr Gln Gln Leu 275 280 285 Pro Gly Ala Ala Pro Lys Leu Leu Ile Tyr Gly Asp Ile Asn Arg Pro 290 295 300 Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Ile Ser Ala 305 310 315 320 Ser Leu Ala Ile Thr Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Tyr 325 330 335 Cys Gln Ser Tyr Asp Ser Ser Leu Ser Gly Gly Val Phe Gly Gly Gly 340 345 350 Thr Lys Leu Thr Val Leu Arg 355 <210> 472 <211> 367 <212> PRT <213> Artificial Sequence <220> <223> ACE-24r-VH amino acid sequence <400> 472 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Thr Trp Asn Ser Gly His Ile Asp Tyr Ala Asp Ser Val 50 55 60 Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Val Ser Tyr Leu Ser Thr Ala Ser Ser Leu Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly 245 250 255 Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser 260 265 270 Gly Phe Asn Ile Lys Asp Thr Tyr Ile His Trp Val Arg Gln Ala Pro 275 280 285 Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Tyr Pro Thr Asn Gly Tyr 290 295 300 Thr Arg Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp 305 310 315 320 Thr Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu 325 330 335 Asp Thr Ala Val Tyr Tyr Cys Ser Arg Trp Gly Gly Asp Gly Phe Tyr 340 345 350 Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 355 360 365 <210> 473 <211> 349 <212> PRT <213> Artificial Sequence <220> <223> ACE-24r-VL amino acid sequence <400> 473 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Thr Trp Asn Ser Gly His Ile Asp Tyr Ala Asp Ser Val 50 55 60 Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Val Ser Tyr Leu Ser Thr Ala Ser Ser Leu Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser 245 250 255 Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn 260 265 270 Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu 275 280 285 Leu Ile Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe 290 295 300 Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu 305 310 315 320 Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr 325 330 335 Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 340 345 <210> 474 <211> 372 <212> PRT <213> Artificial Sequence <220> <223> ACE-25r-VH amino acid sequence <400> 474 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Thr Trp Asn Ser Gly His Ile Asp Tyr Ala Asp Ser Val 50 55 60 Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Val Ser Tyr Leu Ser Thr Ala Ser Ser Leu Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu 245 250 255 Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu 260 265 270 Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr Tyr Ile His Trp 275 280 285 Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Tyr 290 295 300 Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val Lys Gly Arg Phe 305 310 315 320 Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn 325 330 335 Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ser Arg Trp Gly 340 345 350 Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val 355 360 365 Thr Val Ser Ser 370 <210> 475 <211> 349 <212> PRT <213> Artificial Sequence <220> <223> ACE-25r-VL amino acid sequence <400> 475 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Thr Trp Asn Ser Gly His Ile Asp Tyr Ala Asp Ser Val 50 55 60 Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Val Ser Tyr Leu Ser Thr Ala Ser Ser Leu Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser 245 250 255 Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn 260 265 270 Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu 275 280 285 Leu Ile Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe 290 295 300 Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu 305 310 315 320 Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr 325 330 335 Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 340 345 <210> 476 <211> 373 <212> PRT <213> Artificial Sequence <220> <223> ACE-26r-VH amino acid sequence <400> 476 Glu Val Lys Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Lys Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp 50 55 60 Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Ser Ile 65 70 75 80 Leu Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr 85 90 95 Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe 100 105 110 Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala Ala Ser Thr 115 120 125 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140 Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175 Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190 Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys 195 200 205 Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys 225 230 235 240 Pro Ala Pro Glu Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Gln Val 245 250 255 Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln Ser Leu 260 265 270 Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr Gly Val 275 280 285 His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu Gly Val 290 295 300 Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr Ser Arg 305 310 315 320 Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe Lys Met 325 330 335 Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala Arg Ala 340 345 350 Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly Thr Leu 355 360 365 Val Thr Val Ser Ala 370 <210> 477 <211> 361 <212> PRT <213> Artificial Sequence <220> <223> ACE-26r-VL amino acid sequence <400> 477 Glu Val Lys Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Lys Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp 50 55 60 Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Ser Ile 65 70 75 80 Leu Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr 85 90 95 Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe 100 105 110 Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala Ala Ser Thr 115 120 125 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140 Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175 Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190 Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys 195 200 205 Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys 225 230 235 240 Pro Ala Pro Glu Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Asp Ile 245 250 255 Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly Glu Arg 260 265 270 Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile His 275 280 285 Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile Lys Tyr 290 295 300 Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly 305 310 315 320 Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser Glu Asp 325 330 335 Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr Thr Phe 340 345 350 Gly Ala Gly Thr Lys Leu Glu Leu Lys 355 360 <210> 478 <211> 216 <212> PRT <213> Artificial Sequence <220> <223> ACE-26r-LC, ACE-29r-LC, ACE-32r-LC amino acid sequence <400> 478 Gln Ala Val Val Thr Gln Glu Ser Ala Leu Thr Thr Ser Pro Gly Glu 1 5 10 15 Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser 20 25 30 Asn Tyr Ala Asn Trp Val Gln Glu Lys Pro Asp His Leu Phe Thr Gly 35 40 45 Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ala Arg Phe 50 55 60 Ser Gly Ser Leu Ile Gly Asp Lys Ala Ala Leu Thr Ile Thr Gly Ala 65 70 75 80 Gln Thr Glu Asp Glu Ala Ile Tyr Phe Cys Ala Leu Trp Tyr Ser Asn 85 90 95 Leu Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Arg Thr Val 100 105 110 Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys 115 120 125 Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg 130 135 140 Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn 145 150 155 160 Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser 165 170 175 Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys 180 185 190 Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr 195 200 205 Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 479 <211> 375 <212> PRT <213> Artificial Sequence <220> <223> ACE-27r-VH amino acid sequence <400> 479 Glu Val Lys Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Lys Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp 50 55 60 Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Ser Ile 65 70 75 80 Leu Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr 85 90 95 Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe 100 105 110 Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala Ala Ser Thr 115 120 125 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140 Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175 Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190 Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys 195 200 205 Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys 225 230 235 240 Pro Ala Pro Glu Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Gln Met 245 250 255 Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser Ser Val 260 265 270 Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr Ala Ile 275 280 285 Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Arg 290 295 300 Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe Gln Gly 305 310 315 320 Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu 325 330 335 Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys 340 345 350 Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly Gln Gly 355 360 365 Thr Met Val Thr Val Ser Ser 370 375 <210> 480 <211> 363 <212> PRT <213> Artificial Sequence <220> <223> ACE-27r-VL amino acid sequence <400> 480 Glu Val Lys Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Lys Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp 50 55 60 Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Ser Ile 65 70 75 80 Leu Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr 85 90 95 Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe 100 105 110 Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala Ala Ser Thr 115 120 125 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140 Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175 Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190 Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys 195 200 205 Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys 225 230 235 240 Pro Ala Pro Glu Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Gln Ala 245 250 255 Val Val Thr Gln Glu Ser Ala Leu Thr Thr Ser Pro Gly Glu Thr Val 260 265 270 Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser Asn Tyr 275 280 285 Ala Asn Trp Val Gln Glu Lys Pro Asp His Leu Phe Thr Gly Leu Ile 290 295 300 Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ala Arg Phe Ser Gly 305 310 315 320 Ser Leu Ile Gly Asp Lys Ala Ala Leu Thr Ile Thr Gly Ala Gln Thr 325 330 335 Glu Asp Glu Ala Ile Tyr Phe Cys Ala Leu Trp Tyr Ser Asn Leu Trp 340 345 350 Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 355 360 <210> 481 <211> 477 <212> PRT <213> Artificial Sequence <220> <223> ACE-28r-VH amino acid sequence <400> 481 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro 225 230 235 240 Glu Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Gln Val Gln Leu Lys 245 250 255 Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln Ser Leu Ser Ile Thr 260 265 270 Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr Gly Val His Trp Val 275 280 285 Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu Gly Val Ile Trp Ser 290 295 300 Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr Ser Arg Leu Ser Ile 305 310 315 320 Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe Lys Met Asn Ser Leu 325 330 335 Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala Arg Ala Leu Thr Tyr 340 345 350 Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val 355 360 365 Ser Ala Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser 370 375 380 Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys 385 390 395 400 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 405 410 415 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 420 425 430 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln 435 440 445 Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 450 455 460 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 465 470 475 <210> 482 <211> 465 <212> PRT <213> Artificial Sequence <220> <223> ACE-28r-VL amino acid sequence <400> 482 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro 225 230 235 240 Glu Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Asp Ile Leu Leu Thr 245 250 255 Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly Glu Arg Val Ser Phe 260 265 270 Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile His Trp Tyr Gln 275 280 285 Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile Lys Tyr Ala Ser Glu 290 295 300 Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr 305 310 315 320 Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser Glu Asp Ile Ala Asp 325 330 335 Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr Thr Phe Gly Ala Gly 340 345 350 Thr Lys Leu Glu Leu Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 355 360 365 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 370 375 380 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 385 390 395 400 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 405 410 415 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 420 425 430 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 435 440 445 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 450 455 460 Lys 465 <210> 483 <211> 480 <212> PRT <213> Artificial Sequence <220> <223> ACE-29r-VH amino acid sequence <400> 483 Glu Val Lys Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Lys Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp 50 55 60 Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Ser Ile 65 70 75 80 Leu Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr 85 90 95 Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe 100 105 110 Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala Ala Ser Thr 115 120 125 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140 Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175 Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190 Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys 195 200 205 Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys 225 230 235 240 Pro Ala Pro Glu Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Gln Val 245 250 255 Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln Ser Leu 260 265 270 Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr Gly Val 275 280 285 His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu Gly Val 290 295 300 Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr Ser Arg 305 310 315 320 Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe Lys Met 325 330 335 Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala Arg Ala 340 345 350 Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly Thr Leu 355 360 365 Val Thr Val Ser Ala Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 370 375 380 Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys 385 390 395 400 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 405 410 415 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 420 425 430 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 435 440 445 Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 450 455 460 Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 465 470 475 480 <210> 484 <211> 468 <212> PRT <213> Artificial Sequence <220> <223> ACE-29r-VL amino acid sequence <400> 484 Glu Val Lys Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Lys Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp 50 55 60 Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Ser Ile 65 70 75 80 Leu Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr 85 90 95 Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe 100 105 110 Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala Ala Ser Thr 115 120 125 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140 Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175 Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190 Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys 195 200 205 Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys 225 230 235 240 Pro Ala Pro Glu Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Asp Ile 245 250 255 Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly Glu Arg 260 265 270 Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile His 275 280 285 Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile Lys Tyr 290 295 300 Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly 305 310 315 320 Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser Glu Asp 325 330 335 Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr Thr Phe 340 345 350 Gly Ala Gly Thr Lys Leu Glu Leu Lys Gly Gln Pro Arg Glu Pro Gln 355 360 365 Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val 370 375 380 Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 385 390 395 400 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 405 410 415 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 