KR20180037236A - 항체의 삽입가능한 가변 절편 및 NKG2D 리간드의 개질된 α1-α2 도메인, 및 비-천연 NKG2D 수용체에 결합하는 비-천연 NKG2D 리간드 - Google Patents
항체의 삽입가능한 가변 절편 및 NKG2D 리간드의 개질된 α1-α2 도메인, 및 비-천연 NKG2D 수용체에 결합하는 비-천연 NKG2D 리간드 Download PDFInfo
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Abstract
본 출원은 개괄적으로 Fv 도메인의 특이적 항원-결합 특성을 가진 폴리펩티드, 예를 들어 항체의 삽입가능한 가변 절편 및 NKG2D 리간드의 개질된 α1-α2 도메인을 가진 폴리펩티드의 제조에 관한 것이다.
Description
본 출원은 개괄적으로 Fv 도메인의 특이적 항원-결합 특성을 가진 폴리펩티드, 예를 들어 항체의 삽입가능한 가변 절편 및 NKG2D 리간드의 개질된 α1-α2 도메인을 가진 폴리펩티드의 제조에 관한 것이다.
면역글로불린 (Ig) 으로도 공지되어 있는 도 1 의 항체 (Ab) 는, 인간을 포함하는 수많은 포유류에서 박테리아 및 바이러스와 같은 외래 대상체들을 식별 및 중화하기 위해 면역계에 의해 이용되는 대형 Y-형 단백질이다 (Charles Janeway (2001). Immunobiology . (5th ed.), Chapter 3. Garland Publishing. ISBN 0-8153-3642-X. (NCBI Bookshelf 를 통한 전자문서 전문). 항체는 항원으로 지칭되는 외래 표적의 독특한 부분을 인식한다. 항체의 "Y" 의 두 분지 (arm) 의 각 말단은 항원 결합 부위 또는 항원의 한 특별한 에피토프 (열쇠와 유사하게 닮음) 에 특이적인 파라토프 (자물쇠와 유사한 구조) 를 포함하여, 이들 두 구조가 정확하게 함께 결합하도록 한다. 상기 결합 메커니즘을 이용하여, 항체는 면역계의 타 부분에 의한 공격에 대해 미생물 또는 감염된 세포를 태그할 수 있거나, 또는 예를 들어 그의 침입 또는 생존에 필수적인 미생물의 일부분을 차단함으로써 그의 표적을 직접적으로 중화할 수 있다. 항체의 생산은 체액성 또는 "적응" 면역계의 주된 기능이다. 항체는 형질 세포에 의해 분비된다. 항체는 사실상 세포로부터 분비되는 가용성 형태 및 Y 의 "줄기" 를 통해 B 세포의 표면에 부착되어 있는 막-결합 형태의 두가지 물리적 형태로 나타날 수 있다.
항체는 면역글로불린 수퍼패밀리에 속하는 당단백질이며, 일반적으로 각각 2 개의 대형 중쇄 및 2 개의 소형 경쇄가 결합되어 있는 기본 구조 단위체로 되어 있다. 여러가지 상이한 유형의 항체 중쇄 및 여러가지 상이한 종류의 항체가 있는데, 이들은 그들이 보유한 중쇄를 바탕으로 상이한 아형들로 구분되어 진다. 다섯가지 상이한 항체 아형이 포유류에서 공지되어 있다 (Market E, Papavasiliou FN (October 2003). "V(D)J recombination and the evolution of the adaptive immune system". PLoS Biol . 1 (1): E16. doi:10.1371/journal.pbio.0000016. PMC 212695. PMID 14551913). 모든 항체들의 일반적인 구조가 매우 유사함에도, Y-형 단백질의 각 분지 말단의 작은 영역은 극히 가변적이어서, 약간씩 상이한 말단 구조를 가진 수백만 항체 또는 항원-결합 부위들이 존재할 수 있다. 상기 영역은 과도가변 또는 가변 영역으로 공지되어 있다. 각각의 그러한 천연 변이체들은 상이한 항원에 결합할 수 있다. 항체의 그러한 엄청한 다변성은 면역계로 하여금 동등하게 광범위한 상이한 항원들에 맞춰 인식하는 것을 가능하게 한다 (Hozumi N, Tonegawa S (1976). "Evidence for somatic rearrangement of immunoglobulin genes coding for variable and constant regions". Proc . Natl . Acad. Sci . U.S.A. 73 (10): 3628-3632. doi:10.1073/pnas.73.10.3628. PMC 431171. PMID 824647.)
천연 "Y"-형 Ig 분자는 4 개의 폴리펩티드 사슬로 이루어진다; 도 1 에서와 같이 디술파이드 결합에 의해 연결되어 있는 2 개의 동일한 중쇄 및 2 개의 동일한 경쇄. 각각의 중쇄는 불변 영역 (CH) 및 가변 영역 (VH) 의 두가지 주된 영역을 갖고 있다. 불변 영역은 동일한 아형의 모든 항체에서 본질적으로 동일하나, 상이한 아형의 항체에서는 상이하다. 경쇄는 또한 2 개의 연쇄적 도메인을 갖고 있다: 더 작은 불변 영역 (CL) 및 가변 영역 (VL) (Woof J, Burton D (2004). "Human antibody-Fc receptor interactions illuminated by crystal structures." Nat Rev Immunol 4 (2): 89-99. doi:10.1038/nri1266. PMID 15040582).
항체의 일부 부분은 동일한 기능을 갖고 있다. Y 의 두 분지 각각은 예를 들어 항원에 결합할 수 있는 부위를 포함하며, 따라서 특이적 외래 대상체를 인식할 수 있다. 항체의 상기 영역은 Fv (절편, 가변) 영역으로 지칭된다. 이는 항체의 중쇄 유래의 한 가변 도메인 (VH) 및 경쇄 유래의 한 가변 영역 (VL) 으로 이루어져 있다 (Hochman J, Inbar D, Givol D (1973). An active antibody fragment (Fv) composed of the variable portions of heavy and light chains. Biochemistry 12 (6): 1130-1135. doi:10.1021/bi00730a018. PMID 4569769). 파라토프는 Fv 의 한 말단에서 형성되며, 항원에 대한 결합을 위한 영역이다. 이는 각각 VL 및 VH 상의 3 개씩의 β-가닥들의 가변 루프로 이루어지며, 항원에 대한 결합을 담당하고 있다, 도 2 참조. 그러한 6 개의 루프는 상보성 결정 영역 (CDR) 로 지칭된다 (North B, Lehmann A, Dunbrack RL (2010). "A new clustering of antibody CDR loop conformations". J Mol Biol 406 (2): 228-256. doi:10.1016/j.jmb.2010.10.030. PMC 3065967. PMID 21035459).
특이적 항원 결합 기능을 보유하는 유용한 폴리펩티드는 항체들의 가변 영역들의 CDR 로부터 유도될 수 있다. 각각 3 개의 CDR 을 갖는 경쇄로부터의 하나 (VL) 및 중쇄로부터의 하나 (VH) 인, 이들 두 항체 가변 도메인은, 어떤 순서로든 10 내지 약 25 아미노산의 단일한 짧은 링커 펩티드를 이용하여 나란히 융합될 수 있어, 각각 중쇄 및 경쇄 가변 도메인으로 이루어진 선형 단일쇄 가변 절편 (scFv) 폴리펩티드를 조성한다, 도 3 참조 (Bird, R. E., Hardman, K. D., Jacobson, J. W., Johnson, S., Kaufman, B. M., Lee, S. M., Lee, T., Pope, S. H., Riordan, G. S., and Whitlow, M. (1988) Single-chain antigen-binding protein, Science 242, 423-426; Huston, J. S., Levinson, D, Mudgett-Hunter, M, Tai, M-S, Novotny, J, Margolies, M.N., Ridge, R., Bruccoleri, RE., Haber, E., Crea, R., and Opperman, H. (1988). Protein engineering of antibody binding sites: Recovery of specific activity in an anti-digoxin single-chain Fv analogue produced in Escherichia coli . PNAS 85: 5879-5883).
링커에는 일반적으로 유연성을 위해 글리신이 풍부할 뿐 아니라, 가용성을 위해 세린, 트레오닌 또는 하전된 아미노산들이 풍부하고, VH 의 N-말단을 VL 의 C-말단에, 또는 그 반대로 연결할 수 있다. 상기 단백질은 불변 영역의 제거 및 단일 링커의 도입에도 불구하고 본래 면역글로불린의 특이성을 보유하고 있다. 그러한 포맷은 재조합 DNA 기법의 당업자로 하여금 선형 scFv 을 부모 단백질의 N- 또는 C-말단에 유전자적으로 융합시켜 부모 단백질에 scFv 의 항원 결합 특성을 부여할 수 있도록 해 준다. 다가의 탠덤 scFv 영역들의 수많은 여타 제안되거나 또는 조성된 배열이 있으나, 하기에서 중요한 것으로 기재된 바와 같이, 전부 적어도 2 개의 공간적으로 멀리 떨어진 말단을 갖고 있다, 도 4 참조 (Le Gall, F.; Kipriyanov, SM; Moldenhauer, G; Little, M (1999). "Di-, tri- and tetrameric single chain Fv antibody fragments against human CD19: effect of valency on cell binding". FEBS Letters 453 (1): 164-168. doi:10.1016/S0014-5793(99)00713-9. PMID 10403395).
본 개시내용은 폴리펩티드, 일부 구현예에서는 항체들 또는 항체들의 절편에 부착되어 있는 NKG2D 리간드의 개질된 α1-α2 도메인에 관한 것이다. 일부 국면에서, 본 개시내용은 경쇄 및 중쇄 항체 가변 도메인으로부터 유도된 항원-결합 펩티드로서, 2 개의 링커 영역 및 스플릿 (split) 가변 도메인을 포함하고 있는 것에 관한 것이다.
도면의 간단한 설명
특허 또는 출원 파일은 컬러로 발행된 하나 이상의 도면을 포함한다. 관청의 요구 및 필요 비용의 지불로 컬러 도면(들)이 있는 본 특허 또는 특허 출원 공보의 사본이 제공된다.
도 1.
Y-형 구조 및 구조 요소들을 보여주는 전형적 포유류 항체의 밑그림.
도 2.
VH 의 3 개의 표지된 (상보성 결정 영역) CDR 및 VL CDR 의 3 개의 비표지 루프로서, 파라토프 또는 항원 결합 부위를 형성하는 것들을 보여주는 천연 포유류 항체의 Fv 영역의 구조의 밑그림.
도 3.
좌측의 N-말단 및 우측의 C-말단을 포함하는 항원 결합 부위가 있는 단일쇄 가변 절편 (scFv) 의 2 개의 가능한 구조의 밑그림. 각 scFv 에서 단일 링커 영역 또는 링커 펩티드가 화살표로 제시된다.
도 4.
다가 단일쇄 가변 절편 (scFv's). 2 가 (상단) 및 3 가 (하단) scFvs, 탠덤 (좌측) 및 이량체/삼량체 포맷 (우측) 의 구조. 각각은 2 개 이상의 공간적으로 멀리 떨어진 자유로운 말단을 갖고 있음에 유의.
도 5.
삽입가능한 가변 절편, iFv 의 다이어그램. 삽입가능한 가변 절편, iFv 의 다이어그램. (A) iFv 포맷의 도메인 위상을 보여주는 FGFR3-결합 항체 유래의 가변 경쇄 (VL) 및 가변 중쇄 (VH) 도메인의 구조. 회색 화살표는 2 개의 링커 영역 (LR) 을 나타내는데, 1 개 및 이들 중 오직 1 개는 전형적으로 VL 및 VH 의 말단 연결에 이용되어, scFv 를 조성한다. 점선으로 된 경계가 있는 LR 는 VL 의 C-말단을 VH (분자 뒷편에 보임) 의 N-말단에 연결했다. 온전한 선으로 된 경계가 있는 LR 은 VH 의 C-말단을 VL 의 N-말단에 연결했다. 스플릿 VL 도메인의 세절은 본문에 기재된 바와 같이 Nt 및 Ct 로 표지된다. 가닥 1 (S1) 및 가닥 2 (S2) 사이의 N- 및 C-말단의 비-천연 쌍의 조성 결과, VL 은 N-말단 세절 (VLN) 및 C-말단 세절 (VLC) 로 나누어진다. VL 및 VH 의 6 개의 CDR 은 도면의 상단에서 루프로 나타낸다. (B) 스페이서 영역 (SR) 의 존재 또는 부재 하에 MICA-α3 의 루프 1 (L1) 에 iFv 를 삽입하는 도메인 레이아웃의 개념도. iFv 는 또한 루프 2 (L2) 및/또는 루프 3 (L3) 에 유사하게 삽입될 수도 있다.
도 6.
FGFR3 코팅된 웰에 대한 개질된 sMICA 분자 결합에 대한 적정 곡선. 결합된 sMICA 는 NKG2D-Fc 를 이용한 ELISA 에 의해 검출되어 이중특이적 활성을 확인했다. scFv 의 C-말단 융합체 (MICA-scFv) 에 필적하게 삽입된 가변 절편의 두가지 버젼 (MICA-α3-iFv.1 및 MICA-α3-iFv.2) 이 FGFR3 에 결합되었다.
도 7.
MICA-α3-iFv.2 의 열 안정성. 표시된 온도 (섭씨) 에 1 시간 동안 노출 후 FGFR3-코팅된 웰에 결합하는 MICA-scFv (A) 또는 MICA-α3-iFv.2 (B) 의 ELISA 적정 곡선. MICA-α3-iFv 는 80℃ 에 노출 후 FGFR3 에 대한 강력한 결합을 나타낸 반면, MICA-scFv 는 70℃ 에 노출 후 유의한 활성을 잃었다.
도 8.
NK-중재 표적 세포 용해 검정. NKL 효과기 세포는 효과기:표적 비율을 15:1 로 하여 칼세인-담지, FGFR3-발현 P815 표적 세포와 함께 인큐베이션했다. 음성 대조군의 농도를 증가시키면, MICA (sMICA) 은 표적 세포 용해에 아무런 영향을 주지 않은 반면, 표시된 FGFR3-결합 MICA-α3-iFv 변이체들은 표적 세포 용해를 자극했다. MICA-scFv 에 비해, 두 MICA-α3-iFv 변이체들 모두 표적 세포 용해를 더 많이 통제했다.
도 9.
CD20-특이적 sMICA 변이체의 표적 결합 및 세포 용해 활성. MICA-α3-iFv.3 는 ELISA 에서는 CD20-코팅된 웰에 대한 적정가능한 결합을 나타내고 (A), 또한 CD20-발현 Ramos 세포의 NK-중재 세포 용해를 강화했다 (B). (B) 에서 NKL 효과기 세포는 효과기:표적의 비율을 15:1 로 하여 칼세인-담지 CD20-발현 Ramos 세포와 함께 인큐베이션했고, 음성 대조군 (sMICA) 또는 MICA-α3-iFv.3 의 농도를 증가시켰다.
도 10.
FGFR3-코팅된 웰에 결합하는 NKG2DL-α3-iFv.2 단백질에 대한 적정 곡선. 결합된 단백질은 NKG2D-Fc 를 이용하는 ELISA 로 검출되어 이중특이적 활성을 확인했다. 시험한 모든 버젼의 NKG2DL-α3-iFv.2 단백질 (OMCP, ULBP1, 2, 3, 4, 6) 이 FGFR3 에 유사하게 결합했다.
도 11.
NK-중재 표적 세포 용해 검정. NKL 효과기 세포들은 효과기:표적 비율을 15:1 로 하여 칼세인-담지, FGFR3-발현 P815 표적 세포와 함께 인큐베이션했다. 증가된 농도의 음성 대조군 MICA (sMICA) 은 표적 세포 용해에 영향력이 없는 반면, 각각 표시된 NKG2DL-α3-iFv.2 단백질은 표적 세포 용해를 자극했다.
도 12.
강화된 NKG2D 친화성에 대한 MICA 의 α1-α2 도메인의 구조-통제 돌연변이유발. (A) 진회색으로 채색된 57 개 잔기로 맵핑된 NKG2D-결합 표면이 있는 MICA (PDB 1HYR) 의 α1-α2 도메인의 구조. (B) 6 개의 위치들은 NKG2D 친화성 돌연변이들에 대한 중요 부위로 식별되었다. 야생형 아미노산 잔기들은 표지되고, 그들의 측쇄는 진회색 구체로 제시된다.
도 13.
친화성 순위 α1-α2 변이체들에 대한 NKG2D-Fc 경쟁 ELISA. (A) 플레이트-코팅된 MICA 에 대한 인간 NKG2D-Fc 의 결합을 방해하는 α1-α2 친화성 변이체들 (15-18), 야생형 (WT), 또는 WED 가용성 MICA 단백질의 패널에 대한 적정 데이터. (B) 마우스 NKG2D-Fc 에 대해 적정된 (A) 에서와 동일한 설정의 단백질들. 두 검정에서 모두 변이체들 15, 16, 17 및 18 이 WT 및 WED 단백질의 두가지 모두에 대해 유의하게 더 적은 IC50 값을 나타낸다. 평형 IC50 값이 표 3 에 제시된다.
도 14.
Octet 기기 상에서 바이오레이어 간섭법 (biolayer interferometry) 으로 측정되는, NKG2D 에 결합하는 α1-α2 변이체들에 대한 회합 및 해리 동역학의 분석. α1-α2 변이체들의 패널에 대한 동역학 트레이스. 회합 및 해리 상들은 단일 지수 1:1 결합 등식을 이용해 맞췄고, 그러한 핏팅으로부터 유도된 온- 및 오프-레이트 상수 (on- and off-rate constant) 를 표 3 에 나타냈다.
도 15.
FGFR3-발현 표적 세포를 표적화하는 α1-α2 변이체들에 대한 NK-중재 표적 세포 살해 검정. NKL 효과기 세포들을 효과기:표적 비율을 15:1 로 하여 칼세인-담지, FGFR3-발현 P815 표적 세포와 함께 인큐베이션했다. 농도를 증가시킨 음성 대조군 MICA (sMICA) 은 표적 세포 분해에 영향을 주지 않은 반면, 표시된 α1-α2 변이체들은 표적 세포 용해를 자극했다. WT 및 WED-MICA 와 비교하여, 변이체들 16, 17 및 18 은 낮은 농도에서 유의하게 증가된 살해를 나타냈다.
도 16.
NKG2D 에 대한 강화된 친화성에 대한 MICA 의 α1-α2 도메인의 구조-통제 돌연변이유발. 57 개의 특이적 아미노산 부위가 집중적으로 돌연변이화된 진회색으로 채색된 NKG2D-결합 표면을 가진 MICA (PDB 1HYR) 의 α1-α2 도메인의 구조.
도 17.
천연 NKG2D 단독이량체 내부의 타이로신 잔기 Y152 및 Y199.
도 18.
NKG2D 리간드-Fc 융합체들의 천연 및 비-천연 α1-α2 도메인에 결합하는 천연 및 비-천연 NKG2D 수용체의 엑토도메인의 ELISA 결과. (A), α1-α2 도메인 리간드-Fc 패널에 결합하는 야생형 NKG2D 는 MICv25-Fc 에 대한 최고 친화성을 갖고 모든 리간들에 대한 결합을 보여준다. (B), 비-천연 NKG2D 돌연변이 Y199A 는 리간드 결합 활성을 전혀 나타내지 않는다. (C), 비-천연 NKG2D 돌연변이 Y152A 는 MICv25-Fc 에 대해서만 높은 친화성 결합을 보유한다. (D), 비-천연 NKG2D 이중 돌연변이 Y152A 및 Y199A 는 리간드 결합 활성을 전혀 나타내지 않는다.
도 19.
NKG2D 에 결합하는 ULBP 변이체들의 파지 ELISA 적정. 패널 (A) 는 파지 상에 제시된 ULBP2 변이체들을 NKG2D 에 대해 적정하여, 상대적 결합 친화성을 본연의 ULBP2 (WT, 흑색 원) 과 비교하여 측정한 실험을 도시한다. 패널 (B) 는 파지 상에 제시된 ULBP3 변이체들을 NKG2D 에 대해 적정하여, 상대적 결합 친화성을 본연의 ULBP3 (WT, 흑색 원) 과 비교하여 측정한 실험을 도시한다.
도 20.
MICA 및 ULBPs 유래의 α1-α2 도메인의 단백질 서열 정렬 (MICA, SEQ ID NO: 99; ULBP4, SEQ ID NO:103; ULBP3, SEQ ID NO:102; ULBP1, SEQ ID NO:100; ULBP5, SEQ ID NO:104; ULBP2, SEQ ID NO:101; ULBP6, SEQ ID NO:105). 회색으로 강조한 아미노산들은 ULBP2 (60 개 아미노산) 및 ULBP3 (36 개 아미노산) 에서의 NNK 돌연변이유발을 위해 선택되었다. 흑색으로 강조된 잔기들은 NKG2D 에 대한 결합 친화성을 조정한 돌연변이들로서 선택 및 식별된 중요 위치들로서 식별되었다 (표 6 및 7).
도 21.
HER2-특이적 항체의 중쇄에 대한 ULBP2 및 ULBP3 α1-α2 도메인 변이체들의 융합체들이 강화된 NKG2D 결합 친화성을 나타냈다. 개질된 ULBP2 α1-α2 도메인 변이체들 R80W (SEQ ID NO: 87) 및 V151D (SEQ ID NO: 88) 및 개질된 ULBP3 변이체 R162G (SEQ ID NO: 89) 는 그들의 C-대-S 천연 ULBP 융합체들 (각각 SEQ ID NO: 16 및 SEQ ID NO: 17) 에 비해 강화된 NKG2D 결합을 나타냈다.
도 22.
ULBP2 및 ULBP3 α1-α2 도메인 변이체들의 HER2-특이적 항체-중재의 중쇄에 대한 융합체들은 NKL 세포에 의한 SKBR3 표적 세포의 특이적 용해를 나타냈다. 개질된 ULBP2 α1-α2 도메인 변이체들 R80W (SEQ ID NO: 87) 및 V151D (SEQ ID NO: 88) 는 C8S 본연의 ULBP2 (SEQ ID NO: 16) 융합체 (WT) (A) 에 비해 강화된 표적 세포 살해를 나타냈다. 개질된 ULBP3 변이체 R162G (SEQ ID NO: 89) 는 C103S 본연의 ULBP3 (SEQ ID NO: 17) 융합체 (WT) (B) 에 비해 강화된 표적 세포 살해를 나타냈다.
도 23.
Y152A NKG2D-Fc 에 대한 결합에 대해 선택된 비-천연 α1-α2 도메인의 파지 ELISA 결과. (A) 직교성 ULBP2 클론, (B) 직교성 MICA 클론, 및 (C) 직교성 ULBP3 클론.
도 24.
Y152A NKG2D-Fc 에 대한 결합에 대해 선택된 비-천연 α1-α2 도메인에 대한 R3 항체 융합체들에 대한 ELISA 결과. (A) R3 HC25 항체 융합체는 Y152A NKG2D 에 대해서는 선택적이지 않음. (B) R3 HC25.17 (SEQ ID NO.: 97) 항체 융합체는 천연 NKG2D-Fc 을 능가하여 Y152A NKG2D 에 대해 선택적임. (C) R3 HC.U2RW 항체 융합체는 천연 NKG2D-Fc 을 능가하여 Y152A NKG2D 에 대해 선택적이지는 않음. (D) R3 HC.U2S3 (SEQ IN NO.98) 항체 융합체는 천연 NKG2D-Fc 를 능가하여 Y152A NKG2D 에 대해 선택적임.
도 25.
전형적 CAR 의 해부학 (Gill & June, 2015, 앞서 언급한 문헌).
도 26.
표적 세포 살해에 대한 시험관내 CAR-T 검정. (A) 천연 NKG2D CAR-T 세포는 천연 MICA 를 발현하는 P1 표적 세포를 살해하는 반면, Y152A NKG2D CAR-T 세포는 기능불가하게 되며, MICA 발현 표적에 대한 살해 활성이 감소됨. (B) 선택적 직교성 항체 융합체들, R3 HC25.17 (SEQ ID NO.: 97) 및 R3 HC.U2S3 (SEQ ID NO.: 98) 는 FGFR3 발현 세포에 대한 Y152A NKG2D CAR-T 세포들의 살해 활성을 선택적으로 제어한다.
일부 국면에서, 본 발명은 삽입가능한 가변 절편 (iFv) 펩티드에 관한 것이다. 다가 scFv 구조를 포함하고 있는 scFv 분자들의 C-말단 및 N-말단은 공간적으로 멀리 떨어져 있기 때문에, scFv 구조들은 그의 폴드(들)의 교란 또는 탈안정화의 부재 및/또는 그들의 항원-결합 특성을 유지하기 위한 CDR 또는 과가변 영역들을 적절한 위치에 필요로 하는 Fv 프레임워크의 교란 부재 하에 부모 또는 수용자 단백질의 단백질 폴드 내에 내입되는 루프 영역으로 삽입될 수 없다.
가변 절편 또는 부모 단백질의 구조적 폴드 교란 없이 6 개 이하의 CDR 을 포함하는 항체의 가변 절편을 초기 부모 단백질 분자의 하나 이상의 루프 영역으로 삽입하기 위해, 경쇄 및 중쇄 항체 가변 도메인으로부터 유도되는 항원-결합 펩티드의 신규 클래스를 발명했다. 상기 신규 구조는 scFv 구조의 전형적인 단일 링커 외에 스플릿 가변 도메인이 더해진 2 개의 링커 영역을 포함한다. 개념상으로 가변 경쇄 (VL) 및 가변 중쇄 (VH) 도메인의 원형 (canonical) 말단은 연속적 또는 "고리형" 펩티드로 융합되었다. 이어서 Fv 의 6 개 CDR 를 전부 포함하는 그러한 고리형 펩티드 구조는 개념상 여러 가능한 신규 부위들 중 하나에서 스플릿되어 삽입가능한 Fv (iFv) 을 조성할 수 있다. 비-천연 스플릿 부위는 루프의 정점 또는 회전부위에서 또는 그 부근에 경쇄 또는 중쇄 가변 도메인 내부에서 조성되어 서로 공간적으로 근접해, 바람직하게는 0.5 내지 1.5 nm 이내에 위치되는 신규한 독특한 N- 및 C-말단을 조성하게 되어, 구조, 안정성 또는 바람직한 기능을 교란하지 않고 여타 (부모 또는 수용자) 단백질 또는 폴리펩티드의 루프로 삽입가능하게 된다. 그러한 신규한 클래스의 펩티드는 삽입가능한 가변 절편 (iFv) 으로 지칭된다. iFv 에 의해 수용자 분자로 옮겨지는 결합 또는 표적화 특이성은, 상이한 항체 또는 scFv 기재의 수용자인 또다른 또는 상이한 iFV 로의 삽입에 의해 또는 기존 삽입가능한 iFv 의 하나 이상의 CDR 대체에 의해 변경될 수 있다.
Fv 도메인의 특이적 항원-결합 특성을 나타내는 하나 이상의 iFv 폴리펩티드의 여타 단백질로의 삽입 및 그에 따른 신규 결합 특성 부여는 여러 유용성을 가질 것이다. 그러한 용도에는, 이에 제한되는 것은 아니나, 부모 단백질이 특정 항원에 결합하도록 하는 것, 항원을 표적으로 하는 것, 항원의 존재를 검출하는 것, 항원을 제거하는 것, 항원 가까이 접촉하거나 또는 잡아당기는 것, 페이로드 (payload) 를 항원 또는 항원-발현 세포로 전달하는 것, 항원을 유인하는 것, 및 항원의 존재를 영상화하는 것이 포함된다. 페이로드는 iFv 의 아미노-말단 및 카르복시-말단의 한쪽 또는 양쪽에 직접 또는 부모 단백질 또는 펩티드를 통해 iFv 로 간접적으로 컨쥬게이션될 수 있을 것이다. 페이로드의 예시에는, 이에 제한되는 것은 아니나, 발색단, 형광단, 약물분자구조, 원자, 중질 또는 방사성 동위원소, 영상검출 작용제, 화학치료제 또는 독소가 포함된다. 페이로드된 iFv 는 iFv 가 특이적으로 결합하는 표적 분자의 존재를 식별하거나 이의 위치를 찾기 위해 이용될 수 있고, 마찬가지로 시험관내 또는 생체내에서 소형의 안정한 조영제 (영상검출 작용제) 또는 진단제 (diagnostic agent) 로서 제공될 수 있다. 추가로, iFv 펩티드의 아미노-말단 및 카르복시-말단의 한쪽 또는 양쪽에, 화학치료제 또는 독소 분자가 컨쥬게이션되어, 예를 들어 악성종양 또는 감염 치료로서 iFv-약물 콘쥬게이트를 조성할 수 있다. 단일 페이로드는 iFv 펩티드의 아미노-말단 및 카르복시-말단의 양측에 컨쥬게이션되어 두 말단을 포괄 (spanning) 하거나 또는 연결할 수 있는데; 그러한 포괄은 엑소펩티다아제 분해로부터 말단을 차단하거나 또는 iFv 를 변성 또는 폴딩해제로부터 보호하여 iFv 를 추가로 안정화시킬 수 있다.
iFv 펩티드의 삽입을 위한 후보자인 부모 또는 수용자 단백질 또는 폴리펩티드의 예시에는, 이에 제한되는 것은 아니나, 항체들, Ig 폴드 또는 Ig 도메인으로 이루어지는 단백질, 글로불린, 알부민, 피브로넥틴 및 피브로넥틴 도메인, 인테그린, 형광 단백질, 효소, 외부 막 단백질, 수용체 단백질, T-세포 수용체, 키메라성 항원 수용체, 바이러스 항원, 바이러스 캡시드, 세포 수용체에 대한 바이러스 리간드, 고분자량 박테리오신, 히스톤, 호르몬, 노틴 (knottin), 고리형 펩티드 또는 폴리펩티드, 주요 조직적합성 (MHC) 패밀리 단백질, MIC 단백질, 렉틴 및 렉틴에 대한 리간드가 포함된다. iFv 구조를 비-단백질 수용자 분자, 예를 들어 다당류, 덴드리머, 폴리글리콜, 펩티도글리칸, 항생제 및 폴리케티드로 삽입하는 것도 가능하다.
자연 살해 (NK) 세포 및 면역계의 특정 (CD8+ αβ 및 γδ) T-세포들은 인간 및 여타 포유류에서 일선에서 신생물 및 바이러스-감염 세포들에 대한 선천적 방어에 있어 중요한 역할을 한다 (Cerwenka, A., and L.L. Lanier. 2001. NK cells, viruses and cancer. Nat. Rev. Immunol. 1:41-49). NK 세포 및 특정 T-세포들은 그들의 표면 상에서 표적 세포를 인식하고 병원성 세포에 대한 선천적 방어를 활성화시키는 것을 담당하는 NKG2D, 영구적인 단독이량체 표면 면역수용체를 나타낸다 (Lanier, LL, 1998. NK cell receptors. Ann. Rev. Immunol. 16: 359-393; Houchins JP 등, 1991. DNA sequence analysis of NKG2, a family of related cDNA clones encoding type II integral membrane protein on human NK cells. J. Exp. Med. 173: 1017-1020; Bauer, S 등, 1999. Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science 285: 727-730). 인간 NKG2D 분자는 그의 동족 리간드에 결합하는 C-타입 렉틴형 세포외 도메인, 84% 서열 동일성 또는 상동성 단량체 MICA 및 MICB, 주요 조직적합성 복합체 (MHC) 클래스 I 사슬-관련 당단백질 (MIC) 의 다형질상 유사체를 보유한다 (Weis 등, 1998. The C-type lectin superfamily of the immune system. Immunol. Rev. 163: 19-34; Bahram 등, 1994. A second lineage of mammalian MHC class I genes. PNAS 91:6259-6263; Bahram 등, 1996a. Nucleotide sequence of the human MHC class I MICA gene. Immunogenetics 44: 80-81; Bahram and Spies TA. 1996. Nucleotide sequence of human MHC class I MICB cDNA. Immunogenetics 43: 230-233). MICA 및 MICB 의 비병원성 발현은 장 표피, 각질형성세포, 내피 세포 및 단핵구로 제한되나, 그러한 MIC 단백질의 일탈적 표면 발현은 수많은 유형의 세포 스트레스, 예를 들어 증식, 산화 및 열 충격에 응답하여 일어나며, 병원체로 세포를 표시하게 한다 (Groh 등, 1996. Cell stress-regulated human MHC class I gene expressed in GI epithelium. PNAS 93: 12445-12450; Groh 등, 1998. Recognition of stress-induced MHC molecules by intestinal γδT cells. Science 279: 1737-1740; Zwirner 등, 1999. Differential expression of MICA by endothelial cells, fibroblasts, keratinocytes and monocytes. Human Immunol. 60: 323-330). MIC 단백질의 병리학적 발현은 또한 일부 자가면역 질환에 관여된 것으로 보인다 (Ravetch, JV and Lanier LL. 2000. Immune Inhibitory Receptors. Science 290: 84-89; Burgess, SJ. 2008. Immunol. Res. 40: 18-34). NKG2D 리간드, 예를 들어 다형질상 MICA 및 MICB 의 차별적인 조절은 광범위한 응급 신호들을 식별하여 그에 응답하는 수단을 면역계에 제공하는 한편, 원치 않는 공격으로부터 건강한 세포를 보호하기 위해 중요하다 (Stephens HA, (2001) MICA and MICB genes: can the enigma of their polymorphism be resolved? Trends Immunol. 22: 378-85; Spies, T. 2008. Regulation of NKG2D ligands: a purposeful but delicate affair. Nature Immunol. 9: 1013-1015).
바이러스 감염은 MIC 단백질 발현의 공통적 유발자이며, NK 또는 T-세포 공격에 대한 바이러스-감염 세포를 식별해 낸다 (Groh 등, 1998; Groh 등, 2001. Co-stimulation of CD8+ αβT-cells by NKG2D via engagement by MIC induced on virus-infected cells. Nat. Immunol. 2: 255-260; Cerwenka, A., and L.L. Lanier. 2001). 사실, 그의 숙주 세포 상에서 그러한 공격을 피하기 위해, 싸이토메갈로바이러스 및 여타 바이러스들은 선천적 면역계의 진노를 피하기 위해 감염시키는 세포의 표면에서 MIC 단백질의 발현을 막는 진화된 메커니즘을 갖고 있다 (Lodoen, M., K. Ogasawara, J.A. Hamerman, H. Arase, J.P. Houchins, E.S. Mocarski, and L.L. Lanier. 2003. NKG2D-mediated NK cell protection against cytomegalovirus is impaired by gp40 modulation of RAE-1 molecules. J. Exp. Med. 197:1245-1253; Stern-Ginossar 등, (2007) Host immune system gene targeting by viral miRNA. Science 317: 376-381; Stern-Ginossar 등, (2008) Human microRNAs regulate stress-induced immune responses mediated by the receptor NKG2D. Nature Immunology 9: 1065-73; Slavuljica, I A Busche, M Babic, M Mitrovic, I Gasparovic, D Cekinovic, E Markova Car, EP Pugel, A Cikovic, VJ Lisnic, WJ Britt, U Koszinowski, M Messerle, A Krmpotic and S Jonjic. 2010. Recombinant mouse cytomegalovirus expressing a ligand for the NKG2D receptor is attenuated and has improved vaccine properties. J. Clin. Invest. 120: 4532-4545).
그들의 스트레스에도 불구하고, 많은 악성 세포들, 예를 들어 폐암 및 아교모세포종 뇌암 (glioblastoma brain cancer) 의 것들은 MIC 단백질의 발현을 피하며, 그 결과 그들이 역시 선천적 면역계를 벗어나기 때문에 특별히 공격적일 수 있다 (Busche, A 등, 2006, NK cell mediated rejection of experimental human lung cancer by genetic over expression of MHC class I chain-related gene A. Human Gene Therapy 17: 135-146; Doubrovina, ES, MM Doubrovin, E Vider, RB Sisson, RJ O'Reilly, B Dupont, and YM Vyas, 2003. Evasion from NK Cell Immunity by MHC Class I Chain-Related Molecules Expressing Colon Adenocarcinoma (2003) J. Immunology 6891-99; Friese, M. 등, 2003. MICA/NKG2D-mediated immunogene therapy of experimental gliomas. Cancer Research 63: 8996-9006; Fuertes, MB, MV Girart, LL Molinero, CI Domaica, LE Rossi, MM Barrio, J Mordoh, GA Rabinovich and NW Zwirner. (2008) Intracellular Retention of the NKG2D Ligand MHC Class I Chain-Related Gene A in Human Melanomas Confers Immune Privilege and Prevents NK Cell-Mediated Cytotoxicity. J. Immunology, 180: 4606-4614).
NKG2D 에 결합된 인간 MICA 의 고해상도 구조는 MICA 의 α3 도메인이 NKG2D 와는 직접적 상호작용이 없음을 해명하여 입증했다 (Li 등, 2001. Complex structure of the activating immunoreceptor NKG2D and its MHC class I-like ligand MICA. Nature Immunol. 2: 443-451; Protein Data Bank accession code 1HYR). MICA 의 α3 도메인은, MICB 의 것과 마찬가지로, 짧고 유연한 링커 펩티드에 의해 α1-α2 플랫폼 도메인에 연결되며, 자체로 플랫폼과 MIC 발현 세포의 표면 사이의 "스페이서" 로서 자연히 위치된다. 인간 MICA 및 MICB α3 도메인의 3-차원 구조는 거의 일치하며 (94C-αα'들 상에서 평균 제곱근 거리 <1Å), 기능적으로 호환된다 (Holmes 등, 2001. Structural Studies of Allelic Diversity of the MHC Class I Homolog MICB, a Stress-Inducible Ligand for the Activating Immunoreceptor NKG2D. J Immunol. 169: 1395-1400).
천연 α1-α2 도메인 보다 더 높은 친화성을 가진 천연 인간 NKG2D 수용체에 결합하도록 개질된 NKG2D 리간드의 특정 비-천연 α1-α2 도메인이 기재된 바 있다 (Candice S. E. Lengyel, Lindsey J. Willis, Patrick Mann, David Baker, Tanja Kortemme, Roland K. Strong and Benjamin J. McFarland. Mutants Designed to Destabilize the Receptor-Bound Conformation Increase MICA-NKG2D Association Rate and Affinity. Journal of Biological Chemistry Vol. 282, no. 42, pp. 30658-30666, 2007; Samuel H. Henager, Melissa A. Hale, Nicholas J. Maurice, Erin C. Dunnington, Carter J. Swanson, Megan J. Peterson,Joseph J. Ban, David J. Culpepper, Luke D. Davies, Lisa K. Sanders, and Benjamin J. McFarland. Combining different design strategies for rational affinity maturation of the MICA-NKG2D interface. Protein Science 2012 VOL 21:1396-1402). 본문에서는 비-천연 NKG2D 수용체에 결합하도록 개질된 NKG2D 리간드의 비-천연 α1-α2 도메인이, 필연적으로 NKG2D 리간드의 천연 α1-α2 도메인에 결합이 약화 또는 소실되는 결과를 가져오는 부위에서 자체로 돌연변이화됨을 기재한다 (David J. Culpepper, Michael K. Maddox, Andrew B. Caldwell, and Benjamin J. McFarland. Systematic mutants and thermodynamic analysis of central tyrosine pairs in polyspecific NKG2D receptor interactions. Mol Immunol. 2011 January ; 48(4): 516-523; USPTO 출원 14/562,534; USPTO 가출원 제 62/088,456 호)). 본 발명은 특이적으로 개질된 비-천연 α1-α2 도메인으로 이루어지며, 키메라성 항원 수용체 (CAR) 에 결합하는, 이에 제한되는 것은 아니나 이종성 펩티드 또는 폴리펩티드를 포함하는 이종성 분자들을 특이적으로 표적화하는 이중특이적 분자를 조성하게 되는데, 여기서 CAR 의 수용체는 천연 α1-α2 도메인보다 더 큰 친화성으로 개질된 α1-α2 도메인에 결합하는 비-천연 NKG2D 수용체 엑토도메인으로 이루어진다. 그러한 CAR 로 이루어지는 면역계의 유전자적으로 조작된 세포들은 이어서 하기에 기재되는 바와 같은 현존 CAR-T 및 CAR-NK 세포 치료요법의, 공지된 중증 전신적 독성 및 항원 탈출을 포함하는, 수많은 단점들을 극복할 수 있다 (Kalos M, Levine, BL, Porter, DL, Katz, S, Grupp, SA, Bagg, A and June, C.. T Cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med 2011;3:95ra73; Morgan RA, Yang JC, Kitano M, Dudley ME, Laurencot CM, Rosenberg SA. Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol Ther 2010, 18:843-851; Gill and June 2015).