420 425 430 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 435 440 445 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 450 455 460 Ser Pro Gly Lys 465 <210> 485 <211> 369 <212> PRT <213> Artificial Sequence <220> <223> ACE-30r-VH amino acid sequence <400> 485 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Gly Gly Gly Gly Ser Glu Val Gln Leu Gln Gln Ser Gly Pro 245 250 255 Glu Leu Val Lys Pro Gly Pro Ser Met Lys Ile Ser Cys Lys Ala Ser 260 265 270 Gly Tyr Ser Phe Thr Gly Tyr Thr Met Asn Trp Val Lys Gln Ser His 275 280 285 Gly Lys Asn Leu Glu Trp Met Gly Leu Ile Asn Pro Tyr Lys Gly Val 290 295 300 Ser Thr Tyr Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Val Asp 305 310 315 320 Lys Ser Ser Ser Thr Ala Tyr Met Glu Leu Leu Ser Leu Thr Ser Glu 325 330 335 Asp Ser Ala Val Tyr Tyr Cys Ala Arg Ser Gly Tyr Tyr Gly Asp Ser 340 345 350 Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly Thr Thr Leu Thr Val Phe 355 360 365 Ser <210> 486 <211> 355 <212> PRT <213> Artificial Sequence <220> <223> ACE-30r-VL amino acid sequence <400> 486 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Thr Thr Ser 245 250 255 Ser Leu Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Arg Ala 260 265 270 Ser Gln Asp Ile Arg Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp 275 280 285 Gly Thr Val Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu His Ser Gly 290 295 300 Val Pro Ser Lys Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu 305 310 315 320 Thr Ile Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys Gln 325 330 335 Gln Gly Asn Thr Leu Pro Trp Thr Phe Ala Gly Gly Thr Lys Leu Glu 340 345 350 Ile Lys Arg 355 <210> 487 <211> 218 <212> PRT <213> Artificial Sequence <220> <223> ACE-30r-LC, ACE-31r-LC, ACE-33r-LC amino acid sequence <400> 487 Gln Leu Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly 20 25 30 Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Ala Ala Pro Lys Leu 35 40 45 Leu Ile Tyr Gly Asp Ile Asn Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Ile Ser Ala Ser Leu Ala Ile Thr Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser 85 90 95 Leu Ser Gly Gly Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Arg 100 105 110 Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln 115 120 125 Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr 130 135 140 Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser 145 150 155 160 Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr 165 170 175 Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys 180 185 190 His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro 195 200 205 Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 488 <211> 374 <212> PRT <213> Artificial Sequence <220> <223> ACE-31r-VH amino acid sequence <400> 488 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu 245 250 255 Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro Ser Met Lys Ile 260 265 270 Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr Thr Met Asn Trp 275 280 285 Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met Gly Leu Ile Asn 290 295 300 Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe Lys Asp Lys Ala 305 310 315 320 Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr Met Glu Leu Leu 325 330 335 Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg Ser Gly 340 345 350 Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly Thr 355 360 365 Thr Leu Thr Val Phe Ser 370 <210> 489 <211> 355 <212> PRT <213> Artificial Sequence <220> <223> ACE-31r-VL amino acid sequence <400> 489 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Thr Thr Ser 245 250 255 Ser Leu Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Arg Ala 260 265 270 Ser Gln Asp Ile Arg Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp 275 280 285 Gly Thr Val Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu His Ser Gly 290 295 300 Val Pro Ser Lys Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu 305 310 315 320 Thr Ile Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys Gln 325 330 335 Gln Gly Asn Thr Leu Pro Trp Thr Phe Ala Gly Gly Thr Lys Leu Glu 340 345 350 Ile Lys Arg 355 <210> 490 <211> 378 <212> PRT <213> Artificial Sequence <220> <223> ACE-32r-VH amino acid sequence <400> 490 Glu Val Lys Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Lys Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp 50 55 60 Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Ser Ile 65 70 75 80 Leu Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr 85 90 95 Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe 100 105 110 Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala Ala Ser Thr 115 120 125 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140 Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175 Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190 Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys 195 200 205 Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys 225 230 235 240 Pro Ala Pro Glu Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Gly Gly 245 250 255 Gly Gly Ser Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln 260 265 270 Pro Ser Gln Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu 275 280 285 Thr Asn Tyr Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu 290 295 300 Glu Trp Leu Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr 305 310 315 320 Pro Phe Thr Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln 325 330 335 Val Phe Phe Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr 340 345 350 Tyr Cys Ala Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp 355 360 365 Gly Gln Gly Thr Leu Val Thr Val Ser Ala 370 375 <210> 491 <211> 361 <212> PRT <213> Artificial Sequence <220> <223> ACE-32r-VL amino acid sequence <400> 491 Glu Val Lys Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Lys Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp 50 55 60 Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Ser Ile 65 70 75 80 Leu Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr 85 90 95 Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe 100 105 110 Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala Ala Ser Thr 115 120 125 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140 Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175 Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190 Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys 195 200 205 Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys 225 230 235 240 Pro Ala Pro Glu Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Asp Ile 245 250 255 Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly Glu Arg 260 265 270 Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile His 275 280 285 Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile Lys Tyr 290 295 300 Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly 305 310 315 320 Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser Glu Asp 325 330 335 Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr Thr Phe 340 345 350 Gly Ala Gly Thr Lys Leu Glu Leu Lys 355 360 <210> 492 <211> 377 <212> PRT <213> Artificial Sequence <220> <223> ACE-33r-VH amino acid sequence <400> 492 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu 245 250 255 Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro Ser 260 265 270 Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr Thr 275 280 285 Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met Gly 290 295 300 Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe Lys 305 310 315 320 Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr Met 325 330 335 Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala 340 345 350 Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp Gly 355 360 365 Gln Gly Thr Thr Leu Thr Val Phe Ser 370 375 <210> 493 <211> 358 <212> PRT <213> Artificial Sequence <220> <223> ACE-33r-VL amino acid sequence <400> 493 Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln 245 250 255 Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser 260 265 270 Cys Arg Ala Ser Gln Asp Ile Arg Asn Tyr Leu Asn Trp Tyr Gln Gln 275 280 285 Lys Pro Asp Gly Thr Val Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu 290 295 300 His Ser Gly Val Pro Ser Lys Phe Ser Gly Ser Gly Ser Gly Thr Asp 305 310 315 320 Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr 325 330 335 Phe Cys Gln Gln Gly Asn Thr Leu Pro Trp Thr Phe Ala Gly Gly Thr 340 345 350 Lys Leu Glu Ile Lys Arg 355 <210> 494 <211> 366 <212> PRT <213> Artificial Sequence <220> <223> ACE-34r-VH amino acid sequence <400> 494 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Lys 1 5 10 15 Ser Leu Lys Leu Ser Cys Glu Ala Ser Gly Phe Thr Phe Ser Gly Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Arg Gly Leu Glu Ser Val 35 40 45 Ala Tyr Ile Thr Ser Ser Ser Ile Asn Ile Lys Tyr Ala Asp Ala Val 50 55 60 Lys Gly Arg Phe Thr Val Ser Arg Asp Asn Ala Lys Asn Leu Leu Phe 65 70 75 80 Leu Gln Met Asn Ile Leu Lys Ser Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Arg Phe Asp Trp Asp Lys Asn Tyr Trp Gly Gln Gly Thr Met Val 100 105 110 Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala 115 120 125 Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu 130 135 140 Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly 145 150 155 160 Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser 165 170 175 Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu 180 185 190 Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr 195 200 205 Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr 210 215 220 Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230 235 240 Gly Gly Gly Gly Ser Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val 245 250 255 Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly 260 265 270 Thr Phe Ser Ser Tyr Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln 275 280 285 Gly Leu Glu Trp Met Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn 290 295 300 Tyr Ala Gln Lys Phe Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser 305 310 315 320 Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr 325 330 335 Ala Val Tyr Tyr Cys Ala Lys Pro Arg Asp Gly Tyr Asn Leu Val Ala 340 345 350 Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser 355 360 365 <210> 495 <211> 357 <212> PRT <213> Artificial Sequence <220> <223> ACE-34r-VL amino acid sequence <400> 495 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Lys 1 5 10 15 Ser Leu Lys Leu Ser Cys Glu Ala Ser Gly Phe Thr Phe Ser Gly Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Arg Gly Leu Glu Ser Val 35 40 45 Ala Tyr Ile Thr Ser Ser Ser Ile Asn Ile Lys Tyr Ala Asp Ala Val 50 55 60 Lys Gly Arg Phe Thr Val Ser Arg Asp Asn Ala Lys Asn Leu Leu Phe 65 70 75 80 Leu Gln Met Asn Ile Leu Lys Ser Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Arg Phe Asp Trp Asp Lys Asn Tyr Trp Gly Gln Gly Thr Met Val 100 105 110 Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala 115 120 125 Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu 130 135 140 Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly 145 150 155 160 Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser 165 170 175 Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu 180 185 190 Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr 195 200 205 Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr 210 215 220 Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230 235 240 Gly Gly Gly Gly Ser Gln Leu Val Leu Thr Gln Pro Pro Ser Val Ser 245 250 255 Gly Ala Pro Gly Gln Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser 260 265 270 Asn Ile Gly Ala Gly Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly 275 280 285 Ala Ala Pro Lys Leu Leu Ile Tyr Gly Asp Ile Asn Arg Pro Ser Gly 290 295 300 Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Ile Ser Ala Ser Leu 305 310 315 320 Ala Ile Thr Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln 325 330 335 Ser Tyr Asp Ser Ser Leu Ser Gly Gly Val Phe Gly Gly Gly Thr Lys 340 345 350 Leu Thr Val Leu Arg 355 <210> 496 <211> 213 <212> PRT <213> Artificial Sequence <220> <223> ACE-34r-LC amino acid sequence <400> 496 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Pro Ala Ser Leu Gly 1 5 10 15 Asp Arg Val Thr Ile Asn Cys Gln Ala Ser Gln Asp Ile Ser Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Tyr Thr Asn Lys Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Arg Asp Ser Ser Phe Thr Ile Ser Ser Leu Glu Ser 65 70 75 80 Glu Asp Ile Gly Ser Tyr Tyr Cys Gln Gln Tyr Tyr Asn Tyr Pro Trp 85 90 95 Thr Phe Gly Pro Gly Thr Lys Leu Glu Ile Lys Ser Val Ala Ala Pro 100 105 110 Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 115 120 125 Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135 140 Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu 145 150 155 160 Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175 Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190 Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200 205 Asn Arg Gly Glu Cys 210 <210> 497 <211> 370 <212> PRT <213> Artificial Sequence <220> <223> ACE-35r-VH amino acid sequence <400> 497 Gln Val Lys Leu Gln Gln Ser Gly Ser Glu Leu Gly Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Thr Ser Gly Tyr Ile Phe Thr Asp His 20 25 30 Tyr Ile Ser Trp Val Lys Gln Lys Pro Gly Glu Ser Leu Gln Trp Ile 35 40 45 Gly Asn Val Tyr Gly Gly Asn Gly Gly Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Gln Gly Lys Ala Thr Leu Thr Val Asp Lys Ile Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Ile Tyr Tyr Cys 85 90 95 Ala Arg Arg Pro Val Ala Thr Gly His Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Ile Gln Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp 210 215 220 Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Leu 225 230 235 240 Leu Gly Gly Pro Gly Gly Gly Gly Ser Gln Met Gln Leu Val Gln Ser 245 250 255 Gly Ala Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys 260 265 270 Ala Ser Gly Gly Thr Phe Ser Ser Tyr Ala Ile Ser Trp Val Arg Gln 275 280 285 Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Arg Ile Ile Pro Ile Leu 290 295 300 Gly Ile Ala Asn Tyr Ala Gln Lys Phe Gln Gly Arg Val Thr Ile Thr 305 310 315 320 Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg 325 330 335 Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Pro Arg Asp Gly Tyr 340 345 350 Asn Leu Val Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val 355 360 365 Ser Ser 370 <210> 498 <211> 361 <212> PRT <213> Artificial Sequence <220> <223> ACE-35r-VL amino acid sequence <400> 498 Gln Val Lys Leu Gln Gln Ser Gly Ser Glu Leu Gly Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Thr Ser Gly Tyr Ile Phe Thr Asp His 20 25 30 Tyr Ile Ser Trp Val Lys Gln Lys Pro Gly Glu Ser Leu Gln Trp Ile 35 40 45 Gly Asn Val Tyr Gly Gly Asn Gly Gly Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Gln Gly Lys Ala Thr Leu Thr Val Asp Lys Ile Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Ile Tyr Tyr Cys 85 90 95 Ala Arg Arg Pro Val Ala Thr Gly His Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Ile Gln Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp 210 215 220 Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Leu 225 230 235 240 Leu Gly Gly Pro Gly Gly Gly Gly Ser Gln Leu Val Leu Thr Gln Pro 245 250 255 Pro Ser Val Ser Gly Ala Pro Gly Gln Arg Val Thr Ile Ser Cys Thr 260 265 270 Gly Ser Ser Ser Asn Ile Gly Ala Gly Tyr Asp Val His Trp Tyr Gln 275 280 285 Gln Leu Pro Gly Ala Ala Pro Lys Leu Leu Ile Tyr Gly Asp Ile Asn 290 295 300 Arg Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Ile 305 310 315 320 Ser Ala Ser Leu Ala Ile Thr Gly Leu Gln Ala Glu Asp Glu Ala Asp 325 330 335 Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser Leu Ser Gly Gly Val Phe Gly 340 345 350 Gly Gly Thr Lys Leu Thr Val Leu Arg 355 360 <210> 499 <211> 213 <212> PRT <213> Artificial Sequence <220> <223> ACE-35r-LC amino acid sequence <400> 499 Asp Ile Val Leu Thr Gln Thr Pro Ala Thr Leu Ser Leu Ile Pro Gly 1 5 10 15 Glu Arg Val Thr Met Thr Cys Lys Thr Ser Gln Asn Ile Gly Thr Ile 20 25 30 Leu His Trp Tyr His Gln Lys Pro Lys Glu Ala Pro Arg Ala Leu Ile 35 40 45 Lys Tyr Ala Ser Gln Ser Ile Pro Gly Ile Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Glu Thr Asp Phe Thr Leu Ser Ile Asn Asn Leu Glu Pro 65 70 75 80 Asp Asp Ile Gly Ile Tyr Tyr Cys Gln Gln Ser Arg Ser Trp Pro Val 85 90 95 Thr Phe Gly Pro Gly Thr Lys Leu Glu Ile Lys Ser Val Ala Ala Pro 100 105 110 Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 115 120 125 Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135 140 Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu 145 150 155 160 Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175 Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190 Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200 205 Asn Arg Gly Glu Cys 210 <210> 500 <211> 368 <212> PRT <213> Artificial Sequence <220> <223> ACE-36r-VH amino acid sequence <400> 500 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Thr Phe Ile Ser Tyr Asp Gly Asn Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys 85 90 95 Ala Arg Thr Gly Trp Leu Gly Pro Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205 Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215 220 His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Gly Gly Gly Gly Ser Gln Met Gln Leu Val Gln Ser Gly Ala 245 250 255 Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser 260 265 270 Gly Gly Thr Phe Ser Ser Tyr Ala Ile Ser Trp Val Arg Gln Ala Pro 275 280 285 Gly Gln Gly Leu Glu Trp Met Gly Arg Ile Ile Pro Ile Leu Gly Ile 290 295 300 Ala Asn Tyr Ala Gln Lys Phe Gln Gly Arg Val Thr Ile Thr Ala Asp 305 310 315 320 Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu 325 330 335 Asp Thr Ala Val Tyr Tyr Cys Ala Lys Pro Arg Asp Gly Tyr Asn Leu 340 345 350 Val Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser 355 360 365 <210> 501 <211> 351 <212> PRT <213> Artificial Sequence <220> <223> ACE-36r-VL amino acid sequence <400> 501 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Thr Phe Ile Ser Tyr Asp Gly Asn Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys 85 90 95 Ala Arg Thr Gly Trp Leu Gly Pro Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205 Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215 220 His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gln Leu Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln 245 250 255 Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly 260 265 270 Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Ala Ala Pro Lys Leu 275 280 285 Leu Ile Tyr Gly Asp Ile Asn Arg Pro Ser Gly Val Pro Asp Arg Phe 290 295 300 Ser Gly Ser Lys Ser Gly Ile Ser Ala Ser Leu Ala Ile Thr Gly Leu 305 310 315 320 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser 325 330 335 Leu Ser Gly Gly Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 340 345 350 <210> 502 <211> 215 <212> PRT <213> Artificial Sequence <220> <223> ACE-36r-LC, ACE-37r-LC amino acid sequence <400> 502 Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Gly Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Phe Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro 85 90 95 Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Ser Val Ala 100 105 110 Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser 115 120 125 Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu 130 135 140 Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser 145 150 155 160 Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu 165 170 175 Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 180 185 190 Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys 195 200 205 Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 503 <211> 368 <212> PRT <213> Artificial Sequence <220> <223> ACE-37r-VH amino acid sequence <400> 503 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Thr Phe Ile Ser Tyr Asp Gly Asn Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys 85 90 95 Ala Arg Thr Gly Trp Leu Gly Pro Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205 Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215 220 His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Gln Pro Gly Ala 245 250 255 Glu Leu Val Lys Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser 260 265 270 Gly Tyr Thr Phe Thr Ser Tyr Asn Met His Trp Val Lys Gln Thr Pro 275 280 285 Gly Arg Gly Leu Glu Trp Ile Gly Ala Ile Tyr Pro Gly Asn Gly Asp 290 295 300 Thr Ser Tyr Asn Gln Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp 305 310 315 320 Lys Ser Ser Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu 325 330 335 Asp Ser Ala Val Tyr Tyr Cys Ala Arg Ser Thr Tyr Tyr Gly Gly Asp 340 345 350 Trp Tyr Phe Asn Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ala 355 360 365 <210> 504 <211> 346 <212> PRT <213> Artificial Sequence <220> <223> ACE-37r-VL amino acid sequence <400> 504 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Thr Phe Ile Ser Tyr Asp Gly Asn Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys 85 90 95 Ala Arg Thr Gly Trp Leu Gly Pro Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205 Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215 220 His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly 245 250 255 Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Ile 260 265 270 His Trp Phe Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr 275 280 285 Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser 290 295 300 Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Val Glu Ala Glu 305 310 315 320 Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Thr Ser Asn Pro Pro Thr 325 330 335 Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 340 345 <210> 505 <211> 477 <212> PRT <213> Artificial Sequence <220> <223> ACE-38r-VH amino acid sequence <400> 505 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro 225 230 235 240 Glu Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Gln Val Gln Leu Lys 245 250 255 Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln Ser Leu Ser Ile Thr 260 265 270 Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr Gly Val His Trp Val 275 280 285 Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu Gly Val Ile Trp Ser 290 295 300 Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr Ser Arg Leu Ser Ile 305 310 315 320 Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe Lys Met Asn Ser Leu 325 330 335 Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala Arg Ala Leu Thr Tyr 340 345 350 Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val 355 360 365 Ser Ala Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Ser Pro Pro Ser 370 375 380 Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Arg Cys His Val Lys 385 390 395 400 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 405 410 415 Pro Glu Asn Asn Tyr Lys Thr Thr Lys Pro Val Leu Asp Ser Asp Gly 420 425 430 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln 435 440 445 Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 450 455 460 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 465 470 475 <210> 506 <211> 358 <212> PRT <213> Artificial Sequence <220> <223> ACE-38r-VL amino acid sequence <400> 506 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro 225 230 235 240 Glu Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Asp Ile Leu Leu Thr 245 250 255 Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly Glu Arg Val Ser Phe 260 265 270 Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile His Trp Tyr Gln 275 280 285 Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile Lys Tyr Ala Ser Glu 290 295 300 Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr 305 310 315 320 Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser Glu Asp Ile Ala Asp 325 330 335 Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr Thr Phe Gly Ala Gly 340 345 350 Thr Lys Leu Glu Leu Lys 355 <210> 507 <211> 370 <212> PRT <213> Artificial Sequence <220> <223> ACE-39r-VH amino acid sequence <400> 507 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro 225 230 235 240 Glu Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Gln Val Gln Leu Lys 245 250 255 Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln Ser Leu Ser Ile Thr 260 265 270 Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr Gly Val His Trp Val 275 280 285 Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu Gly Val Ile Trp Ser 290 295 300 Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr Ser Arg Leu Ser Ile 305 310 315 320 Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe Lys Met Asn Ser Leu 325 330 335 Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala Arg Ala Leu Thr Tyr 340 345 350 Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val 355 360 365 Ser Ala 370 <210> 508 <211> 465 <212> PRT <213> Artificial Sequence <220> <223> ACE-39r-VL amino acid sequence <400> 508 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro 225 230 235 240 Glu Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Asp Ile Leu Leu Thr 245 250 255 Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly Glu Arg Val Ser Phe 260 265 270 Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile His Trp Tyr Gln 275 280 285 Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile Lys Tyr Ala Ser Glu 290 295 300 Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr 305 310 315 320 Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser Glu Asp Ile Ala Asp 325 330 335 Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr Thr Phe Gly Ala Gly 340 345 350 Thr Lys Leu Glu Leu Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 355 360 365 Ser Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Arg 370 375 380 Cys His Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 385 390 395 400 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Lys Pro Val Leu 405 410 415 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 420 425 430 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 435 440 445 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 450 455 460 Lys 465 <210> 509 <211> 477 <212> PRT <213> Artificial Sequence <220> <223> ACE-40r-VH amino acid sequence <400> 509 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro 225 230 235 240 Glu Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Gln Val Gln Leu Lys 245 250 255 Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln Ser Leu Ser Ile Thr 260 265 270 Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr Gly Val His Trp Val 275 280 285 Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu Gly Val Ile Trp Ser 290 295 300 Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr Ser Arg Leu Ser Ile 305 310 315 320 Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe Lys Met Asn Ser Leu 325 330 335 Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala Arg Ala Leu Thr Tyr 340 345 350 Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val 355 360 365 Ser Ala Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Ser Pro Pro Ser 370 375 380 Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Arg Cys His Val Lys 385 390 395 400 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 405 410 415 Pro Glu Asn Asn Tyr Lys Thr Thr Lys Pro Val Leu Asp Ser Asp Gly 420 425 430 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln 435 440 445 Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 450 455 460 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 465 470 475 <210> 510 <211> 465 <212> PRT <213> Artificial Sequence <220> <223> ACE-40r-VL amino acid sequence <400> 510 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Pro 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Cys Pro Ala Pro 225 230 235 240 Glu Leu Leu Gly Gly Pro Gly Gly Gly Gly Ser Asp Ile Leu Leu Thr 245 250 255 Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly Glu Arg Val Ser Phe 260 265 270 Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile His Trp Tyr Gln 275 280 285 Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile Lys Tyr Ala Ser Glu 290 295 300 Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr 305 310 315 320 Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser Glu Asp Ile Ala Asp 325 330 335 Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr Thr Phe Gly Ala Gly 340 345 350 Thr Lys Leu Glu Leu Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 355 360 365 Ser Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Arg 370 375 380 Cys His Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 385 390 395 400 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Lys Pro Val Leu 405 410 415 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 420 425 430 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 435 440 445 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 450 455 460 Lys 465

Claims (29)

항체의 Fc 영역이 항체의 가변영역으로 치환된 다중 특이적 융합 단백질.A multispecific fusion protein in which the Fc region of the antibody is substituted with the variable region of the antibody. 제1항에 있어서,
상기 융합 단백질은 하기 구조식 (I) 및 (II)를 포함하는 것인, 다중 특이적 융합 단백질:
N'-A-L1-X-C' (I); 및
N'-B-L1-Y-C' (II)
이때, 상기 구조식 (I) 및 (II)에 있어서,
상기 N'은 융합 단백질의 N-말단이고,
상기 C'은 융합 단백질의 C-말단이며,
상기 A 및 B는 각각 제1 항원에 특이적으로 결합하며,
상기 L1은 Cys을 적어도 하나 포함하는 펩타이드 링커이며,
X는 항체 가변 중쇄(VH) 영역 또는 항체 가변 경쇄(VL) 영역이며,
Y는 항체 가변 경쇄(VL) 영역 또는 항체 가변 중쇄(VH) 영역이며,
상기 X 및 Y는 제2 항원에 특이적으로 결합하는 항체 가변 영역을 형성한다.
The method of claim 1,
The fusion protein is a multispecific fusion protein comprising the following structural formulas (I) and (II):
N'-A-L1-XC'(I); And
N'-B-L1-YC' (II)
At this time, in the above structural formulas (I) and (II),
Wherein N'is the N-terminus of the fusion protein,
C'is the C-terminus of the fusion protein,
Each of A and B specifically binds to a first antigen,
The L1 is a peptide linker containing at least one Cys,
X is an antibody variable heavy chain (VH) region or an antibody variable light chain (VL) region,
Y is an antibody variable light chain (VL) region or an antibody variable heavy chain (VH) region,
The X and Y form an antibody variable region that specifically binds to the second antigen.
제2항에 있어서,
상기 A 및 B는 각각 항체 Fab 영역으로서,
(i) 항체 가변 중쇄(VH) 영역 및 항체 CH1 영역을 포함하는 제1 부분; 및
(ii) 항체 가변 경쇄(VL) 영역 및 항체 경쇄 불변 영역(CL)을 포함하는 제2 부분으로 구성된 것인, 다중 특이적 융합 단백질.
The method of claim 2,
Each of A and B is an antibody Fab region,
(i) a first portion comprising an antibody variable heavy chain (VH) region and an antibody CH1 region; And
(ii) A multispecific fusion protein consisting of a second portion comprising an antibody variable light chain (VL) region and an antibody light chain constant region (CL).
제3항에 있어서,
상기 구조식 (I)은 하기 구조식 (I') 및 (I'')을 포함하는 것인, 다중 특이적 융합 단백질.
N'-A'-L1-X-C' (I'); 및
N'-A''-C' (I'')
이때, 상기 구조식 (I') 및 (I'')에 있어서,
A'은 항체의 중쇄 영역으로서 가변영역 및 CH1 영역을 포함하거나, 또는 항체의 경쇄 영역이며;
A''은 항체의 경쇄 영역이거나, 또는 항체의 중쇄 영역으로서 가변영역 및 CH1 영역을 포함하며;
이때, A' 및 A''은 결합하여 항체의 가변 영역을 형성하고, 이때, 상기 가변 영역은 제1 항원에 특이적으로 결합하며,
N', L1, X 및 C'는 제2항에서 정의된 것과 동일하다.
The method of claim 3,
The structural formula (I) is a multi-specific fusion protein comprising the following structural formulas (I') and (I'').
N'-A'-L1-XC'(I'); And
N'-A''-C'(I'')
At this time, in the above structural formulas (I') and (I''),
A'is a heavy chain region of an antibody and includes a variable region and a CH1 region, or is a light chain region of an antibody;
A'' is the light chain region of the antibody, or as the heavy chain region of the antibody comprises a variable region and a CH1 region;
At this time, A'and A'' bind to form a variable region of the antibody, wherein the variable region specifically binds to the first antigen,
N', L1, X and C'are the same as defined in claim 2.
제3항에 있어서,
상기 구조식 (II)는 하기 구조식 (II') 및 (II'')을 포함하는 것인, 다중 특이적 융합 단백질.
N'-B'-L1-Y-C' (II'); 및
N'-B''-C' (II'')
이때, 상기 구조식 (II') 및 (II'')에 있어서,
B'은 항체의 중쇄 영역으로서 가변영역 및 CH1 영역을 포함하거나, 또는 항체의 경쇄 영역이며;
B''은 항체의 경쇄 영역이거나, 또는 항체의 중쇄 영역으로서 가변영역 및 CH1 영역을 포함하며;
이때, B' 및 B''은 결합하여 항체의 가변 영역을 형성하고, 이때, 상기 가변 영역은 제1 항원에 특이적으로 결합하며,
N', L1, Y 및 C'는 제2항에서 정의된 것과 동일하다.
The method of claim 3,
The structural formula (II) is a multi-specific fusion protein comprising the following structural formulas (II') and (II").
N'-B'-L1-YC'(II'); And
N'-B''-C'(II'')
At this time, in the above structural formulas (II') and (II''),
B'is a heavy chain region of an antibody and includes a variable region and a CH1 region, or is a light chain region of an antibody;
B'' is the light chain region of the antibody, or as the heavy chain region of the antibody comprises a variable region and a CH1 region;
At this time, B'and B'' bind to form a variable region of the antibody, wherein the variable region specifically binds to the first antigen,
N', L1, Y and C'are the same as defined in claim 2.
제1항에 있어서,
상기 융합 단백질은 하기 구조식 (III) 및 (IV)를 포함하는 것인, 다중 특이적 융합 단백질:
N'-X-L2-A-C' (III); 및
N'-Y-L2-B-C' (IV)
이때, 상기 구조식 (III) 및 (IV)에 있어서,
상기 N'은 융합 단백질의 N-말단이고,
상기 C'은 융합 단백질의 C-말단이며,
상기 A 및 B는 각각 제1 항원에 특이적으로 결합하며,
상기 L2는 Cys을 적어도 하나 포함하는 펩타이드 링커이며,
X는 항체 가변 중쇄(VH) 영역 또는 항체 가변 경쇄(VL) 영역이며,
Y는 항체 가변 경쇄(VL) 영역 또는 항체 가변 중쇄(VH) 영역이며,
상기 X 및 Y는 제2 항원에 특이적으로 결합하는 항체 가변 영역을 형성한다.
The method of claim 1,
The fusion protein is a multispecific fusion protein comprising the following structural formulas (III) and (IV):
N'-X-L2-AC'(III); And
N'-Y-L2-BC' (IV)
In this case, in the structural formulas (III) and (IV),
Wherein N'is the N-terminus of the fusion protein,
C'is the C-terminus of the fusion protein,
Each of A and B specifically binds to a first antigen,
The L2 is a peptide linker containing at least one Cys,
X is an antibody variable heavy chain (VH) region or an antibody variable light chain (VL) region,
Y is an antibody variable light chain (VL) region or an antibody variable heavy chain (VH) region,
The X and Y form an antibody variable region that specifically binds to the second antigen.
제2항에 있어서,
상기 L1은 면역글로불린 유래의 힌지 영역을 포함하는 것인, 다중 특이적 융합 단백질.
The method of claim 2,
The L1 is a multispecific fusion protein containing an immunoglobulin-derived hinge region.