T-세포 및 NK-세포는 유전자 전달 기술을 사용하여 개질될 수 있어 새로운 항원 특이성을 부여하는 항원의 표면 결합 도메인을 직접적으로 그리고 안정적으로 발현한다 (Saar Gill & Carl H. June. Going viral: chimeric antigen receptor T-cell therapy for hematological malignancies. Immunological Reviews 2015. Vol. 263: 68-89; Wolfgang Glienke, Ruth Esser, Christoph Priesner, Julia D. Suerth, Axel Schambach, Winfried S. Wels, Manuel Grez, Stephan Kloess, Lubomir Arseniev and Ulrike Koehl. 2015. Advantages and applications of CAR-expressing natural killer cells. Front. Pharmacol. doi: 10.3389/fphar.2015.00021). CAR-T 세포는 특이적 항체의 항원 인식 도메인을 CD3-ζ 사슬의 세포내 도메인과 조합하는 그러한 접근법의 적용예인데, 이는 내생적 T-세포 수용체 (TCR) 유래 신호의, 공동-자극 분자, 예를 들어 CD27, CD28, ICOS, 4-1BB 또는 OX40 과 함께 단일 키메라 단백질을 향한 주요한 전송자이다, 도 16 참조. 그렇게 구축된 CAR 는 내생적 T 세포 수용체와 유사한 방식으로, 그러나 주요 조직적합성 복합체 (MHC) 와는 독립적으로 표적화된 항원에 결합시 T 세포 활성화를 촉발할 수 있다.
본원에 사용된 바와 같이, "가용성 MIC 단백질", "가용성 MICA" 및 "가용성 MICB" 은 MIC 단백질의 α1, α2 및 α3 도메인은 포함하나, 막관통 또는 세포내 도메인은 없는 MIC 단백질을 지칭한다. NKG2D 리간드인 ULBP1-6 은 본래 α3 도메인을 보유하지 않는다 (Cerwenka A, Lanier LL. 2004. NKG2D ligands: unconventional MHC class I-like molecules exploited by viruses and cancer. Tissue Antigens 61 (5): 335-43. doi:10.1034/j.1399-0039.2003.00070.x. PMID 12753652). NKG2D 리간드의 "α1-α2 도메인" 은 NKG2D 수용체에 결합하는 리간드의 단백질 도메인을 지칭한다.
일부 구현예에서, 본 발명의 비-천연 NKG2D 리간드 단백질의 α1-α2 도메인은 NKG2D 리간드의 본연 또는 천연의 α1-α2 도메인, SEQ ID NO: 36-54 에 80% 이상 동일하거나 상동이다. 여타 구현예에서, 개질된 α1-α2 도메인은 NKG2D 리간드의 본연 또는 천연의 α1-α2 도메인과 85% 동일하다. 또다른 구현예에서, 개질된 α1-α2 도메인은 천연 NKG2D 리간드 단백질의 본연의 또는 천연 α1-α2 도메인과 90% 동일하며, 비-천연 NKG2D 에 결합한다.
가용성 MIC 단백질의 α1-α2 플랫폼 도메인은 α3 도메인에 결박되어 있고, 포유류의 세포간 또는 혈관내 공간에서 확산가능하다. 바람직하게는, 본 발명의 비-천연 MIC 단백질의 α1-α2 플랫폼 도메인은 인간 MICA 또는 MICB 단백질의 본연의 또는 천연 α1-α2 도메인과 80% 이상 동일하거나 상동이며, NKG2D 에 결합한다. 일부 구현예에서, α1-α2 플랫폼 도메인은 인간 MICA 또는 MICB 단백질의 본연의 또는 천연 α1-α2 플랫폼 도메인과 85% 동일하며, NKG2D 에 결합한다. 여타 구현예에서, α1-α2 플랫폼 도메인은 인간 MICA 또는 MICB 단백질의 본연의 또는 천연 α1-α2 플랫폼 도메인에 90%, 95%, 96%, 97%, 98% 또는 99% 동일하며, NKG2D 에 결합한다.
일부 구현예에서, 이종성 펩티드 태그는 α1-α2 도메인 또는 가용성 MIC 단백질의 N-말단 또는 C-말단에 융합하여 가용성 MIC 단백질의 정제를 보조할 수 있다. 태그 서열은 펩티드, 예를 들어 폴리-히스티딘, myc-펩티드 또는 FLAG 태그를 포함한다. 그러한 태그는 MIC 분자의 단리 후 당업자에게 공지된 방법으로 제거될 수 있다.
본 발명의 여타 구현예에서, NKG2D 리간드의 α1-α2 도메인 중의 특정 돌연변이들이, 비-천연 NKG2D 수용체에 결합하는 비-천연 α1-α2 도메인이 조성되어, 자체로 천연 NKG2D 리간드에 대한 감소된 친화성을 갖도록 조작될 수 있다. 이는 예를 들어 유전자 조작을 통해 실시될 수 있다. 그렇게 개질된 비-천연 NKG2D 수용체는 면역계의 NK- 또는 T-세포 표면 상에 본 발명의 비-천연 α1-α2 도메인으로 이루어지는 분자들을 선호하여 결합할 수 있으며 그에 의해 활성화될 수 있는 NKG2D-기재 키메라 항원 수용체 (CAR) 을 조성하도록 이용될 수 있다. 그러한 짝지어진 비-천연 NKG2D 수용체 및 그의 본 발명의 동족 비-천연 NKG2D 리간드는 하기에 기재되는 바와 같이 현존 CAR-T 세포 및 CAR-NK 세포에 비해 암 및 바이러스 감염 치료에 있어 중요한 안전성, 효능 및 제조 상의 장점을 제공한다.
CAR 를 이용한 T 세포의 조작은 암에 대한 입양 T 세포 치료요법의 유망한 접근법으로 부상했으며, 수많은 상이한 분자들을 표적으로 하는 CAR 는 악성 종양들에 대한 치료제로서 CAR-T 세포에서 시험된 바 있다 (Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. 365:725-733.). CD19-특이적 키메라 항원 수용체를 발현하는 T 세포의 입양 이동을 수용한 수백명의 환자에서 현격한 임상적 효능이 발견되는 한편, 특정 항원을 표적으로 하는 CAR 의 핏팅 조작, 환자로부터 자가 T-세포의 단리, 개별핏팅된 CAR 를 발현하는 자가 T-세포의 유전자 조작, 시험관내에서의 개질 세포의 증량, 및 그들 생산에서의 품질 관리 공정들은 전부 부담스럽고 비용이 많이 든다. 현재 이는 광범위한 전문지식 및 재원이 있는 대규모 학술 기관에서만 실현가능하다 (Gill & June, 2015).
자가 CAR-T 세포가 일단 공여자 환자로 다시 주입되면, 생체내에서의 그의 증량은 제어불가하며 --- "생체 치료요법", 효능과는 투여량-응답 관계가 없다 (Gill & June, 2015). 나아가, CAR T-세포로부터의 종양 탈출은 항원 소실 탈출 (antigen loss escape) 을 통해 일어날 수 있으며 (Stephan A. Grupp, M.D., Ph.D., Michael Kalos, Ph.D., David Barrett, M.D., Ph.D., Richard Aplenc, M.D., Ph.D., David L. Porter, M.D., Susan R. Rheingold, M.D., David T. Teachey, M.D., Anne Chew, Ph.D., Bernd Hauck, Ph.D., J. Fraser Wright, Ph.D., Michael C. Milone, M.D., Ph.D., Bruce L. Levine, Ph.D., and Carl H. June, M.D. Chimeric Antigen Receptor-Modified T Cells for Acute Lymphoid Leukemia. N Engl J Med 2013;368:1509-1518), 그러한 탈출 경로는 상이하게 표적화된 CAR-T 세포를 이용한 순차적 치료요법에 의해 또는 둘 이상의 특이성의 CAR 를 포함하는 T-세포 생성물의 초기 주입에 의해서만 가장 순조롭게 해결될 수 있어, 제조 공정 및 품질 관리를 더욱 복잡하게 만든다.
단일쇄 항체 결합 도메인 (scFv) 이 있는 종양을 표적으로 하는 CAR-T 세포에 추가하여, NKG2D 수용체의 리간드-결합 도메인을 채용하는 CAR-T 세포들이 동물 및 최근에는 인간에서 연구된 바 있다 (Sentman CL, Meehan KR. NKG2D CARs as cell therapy for cancer. Cancer J. 2014 Mar-Apr;20(2):156-9. doi: 10.1097/PPO.0000000000000029; Manfred Lehner, Gabriel Goetz, Julia Proff, Niels Schaft, Jan Doerrie, Florian Full, Armin Ensser, Yves A. Muller, Adelheid Cerwenka, Hinrich Abken, Ornella Parolini, Peter F. Ambros, Heinrich Kovar, Wolfgang Holter. Redirecting T Cells to Ewing's Sarcoma Family of Tumors by a Chimeric NKG2D Receotor Expressed by Lentiviral Transduction or mRNA Transfection Research Article | 2012 년 2 월 15 일 공개 | PLOS ONE 10.1371/journal.pone.0031210; www.clinicaltrials.gov NCT02203825). NKG2D 리간드 발현은 스트레스받은 세포, 예를 들어 종양 세포의 표면 상에서 증가되기 때문에, 그러한 천연 NKG2D 리간드의 패밀리는 암 면역치료요법에 대한 표적으로서 유의하게 관심을 끄는 표적이다 (Spear P, Wu MR, Sentman ML, Sentman CL. NKG2D ligands as therapeutic targets. Cancer Immun. 2013 May 1;13:8.; Song DG, Ye Q, Santoro S, Fang C, Best A, Powell DJ Jr., Chimeric NKG2D CAR-expressing T cell-mediated attack of human ovarian cancer is enhanced by histone deacetylase inhibition. Hum Gene Ther. 2013 Mar;24(3):295-305). 한가지 NKG2D CAR 는 전장 NKG2D 수용체 및 CD3ζ 의 융합체 (NKG2Dζ) 이다; 또다른 것은 CD28 유래의 막관통 및 세포내 도메인 및 CD3ζ 의 신호전달 도메인으로 이루어진 2-세대 CAR 스캐폴드에 반대 배향으로 융합된 NKG2D 의 엑토도메인만을 갖는 것이다 (NKG2D28ζ). NKG2D 의 활성화는 DAP10 의 존재여부에 좌우되기 때문에, CAR-T 세포가 또한 구축되는데, 여기서 DAP10 은 NKG2Dζ 와 공동발현된다 (NKG2Dζ10). 임의의 상기 NKG2D CAR 를 발현하는 T 세포는 NKG2D 리간드 자극에 응답하여 IFNγ 및 TNFα 을 생산하고, 시험관내에서 NKG2D 리간드를 발현하는 종양 표적들을 효율적으로 살해했다 (Heather VanSeggelen, Joanne A. Hammill, Anna Dvorkin-Gheva, Daniela G.M. Tantalo, Jacek M. Kwiecien, Galina F. Denisova, Brian Rabinovich, Yonghong Wan, Jonathan L. Bramson, T cells engineered with chimeric antigen receptors targeting NKG2D ligands display lethal toxicity in mice, Molecular Therapy 2015 년 6 월 30 일에 논문 미리보기 접근허용; doi:10.1038/mt.2015.119). 광범위한 종양 아형들에 대한 NK 세포의 세포독성 잠재성이 또한 NKG2D-DAP10-CD3ζ 기재의 CAR 의 발현에 의해 현격히 강화될 수 있었다 (Yu-Hsiang Chang, John Connolly, Noriko Shimasaki, Kousaku Mimura, Koji Kono, and Dario Campana. Chimeric receptor with NKG2D Specificity Enhances Natural Killer Cell Activation and Killing of Tumor Cells. Cancer Res; 73(6) March 15, 2013).
그러나, 동계 쥐과동물 숙주로의 주입 후, 천연 NKG2D 수용체의 천연 리간드에 의해 결합 및 활성화되는 그러한 CAR-T 구축물로 유의한 독성이 발생했다. 미처리 대조군 마우스들에 비해 열악한 신체 상태, 구부정한 자세, 고통스러운 호흡 및 감소된 체온을 포함하는 독성의 징후가 NKG2D-기재 CAR-T 세포로 처리한 종양-보유 및 무종양 마우스에서 관찰되었다. NKG2D CAR-T 세포 독성의 중증도는 다양했는데, NKG2Dζ10 는 중증 독성이고, NKG2D28ζ 는 경증 독성을 나타냈으며, NKG2Dζ 는 용인가능했다. 독성의 임상적 징후 및 사망률은 마우스가 임의의 NKG2D CAR 를 발현하는 T 세포의 입양 이동에 앞서 화학치료를 받은 경우 악화되었다 (VanSeggelen 등, 2015). 화학치료 및 방사선조사는 여타 건강한 조직 상에 NKG2D 리간드를 유발하는 것으로 공지되어 있다 (Xiulong Xu, Geetha S Rao, Veronika Groh, Thomas Spies, Paolo Gattuso, Howard L Kaufman, Janet Plate and Richard A Prinz. Major histocompatibility complex class I-related chain A/B (MICA/B) expression in tumor tissue and serum of pancreatic cancer: Role of uric acid accumulation in gemcitabine-induced MICA/B expression. BMC Cancer 2011, 11:194 doi:10.1186/1471-2407-11-194; Gannag M, Buzyn A, Bogiatzi SI, Lambert M, Soumelis V, Dal Cortivo L, Cavazzana-Calvo M, Brousse N, Caillat-Zucman Induction of NKG2D ligands by gamma radiation and tumor necrosis factor-alpha may participate in the tissue damage during acute graft-versus-host disease. Transplantation. 2008 Mar 27;85(6):911-5. doi: 10.1097/TP.0b013e31816691ef.). 추가의 특징분석은 독성이 전신적 싸이토카인 발작 및 폐 내부에서의 치사 수준의 염증과 동시에 일어남을 밝혀냈다. 그러한 데이터는 표적화 면역요법을 위해 천연 NKG2D 리간드 사용시 극도의 주의를 요함을 경고하며, 강력 활성화 CAR 의 T 세포 발현의 강화는 생체내에서 해로울 수 있음을 입증한다 (VanSeggelen 등, 2015).
천연 NKG2D 리간드에 결합하지 않거나 또는 저조하게만 결합하는 비-천연 NKG2D 수용체의 엑토도메인들로 이루어진 CAR-T 또는 CAR-NK 세포는 상기의 활성화 유형 대상이 되지 않으며, 따라서 천연 NKG2D 수용체 기재의 CAR 를 발현하는 세포로서 독소발생원이 될 수 없다. 나아가, 세포 상의 비-천연 NKG2D 수용체의 엑토도메인은 가용성 포맷으로 또는 골수 유도성 억제자 세포 (MDSC) 상에서 천연 NKG2D 리간드에 의한 하향조절 대상이 되지 않는다 (Deng W, Gowen BG, Zhang L, Wang L, Lau S, Iannello A, Xu J, Rovis TL, Xiong N,Raulet DH, 2015. Antitumor immunity. A shed NKG2D ligand that promotes natural killer cell activation and tumor rejection. Science. 2015 Apr 3;348(6230):136-9. doi: 10.1126/science.1258867. Epub 2015 Mar 5). 그러나, 비-천연 NKG2D 수용체의 엑토도메인을 보유하는 그러한 CAR 세포들이 본 발명의 동족 비-천연 α1-α2 도메인이 있는 이중특이적 분자 및 그의 의도하는 표적에서 발견되며 그에 결합하는 그의 이종성 표적화 모티프에 의해 관여되어, CAR 는 활성화될 것이며, CAR-세포의 효과기 기능들이 발현될 것이다.
비-천연 NKG2D 수용체 엑토도메인으로 이루어지는 CAR-T 또는 CAR-NK 세포들은 동족 비-천연 α1-α2 도메인으로 이루어지는 관여된 이중특이적 분자의 존재 하에서를 제외하고 활성화되지 않기 때문에, 그들의 활성화는 투여된 이중특이적 분자들에 의해 제어될 수 있는데, 이들은 바이오생약으로서 당 분야에 널리 공지된 약동학 및 약력학을 나타낸다. 부작용 이벤트가 발생하는 이벤트에서, 내과의는 현재 시행되는 주입된 CAR 세포를 파괴할 유도 자살 메커니즘을 배치하기보다는 투여되는 이중특이적 분자의 투약계획을 단순히 변경할 수 있다 (Monica Casucci and Attilio Bondanza. Suicide Gene Therapy to Increase the Safety of Chimeric Antigen Receptor-Redirected T Lymphocytes. J Cancer. 2011; 2: 378-382). 나아가, 상이한 특이적 표적화 모티프를 가진 그러한 이중특이적 분자들은 동시에 또는 순차적으로 투여되어 종양 내성을 해결하고 여러 상이한 자가 CAR 세포들을 조성해, 증식시키고 주입할 필요없이 표적 항원 소실의 결과로서 탈출할 수 있다 (Gill & June, 2015). 모든 CAR 구축물들이 모든 CAR 세포에 대해 동일하고, 표적화 특이성이 본 발명의 생산된 이중특이적 분자의 표적화 모티프에 의해 단순히 결정될 수 있으므로, 제조 프로세스가 단순화되고 비용이 덜 부과될 것이다.
따라서, 본 발명은 CAR-T 세포 및 CAR-NK 세포를 이용해 암을 관리하고, 현존하는 인식된 어려움을 대다수 극복할 그러한 특기할 매우 유망한 면역학적 접근법의 다변성 및 실용성을 확장한다.
본원에 사용된 바와 같이, "펩티드", "폴리펩티드" 및 "단백질"은 호환하여 사용되며; "이종성 분자", "이종성 펩티드", "이종성 서열" 또는 "이종성 원자" 는 자연적으로 또는 정상적으로는 대상 분자와 물리적으로 결합되어 있지 않은 각각의 분자, 펩티드, 핵산 또는 아미노산 서열 또는 원자이다. 본원에 사용된 바와 같이, "비-천연" 및 "개질된" 은 호환하여 사용된다. 본원에 사용된 바와 같이, "천연" 또는 "본연" 은 호환하여 사용되며, "NKG2D" 및 "NKG2D 수용체" 는 호환하여 사용된다. 본원에서 용어 "항체" 는 광범위한 의미로 이용되며, 구체적으로는 그들이 원하는 생물학적 활성을 나타내는 한 모노클로날 항체, 다중특이적 항체 (예를 들어, 이중특이적 항체), 및 항체 절편을 포함한다. "항체 절편" 은 바람직하게는 그의 항원 결합 영역을 포함하며, 온전한 항체의 일부분을 포함한다. 항체 절편의 예시는 Fab, Fab', F(ab')2, 및 Fv 절편; 디아바디들 (diabodies); 선형 항체들; 단일쇄 항체 분자; 및 항체 절편(들)로부터 형성되는 다중특이적 항체들을 포함한다.
"~ 이 포함되는", "~ 을 함유하는" 또는 "~ 을 특징으로 하는" 과 호환하여 이용되는 용어 "~ 을 포함하는" 은 포괄적 또는 개방형 언사로, 추가적, 미언급 구성요소 또는 방법 단계를 배제하지 않는다. 어구 "~ 로 이루어진" 은 청구범위에서 언급되지 않은 임의의 구성요소, 단계 또는 성분을 배제한다. 어구 "~ 로 본질적으로 이루어진" 은 특정한 물질 또는 단계, 및 청구된 발명의 기본적이며 신규한 특징에 실질적으로 영향을 주지 않는 것들로 청구범위의 범위를 제한한다. 본 개시내용은 각각의 그러한 어구들의 범위에 해당하는 본 발명의 구현예 및 방법을 참작한다. 따라서, 언급한 구성요소 또는 단계를 포함하는 조성물 또는 방법은 해당 조성물 또는 방법이 그러한 구성요소 또는 단계로 본질적으로 이루어지거나 또는 그것으로 이루어진 특별한 구현예를 참작한다.
본원에 언급된 모든 참고문헌들은 앞서 구체적으로 포함되는지 여부와 무관하게 그 전체가 참고문헌으로 포함된다. 본원에 사용된 바와 같이, 대표단수 표현용어들은 각각 단수 및 복수 형태를 모두 포함하는 것으로 의도된다.
본 발명을 전부 설명했으니, 당업자는 본 발명의 진의 및 범위를 벗어남없이 과한 실험 없이도 다양한 동등한 파라미터, 농도 및 조건의 범위 내에서 동일한 것을 수행할 수 있음을 알 것이다. 본 발명이 그의 특정 구현예와 연계하여 기술되었지만, 추가로 개질이 가능하다는 것을 이해할 것이다. 본 출원은 일반적으로 본 발명의 원리를 따르고, 본 발명이 속하는 기술 분야의 공지되거나 또는 통상적인 관행에 속하는 본 개시내용으로부터의 그러한 이탈을 포함하는 본 발명의 임의의 변형, 이용 또는 적용을 포괄하는 것을 의도로 하며, 앞서 제시되는 본질적 특징에 적용될 수 있다.
iFv
및
NKG2D
리간드의
개질된
α1-α2 도메인의
실시예
실시예 1 ( iFv ). 특정 실시예로서, 하기 순서로 인코드하는 1126 bp 및 1144 bp DNA 절편 (각각 SEQ ID NO:1 및 2) 을 합성했다: 인간 MICA 의 α3 도메인 (부모 펩티드로서) 아미노산 182 내지 아미노산 194 (α3 도메인의 루프 1 의 시작점), 스페이서 부재 또는 GGS 아미노산 스페이서 영역 (SR), 및 섬유아세포 생장 인자 수용체 3 (GFR3)-결합 항체의 구조 기재의 iFv 펩티드 (MAbR3;Qing, J., Du, X., Chen, Y., Chan, P., Li, H., Wu, P., Marsters, S., Stawicki, S., Tien, J., Totpal, K., Ross, S., Stinson, S., Dornan, D., French, D., Wang, Q. R., Stephan, J. P., Wu, Y., Wiesmann, C., 및 Ashkenazi, A. (2009) Antibody-based targeting of FGFR3 in bladder carcinoma and t(4;14)-positive multiple myeloma in mice, The Journal of clinical investigation 119, 1216-1229.), 스페이서 부재 또는 또다른 GGS 스페이서 영역, 아미노산 196 에서 출발하며, α3 도메인의 나머지 카르복시-말단 부분을 포함하는 가용성 MICA 분자의 아미노산 276 까지의 α3 도메인의 루프 1 의 원거리 부분. 이후 각각의 합성, 이중 가닥 DNA 폴리뉴클레오티드가 MICA 의 α3 도메인의 루프 1 로 삽입되는 iFv 의 형태로 6 개의 CDR 을 포함하는 폴리펩티드를 인코드한다.
SEQ ID NO.:4 에 의해 인코드되는 그러한 iFv 펩티드 자체 (SEQ ID NO.:3) 는 잔기 GGSSRSSSSGGGGSGGGG (SEQ ID NO.:5) 에 해당하는 2 개의 동일한 전형적 링커 영역 (LR) 을 포함한다 (Andris-Widhopf, J., Steinberger, P., Fuller, R., Rader, C., and Barbas, C. F., 3rd. (2011) Generation of human Fab antibody libraries: PCR amplification and assembly of light- and heavy-chain coding sequences, Cold Spring Harbor protocols 2011). 한 LR 은 VL 의 C-말단을 VH 도메인의 N-말단에 결합하며, 두번째 LR 은 VH 도메인의 C-말단을 VL 의 N-말단에 결합한다. 개념상으로 이러한 신규 구조는 앞서 언급되는 연속적 또는 "고리형" 펩티드이며, 출발 Fv 의 6 개의 CDR 을 포함했다. 항체의 가변 VL 사슬은 베타-가닥 1 및 2 (S1 및 S2) 사이의 루프 영역 내에서 유효하게 스플릿되며, 이로써 각각 신규한 비-천연 C- 및 N-말단의 쌍을 동반하는 신규 N-말단 세절 (VLN) 및 신규 C-말단 세절 (VLC) 을 조성하게 된다, 도 5, 패널 A 참조. 그렇게 쌍을 이룬 말단은 단백질과 같은 수용 분자에 대한 iFv 의 부착 또는 컨쥬게이션을 위한 단독 부위를 조성한다. 부모 α3 도메인 중에 삽입된 iFv 의 도식은 도 5, 패널 B 에 제시된다.
α3 도메인 중에 삽입된 이종성 iFv 펩티드가 있는 가용성 MICA 단백질을 생산하기 위해, α3-iFv.1 (SEQ ID NO.:6) 및 α3-iFv.2 (SEQ ID NO.:7) 을 각각 인코드하는 DNA 서열 (SEQ ID NO.:1 및 2) 을 수용하는 바큘로바이러스 발현 벡터를 제조했다. DNA 절편을 PCR 로 증폭시키고, NcoI 및 EcoRI 제한효소를 이용해 소화하고, 바큘로바이러스 발현 벡터, SW403 에 서브클로닝하여, 야생형 α3 도메인을 대체했다. SW403 는 야생형 sMICA (잔기 1 내지 276) 이 5' BamHI 및 3' EcoRI 부위를 이용하여 사전에 클로닝된 pVL1393 (Invitrogen, Inc.) 로부터 유도된 바큘로바이러스 발현 벡터이다. 신규 발현 벡터는 SF9 곤충 세포로 바큘로바이러스 DNA 와 함께 공동-형질주입되었으며, 바큘로바이러스는 2 회의 증폭 싸이클 동안 생장시켜, 제조사의 프로토콜 (Invitrogen) 에 따라 T.ni 곤충 세포에서의 His-태그된 MICA-α3-iFv 단백질 발현에 이용했다. 발현은 3 일 동안 100 mL 부피에 실시되었으며, 생장 배지는 Ni-친화성 크로마토그래피를 이용해 분비된 가용성 단백질을 정제하기 위해 수합되었다. SDS-PAGE 로 결정되는 예측 분자량 60.9 kDa 인 단량체 MICA-α3-iFv 는 90% 초과의 순도로 정제되었다. 기능 특징분석은 결합 ELISA 및 시험관내 표적 세포 살해 검정을 이용해 실시되었다.
정제된 MICA-α3-iFv 단백질은 FGFR3-결합 ELISA 에서 시험하여, FGFR3 표적 및 NKG2D 수용체에 대한 동시적 결합을 확인했다. 인산염 완충 식염수 (PBS) 중의 FGFR3 는 Maxisorp 플레이트 상에 2 ug/ml 농도로 코팅되었다. 각 MICA 단백질을 적정하여, FGFR3 에 1 시간 동안 결합하도록 하고, 세척해 미결합 sMICA 단백질을 제거했다. 결합된 MICA-α3-iFv 단백질은 NKG2D-Fc 및 항-Fc-HRP 컨쥬게이트를 이용해 검출했다. 도 6 은 MICA-α3-iFv.1 및 MICA-α3-iFv.2 의 FGFR3 에 대한 결합이 가용성 MICA 의 C-말단에 MAbR3 로부터 구축된 전형적 scFv 를 융합해 제조되는 MICA-scFv 의 경우와 필적한다는 점을 보여준다. 그러한 ELISA 결과는 또한 scFv 및 α1-α2 도메인의 FGFR3 및 NKG2D 결합 특이성이 각각 개질된 MICA 에 의해 유지됨을 시사하며, 상이한 스페이서 포맷을 이용해 삽입되는 iFv 펩티드가 관능성임을 입증했다.
sMICA-α3-iFv.2 의 열 안정성을 시험해 sMICA-scFv 의 것과 비교했다. 두 단백질 모두 1 시간 동안 60 내지 90℃ 로부터의 온도 상승에 적용한 후, 1 시간 동안 실온으로 평형화하도록 두고, ELISA 로 결합 특성에 대해 검정했다. 도 7 에서의 결과는 MICA-α3-iFv.2 가 FGFR3 에 대한 특이적 결합에서 손실없이 80℃ 만큼 높은 온도에 적용될 수 있음을 보여줬다. 전형적인 MICA-scFv 은 70℃ 에서 결합 활성을 소실했다. 상기 결과는 본 발명의 iFv 포맷을 포함하는 가용성 MICA 가 전형적 scFv 의 말단 융합체들보다 유의하게 더욱 안정함을 시사했다 (Miller, B. R., Demarest, S. J., Lugovskoy, A., Huang, F., Wu, X., Snyder, W. B., Croner, L. J., Wang, N., Amatucci, A., Michaelson, J. S., and Glaser, S. M. (2010) Stability engineering of scFvs for the development of bispecific and multivalent antibodies, Protein engineering, design & selection : PEDS 23, 549-557; Weatherill, E. E., Cain, K. L., Heywood, S. P., Compson, J. E., Heads, J. T., Adams, R., and Humphreys, D. P. (2012) Towards a universal disulphide stabilised single chain Fv format: importance of interchain disulphide bond location and vL-vH orientation, Protein engineering, design & selection : PEDS 25, 321-329).
FGFR3-발현 표적 세포의 NK 세포-중재 용해를 전용하는 MICA-α3-iFv 의 능력은 시험관내 칼세인-방출 검출에서 입증되었다. 자연 살해 (NK) 세포주, NKL 는 이소성으로 (ectopically) FRFR3 을 발현하는 칼세인-담지 P815 표적 세포와 함께 배양했다. 도 8 에서의 결과는 2 개의 MICA-α3-iFv 분자들이 전형적 MICA-scFv 융합체에 비해 유의하게 더 큰 NK-중재 용해를 유발하는 한편, 비-표적화 가용성 MICA 대조군은 살해 활성을 갖지 않음을 보여준다. 그러한 결과로 본 발명의 iFv 가 표적 세포 상의 FGFR3 에 결합하고, 완전한 부모 단백질 분자인 가용성 MICA 와 관련하여 강력한 NK 세포 중재 용해를 유도함을 확인했다.
iFv 포맷의 여타 항체 가변 도메인에 대한 이용가능성은 CD20-특이적 항체로부터 유도된 iFv 를 포함하는 α3-iFv.3 (SEQ ID NO.:8) 를 유사하게 구축함으로써 입증되었다 (Du, J., Wang, H., Zhong, C., Peng, B., Zhang, M., Li, B., Huo, S., Guo, Y., and Ding, J. (2007) Structural basis for recognition of CD20 by therapeutic antibody Rituximab, The Journal of biological chemistry 282, 15073-15080). 도 9 는 MICA-α3-iFv.3 이 상기 기재된 플레이트-기재 ELISA 에서 CD20 으로 코팅된 웰에 특이적으로 결합할 수 있고, 또한 칼세인-방출 검정에서 CD20 를 발현하는 Ramos 세포의 NK-중재 용해를 유도함을 보여준다.
실시예 2 ( NKG2D 리간드의 개질된 α1-α2 도메인). ULBP-1 내지 ULBP-6 로 정한 인간 단백질은, MICA 및 MICB 와 마찬가지로, 자연 발생적이며, 스트레스-유도성의, 인간 NK 세포 및 특정 T-세포 상의 NKG2D 수용체에 결합하여 인간 NK 세포 및 특정 T-세포를 활성화하는 세포 표면 리간드이다 (15; Cerwenka A, Lanier LL (2004). NKG2D ligands: unconventional MHC class I-like molecules exploited by viruses and cancer. Tissue Antigens 61 (5): 335-43. doi:10.1034/j.1399-0039.2003.00070.x. PMID 12753652). 추가로, 우두 바이러스 단백질 OMCP 는 MIC 단백질의 α1-α2 도메인과 같이 NKG2D 에 결합하는 분비된 도메인이다. OMCP 는 NKG2D 에 대한 매우 높은 친화성을 나타내는데, 명백하게 그의 감염된 숙주 세포 상에서 바이러스에 의해 유도되는 천연 스트레스 리간드의 NKG2D 의 인식을 차단하기 위한 것이다 (Eric Lazear, Lance W. Peterson, Chris A. Nelson, David H. Fremont. J Virol. 2013 January; 87(2): 840-850. doi: 10.1128/JVI.01948-12). ULBP 및 OMCP 는 원형 α1-α2 도메인 구조를 공유하는 NKG2D 리간드 (NKG2DL) 로 간주되는데, MICA α1-α2 와의 서열 상동성은 27% 미만이고, 이들은 전부 표적화 도메인을 결박할 α3 도메인이 결핍되어 있다. 각각의 ULBP-1, ULBP-2, ULBP-3, ULBP-4, ULBP-6 및 OMCP 에 대한, 표적화 iFv 가 삽입되어 있는, MICA 의 개질된 α3 도메인의 융합 결과 FGFR3-발현 세포를 특이적으로 표적화하여 살해하는 이종성 폴리펩티드를 부착함으로써 일련의 비-천연 ULB 및 OMCP 단백질을 구축했다. 추가로, MICA 의 α1-α2 도메인을 개질하여 α1-α2 도메인의 NKG2D 에 대한 친화성을 강화한 후, 개질된 α1-α2 도메인 이종성 분자, 예를 들어 폴리펩티드에 부착시켰다. 개질된 α3-iFv 도메인에 부착된 ULBP 및 OMCP α1-α2 도메인으로 이루어진 단백질을 생산하기 위해, ULBP-1, ULBP-2, ULBP-3, ULBP-4, ULBP-6 및 OMCP 의 상이한 α1-α2 도메인 (각각 SEQ ID NO.:15 내지 20) 을 인코드하는 DNA 절편들 (SEQ ID NO:9 내지 14) 을 수용할 바큘로바이러스 발현 벡터를 제작했다. 상기 DNA 절편들을 PCR 로 증폭하고, BlpI 및 NcoI 제한 효소를 이용해 소화하고, 개별적으로 바큘로바이러스 발현 벡터, KLM44 에 서브클로닝하여, MICA α1-α2 도메인을 대체했다. KLM44 는 MICA-α3-iFv.2 가 상기에서 클로닝되어 있는 (실시예 1) SW403 로부터 유도된 바큘로바이러스 발현 벡터이다. α3-iFv.2 에 대한 ULBPs 및 OMCP α1-α2 도메인 융합체들을 포함하는 신규 NKG2DL-α3-iFv.2 구축물들 (각각 ULBP1-α3-iFv.2, ULBP2-α3-iFv.2, ULBP3-α3-iFv.2, ULBP4-α3-iFv.2, ULBP6-α3-iFv.2 및 OMCP-α3-iFv.2; SEQ ID NO.:21-26) 을 SF9 곤충 세포로 바큘로바이러스 DNA 와 함께 형질이식했다. 바큘로바이러스는 2 회의 증폭 싸이클 동안 생장시키고, 제조사의 프로토콜 (Invitrogen) 에 따라 그러한 His-태그된 NKG2DL-α3-iFv.2 단백질을 T.ni 곤충 세포에서 발현시키기 위해 이용했다. 발현은 100 mL 부피에서 3 일 동안 실시했으며, 생장 배지는 Ni-친화성 크로마토그래피를 이용한 분비된 가용성 단백질의 정제를 위해 수합했다. 정확한 분자량의 단량체 단백질은 SDS-PAGE 로 결정하여 90% 초과의 순도로 정제되었다. 관능 특징분석은 결합 ELISA 및 시험관내 표적 세포 살해 검정을 이용해 실시했다.
여섯가지 정제된 NKG2DL-α3-iFv.2 단백질을 FGFR3-결합 ELISA 에서 시험하여 FGFR3 표적 및 NKG2D 수용체에 대한 동시 결합을 확인했다. 인산염 완충 식염수 (PBS) 중의 FGFR3 을 Maxisorp 플레이트 상에 2 ug/ml 농도로 코팅했다. 각 NKG2DL-α3-iFv.2 단백질을 적정하여, FGFR3 와 1 시간 동안 결합하도록 했고, 세척하여 미결합 단백질을 제거했다. 결합된 NKG2DL-α3-iFv.2 단백질은 NKG2D-Fc 및 항-Fc-HRP 컨쥬게이트를 이용해 검출되었다. 도 10 은 여섯가지 NKG2DL-α3-iFv.2 단백질 모두 biFv.2 도메인과의 상호작용을 통해 예상한 바와 같이 FGFR3 와 강력하게 결합했으며, NKG2D 결합 활성이 부착된 NKG2DL α1-α2 도메인에 의해 유지됨을 보여주는데, 이는 부착된 α3-iFv 도메인이 MIC 단백질과 마찬가지로 NKG2D 에 결합하는 ULBP 및 OMPC 단백질에 대한 관능적 FGFR3 결합 활성을 제공함을 입증한다.
FGFR3-발현 표적 세포의 NK 세포-중재 용해를 전용하는 NKG2DL-α3-iFv.2 단백질의 능력은 시험관내 칼세인-방출 검정에서 입증되었다. 자연 살해 (NK) 세포주, NKL 는 이소성으로 FGFR3 를 발현하는 칼세인-담지 P815 표적 세포와 공동배양했다. 도 11 에서의 결과는 OMCP-α3-iFv.2 가 최대 NK-중재 용해를 유발하는 한편, 여타 NKG2DL-α3-iFv.2 단백질이 전부 다양한 정도의 용해 효능 및 양으로 특정 살해 활성을 나타냈음을 보여준다. 그러한 결과로 본 발명의 iFv 가 그들 자체의 관능적 특성을 유지하고, iFv-표적화 세포의 상이한 수준의 세포-중재 용해를 유발했던 여타 단백질들에 대한 특이적 결합 활성을 제공함을 확인했다.
실시예 3 ( NKG2D 리간드의 개질된 α1-α2 도메인). 이들은 인간 NKG2D 수용체에 대한 그들의 결합 친화성을 유의하게 강화하도록 개질된 NKG2DL 에 대한 부착 폴리펩티드의 예시이다. MIC 단백질의 α1-α2 도메인은 NKG2D 수용체에 대한 NKG2DL 이다. 상기 친화성은 NK 세포의 생리학적 활성화 및 "표적 세포" 의 2 차원적 원형질막 표면에 비가역적으로 결박된 본연의 전장 MIC 단백질을 발현하는 세포의 용해 자극에 충분하다 (Bauer S, Groh V, Wu J, Steinle A, Phillips JH, Lanier LL, Spies T., Science. 1999 Jul 30;285(5428):727-9.). 그러나, 본 발명의 조작된 가용성 MIC 단백질은 표적 세포의 표면 상에서 특이적 표적 항원에 비가역적으로 결합하기 때문에, 조작된 가용성 MIC 단백질의 NKG2D 에 대한 결합 친화성은 NK 세포 및 표적 항원 발현 세포 사이에서 형성되는 가용성 MIC-의존형 복합체의 안정성에 직접적으로 영향을 준다. 특히, sMICA 및 NKG2D 사이의 친화성이 NKG2D 유래 개질된 sMICA 의 실질적으로 더 느린 해리 속도 또는 오프-레이트에 의해 증가되는 경우, NK 세포-기재 살해는 표적 세포에 결합된 더 낮은 밀도의 가용성 MIC 분자들에서 더 클 것으로 예상된다. 본 발명의 선행기술에서는, 가용성 MIC 단백질의 살해 활성을 변경하거나 또는 MIC 단백질의 NKG2D 에 대한 친화성을 강화할 결합 오프-레이트를 유의하게 감소시키는 임의의 α1-α2 돌연변이들이 밝혀진 바 없다. 전산 설계 노력에서는 야생형 MICA: N69W, K152E 및 K154D (WED-MICA) 의 α1-α2 도메인에서 조합되는 세가지 돌연변이들이 미결합 MICA 의 안정성에 영향을 줌으로써 NKG2D 결합 친화성에 약하게 영향을 줄 수 있고, 이로써 NKG2D 에 대한 결합의 회합 속도 또는 온-레이트에 영향을 줄 수 있음을 보여줬다 (Lengyel CS, Willis LJ, Mann P, Baker D, Kortemme T, Strong RK, McFarland BJ.J Biol Chem. 2007 Oct 19;282(42):30658-66. Epub 2007 Aug 8); 공개된 구조 설명 (Li P, Morris DL, Willcox BE, Steinle A, Spies T, Strong RK., Nat Immunol. 2001 May;2(5):443-451) 에 따라 이론적으로는 NKG2D 와 접하는 MICA 의 22 개 아미노산 위치의 반복 계산에 의한 동일 그룹 스캐닝에 의한 후속적인 집중적 전산 설계는, 더 이른 시기에 고안된 3 개의 변화와 조합시 총 7 개의 조합된 돌연변이들로, MICA 의 더욱 합리적, 반복적 전산 설계가 NKG2D 에 대한 친화성을 약함 (Kd 약 2.5 μM) 에서 중간 강도 (Kd = 51nM) 로 질적으로 변화시킴을 실험에서 보여줬다 (Henager, Samuel H., Melissa A. Hale, Nicholas J. Maurice, Erin C. Dunnington, Carter J. Swanson, Megan J. Peterson, Joseph J. Ban, David J. Culpepper, Luke D. Davies, Lisa K. Sanders, and Benjamin J. McFarland, 2102, Combining different design strategies for rational affinity maturation of the MICA-NKG2D interface. Protein Science 21:1396-1402). 대조적으로, 본 발명에 기재된 실험적 접근은, Lengyel 등의 문헌 (Lengyel CS, Willis LJ, Mann P, Baker D, Kortemme T, Strong RK, McFarland BJ., J Biol Chem. 2007 Oct 19;282(42):30658-66. Epub 2007 Aug 8) 에 기재된 3 개의 WED 변화에 의해 안정화되는 MICA 로 시작하여, MICA 의 α1-α2 도메인 및 NKG2D 사이의 오프-레이트를 둔화시키는 MICA 의 아미노산 개질을 실험으로 선별했다.