제2항에 있어서,
상기 L1은 2개 또는 3개의 Cys을 포함하는 것인, 다중 특이적 융합 단백질.
The method of claim 2,
The L1 is a multispecific fusion protein containing 2 or 3 Cys.
제7항에 있어서,
상기 L1은 하기 구조식 (V)를 갖는 것인, 다중 특이적 융합단백질:
(L1')n-힌지-(L1'')m (V)
이때, 상기 L1' 및 L1''은 각각 1 내지 15의 아미노산으로 구성된 링커이며,
n 및 m은 0 또는 1의 정수이며,
힌지는 면역글로불린 유래의 힌지 영역이다.
The method of claim 7,
The L1 is a multispecific fusion protein having the following structural formula (V):
(L1')n-hinge-(L1'')m (V)
At this time, the L1' and L1'' are each a linker consisting of 1 to 15 amino acids,
n and m are integers of 0 or 1,
The hinge is an immunoglobulin-derived hinge region.
제2항에 있어서,
상기 제1 항원 및 제2 항원은 각각 PD-L1, EGFR, BCMA, CD22, CD25, CD30, CD33, CD37, CD38, CD52, CD56, CD123, cMET, DLL3, GD2, Nectin-4, RANKL, SLAMF7, TROP2, Claudin 18.2, TNFR, TNF, CD3, HER2, CD20, CD19, CTLA-4, VEGFR, VEGF, NCAM1, ICAM-1, ICAM-2, CEACAM6, Carcinoembryonic antigen(CEA), CA-125, Alphafetoprotein (AFP), MUC-1, Epithelial tumor antigen (ETA), Melanoma-associated antigen (MAGE), Immature laminin receptor, TAG-72, HPV E6/E7, BING-4, Calcium-activated chloride channel 2, Cyclin-B1, 9D7, Ep-CAM, EphA3, Mesothelin, SAP-1, Survivin 및 바이러스 유래 항원으로 이루어진 그룹에서 선택되는 어느 하나인, 다중 특이적 융합 단백질.
The method of claim 2,
The first and second antigens are PD-L1, EGFR, BCMA, CD22, CD25, CD30, CD33, CD37, CD38, CD52, CD56, CD123, cMET, DLL3, GD2, Nectin-4, RANKL, SLAMF7, respectively. TROP2, Claudin 18.2, TNFR, TNF, CD3, HER2, CD20, CD19, CTLA-4, VEGFR, VEGF, NCAM1, ICAM-1, ICAM-2, CEACAM6, Carcinoembryonic antigen (CEA), CA-125, Alphafetoprotein (AFP ), MUC-1, Epithelial tumor antigen (ETA), Melanoma-associated antigen (MAGE), Immature laminin receptor, TAG-72, HPV E6/E7, BING-4, Calcium-activated chloride channel 2, Cyclin-B1, 9D7 , Ep-CAM, EphA3, Mesothelin, SAP-1, Survivin, and any one selected from the group consisting of virus-derived antigens, a multispecific fusion protein.
제2항에 있어서,
상기 제1 항원은 암 항원인, 다중 특이적 융합 단백질.
The method of claim 2,
The first antigen is a cancer antigen, a multispecific fusion protein.
제2항에 있어서,
상기 제2 항원은 면역 세포 표면에 존재하는 단백질인, 다중 특이적 융합 단백질.
The method of claim 2,
The second antigen is a protein present on the surface of immune cells, a multispecific fusion protein.
제2항에 있어서,
상기 구조식에서 A 및 B가 동일한 항원을 인식하거나, 또는 서로 다른 항원을 인식하는 것인, 다중 특이적 융합 단백질.
The method of claim 2,
In the above structural formula, A and B recognize the same antigen, or recognize different antigens, multi-specific fusion protein.
제13항에 있어서,
상기 A 또는 B는 하기의 그룹에서 선택되는 어느 하나의 가변영역을 포함하는, 다중 특이적 융합 단백질:
PD-L1:
1) 서열번호 5(VH-CDR1), 서열번호 6(VH-CDR2) 및 서열번호 7(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 9(VL-CDR1), 서열번호 10(VL-CDR2) 및 서열번호 11(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
2) 서열번호 159(VH-CDR1), 서열번호 160(VH-CDR2) 및 서열번호 161(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 171(VL-CDR1), 서열번호 172(VL-CDR2) 및 서열번호 173(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
3) 서열번호 159(VH-CDR1), 서열번호 160(VH-CDR2) 및 서열번호 161(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 314(VL-CDR1), 서열번호 315(VL-CDR2) 및 서열번호 316(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
4) 서열번호 330(VH-CDR1), 서열번호 331(VH-CDR2) 및 서열번호 332(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 334(VL-CDR1), 서열번호 335(VL-CDR2) 및 서열번호 336(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
HER2:
5) 서열번호 118(VH-CDR1), 서열번호 119(VH-CDR2) 및 서열번호 120(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 121(VL-CDR1), 서열번호 122(VL-CDR2) 및 서열번호 123(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
6) 서열번호 276(VH-CDR1), 서열번호 277(VH-CDR2) 및 서열번호 278(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 288(VL-CDR1), 서열번호 289(VL-CDR2) 및 서열번호 290(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
CD19:
7) 서열번호 140(VH-CDR1), 서열번호 141(VH-CDR2) 및 서열번호 142(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 152(VL-CDR1), 서열번호 153(VL-CDR2) 및 서열번호 154(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
8) 서열번호 62(VH-CDR1), 서열번호 63(VH-CDR2) 및 서열번호 64(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 66(VL-CDR1), 서열번호 67(VL-CDR2) 및 서열번호 68(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
CD20:
9) 서열번호 223(VH-CDR1), 서열번호 224(VH-CDR2) 및 서열번호 225(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 227(VL-CDR1), 서열번호 228(VL-CDR2) 및 서열번호 229(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
10) 서열번호 436(VH-CDR1), 서열번호 437(VH-CDR2) 및 서열번호 438(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 441(VL-CDR1), 서열번호 442(VL-CDR2) 및 서열번호 443(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
EGFR:
11) 서열번호 234(VH-CDR1), 서열번호 235(VH-CDR2) 및 서열번호 236(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 238(VL-CDR1), 서열번호 239(VL-CDR2) 및 서열번호 240(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
12) 서열번호 245(VH-CDR1), 서열번호 246(VH-CDR2) 및 서열번호 247(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 249(VL-CDR1), 서열번호 250(VL-CDR2) 및 서열번호 251(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
13) 서열번호 256(VH-CDR1), 서열번호 257(VH-CDR2) 및 서열번호 258(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 260(VL-CDR1), 서열번호 261(VL-CDR2) 및 서열번호 262(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
14) 서열번호 234(VH-CDR1), 서열번호 235(VH-CDR2) 및 서열번호 236(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 238(VL-CDR1), 서열번호 239(VL-CDR2) 및 서열번호 240(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
CD3:
15) 서열번호 326(VH-CDR1), 서열번호 327(VH-CDR2) 및 서열번호 328(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 338(VL-CDR1), 서열번호 339(VL-CDR2) 및 서열번호 340(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
16) 서열번호 330(VH-CDR1), 서열번호 331(VH-CDR2) 및 서열번호 332(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 334(VL-CDR1), 서열번호 335(VL-CDR2) 및 서열번호 336(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
17) 서열번호 163(VH-CDR1), 서열번호 271(VH-CDR2) 및 서열번호 165(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 167(VL-CDR1), 서열번호 168(VL-CDR2) 및 서열번호 169(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
18) 서열번호 396(VH-CDR1), 서열번호 397(VH-CDR2) 및 서열번호 398(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 402(VL-CDR1), 서열번호 403(VL-CDR2) 및 서열번호 404(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
19) 서열번호 144(VH-CDR1), 서열번호 145(VH-CDR2) 및 서열번호 146(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 148(VL-CDR1), 서열번호 149(VL-CDR2) 및 서열번호 410(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
20) 서열번호 144(VH-CDR1), 서열번호 145(VH-CDR2) 및 서열번호 146(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 148(VL-CDR1), 서열번호 149(VL-CDR2) 및 서열번호 150(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
21) 서열번호 70(VH-CDR1), 서열번호 71(VH-CDR2) 및 서열번호 72(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 74(VL-CDR1), 서열번호 75(VL-CDR2) 및 서열번호 76(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
22) 서열번호 78(VH-CDR1), 서열번호 79(VH-CDR2) 및 서열번호 80(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 82(VL-CDR1), 서열번호 83(VL-CDR2) 및 서열번호 84(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
23) 서열번호 295(VH-CDR1), 서열번호 296(VH-CDR2) 및 서열번호 297(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 299(VL-CDR1), 서열번호 300(VL-CDR2) 및 서열번호 301(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
24) 서열번호 78(VH-CDR1), 서열번호 79(VH-CDR2) 및 서열번호 80(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 82(VL-CDR1), 서열번호 83(VL-CDR2) 및 서열번호 87(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
25) 서열번호 163(VH-CDR1), 서열번호 271(VH-CDR2) 및 서열번호 165(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 167(VL-CDR1), 서열번호 168(VL-CDR2) 및 서열번호 169(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
26) 서열번호 177(VH-CDR1), 서열번호 178(VH-CDR2) 및 서열번호 179(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 181(VL-CDR1), 서열번호 182(VL-CDR2) 및 서열번호 183(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
27) 서열번호 187(VH-CDR1), 서열번호 188(VH-CDR2) 및 서열번호 189(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 191(VL-CDR1), 서열번호 192(VL-CDR2) 및 서열번호 193(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
28) 서열번호 177(VH-CDR1), 서열번호 178(VH-CDR2) 및 서열번호 179(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 181(VL-CDR1), 서열번호 182(VL-CDR2) 및 서열번호 207(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
29) 서열번호 177(VH-CDR1), 서열번호 178(VH-CDR2) 및 서열번호 211(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 181(VL-CDR1), 서열번호 182(VL-CDR2) 및 서열번호 207(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
30) 서열번호 306(VH-CDR1), 서열번호 307(VH-CDR2) 및 서열번호 308(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 310(VL-CDR1), 서열번호 311(VL-CDR2) 및 서열번호 312(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
31) 서열번호 349(VH-CDR1), 서열번호 350(VH-CDR2) 및 서열번호 351(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 353(VL-CDR1), 서열번호 354(VL-CDR2) 및 서열번호 355(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
32) 서열번호 359(VH-CDR1), 서열번호 360(VH-CDR2) 및 서열번호 361(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 363(VL-CDR1), 서열번호 364(VL-CDR2) 및 서열번호 365(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
33) 서열번호 197(VH-CDR1), 서열번호 198(VH-CDR2) 및 서열번호 199(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 201(VL-CDR1), 서열번호 202(VL-CDR2) 및 서열번호 203(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
TNF:
34) 서열번호 124(VH-CDR1), 서열번호 125(VH-CDR2) 및 서열번호 126(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 127(VL-CDR1), 서열번호 128(VL-CDR2) 및 서열번호 129(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
35) 서열번호 280(VH-CDR1), 서열번호 281(VH-CDR2) 및 서열번호 282(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 284(VL-CDR1), 서열번호 285(VL-CDR2) 및 서열번호 286(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
36) 서열번호 276(VH-CDR1), 서열번호 277(VH-CDR2) 및 서열번호 278(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 288(VL-CDR1), 서열번호 289(VL-CDR2) 및 서열번호 290(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역; 및
CTLA-4:
37) 서열번호 369(VH-CDR1), 서열번호 370(VH-CDR2) 및 서열번호 371(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 373(VL-CDR1), 서열번호 374(VL-CDR2) 및 서열번호 375(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역.
The method of claim 13,
A or B is a multi-specific fusion protein comprising any one variable region selected from the following group:
PD-L1:
1) VH region comprising the amino acid sequence of SEQ ID NO: 5 (VH-CDR1), SEQ ID NO: 6 (VH-CDR2) and SEQ ID NO: 7 (VH-CDR3), and SEQ ID NO: 9 (VL-CDR1), SEQ ID NO: 10 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 11 (VL-CDR3);
2) a VH region comprising the amino acid sequence of SEQ ID NO: 159 (VH-CDR1), SEQ ID NO: 160 (VH-CDR2) and SEQ ID NO: 161 (VH-CDR3), and SEQ ID NO: 171 (VL-CDR1), SEQ ID NO: 172 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 173 (VL-CDR3);
3) VH region comprising the amino acid sequence of SEQ ID NO: 159 (VH-CDR1), SEQ ID NO: 160 (VH-CDR2) and SEQ ID NO: 161 (VH-CDR3), and SEQ ID NO: 314 (VL-CDR1), SEQ ID NO: 315 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 316 (VL-CDR3);
4) VH region comprising the amino acid sequence of SEQ ID NO: 330 (VH-CDR1), SEQ ID NO: 331 (VH-CDR2) and SEQ ID NO: 332 (VH-CDR3), and SEQ ID NO: 334 (VL-CDR1), SEQ ID NO: 335 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 336 (VL-CDR3);
HER2:
5) VH region comprising the amino acid sequence of SEQ ID NO: 118 (VH-CDR1), SEQ ID NO: 119 (VH-CDR2) and SEQ ID NO: 120 (VH-CDR3), and SEQ ID NO: 121 (VL-CDR1), SEQ ID NO: 122 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 123 (VL-CDR3);
6) VH region comprising the amino acid sequence of SEQ ID NO: 276 (VH-CDR1), SEQ ID NO: 277 (VH-CDR2) and SEQ ID NO: 278 (VH-CDR3), and SEQ ID NO: 288 (VL-CDR1), SEQ ID NO: 289 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 290 (VL-CDR3);
CD19:
7) VH region comprising the amino acid sequence of SEQ ID NO: 140 (VH-CDR1), SEQ ID NO: 141 (VH-CDR2) and SEQ ID NO: 142 (VH-CDR3), and SEQ ID NO: 152 (VL-CDR1), SEQ ID NO: 153 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 154 (VL-CDR3);
8) VH region comprising the amino acid sequence of SEQ ID NO: 62 (VH-CDR1), SEQ ID NO: 63 (VH-CDR2) and SEQ ID NO: 64 (VH-CDR3), and SEQ ID NO: 66 (VL-CDR1), SEQ ID NO: 67 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 68 (VL-CDR3);
CD20:
9) VH region comprising the amino acid sequence of SEQ ID NO: 223 (VH-CDR1), SEQ ID NO: 224 (VH-CDR2) and SEQ ID NO: 225 (VH-CDR3), and SEQ ID NO: 227 (VL-CDR1), SEQ ID NO: 228 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 229 (VL-CDR3);
10) VH region comprising the amino acid sequence of SEQ ID NO: 436 (VH-CDR1), SEQ ID NO: 437 (VH-CDR2) and SEQ ID NO: 438 (VH-CDR3), and SEQ ID NO: 441 (VL-CDR1), SEQ ID NO: 442 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 443 (VL-CDR3);
EGFR:
11) VH region comprising the amino acid sequence of SEQ ID NO: 234 (VH-CDR1), SEQ ID NO: 235 (VH-CDR2) and SEQ ID NO: 236 (VH-CDR3), and SEQ ID NO: 238 (VL-CDR1), SEQ ID NO: 239 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 240 (VL-CDR3);
12) VH region comprising the amino acid sequence of SEQ ID NO: 245 (VH-CDR1), SEQ ID NO: 246 (VH-CDR2) and SEQ ID NO: 247 (VH-CDR3), and SEQ ID NO: 249 (VL-CDR1), SEQ ID NO: 250 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 251 (VL-CDR3);
13) VH region comprising the amino acid sequence of SEQ ID NO: 256 (VH-CDR1), SEQ ID NO: 257 (VH-CDR2) and SEQ ID NO: 258 (VH-CDR3), and SEQ ID NO: 260 (VL-CDR1), SEQ ID NO: 261 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 262 (VL-CDR3);
14) VH region comprising the amino acid sequence of SEQ ID NO: 234 (VH-CDR1), SEQ ID NO: 235 (VH-CDR2) and SEQ ID NO: 236 (VH-CDR3), and SEQ ID NO: 238 (VL-CDR1), SEQ ID NO: 239 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 240 (VL-CDR3);
CD3:
15) VH region comprising the amino acid sequence of SEQ ID NO: 326 (VH-CDR1), SEQ ID NO: 327 (VH-CDR2) and SEQ ID NO: 328 (VH-CDR3), and SEQ ID NO: 338 (VL-CDR1), SEQ ID NO: 339 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 340 (VL-CDR3);
16) VH region comprising the amino acid sequence of SEQ ID NO: 330 (VH-CDR1), SEQ ID NO: 331 (VH-CDR2) and SEQ ID NO: 332 (VH-CDR3), and SEQ ID NO: 334 (VL-CDR1), SEQ ID NO: 335 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 336 (VL-CDR3);
17) VH region comprising the amino acid sequence of SEQ ID NO: 163 (VH-CDR1), SEQ ID NO: 271 (VH-CDR2) and SEQ ID NO: 165 (VH-CDR3), and SEQ ID NO: 167 (VL-CDR1), SEQ ID NO: 168 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 169 (VL-CDR3);
18) VH region comprising the amino acid sequence of SEQ ID NO: 396 (VH-CDR1), SEQ ID NO: 397 (VH-CDR2) and SEQ ID NO: 398 (VH-CDR3), and SEQ ID NO: 402 (VL-CDR1), SEQ ID NO: 403 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 404 (VL-CDR3);
19) VH region comprising the amino acid sequence of SEQ ID NO: 144 (VH-CDR1), SEQ ID NO: 145 (VH-CDR2) and SEQ ID NO: 146 (VH-CDR3), and SEQ ID NO: 148 (VL-CDR1), SEQ ID NO: 149 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 410 (VL-CDR3);
20) VH region comprising the amino acid sequence of SEQ ID NO: 144 (VH-CDR1), SEQ ID NO: 145 (VH-CDR2) and SEQ ID NO: 146 (VH-CDR3), and SEQ ID NO: 148 (VL-CDR1), SEQ ID NO: 149 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 150 (VL-CDR3);
21) VH region comprising the amino acid sequence of SEQ ID NO: 70 (VH-CDR1), SEQ ID NO: 71 (VH-CDR2) and SEQ ID NO: 72 (VH-CDR3), and SEQ ID NO: 74 (VL-CDR1), SEQ ID NO: 75 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 76 (VL-CDR3);
22) VH region comprising the amino acid sequence of SEQ ID NO: 78 (VH-CDR1), SEQ ID NO: 79 (VH-CDR2) and SEQ ID NO: 80 (VH-CDR3), and SEQ ID NO: 82 (VL-CDR1), SEQ ID NO: 83 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 84 (VL-CDR3);
23) VH region comprising the amino acid sequence of SEQ ID NO: 295 (VH-CDR1), SEQ ID NO: 296 (VH-CDR2) and SEQ ID NO: 297 (VH-CDR3), and SEQ ID NO: 299 (VL-CDR1), SEQ ID NO: 300 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 301 (VL-CDR3);
24) VH region comprising the amino acid sequence of SEQ ID NO: 78 (VH-CDR1), SEQ ID NO: 79 (VH-CDR2) and SEQ ID NO: 80 (VH-CDR3), and SEQ ID NO: 82 (VL-CDR1), SEQ ID NO: 83 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 87 (VL-CDR3);
25) VH region comprising the amino acid sequence of SEQ ID NO: 163 (VH-CDR1), SEQ ID NO: 271 (VH-CDR2) and SEQ ID NO: 165 (VH-CDR3), and SEQ ID NO: 167 (VL-CDR1), SEQ ID NO: 168 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 169 (VL-CDR3);
26) VH region comprising the amino acid sequence of SEQ ID NO: 177 (VH-CDR1), SEQ ID NO: 178 (VH-CDR2) and SEQ ID NO: 179 (VH-CDR3), and SEQ ID NO: 181 (VL-CDR1), SEQ ID NO: 182 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 183 (VL-CDR3);
27) VH region comprising the amino acid sequence of SEQ ID NO: 187 (VH-CDR1), SEQ ID NO: 188 (VH-CDR2) and SEQ ID NO: 189 (VH-CDR3), and SEQ ID NO: 191 (VL-CDR1), SEQ ID NO: 192 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 193 (VL-CDR3);
28) VH region comprising the amino acid sequence of SEQ ID NO: 177 (VH-CDR1), SEQ ID NO: 178 (VH-CDR2) and SEQ ID NO: 179 (VH-CDR3), and SEQ ID NO: 181 (VL-CDR1), SEQ ID NO: 182 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 207 (VL-CDR3);
29) VH region comprising the amino acid sequence of SEQ ID NO: 177 (VH-CDR1), SEQ ID NO: 178 (VH-CDR2) and SEQ ID NO: 211 (VH-CDR3), and SEQ ID NO: 181 (VL-CDR1), SEQ ID NO: 182 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 207 (VL-CDR3);
30) VH region comprising the amino acid sequence of SEQ ID NO: 306 (VH-CDR1), SEQ ID NO: 307 (VH-CDR2) and SEQ ID NO: 308 (VH-CDR3), and SEQ ID NO: 310 (VL-CDR1), SEQ ID NO: 311 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 312 (VL-CDR3);
31) VH region comprising the amino acid sequence of SEQ ID NO: 349 (VH-CDR1), SEQ ID NO: 350 (VH-CDR2) and SEQ ID NO: 351 (VH-CDR3), and SEQ ID NO: 353 (VL-CDR1), SEQ ID NO: 354 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 355 (VL-CDR3);
32) VH region comprising the amino acid sequence of SEQ ID NO: 359 (VH-CDR1), SEQ ID NO: 360 (VH-CDR2) and SEQ ID NO: 361 (VH-CDR3), and SEQ ID NO: 363 (VL-CDR1), SEQ ID NO: 364 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 365 (VL-CDR3);
33) VH region comprising the amino acid sequence of SEQ ID NO: 197 (VH-CDR1), SEQ ID NO: 198 (VH-CDR2) and SEQ ID NO: 199 (VH-CDR3), and SEQ ID NO: 201 (VL-CDR1), SEQ ID NO: 202 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 203 (VL-CDR3);
TNF:
34) VH region comprising the amino acid sequence of SEQ ID NO: 124 (VH-CDR1), SEQ ID NO: 125 (VH-CDR2) and SEQ ID NO: 126 (VH-CDR3), and SEQ ID NO: 127 (VL-CDR1), SEQ ID NO: 128 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 129 (VL-CDR3);
35) VH region comprising the amino acid sequence of SEQ ID NO: 280 (VH-CDR1), SEQ ID NO: 281 (VH-CDR2) and SEQ ID NO: 282 (VH-CDR3), and SEQ ID NO: 284 (VL-CDR1), SEQ ID NO: 285 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 286 (VL-CDR3);
36) VH region comprising the amino acid sequence of SEQ ID NO: 276 (VH-CDR1), SEQ ID NO: 277 (VH-CDR2) and SEQ ID NO: 278 (VH-CDR3), and SEQ ID NO: 288 (VL-CDR1), SEQ ID NO: 289 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 290 (VL-CDR3); And
CTLA-4:
37) VH region comprising the amino acid sequence of SEQ ID NO: 369 (VH-CDR1), SEQ ID NO: 370 (VH-CDR2) and SEQ ID NO: 371 (VH-CDR3), and SEQ ID NO: 373 (VL-CDR1), SEQ ID NO: 374 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 375 (VL-CDR3).
제14항에 있어서,
상기 A 또는 B는 하기의 그룹에서 선택되는 어느 하나의 가변영역을 포함하는, 다중 특이적 융합 단백질:
PD-L1:
1) 서열번호 4의 중쇄 가변 영역(VH) 및 서열번호 8의 경쇄 가변 영역(VL);
2) 서열번호 158의 중쇄 가변 영역(VH) 및 서열번호 170의 경쇄 가변 영역(VL);
3) 서열번호 158의 중쇄 가변 영역(VH) 및 서열번호 313의 경쇄 가변 영역(VL);
4) 서열번호 329의 중쇄 가변 영역(VH) 및 서열번호 333의 경쇄 가변 영역(VL);
5) 서열번호 329의 중쇄 가변 영역(VH) 및 서열번호 376의 경쇄 가변 영역(VL);
HER2:
6) 서열번호 51의 중쇄 가변 영역(VH) 및 서열번호 52의 경쇄 가변 영역(VL);
7) 서열번호 275의 중쇄 가변 영역(VH) 및 서열번호 287의 경쇄 가변 영역(VL);
CD19:
8) 서열번호 139의 중쇄 가변 영역(VH) 및 서열번호 151의 경쇄 가변 영역(VL);
9) 서열번호 61의 중쇄 가변 영역(VH) 및 서열번호 65의 경쇄 가변 영역(VL);
CD20:
10) 서열번호 222의 중쇄 가변 영역(VH) 및 서열번호 226의 경쇄 가변 영역(VL);
11) 서열번호 435의 중쇄 가변 영역(VH) 및 서열번호 440의 경쇄 가변 영역(VL);
EGFR:
12) 서열번호 233의 중쇄 가변 영역(VH) 및 서열번호 237의 경쇄 가변 영역(VL);
13) 서열번호 244의 중쇄 가변 영역(VH) 및 서열번호 248의 경쇄 가변 영역(VL);
14) 서열번호 255의 중쇄 가변 영역(VH) 및 서열번호 259의 경쇄 가변 영역(VL);
CD3:
15) 서열번호 325의 중쇄 가변 영역(VH) 및 서열번호 337의 경쇄 가변 영역(VL);
16) 서열번호 329의 중쇄 가변 영역(VH) 및 서열번호 376의 경쇄 가변 영역(VL);
17) 서열번호 162의 중쇄 가변 영역(VH) 및 서열번호 166의 경쇄 가변 영역(VL);
18) 서열번호 395의 중쇄 가변 영역(VH) 및 서열번호 401의 경쇄 가변 영역(VL);
19) 서열번호 406의 중쇄 가변 영역(VH) 및 서열번호 409의 경쇄 가변 영역(VL);
20) 서열번호 143의 중쇄 가변 영역(VH) 및 서열번호 147의 경쇄 가변 영역(VL);
21) 서열번호 69의 중쇄 가변 영역(VH) 및 서열번호 73의 경쇄 가변 영역(VL);
22) 서열번호 77의 중쇄 가변 영역(VH) 및 서열번호 81의 경쇄 가변 영역(VL);
23) 서열번호 294의 중쇄 가변 영역(VH) 및 서열번호 298의 경쇄 가변 영역(VL);
24) 서열번호 85의 중쇄 가변 영역(VH) 및 서열번호 86의 경쇄 가변 영역(VL);
25) 서열번호 176의 중쇄 가변 영역(VH) 및 서열번호 180의 경쇄 가변 영역(VL);
26) 서열번호 186의 중쇄 가변 영역(VH) 및 서열번호 190의 경쇄 가변 영역(VL);
27) 서열번호 176의 중쇄 가변 영역(VH) 및 서열번호 206의 경쇄 가변 영역(VL);
28) 서열번호 210의 중쇄 가변 영역(VH) 및 서열번호 212의 경쇄 가변 영역(VL);
29) 서열번호 215의 중쇄 가변 영역(VH) 및 서열번호 216의 경쇄 가변 영역(VL);
30) 서열번호 305의 중쇄 가변 영역(VH) 및 서열번호 309의 경쇄 가변 영역(VL);
31) 서열번호 348의 중쇄 가변 영역(VH) 및 서열번호 352의 경쇄 가변 영역(VL);
32) 서열번호 358의 중쇄 가변 영역(VH) 및 서열번호 362의 경쇄 가변 영역(VL);
33) 서열번호 196의 중쇄 가변 영역(VH) 및 서열번호 200의 경쇄 가변 영역(VL);
TNF:
34) 서열번호 53의 중쇄 가변 영역(VH) 및 서열번호 54의 경쇄 가변 영역(VL);
35) 서열번호 279의 중쇄 가변 영역(VH) 및 서열번호 283의 경쇄 가변 영역(VL);
36) 서열번호 275의 중쇄 가변 영역(VH) 및 서열번호 287의 경쇄 가변 영역(VL); 및
CTLA-4:
37) 서열번호 368의 중쇄 가변 영역(VH) 및 서열번호 372의 경쇄 가변 영역(VL).