본 발명의 본 실시예는 오프-레이트 결합 동역학에 영향을 주어 그에 따른 본 발명의 비-천연 표적화 MIC 분자들의 NK 세포 중재 살해 활성을 변경하는 α1-α2 도메인 내부의 선택된 아미노산 위치에서의 특정 돌연변이들의 조작을 통한 가용성 MIC 단백질의 NKG2D 결합 친화성 개질에 관한 것이다.
NKG2D 에 대한 친화성이 변경된 가용성 비-천연 α1-α2 도메인을 조작하기 위해, α1-α2 도메인 내 NKG2D 57 개 잔기들을 집중적 돌연변이유발용으로 선택했다 (도 12). α1-α2 도메인을 코드하고, 57 개 아미노산 위치 각각에 NNK 돌연변이유발 코돈을 포함하는 합성 DNA 라이브러리를 합성하여, 개별적으로 융합체들로서 M13 파지의 pIII 마이너 코트에 대해 클로닝하고, 돌연변이유발된 α1-α2 변이체들을 제시하는 파지 입자들을 표준 방법론에 따라 SS320 대장균 세포에서 생산했다 (Andris-Widhopf, J., Steinberger, P., Fuller, R., Rader, C., 및 Barbas, C. F., 3rd. (2011) Generation of human Fab antibody libraries: PCR amplification and assembly of light- and heavy-chain coding sequences, Cold Spring Harbor protocols 2011). α1-α2 파지 라이브러리는 표적 항원으로서 재조합 바이오티닐화 NKG2D 를 이용해 증가된 결합 친화성에 대해 분류하여, 의도적으로 연장시킨 결합, 의도적으로 연장시킨 세척 및 파지 클론 용리의 반복적 순회를 통해 순환시켜, 느린 해리- 또는 오프-레이트를 위해 풍부화된 고친화성 변이체들을 선별했다. α1-α2 내 6 개 위치에서 특정 아미노산 돌연변이들의 셋트가 고빈도로 발생했으며, 강화된 NKG2D 결합 친화성을 가진 바람직한 아미노산 치환으로서 선택되었다 (도 12, 표 1).
표 1.
MIC 의 α1-α2 도메인의 표시된 6 개 아미노산 위치에서의 선택된 친화성 돌연변이들. 각 6 개 위치에서의 SEQ ID NO.: 35 의 아미노산들은 표의 첫째줄에서 볼드체로 나타낸다. 식별된 친화성 돌연변이들을 상단부터 하단까지 빈도 내림차로 수록한다. 모든 아미노산들은 단일자 IUPAC 약어로 표기한다.
특정한 발견된 돌연변이들의 상이한 조합을 포함하는 4 가지 대표 변이체들 15, 16, 17, 18 (표 2) 의 α1-α2 도메인을 인코드하는 DNA 폴리뉴클레오티드 (SEQ ID NO. 27 내지 30) 를 합성했다.
표 2.
특정 α1-α2 도메인 변이체들의 서열. 변이체들 15, 16, 17 및 18 (각각 SEQ ID NO.: 31 내지 34) 에 대한 특정 아미노산 치환을 SEQ ID NO.:35 의 아미노산과 비교해 볼드체로 열거한다. 모든 아미노산들을 단일자 IUPAC 약어로 표기한다.
상기 실시예에서 NKG2DL 에, 이종성 분자들, 예를 들어 폴리펩티드를 링커 펩티드를 이용해 이들 4 개의 개질된 α1-α2 NKG2DL 의 각각에 직접 부착했다. 부착된 이종성 분자들이 있는 개질된 NKG2DL 들로 이루어진 4 개의 His-태그된 단백질 (SEQ ID NO.: 31 내지 34) 을 곤충 세포에서 발현시키고, 정제하여 그들의 NKG2D 결합 친화성 및 동역학 결합 파라미터를 특징분석했다. 경쟁 결합 ELISA 를 이용하여, 4 개의 개질된 α1-α2 변이체들의 상대적 NKG2D 결합 친화성을 측정했다. 가용성 야생형 (WT) NKG2DL, sMICA 단백질을 maxisorp ELISA 플레이트의 모든 웰에 코팅하여 인간 NKG2D-Fc 시약에 대한 결합 파트너를 제공했다. 4 개의 α1-α2 변이체들 뿐 아니라 WT 및 WED- α1-α2 도메인 (SEQ ID NO.: 35) 의 용액을 ELISA 웰에서 적정하고, 플레이트 상에 코팅된 WT sMICA 에 대한 2nM 인간 NKG2D-Fc 의 결합을 경쟁적으로 억제하도록 했다. 플레이트 상에서 WT NKG2DL 에 결합된 인간 NKG2D-Fc 의 수준은 항-Fc-HRP 항체를 이용해 검출했다. 도 13, 패널 A 는 변이체들 16, 17 및 18 이 0.7, 0.6, 0.5 nM 의 IC50 값을 나타내는 반면, 변이체 15 는 1.7 nM 의 IC50 값을 나타냄을 보여주는데, 전부 NKG2D 에 대해 WT NKG2DL 보다 각각 27, 32-, 38- 및 11-배 더 나을 뿐 아니라, WED-MICA 보다도 실질적으로 더 나은 결합을 보유했다 (표 3).
표 3.
α1-α2 변이체들에 대한 평형 및 동역학 결합 파라미터. IC50 값은 경쟁 결합 적정에 대한 4-파라미터 핏팅으로부터 유도되었고 (도 12), 동역학 결합 파라미터는 결합 동역학에 대한 단일 지수 핏팅으로부터 유도되었다 (도 13). 평형 결합 상수 (Kd) 는 하기 등식을 이용해 동역학 결합 파라미터로부터 유도되었다: Kd = kOFF/kON.
중요하게는, 상대적 IC50 차이는 또한 쥐과동물 NKG2D-Fc 에 대한 더 나은 결합으로 변환되며 (도 13, 패널 B), 전임상 약물 개발에 중요한 특성인 인간 및 비-인간 NKG2D 수용체를 넘나드는 가용성의, 개질된 α1-α2 도메인의 결합을 개선하는 능력을 입증했다.
변경된 친화성에 대한 동역학적 근거를 이해하기 위해, α1-α2 변이체 NKG2DL 의 표면 코팅된 바이오티닐화된 인간 NKG2D 에 대한 결합에 대한 온-레이트 및 오프-레이트 모두를 각각의 개질된 α1-α2 단백질 100 nM 에서 바이오레이어 간섭법 (Octec) 을 이용해 측정했다. IC50 ELISA 의 결과와 일치하게, 변이체들 16, 17 및 18 은 각각 오프-레이트에서 유의한 감소 (WT 에 비해 18-배) 를 나타냈는데, 이는 친화성 증가에 매우 큰 기여를 한다 (WT a1-a2 에 비해 약 30 배)(도 14; 표 3). 변이체 15 가 16, 17, 및 18 과 유사한 느린 오프-레이트를 나타냄에도, 그의 온-레이트는 감소하여, WT 보다는 강력하나, 변이체들 16, 17 및 18 보다는 더 약한 친화성을 제공하는 결과를 가져왔다. 변이체 15 (SEQ ID NO.:31) 및 16 (SEQ ID NO.:32) 사이의 유일한 차이점은 K125N 대 K125L 이므로, 위치 125 에서의 돌연변이는 명백하게 온-레이트를 변경하는 한편, 감소된 오프-레이트는 H161R 돌연변이에서 기인한다. 따라서, NKG2DL 돌연변이들의 선택된 셋트 (표 1) 는 유의한 오프-레이트 감소를 통해 NKG2DL 에 대한 α1-α2 친화성 증가에 이용되었으며, 특정 치환들이 또한 온-레이트를 변경하여, 그 결과 본 발명에서 제시된 다양한 점증적 친화성 증가를 초래해, NK 세포-중재 살해 검정에서 하기 기재된 바와 같은 차별적 활성을 갖게 되었다.
α1-α2 친화성 변이체들이 FGFR3-발현 표적 세포들의 NK 세포-중재 용해를 전용하는 능력이 시험관내 칼세인-방출 검정에서 입증되었다. 인간 자연 살해 (NK) 세포주, NKL 을 이소성으로 FGFR3 를 발현하는 칼세인-담지 P815 표적 세포와 공동배양하고, 가용성의 개질된 MIC 단백질로 적정했다. 도 15 에서의 결과는 FGFR3-특이적 가용성 MIC 변이체들의 살해 활성이 그들의 조작된 α1-α2 친화성과 상관있음을 보여준다. 구체적으로, 변이체들 16, 17 및 18 은 0.78 nM 에서 WT 보다도 약 15 배 더 큰 살해를 나타냈다. WED-MICA (SEQ ID NO.:35) 는 WT 보다 약간 더 나을 뿐이었다. 따라서, 본 발명은 가용성 MIC 단백질의 인간 NKG2D 에 대한 결합의 오프-레이트 감소에 의해 NKG2D 결합 친화성을 증가시키며, 결과적으로 예측가능한 증가된 살생 효능을 나타낼 α1-α2 도메인 내 아미노산 치환을 기재한다. WED-MICA 는, 오프-레이트를 감소시키기 보다는 온-레이트를 증가시켜 (도 14) WT MICA 보다도 약간 더 큰 NKG2D 에 대한 친화성을 나타내는데 (도 13, 패널 A), 표적 세포 살해의 실질적 개선을 나타내지 않았다 (도 15). 나아가, 도 13, 패널 B 에 제시된 바와 같이, WED-MICA 는 심지어 WT MICA 보다도 쥐과동물 NKG2D 에 대해서는 실질적으로 더욱 열악한 결합을 나타내며, 변이체들 15, 16, 17 및 18 은 각각 인간 및 쥐과동물 NKG2D 의 모두에 대해 더 큰 친화성을 나타냈다, 도 13, 패널 A 및 B 참조.
그러한 α1-α2 NKG2DL 친화성 변이체들 15, 16, 17 및 18 은 부착된 폴리펩티드의 NKG2D 수용체에 대한 결합 친화성을 강화함으로써, 표적화 세포들의 NK세포-중재 용해를 강화했다, 도 15 참조.
실시예
4 (
NKG2D
리간드의
비-천연 α1-α2 도메인 및 그들이 결합하는 동족 비-천연
NKG2D
수용체)
MICA 의 α1-α2 도메인 및 여타 NKG2D 리간드들은 공지된 특이적 부위에서 NKG2D 수용체와 결합하고 (Li 등, 2001; Benjamin J. McFarland, Tanja Kortemme, Shuyuarn F. Yu, David Baker, and Roland K. Strong. Symmetry Recognizing Asymmetry: Analysis of the Interactions between the C-Type Lectin-like Immunoreceptor NKG2D and MHC Class I-like Ligands. Structure, Vol. 11, 411-422, April, 2003), NKG2D 수용체-보유 면역 세포의 활성화를 구동하는데, 이는 결과적으로 MICA 또는 여타 리간드를 제시하는 표적 세포를 살해한다. NKG2D 에 대한 결합에 관여되는 것으로 추정되는 57 개 특이적 부위에서 집중적 돌연변이유발에 의해 MICA 의 비-천연 α1-α2 도메인을 조작하기 위해 파지 디스플레이를 이용했다 (도 16). α1-α2 도메인을 코드하고, 각각의 57 개 아미노산 위치에서 NNK 돌연변이유발 코돈을 포함하는 합성 DNA 라이브러리를 합성했으며, M13 파지의 pIII 마이너 코트 단백질에 대한 융합체들로 개별적으로 클로닝했고, 돌연변이화된 α1-α2 변이체들을 제시하는 파지 입자들을 표준 방법론에 따라 SS320 대장균 세포에서 생산했다 (Andris-Widhopf, J., Steinberger, P., Fuller, R., Rader, C., and Barbas, C. F., 3rd, 2011. Generation of human Fab antibody libraries: PCR amplification and assembly of light- and heavy-chain coding sequences, Cold Spring Harbor protocols 2011). α1-α2 파지 라이브러리를 표적 항원으로서의 재조합 바이오티닐화된 NKG2D 는 이용하여 증가되는 결합 친화성에 대해 분류되고, 의도적으로 연장된 결합, 의도적으로 연장된 세척 및 파지 클론 용리의 반복적 순회를 통해 순환되었는데, 이는 느린 해리- 또는 오프-레이트를 위해 풍부화된 고친화성 변이체들을 선별하기 위한 것이었다. α1-α2 도메인 중의 9 개 위치에서 특정 아미노산 돌연변이들의 셋트는 강화된 NKG2D 결합 친화성을 가진 아미노산 치환기들의 선호 부위로서 선택되었다. 특정한 돌연변이들의 상이한 조합을 포함하는 8 개의 대표적인 변이체들 (SEQ ID NO: 55 내지 62) 의 α1-α2 도메인을 인코드하는 DNA 폴리뉴클레오티드를 합성했다 (표 4).
표 4.
천연 NKG2D 수용체에 대한 증가된 친화성에 대해 선택된 비-천연 α1-α2 도메인 변이체들 및 선행기술 (McFarland 등, 2003) 에 기재된 MICwed 변이체. SEQ ID NO.: 42 에서의 잔기 위치를 기준으로 하여 표시된 아미노산 변화의 위치들 및 변이체들의 일반명 및 그들의 SEQ ID NO 가 제공된다.
[표 4]
8 개의 변이체 α1-α2 도메인을 인코드하는 DNA 폴리뉴클레오티드는 PCR 프라이머 (SEQ ID NO.: 63 내지 64) 를 이용해 증폭했다. Blp1 및 Sap1 제한효소를 이용해, 각각을 His-태그된 α1-α2-α3-Fv 융합체 발현 구축체 (SEQ ID NO.:65) 로 서브클로닝하여, 천연 (wt) α1-α2 서열을 인코드하는 서열을 돌연변이화된 α1-α2 서열로 대체했다. 9 개의 융합체 단백질 (SEQ ID NO.: 66 내지 74) 을 293 세포 (Expi293™Expression System, Life Technologies, Thermo Fisher, Inc.) 에서 발현시키고, Ni-친화성 크로마토그래피 (HisTrap HP, GE Healthcare Life Sciences) 를 이용해 친화성 정제했다.
NKG2D 수용체 단백질을 구축하기 위해, 야생형 수용체의 세포외 도메인 ("엑토도메인") (SEQ ID No.:75) 을 인코드하는 DNA 를 합성하고, PCR 프라이머 (SEQ ID NO.: 76 내지 77) 및, XbaI 및 BamHI 부위를 이용해 합성 DNA 를 N-말단 His-avitag 발현 벡터로 클로닝했다 (SEQ ID NO.: 78). 상기 His-avitag-천연 NKG2D (SEQ ID NO.:79) 를 293 세포에서 일시적으로 발현시키고, Ni-친화성 크로마토그래피를 이용해 정제했다. 정제에 후속하여, NKG2D 단백질을 BirA 를 이용하여 부위특이적으로 바이오티닐화하여 바이오틴기를 avitag 서열 상에 부착시켰다 (BirA 바이오틴-단백질 리가아제 표준 반응 키트, Avidity, LLC, Aurora, CO.).
천연 및 8 개의 변이체 α1-α2 도메인의 천연 NKG2D 에 대한 동역학 결합 파라미터를 특징분석하고 비교하기 위해, 바이오레이어 간섭법 (Octet) 을 이용하여 100 nM 의 각각의 α1-α2-α3-Fv 융합체 단백질에서 표면 코팅된 바이오티닐화된 천연 NKG2D 엑토도메인에 대한 그들의 결합을 측정했다. 결과는 표 5 에 제시한다.
표 5:
야생형 (wt 또는 천연) 및 8 개의 변이체 α1-α2 도메인 α3-Fv 융합체 단백질의 천연 NKG2D 에 대한 결합의 동역학 파라미터. 여기서, MICwed-Fv 는 두 번의 별개 Octet 분석에서 연구했는데, 한번은 wt α1-α2 도메인 α3-Fv 융합체와 비교했고, 나머지 한번은 7 개의 나머지 비-천연 α1-α2 도메인 α3-Fv 융합체들과 비교했다. 각 α1-α2 도메인 변이체들의 일반명 및 그들의 α3-Fv 융합체 단백질의 SEQ ID NO. 는, 몰 농도 (M) 로 나타낸 그들의 친화성 (Kd) 값, 몰농도-초의 역수 (1/Ms) 인 온-레이트 (kon), 및 초의 역수인 해리- 또는 오프-레이트 (kdis) 와 함께 제공되었다.
[표 5]
표 5 에 제시된 바와 같이, SEQ ID NO.: 68 내지 74 의 이종성 폴리펩티드 α3-Fv 에 대한 융합체들로서의 선택된 α1-α2 도메인 돌연변이들은 오프-레이트의 유의한 감소를 통해 천연 NKG2D 에 대한 α1-α2 도메인 친화성을 증가시켰다. 오프-레이트 범위는 wt (SEQ ID NO.:66) 및 선행기술에 기재된 MICwed α1-α2 도메인 변이체 (SEQ ID NO.:67) 의 것에 비해 20- 내지 100-배 더 느린 범위였다.
본 발명의 본 실시예에서, 하기 기재된 바와 같이 α1-α2-α3-Fv 융합체와 같이 천연 NKG2D 에 대한 높은 친화성, 그로부터의 매우 느린 오프-레이트 (표 2; SEQ ID NO.:69) 를 가진 비-천연 α1-α2 도메인 (DSM25, SEQ ID NO.:57, 표 4) 이, 천연 NKG2D 리간드에 대한 그의 결합을 파하는 특정 돌연변이를 포함하는 비-천연 NKG2D 수용체에 대한 밀접한 결합 친화성을 나타낸다는 점을 입증했다. 타인에 의해 NKG2D 엑토도메인 (SEQ ID NO.:75 및 도 17) 의 위치 73 및 120 과 동등한 인간 NKG2D 에서의 타이로신 152 및 타이로신 199 에서의 돌연변이들은 천연 리간드, MICA 에 대한 결합을 파하는 것으로 입증된 바 있다 (David J. Culpepper, Michael K. Maddox1, Andrew B. Caldwell, and Benjamin J. McFarland. Systematic mutants and thermodynamic analysis of central tyrosine pairs in polyspecific NKG2D receptor interactions. Mol Immunol. 2011 January ; 48(4): 516-523).
비-천연 NKG2D 수용체 단백질을 구축하기 위해, PCR 프라이머 (SEQ ID NO.:76 내지 77) 를 이용해 천연 NKG2D 엑토도메인 (SEQ ID NO.:75) 을 인코드하는 DNA 를 클로닝하고, 그것을 N-말단 His-avitag 발현 벡터 SEQ ID NO.:78 에 삽입하여 His-avitag-NKG2D (SEQ ID NO.:79) 를 생산했다. 부위-지정 돌연변이유발을 천연 NKG2D 엑토도메인 DNA 구축체 상에서 실행하여 Y152A, Y199A, 또는 Y152A 에 더해 Y199A 돌연변이들을 도입하고, 인간 NKG2D 의 세가지 비-천연 변이체들 (SEQ ID NO. 는 각각: 80 내지 82) 을 조성했다. 천연 NKG2D 및 His-avitag 가 있는 세가지 비-천연 NKG2D 돌연변이를 293 개의 세포에서 일시적으로 발현시키고, Ni-친화성 크로마토그래피를 이용해 정제했다. 정제 후, NKG2D 단백질은 BirA 을 이용해 부위특이적으로 바이오티닐화하여 바이오틴기를 avitag 서열 상에 부착시켰다 (BirA 바이오틴-단백질 리가아제 표준 반응 키트, Avidity, LLC, Aurora, CO.).
α3-Fc 이종성 폴리펩티드의 MICwed (SEQ ID NO.:55) 의 α1-α2 도메인 및 DSM25 α1-α2 도메인 (SEQ ID NO.: 57) 으로의 융합체들을 생성하기 위해, α1-α2 도메인을 인코드하는 DNA 폴리뉴클레오티드를 PCR 프라이머 (SEQ ID NO.: 63-64) 를 이용해 증폭했다. XbaI 및 NcoI 제한 효소를 이용하여, 각각을 α1-α2-α3-Fc 융합체 발현 구축체 (SEQ ID NO.:83) 에 서브클로닝하여, 천연 (wt) α1-α2 서열을 인코드하는 서열을 돌연변이화된 α1-α2 서열로 대체했다. 세가지 융합체 단백질, MICA-Fc (SEQ ID NO.: 84), MICwed-Fc (SEQ ID NO.: 85) 및 MICv25-Fc (SEQ ID NO.: 86) 을 293 개의 세포 (Expi293™ Expression System, Life Technologies, Thermo Fisher, Inc.) 에서 발현시키고, 단백질 A 친화성 크로마토그래피 (카탈로그 번호 20334, Pierce Biotechnology, Rockford, IL) 를 이용해 친화성 정제했다.
상기 세가지 Fc-융합체 단백질 NKG2D 리간드-Fc 융합체 단백질, MICB-Fc 을 정제하는 것에 추가하여, ULBP1-Fc, ULBP2-Fc, ULBP3-Fc 및 ULBP4-Fc 을 R&D Systems, Inc. 사 (Minneapolis, MN) 에서 구매했다. 상이한 α1-α2 도메인-Fc 융합체들의 천연 및 비-천연 NKG2D 엑토도메인 단백질의 두가지 모두에 대한 결합을 플레이트-기재 ELISA 방법을 이용해 분석했다. 모든 천연 및 비-천연 α1-α2 도메인-Fc 융합체들을 밤새 4℃ 에서 인산염-완충 식염수 (PBS) 중 2 ㎍/ml 의 농도인 코팅을 이용해 Maxisorp 96 웰 플레이트의 별개 웰들 상에 코팅하였다. 플레이트를 PBS/0.05% Tween20 으로 20 내지 22℃ 에서 3 회 세척하고, 0.5% 소혈청 알부민으로 2 시간 동안 블로킹했다. 바이오티닐화된 천연 및 비-천연 NKG2D 수용체 단백질을 플레이트-결합 NKG2D 리간드에 대해 2 시간 동안 20 내지 22℃ 에서 적정하고, PBS/0.05% Tween20 로 20 내지 22℃ 에서 3 회 세척하고, 후속하여 결합된 NKG2D 단백질을 스트렙타비딘-HRP 2차 검출 단계를 이용해 검출하고, 1-Step Ultra TMB Elisa 를 이용해 현출시켰다. NKG2D (SEQ ID NO.:75) 의 엑토도메인의 천연형은 시험한 모든 α1-α2 도메인-Fc 융합체들과 결합할 수 있었다 (도 18, 패널 A). 비-천연 MIC-v25 α1-α2 도메인 리간드는 MICwed 보다는 8-배 더, 시험한 모든 천연 α1-α2 도메인 리간드보다는 100-배 초과하여 높은 최고 친화성 (EC50= 14 nM) 으로 결합했다 (도 18, 패널 A). 시험한 모든 리간드는, 천연 및 비-천연 α1-α2 도메인 모두, Y199A 돌연변이 (SEQ ID NO.:81; 도 18, 패널 B) 및 이중의 Y152A 에 더하여 Y199A 돌연변이 (SEQ ID NO.:82; 도 18, 패널 D) NKG2D 수용체에 대한 결합을 상실했다. 그러나, 시험한 모든 천연 및 비-천연 α1-α2 도메인 리간드에서, 오직 MICv25-Fc (SEQ ID NO.:86) 의 비-천연 α1-α2 도메인 (SEQ ID NO.:57) 만이 Y152A 돌연변이 NKG2D 엑토도메인 (SEQ ID NO.:80) 에 대한 결합을 50 nM 의 EC50 으로 유지했다 (도 18, 패널 C).
천연 NKG2D 의 결합 특이성은 고친화성 비-천연 리간드에 대해 선호를 나타내는데, 현존 NKG2D CAR 접근법 (VanSeggelen 등, 2015) 을 이용하면, 특정한 건강한 조직 및 다수의 스트레스를 받은 조직에 존재하는 천연 NKG2D 리간드에 대한 그의 강력한 결합은 독성에 대한 극단적 위험을 제공한다. Y152A 비-천연 NKG2D 수용체는 현격히 감소된 오프-레이트를 위해 조작된 고친화성 비-천연 α1-α2 도메인으로 이루어지는 단백질에만 특이적으로 결합했다. 이러한 원형적 예시는 비-천연 NKG2D 수용체에 결합하는 비-천연 α1-α2 도메인의 능력을 강조하여, 본 발명의 비-천연 NKG2D 리간드의 α1-α2 도메인을 포함하는 이중특이적 단백질을 이용하는 비-천연 NKG2D CAR 의 선택적 제어를 제공했다.
실시예 5 (NKG2D 리간드의 개질된 α1-α2 도메인).
본 구현예는 ULBP 단백질의 α1-α2 도메인 조작을 통해 유도된 추가적인 α1-α2 NKG2DL 친화성 변이체들에 관한 것이다. ULBP 단백질은 α1-α2 도메인을 포함하는데, 이는 NKG2D 수용체에 결합할 수 있는 NKG2D 리간드이다 (Cerwenka A, Lanier LL (2004). NKG2D Ligands: unconventional MHC class I-like molecules exploited by viruses and cancer. Tissue Antigens 61 (5): 335-43. doi:10.1034/j.1399-0039.2003.00070.x. PMID 12753652). NKG2D 결합의 그러한 친화성은 NK 세포의 생리학적 활성화 및 "표적 세포" 의 2-차원 형질막 표면에 본래 비가역적으로 결박되어 있는 본연의 전장 ULBP 단백질을 발현하는 세포의 용해 자극에 충분하다 (Cerwenka A, Lanier LL (2004). NKG2D Ligands: unconventional MHC class I-like molecules exploited by viruses and cancer. Tissue Antigens 61 (5): 335-43. doi:10.1034/j.1399-0039.2003.00070.x. PMID 12753652). 그러나, 본 발명의 특정 구현예에서 이종성 폴리펩티드에 융합된 조작된 가용성 α1-α2 도메인이 표적 세포 표면 상의 특이적 표적 항원에 가역적으로 결합하기 때문에, 조작된 가용성 MIC 단백질에 의해 이미 제시된 바와 같이 (실시예 2 내지 4) 조작된 ULBP α1-α2 도메인의 NKG2D 에 대한 결합 친화성은, NK 세포와 표적 항원 발현 세포 사이에 형성되는 인공적 시냅스의 안정성에 직접적으로 영향을 줄 것이다. NKG2D 리간드와 같이 조작된 비-천연 α1-α2 도메인의 레퍼토리를 다변화하기 위해, ULBP 단백질을 그들의 NKG2D 결합 친화성의 파지-디스플레이-기반 조작을 위한 기질 또는 출발점으로서 이용하였다. ULBP 및 MICA 사이에서 관찰되는 구조적 상동성에도 불구하고 (Radaev, S., Rostro, B., Brooks, AG., Colonna, M., Sun, PD. (2001) Conformational plasticity revealed by the cocrystal structure of NKG2D and its class I MHC-like Ligand ULBP3. Immunity 15, 1039-49.), MICA 에 비교한 ULBP α1-α2 도메인에 대한 서열 상동성이 50% 미만이다. 따라서, NKG2D 결합 친화성을 개선하는 ULBP α1-α2 도메인에서의 코돈 위치의 동일성에 관심을 두게 되었다.
ULBP 단백질 유래의 가용성인 비-천연 α1-α2 도메인을 조작하기 위해, ULBP2 및 ULBP3 를 파지 디스플레이 및 고친화성 NKG2D 결합이 있는 돌연변이의 선별용으로 선택했다. ULBP2 (SEQ ID NO: 16) 의 α1-α2 도메인 중 60 개 아미노산 위치 및 ULBP3 (SEQ ID NO: 17) 의 α1-α2 도메인 중 36 개 아미노산 위치를 집중적 돌연변이유발용으로 선택했다. 추가로, 시스테인에서 세린으로의 보존적인 돌연변이들이 ULBP2 (SEQ ID NO: 16) 중의 C8S 및 ULBP3 (SEQ ID NO: 17) 중의 C103S 에서 일어나, 짝지어지지 않은 유리된 시스테인이 제거되어, 부착된 폴리펩티드가 있는 NKG2D 리간드의 안정성 및 기능이 증가될 뿐 아니라, 파지 패닝 프로세스 (phage panning process) 가 개선된다. 시스테인에서 세린으로 개질된 그러한 α1-α2 도메인을 코드하며, 각각의 선택된 아미노산 위치에서 NKN 돌연변이유발 코돈을 포함하는 합성 DNA 라이브러리가 개별적으로 합성되었고; M13 파지의 pIII 마이너 코트 단백질에 대한 융합체들로서 클로닝되고; 돌연변이화된 α1-α2 ULBP2 또는 ULBP3 변이체들을 제시하는 파지 입자들이 표준 방법론에 따라 SS320 대장균 세포에서 생산되었다 (Andris-Widhopf, J., Steinberger, P., Fuller, R., Rader, C., and Barbas, C. F., 3rd. (2011). Generation of human Fab antibody libraries: PCR amplification and assembly of light- and heavy-chain coding sequences, Cold Spring Harbor protocols 2011). 상기 α1-α2 파지 디스플레이 라이브러리는 표적 단백질로서의 인간 NKG2D-Fc 를 이용하는 NKG2D 에 대한 증가된 결합 친화성에 대해 분류되고, 의도적으로 연장된 결합, 의도적으로 연장된 세척 및 파지 클론 용리의 반복적 순회를 통해 순환되었는데, 이는 느린 해리- 또는 오프-레이트를 위해 풍부화된 고친화성 변이체들을 선별하기 위한 것이었다. ULBP2 에 대해서는, 특정 아미노산 돌연변이들이 α1-α2 내의 위치 R80, V151, V152 및 A153 에서 높은 빈도로 발견되었으며, 강화된 NKG2D-결합 친화성을 가진 바람직한 아미노산 치환으로 식별되었다 (도 19, 패널 A; 및 표 6).
표 6.
ULBP2 의 α1-α2 도메인의 표시된 4 개 아미노산 위치에서 선택된 친화성 돌연변이들. 각각의 4 개 위치에서의 SEQ ID NO: 16 의 아미노산은 표의 첫번째 열에서 볼드체로 나타낸다. 식별된 친화성 돌연변이들은 위에서 아래로 빈도 내림차순으로 수록된다. 모든 아미노산은 단일자 IUPAC 약어로 표시된다.
ULBP3 에 대해, 특이적 아미노산 돌연변이들이 ULBP2 에 비해 상이한 위치에서 높은 빈도로 발견되었다. ULBP3 의 α1-α2 도메인 내 위치 R162 및 K165 는 강화된 NKG2D-결합 친화성을 가진 바람직한 아미노산 치환으로 식별되는 특정 돌연변이들을 포함했다 (도 19, 패널 B; 및 표 7). ULBP2 및 ULBP3 로부터 유도된 그러한 개질된 비-천연 α1-α2 도메인은 이종성 펩티드 또는 폴리펩티드에 대한 단일 단백질 또는 융합체들로서의 다중 치료 포맷에서 강화된 NKG2D 결합에 이용될 수 있다.
표 7.
SULBP3 의 α1-α2 도메인의 표시된 2 개의 아미노산 위치들에서 선택된 친화성 돌연변이들. 각각의 2 개 위치에서의 SEQ ID NO: 17 의 아미노산은 표의 첫번째 열에서 볼드체로 나타낸다. 식별된 친화성 돌연변이들은 위에서 아래로 빈도 내림차순으로 수록된다. 모든 아미노산은 단일자 IUPAC 약어로 표시된다.
실시예
6 (항체 펩티드에 융합된
ULBP 의
개질된
α1-α2 도메인에 의한 결합 및 세포용해)
하기의 실시예는 인간 및 쥐과동물 NKG2D 수용체에 대한 그들의 결합 친화성을 유의하게 강화하도록 개질된 NKG2DL 에 항체 폴리펩티드를 부착시키는 것에 관한 것이다. 각 ULBP 단백질의 α1-α2 도메인은 NKG2D 수용체에 대한 천연 리간드, 즉 NKG2DL 이다. 항체들은 2 개의 대형 중쇄 및 2 개의 소형 경쇄로 이루어진 매우 안정한 당단백질이다 (도 1). 본연의 ULBP 도메인보다 더욱 단단하게 NKG2D 수용체에 결합하는 비-천연 ULBP α1-α2 도메인을 이용하여 면역 세포를 직접 활성화시킬 수 있는 IgG 항체 포맷은 당업계에 존재하지 않았다. 나아가, ULBP α1-α2 도메인은 MICA α1-α2 도메인에 비해 차별적인 생체내 특성을 가질 수 있는 항체 융합체들을 구축하도록 대안적 NKG2DL 을 제공한다. 예를 들어, 항체 융합체 내에서의 MICA α1-α2 도메인에 대한 생체내 항-약물 항체 응답은, ULBP 및 MICA α1-α2 도메인 사이의 낮은 서열 상동성으로 인해 개질된 ULBP α1-α2 도메인과 반응하거나 또는 그와 상호작용할 공산이 없다 (도 20). 그러한 예시는 조작된 ULBP α1-α2 NKG2D 리간드들 (표 6 및 7) 및 IgG 분자의 중쇄 사이의 융합체들이 천연 ULBP α1-α2 NKG2D 리간드에 비해 강화된 NKG2D 결합 및 표적 세포 살해 능력을 갖고 있음을 보여준다. 이는 개질된 α1-α2 도메인의 이종성 단백질 또는 펩티드에 대한 융합체들의 유용성을 입증한다.
항체들에 대한 조작된 α1-α2 도메인 융합체들 생성을 위해, ULBP2 (SEQ ID NO.: 16) 의 C8S 개질 α1-α2 도메인 변이체들 R80W 및 V151D (각각 SEQ ID NO.: 87 및 88) 및 ULBP3 (SEQ ID NO.: 17) 의 C103S 개질 α1-α2 도메인 변이체 R162G (SEQ ID NO.: 89) 를 인코드하는 DNA 서열을 합성하여 C-말단 융합체들로서 Her2-특이적 항체 유래의 중쇄 서열에 클로닝했다 (Carter, P., Presta, L., Gorman, CM., Ridgway, JB., Henner, D., Wong, WL., Rowland, AM., Kotts, C., Carver, ME., Shepard, HM. (1992) Proc Natl Acad Sci 15, 4285-9.). 결과로서 수득한 융합체들은 포유류 발현 벡터 pD2509 로 클로닝하고, 짝을 이룬 전장 IgG 항체로서 부모 항체의 경쇄와 발현시켰다. 제조사의 프로토콜 (Life Technologies) 에 따라 Expi293 발현 시스템을 이용해 HEK293 세포에서 일시적 발현을 실시했으며, 표준 단백질 A 친화성 크로마토그래피를 이용해 정제했다. ULBP2 및 ULBP3 α1-α2 항체 중쇄 융합체들 상에서 실시된 결합 ELISA 는 개질된 ULBP2 융합체들 (HC_R80W 및 HC_V151D) 및 UBLP3 융합체 (HC_R162G) 가 동일한 중쇄에 융합된 그들 각각의 천연 α1-α2 도메인에 비해 인간 NKG2D 에 대해 더 높은 친화성으로 결합함을 입증했다 (도 21, 패널 A 및 B).
개질된 ULBP 항체 융합체들의 표적 세포 살해 특성을 특징분석하기 위해, 인간 자연 살해 (NK) 세포주, NKL 을 Her2 을 발현하는 칼세인-담지 SKBR3 표적 세포와 공동배양하고, 조작된 항체 융합체 단백질로 적정했다. 도 22, 패널 A 및 B 에서의 결과는, Her2-특이적 비-천연 ULBP2 및 비-천연 ULBP3 α1-α2-항체 융합체들의 강화된 세포용해 (살해) 활성이 그들의 조작된 α1-α2 도메인의 NKG2D 에 대한 강화된 친화성을 반영함을 보여줬다. 구체적으로, ULBP2 변이체 융합체들 HC_R80W 및 HC_V151D, 및 ULBP3 변이체 융합체 HC_R162G 가 본연의 α1-α2 도메인을 포함하는 항체 융합체들에 비해 더욱 유효하게 SKBR3 세포를 살해했다. 이들 데이터는 개질된 α1-α2 변이체-항체 융합체들이 IgG 분자가 NKG2D 에 단단히 결합할 수 있게 하고, 항원-특이적 세포 용해를 통제하도록 하는 일반적인 플랫폼임을 추가로 보여줬다.
실시예 7 (
Y152A
비-천연
NKG2D 에 대한 선택적 결합을 하는
직교성 비-천연 α1-α2 도메인의 구축)
CAR-T 세포 치료요법을 선택적으로 제어하는 수단은 독성을 경감시키고 종양에 대한 효능을 개선하기 위해 심도있게 고려된다 (Gill and June, 앞서 언급된 문헌). CAR-T 표적화의 항체-기반 제어가 가능하도록 치료용 모노클로날 항체들의 Fc 도메인을 통해 이후 관여될 수 있는 CD16 의 엑토도메인을 이용하는 CAR 개발을 선행기술에서 시도한 바 있다 (Chang 등, 앞서 언급된 문헌). 그러나, CD16-기반의 CAR-T 세포들은 혈액 및 조직 중의 모든 내생적 항체 분자들을 인식할 수 있고, 그러한 세포 제어에 이용되는 치료용 항체들은 NK 세포 상의 내생적 CD16 수용체 분자들 유래의 간섭을 경험할 것이다. 그러한 특징들은 모두 종양외 독성 (off-tumor toxicity) 및 열악한 약동학의 문제점을 각각 야기한다.
그러한 문제들을 해결하기 위해, 실시예 4 에서 입증되는 바와 같이 모든 천연 NKG2D 리간드에 대한 결합이 결핍되고, 고-친화성 비-천연 α1-α2 도메인의 결합을 통해 제어될 수 있는 비-천연 NKG2D CAR-T 세포를 조작했다. 추가적인 필요조건은 비-천연 α1-α2 도메인이 비-천연 NKG2D 에 대한 높은 친화성을 유지하고, 천연 NKG2D 도메인에 대한 결합을 피하도록 하는 것이다. 따라서, 천연 NKG2D 보다도 비-천연 NKG2D 수용체에 대해 강력한 선택성을 나타내는 조작된 α1-α2 도메인은 비-천연 NKG2D CAR 수용체, 또는 비-천연 α1-α2 도메인에 의해 선택적으로 관여될 수 있는 비-천연 NKG2D 엑토도메인에 융합된 임의의 수용체 또는 단백질의 선택적 제어를 위한 이상적 시스템을 나타낸다.
Y152A NKG2D 수용체에 대한 선택적 결합을 나타내는 직교성 비-천연 α1-α2 도메인을 조작하는 파지 디스플레이를 채용했다. 출발점으로서, 천연 NKG2D 에 대한 높은 친화성을 가진 세가지 비-천연 α1-α2 도메인을 추가 돌연변이유발 및 파지 디스플레이에 의한 스크리닝을 위한 부모 도메인으로서 선택했다. 합성 DNA 라이브러리는 개별 α1-α2 도메인 변이체들 DSM25, ULBP2 R80W 및 ULBP3 R162G (SEQ ID NO.: 57, 87 및 89) 에 대해 생성되어, 이로써 결합된 상태의 아미노산 잔기들의 코돈이 NNK 코돈으로 대체된 NKG2D 수용체 상의 Y152 위치에 가까이 근접하게 위치된다. DSM 25 라이브러리는 잔기 71 내지 75 및 155 내지 159 에서의 NNK 위치들로 이루어지며, ULBP2 R80W 라이브러리에는 위치 154 내지 159 에 NNK 코돈이 있고, ULBP3 R162G 라이브러리에는 위치 155 내지 159 에 NNK 코돈이 있다. 라이브러리들은 M13 파지의 pIII 마이너 코트 단백질에 대한 융합체들로서 클로닝되며; 돌연변이화된 α1-α2 도메인 변이체들을 제시하는 파지 입자들은 표준 방법에 따라 SS320 대장균 세포에서 생산된다 (Andris-Widhopf, J., Steinberger, P., Fuller, R., Rader, C., and Barbas, C. F., 3rd. (2011). Generation of human Fab antibody libraries: PCR amplification and assembly of light- and heavy-chain coding sequences, Cold Spring Harbor protocols 2011). 상기 α1-α2 파지 디스플레이 라이브러리는, 비-바이오티닐화 천연 NKG2D-Fc 경쟁자 단백질 존재 하의 바이오티닐화된 Y152A NKG2D-Fc 단백질에 결합된 파지 클론들을 선택적 포획으로 비-천연 Y152A NKG2D 수용체에 대한 높은 결합 친화성에 대해 분류된다. 선택적 클론들은 비-바이오티닐화 천연 NKG2D-Fc 의 농도를 증가시키면서 경쟁적 선택을 여러 회 순환하여 풍부해졌다.