The method of claim 14,
A or B is a multi-specific fusion protein comprising any one variable region selected from the following group:
PD-L1:
1) the heavy chain variable region of SEQ ID NO: 4 (VH) and the light chain variable region of SEQ ID NO: 8 (VL);
2) the heavy chain variable region of SEQ ID NO: 158 (VH) and the light chain variable region of SEQ ID NO: 170 (VL);
3) the heavy chain variable region of SEQ ID NO: 158 (VH) and the light chain variable region of SEQ ID NO: 313 (VL);
4) the heavy chain variable region of SEQ ID NO: 329 (VH) and the light chain variable region of SEQ ID NO: 333 (VL);
5) the heavy chain variable region of SEQ ID NO: 329 (VH) and the light chain variable region of SEQ ID NO: 376 (VL);
HER2:
6) the heavy chain variable region of SEQ ID NO: 51 (VH) and the light chain variable region of SEQ ID NO: 52 (VL);
7) the heavy chain variable region of SEQ ID NO: 275 (VH) and the light chain variable region of SEQ ID NO: 287 (VL);
CD19:
8) the heavy chain variable region of SEQ ID NO: 139 (VH) and the light chain variable region of SEQ ID NO: 151 (VL);
9) the heavy chain variable region of SEQ ID NO: 61 (VH) and the light chain variable region of SEQ ID NO: 65 (VL);
CD20:
10) the heavy chain variable region of SEQ ID NO: 222 (VH) and the light chain variable region of SEQ ID NO: 226 (VL);
11) the heavy chain variable region of SEQ ID NO: 435 (VH) and the light chain variable region of SEQ ID NO: 440 (VL);
EGFR:
12) the heavy chain variable region of SEQ ID NO: 233 (VH) and the light chain variable region of SEQ ID NO: 237 (VL);
13) the heavy chain variable region of SEQ ID NO: 244 (VH) and the light chain variable region of SEQ ID NO: 248 (VL);
14) the heavy chain variable region of SEQ ID NO: 255 (VH) and the light chain variable region of SEQ ID NO: 259 (VL);
CD3:
15) the heavy chain variable region of SEQ ID NO: 325 (VH) and the light chain variable region of SEQ ID NO: 337 (VL);
16) the heavy chain variable region of SEQ ID NO: 329 (VH) and the light chain variable region of SEQ ID NO: 376 (VL);
17) the heavy chain variable region of SEQ ID NO: 162 (VH) and the light chain variable region of SEQ ID NO: 166 (VL);
18) the heavy chain variable region of SEQ ID NO: 395 (VH) and the light chain variable region of SEQ ID NO: 401 (VL);
19) the heavy chain variable region of SEQ ID NO: 406 (VH) and the light chain variable region of SEQ ID NO: 409 (VL);
20) the heavy chain variable region of SEQ ID NO: 143 (VH) and the light chain variable region of SEQ ID NO: 147 (VL);
21) the heavy chain variable region of SEQ ID NO: 69 (VH) and the light chain variable region of SEQ ID NO: 73 (VL);
22) the heavy chain variable region of SEQ ID NO: 77 (VH) and the light chain variable region of SEQ ID NO: 81 (VL);
23) the heavy chain variable region of SEQ ID NO: 294 (VH) and the light chain variable region of SEQ ID NO: 298 (VL);
24) the heavy chain variable region of SEQ ID NO: 85 (VH) and the light chain variable region of SEQ ID NO: 86 (VL);
25) the heavy chain variable region of SEQ ID NO: 176 (VH) and the light chain variable region of SEQ ID NO: 180 (VL);
26) the heavy chain variable region of SEQ ID NO: 186 (VH) and the light chain variable region of SEQ ID NO: 190 (VL);
27) the heavy chain variable region of SEQ ID NO: 176 (VH) and the light chain variable region of SEQ ID NO: 206 (VL);
28) the heavy chain variable region of SEQ ID NO: 210 (VH) and the light chain variable region of SEQ ID NO: 212 (VL);
29) the heavy chain variable region of SEQ ID NO: 215 (VH) and the light chain variable region of SEQ ID NO: 216 (VL);
30) the heavy chain variable region of SEQ ID NO: 305 (VH) and the light chain variable region of SEQ ID NO: 309 (VL);
31) the heavy chain variable region of SEQ ID NO: 348 (VH) and the light chain variable region of SEQ ID NO: 352 (VL);
32) the heavy chain variable region of SEQ ID NO: 358 (VH) and the light chain variable region of SEQ ID NO: 362 (VL);
33) the heavy chain variable region of SEQ ID NO: 196 (VH) and the light chain variable region of SEQ ID NO: 200 (VL);
TNF:
34) the heavy chain variable region of SEQ ID NO: 53 (VH) and the light chain variable region of SEQ ID NO: 54 (VL);
35) the heavy chain variable region of SEQ ID NO: 279 (VH) and the light chain variable region of SEQ ID NO: 283 (VL);
36) the heavy chain variable region of SEQ ID NO: 275 (VH) and the light chain variable region of SEQ ID NO: 287 (VL); And
CTLA-4:
37) The heavy chain variable region of SEQ ID NO: 368 (VH) and the light chain variable region of SEQ ID NO: 372 (VL).
제2항에 있어서,
상기 X 또는 Y는 하기의 그룹에서 선택되는 어느 하나의 가변 영역 중의 가변 중쇄 영역 또는 가변 경쇄 영역을 포함하는, 다중 특이적 융합 단백질:
PD-L1:
1) 서열번호 5(VH-CDR1), 서열번호 6(VH-CDR2) 및 서열번호 7(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 9(VL-CDR1), 서열번호 10(VL-CDR2) 및 서열번호 11(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
2) 서열번호 159(VH-CDR1), 서열번호 160(VH-CDR2) 및 서열번호 161(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 171(VL-CDR1), 서열번호 172(VL-CDR2) 및 서열번호 173(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
3) 서열번호 159(VH-CDR1), 서열번호 160(VH-CDR2) 및 서열번호 161(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 314(VL-CDR1), 서열번호 315(VL-CDR2) 및 서열번호 316(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
4) 서열번호 330(VH-CDR1), 서열번호 331(VH-CDR2) 및 서열번호 332(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 334(VL-CDR1), 서열번호 335(VL-CDR2) 및 서열번호 336(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
HER2:
5) 서열번호 118(VH-CDR1), 서열번호 119(VH-CDR2) 및 서열번호 120(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 121(VL-CDR1), 서열번호 122(VL-CDR2) 및 서열번호 123(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
6) 서열번호 276(VH-CDR1), 서열번호 277(VH-CDR2) 및 서열번호 278(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 288(VL-CDR1), 서열번호 289(VL-CDR2) 및 서열번호 290(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
CD19:
7) 서열번호 140(VH-CDR1), 서열번호 141(VH-CDR2) 및 서열번호 142(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 152(VL-CDR1), 서열번호 153(VL-CDR2) 및 서열번호 154(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
8) 서열번호 62(VH-CDR1), 서열번호 63(VH-CDR2) 및 서열번호 64(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 66(VL-CDR1), 서열번호 67(VL-CDR2) 및 서열번호 68(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
CD20:
9) 서열번호 223(VH-CDR1), 서열번호 224(VH-CDR2) 및 서열번호 225(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 227(VL-CDR1), 서열번호 228(VL-CDR2) 및 서열번호 229(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
10) 서열번호 436(VH-CDR1), 서열번호 437(VH-CDR2) 및 서열번호 438(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 441(VL-CDR1), 서열번호 442(VL-CDR2) 및 서열번호 443(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
EGFR:
11) 서열번호 234(VH-CDR1), 서열번호 235(VH-CDR2) 및 서열번호 236(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 238(VL-CDR1), 서열번호 239(VL-CDR2) 및 서열번호 240(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
12) 서열번호 245(VH-CDR1), 서열번호 246(VH-CDR2) 및 서열번호 247(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 249(VL-CDR1), 서열번호 250(VL-CDR2) 및 서열번호 251(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
13) 서열번호 256(VH-CDR1), 서열번호 257(VH-CDR2) 및 서열번호 258(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 260(VL-CDR1), 서열번호 261(VL-CDR2) 및 서열번호 262(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
14) 서열번호 234(VH-CDR1), 서열번호 235(VH-CDR2) 및 서열번호 236(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 238(VL-CDR1), 서열번호 239(VL-CDR2) 및 서열번호 240(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
CD3:
15) 서열번호 326(VH-CDR1), 서열번호 327(VH-CDR2) 및 서열번호 328(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 338(VL-CDR1), 서열번호 339(VL-CDR2) 및 서열번호 340(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
16) 서열번호 330(VH-CDR1), 서열번호 331(VH-CDR2) 및 서열번호 332(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 334(VL-CDR1), 서열번호 335(VL-CDR2) 및 서열번호 336(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
17) 서열번호 163(VH-CDR1), 서열번호 271(VH-CDR2) 및 서열번호 165(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 167(VL-CDR1), 서열번호 168(VL-CDR2) 및 서열번호 169(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
18) 서열번호 396(VH-CDR1), 서열번호 397(VH-CDR2) 및 서열번호 398(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 402(VL-CDR1), 서열번호 403(VL-CDR2) 및 서열번호 404(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
19) 서열번호 144(VH-CDR1), 서열번호 145(VH-CDR2) 및 서열번호 146(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 148(VL-CDR1), 서열번호 149(VL-CDR2) 및 서열번호 410(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
20) 서열번호 144(VH-CDR1), 서열번호 145(VH-CDR2) 및 서열번호 146(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 148(VL-CDR1), 서열번호 149(VL-CDR2) 및 서열번호 150(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
21) 서열번호 70(VH-CDR1), 서열번호 71(VH-CDR2) 및 서열번호 72(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 74(VL-CDR1), 서열번호 75(VL-CDR2) 및 서열번호 76(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
22) 서열번호 78(VH-CDR1), 서열번호 79(VH-CDR2) 및 서열번호 80(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 82(VL-CDR1), 서열번호 83(VL-CDR2) 및 서열번호 84(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
23) 서열번호 295(VH-CDR1), 서열번호 296(VH-CDR2) 및 서열번호 297(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 299(VL-CDR1), 서열번호 300(VL-CDR2) 및 서열번호 301(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
24) 서열번호 78(VH-CDR1), 서열번호 79(VH-CDR2) 및 서열번호 80(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 82(VL-CDR1), 서열번호 83(VL-CDR2) 및 서열번호 87(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
25) 서열번호 163(VH-CDR1), 서열번호 271(VH-CDR2) 및 서열번호 165(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 167(VL-CDR1), 서열번호 168(VL-CDR2) 및 서열번호 169(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
26) 서열번호 177(VH-CDR1), 서열번호 178(VH-CDR2) 및 서열번호 179(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 181(VL-CDR1), 서열번호 182(VL-CDR2) 및 서열번호 183(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
27) 서열번호 187(VH-CDR1), 서열번호 188(VH-CDR2) 및 서열번호 189(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 191(VL-CDR1), 서열번호 192(VL-CDR2) 및 서열번호 193(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
28) 서열번호 177(VH-CDR1), 서열번호 178(VH-CDR2) 및 서열번호 179(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 181(VL-CDR1), 서열번호 182(VL-CDR2) 및 서열번호 207(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
29) 서열번호 177(VH-CDR1), 서열번호 178(VH-CDR2) 및 서열번호 211(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 181(VL-CDR1), 서열번호 182(VL-CDR2) 및 서열번호 207(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
30) 서열번호 306(VH-CDR1), 서열번호 307(VH-CDR2) 및 서열번호 308(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 310(VL-CDR1), 서열번호 311(VL-CDR2) 및 서열번호 312(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
31) 서열번호 349(VH-CDR1), 서열번호 350(VH-CDR2) 및 서열번호 351(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 353(VL-CDR1), 서열번호 354(VL-CDR2) 및 서열번호 355(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
32) 서열번호 359(VH-CDR1), 서열번호 360(VH-CDR2) 및 서열번호 361(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 363(VL-CDR1), 서열번호 364(VL-CDR2) 및 서열번호 365(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
33) 서열번호 197(VH-CDR1), 서열번호 198(VH-CDR2) 및 서열번호 199(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 201(VL-CDR1), 서열번호 202(VL-CDR2) 및 서열번호 203(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
TNF:
34) 서열번호 124(VH-CDR1), 서열번호 125(VH-CDR2) 및 서열번호 126(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 127(VL-CDR1), 서열번호 128(VL-CDR2) 및 서열번호 129(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
35) 서열번호 280(VH-CDR1), 서열번호 281(VH-CDR2) 및 서열번호 282(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 284(VL-CDR1), 서열번호 285(VL-CDR2) 및 서열번호 286(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역;
36) 서열번호 276(VH-CDR1), 서열번호 277(VH-CDR2) 및 서열번호 278(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 288(VL-CDR1), 서열번호 289(VL-CDR2) 및 서열번호 290(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역; 및
CTLA-4:
37) 서열번호 369(VH-CDR1), 서열번호 370(VH-CDR2) 및 서열번호 371(VH-CDR3)의 아미노산 서열을 포함하는 VH 영역, 및 서열번호 373(VL-CDR1), 서열번호 374(VL-CDR2) 및 서열번호 375(VL-CDR3)의 아미노산 서열을 포함하는 VL 영역.