선별 4 회차 순환 후, NNK 돌연변이유발 영역 내 특이적 돌연변이를 식별해 내기 위해 파지 클론들을 서열분석했다. 표 8, 9 및 10 는 Y152A NKG2D 선택적 스크리닝 결과로 제공된 각 α1-α2 도메인에 대해 우세한 것으로 나타나 선택된 아미노산 잔기들을 제시한다.
표 8.
Y152A-특이적 파지 클론들을 결과물로 제공하는 DSM25 내부의 선택된 돌연변이들.
표 9.
Y152A-특이적 파지 클론들을 결과물로 제공하는 ULBP2 R80W 내부의 선택된 돌연변이들.
표 10.
Y152A-특이적 파지 클론들을 결과물로 제공하는 ULBP3 R162G 내부의 선택된 돌연변이들.
파지 클론들이 적절한 선택적 결합을 제시한다는 점을 확인하기 위해, 개별 클론들: MICA25.17, MICA25.18, ULBP2.S1, ULBP2.S2, ULBP2.S3, ULBP3.S1 및 ULBP3.S2 (각각 SEQ ID NO: 90, 91, 92, 93, 94, 95, 및 96) 에 대한 파지를 제작하고, 결합 ELISA 에서 Y152A 또는 천연 NKG2D 에 대해 적정했다. 도 23, 패널 A 내지 C 는, 7 가지 파지 클론 모두 천연 또는 야생형 NKG2D 에 비해 비-천연 Y152A NKG2D 에 대해 10 배 더 큰 선택적 결합을 제시함을 보여준다.
Y152A-선택적 α1-α2 도메인 변이체들이 항체 융합체 맥락에서 특이적 결합 특성을 보유한다는 것을 확인하기 위해, 선행기술에서 기재된 바 있는 FGFR3 특이적 항체의 중쇄 (Qing 등, 2009. 상기 언급한 문헌; 각각 SEQ ID NO.: 97 및 98) 에 대한 C-말단 융합체들로서 MICA25.17 및 ULBP2.S3 를 클로닝했다. 결과로서 수득한 융합체들은 포유류 발현 벡터 pD2509 로 클로닝했으며, 부모 항체의 경쇄와 함께 짝을 이룬 전장 IgG 항체들 (R3 HC25.17 및 R3 HC.U2S3) 로서 공동발현시켰다. 일시적 발현은 제조사의 프로토콜 (Life Technologies) 에 따라 Expi293 발현 시스템을 이용하여 HEK293 세포에서 수행했으며, 표준 단백질-A 친화성 크로마토그래피를 이용해 정제했다. R3 HC25.17 및 R3 HC.U2S3 α1-α2 항체 중쇄 융합체들의 비-천연 Y152A NKG2D 및 천연 NKG2D 에 대한 결합의 ELISA 측정은 천연 NKG2D 에 비해 Y152A NKG2D 에 대한 그들의 유의하게 더 큰 친화성을 입증했다 (도 24, 패널 B 및 D). 대조적으로, DSM25 및 ULBP2 R80W 에 대한 항체 융합체들은 천연 NKG2D-Fc 에 대한 우선 결합을 나타냈다 (도 24, 패널 A 및 C). 취합하면, 이들 데이터는 비-천연 NKG2D 수용체에 대한 고친화성 결합 및 천연 NKG2D 수용체에 대한 유의하게 감소된 결합 친화성을 보유하는 비-천연 직교성 α1-α2 도메인의 발명을 입증했다. 나아가, 직교성 α1-α2 도메인의 항체 폴리펩티드에 대한 융합체들은 그들의 선택적 결합 특성을 보유하며, 예를 들어 CAR-T 세포의 맥락에서 신규 항원에 대해 비-천연 NKG2D 수용체를 전용하기 위해 이용될 수 있다.
실시예
8 (비-천연
NKG2D
엑토도메인이
있는 CAR-T 세포의
표적화
및 살해 활성은
표적화
항체들에 융합된
직교성
α1-α2 도메인을 이용하여 제어된다).
비-천연 NKG2D 엑토도메인을 배치하는 키메라성 수용체로 구축되는 CAR-T 세포들의 선택적 제어를 입증하기 위해, CAR 의 각 NKG2D 엑토도메인을 CAR 의 CD8 힌지 영역에 융합하는 4-1BB/CD3zeta CAR 구축체를 이용한 선행기술 업적 (Campana 특허 제 8,399,645 호) 을 기반으로 천연 NKG2D 또는 비-천연 Y152A NKG2D 엑토도메인이 있는 CAR 를 구축했다 (도 25). 그러한 구축체들은 렌티바이러스 벡터에 클로닝되어, 렌티바이러스 형질유도를 이용해 프라이머리 인간 CD8-양성 T-세포에서 발현시켰다. 결과로서 수득한 천연 NKG2D CAR-T 세포는 표적 세포 상에서 발현되는 천연 MICA 리간드의 인식과 함께 시험관내 특이적 세포 살해 활성을 나타냈다. 구체적으로, 도 26, 패널 A 는, 천연 NKG2D CAR-T 세포가 천연 MICA 리간드를 발현하는 P1 세포를 살해하기는 하지만, 비-천연 Y152A NKG2D CAR-T 세포들은 유의하게 불능이 되며, 훨씬 더 감소된 MICA 발현 P1 세포의 살해를 나타냈다는 점을 보여준다. 나아가, 도 26, 패널 B 는, 직교성 α1-α2 항체 중쇄 융합체들, R3 HC25.17 및 R3 HC.U2S3 이, 비-천연 Y152A CAR-T 세포를 선택적으로 활성화하여 FGFR3 발현 P1 표적 세포를 살해하나, 천연 NKG2D CAR-T 세포의 살해 활성을 전용하지는 못함을 보여준다. 이것은 비-천연 Y152A NKG2D 에 대해 선택적이 아니며, 천연 및 비-천연 CAR-T 세포를 모두 활성화하여 P1 표적 세포를 살해하는 R3 HC25 및 R3 HC.U2R80W α1-α2 항체 중쇄 융합체들과 대조적이다. 이들 데이터는 비-천연 Y152A NKG2D 에 선택적으로 결합하도록 조작된 비-천연 직교성 α1-α2 도메인이, 천연 NKG2D 수용체는 피하면서, 비-천연 Y152A NKG2D CAR-T 세포는 특이적으로 활성화시킴을 보여줬다.
<110> AvidBiotics Corp.
<120> INSERTABLE VARIABLE FRAGMENTS OF ANTIBODIES AND MODIFIED
ALPHA1-ALPHA2 DOMAINS OF NKG2D LIGANDS, AND NON-NATURAL NKG2D
LIGANDS THAT BIND NON-NATURAL NKG2D RECEPTORS
<130> A228394
<150> US 62/200,949
<151> 2015-08-04
<160> 105
<170> PatentIn version 3.5
<210> 1
<211> 1126
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic polynucleotide, encoding alpha3-iFv.1
<400> 1
ccccccatgg tgcaagttac ccgcagcgag gcctcaggag atcgcgtaac tatcacttgc 60
agagcttctc aggacgtgtc caccgcggtt gcttggtacc agcaaaagcc tggaaaggcg 120
ccgaagctgc tgatctactc cgcctcattc ttgtactcag gagtgcccag tcgatttagt 180
ggtagcggtt ctggtactga tttcaccctt accatcagca gtctccagcc cgaggatttc 240
gctacttatt actgccagca gtcatacacc actcctccca ctttcggcca aggtaccaag 300
gtcgagatta aaggcggaag ctctaggtcc tctagctccg gaggaggtgg ctctggcggc 360
ggcggagaag tccaactggt ggagagcgga ggcggactgg tgcagccagg cggatccttg 420
agacttagct gtgcggcttc gggttttacc tttacttcta ctggcatcag ttgggtcaga 480
caagcgcctg gcaagggact ggaatgggtt ggacgtatct accccactaa tggttcgacg 540
aactatgcgg atagtgtgaa aggtagattc acgatatctg ctgacacctc gaagaatacc 600
gcttaccttc aaatgaatag tttgcgtgcc gaagatactg ctgtctacta ttgcgccaga 660
acctatggaa tatacgacct ttatgtggac tacaccgagt acgtcatgga ttattggggc 720
cagggtacgt tggtgacagt gtcgagtggc ggaagctcta ggtcctctag ctccggagga 780
ggtggctctg gcggcggcgg agacattcag atgactcagt ctcccagttc tcttagtgcc 840
tctggccaaa ttaccgtcac gtgtcgtgct agcggcttct acccgtggaa tatcaccctg 900
agctggcgcc aagacggtgt tagcctgagc cacgacaccc aacaatgggg cgacgtgttg 960
ccagatggcc aaggtaccta ccagacgtgg gttgccaccc gtatttccca gggtgaagag 1020
cagcgtttta cctgctatat ggaacacagc ggccaacata gcacgcatcc ggtgccgagc 1080
ggtaaaggta gccaccatca tcaccaccat tagtaggaat tccgga 1126
<210> 2
<211> 1144
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic polynucleotide, encoding alpha3-iFv.2
<400> 2
ccccccatgg tgcaagttac ccgcagcgag gcctcaggcg gaagcggaga tcgcgtaact 60
atcacttgca gagcttctca ggacgtgtcc accgcggttg cttggtacca gcaaaagcct 120
ggaaaggcgc cgaagctgct gatctactcc gcctcattct tgtactcagg agtgcccagt 180
cgatttagtg gtagcggttc tggtactgat ttcaccctta ccatcagcag tctccagccc 240
gaggatttcg ctacttatta ctgccagcag tcatacacca ctcctcccac tttcggccaa 300
ggtaccaagg tcgagattaa aggcggaagc tctaggtcct ctagctccgg aggaggtggc 360
tctggcggcg gcggagaagt ccaactggtg gagagcggag gcggactggt gcagccaggc 420
ggatccttga gacttagctg tgcggcttcg ggttttacct ttacttctac tggcatcagt 480
tgggtcagac aagcgcctgg caagggactg gaatgggttg gacgtatcta ccccactaat 540
ggttcgacga actatgcgga tagtgtgaaa ggtagattca cgatatctgc tgacacctcg 600
aagaataccg cttaccttca aatgaatagt ttgcgtgccg aagatactgc tgtctactat 660
tgcgccagaa cctatggaat atacgacctt tatgtggact acaccgagta cgtcatggat 720
tattggggcc agggtacgtt ggtgacagtg tcgagtggcg gaagctctag gtcctctagc 780
tccggaggag gtggctctgg cggcggcgga gacattcaga tgactcagtc tcccagttct 840
cttagtgcct ctggcggaag cggccaaatt accgtcacgt gtcgtgctag cggcttctac 900
ccgtggaata tcaccctgag ctggcgccaa gacggtgtta gcctgagcca cgacacccaa 960
caatggggcg acgtgttgcc agatggccaa ggtacctacc agacgtgggt tgccacccgt 1020
atttcccagg gtgaagagca gcgttttacc tgctatatgg aacacagcgg ccaacatagc 1080
acgcatccgg tgccgagcgg taaaggtagc caccatcatc accaccatta gtaggaattc 1140
cgga 1144
<210> 3
<211> 269
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide iFv (fgfr3)
<400> 3
Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr
1 5 10 15
Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu
20 25 30
Ile Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser
35 40 45
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln
50 55 60
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Thr Thr Pro
65 70 75 80
Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Gly Gly Ser Ser
85 90 95
Arg Ser Ser Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Glu Val
100 105 110
Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu
115 120 125
Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Ser Thr Gly Ile
130 135 140
Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Arg
145 150 155 160
Ile Tyr Pro Thr Asn Gly Ser Thr Asn Tyr Ala Asp Ser Val Lys Gly
165 170 175
Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gln
180 185 190
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
195 200 205
Thr Tyr Gly Ile Tyr Asp Leu Tyr Val Asp Tyr Thr Glu Tyr Val Met
210 215 220
Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Ser
225 230 235 240
Ser Arg Ser Ser Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Asp
245 250 255
Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser
260 265
<210> 4
<211> 807
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic polynucleotide, encoding iFv (fgfr3)
<400> 4
ggagatcgcg taactatcac ttgcagagct tctcaggacg tgtccaccgc ggttgcttgg 60
taccagcaaa agcctggaaa ggcgccgaag ctgctgatct actccgcctc attcttgtac 120
tcaggagtgc ccagtcgatt tagtggtagc ggttctggta ctgatttcac ccttaccatc 180
agcagtctcc agcccgagga tttcgctact tattactgcc agcagtcata caccactcct 240
cccactttcg gccaaggtac caaggtcgag attaaaggcg gaagctctag gtcctctagc 300
tccggaggag gtggctctgg cggcggcgga gaagtccaac tggtggagag cggaggcgga 360
ctggtgcagc caggcggatc cttgagactt agctgtgcgg cttcgggttt tacctttact 420
tctactggca tcagttgggt cagacaagcg cctggcaagg gactggaatg ggttggacgt 480
atctacccca ctaatggttc gacgaactat gcggatagtg tgaaaggtag attcacgata 540
tctgctgaca cctcgaagaa taccgcttac cttcaaatga atagtttgcg tgccgaagat 600
actgctgtct actattgcgc cagaacctat ggaatatacg acctttatgt ggactacacc 660
gagtacgtca tggattattg gggccagggt acgttggtga cagtgtcgag tggcggaagc 720
tctaggtcct ctagctccgg aggaggtggc tctggcggcg gcggagacat tcagatgact 780
cagtctccca gttctcttag tgcctct 807
<210> 5
<211> 18
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide linker region
<400> 5
Gly Gly Ser Ser Arg Ser Ser Ser Ser Gly Gly Gly Gly Ser Gly Gly
1 5 10 15
Gly Gly
<210> 6
<211> 370
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide alpha3-iFv.1
<400> 6
Pro Pro Met Val Gln Val Thr Arg Ser Glu Ala Ser Gly Asp Arg Val
1 5 10 15
Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala Val Ala Trp
20 25 30
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala
35 40 45
Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser
50 55 60
Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe
65 70 75 80
Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Thr Thr Pro Pro Thr Phe Gly
85 90 95
Gln Gly Thr Lys Val Glu Ile Lys Gly Gly Ser Ser Arg Ser Ser Ser
100 105 110
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Glu Val Gln Leu Val Glu
115 120 125
Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys
130 135 140
Ala Ala Ser Gly Phe Thr Phe Thr Ser Thr Gly Ile Ser Trp Val Arg
145 150 155 160
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Arg Ile Tyr Pro Thr
165 170 175
Asn Gly Ser Thr Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile
180 185 190
Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu
195 200 205
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Thr Tyr Gly Ile
210 215 220
Tyr Asp Leu Tyr Val Asp Tyr Thr Glu Tyr Val Met Asp Tyr Trp Gly
225 230 235 240
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Ser Ser Arg Ser Ser
245 250 255
Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Asp Ile Gln Met Thr
260 265 270
Gln Ser Pro Ser Ser Leu Ser Ala Ser Gly Gln Ile Thr Val Thr Cys
275 280 285
Arg Ala Ser Gly Phe Tyr Pro Trp Asn Ile Thr Leu Ser Trp Arg Gln
290 295 300
Asp Gly Val Ser Leu Ser His Asp Thr Gln Gln Trp Gly Asp Val Leu
305 310 315 320
Pro Asp Gly Gln Gly Thr Tyr Gln Thr Trp Val Ala Thr Arg Ile Ser
325 330 335
Gln Gly Glu Glu Gln Arg Phe Thr Cys Tyr Met Glu His Ser Gly Gln
340 345 350
His Ser Thr His Pro Val Pro Ser Gly Lys Gly Ser His His His His
355 360 365
His His
370
<210> 7
<211> 376
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide alpha3-iFv.2
<400> 7
Pro Pro Met Val Gln Val Thr Arg Ser Glu Ala Ser Gly Gly Ser Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser 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 Gly 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 Ser Tyr Thr Thr Pro Pro
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Gly Gly Ser Ser Arg
100 105 110
Ser Ser Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Glu Val Gln
115 120 125
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
130 135 140
Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Ser Thr Gly Ile Ser
145 150 155 160
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Arg Ile
165 170 175
Tyr Pro Thr Asn Gly Ser Thr Asn Tyr Ala Asp Ser Val Lys Gly Arg
180 185 190
Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gln Met
195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Thr
210 215 220
Tyr Gly Ile Tyr Asp Leu Tyr Val Asp Tyr Thr Glu Tyr Val Met Asp
225 230 235 240
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Ser Ser
245 250 255
Arg Ser Ser Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Asp Ile
260 265 270
Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Gly Gly Ser Gly
275 280 285
Gln Ile Thr Val Thr Cys Arg Ala Ser Gly Phe Tyr Pro Trp Asn Ile
290 295 300
Thr Leu Ser Trp Arg Gln Asp Gly Val Ser Leu Ser His Asp Thr Gln
305 310 315 320
Gln Trp Gly Asp Val Leu Pro Asp Gly Gln Gly Thr Tyr Gln Thr Trp
325 330 335
Val Ala Thr Arg Ile Ser Gln Gly Glu Glu Gln Arg Phe Thr Cys Tyr
340 345 350
Met Glu His Ser Gly Gln His Ser Thr His Pro Val Pro Ser Gly Lys
355 360 365
Gly Ser His His His His His His
370 375
<210> 8
<211> 368
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide alpha3-iFv.3(CD20)
<400> 8
Pro Pro Met Val Gln Val Thr Arg Ser Glu Ala Ser Gly Gly Ser 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 Gly Gly Ser Ser Arg Ser
100 105 110
Ser Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Gln Val Gln Leu
115 120 125
Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala Ser Val Lys Met
130 135 140
Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr Asn Met His Trp
145 150 155 160
Val Lys Gln Thr Pro Gly Arg Gly Leu Glu Trp Ile Gly Ala Ile Tyr
165 170 175
Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe Lys Gly Lys Ala
180 185 190
Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr Met Gln Leu Ser
195 200 205
Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg Ser Thr
210 215 220
Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val Trp Gly Ala Gly Thr Thr
225 230 235 240
Val Thr Val Ser Ala Gly Gly Ser Ser Arg Ser Ser Ser Ser Gly Gly
245 250 255
Gly Gly Ser Gly Gly Gly Gly Gln Ile Val Leu Ser Gln Ser Pro Ala
260 265 270
Ile Leu Ser Ala Ser Gly Gly Ser Gln Ile Thr Val Thr Cys Arg Ala
275 280 285
Ser Gly Phe Tyr Pro Trp Asn Ile Thr Leu Ser Trp Arg Gln Asp Gly
290 295 300
Val Ser Leu Ser His Asp Thr Gln Gln Trp Gly Asp Val Leu Pro Asp
305 310 315 320
Gly Gln Gly Thr Tyr Gln Thr Trp Val Ala Thr Arg Ile Ser Gln Gly
325 330 335
Glu Glu Gln Arg Phe Thr Cys Tyr Met Glu His Ser Gly Gln His Ser
340 345 350
Thr His Pro Val Pro Ser Gly Lys Gly Ser His His His His His His
355 360 365
<210> 9
<211> 561
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic polynucleotide, encoding ULBP1 alpha1-alpha2
<400> 9
gctgctgagc cccactgtct ctgctacgac tttattataa ctcctaagtc aagaccagag 60
cctcagtggt gcgaagtaca aggtttggtt gacgaaaggc ctttccttca ctacgattgt 120
gtgaaccata aggcaaaggc tttcgccagc ctgggtaaga aggtaaacgt tactaagacg 180
tgggaggagc agacggaaac cctccgtgat gtggttgact ttcttaaggg tcagctcctc 240
gatatccaag tggagaattt aatccctatc gaaccgctca ctctgcaggc cagaatgtca 300
tgcgaacatg aagcacacgg tcatggaaga ggtagttggc aatttttatt taacggtcaa 360
aaattcctgc tgttcgactc aaacaaccgc aaatggactg cgctgcaccc tggagctaag 420
aagatgactg aaaaatggga gaagaacaga gacgttacca tgttcttcca gaagatttcc 480
ctgggagatt gtaagatgtg gttagaggag ttcttaatgt actgggaaca gatgctggac 540
cccacaaaac cccccatggt g 561
<210> 10
<211> 567
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic polynucleotide, encoding ULBP2 alpha1-alpha2
<400> 10
gctgctgagc cccatagtct gtgttacgac atcacagtta ttcccaagtt caggcccgga 60
ccgcgctggt gtgccgtgca aggacaagtc gacgaaaaaa cctttcttca ttacgattgc 120
ggaaataaga ctgtaacgcc agtctctcct ttaggtaaga agttaaacgt cactacggcg 180
tggaaggcac aaaaccccgt cctgcgcgag gtcgtcgaca tcctgactga acaattgcgc 240
gacatccagc tcgagaatta cactccaaag gagcctctta ccctgcaggc tagaatgtct 300
tgcgagcaaa aggcagaggg ccactcctcc ggcagctggc agttcagttt cgacggacaa 360
atctttctgt tattcgattc agagaagaga atgtggacta cagttcaccc cggtgcccgt 420
aaaatgaagg agaagtggga aaacgacaaa gtggtggcga tgtcattcca ctatttctcg 480
atgggagact gcatcggttg gctggaagat ttcctcatgg gtatggactc cactttggag 540
ccatcggctg gtgccccccc catggtg 567
<210> 11
<211> 561
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic polynucleotide, encoding ULBP3 alpha1-alpha2
<400> 11
gctgctgagc cccacagctt gtggtacaac ttcaccatta tccacttgcc gagacatggc 60
cagcagtggt gcgaagtgca atcgcaagtc gaccaaaaaa acttcttatc atacgactgc 120
ggcagcgata aggtcttatc tatgggtcat ttggaggaac agctctacgc gaccgacgcc 180
tggggtaaac agctcgagat gctccgtgag gttggacaga ggctgagact ggaactggct 240
gacactgagc tggaagattt cacacctagt ggtccactca cattgcaagt acgcatgagc 300
tgcgagtgtg aggccgatgg atacattagg ggcagctggc agtttagctt cgacggaagg 360
aaattcctgc tcttcgacag taacaatagg aagtggactg ttgtgcatgc tggtgcgcgc 420
agaatgaagg aaaagtggga gaaagatagc ggcctgacga ccttcttcaa gatggtgtct 480
atgcgtgact gtaagagctg gctcagagat ttcctcatgc atcgcaagaa gaggttagaa 540
cctaccgctc cccccatggt g 561
<210> 12
<211> 561
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic polynucleotide, encoding ULBP4 alpha1-alpha2
<400> 12
gctgctgagc cccactctct ttgcttcaac ttcaccatta aatccctgag caggcctggt 60
cagccgtggt gtgaggcgca ggtctttctt aacaagaatc tcttcctcca atacaactct 120
gataacaaca tggtaaagcc actgggtctc ctgggtaaaa aagtctatgc tacgagcact 180
tggggagaac tcacccagac tcttggcgag gtaggaagag acctgcgcat gctcctctgc 240
gatataaagc cccaaattaa gaccagtgat ccgtccactt tacaagtcga aatgttctgc 300
caaagggagg ctgaacgctg caccggagcc tcttggcagt tcgcgaccaa tggcgaaaag 360
tccctcttgt tcgatgccat gaatatgacc tggaccgtga tcaatcatga ggcctctaag 420
atcaaggaga cgtggaaaaa ggaccgcggc cttgaaaagt actttaggaa gttgtctaaa 480
ggagactgcg accattggtt acgcgagttc ctcggccatt gggaagcgat gcccgagcca 540
acggttagcc cccccatggt g 561
<210> 13
<211> 567
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic polynucleotide, encoding ULBP6 alpha1-alpha2
<400> 13
gctgctgagc cccactcctt atgctatgat atcaccgtga ttccaaagtt ccgaccagga 60
ccccgatggt gcgccgtaca gggacaggtc gacgaaaaga cttttttaca ttacgactgc 120
ggtaacaaga cagtcacacc ggtaagtcct ttgggaaaaa agttaaacgt aaccactgct 180
tggaaggccc agaaccccgt ccttcgagaa gtagtggata ttttgactga acagctgctt 240
gacatccagc tggaaaacta cacacccaaa gagcccctga ctcttcaagc gcgtatgtcg 300
tgtgagcaaa aggccgaagg acacagctcc ggatcctggc agttcagtat cgacggtcag 360
accttcctcc tcttcgattc agaaaagcgc atgtggacta ctgtgcaccc cggcgctcgt 420
aagatgaagg aaaagtggga gaatgataag gacgttgcca tgagttttca ttacattagt 480
atgggagatt gcatcggttg gctggaagac ttcctgatgg gtatggatag tacccttgaa 540
cctagtgccg gagctccccc catggtg 567
<210> 14
<211> 483
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic polynucleotide, encoding OMCP alpha1-alpha2
<400> 14
gctgctgctg agccccacaa gcttgcgttc aacttcaatc tggaaataaa cggttcagat 60
acccattcaa ccgtggacgt ttatttagac gattcgcaga taatcacctt tgacggcaag 120
gacatccgcc caactatccc gttcatgata ggtgacgaaa tcttccttcc tttttataag 180
aatgtgttct ctgagttctt cagtttgttc cgccgcgtcc ctacctcaac cccctacgaa 240
gacttgactt atttctatga atgcgactac accgacaaca aatctacatt cgatcaattc 300
tacctgtaca acggtgaaga gtacaccgtg aagactcaag aggctactaa caagaacatg 360
tggctgacca cttccgagtt cagactgaag aagtggttcg acggcgagga ctgtatcatg 420
caccttagaa gtttagtgag gaaaatggaa gatagcaaga gaagaacagt gccccccatg 480
gtg 483
<210> 15
<211> 187
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide ULBP1 alpha1-alpha2
<400> 15
Ala Ala Glu Pro His Cys Leu Cys Tyr Asp Phe Ile Ile Thr Pro Lys
1 5 10 15
Ser Arg Pro Glu Pro Gln Trp Cys Glu Val Gln Gly Leu Val Asp Glu
20 25 30
Arg Pro Phe Leu His Tyr Asp Cys Val Asn His Lys Ala Lys Ala Phe
35 40 45
Ala Ser Leu Gly Lys Lys Val Asn Val Thr Lys Thr Trp Glu Glu Gln
50 55 60
Thr Glu Thr Leu Arg Asp Val Val Asp Phe Leu Lys Gly Gln Leu Leu
65 70 75 80
Asp Ile Gln Val Glu Asn Leu Ile Pro Ile Glu Pro Leu Thr Leu Gln
85 90 95
Ala Arg Met Ser Cys Glu His Glu Ala His Gly His Gly Arg Gly Ser
100 105 110
Trp Gln Phe Leu Phe Asn Gly Gln Lys Phe Leu Leu Phe Asp Ser Asn
115 120 125
Asn Arg Lys Trp Thr Ala Leu His Pro Gly Ala Lys Lys Met Thr Glu
130 135 140
Lys Trp Glu Lys Asn Arg Asp Val Thr Met Phe Phe Gln Lys Ile Ser
145 150 155 160
Leu Gly Asp Cys Lys Met Trp Leu Glu Glu Phe Leu Met Tyr Trp Glu
165 170 175
Gln Met Leu Asp Pro Thr Lys Pro Pro Met Val
180 185
<210> 16
<211> 189
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide ULBP2 alpha1-alpha2
<400> 16
Ala Ala Glu Pro His Ser Leu Ser Tyr Asp Ile Thr Val Ile Pro Lys
1 5 10 15
Phe Arg Pro Gly Pro Arg Trp Cys Ala Val Gln Gly Gln Val Asp Glu
20 25 30
Lys Thr Phe Leu His Tyr Asp Cys Gly Asn Lys Thr Val Thr Pro Val
35 40 45
Ser Pro Leu Gly Lys Lys Leu Asn Val Thr Thr Ala Trp Lys Ala Gln
50 55 60
Asn Pro Val Leu Arg Glu Val Val Asp Ile Leu Thr Glu Gln Leu Arg
65 70 75 80
Asp Ile Gln Leu Glu Asn Tyr Thr Pro Lys Glu Pro Leu Thr Leu Gln
85 90 95
Ala Arg Met Ser Cys Glu Gln Lys Ala Glu Gly His Ser Ser Gly Ser
100 105 110
Trp Gln Phe Ser Phe Asp Gly Gln Ile Phe Leu Leu Phe Asp Ser Glu
115 120 125
Lys Arg Met Trp Thr Thr Val His Pro Gly Ala Arg Lys Met Lys Glu
130 135 140
Lys Trp Glu Asn Asp Lys Val Val Ala Met Ser Phe His Tyr Phe Ser
145 150 155 160
Met Gly Asp Cys Ile Gly Trp Leu Glu Asp Phe Leu Met Gly Met Asp
165 170 175
Ser Thr Leu Glu Pro Ser Ala Gly Ala Pro Pro Met Val
180 185
<210> 17
<211> 187
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide ULBP3 alpha1-alpha2
<400> 17
Ala Ala Glu Pro His Ser Leu Trp Tyr Asn Phe Thr Ile Ile His Leu
1 5 10 15
Pro Arg His Gly Gln Gln Trp Cys Glu Val Gln Ser Gln Val Asp Gln
20 25 30
Lys Asn Phe Leu Ser Tyr Asp Cys Gly Ser Asp Lys Val Leu Ser Met
35 40 45
Gly His Leu Glu Glu Gln Leu Tyr Ala Thr Asp Ala Trp Gly Lys Gln
50 55 60
Leu Glu Met Leu Arg Glu Val Gly Gln Arg Leu Arg Leu Glu Leu Ala
65 70 75 80
Asp Thr Glu Leu Glu Asp Phe Thr Pro Ser Gly Pro Leu Thr Leu Gln
85 90 95
Val Arg Met Ser Cys Glu Ser Glu Ala Asp Gly Tyr Ile Arg Gly Ser
100 105 110
Trp Gln Phe Ser Phe Asp Gly Arg Lys Phe Leu Leu Phe Asp Ser Asn
115 120 125
Asn Arg Lys Trp Thr Val Val His Ala Gly Ala Arg Arg Met Lys Glu
130 135 140
Lys Trp Glu Lys Asp Ser Gly Leu Thr Thr Phe Phe Lys Met Val Ser
145 150 155 160
Met Arg Asp Cys Lys Ser Trp Leu Arg Asp Phe Leu Met His Arg Lys
165 170 175
Lys Arg Leu Glu Pro Thr Ala Pro Pro Met Val
180 185
<210> 18
<211> 187
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide ULBP4 alpha1-alpha2
<400> 18
Ala Ala Glu Pro His Ser Leu Cys Phe Asn Phe Thr Ile Lys Ser Leu
1 5 10 15
Ser Arg Pro Gly Gln Pro Trp Cys Glu Ala Gln Val Phe Leu Asn Lys
20 25 30
Asn Leu Phe Leu Gln Tyr Asn Ser Asp Asn Asn Met Val Lys Pro Leu
35 40 45
Gly Leu Leu Gly Lys Lys Val Tyr Ala Thr Ser Thr Trp Gly Glu Leu
50 55 60
Thr Gln Thr Leu Gly Glu Val Gly Arg Asp Leu Arg Met Leu Leu Cys
65 70 75 80
Asp Ile Lys Pro Gln Ile Lys Thr Ser Asp Pro Ser Thr Leu Gln Val
85 90 95
Glu Met Phe Cys Gln Arg Glu Ala Glu Arg Cys Thr Gly Ala Ser Trp
100 105 110
Gln Phe Ala Thr Asn Gly Glu Lys Ser Leu Leu Phe Asp Ala Met Asn
115 120 125
Met Thr Trp Thr Val Ile Asn His Glu Ala Ser Lys Ile Lys Glu Thr
130 135 140
Trp Lys Lys Asp Arg Gly Leu Glu Lys Tyr Phe Arg Lys Leu Ser Lys
145 150 155 160
Gly Asp Cys Asp His Trp Leu Arg Glu Phe Leu Gly His Trp Glu Ala
165 170 175
Met Pro Glu Pro Thr Val Ser Pro Pro Met Val
180 185
<210> 19
<211> 189
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide ULBP6 alpha1-alpha2
<400> 19
Ala Ala Glu Pro His Ser Leu Cys Tyr Asp Ile Thr Val Ile Pro Lys
1 5 10 15
Phe Arg Pro Gly Pro Arg Trp Cys Ala Val Gln Gly Gln Val Asp Glu
20 25 30
Lys Thr Phe Leu His Tyr Asp Cys Gly Asn Lys Thr Val Thr Pro Val
35 40 45
Ser Pro Leu Gly Lys Lys Leu Asn Val Thr Thr Ala Trp Lys Ala Gln
50 55 60
Asn Pro Val Leu Arg Glu Val Val Asp Ile Leu Thr Glu Gln Leu Leu
65 70 75 80
Asp Ile Gln Leu Glu Asn Tyr Thr Pro Lys Glu Pro Leu Thr Leu Gln
85 90 95
Ala Arg Met Ser Cys Glu Gln Lys Ala Glu Gly His Ser Ser Gly Ser
100 105 110
Trp Gln Phe Ser Ile Asp Gly Gln Thr Phe Leu Leu Phe Asp Ser Glu
115 120 125
Lys Arg Met Trp Thr Thr Val His Pro Gly Ala Arg Lys Met Lys Glu
130 135 140
Lys Trp Glu Asn Asp Lys Asp Val Ala Met Ser Phe His Tyr Ile Ser
145 150 155 160
Met Gly Asp Cys Ile Gly Trp Leu Glu Asp Phe Leu Met Gly Met Asp
165 170 175
Ser Thr Leu Glu Pro Ser Ala Gly Ala Pro Pro Met Val
180 185
<210> 20
<211> 161
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide OMCP alpha1-alpha2
<400> 20
Ala Ala Ala Glu Pro His Lys Leu Ala Phe Asn Phe Asn Leu Glu Ile
1 5 10 15
Asn Gly Ser Asp Thr His Ser Thr Val Asp Val Tyr Leu Asp Asp Ser
20 25 30
Gln Ile Ile Thr Phe Asp Gly Lys Asp Ile Arg Pro Thr Ile Pro Phe
35 40 45
Met Ile Gly Asp Glu Ile Phe Leu Pro Phe Tyr Lys Asn Val Phe Ser
50 55 60
Glu Phe Phe Ser Leu Phe Arg Arg Val Pro Thr Ser Thr Pro Tyr Glu
65 70 75 80
Asp Leu Thr Tyr Phe Tyr Glu Cys Asp Tyr Thr Asp Asn Lys Ser Thr
85 90 95
Phe Asp Gln Phe Tyr Leu Tyr Asn Gly Glu Glu Tyr Thr Val Lys Thr
100 105 110
Gln Glu Ala Thr Asn Lys Asn Met Trp Leu Thr Thr Ser Glu Phe Arg
115 120 125
Leu Lys Lys Trp Phe Asp Gly Glu Asp Cys Ile Met His Leu Arg Ser
130 135 140
Leu Val Arg Lys Met Glu Asp Ser Lys Arg Arg Thr Val Pro Pro Met
145 150 155 160
Val
<210> 21
<211> 580
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide ULBP1-alpha3-iFv.2
<400> 21
Met Gly Leu Gly Pro Val Phe Leu Leu Leu Ala Gly Ile Phe Pro Phe
1 5 10 15
Ala Pro Pro Gly Ala Ala Ala Glu Pro His Cys Leu Cys Tyr Asp Phe
20 25 30
Ile Ile Thr Pro Lys Ser Arg Pro Glu Pro Gln Trp Cys Glu Val Gln
35 40 45
Gly Leu Val Asp Glu Arg Pro Phe Leu His Tyr Asp Cys Val Asn His
50 55 60
Lys Ala Lys Ala Phe Ala Ser Leu Gly Lys Lys Val Asn Val Thr Lys
65 70 75 80
Thr Trp Glu Glu Gln Thr Glu Thr Leu Arg Asp Val Val Asp Phe Leu
85 90 95
Lys Gly Gln Leu Leu Asp Ile Gln Val Glu Asn Leu Ile Pro Ile Glu
100 105 110
Pro Leu Thr Leu Gln Ala Arg Met Ser Cys Glu His Glu Ala His Gly
115 120 125
His Gly Arg Gly Ser Trp Gln Phe Leu Phe Asn Gly Gln Lys Phe Leu
130 135 140
Leu Phe Asp Ser Asn Asn Arg Lys Trp Thr Ala Leu His Pro Gly Ala
145 150 155 160
Lys Lys Met Thr Glu Lys Trp Glu Lys Asn Arg Asp Val Thr Met Phe
165 170 175
Phe Gln Lys Ile Ser Leu Gly Asp Cys Lys Met Trp Leu Glu Glu Phe
180 185 190
Leu Met Tyr Trp Glu Gln Met Leu Asp Pro Thr Lys Pro Pro Met Val
195 200 205
Gln Val Thr Arg Ser Glu Ala Ser Gly Gly Ser Gly Asp Arg Val Thr
210 215 220
Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala Val Ala Trp Tyr
225 230 235 240
Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser
245 250 255
Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
260 265 270
Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala
275 280 285
Thr Tyr Tyr Cys Gln Gln Ser Tyr Thr Thr Pro Pro Thr Phe Gly Gln
290 295 300
Gly Thr Lys Val Glu Ile Lys Gly Gly Ser Ser Arg Ser Ser Ser Ser
305 310 315 320
Gly Gly Gly Gly Ser Gly Gly Gly Gly Glu Val Gln Leu Val Glu Ser
325 330 335
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
340 345 350
Ala Ser Gly Phe Thr Phe Thr Ser Thr Gly Ile Ser Trp Val Arg Gln
355 360 365
Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Arg Ile Tyr Pro Thr Asn
370 375 380
Gly Ser Thr Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
385 390 395 400
Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg
405 410 415
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Thr Tyr Gly Ile Tyr
420 425 430
Asp Leu Tyr Val Asp Tyr Thr Glu Tyr Val Met Asp Tyr Trp Gly Gln
435 440 445
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Ser Ser Arg Ser Ser Ser
450 455 460
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Asp Ile Gln Met Thr Gln
465 470 475 480
Ser Pro Ser Ser Leu Ser Ala Ser Gly Gly Ser Gly Gln Ile Thr Val
485 490 495
Thr Cys Arg Ala Ser Gly Phe Tyr Pro Trp Asn Ile Thr Leu Ser Trp
500 505 510
Arg Gln Asp Gly Val Ser Leu Ser His Asp Thr Gln Gln Trp Gly Asp
515 520 525
Val Leu Pro Asp Gly Gln Gly Thr Tyr Gln Thr Trp Val Ala Thr Arg
530 535 540
Ile Ser Gln Gly Glu Glu Gln Arg Phe Thr Cys Tyr Met Glu His Ser
545 550 555 560
Gly Gln His Ser Thr His Pro Val Pro Ser Gly Lys Gly Ser His His
565 570 575
His His His His
580
<210> 22
<211> 582
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide ULBP2-alpha3-iFv.2
<400> 22
Met Gly Leu Gly Pro Val Phe Leu Leu Leu Ala Gly Ile Phe Pro Phe
1 5 10 15
Ala Pro Pro Gly Ala Ala Ala Glu Pro His Ser Leu Cys Tyr Asp Ile
20 25 30
Thr Val Ile Pro Lys Phe Arg Pro Gly Pro Arg Trp Cys Ala Val Gln
35 40 45
Gly Gln Val Asp Glu Lys Thr Phe Leu His Tyr Asp Cys Gly Asn Lys
50 55 60
Thr Val Thr Pro Val Ser Pro Leu Gly Lys Lys Leu Asn Val Thr Thr
65 70 75 80
Ala Trp Lys Ala Gln Asn Pro Val Leu Arg Glu Val Val Asp Ile Leu
85 90 95
Thr Glu Gln Leu Arg Asp Ile Gln Leu Glu Asn Tyr Thr Pro Lys Glu
100 105 110
Pro Leu Thr Leu Gln Ala Arg Met Ser Cys Glu Gln Lys Ala Glu Gly
115 120 125
His Ser Ser Gly Ser Trp Gln Phe Ser Phe Asp Gly Gln Ile Phe Leu
130 135 140
Leu Phe Asp Ser Glu Lys Arg Met Trp Thr Thr Val His Pro Gly Ala
145 150 155 160
Arg Lys Met Lys Glu Lys Trp Glu Asn Asp Lys Val Val Ala Met Ser
165 170 175
Phe His Tyr Phe Ser Met Gly Asp Cys Ile Gly Trp Leu Glu Asp Phe
180 185 190
Leu Met Gly Met Asp Ser Thr Leu Glu Pro Ser Ala Gly Ala Pro Pro
195 200 205
Met Val Gln Val Thr Arg Ser Glu Ala Ser Gly Gly Ser Gly Asp Arg
210 215 220
Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala Val Ala
225 230 235 240
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser
245 250 255
Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly
260 265 270
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp
275 280 285
Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Thr Thr Pro Pro Thr Phe
290 295 300
Gly Gln Gly Thr Lys Val Glu Ile Lys Gly Gly Ser Ser Arg Ser Ser
305 310 315 320
Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Glu Val Gln Leu Val
325 330 335
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser
340 345 350