The method of claim 2,
The X or Y is a multi-specific fusion protein comprising a variable heavy chain region or a variable light chain region in any one of the variable regions selected from the following group:
PD-L1:
1) VH region comprising the amino acid sequence of SEQ ID NO: 5 (VH-CDR1), SEQ ID NO: 6 (VH-CDR2) and SEQ ID NO: 7 (VH-CDR3), and SEQ ID NO: 9 (VL-CDR1), SEQ ID NO: 10 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 11 (VL-CDR3);
2) a VH region comprising the amino acid sequence of SEQ ID NO: 159 (VH-CDR1), SEQ ID NO: 160 (VH-CDR2) and SEQ ID NO: 161 (VH-CDR3), and SEQ ID NO: 171 (VL-CDR1), SEQ ID NO: 172 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 173 (VL-CDR3);
3) VH region comprising the amino acid sequence of SEQ ID NO: 159 (VH-CDR1), SEQ ID NO: 160 (VH-CDR2) and SEQ ID NO: 161 (VH-CDR3), and SEQ ID NO: 314 (VL-CDR1), SEQ ID NO: 315 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 316 (VL-CDR3);
4) VH region comprising the amino acid sequence of SEQ ID NO: 330 (VH-CDR1), SEQ ID NO: 331 (VH-CDR2) and SEQ ID NO: 332 (VH-CDR3), and SEQ ID NO: 334 (VL-CDR1), SEQ ID NO: 335 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 336 (VL-CDR3);
HER2:
5) VH region comprising the amino acid sequence of SEQ ID NO: 118 (VH-CDR1), SEQ ID NO: 119 (VH-CDR2) and SEQ ID NO: 120 (VH-CDR3), and SEQ ID NO: 121 (VL-CDR1), SEQ ID NO: 122 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 123 (VL-CDR3);
6) VH region comprising the amino acid sequence of SEQ ID NO: 276 (VH-CDR1), SEQ ID NO: 277 (VH-CDR2) and SEQ ID NO: 278 (VH-CDR3), and SEQ ID NO: 288 (VL-CDR1), SEQ ID NO: 289 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 290 (VL-CDR3);
CD19:
7) VH region comprising the amino acid sequence of SEQ ID NO: 140 (VH-CDR1), SEQ ID NO: 141 (VH-CDR2) and SEQ ID NO: 142 (VH-CDR3), and SEQ ID NO: 152 (VL-CDR1), SEQ ID NO: 153 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 154 (VL-CDR3);
8) VH region comprising the amino acid sequence of SEQ ID NO: 62 (VH-CDR1), SEQ ID NO: 63 (VH-CDR2) and SEQ ID NO: 64 (VH-CDR3), and SEQ ID NO: 66 (VL-CDR1), SEQ ID NO: 67 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 68 (VL-CDR3);
CD20:
9) VH region comprising the amino acid sequence of SEQ ID NO: 223 (VH-CDR1), SEQ ID NO: 224 (VH-CDR2) and SEQ ID NO: 225 (VH-CDR3), and SEQ ID NO: 227 (VL-CDR1), SEQ ID NO: 228 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 229 (VL-CDR3);
10) VH region comprising the amino acid sequence of SEQ ID NO: 436 (VH-CDR1), SEQ ID NO: 437 (VH-CDR2) and SEQ ID NO: 438 (VH-CDR3), and SEQ ID NO: 441 (VL-CDR1), SEQ ID NO: 442 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 443 (VL-CDR3);
EGFR:
11) VH region comprising the amino acid sequence of SEQ ID NO: 234 (VH-CDR1), SEQ ID NO: 235 (VH-CDR2) and SEQ ID NO: 236 (VH-CDR3), and SEQ ID NO: 238 (VL-CDR1), SEQ ID NO: 239 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 240 (VL-CDR3);
12) VH region comprising the amino acid sequence of SEQ ID NO: 245 (VH-CDR1), SEQ ID NO: 246 (VH-CDR2) and SEQ ID NO: 247 (VH-CDR3), and SEQ ID NO: 249 (VL-CDR1), SEQ ID NO: 250 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 251 (VL-CDR3);
13) VH region comprising the amino acid sequence of SEQ ID NO: 256 (VH-CDR1), SEQ ID NO: 257 (VH-CDR2) and SEQ ID NO: 258 (VH-CDR3), and SEQ ID NO: 260 (VL-CDR1), SEQ ID NO: 261 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 262 (VL-CDR3);
14) VH region comprising the amino acid sequence of SEQ ID NO: 234 (VH-CDR1), SEQ ID NO: 235 (VH-CDR2) and SEQ ID NO: 236 (VH-CDR3), and SEQ ID NO: 238 (VL-CDR1), SEQ ID NO: 239 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 240 (VL-CDR3);
CD3:
15) VH region comprising the amino acid sequence of SEQ ID NO: 326 (VH-CDR1), SEQ ID NO: 327 (VH-CDR2) and SEQ ID NO: 328 (VH-CDR3), and SEQ ID NO: 338 (VL-CDR1), SEQ ID NO: 339 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 340 (VL-CDR3);
16) VH region comprising the amino acid sequence of SEQ ID NO: 330 (VH-CDR1), SEQ ID NO: 331 (VH-CDR2) and SEQ ID NO: 332 (VH-CDR3), and SEQ ID NO: 334 (VL-CDR1), SEQ ID NO: 335 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 336 (VL-CDR3);
17) VH region comprising the amino acid sequence of SEQ ID NO: 163 (VH-CDR1), SEQ ID NO: 271 (VH-CDR2) and SEQ ID NO: 165 (VH-CDR3), and SEQ ID NO: 167 (VL-CDR1), SEQ ID NO: 168 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 169 (VL-CDR3);
18) VH region comprising the amino acid sequence of SEQ ID NO: 396 (VH-CDR1), SEQ ID NO: 397 (VH-CDR2) and SEQ ID NO: 398 (VH-CDR3), and SEQ ID NO: 402 (VL-CDR1), SEQ ID NO: 403 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 404 (VL-CDR3);
19) VH region comprising the amino acid sequence of SEQ ID NO: 144 (VH-CDR1), SEQ ID NO: 145 (VH-CDR2) and SEQ ID NO: 146 (VH-CDR3), and SEQ ID NO: 148 (VL-CDR1), SEQ ID NO: 149 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 410 (VL-CDR3);
20) VH region comprising the amino acid sequence of SEQ ID NO: 144 (VH-CDR1), SEQ ID NO: 145 (VH-CDR2) and SEQ ID NO: 146 (VH-CDR3), and SEQ ID NO: 148 (VL-CDR1), SEQ ID NO: 149 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 150 (VL-CDR3);
21) VH region comprising the amino acid sequence of SEQ ID NO: 70 (VH-CDR1), SEQ ID NO: 71 (VH-CDR2) and SEQ ID NO: 72 (VH-CDR3), and SEQ ID NO: 74 (VL-CDR1), SEQ ID NO: 75 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 76 (VL-CDR3);
22) VH region comprising the amino acid sequence of SEQ ID NO: 78 (VH-CDR1), SEQ ID NO: 79 (VH-CDR2) and SEQ ID NO: 80 (VH-CDR3), and SEQ ID NO: 82 (VL-CDR1), SEQ ID NO: 83 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 84 (VL-CDR3);
23) VH region comprising the amino acid sequence of SEQ ID NO: 295 (VH-CDR1), SEQ ID NO: 296 (VH-CDR2) and SEQ ID NO: 297 (VH-CDR3), and SEQ ID NO: 299 (VL-CDR1), SEQ ID NO: 300 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 301 (VL-CDR3);
24) VH region comprising the amino acid sequence of SEQ ID NO: 78 (VH-CDR1), SEQ ID NO: 79 (VH-CDR2) and SEQ ID NO: 80 (VH-CDR3), and SEQ ID NO: 82 (VL-CDR1), SEQ ID NO: 83 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 87 (VL-CDR3);
25) VH region comprising the amino acid sequence of SEQ ID NO: 163 (VH-CDR1), SEQ ID NO: 271 (VH-CDR2) and SEQ ID NO: 165 (VH-CDR3), and SEQ ID NO: 167 (VL-CDR1), SEQ ID NO: 168 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 169 (VL-CDR3);
26) VH region comprising the amino acid sequence of SEQ ID NO: 177 (VH-CDR1), SEQ ID NO: 178 (VH-CDR2) and SEQ ID NO: 179 (VH-CDR3), and SEQ ID NO: 181 (VL-CDR1), SEQ ID NO: 182 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 183 (VL-CDR3);
27) VH region comprising the amino acid sequence of SEQ ID NO: 187 (VH-CDR1), SEQ ID NO: 188 (VH-CDR2) and SEQ ID NO: 189 (VH-CDR3), and SEQ ID NO: 191 (VL-CDR1), SEQ ID NO: 192 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 193 (VL-CDR3);
28) VH region comprising the amino acid sequence of SEQ ID NO: 177 (VH-CDR1), SEQ ID NO: 178 (VH-CDR2) and SEQ ID NO: 179 (VH-CDR3), and SEQ ID NO: 181 (VL-CDR1), SEQ ID NO: 182 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 207 (VL-CDR3);
29) VH region comprising the amino acid sequence of SEQ ID NO: 177 (VH-CDR1), SEQ ID NO: 178 (VH-CDR2) and SEQ ID NO: 211 (VH-CDR3), and SEQ ID NO: 181 (VL-CDR1), SEQ ID NO: 182 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 207 (VL-CDR3);
30) VH region comprising the amino acid sequence of SEQ ID NO: 306 (VH-CDR1), SEQ ID NO: 307 (VH-CDR2) and SEQ ID NO: 308 (VH-CDR3), and SEQ ID NO: 310 (VL-CDR1), SEQ ID NO: 311 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 312 (VL-CDR3);
31) VH region comprising the amino acid sequence of SEQ ID NO: 349 (VH-CDR1), SEQ ID NO: 350 (VH-CDR2) and SEQ ID NO: 351 (VH-CDR3), and SEQ ID NO: 353 (VL-CDR1), SEQ ID NO: 354 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 355 (VL-CDR3);
32) VH region comprising the amino acid sequence of SEQ ID NO: 359 (VH-CDR1), SEQ ID NO: 360 (VH-CDR2) and SEQ ID NO: 361 (VH-CDR3), and SEQ ID NO: 363 (VL-CDR1), SEQ ID NO: 364 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 365 (VL-CDR3);
33) VH region comprising the amino acid sequence of SEQ ID NO: 197 (VH-CDR1), SEQ ID NO: 198 (VH-CDR2) and SEQ ID NO: 199 (VH-CDR3), and SEQ ID NO: 201 (VL-CDR1), SEQ ID NO: 202 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 203 (VL-CDR3);
TNF:
34) VH region comprising the amino acid sequence of SEQ ID NO: 124 (VH-CDR1), SEQ ID NO: 125 (VH-CDR2) and SEQ ID NO: 126 (VH-CDR3), and SEQ ID NO: 127 (VL-CDR1), SEQ ID NO: 128 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 129 (VL-CDR3);
35) VH region comprising the amino acid sequence of SEQ ID NO: 280 (VH-CDR1), SEQ ID NO: 281 (VH-CDR2) and SEQ ID NO: 282 (VH-CDR3), and SEQ ID NO: 284 (VL-CDR1), SEQ ID NO: 285 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 286 (VL-CDR3);
36) VH region comprising the amino acid sequence of SEQ ID NO: 276 (VH-CDR1), SEQ ID NO: 277 (VH-CDR2) and SEQ ID NO: 278 (VH-CDR3), and SEQ ID NO: 288 (VL-CDR1), SEQ ID NO: 289 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 290 (VL-CDR3); And
CTLA-4:
37) VH region comprising the amino acid sequence of SEQ ID NO: 369 (VH-CDR1), SEQ ID NO: 370 (VH-CDR2) and SEQ ID NO: 371 (VH-CDR3), and SEQ ID NO: 373 (VL-CDR1), SEQ ID NO: 374 (VL-CDR2) and a VL region comprising the amino acid sequence of SEQ ID NO: 375 (VL-CDR3).