Cys Ala Ala Ser Gly Phe Thr Phe Thr Ser Thr Gly Ile Ser Trp Val
355 360 365
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Arg Ile Tyr Pro
370 375 380
Thr Asn Gly Ser Thr Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr
385 390 395 400
Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser
405 410 415
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Thr Tyr Gly
420 425 430
Ile Tyr Asp Leu Tyr Val Asp Tyr Thr Glu Tyr Val Met Asp Tyr Trp
435 440 445
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Ser Ser Arg Ser
450 455 460
Ser Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Asp Ile Gln Met
465 470 475 480
Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Gly Gly Ser Gly Gln Ile
485 490 495
Thr Val Thr Cys Arg Ala Ser Gly Phe Tyr Pro Trp Asn Ile Thr Leu
500 505 510
Ser Trp Arg Gln Asp Gly Val Ser Leu Ser His Asp Thr Gln Gln Trp
515 520 525
Gly Asp Val Leu Pro Asp Gly Gln Gly Thr Tyr Gln Thr Trp Val Ala
530 535 540
Thr Arg Ile Ser Gln Gly Glu Glu Gln Arg Phe Thr Cys Tyr Met Glu
545 550 555 560
His Ser Gly Gln His Ser Thr His Pro Val Pro Ser Gly Lys Gly Ser
565 570 575
His His His His His His
580
<210> 23
<211> 580
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide ULBP3-alpha3-iFv.2
<400> 23
Met Gly Leu Gly Pro Val Phe Leu Leu Leu Ala Gly Ile Phe Pro Phe
1 5 10 15
Ala Pro Pro Gly Ala Ala Ala Glu Pro His Ser Leu Trp Tyr Asn Phe
20 25 30
Thr Ile Ile His Leu Pro Arg His Gly Gln Gln Trp Cys Glu Val Gln
35 40 45
Ser Gln Val Asp Gln Lys Asn Phe Leu Ser Tyr Asp Cys Gly Ser Asp
50 55 60
Lys Val Leu Ser Met Gly His Leu Glu Glu Gln Leu Tyr Ala Thr Asp
65 70 75 80
Ala Trp Gly Lys Gln Leu Glu Met Leu Arg Glu Val Gly Gln Arg Leu
85 90 95
Arg Leu Glu Leu Ala Asp Thr Glu Leu Glu Asp Phe Thr Pro Ser Gly
100 105 110
Pro Leu Thr Leu Gln Val Arg Met Ser Cys Glu Cys Glu Ala Asp Gly
115 120 125
Tyr Ile Arg Gly Ser Trp Gln Phe Ser Phe Asp Gly Arg Lys Phe Leu
130 135 140
Leu Phe Asp Ser Asn Asn Arg Lys Trp Thr Val Val His Ala Gly Ala
145 150 155 160
Arg Arg Met Lys Glu Lys Trp Glu Lys Asp Ser Gly Leu Thr Thr Phe
165 170 175
Phe Lys Met Val Ser Met Arg Asp Cys Lys Ser Trp Leu Arg Asp Phe
180 185 190
Leu Met His Arg Lys Lys Arg Leu Glu Pro Thr Ala Pro Pro Met Val
195 200 205
Gln Val Thr Arg Ser Glu Ala Ser Gly Gly Ser Gly Asp Arg Val Thr
210 215 220
Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala Val Ala Trp Tyr
225 230 235 240
Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser
245 250 255
Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
260 265 270
Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala
275 280 285
Thr Tyr Tyr Cys Gln Gln Ser Tyr Thr Thr Pro Pro Thr Phe Gly Gln
290 295 300
Gly Thr Lys Val Glu Ile Lys Gly Gly Ser Ser Arg Ser Ser Ser Ser
305 310 315 320
Gly Gly Gly Gly Ser Gly Gly Gly Gly Glu Val Gln Leu Val Glu Ser
325 330 335
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
340 345 350
Ala Ser Gly Phe Thr Phe Thr Ser Thr Gly Ile Ser Trp Val Arg Gln
355 360 365
Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Arg Ile Tyr Pro Thr Asn
370 375 380
Gly Ser Thr Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
385 390 395 400
Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg
405 410 415
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Thr Tyr Gly Ile Tyr
420 425 430
Asp Leu Tyr Val Asp Tyr Thr Glu Tyr Val Met Asp Tyr Trp Gly Gln
435 440 445
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Ser Ser Arg Ser Ser Ser
450 455 460
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Asp Ile Gln Met Thr Gln
465 470 475 480
Ser Pro Ser Ser Leu Ser Ala Ser Gly Gly Ser Gly Gln Ile Thr Val
485 490 495
Thr Cys Arg Ala Ser Gly Phe Tyr Pro Trp Asn Ile Thr Leu Ser Trp
500 505 510
Arg Gln Asp Gly Val Ser Leu Ser His Asp Thr Gln Gln Trp Gly Asp
515 520 525
Val Leu Pro Asp Gly Gln Gly Thr Tyr Gln Thr Trp Val Ala Thr Arg
530 535 540
Ile Ser Gln Gly Glu Glu Gln Arg Phe Thr Cys Tyr Met Glu His Ser
545 550 555 560
Gly Gln His Ser Thr His Pro Val Pro Ser Gly Lys Gly Ser His His
565 570 575
His His His His
580
<210> 24
<211> 580
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide ULBP4-alpha3-iFv.2
<400> 24
Met Gly Leu Gly Pro Val Phe Leu Leu Leu Ala Gly Ile Phe Pro Phe
1 5 10 15
Ala Pro Pro Gly Ala Ala Ala Glu Pro His Ser Leu Cys Phe Asn Phe
20 25 30
Thr Ile Lys Ser Leu Ser Arg Pro Gly Gln Pro Trp Cys Glu Ala Gln
35 40 45
Val Phe Leu Asn Lys Asn Leu Phe Leu Gln Tyr Asn Ser Asp Asn Asn
50 55 60
Met Val Lys Pro Leu Gly Leu Leu Gly Lys Lys Val Tyr Ala Thr Ser
65 70 75 80
Thr Trp Gly Glu Leu Thr Gln Thr Leu Gly Glu Val Gly Arg Asp Leu
85 90 95
Arg Met Leu Leu Cys Asp Ile Lys Pro Gln Ile Lys Thr Ser Asp Pro
100 105 110
Ser Thr Leu Gln Val Glu Met Phe Cys Gln Arg Glu Ala Glu Arg Cys
115 120 125
Thr Gly Ala Ser Trp Gln Phe Ala Thr Asn Gly Glu Lys Ser Leu Leu
130 135 140
Phe Asp Ala Met Asn Met Thr Trp Thr Val Ile Asn His Glu Ala Ser
145 150 155 160
Lys Ile Lys Glu Thr Trp Lys Lys Asp Arg Gly Leu Glu Lys Tyr Phe
165 170 175
Arg Lys Leu Ser Lys Gly Asp Cys Asp His Trp Leu Arg Glu Phe Leu
180 185 190
Gly His Trp Glu Ala Met Pro Glu Pro Thr Val Ser Pro Pro Met Val
195 200 205
Gln Val Thr Arg Ser Glu Ala Ser Gly Gly Ser Gly Asp Arg Val Thr
210 215 220
Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala Val Ala Trp Tyr
225 230 235 240
Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser
245 250 255
Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
260 265 270
Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala
275 280 285
Thr Tyr Tyr Cys Gln Gln Ser Tyr Thr Thr Pro Pro Thr Phe Gly Gln
290 295 300
Gly Thr Lys Val Glu Ile Lys Gly Gly Ser Ser Arg Ser Ser Ser Ser
305 310 315 320
Gly Gly Gly Gly Ser Gly Gly Gly Gly Glu Val Gln Leu Val Glu Ser
325 330 335
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
340 345 350
Ala Ser Gly Phe Thr Phe Thr Ser Thr Gly Ile Ser Trp Val Arg Gln
355 360 365
Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Arg Ile Tyr Pro Thr Asn
370 375 380
Gly Ser Thr Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
385 390 395 400
Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg
405 410 415
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Thr Tyr Gly Ile Tyr
420 425 430
Asp Leu Tyr Val Asp Tyr Thr Glu Tyr Val Met Asp Tyr Trp Gly Gln
435 440 445
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Ser Ser Arg Ser Ser Ser
450 455 460
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Asp Ile Gln Met Thr Gln
465 470 475 480
Ser Pro Ser Ser Leu Ser Ala Ser Gly Gly Ser Gly Gln Ile Thr Val
485 490 495
Thr Cys Arg Ala Ser Gly Phe Tyr Pro Trp Asn Ile Thr Leu Ser Trp
500 505 510
Arg Gln Asp Gly Val Ser Leu Ser His Asp Thr Gln Gln Trp Gly Asp
515 520 525
Val Leu Pro Asp Gly Gln Gly Thr Tyr Gln Thr Trp Val Ala Thr Arg
530 535 540
Ile Ser Gln Gly Glu Glu Gln Arg Phe Thr Cys Tyr Met Glu His Ser
545 550 555 560
Gly Gln His Ser Thr His Pro Val Pro Ser Gly Lys Gly Ser His His
565 570 575
His His His His
580
<210> 25
<211> 582
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide ULBP6-alpha3-iFv.2
<400> 25
Met Gly Leu Gly Pro Val Phe Leu Leu Leu Ala Gly Ile Phe Pro Phe
1 5 10 15
Ala Pro Pro Gly Ala Ala Ala Glu Pro His Ser Leu Cys Tyr Asp Ile
20 25 30
Thr Val Ile Pro Lys Phe Arg Pro Gly Pro Arg Trp Cys Ala Val Gln
35 40 45
Gly Gln Val Asp Glu Lys Thr Phe Leu His Tyr Asp Cys Gly Asn Lys
50 55 60
Thr Val Thr Pro Val Ser Pro Leu Gly Lys Lys Leu Asn Val Thr Thr
65 70 75 80
Ala Trp Lys Ala Gln Asn Pro Val Leu Arg Glu Val Val Asp Ile Leu
85 90 95
Thr Glu Gln Leu Leu Asp Ile Gln Leu Glu Asn Tyr Thr Pro Lys Glu
100 105 110
Pro Leu Thr Leu Gln Ala Arg Met Ser Cys Glu Gln Lys Ala Glu Gly
115 120 125
His Ser Ser Gly Ser Trp Gln Phe Ser Ile Asp Gly Gln Thr Phe Leu
130 135 140
Leu Phe Asp Ser Glu Lys Arg Met Trp Thr Thr Val His Pro Gly Ala
145 150 155 160
Arg Lys Met Lys Glu Lys Trp Glu Asn Asp Lys Asp Val Ala Met Ser
165 170 175
Phe His Tyr Ile Ser Met Gly Asp Cys Ile Gly Trp Leu Glu Asp Phe
180 185 190
Leu Met Gly Met Asp Ser Thr Leu Glu Pro Ser Ala Gly Ala Pro Pro
195 200 205
Met Val Gln Val Thr Arg Ser Glu Ala Ser Gly Gly Ser Gly Asp Arg
210 215 220
Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala Val Ala
225 230 235 240
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser
245 250 255
Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly
260 265 270
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp
275 280 285
Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Thr Thr Pro Pro Thr Phe
290 295 300
Gly Gln Gly Thr Lys Val Glu Ile Lys Gly Gly Ser Ser Arg Ser Ser
305 310 315 320
Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Glu Val Gln Leu Val
325 330 335
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser
340 345 350
Cys Ala Ala Ser Gly Phe Thr Phe Thr Ser Thr Gly Ile Ser Trp Val
355 360 365
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Arg Ile Tyr Pro
370 375 380
Thr Asn Gly Ser Thr Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr
385 390 395 400
Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser
405 410 415
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Thr Tyr Gly
420 425 430
Ile Tyr Asp Leu Tyr Val Asp Tyr Thr Glu Tyr Val Met Asp Tyr Trp
435 440 445
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Ser Ser Arg Ser
450 455 460
Ser Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Asp Ile Gln Met
465 470 475 480
Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Gly Gly Ser Gly Gln Ile
485 490 495
Thr Val Thr Cys Arg Ala Ser Gly Phe Tyr Pro Trp Asn Ile Thr Leu
500 505 510
Ser Trp Arg Gln Asp Gly Val Ser Leu Ser His Asp Thr Gln Gln Trp
515 520 525
Gly Asp Val Leu Pro Asp Gly Gln Gly Thr Tyr Gln Thr Trp Val Ala
530 535 540
Thr Arg Ile Ser Gln Gly Glu Glu Gln Arg Phe Thr Cys Tyr Met Glu
545 550 555 560
His Ser Gly Gln His Ser Thr His Pro Val Pro Ser Gly Lys Gly Ser
565 570 575
His His His His His His
580
<210> 26
<211> 553
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide OMCP-alpha3-iFv.2
<400> 26
Met Gly Leu Gly Pro Val Phe Leu Leu Leu Ala Gly Ile Phe Pro Phe
1 5 10 15
Ala Pro Pro Gly Ala Ala Ala Glu Pro His Lys Leu Ala Phe Asn Phe
20 25 30
Asn Leu Glu Ile Asn Gly Ser Asp Thr His Ser Thr Val Asp Val Tyr
35 40 45
Leu Asp Asp Ser Gln Ile Ile Thr Phe Asp Gly Lys Asp Ile Arg Pro
50 55 60
Thr Ile Pro Phe Met Ile Gly Asp Glu Ile Phe Leu Pro Phe Tyr Lys
65 70 75 80
Asn Val Phe Ser Glu Phe Phe Ser Leu Phe Arg Arg Val Pro Thr Ser
85 90 95
Thr Pro Tyr Glu Asp Leu Thr Tyr Phe Tyr Glu Cys Asp Tyr Thr Asp
100 105 110
Asn Lys Ser Thr Phe Asp Gln Phe Tyr Leu Tyr Asn Gly Glu Glu Tyr
115 120 125
Thr Val Lys Thr Gln Glu Ala Thr Asn Lys Asn Met Trp Leu Thr Thr
130 135 140
Ser Glu Phe Arg Leu Lys Lys Trp Phe Asp Gly Glu Asp Cys Ile Met
145 150 155 160
His Leu Arg Ser Leu Val Arg Lys Met Glu Asp Ser Lys Arg Arg Thr
165 170 175
Val Pro Pro Met Val Gln Val Thr Arg Ser Glu Ala Ser Gly Gly Ser
180 185 190
Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr
195 200 205
Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu
210 215 220
Ile Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser
225 230 235 240
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln
245 250 255
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Thr Thr Pro
260 265 270
Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Gly Gly Ser Ser
275 280 285
Arg Ser Ser Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Glu Val
290 295 300
Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu
305 310 315 320
Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Ser Thr Gly Ile
325 330 335
Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Arg
340 345 350
Ile Tyr Pro Thr Asn Gly Ser Thr Asn Tyr Ala Asp Ser Val Lys Gly
355 360 365
Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gln
370 375 380
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
385 390 395 400
Thr Tyr Gly Ile Tyr Asp Leu Tyr Val Asp Tyr Thr Glu Tyr Val Met
405 410 415
Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Ser
420 425 430
Ser Arg Ser Ser Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Asp
435 440 445
Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Gly Gly Ser
450 455 460
Gly Gln Ile Thr Val Thr Cys Arg Ala Ser Gly Phe Tyr Pro Trp Asn
465 470 475 480
Ile Thr Leu Ser Trp Arg Gln Asp Gly Val Ser Leu Ser His Asp Thr
485 490 495
Gln Gln Trp Gly Asp Val Leu Pro Asp Gly Gln Gly Thr Tyr Gln Thr
500 505 510
Trp Val Ala Thr Arg Ile Ser Gln Gly Glu Glu Gln Arg Phe Thr Cys
515 520 525
Tyr Met Glu His Ser Gly Gln His Ser Thr His Pro Val Pro Ser Gly
530 535 540
Lys Gly Ser His His His His His His
545 550
<210> 27
<211> 507
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic polynucleotide, encoding alpha1-alpha2 variant 15
<400> 27
gctgctgagc cacacagtct ccgctacaac cttacggtgt tgagctggga cggctctgtc 60
cagagtggct ttctgactga ggtacatctc gatggtcagc ccttcctccg atgcgacaga 120
caaaagtgca gggccaagcc acagggccaa tgggccgaag atgtacttgg caataagact 180
tgggacagag aaaccagaga tctgactggc tggggtaagg acttacgcat gactctcgca 240
cacattaaag accagaagga aggtcttcat tcgctccagg aaattagagt ctgtgaaatc 300
catgaagaca acagcacaag aagttcccaa catttctact acgacggcga gctgttctta 360
tcacagaatt tagagaccaa cgagtggaca atgccccaaa gctcgagggc ccagaccctc 420
gctatgaatg tgaggaattt ccttaaggag gacgctatgg aaactgacac ccactaccat 480
gcgatgcgcg ccgattgcct gcaggaa 507
<210> 28
<211> 507
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic polynucleotide, encoding alpha1-alpha2 variant 16
<400> 28
gctgctgagc cacacagtct ccgctacaac cttacggtgt tgagctggga cggctctgtc 60
cagagtggct ttctgactga ggtacatctc gatggtcagc ccttcctccg atgcgacaga 120
caaaagtgca gggccaagcc acagggccaa tgggccgaag atgtacttgg caataagact 180
tgggacagag aaaccagaga tctgactggc tggggtaagg acttacgcat gactctcgca 240
cacattaaag accagaagga aggtcttcat tcgctccagg aaattagagt ctgtgaaatc 300
catgaagaca acagcacaag aagttcccaa catttctact acgacggcga gctgttctta 360
tcacagaatt tagagaccct cgagtggaca atgccccaaa gctcgagggc ccagaccctc 420
gctatgaatg tgaggaattt ccttaaggag gacgctatgg aaactgacac ccactaccat 480
gcgatgcgcg ccgattgcct gcaggaa 507
<210> 29
<211> 507
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic polynucleotide, encoding alpha1-alpha2 variant 17
<400> 29
gctgctgagc cacacagtct ccgctacaac cttacggtgt tgagctggga cggctctgtc 60
cagagtggct ttctgactga ggtacatctc gatggtcagc ccttcctccg atgcgacaga 120
caaaagtgca gggccaagcc acagggccaa tgggccgaag atgtacttgg caataagact 180
tgggacagag aaaccagaga tctgactctc tggggtaagg acttacgcat gactctcgca 240
cacattaaag accagaagga aggtcttcat tcgctccagg aaattagagt ctgtgaaatc 300
catgaagaca acagcacaag aagttcccaa catttctact acgacggcga gctgttctta 360
tcacagaatt tagagaccct cgagtggaca atgccccaaa gctcgagggc ccagaccctc 420
gctatgaatg tgaggaattt ccttaaggag gacgctatgg aaactgacac ccactaccat 480
gcgatgcgcg ccgattgcct gcaggaa 507
<210> 30
<211> 507
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic polynucleotide, encoding alpha1-alpha2 variant 18
<400> 30
gctgctgagc cacacagtct ccgctacaac cttacggtgt tgagctggga cggctctgtc 60
cagcccggct ttctgactga ggtacatctc gatggtcagc ccttcctccg atgcgacaga 120
caaaagtgca gggccaagcc acagggccaa tgggccgaag atgtacttgg caataagact 180
tgggacagag aaaccagaga tctgactctc tggggtaagg acttacgcat gactctcgca 240
cacattaaag accagaagga aggtcttcat tcgctccagg aaattagagt ctgtgaaatc 300
catgaagaca acagcacaag aagttcccaa catttctact acgacggcga gctgttctta 360
tcacagaatt tagagaccct cgagtggaca atgccccaaa gctcgagggc ccagaccctc 420
gctatgaatg tgaggaattt ccttaaggag gacgctatgg aaactgacac ccactaccat 480
gcgatgcgcg ccgattgcct gcaggaa 507
<210> 31
<211> 558
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide MICA alpha1-alpha2 variant 15
<400> 31
Glu Pro His Ser Leu Arg Tyr Asn Leu Thr Val Leu Ser Trp Asp Gly
1 5 10 15
Ser Val Gln Ser Gly Phe Leu Thr Glu Val His Leu Asp Gly Gln Pro
20 25 30
Phe Leu Arg Cys Asp Arg Gln Lys Cys Arg Ala Lys Pro Gln Gly Gln
35 40 45
Trp Ala Glu Asp Val Leu Gly Asn Lys Thr Trp Asp Arg Glu Thr Arg
50 55 60
Asp Leu Thr Gly Trp Gly Lys Asp Leu Arg Met Thr Leu Ala His Ile
65 70 75 80
Lys Asp Gln Lys Glu Gly Leu His Ser Leu Gln Glu Ile Arg Val Cys
85 90 95
Glu Ile His Glu Asp Asn Ser Thr Arg Ser Ser Gln His Phe Tyr Tyr
100 105 110
Asp Gly Glu Leu Phe Leu Ser Gln Asn Leu Glu Thr Asn Glu Trp Thr
115 120 125
Met Pro Gln Ser Ser Arg Ala Gln Thr Leu Ala Met Asn Val Arg Asn
130 135 140
Phe Leu Lys Glu Asp Ala Met Glu Thr Asp Thr His Tyr His Ala Met
145 150 155 160
Arg Ala Asp Cys Leu Gln Glu Leu Arg Arg Tyr Leu Lys Ser Gly Val
165 170 175
Val Leu Arg Arg Thr Val Pro Pro Met Val Gln Val Thr Arg Ser Glu
180 185 190
Ala Ser Gly Gly Ser Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
195 200 205
Gln Asp Val Ser Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys
210 215 220
Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val
225 230 235 240
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
245 250 255
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
260 265 270
Ser Tyr Thr Thr Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
275 280 285
Lys Gly Gly Ser Ser Arg Ser Ser Ser Ser Gly Gly Gly Gly Ser Gly
290 295 300
Gly Gly Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
305 310 315 320
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
325 330 335
Thr Ser Thr Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
340 345 350
Glu Trp Val Gly Arg Ile Tyr Pro Thr Asn Gly Ser Thr Asn Tyr Ala
355 360 365
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn
370 375 380
Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
385 390 395 400
Tyr Tyr Cys Ala Arg Thr Tyr Gly Ile Tyr Asp Leu Tyr Val Asp Tyr
405 410 415
Thr Glu Tyr Val Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
420 425 430
Ser Ser Gly Gly Ser Ser Arg Ser Ser Ser Ser Gly Gly Gly Gly Ser
435 440 445
Gly Gly Gly Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser
450 455 460
Ala Ser Gly Gly Ser Gly Gln Ile Thr Val Thr Cys Arg Ala Ser Gly
465 470 475 480
Phe Tyr Pro Trp Asn Ile Thr Leu Ser Trp Arg Gln Asp Gly Val Ser
485 490 495
Leu Ser His Asp Thr Gln Gln Trp Gly Asp Val Leu Pro Asp Gly Gln
500 505 510
Gly Thr Tyr Gln Thr Trp Val Ala Thr Arg Ile Ser Gln Gly Glu Glu
515 520 525
Gln Arg Phe Thr Cys Tyr Met Glu His Ser Gly Gln His Ser Thr His
530 535 540
Pro Val Pro Ser Gly Lys Gly Ser His His His His His His
545 550 555
<210> 32
<211> 558
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide MICA alpha1-alpha2 variant 16
<400> 32
Glu Pro His Ser Leu Arg Tyr Asn Leu Thr Val Leu Ser Trp Asp Gly
1 5 10 15
Ser Val Gln Ser Gly Phe Leu Thr Glu Val His Leu Asp Gly Gln Pro
20 25 30
Phe Leu Arg Cys Asp Arg Gln Lys Cys Arg Ala Lys Pro Gln Gly Gln
35 40 45
Trp Ala Glu Asp Val Leu Gly Asn Lys Thr Trp Asp Arg Glu Thr Arg
50 55 60
Asp Leu Thr Gly Trp Gly Lys Asp Leu Arg Met Thr Leu Ala His Ile
65 70 75 80
Lys Asp Gln Lys Glu Gly Leu His Ser Leu Gln Glu Ile Arg Val Cys
85 90 95
Glu Ile His Glu Asp Asn Ser Thr Arg Ser Ser Gln His Phe Tyr Tyr
100 105 110
Asp Gly Glu Leu Phe Leu Ser Gln Asn Leu Glu Thr Leu Glu Trp Thr
115 120 125
Met Pro Gln Ser Ser Arg Ala Gln Thr Leu Ala Met Asn Val Arg Asn
130 135 140
Phe Leu Lys Glu Asp Ala Met Glu Thr Asp Thr His Tyr His Ala Met
145 150 155 160
Arg Ala Asp Cys Leu Gln Glu Leu Arg Arg Tyr Leu Lys Ser Gly Val
165 170 175
Val Leu Arg Arg Thr Val Pro Pro Met Val Gln Val Thr Arg Ser Glu
180 185 190
Ala Ser Gly Gly Ser Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
195 200 205
Gln Asp Val Ser Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys
210 215 220
Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val
225 230 235 240
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
245 250 255
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
260 265 270
Ser Tyr Thr Thr Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
275 280 285
Lys Gly Gly Ser Ser Arg Ser Ser Ser Ser Gly Gly Gly Gly Ser Gly
290 295 300
Gly Gly Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
305 310 315 320
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
325 330 335
Thr Ser Thr Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
340 345 350
Glu Trp Val Gly Arg Ile Tyr Pro Thr Asn Gly Ser Thr Asn Tyr Ala
355 360 365
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn
370 375 380
Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
385 390 395 400
Tyr Tyr Cys Ala Arg Thr Tyr Gly Ile Tyr Asp Leu Tyr Val Asp Tyr
405 410 415
Thr Glu Tyr Val Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
420 425 430
Ser Ser Gly Gly Ser Ser Arg Ser Ser Ser Ser Gly Gly Gly Gly Ser
435 440 445
Gly Gly Gly Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser
450 455 460
Ala Ser Gly Gly Ser Gly Gln Ile Thr Val Thr Cys Arg Ala Ser Gly
465 470 475 480
Phe Tyr Pro Trp Asn Ile Thr Leu Ser Trp Arg Gln Asp Gly Val Ser
485 490 495
Leu Ser His Asp Thr Gln Gln Trp Gly Asp Val Leu Pro Asp Gly Gln
500 505 510
Gly Thr Tyr Gln Thr Trp Val Ala Thr Arg Ile Ser Gln Gly Glu Glu
515 520 525
Gln Arg Phe Thr Cys Tyr Met Glu His Ser Gly Gln His Ser Thr His
530 535 540
Pro Val Pro Ser Gly Lys Gly Ser His His His His His His
545 550 555
<210> 33
<211> 558
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide MICA alpha1-alpha2 variant 17
<400> 33
Glu Pro His Ser Leu Arg Tyr Asn Leu Thr Val Leu Ser Trp Asp Gly
1 5 10 15
Ser Val Gln Ser Gly Phe Leu Thr Glu Val His Leu Asp Gly Gln Pro
20 25 30
Phe Leu Arg Cys Asp Arg Gln Lys Cys Arg Ala Lys Pro Gln Gly Gln
35 40 45
Trp Ala Glu Asp Val Leu Gly Asn Lys Thr Trp Asp Arg Glu Thr Arg
50 55 60
Asp Leu Thr Leu Trp Gly Lys Asp Leu Arg Met Thr Leu Ala His Ile
65 70 75 80
Lys Asp Gln Lys Glu Gly Leu His Ser Leu Gln Glu Ile Arg Val Cys
85 90 95
Glu Ile His Glu Asp Asn Ser Thr Arg Ser Ser Gln His Phe Tyr Tyr
100 105 110
Asp Gly Glu Leu Phe Leu Ser Gln Asn Leu Glu Thr Leu Glu Trp Thr
115 120 125
Met Pro Gln Ser Ser Arg Ala Gln Thr Leu Ala Met Asn Val Arg Asn
130 135 140
Phe Leu Lys Glu Asp Ala Met Glu Thr Asp Thr His Tyr His Ala Met
145 150 155 160
Arg Ala Asp Cys Leu Gln Glu Leu Arg Arg Tyr Leu Lys Ser Gly Val
165 170 175
Val Leu Arg Arg Thr Val Pro Pro Met Val Gln Val Thr Arg Ser Glu
180 185 190
Ala Ser Gly Gly Ser Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
195 200 205
Gln Asp Val Ser Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys
210 215 220
Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val
225 230 235 240
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
245 250 255
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
260 265 270
Ser Tyr Thr Thr Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
275 280 285
Lys Gly Gly Ser Ser Arg Ser Ser Ser Ser Gly Gly Gly Gly Ser Gly
290 295 300
Gly Gly Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
305 310 315 320
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
325 330 335
Thr Ser Thr Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
340 345 350
Glu Trp Val Gly Arg Ile Tyr Pro Thr Asn Gly Ser Thr Asn Tyr Ala
355 360 365
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn
370 375 380
Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
385 390 395 400
Tyr Tyr Cys Ala Arg Thr Tyr Gly Ile Tyr Asp Leu Tyr Val Asp Tyr
405 410 415
Thr Glu Tyr Val Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
420 425 430
Ser Ser Gly Gly Ser Ser Arg Ser Ser Ser Ser Gly Gly Gly Gly Ser
435 440 445
Gly Gly Gly Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser
450 455 460
Ala Ser Gly Gly Ser Gly Gln Ile Thr Val Thr Cys Arg Ala Ser Gly
465 470 475 480
Phe Tyr Pro Trp Asn Ile Thr Leu Ser Trp Arg Gln Asp Gly Val Ser
485 490 495
Leu Ser His Asp Thr Gln Gln Trp Gly Asp Val Leu Pro Asp Gly Gln
500 505 510
Gly Thr Tyr Gln Thr Trp Val Ala Thr Arg Ile Ser Gln Gly Glu Glu
515 520 525
Gln Arg Phe Thr Cys Tyr Met Glu His Ser Gly Gln His Ser Thr His
530 535 540
Pro Val Pro Ser Gly Lys Gly Ser His His His His His His
545 550 555
<210> 34
<211> 558
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide MICA alpha1-alpha2 variant 18
<400> 34
Glu Pro His Ser Leu Arg Tyr Asn Leu Thr Val Leu Ser Trp Asp Gly
1 5 10 15
Ser Val Gln Pro Gly Phe Leu Thr Glu Val His Leu Asp Gly Gln Pro
20 25 30
Phe Leu Arg Cys Asp Arg Gln Lys Cys Arg Ala Lys Pro Gln Gly Gln
35 40 45
Trp Ala Glu Asp Val Leu Gly Asn Lys Thr Trp Asp Arg Glu Thr Arg
50 55 60
Asp Leu Thr Leu Trp Gly Lys Asp Leu Arg Met Thr Leu Ala His Ile
65 70 75 80
Lys Asp Gln Lys Glu Gly Leu His Ser Leu Gln Glu Ile Arg Val Cys
85 90 95
Glu Ile His Glu Asp Asn Ser Thr Arg Ser Ser Gln His Phe Tyr Tyr
100 105 110
Asp Gly Glu Leu Phe Leu Ser Gln Asn Leu Glu Thr Leu Glu Trp Thr
115 120 125
Met Pro Gln Ser Ser Arg Ala Gln Thr Leu Ala Met Asn Val Arg Asn
130 135 140
Phe Leu Lys Glu Asp Ala Met Glu Thr Asp Thr His Tyr His Ala Met
145 150 155 160
Arg Ala Asp Cys Leu Gln Glu Leu Arg Arg Tyr Leu Lys Ser Gly Val
165 170 175
Val Leu Arg Arg Thr Val Pro Pro Met Val Gln Val Thr Arg Ser Glu
180 185 190
Ala Ser Gly Gly Ser Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
195 200 205
Gln Asp Val Ser Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys
210 215 220
Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val
225 230 235 240
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
245 250 255
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
260 265 270
Ser Tyr Thr Thr Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
275 280 285
Lys Gly Gly Ser Ser Arg Ser Ser Ser Ser Gly Gly Gly Gly Ser Gly
290 295 300
Gly Gly Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
305 310 315 320
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
325 330 335
Thr Ser Thr Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
340 345 350
Glu Trp Val Gly Arg Ile Tyr Pro Thr Asn Gly Ser Thr Asn Tyr Ala
355 360 365
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn
370 375 380
Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
385 390 395 400
Tyr Tyr Cys Ala Arg Thr Tyr Gly Ile Tyr Asp Leu Tyr Val Asp Tyr
405 410 415
Thr Glu Tyr Val Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
420 425 430
Ser Ser Gly Gly Ser Ser Arg Ser Ser Ser Ser Gly Gly Gly Gly Ser
435 440 445
Gly Gly Gly Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser
450 455 460
Ala Ser Gly Gly Ser Gly Gln Ile Thr Val Thr Cys Arg Ala Ser Gly
465 470 475 480
Phe Tyr Pro Trp Asn Ile Thr Leu Ser Trp Arg Gln Asp Gly Val Ser
485 490 495
Leu Ser His Asp Thr Gln Gln Trp Gly Asp Val Leu Pro Asp Gly Gln
500 505 510
Gly Thr Tyr Gln Thr Trp Val Ala Thr Arg Ile Ser Gln Gly Glu Glu
515 520 525
Gln Arg Phe Thr Cys Tyr Met Glu His Ser Gly Gln His Ser Thr His
530 535 540
Pro Val Pro Ser Gly Lys Gly Ser His His His His His His
545 550 555
<210> 35
<211> 558
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide MICA-WED
<400> 35
Glu Pro His Ser Leu Arg Tyr Asn Leu Thr Val Leu Ser Trp Asp Gly
1 5 10 15
Ser Val Gln Ser Gly Phe Leu Thr Glu Val His Leu Asp Gly Gln Pro
20 25 30
Phe Leu Arg Cys Asp Arg Gln Lys Cys Arg Ala Lys Pro Gln Gly Gln
35 40 45
Trp Ala Glu Asp Val Leu Gly Asn Lys Thr Trp Asp Arg Glu Thr Arg
50 55 60
Asp Leu Thr Gly Trp Gly Lys Asp Leu Arg Met Thr Leu Ala His Ile
65 70 75 80
Lys Asp Gln Lys Glu Gly Leu His Ser Leu Gln Glu Ile Arg Val Cys
85 90 95
Glu Ile His Glu Asp Asn Ser Thr Arg Ser Ser Gln His Phe Tyr Tyr
100 105 110
Asp Gly Glu Leu Phe Leu Ser Gln Asn Leu Glu Thr Lys Glu Trp Thr
115 120 125
Met Pro Gln Ser Ser Arg Ala Gln Thr Leu Ala Met Asn Val Arg Asn
130 135 140
Phe Leu Lys Glu Asp Ala Met Glu Thr Asp Thr His Tyr His Ala Met
145 150 155 160
His Ala Asp Cys Leu Gln Glu Leu Arg Arg Tyr Leu Lys Ser Gly Val
165 170 175
Val Leu Arg Arg Thr Val Pro Pro Met Val Gln Val Thr Arg Ser Glu
180 185 190
Ala Ser Gly Gly Ser Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
195 200 205
Gln Asp Val Ser Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys
210 215 220
Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val
225 230 235 240
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
245 250 255
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
260 265 270
Ser Tyr Thr Thr Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
275 280 285
Lys Gly Gly Ser Ser Arg Ser Ser Ser Ser Gly Gly Gly Gly Ser Gly
290 295 300
Gly Gly Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
305 310 315 320
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
325 330 335
Thr Ser Thr Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
340 345 350
Glu Trp Val Gly Arg Ile Tyr Pro Thr Asn Gly Ser Thr Asn Tyr Ala
355 360 365
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn
370 375 380
Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
385 390 395 400
Tyr Tyr Cys Ala Arg Thr Tyr Gly Ile Tyr Asp Leu Tyr Val Asp Tyr
405 410 415
Thr Glu Tyr Val Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
420 425 430
Ser Ser Gly Gly Ser Ser Arg Ser Ser Ser Ser Gly Gly Gly Gly Ser
435 440 445
Gly Gly Gly Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser
450 455 460
Ala Ser Gly Gly Ser Gly Gln Ile Thr Val Thr Cys Arg Ala Ser Gly
465 470 475 480
Phe Tyr Pro Trp Asn Ile Thr Leu Ser Trp Arg Gln Asp Gly Val Ser
485 490 495
Leu Ser His Asp Thr Gln Gln Trp Gly Asp Val Leu Pro Asp Gly Gln
500 505 510
Gly Thr Tyr Gln Thr Trp Val Ala Thr Arg Ile Ser Gln Gly Glu Glu
515 520 525
Gln Arg Phe Thr Cys Tyr Met Glu His Ser Gly Gln His Ser Thr His
530 535 540
Pro Val Pro Ser Gly Lys Gly Ser His His His His His His
545 550 555
<210> 36
<211> 274
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide MICA
<400> 36
Glu Pro His Ser Leu Arg Tyr Asn Leu Thr Val Leu Ser Trp Asp Gly
1 5 10 15
Ser Val Gln Ser Gly Phe Leu Thr Glu Val His Leu Asp Gly Gln Pro
20 25 30
Phe Leu Arg Cys Asp Arg Gln Lys Cys Arg Ala Lys Pro Gln Gly Gln
35 40 45
Trp Ala Glu Asp Val Leu Gly Asn Lys Thr Trp Asp Arg Glu Thr Arg
50 55 60
Asp Leu Thr Gly Asn Gly Lys Asp Leu Arg Met Thr Leu Ala His Ile
65 70 75 80
Lys Asp Gln Lys Glu Gly Leu His Ser Leu Gln Glu Ile Arg Val Cys
85 90 95
Glu Ile His Glu Asp Asn Ser Thr Arg Ser Ser Gln His Phe Tyr Tyr
100 105 110
Asp Gly Glu Leu Phe Leu Ser Gln Asn Leu Glu Thr Glu Glu Trp Thr
115 120 125
Met Pro Gln Ser Ser Arg Ala Gln Thr Leu Ala Met Asn Val Arg Asn
130 135 140
Phe Leu Lys Glu Asp Ala Met Lys Thr Lys Thr Leu Tyr His Ala Met
145 150 155 160
His Ala Asp Cys Leu Gln Glu Leu Arg Arg Tyr Leu Lys Ser Gly Val
165 170 175
Val Leu Arg Arg Thr Val Pro Pro Met Val Asn Val Thr Arg Ser Glu
180 185 190
Ala Ser Glu Gly Asn Ile Thr Val Thr Cys Arg Ala Ser Gly Phe Tyr
195 200 205
Pro Trp Asn Ile Thr Leu Ser Trp Arg Gln Asp Gly Val Ser Leu Ser
210 215 220
His Asp Thr Gln Gln Trp Gly Asp Val Leu Pro Asp Gly Asn Gly Thr
225 230 235 240
Tyr Gln Thr Trp Val Ala Thr Arg Ile Cys Gln Gly Glu Glu Gln Arg
245 250 255
Phe Thr Cys Tyr Met Glu His Ser Gly Asn His Ser Thr His Pro Val
260 265 270
Pro Ser
<210> 37
<211> 274
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide MICA
<400> 37
Glu Pro His Ser Leu Arg Tyr Asn Leu Thr Val Leu Ser Trp Asp Gly
1 5 10 15
Ser Val Gln Ser Gly Phe Leu Ala Glu Val His Leu Asp Gly Gln Pro
20 25 30
Phe Leu Arg Cys Asp Arg Gln Lys Cys Arg Ala Lys Pro Gln Gly Gln
35 40 45
Trp Ala Glu Asp Val Leu Gly Asn Lys Thr Trp Asp Arg Glu Thr Arg
50 55 60
Asp Leu Thr Gly Asn Gly Lys Asp Leu Arg Met Thr Leu Ala His Ile
65 70 75 80
Lys Asp Gln Lys Glu Gly Leu His Ser Leu Gln Glu Ile Arg Val Cys
85 90 95
Glu Ile His Glu Asp Asn Ser Thr Arg Ser Ser Gln His Phe Tyr Tyr
100 105 110
Asp Gly Glu Leu Phe Leu Ser Gln Asn Leu Glu Thr Glu Glu Trp Thr
115 120 125
Met Pro Gln Ser Ser Arg Ala Gln Thr Leu Ala Met Asn Ile Arg Asn
130 135 140
Phe Leu Lys Glu Asp Ala Met Lys Thr Lys Thr His Tyr His Ala Met
145 150 155 160
His Ala Asp Cys Leu Gln Glu Leu Arg Arg Tyr Leu Lys Ser Gly Val
165 170 175
Val Leu Arg Arg Thr Val Pro Pro Met Val Asn Val Thr Arg Ser Glu
180 185 190
Ala Ser Glu Gly Asn Ile Thr Val Thr Cys Arg Ala Ser Gly Phe Tyr
195 200 205
Pro Trp Asn Ile Thr Leu Ser Trp Arg Gln Asp Gly Val Ser Leu Ser
210 215 220
His Asp Thr Gln Gln Trp Gly Asp Val Leu Pro Asp Gly Asn Gly Thr
225 230 235 240
Tyr Gln Thr Trp Val Ala Thr Arg Ile Cys Gln Gly Glu Glu Gln Arg
245 250 255
Phe Thr Cys Tyr Met Glu His Ser Gly Asn His Ser Thr His Pro Val
260 265 270
Pro Ser
<210> 38
<211> 274
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide MICA
<400> 38
Glu Pro His Ser Leu Pro Tyr Asn Leu Thr Val Leu Ser Trp Asp Gly
1 5 10 15
Ser Val Gln Ser Gly Phe Leu Ala Glu Val His Leu Asp Gly Gln Pro
20 25 30
Phe Leu Arg Tyr Asp Arg Gln Lys Cys Arg Ala Lys Pro Gln Gly Gln
35 40 45
Trp Ala Glu Asp Val Leu Gly Asn Lys Thr Trp Asp Arg Glu Thr Arg
50 55 60
Asp Leu Thr Gly Asn Gly Lys Asp Leu Arg Met Thr Leu Ala His Ile
65 70 75 80
Lys Asp Gln Lys Glu Gly Leu His Ser Leu Gln Glu Ile Arg Val Cys
85 90 95
Glu Ile His Glu Asp Asn Ser Thr Arg Ser Ser Gln His Phe Tyr Tyr
100 105 110
Asp Gly Glu Leu Phe Leu Ser Gln Asn Leu Glu Thr Glu Glu Trp Thr
115 120 125
Met Pro Gln Ser Ser Arg Ala Gln Thr Leu Ala Met Asn Val Arg Asn
130 135 140
Phe Leu Lys Glu Asp Ala Met Lys Thr Lys Thr His Tyr His Ala Met
145 150 155 160
His Ala Asp Cys Leu Gln Glu Leu Arg Arg Tyr Leu Lys Ser Gly Val
165 170 175
Val Leu Arg Arg Thr Val Pro Pro Met Val Asn Val Thr Arg Ser Glu
180 185 190
Ala Ser Glu Gly Asn Ile Thr Val Thr Cys Arg Ala Ser Gly Phe Tyr
195 200 205
Pro Trp Asn Ile Thr Leu Ser Trp Arg Gln Asp Gly Val Ser Leu Ser
210 215 220
His Asp Thr Gln Gln Trp Gly Asp Val Leu Pro Asp Gly Asn Gly Thr
225 230 235 240
Tyr Gln Thr Trp Val Ala Thr Arg Ile Cys Gln Gly Glu Glu Gln Arg
245 250 255
Phe Thr Cys Tyr Met Glu His Ser Gly Asn His Ser Thr His Pro Val
260 265 270
Pro Ser
<210> 39
<211> 274
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide MICA
<400> 39
Glu Pro His Ser Leu Arg Tyr Asn Leu Thr Val Leu Ser Trp Asp Gly
1 5 10 15
Ser Val Gln Ser Gly Phe Leu Ala Glu Val His Leu Asp Gly Gln Pro
20 25 30
Phe Leu Arg Tyr Asp Arg Gln Lys Cys Arg Ala Lys Pro Gln Gly Gln
35 40 45
Trp Ala Glu Asp Val Leu Gly Asn Lys Thr Trp Asp Arg Glu Thr Arg
50 55 60
Asp Leu Thr Gly Asn Gly Lys Asp Leu Arg Met Thr Leu Ala His Ile
65 70 75 80
Lys Asp Gln Lys Glu Gly Leu His Ser Leu Gln Glu Ile Arg Val Cys
85 90 95
Glu Ile His Glu Asp Asn Ser Thr Arg Ser Ser Gln His Phe Tyr Tyr
100 105 110
Asp Gly Glu Leu Phe Leu Ser Gln Asn Leu Glu Thr Glu Glu Trp Thr
115 120 125
Val Pro Gln Ser Ser Arg Ala Gln Thr Leu Ala Met Asn Val Arg Asn
130 135 140
Phe Leu Lys Glu Asp Ala Met Lys Thr Lys Thr His Tyr His Ala Met
145 150 155 160
His Ala Asp Cys Leu Gln Glu Leu Arg Arg Tyr Leu Glu Ser Gly Val
165 170 175
Val Leu Arg Arg Thr Val Pro Pro Met Val Asn Val Thr Arg Ser Glu
180 185 190
Ala Ser Glu Gly Asn Ile Thr Val Thr Cys Arg Ala Ser Ser Phe Tyr
195 200 205
Pro Arg Asn Ile Thr Leu Thr Trp Arg Gln Asp Gly Val Ser Leu Ser
210 215 220
His Asp Thr Gln Gln Trp Gly Asp Val Leu Pro Asp Gly Asn Gly Thr
225 230 235 240
Tyr Gln Thr Trp Val Ala Thr Arg Ile Cys Gln Gly Glu Glu Gln Arg
245 250 255
Phe Thr Cys Tyr Met Glu His Ser Gly Asn His Ser Thr His Pro Val
260 265 270
Pro Ser
<210> 40
<211> 274
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide MICA
<400> 40
Glu Pro His Ser Leu Arg Tyr Asn Leu Thr Val Leu Ser Trp Asp Gly
1 5 10 15
Ser Val Gln Ser Gly Phe Leu Thr Glu Val His Leu Asp Gly Gln Pro
20 25 30
Phe Leu Arg Cys Asp Arg Gln Lys Cys Arg Ala Lys Pro Gln Gly Gln
35 40 45
Trp Ala Glu Asp Val Leu Gly Asn Lys Thr Trp Asp Arg Glu Thr Arg
50 55 60
Asp Leu Thr Gly Asn Gly Lys Asp Leu Arg Met Thr Leu Ala His Ile
65 70 75 80
Lys Asp Gln Lys Glu Gly Leu His Ser Leu Gln Glu Ile Arg Val Cys
85 90 95
Glu Ile His Glu Asp Asn Ser Thr Arg Ser Ser Gln His Phe Tyr Tyr
100 105 110
Asp Gly Glu Leu Phe Leu Ser Gln Asn Leu Glu Thr Glu Glu Trp Thr
115 120 125
Met Pro Gln Ser Ser Arg Ala Gln Thr Leu Ala Met Asn Val Arg Asn
130 135 140
Phe Leu Lys Glu Asp Ala Met Lys Thr Lys Thr His Tyr His Ala Met
145 150 155 160
His Ala Asp Cys Leu Gln Glu Leu Arg Arg Tyr Leu Lys Ser Gly Val
165 170 175
Val Leu Arg Arg Thr Val Pro Pro Met Val Asn Val Thr Arg Ser Glu
180 185 190
Ala Ser Glu Gly Asn Ile Thr Val Thr Cys Arg Ala Ser Gly Phe Tyr
195 200 205
Pro Trp Asn Ile Thr Leu Ser Trp Arg Gln Asp Gly Val Ser Leu Ser
210 215 220
His Asp Thr Gln Gln Trp Gly Asp Val Leu Pro Asp Gly Asn Gly Thr
225 230 235 240
Tyr Gln Thr Trp Val Ala Thr Arg Ile Cys Gln Gly Glu Glu Gln Arg
245 250 255
Phe Thr Cys Tyr Met Glu His Ser Gly Asn His Ser Thr His Pro Val
260 265 270
Pro Ser
<210> 41
<211> 274
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide MICA
<400> 41
Glu Pro His Ser Leu Arg Tyr Asn Leu Thr Val Leu Ser Trp Asp Gly
1 5 10 15
Ser Val Gln Ser Gly Phe Leu Ala Glu Val His Leu Asp Gly Gln Pro
20 25 30
Phe Leu Arg Cys Asp Arg Gln Lys Cys Arg Ala Lys Pro Gln Gly Gln
35 40 45
Trp Ala Glu Asp Val Leu Gly Asn Lys Thr Trp Asp Arg Glu Thr Arg
50 55 60
Asp Leu Thr Gly Asn Gly Lys Asp Leu Arg Met Thr Leu Ala His Ile
65 70 75 80
Lys Asp Gln Lys Glu Gly Leu His Ser Leu Gln Glu Ile Arg Val Cys
85 90 95
Glu Ile His Glu Asp Asn Ser Thr Arg Ser Ser Gln His Phe Tyr Tyr
100 105 110
Asp Gly Glu Leu Phe Leu Ser Gln Asn Leu Glu Thr Glu Glu Trp Thr
115 120 125
Met Pro Gln Ser Ser Arg Ala Gln Thr Leu Ala Met Asn Val Arg Asn
130 135 140
Phe Leu Lys Glu Asp Ala Met Lys Thr Lys Thr His Tyr His Ala Met
145 150 155 160
His Ala Asp Cys Leu Gln Glu Leu Arg Arg Tyr Leu Lys Ser Gly Val
165 170 175
Val Leu Arg Arg Thr Val Pro Pro Met Val Asn Val Thr Arg Ser Glu
180 185 190
Ala Ser Glu Gly Asn Ile Thr Val Thr Cys Arg Ala Ser Gly Phe Tyr
195 200 205
Pro Trp Asn Ile Thr Leu Ser Trp Arg Gln Asp Gly Val Ser Leu Ser
210 215 220
His Asp Thr Gln Gln Trp Gly Asp Val Leu Pro Asp Gly Asn Gly Thr
225 230 235 240
Tyr Gln Thr Trp Val Ala Thr Arg Ile Cys Gln Gly Glu Glu Gln Arg
245 250 255
Phe Thr Cys Tyr Met Glu His Ser Gly Asn His Ser Thr His Pro Val
260 265 270
Pro Ser
<210> 42
<211> 276
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide MICA
<400> 42
Glu Pro His Ser Leu Arg Tyr Asn Leu Thr Val Leu Ser Trp Asp Gly
1 5 10 15
Ser Val Gln Ser Gly Phe Leu Thr Glu Val His Leu Asp Gly Gln Pro
20 25 30
Phe Leu Arg Cys Asp Arg Gln Lys Cys Arg Ala Lys Pro Gln Gly Gln
35 40 45
Trp Ala Glu Asp Val Leu Gly Asn Lys Thr Trp Asp Arg Glu Thr Arg
50 55 60
Asp Leu Thr Gly Asn Gly Lys Asp Leu Arg Met Thr Leu Ala His Ile
65 70 75 80
Lys Asp Gln Lys Glu Gly Leu His Ser Leu Gln Glu Ile Arg Val Cys
85 90 95
Glu Ile His Glu Asp Asn Ser Thr Arg Ser Ser Gln His Phe Tyr Tyr
100 105 110
Asp Gly Glu Leu Phe Leu Ser Gln Asn Leu Glu Thr Lys Glu Trp Thr
115 120 125
Met Pro Gln Ser Ser Arg Ala Gln Thr Leu Ala Met Asn Val Arg Asn
130 135 140
Phe Leu Lys Glu Asp Ala Met Lys Thr Lys Thr His Tyr His Ala Met
145 150 155 160
His Ala Asp Cys Leu Gln Glu Leu Arg Arg Tyr Leu Lys Ser Gly Val
165 170 175
Val Leu Arg Arg Thr Val Pro Pro Met Val Asn Val Thr Arg Ser Glu
180 185 190
Ala Ser Glu Gly Asn Ile Thr Val Thr Cys Arg Ala Ser Gly Phe Tyr
195 200 205
Pro Trp Asn Ile Thr Leu Ser Trp Arg Gln Asp Gly Val Ser Leu Ser
210 215 220
His Asp Thr Gln Gln Trp Gly Asp Val Leu Pro Asp Gly Asn Gly Thr
225 230 235 240
Tyr Gln Thr Trp Val Ala Thr Arg Ile Cys Gln Gly Glu Glu Gln Arg
245 250 255
Phe Thr Cys Tyr Met Glu His Ser Gly Asn His Ser Thr His Pro Val
260 265 270
Pro Ser Gly Lys
275
<210> 43
<211> 306
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide MICB
<400> 43
Glu Pro His Ser Leu Arg Tyr Asn Leu Met Val Leu Ser Gln Asp Gly
1 5 10 15
Ser Val Gln Ser Gly Phe Leu Ala Glu Gly His Leu Asp Gly Gln Pro
20 25 30
Phe Leu Arg Tyr Asp Arg Gln Lys Arg Arg Ala Lys Pro Gln Gly Gln
35 40 45
Trp Ala Glu Asp Val Leu Gly Ala Lys Thr Trp Asp Thr Glu Thr Glu
50 55 60
Asp Leu Thr Glu Asn Gly Gln Asp Leu Arg Arg Thr Leu Thr His Ile
65 70 75 80
Lys Asp Gln Lys Gly Gly Leu His Ser Leu Gln Glu Ile Arg Val Cys
85 90 95
Glu Ile His Glu Asp Ser Ser Thr Arg Gly Ser Arg His Phe Tyr Tyr
100 105 110
Asp Gly Glu Leu Phe Leu Ser Gln Asn Leu Glu Thr Gln Glu Ser Thr
115 120 125
Val Pro Gln Ser Ser Arg Ala Gln Thr Leu Ala Met Asn Val Thr Asn
130 135 140
Phe Trp Lys Glu Asp Ala Met Lys Thr Lys Thr His Tyr Arg Ala Met
145 150 155 160
Gln Ala Asp Cys Leu Gln Lys Leu Gln Leu Pro Pro Met Val Asn Val
165 170 175
Ile Cys Ser Glu Val Ser Glu Gly Asn Ile Thr Val Thr Cys Arg Ala
180 185 190
Ser Ser Phe Tyr Pro Arg Asn Ile Thr Leu Thr Trp Arg Gln Asp Gly
195 200 205
Val Ser Leu Ser His Asn Thr Gln Gln Trp Gly Asp Val Leu Pro Asp
210 215 220
Gly Asn Gly Thr Tyr Gln Thr Trp Val Ala Thr Arg Ile Arg Gln Gly
225 230 235 240
Glu Glu Gln Arg Phe Thr Cys Tyr Met Glu His Ser Gly Asn His Gly
245 250 255
Thr His Pro Val Pro Ser Gly Lys Ala Leu Val Leu Gln Ser Gln Arg
260 265 270
Thr Asp Phe Pro Tyr Val Ser Ala Ala Met Pro Cys Phe Val Ile Ile
275 280 285
Ile Ile Leu Cys Val Pro Cys Cys Lys Lys Lys Thr Ser Ala Ala Glu
290 295 300
Gly Pro
305
<210> 44
<211> 318
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide MICB
<400> 44
Glu Pro His Ser Leu Arg Tyr Asn Leu Met Val Leu Ser Gln Asp Gly
1 5 10 15
Ser Val Gln Ser Gly Phe Leu Ala Glu Gly His Leu Asp Gly Gln Pro
20 25 30
Phe Leu Arg Tyr Asp Arg Gln Lys Arg Arg Ala Lys Pro Gln Gly Gln
35 40 45
Trp Ala Glu Asp Val Leu Gly Ala Glu Thr Trp Asp Thr Glu Thr Glu
50 55 60
Asp Leu Thr Glu Asn Gly Gln Asp Leu Arg Arg Thr Leu Thr His Ile
65 70 75 80
Lys Asp Gln Lys Gly Gly Leu His Ser Leu Gln Glu Ile Arg Val Cys
85 90 95
Glu Met His Glu Asp Ser Ser Thr Arg Gly Ser Arg His Phe Tyr Tyr
100 105 110
Asn Gly Glu Leu Phe Leu Ser Gln Asn Leu Glu Thr Gln Glu Ser Thr
115 120 125
Val Pro Gln Ser Ser Arg Ala Gln Thr Leu Ala Met Asn Val Thr Asn
130 135 140
Phe Trp Lys Glu Asp Ala Met Lys Thr Lys Thr His Tyr Arg Ala Met
145 150 155 160
Gln Ala Asp Cys Leu Gln Lys Leu Gln Arg Tyr Leu Lys Ser Gly Val
165 170 175
Ala Ile Arg Arg Thr Val Pro Pro Met Val Asn Val Thr Cys Ser Glu
180 185 190
Val Ser Glu Gly Asn Ile Thr Val Thr Cys Arg Ala Ser Ser Phe Tyr
195 200 205
Pro Arg Asn Ile Thr Leu Thr Trp Arg Gln Asp Gly Val Ser Leu Ser
210 215 220
His Asn Thr Gln Gln Trp Gly Asp Val Leu Pro Asp Gly Asn Gly Thr
225 230 235 240
Tyr Gln Thr Trp Val Ala Thr Arg Ile Arg Gln Gly Glu Glu Gln Arg
245 250 255
Phe Thr Cys Tyr Met Glu His Ser Gly Asn His Gly Thr His Pro Val
260 265 270
Pro Ser Gly Lys Ala Leu Val Leu Gln Ser Gln Arg Thr Asp Phe Pro
275 280 285
Tyr Val Ser Ala Ala Met Pro Cys Phe Val Ile Ile Ile Ile Leu Cys
290 295 300
Val Pro Cys Cys Lys Lys Lys Thr Ser Ala Ala Glu Gly Pro
305 310 315
<210> 45
<211> 318
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide MICB
<400> 45
Glu Pro His Ser Leu Arg Tyr Asn Leu Met Val Leu Ser Gln Asp Gly
1 5 10 15
Ser Val Gln Ser Gly Phe Leu Ala Glu Gly His Leu Asp Gly Gln Pro
20 25 30
Phe Leu Arg Tyr Asp Arg Gln Lys Arg Arg Ala Lys Pro Gln Gly Gln
35 40 45
Trp Ala Glu Asp Val Leu Gly Ala Lys Thr Trp Asp Thr Glu Thr Glu
50 55 60
Asp Leu Thr Glu Asn Gly Gln Asp Leu Arg Arg Thr Leu Thr His Ile
65 70 75 80
Lys Asp Gln Lys Gly Gly Leu His Ser Leu Gln Glu Ile Arg Val Cys
85 90 95
Glu Ile His Glu Asp Ser Ser Thr Arg Gly Ser Arg His Phe Tyr Tyr
100 105 110
Asp Gly Glu Leu Phe Leu Ser Gln Asn Leu Glu Thr Gln Glu Ser Thr
115 120 125
Val Pro Gln Ser Ser Arg Ala Gln Thr Leu Ala Met Asn Val Thr Asn
130 135 140
Phe Trp Lys Glu Asp Ala Met Lys Thr Lys Thr His Tyr Arg Ala Met
145 150 155 160
Gln Ala Asp Cys Leu Gln Lys Leu Gln Arg Tyr Leu Lys Ser Gly Val
165 170 175
Ala Ile Arg Arg Thr Val Pro Pro Met Val Asn Val Ile Cys Ser Glu
180 185 190
Val Ser Glu Gly Asn Ile Thr Val Thr Cys Arg Ala Ser Ser Phe Tyr
195 200 205
Pro Arg Asn Ile Thr Leu Thr Trp Arg Gln Asp Gly Val Ser Leu Ser
210 215 220
His Asn Thr Gln Gln Trp Gly Asp Val Leu Pro Asp Gly Asn Gly Thr
225 230 235 240
Tyr Gln Thr Trp Val Ala Thr Arg Ile Arg Gln Gly Glu Glu Gln Arg
245 250 255
Phe Thr Cys Tyr Met Glu His Ser Gly Asn His Gly Thr His Pro Val
260 265 270
Pro Ser Gly Lys Ala Leu Val Leu Gln Ser Gln Arg Thr Asp Phe Pro
275 280 285
Tyr Val Ser Ala Ala Met Pro Cys Phe Val Ile Ile Ile Ile Leu Cys
290 295 300
Val Pro Cys Cys Lys Lys Lys Thr Ser Ala Ala Glu Gly Pro
305 310 315
<210> 46
<211> 318
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide MICB
<400> 46
Glu Pro His Ser Leu Arg Tyr Asn Leu Met Val Leu Ser Gln Asp Gly
1 5 10 15
Ser Val Gln Ser Gly Phe Leu Ala Glu Gly His Leu Asp Gly Gln Pro
20 25 30
Phe Leu Arg Tyr Asp Arg Gln Lys Arg Arg Ala Lys Pro Gln Gly Gln
35 40 45
Trp Ala Glu Asn Val Leu Gly Ala Lys Thr Trp Asp Thr Glu Thr Glu
50 55 60
Asp Leu Thr Glu Asn Gly Gln Asp Leu Arg Arg Thr Leu Thr His Ile
65 70 75 80
Lys Asp Gln Lys Gly Gly Leu His Ser Leu Gln Glu Ile Arg Val Cys
85 90 95
Glu Ile His Glu Asp Ser Ser Thr Arg Gly Ser Arg His Phe Tyr Tyr
100 105 110
Asp Gly Glu Leu Phe Leu Ser Gln Asn Leu Glu Thr Gln Glu Ser Thr
115 120 125
Val Pro Gln Ser Ser Arg Ala Gln Thr Leu Ala Met Asn Val Thr Asn
130 135 140
Phe Trp Lys Glu Asp Ala Met Lys Thr Lys Thr His Tyr Arg Ala Met
145 150 155 160
Gln Ala Asp Cys Leu Gln Lys Leu Gln Arg Tyr Leu Lys Ser Gly Val
165 170 175
Ala Ile Arg Arg Thr Val Pro Pro Met Val Asn Val Thr Cys Ser Glu
180 185 190
Val Ser Glu Gly Asn Ile Thr Val Thr Cys Arg Ala Ser Ser Phe Tyr
195 200 205
Pro Arg Asn Ile Thr Leu Thr Trp Arg Gln Asp Gly Val Ser Leu Ser
210 215 220
His Asn Thr Gln Gln Trp Gly Asp Val Leu Pro Asp Gly Asn Gly Thr
225 230 235 240
Tyr Gln Thr Trp Val Ala Thr Arg Ile Arg Gln Gly Glu Glu Gln Arg
245 250 255
Phe Thr Cys Tyr Met Glu His Ser Gly Asn His Gly Thr His Pro Val
260 265 270
Pro Ser Gly Lys Ala Leu Val Leu Gln Ser Gln Arg Thr Asp Phe Pro
275 280 285
Tyr Val Ser Ala Ala Met Pro Cys Phe Val Ile Ile Ile Ile Leu Cys
290 295 300
Val Pro Cys Cys Lys Lys Lys Thr Ser Ala Ala Glu Gly Pro
305 310 315
<210> 47
<211> 318
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide MICB
<400> 47
Glu Pro His Ser Leu Arg Tyr Asn Leu Met Val Leu Ser Gln Asp Gly
1 5 10 15
Ser Val Gln Ser Gly Phe Leu Ala Glu Gly His Leu Asp Gly Gln Pro
20 25 30
Phe Leu Arg Tyr Asp Arg Gln Lys Arg Arg Ala Lys Pro Gln Gly Gln
35 40 45
Trp Ala Glu Asp Val Leu Gly Ala Glu Thr Trp Asp Thr Glu Thr Glu
50 55 60
Asp Leu Thr Glu Asn Gly Gln Asp Leu Arg Arg Thr Leu Thr His Ile
65 70 75 80
Lys Asp Gln Lys Gly Gly Leu His Ser Leu Gln Glu Ile Arg Val Cys
85 90 95
Glu Ile His Glu Asp Ser Ser Thr Arg Gly Ser Arg His Phe Tyr Tyr
100 105 110
Asn Gly Glu Leu Phe Leu Ser Gln Asn Leu Glu Thr Gln Glu Ser Thr
115 120 125
Val Pro Gln Ser Ser Arg Ala Gln Thr Leu Ala Met Asn Val Thr Asn
130 135 140
Phe Trp Lys Glu Asp Ala Met Lys Thr Lys Thr His Tyr Arg Ala Met
145 150 155 160
Gln Ala Asp Cys Leu Gln Lys Leu Gln Arg Tyr Leu Lys Ser Gly Val
165 170 175
Ala Ile Arg Arg Thr Val Pro Pro Met Val Asn Val Thr Cys Ser Glu
180 185 190
Val Ser Glu Gly Asn Ile Thr Val Thr Cys Arg Ala Ser Ser Phe Tyr
195 200 205
Pro Arg Asn Ile Thr Leu Thr Trp Arg Gln Asp Gly Val Ser Leu Ser
210 215 220
His Asn Thr Gln Gln Trp Gly Asp Val Leu Pro Asp Gly Asn Gly Thr
225 230 235 240
Tyr Gln Thr Trp Val Ala Thr Arg Ile Arg Gln Gly Glu Glu Gln Lys
245 250 255
Phe Thr Cys Tyr Met Glu His Ser Gly Asn His Gly Thr His Pro Val
260 265 270
Pro Ser Gly Lys Ala Leu Val Leu Gln Ser Gln Arg Thr Asp Phe Pro
275 280 285
Tyr Val Ser Ala Ala Met Pro Cys Phe Val Ile Ile Ile Ile Leu Cys
290 295 300
Val Pro Cys Cys Lys Lys Lys Thr Ser Ala Ala Glu Gly Pro
305 310 315
<210> 48
<211> 318
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide MICB
<400> 48
Glu Pro His Ser Leu Arg Tyr Asn Leu Met Val Leu Ser Gln Asp Gly
1 5 10 15
Ser Val Gln Ser Gly Phe Leu Ala Glu Gly His Leu Asp Gly Gln Pro
20 25 30
Phe Leu Arg Tyr Asp Arg Gln Lys Arg Arg Ala Lys Pro Gln Gly Gln
35 40 45
Trp Ala Glu Asp Val Leu Gly Ala Glu Thr Trp Asp Thr Glu Thr Glu
50 55 60
Asp Leu Thr Glu Asn Gly Gln Asp Leu Arg Arg Thr Leu Thr His Ile
65 70 75 80
Lys Asp Gln Lys Gly Gly Leu His Ser Leu Gln Glu Ile Arg Val Cys
85 90 95
Glu Ile His Glu Asp Ser Ser Thr Arg Gly Ser Arg His Phe Tyr Tyr
100 105 110
Asn Gly Glu Leu Phe Leu Ser Gln Asn Leu Glu Thr Gln Glu Ser Thr
115 120 125
Val Pro Gln Ser Ser Arg Ala Gln Thr Leu Ala Met Asn Val Thr Asn
130 135 140
Phe Trp Lys Glu Asp Ala Met Lys Thr Lys Thr His Tyr Arg Ala Met
145 150 155 160
Gln Ala Asp Cys Leu Gln Lys Leu Gln Arg Tyr Leu Lys Ser Gly Val
165 170 175
Ala Ile Arg Arg Thr Val Pro Pro Met Val Asn Val Thr Cys Ser Glu
180 185 190
Val Ser Glu Gly Asn Ile Thr Val Thr Cys Arg Ala Ser Ser Phe Tyr
195 200 205
Pro Arg Asn Ile Thr Leu Thr Trp Arg Gln Asp Gly Val Ser Leu Ser
210 215 220
His Asn Thr Gln Gln Trp Gly Asp Val Leu Pro Asp Gly Asn Gly Thr
225 230 235 240
Tyr Gln Thr Trp Val Ala Thr Arg Ile Arg Gln Gly Glu Glu Gln Arg
245 250 255
Phe Thr Cys Tyr Met Glu His Ser Gly Asn His Gly Thr His Pro Val
260 265 270
Pro Ser Gly Lys Ala Leu Val Leu Gln Ser Gln Arg Thr Asp Phe Pro
275 280 285
Tyr Val Ser Ala Ala Met Pro Cys Phe Val Ile Ile Ile Ile Leu Cys
290 295 300
Val Pro Cys Cys Lys Lys Lys Thr Ser Ala Ala Glu Gly Pro
305 310 315
<210> 49
<211> 244
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide ULBP-1 (ACCESSION NO Q9BZM6)
<400> 49
Met Ala Ala Ala Ala Ser Pro Ala Phe Leu Leu Cys Leu Pro Leu Leu
1 5 10 15
His Leu Leu Ser Gly Trp Ser Arg Ala Gly Trp Val Asp Thr His Cys
20 25 30
Leu Cys Tyr Asp Phe Ile Ile Thr Pro Lys Ser Arg Pro Glu Pro Gln
35 40 45
Trp Cys Glu Val Gln Gly Leu Val Asp Glu Arg Pro Phe Leu His Tyr
50 55 60
Asp Cys Val Asn His Lys Ala Lys Ala Phe Ala Ser Leu Gly Lys Lys
65 70 75 80
Val Asn Val Thr Lys Thr Trp Glu Glu Gln Thr Glu Thr Leu Arg Asp
85 90 95
Val Val Asp Phe Leu Lys Gly Gln Leu Leu Asp Ile Gln Val Glu Asn
100 105 110
Leu Ile Pro Ile Glu Pro Leu Thr Leu Gln Ala Arg Met Ser Cys Glu
115 120 125
His Glu Ala His Gly His Gly Arg Gly Ser Trp Gln Phe Leu Phe Asn
130 135 140
Gly Gln Lys Phe Leu Leu Phe Asp Ser Asn Asn Arg Lys Trp Thr Ala
145 150 155 160
Leu His Pro Gly Ala Lys Lys Met Thr Glu Lys Trp Glu Lys Asn Arg
165 170 175
Asp Val Thr Met Phe Phe Gln Lys Ile Ser Leu Gly Asp Cys Lys Met
180 185 190
Trp Leu Glu Glu Phe Leu Met Tyr Trp Glu Gln Met Leu Asp Pro Thr
195 200 205
Lys Pro Pro Ser Leu Ala Pro Gly Thr Thr Gln Pro Lys Ala Met Ala
210 215 220
Thr Thr Leu Ser Pro Trp Ser Leu Leu Ile Ile Phe Leu Cys Phe Ile
225 230 235 240
Leu Ala Gly Arg
<210> 50
<211> 246
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide ULBP-2 (ACCESSION NO Q9BZM5)
<400> 50
Met Ala Ala Ala Ala Ala Thr Lys Ile Leu Leu Cys Leu Pro Leu Leu
1 5 10 15
Leu Leu Leu Ser Gly Trp Ser Arg Ala Gly Arg Ala Asp Pro His Ser
20 25 30
Leu Cys Tyr Asp Ile Thr Val Ile Pro Lys Phe Arg Pro Gly Pro Arg
35 40 45
Trp Cys Ala Val Gln Gly Gln Val Asp Glu Lys Thr Phe Leu His Tyr
50 55 60
Asp Cys Gly Asn Lys Thr Val Thr Pro Val Ser Pro Leu Gly Lys Lys
65 70 75 80
Leu Asn Val Thr Thr Ala Trp Lys Ala Gln Asn Pro Val Leu Arg Glu
85 90 95
Val Val Asp Ile Leu Thr Glu Gln Leu Arg Asp Ile Gln Leu Glu Asn
100 105 110
Tyr Thr Pro Lys Glu Pro Leu Thr Leu Gln Ala Arg Met Ser Cys Glu
115 120 125
Gln Lys Ala Glu Gly His Ser Ser Gly Ser Trp Gln Phe Ser Phe Asp
130 135 140
Gly Gln Ile Phe Leu Leu Phe Asp Ser Glu Lys Arg Met Trp Thr Thr
145 150 155 160
Val His Pro Gly Ala Arg Lys Met Lys Glu Lys Trp Glu Asn Asp Lys
165 170 175
Val Val Ala Met Ser Phe His Tyr Phe Ser Met Gly Asp Cys Ile Gly
180 185 190
Trp Leu Glu Asp Phe Leu Met Gly Met Asp Ser Thr Leu Glu Pro Ser
195 200 205
Ala Gly Ala Pro Leu Ala Met Ser Ser Gly Thr Thr Gln Leu Arg Ala
210 215 220
Thr Ala Thr Thr Leu Ile Leu Cys Cys Leu Leu Ile Ile Leu Pro Cys
225 230 235 240
Phe Ile Leu Pro Gly Ile
245
<210> 51
<211> 244
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide ULBP-3 (ACCESSION NO NP_078794)
<400> 51
Met Ala Ala Ala Ala Ser Pro Ala Ile Leu Pro Arg Leu Ala Ile Leu
1 5 10 15
Pro Tyr Leu Leu Phe Asp Trp Ser Gly Thr Gly Arg Ala Asp Ala His
20 25 30
Ser Leu Trp Tyr Asn Phe Thr Ile Ile His Leu Pro Arg His Gly Gln
35 40 45
Gln Trp Cys Glu Val Gln Ser Gln Val Asp Gln Lys Asn Phe Leu Ser
50 55 60
Tyr Asp Cys Gly Ser Asp Lys Val Leu Ser Met Gly His Leu Glu Glu
65 70 75 80
Gln Leu Tyr Ala Thr Asp Ala Trp Gly Lys Gln Leu Glu Met Leu Arg
85 90 95
Glu Val Gly Gln Arg Leu Arg Leu Glu Leu Ala Asp Thr Glu Leu Glu
100 105 110
Asp Phe Thr Pro Ser Gly Pro Leu Thr Leu Gln Val Arg Met Ser Cys
115 120 125
Glu Cys Glu Ala Asp Gly Tyr Ile Arg Gly Ser Trp Gln Phe Ser Phe
130 135 140
Asp Gly Arg Lys Phe Leu Leu Phe Asp Ser Asn Asn Arg Lys Trp Thr
145 150 155 160
Val Val His Ala Gly Ala Arg Arg Met Lys Glu Lys Trp Glu Lys Asp
165 170 175
Ser Gly Leu Thr Thr Phe Phe Lys Met Val Ser Met Arg Asp Cys Lys
180 185 190
Ser Trp Leu Arg Asp Phe Leu Met His Arg Lys Lys Arg Leu Glu Pro
195 200 205
Thr Ala Pro Pro Thr Met Ala Pro Gly Leu Ala Gln Pro Lys Ala Ile
210 215 220
Ala Thr Thr Leu Ser Pro Trp Ser Phe Leu Ile Ile Leu Cys Phe Ile
225 230 235 240
Leu Pro Gly Ile
<210> 52
<211> 263
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide ULBP-4/RAET1E (ACCESSION NO Q8TD07)
<400> 52
Met Arg Arg Ile Ser Leu Thr Ser Ser Pro Val Arg Leu Leu Leu Phe
1 5 10 15
Leu Leu Leu Leu Leu Ile Ala Leu Glu Ile Met Val Gly Gly His Ser
20 25 30
Leu Cys Phe Asn Phe Thr Ile Lys Ser Leu Ser Arg Pro Gly Gln Pro
35 40 45
Trp Cys Glu Ala Gln Val Phe Leu Asn Lys Asn Leu Phe Leu Gln Tyr
50 55 60
Asn Ser Asp Asn Asn Met Val Lys Pro Leu Gly Leu Leu Gly Lys Lys
65 70 75 80
Val Tyr Ala Thr Ser Thr Trp Gly Glu Leu Thr Gln Thr Leu Gly Glu
85 90 95
Val Gly Arg Asp Leu Arg Met Leu Leu Cys Asp Ile Lys Pro Gln Ile
100 105 110
Lys Thr Ser Asp Pro Ser Thr Leu Gln Val Glu Met Phe Cys Gln Arg
115 120 125
Glu Ala Glu Arg Cys Thr Gly Ala Ser Trp Gln Phe Ala Thr Asn Gly
130 135 140
Glu Lys Ser Leu Leu Phe Asp Ala Met Asn Met Thr Trp Thr Val Ile
145 150 155 160
Asn His Glu Ala Ser Lys Ile Lys Glu Thr Trp Lys Lys Asp Arg Gly
165 170 175
Leu Glu Lys Tyr Phe Arg Lys Leu Ser Lys Gly Asp Cys Asp His Trp
180 185 190
Leu Arg Glu Phe Leu Gly His Trp Glu Ala Met Pro Glu Pro Thr Val
195 200 205
Ser Pro Val Asn Ala Ser Asp Ile His Trp Ser Ser Ser Ser Leu Pro
210 215 220
Asp Arg Trp Ile Ile Leu Gly Ala Phe Ile Leu Leu Val Leu Met Gly
225 230 235 240
Ile Val Leu Ile Cys Val Trp Trp Gln Asn Gly Glu Trp Gln Ala Gly
245 250 255
Leu Trp Pro Leu Arg Thr Ser
260
<210> 53
<211> 332
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide ULBP-5 (ACCESSION NO Q6H3X3)
<400> 53
Met Ala Ala Ala Ala Ser Pro Ala Phe Leu Leu Arg Leu Pro Leu Leu
1 5 10 15
Leu Leu Leu Ser Ser Trp Cys Arg Thr Gly Leu Ala Asp Pro His Ser
20 25 30
Leu Cys Tyr Asp Ile Thr Val Pro Lys Phe Arg Pro Gly Pro Arg Trp
35 40 45
Cys Ala Val Gln Gly Gln Val Asp Glu Lys Thr Phe Leu His Tyr Asp
50 55 60
Cys Gly Ser Lys Thr Val Thr Pro Val Ser Pro Leu Gly Lys Lys Leu
65 70 75 80
Asn Val Thr Thr Ala Trp Lys Ala Gln Asn Pro Val Leu Arg Glu Val
85 90 95
Val Asp Leu Thr Glu Gln Leu Leu Asp Ile Gln Leu Glu Asn Tyr Ile
100 105 110
Pro Lys Glu Pro Leu Thr Leu Gln Ala Arg Met Ser Cys Glu Gln Lys
115 120 125
Ala Glu Gly His Gly Ser Gly Ser Trp Gln Leu Ser Phe Asp Gly Gln
130 135 140
Ile Phe Leu Leu Phe Asp Ser Glu Asn Arg Met Trp Thr Thr Val His
145 150 155 160
Pro Gly Ala Arg Lys Met Lys Glu Lys Trp Glu Asn Asp Lys Asp Met
165 170 175
Thr Met Ser Phe His Tyr Ile Ser Met Gly Asp Cys Thr Gly Trp Leu
180 185 190
Glu Asp Phe Leu Met Gly Met Asp Ser Thr Leu Glu Pro Ser Ala Gly
195 200 205
Ala Pro Pro Thr Met Ser Ser Gly Thr Ala Gln Pro Arg Ala Thr Ala
210 215 220
Thr Thr Leu Ile Leu Cys Cys Leu Leu Ile Met Cys Leu Leu Ile Cys
225 230 235 240
Ser Arg His Ser Leu Thr Gln Ser His Gly His His Pro Gln Ser Leu
245 250 255
Gln Pro Pro Pro His Pro Pro Leu Leu His Pro Thr Trp Leu Leu Arg
260 265 270
Arg Val Leu Trp Ser Asp Ser Tyr Gln Ile Ala Lys Arg Pro Leu Ser
275 280 285
Gly Gly His Val Thr Arg Val Thr Leu Pro Ile Ile Gly Asp Asp Ser
290 295 300
His Ser Leu Pro Cys Pro Leu Ala Leu Tyr Thr Ile Asn Asn Gly Ala
305 310 315 320
Ala Arg Tyr Ser Glu Pro Leu Gln Val Ser Ile Ser
325 330
<210> 54
<211> 246
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide ULBP-6 (ACCESSION NO NP_570970)
<400> 54
Met Ala Ala Ala Ala Ile Pro Ala Leu Leu Leu Cys Leu Pro Leu Leu
1 5 10 15
Phe Leu Leu Phe Gly Trp Ser Arg Ala Arg Arg Asp Asp Pro His Ser
20 25 30
Leu Cys Tyr Asp Ile Thr Val Ile Pro Lys Phe Arg Pro Gly Pro Arg
35 40 45
Trp Cys Ala Val Gln Gly Gln Val Asp Glu Lys Thr Phe Leu His Tyr
50 55 60
Asp Cys Gly Asn Lys Thr Val Thr Pro Val Ser Pro Leu Gly Lys Lys
65 70 75 80
Leu Asn Val Thr Met Ala Trp Lys Ala Gln Asn Pro Val Leu Arg Glu
85 90 95
Val Val Asp Ile Leu Thr Glu Gln Leu Leu Asp Ile Gln Leu Glu Asn
100 105 110
Tyr Thr Pro Lys Glu Pro Leu Thr Leu Gln Ala Arg Met Ser Cys Glu
115 120 125
Gln Lys Ala Glu Gly His Ser Ser Gly Ser Trp Gln Phe Ser Ile Asp
130 135 140
Gly Gln Thr Phe Leu Leu Phe Asp Ser Glu Lys Arg Met Trp Thr Thr
145 150 155 160
Val His Pro Gly Ala Arg Lys Met Lys Glu Lys Trp Glu Asn Asp Lys
165 170 175
Asp Val Ala Met Ser Phe His Tyr Ile Ser Met Gly Asp Cys Ile Gly
180 185 190
Trp Leu Glu Asp Phe Leu Met Gly Met Asp Ser Thr Leu Glu Pro Ser
195 200 205
Ala Gly Ala Pro Leu Ala Met Ser Ser Gly Thr Thr Gln Leu Arg Ala
210 215 220
Thr Ala Thr Thr Leu Ile Leu Cys Cys Leu Leu Ile Ile Leu Pro Cys
225 230 235 240
Phe Ile Leu Pro Gly Ile
245
<210> 55
<211> 182
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide MICwed alpha1-alpha2
<400> 55
Glu Pro His Ser Leu Arg Tyr Asn Leu Thr Val Leu Ser Trp Asp Gly
1 5 10 15
Ser Val Gln Ser Gly Phe Leu Thr Glu Val His Leu Asp Gly Gln Pro
20 25 30
Phe Leu Arg Cys Asp Arg Gln Lys Cys Arg Ala Lys Pro Gln Gly Gln
35 40 45
Trp Ala Glu Asp Val Leu Gly Asn Lys Thr Trp Asp Arg Glu Thr Arg
50 55 60
Asp Leu Thr Gly Trp Gly Lys Asp Leu Arg Met Thr Leu Ala His Ile
65 70 75 80
Lys Asp Gln Lys Glu Gly Leu His Ser Leu Gln Glu Ile Arg Val Cys
85 90 95
Glu Ile His Glu Asp Asn Ser Thr Arg Ser Ser Gln His Phe Tyr Tyr
100 105 110
Asp Gly Glu Leu Phe Leu Ser Gln Asn Leu Glu Thr Lys Glu Trp Thr
115 120 125
Met Pro Gln Ser Ser Arg Ala Gln Thr Leu Ala Met Asn Val Arg Asn
130 135 140