제2항에 있어서,
상기 X 또는 Y는 하기의 그룹에서 선택되는 어느 하나의 가변 영역 중의 가변 중쇄 영역 또는 가변 경쇄 영역인, 다중 특이적 융합 단백질:
PD-L1:
1) 서열번호 4의 중쇄 가변 영역(VH) 및 서열번호 8의 경쇄 가변 영역(VL);
2) 서열번호 158의 중쇄 가변 영역(VH) 및 서열번호 170의 경쇄 가변 영역(VL);
3) 서열번호 158의 중쇄 가변 영역(VH) 및 서열번호 313의 경쇄 가변 영역(VL);
4) 서열번호 329의 중쇄 가변 영역(VH) 및 서열번호 333의 경쇄 가변 영역(VL);
5) 서열번호 329의 중쇄 가변 영역(VH) 및 서열번호 376의 경쇄 가변 영역(VL);
HER2:
6) 서열번호 51의 중쇄 가변 영역(VH) 및 서열번호 52의 경쇄 가변 영역(VL);
7) 서열번호 275의 중쇄 가변 영역(VH) 및 서열번호 287의 경쇄 가변 영역(VL);
CD19:
8) 서열번호 139의 중쇄 가변 영역(VH) 및 서열번호 151의 경쇄 가변 영역(VL);
9) 서열번호 61의 중쇄 가변 영역(VH) 및 서열번호 65의 경쇄 가변 영역(VL);
CD20:
10) 서열번호 222의 중쇄 가변 영역(VH) 및 서열번호 226의 경쇄 가변 영역(VL);
11) 서열번호 435의 중쇄 가변 영역(VH) 및 서열번호 440의 경쇄 가변 영역(VL);
EGFR:
12) 서열번호 233의 중쇄 가변 영역(VH) 및 서열번호 237의 경쇄 가변 영역(VL);
13) 서열번호 244의 중쇄 가변 영역(VH) 및 서열번호 248의 경쇄 가변 영역(VL);
14) 서열번호 255의 중쇄 가변 영역(VH) 및 서열번호 259의 경쇄 가변 영역(VL);
CD3:
15) 서열번호 325의 중쇄 가변 영역(VH) 및 서열번호 337의 경쇄 가변 영역(VL);
16) 서열번호 329의 중쇄 가변 영역(VH) 및 서열번호 376의 경쇄 가변 영역(VL);
17) 서열번호 162의 중쇄 가변 영역(VH) 및 서열번호 166의 경쇄 가변 영역(VL);
18) 서열번호 395의 중쇄 가변 영역(VH) 및 서열번호 401의 경쇄 가변 영역(VL);
19) 서열번호 406의 중쇄 가변 영역(VH) 및 서열번호 409의 경쇄 가변 영역(VL);
20) 서열번호 143의 중쇄 가변 영역(VH) 및 서열번호 147의 경쇄 가변 영역(VL);
21) 서열번호 69의 중쇄 가변 영역(VH) 및 서열번호 73의 경쇄 가변 영역(VL);
22) 서열번호 77의 중쇄 가변 영역(VH) 및 서열번호 81의 경쇄 가변 영역(VL);
23) 서열번호 294의 중쇄 가변 영역(VH) 및 서열번호 298의 경쇄 가변 영역(VL);
24) 서열번호 85의 중쇄 가변 영역(VH) 및 서열번호 86의 경쇄 가변 영역(VL);
25) 서열번호 176의 중쇄 가변 영역(VH) 및 서열번호 180의 경쇄 가변 영역(VL);
26) 서열번호 186의 중쇄 가변 영역(VH) 및 서열번호 190의 경쇄 가변 영역(VL);
27) 서열번호 176의 중쇄 가변 영역(VH) 및 서열번호 206의 경쇄 가변 영역(VL);
28) 서열번호 210의 중쇄 가변 영역(VH) 및 서열번호 212의 경쇄 가변 영역(VL);
29) 서열번호 215의 중쇄 가변 영역(VH) 및 서열번호 216의 경쇄 가변 영역(VL);
30) 서열번호 305의 중쇄 가변 영역(VH) 및 서열번호 309의 경쇄 가변 영역(VL);
31) 서열번호 348의 중쇄 가변 영역(VH) 및 서열번호 352의 경쇄 가변 영역(VL);
32) 서열번호 358의 중쇄 가변 영역(VH) 및 서열번호 362의 경쇄 가변 영역(VL);
33) 서열번호 196의 중쇄 가변 영역(VH) 및 서열번호 200의 경쇄 가변 영역(VL);
TNF:
34) 서열번호 53의 중쇄 가변 영역(VH) 및 서열번호 54의 경쇄 가변 영역(VL);
35) 서열번호 279의 중쇄 가변 영역(VH) 및 서열번호 283의 경쇄 가변 영역(VL);
36) 서열번호 275의 중쇄 가변 영역(VH) 및 서열번호 287의 경쇄 가변 영역(VL); 및
CTLA-4:
37) 서열번호 368의 중쇄 가변 영역(VH) 및 서열번호 372의 경쇄 가변 영역(VL).
The method of claim 2,
The X or Y is a variable heavy chain region or a variable light chain region of any one variable region selected from the following group, a multi-specific fusion protein:
PD-L1:
1) the heavy chain variable region of SEQ ID NO: 4 (VH) and the light chain variable region of SEQ ID NO: 8 (VL);
2) the heavy chain variable region of SEQ ID NO: 158 (VH) and the light chain variable region of SEQ ID NO: 170 (VL);
3) the heavy chain variable region of SEQ ID NO: 158 (VH) and the light chain variable region of SEQ ID NO: 313 (VL);
4) the heavy chain variable region of SEQ ID NO: 329 (VH) and the light chain variable region of SEQ ID NO: 333 (VL);
5) the heavy chain variable region of SEQ ID NO: 329 (VH) and the light chain variable region of SEQ ID NO: 376 (VL);
HER2:
6) the heavy chain variable region of SEQ ID NO: 51 (VH) and the light chain variable region of SEQ ID NO: 52 (VL);
7) the heavy chain variable region of SEQ ID NO: 275 (VH) and the light chain variable region of SEQ ID NO: 287 (VL);
CD19:
8) the heavy chain variable region of SEQ ID NO: 139 (VH) and the light chain variable region of SEQ ID NO: 151 (VL);
9) the heavy chain variable region of SEQ ID NO: 61 (VH) and the light chain variable region of SEQ ID NO: 65 (VL);
CD20:
10) the heavy chain variable region of SEQ ID NO: 222 (VH) and the light chain variable region of SEQ ID NO: 226 (VL);
11) the heavy chain variable region of SEQ ID NO: 435 (VH) and the light chain variable region of SEQ ID NO: 440 (VL);
EGFR:
12) the heavy chain variable region of SEQ ID NO: 233 (VH) and the light chain variable region of SEQ ID NO: 237 (VL);
13) the heavy chain variable region of SEQ ID NO: 244 (VH) and the light chain variable region of SEQ ID NO: 248 (VL);
14) the heavy chain variable region of SEQ ID NO: 255 (VH) and the light chain variable region of SEQ ID NO: 259 (VL);
CD3:
15) the heavy chain variable region of SEQ ID NO: 325 (VH) and the light chain variable region of SEQ ID NO: 337 (VL);
16) the heavy chain variable region of SEQ ID NO: 329 (VH) and the light chain variable region of SEQ ID NO: 376 (VL);
17) the heavy chain variable region of SEQ ID NO: 162 (VH) and the light chain variable region of SEQ ID NO: 166 (VL);
18) the heavy chain variable region of SEQ ID NO: 395 (VH) and the light chain variable region of SEQ ID NO: 401 (VL);
19) the heavy chain variable region of SEQ ID NO: 406 (VH) and the light chain variable region of SEQ ID NO: 409 (VL);
20) the heavy chain variable region of SEQ ID NO: 143 (VH) and the light chain variable region of SEQ ID NO: 147 (VL);
21) the heavy chain variable region of SEQ ID NO: 69 (VH) and the light chain variable region of SEQ ID NO: 73 (VL);
22) the heavy chain variable region of SEQ ID NO: 77 (VH) and the light chain variable region of SEQ ID NO: 81 (VL);
23) the heavy chain variable region of SEQ ID NO: 294 (VH) and the light chain variable region of SEQ ID NO: 298 (VL);
24) the heavy chain variable region of SEQ ID NO: 85 (VH) and the light chain variable region of SEQ ID NO: 86 (VL);
25) the heavy chain variable region of SEQ ID NO: 176 (VH) and the light chain variable region of SEQ ID NO: 180 (VL);
26) the heavy chain variable region of SEQ ID NO: 186 (VH) and the light chain variable region of SEQ ID NO: 190 (VL);
27) the heavy chain variable region of SEQ ID NO: 176 (VH) and the light chain variable region of SEQ ID NO: 206 (VL);
28) the heavy chain variable region of SEQ ID NO: 210 (VH) and the light chain variable region of SEQ ID NO: 212 (VL);
29) the heavy chain variable region of SEQ ID NO: 215 (VH) and the light chain variable region of SEQ ID NO: 216 (VL);
30) the heavy chain variable region of SEQ ID NO: 305 (VH) and the light chain variable region of SEQ ID NO: 309 (VL);
31) the heavy chain variable region of SEQ ID NO: 348 (VH) and the light chain variable region of SEQ ID NO: 352 (VL);
32) the heavy chain variable region of SEQ ID NO: 358 (VH) and the light chain variable region of SEQ ID NO: 362 (VL);
33) the heavy chain variable region of SEQ ID NO: 196 (VH) and the light chain variable region of SEQ ID NO: 200 (VL);
TNF:
34) the heavy chain variable region of SEQ ID NO: 53 (VH) and the light chain variable region of SEQ ID NO: 54 (VL);
35) the heavy chain variable region of SEQ ID NO: 279 (VH) and the light chain variable region of SEQ ID NO: 283 (VL);
36) the heavy chain variable region of SEQ ID NO: 275 (VH) and the light chain variable region of SEQ ID NO: 287 (VL); And
CTLA-4:
37) The heavy chain variable region of SEQ ID NO: 368 (VH) and the light chain variable region of SEQ ID NO: 372 (VL).
제2항에 있어서,
상기 X 및 Y 중 하나 이상은 CH3를 더 포함하는 것인, 다중 특이적 융합 단백질.
The method of claim 2,
At least one of the X and Y will further comprise CH3, a multispecific fusion protein.
제2항에 있어서,
상기 A 및 B는 PD-L1, EGFR, CD20, HER2, TNF, CD19, CD3 및 CTLA4로 구성된 군에서 선택되는 제1 항원에 특이적으로 결합하며,
X 및 Y가 결합하여 형성된 Fv는 PD-L1, EGFR, CD20, HER2, TNF, CD19, CD3 및 CTLA4로 구성된 군에서 선택되는 제2 항원에 특이적으로 결합하되,
상기 A 및 B와 X 및 Y로 형성된 Fv는 동일한 항원에 결합하지 않는 것을 특징으로 하는,
다중 특이적 융합 단백질.
The method of claim 2,
The A and B specifically bind to a first antigen selected from the group consisting of PD-L1, EGFR, CD20, HER2, TNF, CD19, CD3 and CTLA4,
Fv formed by binding X and Y specifically binds to a second antigen selected from the group consisting of PD-L1, EGFR, CD20, HER2, TNF, CD19, CD3 and CTLA4,
The Fv formed of A and B and X and Y is characterized in that it does not bind to the same antigen,
Multi-specific fusion proteins.
상기 구조식 (I), (I'), (I''), (II), (II') 또는 (II'')을 코딩하는 폴리뉴클레오티드.A polynucleotide encoding the above structural formula (I), (I'), (I''), (II), (II') or (II''). 제20항의 폴리뉴클레오티드를 포함하는 벡터.A vector comprising the polynucleotide of claim 20. 제21항의 벡터가 도입된 형질전환 세포.A transformed cell into which the vector of claim 21 has been introduced. 제1항 내지 제19항 중 어느 한 항의 다중 특이적 융합 단백질을 유효성분으로 포함하는 암 치료 또는 예방용 약학 조성물.A pharmaceutical composition for the treatment or prevention of cancer comprising the multispecific fusion protein of any one of claims 1 to 19 as an active ingredient. 제23항에 있어서,
상기 암은 PD-L1, EGFR, 및 HER2로 이루어진 군에서 선택되는 어느 하나의 단백질이 과발현된 것인, 암 치료 또는 예방용 약학 조성물.
The method of claim 23,
The cancer is PD-L1, EGFR, and any one protein selected from the group consisting of HER2 is overexpressed, a pharmaceutical composition for cancer treatment or prevention.
제23항에 있어서,
상기 암은 위암, 간암, 폐암, 대장암, 유방암, 전립선암, 난소암, 췌장암, 자궁경부암, 갑상선암, 후두암, 급성 골수성 백혈병, 뇌종양, 신경모세포종, 망막 모세포종, 두경부암, 침샘암 및 림프종으로 구성된 군에서 선택되는 어느 하나인, 암 치료 또는 예방용 약학 조성물.
The method of claim 23,
The cancer is gastric cancer, liver cancer, lung cancer, colon cancer, breast cancer, prostate cancer, ovarian cancer, pancreatic cancer, cervical cancer, thyroid cancer, laryngeal cancer, acute myelogenous leukemia, brain tumor, neuroblastoma, retinoblastoma, head and neck cancer, salivary gland cancer and lymphoma. Any one selected from the group, a pharmaceutical composition for the treatment or prevention of cancer.
제23항에 있어서,
추가적으로 항암제를 더 포함하는 것인, 암 치료 또는 예방용 약학 조성물.
The method of claim 23,
In addition, a pharmaceutical composition for the treatment or prevention of cancer that further comprises an anticancer agent.
암을 치료하기 위한 제1항 내지 제19항 중 어느 한 항의 다중 특이적 융합 단백질의 용도.Use of the multispecific fusion protein of any one of claims 1 to 19 for the treatment of cancer. 세포결합자(cell engager)로서 이용하기 위한 제1항 내지 제19항 중 어느 한 항의 다중 특이적 융합 단백질의 용도.Use of the multispecific fusion protein of any one of claims 1 to 19 for use as a cell engager. 제1항 내지 제19항 중 어느 한 항의 다중 특이적 융합 단백질을 개체에 투여하는 단계를 포함하는 암 치료 방법.A method of treating cancer comprising administering the multispecific fusion protein of any one of claims 1 to 19 to an individual.
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