Phe Leu Lys Glu Asp Ala Met Glu Thr Asp Thr His Tyr His Ala Met
145 150 155 160
His Ala Asp Cys Leu Gln Glu Leu Arg Arg Tyr Leu Lys Ser Gly Val
165 170 175
Val Leu Arg Arg Thr Val
180
<210> 56
<211> 182
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide DSM20 alpha1-alpha2
<400> 56
Glu Pro His Ser Leu Arg Tyr Asn Leu Thr Val Leu Ser Trp Asp Gly
1 5 10 15
Ser Val Gln Ser Gly Phe Leu Thr Glu Val His Leu Asp Gly Gln Pro
20 25 30
Phe Leu Arg Cys Asp Arg Gln Lys Cys Arg Ala Lys Pro Gln Gly Gln
35 40 45
Trp Ala Glu Asp Val Leu Gly Asn Lys Thr Trp Asp Arg Glu Thr Arg
50 55 60
Asp Leu Thr Ala Trp Gly Lys Asp Leu Arg Met Thr Leu Ala His Ile
65 70 75 80
Lys Asp Gln Lys Glu Gly Leu His Ser Leu Gln Glu Ile Arg Val Cys
85 90 95
Glu Ile His Glu Asp Asn Ser Thr Arg Ser Ser Gln His Phe Tyr Tyr
100 105 110
Asp Gly Glu Leu Phe Leu Ser Gln Asn Leu Glu Thr Leu Glu Trp Thr
115 120 125
Met Pro Gln Ser Ser Arg Ala Gln Thr Leu Ala Met Asn Val Arg Asn
130 135 140
Phe Leu Lys Glu Asp Ala Met Gln Thr Asp Thr His Tyr Arg Ala Met
145 150 155 160
His Ala Asp Cys Leu Phe Glu Leu Arg Arg Tyr Leu Lys Ser Gly Val
165 170 175
Val Leu Arg Arg Thr Val
180
<210> 57
<211> 182
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide DSM25 alpha1-alpha2
<400> 57
Glu Pro His Ser Leu Arg Tyr Asn Leu Thr Val Leu Ser Trp Asp Gly
1 5 10 15
Ser Val Gln Ser Gly Phe Leu Thr Glu Val His Leu Asp Gly Gln Pro
20 25 30
Phe Leu Arg Cys Asp Arg Gln Lys Cys Arg Ala Lys Pro Gln Gly Gln
35 40 45
Trp Ala Glu Asp Val Leu Gly Asn Lys Thr Trp Asp Arg Glu Thr Arg
50 55 60
Asp Leu Thr Gly Trp Gly Lys Asp Leu Arg Met Thr Leu Ala His Ile
65 70 75 80
Lys Asp Gln Lys Glu Gly Leu His Ser Leu Gln Glu Ile Arg Val Cys
85 90 95
Glu Ile His Glu Asp Asn Ser Thr Arg Ser Ser Gln His Phe Tyr Tyr
100 105 110
Asp Gly Glu Leu Phe Leu Ser Gln Asn Leu Glu Thr Leu Glu Trp Thr
115 120 125
Met Pro Gln Ser Ser Arg Ala Gln Thr Leu Ala Met Asn Val Arg Asn
130 135 140
Phe Leu Lys Glu Asp Ala Met Glu Thr Asp Thr His Tyr His Ala Met
145 150 155 160
Arg Ala Asp Cys Leu Ser Glu Leu Arg Arg Tyr Leu Lys Ser Gly Val
165 170 175
Val Leu Arg Arg Thr Val
180
<210> 58
<211> 182
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide DSM27 alpha1-alpha2
<400> 58
Glu Pro His Ser Leu Arg Tyr Asn Leu Thr Val Leu Ser Trp Asp Gly
1 5 10 15
Ser Val Gln Ser Gly Phe Leu Thr Glu Val His Leu Asp Gly Gln Pro
20 25 30
Phe Leu Arg Cys Asp Arg Gln Lys Cys Arg Ala Lys Pro Gln Gly Gln
35 40 45
Trp Ala Glu Asp Val Leu Gly Asn Lys Thr Trp Asp Arg Glu Thr Arg
50 55 60
Asp Leu Thr Gly Trp Gly Lys Asp Leu Arg Met Thr Leu Ala His Ile
65 70 75 80
Lys Asp Gln Lys Glu Gly Leu His Ser Leu Gln Glu Ile Arg Val Cys
85 90 95
Glu Ile His Glu Asp Asn Ser Thr Arg Ser Ser Gln His Phe Tyr Tyr
100 105 110
Asp Gly Glu Leu Phe Leu Ser Gln Asn Leu Glu Thr Leu Glu Trp Thr
115 120 125
Met Pro Gln Ser Ser Arg Ala Gln Thr Leu Ala Met Asn Val Arg Asn
130 135 140
Phe Leu Lys Glu Asp Ala Met Lys Thr Lys Thr His Tyr His Ala Met
145 150 155 160
Arg Ala Asp Cys Leu Ser Glu Leu Arg Arg Tyr Leu Lys Ser Gly Val
165 170 175
Val Leu Arg Arg Thr Val
180
<210> 59
<211> 182
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide DSM28 alpha1-alpha2
<400> 59
Glu Pro His Ser Leu Arg Tyr Asn Leu Thr Val Leu Ser Trp Asp Gly
1 5 10 15
Ser Val Gln Ser Gly Phe Leu Thr Glu Val His Leu Asp Gly Gln Pro
20 25 30
Phe Leu Arg Cys Asp Arg Gln Lys Cys Arg Ala Lys Pro Gln Gly Gln
35 40 45
Trp Ala Glu Asp Val Leu Gly Asn Lys Thr Trp Asp Arg Glu Thr Arg
50 55 60
Asp Leu Thr Gly Asn Gly Lys Asp Leu Arg Met Thr Leu Ala His Ile
65 70 75 80
Lys Asp Gln Lys Glu Gly Leu His Ser Leu Gln Glu Ile Arg Val Cys
85 90 95
Glu Ile His Glu Asp Asn Ser Thr Arg Ser Ser Gln His Phe Tyr Tyr
100 105 110
Asp Gly Glu Leu Phe Leu Ser Gln Asn Leu Glu Thr Leu Glu Trp Thr
115 120 125
Met Pro Gln Ser Ser Arg Ala Gln Thr Leu Ala Met Asn Val Arg Asn
130 135 140
Phe Leu Lys Glu Asp Ala Met Lys Thr Lys Thr His Tyr His Ala Met
145 150 155 160
Arg Ala Asp Cys Leu Ser Glu Leu Arg Arg Tyr Leu Lys Ser Gly Val
165 170 175
Val Leu Arg Arg Thr Val
180
<210> 60
<211> 182
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide DSM42 alpha1-alpha2
<400> 60
Glu Pro His Ser Leu Arg Tyr Asn Leu Thr Val Leu Ser Trp Asp Gly
1 5 10 15
Ser Val Gln Ser Gly Phe Leu Thr Glu Val His Leu Asp Gly Gln Pro
20 25 30
Phe Leu Arg Cys Asp Arg Gln Lys Cys Arg Ala Lys Pro Gln Gly Gln
35 40 45
Trp Ala Glu Asp Val Leu Gly Asn Lys Thr Trp Asp Arg Glu Thr Arg
50 55 60
Asp Leu Thr Gly Trp Gly Lys Asp Leu Arg Met Thr Leu Ala His Ile
65 70 75 80
Lys Asp Gln Lys Glu Gly Leu His Ser Leu Gln Glu Ile Arg Val Cys
85 90 95
Glu Ile His Glu Asp Asn Ser Thr Arg Ser Ser Gln His Phe Tyr Tyr
100 105 110
Asp Gly Glu Leu Phe Leu Ser Gln Asn Leu Glu Thr Leu Glu Trp Thr
115 120 125
Met Pro Gln Ser Ser Arg Ala Gln Thr Leu Ala Met Asn Val Arg Asn
130 135 140
Phe Leu Lys Glu Asp Ala Met Glu Thr Asp Thr His Tyr His Ala Met
145 150 155 160
Arg Ala Asp Cys Leu Gln Glu Leu Arg Arg Tyr Leu Lys Ser Gly Val
165 170 175
Val Leu Arg Arg Thr Val
180
<210> 61
<211> 182
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide DSM48 alpha1-alpha2
<400> 61
Glu Pro His Ser Leu Arg Tyr Asn Leu Thr Val Leu Ser Trp Asp Gly
1 5 10 15
Ser Val Gln Ser Gly Phe Leu Thr Glu Val His Leu Asp Gly Gln Pro
20 25 30
Phe Leu Arg Cys Asp Arg Gln Lys Cys Arg Ala Lys Pro Gln Gly Gln
35 40 45
Trp Ala Glu Asp Val Leu Gly Asn Lys Thr Trp Asp Arg Glu Thr Arg
50 55 60
Asp Leu Thr Gly Trp Gly Lys Asp Leu Arg Met Thr Leu Ala His Ile
65 70 75 80
Lys Asp Gln Lys Glu Gly Leu His Ser Leu Gln Glu Ile Arg Val Cys
85 90 95
Glu Ile His Glu Asp Asn Ser Thr Arg Ser Ser Gln His Phe Tyr Tyr
100 105 110
Asp Gly Glu Leu Phe Leu Ser Gln Asn Leu Glu Thr Leu Glu Trp Thr
115 120 125
Met Pro Gln Ser Ser Arg Ala Gln Thr Leu Ala Met Asn Val Arg Asn
130 135 140
Phe Leu Lys Glu Asp Ala Met Ala Thr Asp Thr His Tyr Ile Ala Met
145 150 155 160
Arg Ala Asp Cys Leu Ala Glu Leu Arg Arg Tyr Leu Lys Ser Gly Val
165 170 175
Val Leu Arg Arg Thr Val
180
<210> 62
<211> 182
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide DSM49 alpha1-alpha2
<400> 62
Glu Pro His Ser Leu Arg Tyr Asn Leu Thr Val Leu Ser Trp Asp Gly
1 5 10 15
Ser Val Gln Thr Gly Phe Leu Thr Glu Val His Leu Asp Gly Gln Pro
20 25 30
Phe Leu Arg Cys Asp Arg Gln Lys Cys Arg Ala Lys Pro Gln Gly Gln
35 40 45
Trp Ala Glu Asp Val Leu Gly Asn Lys Thr Trp Asp Arg Glu Thr Arg
50 55 60
Asp Leu Thr Gln Trp Gly Lys Asp Leu Arg Met Thr Leu Ala His Ile
65 70 75 80
Lys Asp Gln Lys Glu Gly Leu His Ser Leu Gln Glu Ile Arg Val Cys
85 90 95
Glu Ile His Glu Asp Asn Ser Thr Arg Ser Ser Gln His Phe Tyr Tyr
100 105 110
Asp Gly Glu Leu Phe Leu Ser Gln Asn Leu Glu Thr Lys Glu Trp Thr
115 120 125
Met Pro Gln Ser Ser Arg Ala Gln Thr Leu Ala Met Asn Val Arg Asn
130 135 140
Phe Leu Lys Glu Asp Ala Met Phe Thr Asp Thr His Tyr Arg Ala Met
145 150 155 160
Thr Ala Asp Cys Leu Thr Glu Leu Arg Arg Tyr Leu Lys Ser Gly Val
165 170 175
Val Leu Arg Arg Thr Val
180
<210> 63
<211> 29
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic oligonucleotide primer
<400> 63
atctataatg ctgagcccca cagtcttcg 29
<210> 64
<211> 27
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic oligonucleotide primer
<400> 64
cttgctcttc agatatcgcc gtagttc 27
<210> 65
<211> 7556
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic DNA construct expressing wt a1a2 domain-Fv
<400> 65
ggagagacca cacccaagct gtctagagcc gccacgatgg ggctgggccc ggtcttcctg 60
cttctggctg gcatcttccc ttttgcacct ccgggagctg ctgctgagcc ccacagtctt 120
cgttataacc tcacggtgct gtcctgggat ggatctgtgc agtcagggtt tctcactgag 180
gtacatctgg atggtcagcc cttcctgcgc tgtgacaggc agaaatgcag ggcaaagccc 240
cagggacagt gggcagaaga tgtcctggga aataagacat gggacagaga gaccagagac 300
ttgacaggga atggaaagga cctcaggatg accctggctc atatcaagga ccagaaagaa 360
ggcttgcatt ccctccagga gattagggtc tgtgagatcc atgaagacaa cagcaccagg 420
agctcccagc atttctacta cgatggggag ctctttctct cccaaaacct ggagactaag 480
gaatggacaa tgccccagtc ctccagagct cagaccttgg ccatgaacgt caggaatttc 540
ttgaaggaag atgcaatgaa gaccaagaca cactatcacg ctatgcatgc agactgcctg 600
caggaactac ggcgatatct aaaatccggc gtagtcctga ggagaacagt gccccccatg 660
gtgcaggtga ctcgctctga ggcctctggc ggatctgggg accgtgtgac aatcacctgc 720
agagcctccc aggacgtctc cactgccgtg gcgtggtacc aacagaagcc cgggaaggca 780
cccaaactgc tcatttacag cgcatccttt ctctactctg gcgtgccgtc tcgctttagc 840
gggtccggca gcggtacaga ctttactctg accatctcct ctctgcaacc ggaggatttt 900
gcaacctatt attgccagca atcctacaca acccccccca cctttggcca gggcaccaag 960
gtggagatca agggaggttc tagccgctcc agcagctctg gaggtggagg ctctggcgga 1020
ggaggcgagg tgcaactggt ggagtctggg ggcggcctgg tccagcccgg cggaagcttg 1080
cgcctgagct gtgccgcctc cggttttacc ttcaccagca ctggaatctc ctgggtgcgc 1140
caagctcccg gcaaagggct cgaatgggtg ggccgtatct accccaccaa cggaagcacc 1200
aactatgcag acagcgtgaa ggggcgcttc actatctccg ccgacaccag caaaaacacc 1260
gcgtacctgc agatgaattc tttgagggca gaggatactg ccgtgtacta ctgcgcgagg 1320
acatacggca tttacgatct gtatgtggat tacaccgaat acgtgatgga ctattggggc 1380
cagggcactc tggtcacagt gtctagcggt ggcagctccc gcagctccag cagcggtggt 1440
ggcggtagcg gaggcggagg cgatatccag atgactcaga gtccctcttc tctgagtgct 1500
tctggcggaa gtgggcagat caccgtcaca tgtcgcgcaa gcggctttta tccttggaac 1560
atcaccctga gctggcggca ggacggcgtc agcctgtccc atgataccca acagtgggga 1620
gatgtgctcc cggacggtca gggaacttac cagacctggg ttgcaactcg catctcccag 1680
ggggaggagc agcgtttcac atgttatatg gagcactctg gccagcacag cactcatccg 1740
gtgccgtccg gaaagggatc tcatcaccat caccaccact aggatccgtt gaggtctcta 1800
aaagcgtctt cctgttctca tcacatcata tcaaggttat ataccatcaa tattgccaca 1860
gatgttactt agccttttaa tatttctcta atttagtgta tatgcaatga tagttctctg 1920
atttctgaga ttgagtttct catgtgtaat gattatttag agtttctctt tcatctgttc 1980
aaatttttgt ctagttttat tttttactga tttgtaagac ttctttttat aatctgcata 2040
ttacaattct ctttactggg gtgttgcaaa tattttctgt cattctatgg cctgactttt 2100
cttaatggtt ttttaatttt aaaaataagt cttaatattc atgcaatcta attaacaatc 2160
ttttctttgt ggttaggact ttgagtcata agaaattttt ctctacactg aagtcatgat 2220
ggcatgcttc tatattattt tctaaaagat ttaaagtttt gccttctcca tttagactta 2280
taattcactg gaattttttt gtgtgtatgg tatgacatat gggttccctt ttatttttta 2340
catataaata tatttccctg tttttctaaa aaagaaaaag atcatcattt tcccattgta 2400
aaatgccata tttttttcat aggtcactta catatatcaa tgggtctgtt tctgagctct 2460
actctatttt atcagcctca ctgtctatcc ccacacatct catgctttgc tctaaatctt 2520
gatatttagt ggaacattct ttcccatttt gttctacaag aatatttttg ttattgtctt 2580
tgggctttct atatacattt tgaaatgagg ttgacaagtt aataatcaac ctctggatta 2640
caaaatttgt gaaagattga ctggtattct taactatgtt gctcctttta cgctatgtgg 2700
atacgctgct ttaatgcctt tgtatcatgc tattgcttcc cgtatggctt tcattttctc 2760
ctccttgtat aaatcctggt tgctgtctct ttatgaggag ttgtggcccg ttgtcaggca 2820
acgtggcgtg gtgtgcactg tgtttgctga cgcaaccccc actggttggg gcattgccac 2880
cacctgtcag ctcctttccg ggactttcgc tttccccctc cctattgcca cggcggaact 2940
catcgccgcc tgccttgccc gctgctggac aggggctcgg ctgttgggca ctgacaattc 3000
cgtggtgttg tcggggaaat catcgtcctt tccttggctg ctcgcctgtg ttgccacctg 3060
gattctgcgc gggacgtcct tctgctacgt cccttcggcc ctcaatccag cggaccttcc 3120
ttcccgcggc ctgctgccgg ctctgcggcc tcttccgcct cttcgccttc gccctcagac 3180
gagtcggatc tccctttggg ccgcctcccc gcatctgtgc cttctagttg ccagccatct 3240
gttgtttgcc cctcccccgt gccttccttg accctggaag gtgccactcc cactgtcctt 3300
tcctaataaa atgaggaaat tgcatcgcat tgtctgagta ggtgtcattc tattctgggg 3360
ggtggggtgg ggcaggacag caagggggag gattggcaag acaatagcag gctttgcatt 3420
tttagacatt tagaagccta tatcttgtta cagaattgga attacacaaa aattctacca 3480
tattttgaaa gcttaggttg ttctgaaaaa aacaatatat tgttttcctg ggtaaactaa 3540
aagtcccctc gaggaaaggc ccctaaagtg aaacagtgca aaacgttcaa aaactgtctg 3600
gcaatacaag ttccactttg accaaaacgg ctggcagtaa aagggttaag aagactgtca 3660
gccttgagcg gtatcagctc actcaaaggc ggtaatacgg ttatccacag aatcagggga 3720
taacgcagga aagaacatgt gagcaaaagg ccagcaaaag gccaggaacc gtaaaaaggc 3780
cgcgttgctg gcgtttttcc ataggctccg cccccctgac gagcatcaca aaaatcgacg 3840
ctcaagtcag aggtggcgaa acccgacagg actataaaga taccaggcgt ttccccctgg 3900
aagctccctc gtgcgctctc ctgttccgac cctgccgctt accggatacc tgtccgcctt 3960
tctcccttcg ggaagcgtgg cgctttctca tagctcacgc tgtaggtatc tcagttcggt 4020
gtaggtcgtt cgctccaagc tgggctgtgt gcacgaaccc cccgttcagc ccgaccgctg 4080
cgccttatcc ggtaactatc gtcttgagtc caacccggta agacacgact tatcgccact 4140
ggcagcagcc actggtaaca ggattagcag agcgaggtat gtaggcggtg ctacagagtt 4200
cttgaagtgg tgggctaact acggctacac tagaagaaca gtatttggta tctgcgctct 4260
gctgaagcca gttaccttcg gaaaaagagt tggtagctct tgatccggca aacaaaccac 4320
cgctggtagc ggtggttttt ttgtttgcaa gcagcagatt acgcgcagaa aaaaaggatc 4380
tcaagaagat cctttgatct tttctacggg gtctgacgct cagtggaacg acgcgcgcgt 4440
aactcacgtt aagggatttt ggtcatgagt tagaaaaact catcgagcat caaatgaaac 4500
tgcaatttat tcatatcagg attatcaata ccatattttt gaaaaagccg tttctgtaat 4560
gaaggagaaa actcaccgag gcagttccat aggatggcaa gatcctggta tcggtctgcg 4620
attccgactc gtccaacatc aatacaacct attaatttcc cctcgtcaaa aataaggtta 4680
tcaagtgaga aatcaccatg agtgacgact gaatccggtg agaatggcaa aagtttatgc 4740
atttctttcc agacttgttc aacaggccag ccattacgct cgtcatcaaa atcactcgca 4800
tcaaccaaac cgttattcat tcgtgattgc gcctgagcga ggcgaaatac gcgatcgctg 4860
ttaaaaggac aattacaaac aggaatcgag tgcaaccggc gcaggaacac tgccagcgca 4920
tcaacaatat tttcacctga atcaggatat tcttctaata cctggaacgc tgtttttccg 4980
gggatcgcag tggtgagtaa ccatgcatca tcaggagtac ggataaaatg cttgatggtc 5040
ggaagtggca taaattccgt cagccagttt agtctgacca tctcatctgt aacatcattg 5100
gcaacgctac ctttgccatg tttcagaaac aactctggcg catcgggctt cccatacaag 5160
cgatagattg tcgcacctga ttgcccgaca ttatcgcgag cccatttata cccatataaa 5220
tcagcatcca tgttggaatt taatcgcggc ctcgacgttt cccgttggat atggctcatt 5280
ttttacttcc tcaccttgtc gtattatact atgccgatat actatgccga tgattaattg 5340
tcgacactgc gggggctctg tgtggtaagc aggtcttaac ctttttactg ccaatgacgc 5400
atgggatacg tcgtggcagt aaaagggctt aaatgccaac gacgcgtccc atacgttgtt 5460
ggcattttaa ttcttctctc tgcagcggca gcatgtgccg ccgctgcaga gagtttctag 5520
cgatgacagc ccctctgggc aacgagccgg gggggctgtc tttctttatg ttttaaatgc 5580
actgacctcc cacattccct ttttagtaaa atattcagaa ataatttaaa tacatcattg 5640
caatgaaaat aaatgttttt tattaggcag aatccagatg ctcaaggccc ttcataatat 5700
cccccagttt agtagttgga cttagggaac aaaggaacct ttaatagaaa ttggacagca 5760
agaaagcgag tcaggcaccg ggcttgcggg tcatgcacca ggtgcgcggt ccttcgggca 5820
cctcgacgtc ggcggtgacg gtgaagccga gccgctcgta gaaggggagg ttgcggggcg 5880
cggatgtctc caggaaggcg ggcaccccgg cgcgctcggc cgcctccact ccggggagca 5940
cgacggcgct gcccagaccc ttgccctggt ggtcgggcga cacgccgacg gtggccagga 6000
accacgcggg ctccttgggc cggtgcggcg ccaggaggcc ttccatctgt tgctgcgcgg 6060
ccagccggga accgctcaac tcggccatgc gcgggccgat ctcggcgaac accgcccccg 6120
cttcgacgct ctccggcgtg gtccagaccg ccaccgcggc gccgtcgtcc gcgacccaca 6180
ccttgccgat gtcgagcccg acgcgcgtga ggaagagttc ttgcagctcg gtgacccgct 6240
cgatgtggcg gtccggatcg acggtgtggc gcgtggcggg gtagtcggcg aacgcggcgg 6300
cgagggtgcg tacggccctg gggacgtcgt cgcgggtggc gaggcgcacc gtgggcttgt 6360
actcggtcat ggtggcggac gaaaggcccg gagatgagga agaggagaac agcgcggcag 6420
acgtgcgctt ttgaagcgtg cagaatgccg ggcctccgga ggaccttcgg gcgcccgccc 6480
cgcccctgag cccgcccctg agcccgcccc cggacccacc ccttcccagc ctctgagccc 6540
agaaagcgaa ggagcaaagc tgctattggc cgctgcccca aaggcctacc cgcttccatt 6600
gctcagcggt gctgtccatc tgcacgagac tagtgagtcg tgctacttcc atttgtcacg 6660
tcctgcacga cgcgagctgc ggggcggggg ggaacttcct gactagggga ggagtagaag 6720
gtggcgcgaa ggggccacca aagaacggag ccggttggcg cctaccggtg gatgtggaat 6780
gtgtgcgagg ccagaggcca cttgtgtagc gccaagtgcc cagcggggct gctaaagcgc 6840
atgctccaga ctgccttggg aaaagcgcct cccctacccg gtagagaaac ttgatctgtc 6900
gccgcaattc aaacttcgtg aggctccggt gcccgtcagt gacctgctat actctggaga 6960
cgacttacgg taaatggccc gcctggctga ccgcccaacg acccccgccc attgacgtca 7020
ataatgacgt atgttcccat agtaacgcca atagggactt tccattgacg tcaatgggtg 7080
gagtatttac ggtaaactgc ccacttggca gtacatcaag tgtatcatat gccaagtccg 7140
ccccctattg acgtcaatga cggtaaatgg cccgcctggc attatgccca gtacatgacc 7200
ttacgggact ttcctacttg gcagtacatc tacgtattag tcatcgctat taccatgctg 7260
atgcggtttt ggcagtacac caatgggcgt ggatagcggt ttgactcacg gggatttcca 7320
agtctccacc ccattgacgt caatgggagt ttgttttggc accaaaatca acgggacttt 7380
ccaaaatgtc gtaataaccc cgccccgttg acgcaaatgg gcggtaggcg tgtacggtgg 7440
gaggtctata taagcagagc tcgtttagtg aaccgtcaga tcgcctggag aggccatcca 7500
cgctgttttg acctccatag tggacaccgg gaccgatcca gcctccgcgt ctcagg 7556
<210> 66
<211> 558
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide wt MICA-Fv
<400> 66
Glu Pro His Ser Leu Arg Tyr Asn Leu Thr Val Leu Ser Trp Asp Gly
1 5 10 15
Ser Val Gln Ser Gly Phe Leu Thr Glu Val His Leu Asp Gly Gln Pro
20 25 30
Phe Leu Arg Cys Asp Arg Gln Lys Cys Arg Ala Lys Pro Gln Gly Gln
35 40 45
Trp Ala Glu Asp Val Leu Gly Asn Lys Thr Trp Asp Arg Glu Thr Arg
50 55 60
Asp Leu Thr Gly Asn Gly Lys Asp Leu Arg Met Thr Leu Ala His Ile
65 70 75 80
Lys Asp Gln Lys Glu Gly Leu His Ser Leu Gln Glu Ile Arg Val Cys
85 90 95
Glu Ile His Glu Asp Asn Ser Thr Arg Ser Ser Gln His Phe Tyr Tyr
100 105 110
Asp Gly Glu Leu Phe Leu Ser Gln Asn Leu Glu Thr Lys Glu Trp Thr
115 120 125
Met Pro Gln Ser Ser Arg Ala Gln Thr Leu Ala Met Asn Val Arg Asn
130 135 140
Phe Leu Lys Glu Asp Ala Met Lys Thr Lys Thr His Tyr His Ala Met
145 150 155 160
His Ala Asp Cys Leu Gln Glu Leu Arg Arg Tyr Leu Lys Ser Gly Val
165 170 175
Val Leu Arg Arg Thr Val Pro Pro Met Val Gln Val Thr Arg Ser Glu
180 185 190
Ala Ser Gly Gly Ser Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
195 200 205
Gln Asp Val Ser Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys
210 215 220
Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val
225 230 235 240
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
245 250 255
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
260 265 270
Ser Tyr Thr Thr Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
275 280 285
Lys Gly Gly Ser Ser Arg Ser Ser Ser Ser Gly Gly Gly Gly Ser Gly
290 295 300
Gly Gly Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
305 310 315 320
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
325 330 335
Thr Ser Thr Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
340 345 350
Glu Trp Val Gly Arg Ile Tyr Pro Thr Asn Gly Ser Thr Asn Tyr Ala
355 360 365
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn
370 375 380
Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
385 390 395 400
Tyr Tyr Cys Ala Arg Thr Tyr Gly Ile Tyr Asp Leu Tyr Val Asp Tyr
405 410 415
Thr Glu Tyr Val Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
420 425 430
Ser Ser Gly Gly Ser Ser Arg Ser Ser Ser Ser Gly Gly Gly Gly Ser
435 440 445
Gly Gly Gly Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser
450 455 460
Ala Ser Gly Gly Ser Gly Gln Ile Thr Val Thr Cys Arg Ala Ser Gly
465 470 475 480
Phe Tyr Pro Trp Asn Ile Thr Leu Ser Trp Arg Gln Asp Gly Val Ser
485 490 495
Leu Ser His Asp Thr Gln Gln Trp Gly Asp Val Leu Pro Asp Gly Gln
500 505 510
Gly Thr Tyr Gln Thr Trp Val Ala Thr Arg Ile Ser Gln Gly Glu Glu
515 520 525
Gln Arg Phe Thr Cys Tyr Met Glu His Ser Gly Gln His Ser Thr His
530 535 540
Pro Val Pro Ser Gly Lys Gly Ser His His His His His His
545 550 555
<210> 67
<211> 558
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide MICwed-Fv
<400> 67
Glu Pro His Ser Leu Arg Tyr Asn Leu Thr Val Leu Ser Trp Asp Gly
1 5 10 15
Ser Val Gln Ser Gly Phe Leu Thr Glu Val His Leu Asp Gly Gln Pro
20 25 30
Phe Leu Arg Cys Asp Arg Gln Lys Cys Arg Ala Lys Pro Gln Gly Gln
35 40 45
Trp Ala Glu Asp Val Leu Gly Asn Lys Thr Trp Asp Arg Glu Thr Arg
50 55 60
Asp Leu Thr Gly Trp Gly Lys Asp Leu Arg Met Thr Leu Ala His Ile
65 70 75 80
Lys Asp Gln Lys Glu Gly Leu His Ser Leu Gln Glu Ile Arg Val Cys
85 90 95
Glu Ile His Glu Asp Asn Ser Thr Arg Ser Ser Gln His Phe Tyr Tyr
100 105 110
Asp Gly Glu Leu Phe Leu Ser Gln Asn Leu Glu Thr Lys Glu Trp Thr
115 120 125
Met Pro Gln Ser Ser Arg Ala Gln Thr Leu Ala Met Asn Val Arg Asn
130 135 140
Phe Leu Lys Glu Asp Ala Met Glu Thr Asp Thr His Tyr His Ala Met
145 150 155 160
His Ala Asp Cys Leu Gln Glu Leu Arg Arg Tyr Leu Lys Ser Gly Val
165 170 175
Val Leu Arg Arg Thr Val Pro Pro Met Val Gln Val Thr Arg Ser Glu
180 185 190
Ala Ser Gly Gly Ser Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
195 200 205
Gln Asp Val Ser Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys
210 215 220
Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val
225 230 235 240
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
245 250 255
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
260 265 270
Ser Tyr Thr Thr Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
275 280 285
Lys Gly Gly Ser Ser Arg Ser Ser Ser Ser Gly Gly Gly Gly Ser Gly
290 295 300
Gly Gly Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
305 310 315 320
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
325 330 335
Thr Ser Thr Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
340 345 350
Glu Trp Val Gly Arg Ile Tyr Pro Thr Asn Gly Ser Thr Asn Tyr Ala
355 360 365
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn
370 375 380
Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
385 390 395 400
Tyr Tyr Cys Ala Arg Thr Tyr Gly Ile Tyr Asp Leu Tyr Val Asp Tyr
405 410 415
Thr Glu Tyr Val Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
420 425 430
Ser Ser Gly Gly Ser Ser Arg Ser Ser Ser Ser Gly Gly Gly Gly Ser
435 440 445
Gly Gly Gly Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser
450 455 460
Ala Ser Gly Gly Ser Gly Gln Ile Thr Val Thr Cys Arg Ala Ser Gly
465 470 475 480
Phe Tyr Pro Trp Asn Ile Thr Leu Ser Trp Arg Gln Asp Gly Val Ser
485 490 495
Leu Ser His Asp Thr Gln Gln Trp Gly Asp Val Leu Pro Asp Gly Gln
500 505 510
Gly Thr Tyr Gln Thr Trp Val Ala Thr Arg Ile Ser Gln Gly Glu Glu
515 520 525
Gln Arg Phe Thr Cys Tyr Met Glu His Ser Gly Gln His Ser Thr His
530 535 540
Pro Val Pro Ser Gly Lys Gly Ser His His His His His His
545 550 555
<210> 68
<211> 558
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide MICv20-Fv
<400> 68
Glu Pro His Ser Leu Arg Tyr Asn Leu Thr Val Leu Ser Trp Asp Gly
1 5 10 15
Ser Val Gln Ser Gly Phe Leu Thr Glu Val His Leu Asp Gly Gln Pro
20 25 30
Phe Leu Arg Cys Asp Arg Gln Lys Cys Arg Ala Lys Pro Gln Gly Gln
35 40 45
Trp Ala Glu Asp Val Leu Gly Asn Lys Thr Trp Asp Arg Glu Thr Arg
50 55 60
Asp Leu Thr Ala Trp Gly Lys Asp Leu Arg Met Thr Leu Ala His Ile
65 70 75 80
Lys Asp Gln Lys Glu Gly Leu His Ser Leu Gln Glu Ile Arg Val Cys
85 90 95
Glu Ile His Glu Asp Asn Ser Thr Arg Ser Ser Gln His Phe Tyr Tyr
100 105 110
Asp Gly Glu Leu Phe Leu Ser Gln Asn Leu Glu Thr Leu Glu Trp Thr
115 120 125
Met Pro Gln Ser Ser Arg Ala Gln Thr Leu Ala Met Asn Val Arg Asn
130 135 140
Phe Leu Lys Glu Asp Ala Met Gln Thr Asp Thr His Tyr Arg Ala Met
145 150 155 160
His Ala Asp Cys Leu Phe Glu Leu Arg Arg Tyr Leu Lys Ser Gly Val
165 170 175
Val Leu Arg Arg Thr Val Pro Pro Met Val Gln Val Thr Arg Ser Glu
180 185 190
Ala Ser Gly Gly Ser Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
195 200 205
Gln Asp Val Ser Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys
210 215 220
Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val
225 230 235 240
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
245 250 255
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
260 265 270
Ser Tyr Thr Thr Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
275 280 285
Lys Gly Gly Ser Ser Arg Ser Ser Ser Ser Gly Gly Gly Gly Ser Gly
290 295 300
Gly Gly Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
305 310 315 320
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
325 330 335
Thr Ser Thr Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
340 345 350
Glu Trp Val Gly Arg Ile Tyr Pro Thr Asn Gly Ser Thr Asn Tyr Ala
355 360 365
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn
370 375 380
Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
385 390 395 400
Tyr Tyr Cys Ala Arg Thr Tyr Gly Ile Tyr Asp Leu Tyr Val Asp Tyr
405 410 415
Thr Glu Tyr Val Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
420 425 430
Ser Ser Gly Gly Ser Ser Arg Ser Ser Ser Ser Gly Gly Gly Gly Ser
435 440 445
Gly Gly Gly Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser
450 455 460
Ala Ser Gly Gly Ser Gly Gln Ile Thr Val Thr Cys Arg Ala Ser Gly
465 470 475 480
Phe Tyr Pro Trp Asn Ile Thr Leu Ser Trp Arg Gln Asp Gly Val Ser
485 490 495
Leu Ser His Asp Thr Gln Gln Trp Gly Asp Val Leu Pro Asp Gly Gln
500 505 510
Gly Thr Tyr Gln Thr Trp Val Ala Thr Arg Ile Ser Gln Gly Glu Glu
515 520 525
Gln Arg Phe Thr Cys Tyr Met Glu His Ser Gly Gln His Ser Thr His
530 535 540
Pro Val Pro Ser Gly Lys Gly Ser His His His His His His
545 550 555
<210> 69
<211> 558
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide MICv25-Fv
<400> 69
Glu Pro His Ser Leu Arg Tyr Asn Leu Thr Val Leu Ser Trp Asp Gly
1 5 10 15
Ser Val Gln Ser Gly Phe Leu Thr Glu Val His Leu Asp Gly Gln Pro
20 25 30
Phe Leu Arg Cys Asp Arg Gln Lys Cys Arg Ala Lys Pro Gln Gly Gln
35 40 45
Trp Ala Glu Asp Val Leu Gly Asn Lys Thr Trp Asp Arg Glu Thr Arg
50 55 60
Asp Leu Thr Gly Trp Gly Lys Asp Leu Arg Met Thr Leu Ala His Ile
65 70 75 80
Lys Asp Gln Lys Glu Gly Leu His Ser Leu Gln Glu Ile Arg Val Cys
85 90 95
Glu Ile His Glu Asp Asn Ser Thr Arg Ser Ser Gln His Phe Tyr Tyr
100 105 110
Asp Gly Glu Leu Phe Leu Ser Gln Asn Leu Glu Thr Leu Glu Trp Thr
115 120 125
Met Pro Gln Ser Ser Arg Ala Gln Thr Leu Ala Met Asn Val Arg Asn
130 135 140
Phe Leu Lys Glu Asp Ala Met Glu Thr Asp Thr His Tyr His Ala Met
145 150 155 160
Arg Ala Asp Cys Leu Ser Glu Leu Arg Arg Tyr Leu Lys Ser Gly Val
165 170 175
Val Leu Arg Arg Thr Val Pro Pro Met Val Gln Val Thr Arg Ser Glu
180 185 190
Ala Ser Gly Gly Ser Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
195 200 205
Gln Asp Val Ser Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys
210 215 220
Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val
225 230 235 240
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
245 250 255
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
260 265 270
Ser Tyr Thr Thr Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
275 280 285
Lys Gly Gly Ser Ser Arg Ser Ser Ser Ser Gly Gly Gly Gly Ser Gly
290 295 300
Gly Gly Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
305 310 315 320
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
325 330 335
Thr Ser Thr Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
340 345 350
Glu Trp Val Gly Arg Ile Tyr Pro Thr Asn Gly Ser Thr Asn Tyr Ala
355 360 365
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn
370 375 380
Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
385 390 395 400
Tyr Tyr Cys Ala Arg Thr Tyr Gly Ile Tyr Asp Leu Tyr Val Asp Tyr
405 410 415
Thr Glu Tyr Val Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
420 425 430
Ser Ser Gly Gly Ser Ser Arg Ser Ser Ser Ser Gly Gly Gly Gly Ser
435 440 445
Gly Gly Gly Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser
450 455 460
Ala Ser Gly Gly Ser Gly Gln Ile Thr Val Thr Cys Arg Ala Ser Gly
465 470 475 480
Phe Tyr Pro Trp Asn Ile Thr Leu Ser Trp Arg Gln Asp Gly Val Ser
485 490 495
Leu Ser His Asp Thr Gln Gln Trp Gly Asp Val Leu Pro Asp Gly Gln
500 505 510
Gly Thr Tyr Gln Thr Trp Val Ala Thr Arg Ile Ser Gln Gly Glu Glu
515 520 525
Gln Arg Phe Thr Cys Tyr Met Glu His Ser Gly Gln His Ser Thr His
530 535 540
Pro Val Pro Ser Gly Lys Gly Ser His His His His His His
545 550 555
<210> 70
<211> 558
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide MICv27-Fv
<400> 70
Glu Pro His Ser Leu Arg Tyr Asn Leu Thr Val Leu Ser Trp Asp Gly
1 5 10 15
Ser Val Gln Ser Gly Phe Leu Thr Glu Val His Leu Asp Gly Gln Pro
20 25 30
Phe Leu Arg Cys Asp Arg Gln Lys Cys Arg Ala Lys Pro Gln Gly Gln
35 40 45
Trp Ala Glu Asp Val Leu Gly Asn Lys Thr Trp Asp Arg Glu Thr Arg
50 55 60
Asp Leu Thr Gly Trp Gly Lys Asp Leu Arg Met Thr Leu Ala His Ile
65 70 75 80
Lys Asp Gln Lys Glu Gly Leu His Ser Leu Gln Glu Ile Arg Val Cys
85 90 95
Glu Ile His Glu Asp Asn Ser Thr Arg Ser Ser Gln His Phe Tyr Tyr
100 105 110
Asp Gly Glu Leu Phe Leu Ser Gln Asn Leu Glu Thr Leu Glu Trp Thr
115 120 125
Met Pro Gln Ser Ser Arg Ala Gln Thr Leu Ala Met Asn Val Arg Asn
130 135 140
Phe Leu Lys Glu Asp Ala Met Lys Thr Lys Thr His Tyr His Ala Met
145 150 155 160
Arg Ala Asp Cys Leu Ser Glu Leu Arg Arg Tyr Leu Lys Ser Gly Val
165 170 175
Val Leu Arg Arg Thr Val Pro Pro Met Val Gln Val Thr Arg Ser Glu
180 185 190
Ala Ser Gly Gly Ser Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
195 200 205
Gln Asp Val Ser Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys
210 215 220
Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val
225 230 235 240
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
245 250 255
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
260 265 270
Ser Tyr Thr Thr Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
275 280 285
Lys Gly Gly Ser Ser Arg Ser Ser Ser Ser Gly Gly Gly Gly Ser Gly
290 295 300
Gly Gly Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
305 310 315 320
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
325 330 335
Thr Ser Thr Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
340 345 350
Glu Trp Val Gly Arg Ile Tyr Pro Thr Asn Gly Ser Thr Asn Tyr Ala
355 360 365
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn
370 375 380
Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
385 390 395 400
Tyr Tyr Cys Ala Arg Thr Tyr Gly Ile Tyr Asp Leu Tyr Val Asp Tyr
405 410 415
Thr Glu Tyr Val Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
420 425 430
Ser Ser Gly Gly Ser Ser Arg Ser Ser Ser Ser Gly Gly Gly Gly Ser
435 440 445
Gly Gly Gly Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser
450 455 460
Ala Ser Gly Gly Ser Gly Gln Ile Thr Val Thr Cys Arg Ala Ser Gly
465 470 475 480
Phe Tyr Pro Trp Asn Ile Thr Leu Ser Trp Arg Gln Asp Gly Val Ser
485 490 495
Leu Ser His Asp Thr Gln Gln Trp Gly Asp Val Leu Pro Asp Gly Gln
500 505 510
Gly Thr Tyr Gln Thr Trp Val Ala Thr Arg Ile Ser Gln Gly Glu Glu
515 520 525
Gln Arg Phe Thr Cys Tyr Met Glu His Ser Gly Gln His Ser Thr His
530 535 540
Pro Val Pro Ser Gly Lys Gly Ser His His His His His His
545 550 555
<210> 71
<211> 558
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide MICv28-Fv
<400> 71
Glu Pro His Ser Leu Arg Tyr Asn Leu Thr Val Leu Ser Trp Asp Gly
1 5 10 15
Ser Val Gln Ser Gly Phe Leu Thr Glu Val His Leu Asp Gly Gln Pro
20 25 30
Phe Leu Arg Cys Asp Arg Gln Lys Cys Arg Ala Lys Pro Gln Gly Gln
35 40 45
Trp Ala Glu Asp Val Leu Gly Asn Lys Thr Trp Asp Arg Glu Thr Arg
50 55 60
Asp Leu Thr Gly Asn Gly Lys Asp Leu Arg Met Thr Leu Ala His Ile
65 70 75 80
Lys Asp Gln Lys Glu Gly Leu His Ser Leu Gln Glu Ile Arg Val Cys
85 90 95
Glu Ile His Glu Asp Asn Ser Thr Arg Ser Ser Gln His Phe Tyr Tyr
100 105 110
Asp Gly Glu Leu Phe Leu Ser Gln Asn Leu Glu Thr Leu Glu Trp Thr
115 120 125
Met Pro Gln Ser Ser Arg Ala Gln Thr Leu Ala Met Asn Val Arg Asn
130 135 140
Phe Leu Lys Glu Asp Ala Met Lys Thr Lys Thr His Tyr His Ala Met
145 150 155 160
Arg Ala Asp Cys Leu Ser Glu Leu Arg Arg Tyr Leu Lys Ser Gly Val
165 170 175
Val Leu Arg Arg Thr Val Pro Pro Met Val Gln Val Thr Arg Ser Glu
180 185 190
Ala Ser Gly Gly Ser Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
195 200 205
Gln Asp Val Ser Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys
210 215 220
Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val
225 230 235 240
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
245 250 255
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
260 265 270
Ser Tyr Thr Thr Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
275 280 285
Lys Gly Gly Ser Ser Arg Ser Ser Ser Ser Gly Gly Gly Gly Ser Gly
290 295 300
Gly Gly Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
305 310 315 320
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
325 330 335
Thr Ser Thr Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
340 345 350
Glu Trp Val Gly Arg Ile Tyr Pro Thr Asn Gly Ser Thr Asn Tyr Ala
355 360 365
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn
370 375 380
Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
385 390 395 400
Tyr Tyr Cys Ala Arg Thr Tyr Gly Ile Tyr Asp Leu Tyr Val Asp Tyr
405 410 415
Thr Glu Tyr Val Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
420 425 430
Ser Ser Gly Gly Ser Ser Arg Ser Ser Ser Ser Gly Gly Gly Gly Ser
435 440 445
Gly Gly Gly Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser
450 455 460
Ala Ser Gly Gly Ser Gly Gln Ile Thr Val Thr Cys Arg Ala Ser Gly
465 470 475 480
Phe Tyr Pro Trp Asn Ile Thr Leu Ser Trp Arg Gln Asp Gly Val Ser
485 490 495
Leu Ser His Asp Thr Gln Gln Trp Gly Asp Val Leu Pro Asp Gly Gln
500 505 510
Gly Thr Tyr Gln Thr Trp Val Ala Thr Arg Ile Ser Gln Gly Glu Glu
515 520 525
Gln Arg Phe Thr Cys Tyr Met Glu His Ser Gly Gln His Ser Thr His
530 535 540
Pro Val Pro Ser Gly Lys Gly Ser His His His His His His
545 550 555
<210> 72
<211> 558
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide MICv42-Fv
<400> 72
Glu Pro His Ser Leu Arg Tyr Asn Leu Thr Val Leu Ser Trp Asp Gly
1 5 10 15
Ser Val Gln Ser Gly Phe Leu Thr Glu Val His Leu Asp Gly Gln Pro
20 25 30
Phe Leu Arg Cys Asp Arg Gln Lys Cys Arg Ala Lys Pro Gln Gly Gln
35 40 45
Trp Ala Glu Asp Val Leu Gly Asn Lys Thr Trp Asp Arg Glu Thr Arg
50 55 60
Asp Leu Thr Gly Trp Gly Lys Asp Leu Arg Met Thr Leu Ala His Ile
65 70 75 80
Lys Asp Gln Lys Glu Gly Leu His Ser Leu Gln Glu Ile Arg Val Cys
85 90 95
Glu Ile His Glu Asp Asn Ser Thr Arg Ser Ser Gln His Phe Tyr Tyr
100 105 110
Asp Gly Glu Leu Phe Leu Ser Gln Asn Leu Glu Thr Leu Glu Trp Thr
115 120 125
Met Pro Gln Ser Ser Arg Ala Gln Thr Leu Ala Met Asn Val Arg Asn
130 135 140
Phe Leu Lys Glu Asp Ala Met Glu Thr Asp Thr His Tyr His Ala Met
145 150 155 160
Arg Ala Asp Cys Leu Gln Glu Leu Arg Arg Tyr Leu Lys Ser Gly Val
165 170 175
Val Leu Arg Arg Thr Val Pro Pro Met Val Gln Val Thr Arg Ser Glu
180 185 190
Ala Ser Gly Gly Ser Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
195 200 205
Gln Asp Val Ser Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys
210 215 220
Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val
225 230 235 240
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
245 250 255
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
260 265 270
Ser Tyr Thr Thr Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
275 280 285
Lys Gly Gly Ser Ser Arg Ser Ser Ser Ser Gly Gly Gly Gly Ser Gly
290 295 300
Gly Gly Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
305 310 315 320
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
325 330 335
Thr Ser Thr Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
340 345 350
Glu Trp Val Gly Arg Ile Tyr Pro Thr Asn Gly Ser Thr Asn Tyr Ala
355 360 365
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn
370 375 380
Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
385 390 395 400
Tyr Tyr Cys Ala Arg Thr Tyr Gly Ile Tyr Asp Leu Tyr Val Asp Tyr
405 410 415
Thr Glu Tyr Val Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
420 425 430
Ser Ser Gly Gly Ser Ser Arg Ser Ser Ser Ser Gly Gly Gly Gly Ser
435 440 445
Gly Gly Gly Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser
450 455 460
Ala Ser Gly Gly Ser Gly Gln Ile Thr Val Thr Cys Arg Ala Ser Gly
465 470 475 480
Phe Tyr Pro Trp Asn Ile Thr Leu Ser Trp Arg Gln Asp Gly Val Ser
485 490 495
Leu Ser His Asp Thr Gln Gln Trp Gly Asp Val Leu Pro Asp Gly Gln
500 505 510
Gly Thr Tyr Gln Thr Trp Val Ala Thr Arg Ile Ser Gln Gly Glu Glu
515 520 525
Gln Arg Phe Thr Cys Tyr Met Glu His Ser Gly Gln His Ser Thr His
530 535 540
Pro Val Pro Ser Gly Lys Gly Ser His His His His His His
545 550 555
<210> 73
<211> 558
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide MICv48-Fc
<400> 73
Glu Pro His Ser Leu Arg Tyr Asn Leu Thr Val Leu Ser Trp Asp Gly
1 5 10 15
Ser Val Gln Ser Gly Phe Leu Thr Glu Val His Leu Asp Gly Gln Pro
20 25 30
Phe Leu Arg Cys Asp Arg Gln Lys Cys Arg Ala Lys Pro Gln Gly Gln
35 40 45
Trp Ala Glu Asp Val Leu Gly Asn Lys Thr Trp Asp Arg Glu Thr Arg
50 55 60
Asp Leu Thr Gly Trp Gly Lys Asp Leu Arg Met Thr Leu Ala His Ile
65 70 75 80
Lys Asp Gln Lys Glu Gly Leu His Ser Leu Gln Glu Ile Arg Val Cys
85 90 95
Glu Ile His Glu Asp Asn Ser Thr Arg Ser Ser Gln His Phe Tyr Tyr
100 105 110
Asp Gly Glu Leu Phe Leu Ser Gln Asn Leu Glu Thr Leu Glu Trp Thr
115 120 125
Met Pro Gln Ser Ser Arg Ala Gln Thr Leu Ala Met Asn Val Arg Asn
130 135 140
Phe Leu Lys Glu Asp Ala Met Ala Thr Asp Thr His Tyr Ile Ala Met
145 150 155 160
Arg Ala Asp Cys Leu Ala Glu Leu Arg Arg Tyr Leu Lys Ser Gly Val
165 170 175
Val Leu Arg Arg Thr Val Pro Pro Met Val Gln Val Thr Arg Ser Glu
180 185 190
Ala Ser Gly Gly Ser Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
195 200 205
Gln Asp Val Ser Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys
210 215 220
Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val
225 230 235 240
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
245 250 255
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
260 265 270
Ser Tyr Thr Thr Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
275 280 285
Lys Gly Gly Ser Ser Arg Ser Ser Ser Ser Gly Gly Gly Gly Ser Gly
290 295 300
Gly Gly Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
305 310 315 320
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
325 330 335
Thr Ser Thr Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
340 345 350
Glu Trp Val Gly Arg Ile Tyr Pro Thr Asn Gly Ser Thr Asn Tyr Ala
355 360 365
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn
370 375 380
Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
385 390 395 400
Tyr Tyr Cys Ala Arg Thr Tyr Gly Ile Tyr Asp Leu Tyr Val Asp Tyr
405 410 415
Thr Glu Tyr Val Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
420 425 430
Ser Ser Gly Gly Ser Ser Arg Ser Ser Ser Ser Gly Gly Gly Gly Ser
435 440 445
Gly Gly Gly Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser
450 455 460
Ala Ser Gly Gly Ser Gly Gln Ile Thr Val Thr Cys Arg Ala Ser Gly
465 470 475 480
Phe Tyr Pro Trp Asn Ile Thr Leu Ser Trp Arg Gln Asp Gly Val Ser
485 490 495
Leu Ser His Asp Thr Gln Gln Trp Gly Asp Val Leu Pro Asp Gly Gln
500 505 510
Gly Thr Tyr Gln Thr Trp Val Ala Thr Arg Ile Ser Gln Gly Glu Glu
515 520 525
Gln Arg Phe Thr Cys Tyr Met Glu His Ser Gly Gln His Ser Thr His
530 535 540
Pro Val Pro Ser Gly Lys Gly Ser His His His His His His
545 550 555
<210> 74
<211> 558
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide MICv49-Fv
<400> 74
Glu Pro His Ser Leu Arg Tyr Asn Leu Thr Val Leu Ser Trp Asp Gly
1 5 10 15
Ser Val Gln Thr Gly Phe Leu Thr Glu Val His Leu Asp Gly Gln Pro
20 25 30
Phe Leu Arg Cys Asp Arg Gln Lys Cys Arg Ala Lys Pro Gln Gly Gln
35 40 45
Trp Ala Glu Asp Val Leu Gly Asn Lys Thr Trp Asp Arg Glu Thr Arg
50 55 60
Asp Leu Thr Gln Trp Gly Lys Asp Leu Arg Met Thr Leu Ala His Ile
65 70 75 80
Lys Asp Gln Lys Glu Gly Leu His Ser Leu Gln Glu Ile Arg Val Cys
85 90 95
Glu Ile His Glu Asp Asn Ser Thr Arg Ser Ser Gln His Phe Tyr Tyr
100 105 110
Asp Gly Glu Leu Phe Leu Ser Gln Asn Leu Glu Thr Lys Glu Trp Thr
115 120 125
Met Pro Gln Ser Ser Arg Ala Gln Thr Leu Ala Met Asn Val Arg Asn
130 135 140
Phe Leu Lys Glu Asp Ala Met Phe Thr Asp Thr His Tyr Arg Ala Met
145 150 155 160
Thr Ala Asp Cys Leu Thr Glu Leu Arg Arg Tyr Leu Lys Ser Gly Val
165 170 175
Val Leu Arg Arg Thr Val Pro Pro Met Val Gln Val Thr Arg Ser Glu
180 185 190
Ala Ser Gly Gly Ser Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
195 200 205
Gln Asp Val Ser Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys
210 215 220
Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val
225 230 235 240
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
245 250 255
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
260 265 270
Ser Tyr Thr Thr Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
275 280 285
Lys Gly Gly Ser Ser Arg Ser Ser Ser Ser Gly Gly Gly Gly Ser Gly
290 295 300
Gly Gly Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
305 310 315 320
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
325 330 335
Thr Ser Thr Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
340 345 350
Glu Trp Val Gly Arg Ile Tyr Pro Thr Asn Gly Ser Thr Asn Tyr Ala
355 360 365
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn
370 375 380
Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
385 390 395 400
Tyr Tyr Cys Ala Arg Thr Tyr Gly Ile Tyr Asp Leu Tyr Val Asp Tyr
405 410 415
Thr Glu Tyr Val Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
420 425 430
Ser Ser Gly Gly Ser Ser Arg Ser Ser Ser Ser Gly Gly Gly Gly Ser
435 440 445
Gly Gly Gly Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser
450 455 460
Ala Ser Gly Gly Ser Gly Gln Ile Thr Val Thr Cys Arg Ala Ser Gly
465 470 475 480
Phe Tyr Pro Trp Asn Ile Thr Leu Ser Trp Arg Gln Asp Gly Val Ser
485 490 495
Leu Ser His Asp Thr Gln Gln Trp Gly Asp Val Leu Pro Asp Gly Gln
500 505 510
Gly Thr Tyr Gln Thr Trp Val Ala Thr Arg Ile Ser Gln Gly Glu Glu
515 520 525
Gln Arg Phe Thr Cys Tyr Met Glu His Ser Gly Gln His Ser Thr His
530 535 540
Pro Val Pro Ser Gly Lys Gly Ser His His His His His His
545 550 555
<210> 75
<211> 137
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic NKG2D ectodomain
<400> 75
Asn Ser Leu Phe Asn Gln Glu Val Gln Ile Pro Leu Thr Glu Ser Tyr
1 5 10 15
Cys Gly Pro Cys Pro Lys Asn Trp Ile Cys Tyr Lys Asn Asn Cys Tyr
20 25 30
Gln Phe Phe Asp Glu Ser Lys Asn Trp Tyr Glu Ser Gln Ala Ser Cys
35 40 45
Met Ser Gln Asn Ala Ser Leu Leu Lys Val Tyr Ser Lys Glu Asp Gln
50 55 60
Asp Leu Leu Lys Leu Val Lys Ser Tyr His Trp Met Gly Leu Val His
65 70 75 80
Ile Pro Thr Asn Gly Ser Trp Gln Trp Glu Asp Gly Ser Ile Leu Ser
85 90 95
Pro Asn Leu Leu Thr Ile Ile Glu Met Gln Lys Gly Asp Cys Ala Leu
100 105 110
Tyr Ala Ser Ser Phe Lys Gly Tyr Ile Glu Asn Cys Ser Thr Pro Asn
115 120 125
Thr Tyr Ile Cys Met Gln Arg Thr Val
130 135
<210> 76
<211> 40
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic oligonucleotide
<400> 76
ctgtctagag ccgccaacat ggggctgggc ccggtcttcc 40
<210> 77
<211> 30
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic oligonucleotide
<400> 77
aacggatcct acacagtcct ttgcatgcag 30
<210> 78
<211> 6362
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic polynucleotide, pD2509-CMV-Avi-His-natural NKG2D
ectodomain
<400> 78
ggagagacca cacccaagct gtctagagcc gccaacatgg ggctgggccc ggtcttcctg 60
cttctggctg gcatcttccc ttttgcacct ccgggagctg ctgctgagcc ccaccatcat 120
caccaccatg gccttaacga catcttcgaa gctcaaaaga tcgaatggca tgaaaactca 180
ttattcaacc aagaagttca aattcccttg accgaaagtt actgtggccc atgtcctaaa 240
aactggatat gttacaaaaa taactgctac caattttttg atgagagtaa aaactggtat 300
gagagccagg cttcttgtat gtctcaaaat gccagccttc tgaaagtata cagcaaagag 360
gaccaggatt tacttaaact ggtgaagtca tatcattgga tgggactagt acacattcca 420
acaaatggat cttggcagtg ggaagatggc tccattctct cacccaacct actaacaata 480
attgaaatgc agaagggaga ctgtgcactc tatgcctcga gctttaaagg ctatatagaa 540
aactgttcaa ctccaaatac atacatctgc atgcaaagga ctgtgtagga tccgttgagg 600
tctctaaaag cgtcttcctg ttctcatcac atcatatcaa ggttatatac catcaatatt 660
gccacagatg ttacttagcc ttttaatatt tctctaattt agtgtatatg caatgatagt 720
tctctgattt ctgagattga gtttctcatg tgtaatgatt atttagagtt tctctttcat 780
ctgttcaaat ttttgtctag ttttattttt tactgatttg taagacttct ttttataatc 840
tgcatattac aattctcttt actggggtgt tgcaaatatt ttctgtcatt ctatggcctg 900
acttttctta atggtttttt aattttaaaa ataagtctta atattcatgc aatctaatta 960
acaatctttt ctttgtggtt aggactttga gtcataagaa atttttctct acactgaagt 1020
catgatggca tgcttctata ttattttcta aaagatttaa agttttgcct tctccattta 1080
gacttataat tcactggaat ttttttgtgt gtatggtatg acatatgggt tcccttttat 1140
tttttacata taaatatatt tccctgtttt tctaaaaaag aaaaagatca tcattttccc 1200
attgtaaaat gccatatttt tttcataggt cacttacata tatcaatggg tctgtttctg 1260
agctctactc tattttatca gcctcactgt ctatccccac acatctcatg ctttgctcta 1320
aatcttgata tttagtggaa cattctttcc cattttgttc tacaagaata tttttgttat 1380
tgtctttggg ctttctatat acattttgaa atgaggttga caagttaata atcaacctct 1440
ggattacaaa atttgtgaaa gattgactgg tattcttaac tatgttgctc cttttacgct 1500
atgtggatac gctgctttaa tgcctttgta tcatgctatt gcttcccgta tggctttcat 1560
tttctcctcc ttgtataaat cctggttgct gtctctttat gaggagttgt ggcccgttgt 1620
caggcaacgt ggcgtggtgt gcactgtgtt tgctgacgca acccccactg gttggggcat 1680
tgccaccacc tgtcagctcc tttccgggac tttcgctttc cccctcccta ttgccacggc 1740
ggaactcatc gccgcctgcc ttgcccgctg ctggacaggg gctcggctgt tgggcactga 1800
caattccgtg gtgttgtcgg ggaaatcatc gtcctttcct tggctgctcg cctgtgttgc 1860
cacctggatt ctgcgcggga cgtccttctg ctacgtccct tcggccctca atccagcgga 1920
ccttccttcc cgcggcctgc tgccggctct gcggcctctt ccgcctcttc gccttcgccc 1980
tcagacgagt cggatctccc tttgggccgc ctccccgcat ctgtgccttc tagttgccag 2040
ccatctgttg tttgcccctc ccccgtgcct tccttgaccc tggaaggtgc cactcccact 2100
gtcctttcct aataaaatga ggaaattgca tcgcattgtc tgagtaggtg tcattctatt 2160
ctggggggtg gggtggggca ggacagcaag ggggaggatt ggcaagacaa tagcaggctt 2220
tgcattttta gacatttaga agcctatatc ttgttacaga attggaatta cacaaaaatt 2280
ctaccatatt ttgaaagctt aggttgttct gaaaaaaaca atatattgtt ttcctgggta 2340
aactaaaagt cccctcgagg aaaggcccct aaagtgaaac agtgcaaaac gttcaaaaac 2400
tgtctggcaa tacaagttcc actttgacca aaacggctgg cagtaaaagg gttaagaaga 2460
ctgtcagcct tgagcggtat cagctcactc aaaggcggta atacggttat ccacagaatc 2520
aggggataac gcaggaaaga acatgtgagc aaaaggccag caaaaggcca ggaaccgtaa 2580
aaaggccgcg ttgctggcgt ttttccatag gctccgcccc cctgacgagc atcacaaaaa 2640
tcgacgctca agtcagaggt ggcgaaaccc gacaggacta taaagatacc aggcgtttcc 2700
ccctggaagc tccctcgtgc gctctcctgt tccgaccctg ccgcttaccg gatacctgtc 2760
cgcctttctc ccttcgggaa gcgtggcgct ttctcatagc tcacgctgta ggtatctcag 2820
ttcggtgtag gtcgttcgct ccaagctggg ctgtgtgcac gaaccccccg ttcagcccga 2880
ccgctgcgcc ttatccggta actatcgtct tgagtccaac ccggtaagac acgacttatc 2940
gccactggca gcagccactg gtaacaggat tagcagagcg aggtatgtag gcggtgctac 3000
agagttcttg aagtggtggg ctaactacgg ctacactaga agaacagtat ttggtatctg 3060
cgctctgctg aagccagtta ccttcggaaa aagagttggt agctcttgat ccggcaaaca 3120
aaccaccgct ggtagcggtg gtttttttgt ttgcaagcag cagattacgc gcagaaaaaa 3180
aggatctcaa gaagatcctt tgatcttttc tacggggtct gacgctcagt ggaacgacgc 3240
gcgcgtaact cacgttaagg gattttggtc atgagttaga aaaactcatc gagcatcaaa 3300
tgaaactgca atttattcat atcaggatta tcaataccat atttttgaaa aagccgtttc 3360
tgtaatgaag gagaaaactc accgaggcag ttccatagga tggcaagatc ctggtatcgg 3420
tctgcgattc cgactcgtcc aacatcaata caacctatta atttcccctc gtcaaaaata 3480
aggttatcaa gtgagaaatc accatgagtg acgactgaat ccggtgagaa tggcaaaagt 3540
ttatgcattt ctttccagac ttgttcaaca ggccagccat tacgctcgtc atcaaaatca 3600
ctcgcatcaa ccaaaccgtt attcattcgt gattgcgcct gagcgaggcg aaatacgcga 3660
tcgctgttaa aaggacaatt acaaacagga atcgagtgca accggcgcag gaacactgcc 3720
agcgcatcaa caatattttc acctgaatca ggatattctt ctaatacctg gaacgctgtt 3780
tttccgggga tcgcagtggt gagtaaccat gcatcatcag gagtacggat aaaatgcttg 3840
atggtcggaa gtggcataaa ttccgtcagc cagtttagtc tgaccatctc atctgtaaca 3900
tcattggcaa cgctaccttt gccatgtttc agaaacaact ctggcgcatc gggcttccca 3960
tacaagcgat agattgtcgc acctgattgc ccgacattat cgcgagccca tttataccca 4020
tataaatcag catccatgtt ggaatttaat cgcggcctcg acgtttcccg ttggatatgg 4080
ctcatttttt acttcctcac cttgtcgtat tatactatgc cgatatacta tgccgatgat 4140
taattgtcga cactgcgggg gctctgtgtg gtaagcaggt cttaaccttt ttactgccaa 4200
tgacgcatgg gatacgtcgt ggcagtaaaa gggcttaaat gccaacgacg cgtcccatac 4260
gttgttggca ttttaattct tctctctgca gcggcagcat gtgccgccgc tgcagagagt 4320
ttctagcgat gacagcccct ctgggcaacg agccgggggg gctgtctttc tttatgtttt 4380
aaatgcactg acctcccaca ttcccttttt agtaaaatat tcagaaataa tttaaataca 4440
tcattgcaat gaaaataaat gttttttatt aggcagaatc cagatgctca aggcccttca 4500
taatatcccc cagtttagta gttggactta gggaacaaag gaacctttaa tagaaattgg 4560
acagcaagaa agcgagtcag gcaccgggct tgcgggtcat gcaccaggtg cgcggtcctt 4620
cgggcacctc gacgtcggcg gtgacggtga agccgagccg ctcgtagaag gggaggttgc 4680
ggggcgcgga tgtctccagg aaggcgggca ccccggcgcg ctcggccgcc tccactccgg 4740
ggagcacgac ggcgctgccc agacccttgc cctggtggtc gggcgacacg ccgacggtgg 4800
ccaggaacca cgcgggctcc ttgggccggt gcggcgccag gaggccttcc atctgttgct 4860
gcgcggccag ccgggaaccg ctcaactcgg ccatgcgcgg gccgatctcg gcgaacaccg 4920
cccccgcttc gacgctctcc ggcgtggtcc agaccgccac cgcggcgccg tcgtccgcga 4980
cccacacctt gccgatgtcg agcccgacgc gcgtgaggaa gagttcttgc agctcggtga 5040
cccgctcgat gtggcggtcc ggatcgacgg tgtggcgcgt ggcggggtag tcggcgaacg 5100
cggcggcgag ggtgcgtacg gccctgggga cgtcgtcgcg ggtggcgagg cgcaccgtgg 5160
gcttgtactc ggtcatggtg gcggacgaaa ggcccggaga tgaggaagag gagaacagcg 5220
cggcagacgt gcgcttttga agcgtgcaga atgccgggcc tccggaggac cttcgggcgc 5280
ccgccccgcc cctgagcccg cccctgagcc cgcccccgga cccacccctt cccagcctct 5340
gagcccagaa agcgaaggag caaagctgct attggccgct gccccaaagg cctacccgct 5400
tccattgctc agcggtgctg tccatctgca cgagactagt gagtcgtgct acttccattt 5460
gtcacgtcct gcacgacgcg agctgcgggg cgggggggaa cttcctgact aggggaggag 5520
tagaaggtgg cgcgaagggg ccaccaaaga acggagccgg ttggcgccta ccggtggatg 5580
tggaatgtgt gcgaggccag aggccacttg tgtagcgcca agtgcccagc ggggctgcta 5640
aagcgcatgc tccagactgc cttgggaaaa gcgcctcccc tacccggtag agaaacttga 5700
tctgtcgccg caattcaaac ttcgtgaggc tccggtgccc gtcagtgacc tgctatactc 5760
tggagacgac ttacggtaaa tggcccgcct ggctgaccgc ccaacgaccc ccgcccattg 5820
acgtcaataa tgacgtatgt tcccatagta acgccaatag ggactttcca ttgacgtcaa 5880
tgggtggagt atttacggta aactgcccac ttggcagtac atcaagtgta tcatatgcca 5940
agtccgcccc ctattgacgt caatgacggt aaatggcccg cctggcatta tgcccagtac 6000
atgaccttac gggactttcc tacttggcag tacatctacg tattagtcat cgctattacc 6060
atgctgatgc ggttttggca gtacaccaat gggcgtggat agcggtttga ctcacgggga 6120
tttccaagtc tccaccccat tgacgtcaat gggagtttgt tttggcacca aaatcaacgg 6180
gactttccaa aatgtcgtaa taaccccgcc ccgttgacgc aaatgggcgg taggcgtgta 6240
cggtgggagg tctatataag cagagctcgt ttagtgaacc gtcagatcgc ctggagaggc 6300
catccacgct gttttgacct ccatagtgga caccgggacc gatccagcct ccgcgtctca 6360
gg 6362
<210> 79
<211> 160
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide, His-avitag-natural NKG2D ectodomain
<400> 79
Glu Pro His His His His His His Gly Leu Asn Asp Ile Phe Glu Ala
1 5 10 15
Gln Lys Ile Glu Trp His Glu Asn Ser Leu Phe Asn Gln Glu Val Gln
20 25 30
Ile Pro Leu Thr Glu Ser Tyr Cys Gly Pro Cys Pro Lys Asn Trp Ile
35 40 45
Cys Tyr Lys Asn Asn Cys Tyr Gln Phe Phe Asp Glu Ser Lys Asn Trp
50 55 60
Tyr Glu Ser Gln Ala Ser Cys Met Ser Gln Asn Ala Ser Leu Leu Lys
65 70 75 80
Val Tyr Ser Lys Glu Asp Gln Asp Leu Leu Lys Leu Val Lys Ser Tyr
85 90 95
His Trp Met Gly Leu Val His Ile Pro Thr Asn Gly Ser Trp Gln Trp
100 105 110
Glu Asp Gly Ser Ile Leu Ser Pro Asn Leu Leu Thr Ile Ile Glu Met
115 120 125
Gln Lys Gly Asp Cys Ala Leu Tyr Ala Ser Ser Phe Lys Gly Tyr Ile
130 135 140
Glu Asn Cys Ser Thr Pro Asn Thr Tyr Ile Cys Met Gln Arg Thr Val
145 150 155 160
<210> 80
<211> 160
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide, His-avitag-non-natural NKG2D Y152A ectodomain
<400> 80
Glu Pro His His His His His His Gly Leu Asn Asp Ile Phe Glu Ala
1 5 10 15
Gln Lys Ile Glu Trp His Glu Asn Ser Leu Phe Asn Gln Glu Val Gln
20 25 30
Ile Pro Leu Thr Glu Ser Tyr Cys Gly Pro Cys Pro Lys Asn Trp Ile
35 40 45
Cys Tyr Lys Asn Asn Cys Tyr Gln Phe Phe Asp Glu Ser Lys Asn Trp
50 55 60
Tyr Glu Ser Gln Ala Ser Cys Met Ser Gln Asn Ala Ser Leu Leu Lys
65 70 75 80
Val Tyr Ser Lys Glu Asp Gln Asp Leu Leu Lys Leu Val Lys Ser Ala
85 90 95
His Trp Met Gly Leu Val His Ile Pro Thr Asn Gly Ser Trp Gln Trp
100 105 110
Glu Asp Gly Ser Ile Leu Ser Pro Asn Leu Leu Thr Ile Ile Glu Met
115 120 125
Gln Lys Gly Asp Cys Ala Leu Tyr Ala Ser Ser Phe Lys Gly Tyr Ile
130 135 140
Glu Asn Cys Ser Thr Pro Asn Thr Tyr Ile Cys Met Gln Arg Thr Val
145 150 155 160
<210> 81
<211> 160
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide, His-avitag-non-natural NKG2D Y199A ectodomain
<400> 81
Glu Pro His His His His His His Gly Leu Asn Asp Ile Phe Glu Ala
1 5 10 15
Gln Lys Ile Glu Trp His Glu Asn Ser Leu Phe Asn Gln Glu Val Gln
20 25 30
Ile Pro Leu Thr Glu Ser Tyr Cys Gly Pro Cys Pro Lys Asn Trp Ile
35 40 45
Cys Tyr Lys Asn Asn Cys Tyr Gln Phe Phe Asp Glu Ser Lys Asn Trp
50 55 60
Tyr Glu Ser Gln Ala Ser Cys Met Ser Gln Asn Ala Ser Leu Leu Lys
65 70 75 80
Val Tyr Ser Lys Glu Asp Gln Asp Leu Leu Lys Leu Val Lys Ser Tyr
85 90 95
His Trp Met Gly Leu Val His Ile Pro Thr Asn Gly Ser Trp Gln Trp
100 105 110
Glu Asp Gly Ser Ile Leu Ser Pro Asn Leu Leu Thr Ile Ile Glu Met
115 120 125
Gln Lys Gly Asp Cys Ala Leu Tyr Ala Ser Ser Phe Lys Gly Ala Ile
130 135 140
Glu Asn Cys Ser Thr Pro Asn Thr Tyr Ile Cys Met Gln Arg Thr Val
145 150 155 160
<210> 82
<211> 160
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide, His-avitag-non-natural NKG2D Y152A +Y199A
ectodomain
<400> 82
Glu Pro His His His His His His Gly Leu Asn Asp Ile Phe Glu Ala
1 5 10 15
Gln Lys Ile Glu Trp His Glu Asn Ser Leu Phe Asn Gln Glu Val Gln
20 25 30
Ile Pro Leu Thr Glu Ser Tyr Cys Gly Pro Cys Pro Lys Asn Trp Ile
35 40 45
Cys Tyr Lys Asn Asn Cys Tyr Gln Phe Phe Asp Glu Ser Lys Asn Trp
50 55 60
Tyr Glu Ser Gln Ala Ser Cys Met Ser Gln Asn Ala Ser Leu Leu Lys
65 70 75 80
Val Tyr Ser Lys Glu Asp Gln Asp Leu Leu Lys Leu Val Lys Ser Ala
85 90 95
His Trp Met Gly Leu Val His Ile Pro Thr Asn Gly Ser Trp Gln Trp
100 105 110
Glu Asp Gly Ser Ile Leu Ser Pro Asn Leu Leu Thr Ile Ile Glu Met
115 120 125
Gln Lys Gly Asp Cys Ala Leu Tyr Ala Ser Ser Phe Lys Gly Ala Ile
130 135 140
Glu Asn Cys Ser Thr Pro Asn Thr Tyr Ile Cys Met Gln Arg Thr Val
145 150 155 160
<210> 83
<211> 7640
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic polynucleotide, wt MIC-Fc expression vector
<400> 83
ggagagacca cacccaagct gtctagagcc gccaacatgg ggctgggccc ggtcttcctg 60
cttctggctg gcatcttccc ttttgcacct ccgggagctg ctgctgagcc ccacagtctt 120
cgttataacc tcacggtgct gtcctgggat ggatctgtgc agtcagggtt tctcactgag 180
gtacatctgg atggtcagcc cttcctgcgc tgtgacaggc agaaatgcag ggcaaagccc 240
cagggacagt gggcagaaga tgtcctggga aataagacat gggacagaga gaccagagac 300
ttgacagggt ggggaaagga cctcaggatg accctggctc atatcaagga ccagaaagaa 360
ggcttgcatt ccctccagga gattagggtc tgtgagatcc atgaagacaa cagcaccagg 420
agctcccagc atttctacta cgatggggag ctctttctct cccaaaacct ggagactaag 480
gaatggacaa tgccccagtc ctccagagct cagaccttgg ccatgaacgt caggaatttc 540
ttgaaggaag atgcaatgga gaccgataca cactatcacg ctatgcatgc agactgcctg 600
caggaactac ggcgatatct aaaatccggc gtagtcctga ggagaacagt gccccccatg 660
gtgaatgtca cccgcagcga ggcctcagag ggcaacatta ccgtgacatg cagggcttct 720
ggcttctatc cctggaatat cacactgagc tggcgtcagg atggggtatc tttgagccac 780
gacacccagc agtgggggga tgtcctgcct gatgggaatg gaacctacca gacctgggtg 840
gccaccagga tttgccaagg agaggagcag aggttcacct gctacatgga acacagcggg 900
aatcacagca ctcaccctgt gccctctggg aaaatcgaag gacgcatgga cccaaagagt 960
tgcgacaaaa ctcacacatg cccaccgtgc ccaggtaagc cagcccaggc ctcgccctcc 1020
agctcaaggc gggacaggtg ccctagagta gcctgcatcc agggacaggc cccagccggg 1080
tgctgacacg tccacctcca tctcttcctc agcacctgaa ctcctggggg gaccgtcagt 1140
cttcctcttc cccccaaaac ccaaggacac cctcatgatc tcccggaccc ctgaggtcac 1200
atgcgtggtg gtggacgtga gccacgaaga ccctgaggtc aagttcaact ggtacgtgga 1260
cggcgtggag gtgcataatg ccaagacaaa gccgcgggag gagcagtaca acagcacgta 1320
ccgtgtggtc agcgtcctca ccgtcctgca ccaggactgg ctgaatggca aggagtacaa 1380
gtgcaaggtc tccaacaaag ccctcccagc ccccatcgag aaaaccatct ccaaagccaa 1440
aggtgggacc cgtggggtgc gagggccaca tggacagagg ccggctcggc ccaccctctg 1500
ccctgagagt gactgctgta ccaacctctg tccctacagg gcagccccga gaaccacagg 1560
tgtacaccct gcccccatcc cgggatgagc tgaccaagaa ccaggtcagc ctgacctgcc 1620
tggtcaaagg cttctatccc agcgacatcg ccgtggagtg ggagagcaat gggcagccgg 1680
agaacaacta caagaccacg cctcccgtgc tggactccga cggctccttc ttcctctaca 1740
gcaagctcac cgtggacaag agcaggtggc agcaggggaa cgtcttctca tgctccgtga 1800
tgcatgaggc tctgcacaac cactacacgc agaagagcct ctccctgtct ccgggtaaat 1860
gataggatcc ggttgaggtc tctaaaagcg tcttcctgtt ctcatcacat catatcaagg 1920
ttatatacca tcaatattgc cacagatgtt acttagcctt ttaatatttc tctaatttag 1980
tgtatatgca atgatagttc tctgatttct gagattgagt ttctcatgtg taatgattat 2040
ttagagtttc tctttcatct gttcaaattt ttgtctagtt ttatttttta ctgatttgta 2100
agacttcttt ttataatctg catattacaa ttctctttac tggggtgttg caaatatttt 2160
ctgtcattct atggcctgac ttttcttaat ggttttttaa ttttaaaaat aagtcttaat 2220
attcatgcaa tctaattaac aatcttttct ttgtggttag gactttgagt cataagaaat 2280
ttttctctac actgaagtca tgatggcatg cttctatatt attttctaaa agatttaaag 2340
ttttgccttc tccatttaga cttataattc actggaattt ttttgtgtgt atggtatgac 2400
atatgggttc ccttttattt tttacatata aatatatttc cctgtttttc taaaaaagaa 2460
aaagatcatc attttcccat tgtaaaatgc catatttttt tcataggtca cttacatata 2520
tcaatgggtc tgtttctgag ctctactcta ttttatcagc ctcactgtct atccccacac 2580
atctcatgct ttgctctaaa tcttgatatt tagtggaaca ttctttccca ttttgttcta 2640
caagaatatt tttgttattg tctttgggct ttctatatac attttgaaat gaggttgaca 2700
agttaataat caacctctgg attacaaaat ttgtgaaaga ttgactggta ttcttaacta 2760
tgttgctcct tttacgctat gtggatacgc tgctttaatg cctttgtatc atgctattgc 2820
ttcccgtatg gctttcattt tctcctcctt gtataaatcc tggttgctgt ctctttatga 2880
ggagttgtgg cccgttgtca ggcaacgtgg cgtggtgtgc actgtgtttg ctgacgcaac 2940
ccccactggt tggggcattg ccaccacctg tcagctcctt tccgggactt tcgctttccc 3000
cctccctatt gccacggcgg aactcatcgc cgcctgcctt gcccgctgct ggacaggggc 3060
tcggctgttg ggcactgaca attccgtggt gttgtcgggg aaatcatcgt cctttccttg 3120
gctgctcgcc tgtgttgcca cctggattct gcgcgggacg tccttctgct acgtcccttc 3180
ggccctcaat ccagcggacc ttccttcccg cggcctgctg ccggctctgc ggcctcttcc 3240
gcctcttcgc cttcgccctc agacgagtcg gatctccctt tgggccgcct ccccgcatct 3300
gtgccttcta gttgccagcc atctgttgtt tgcccctccc ccgtgccttc cttgaccctg 3360
gaaggtgcca ctcccactgt cctttcctaa taaaatgagg aaattgcatc gcattgtctg 3420
agtaggtgtc attctattct ggggggtggg gtggggcagg acagcaaggg ggaggattgg 3480
caagacaata gcaggctttg catttttaga catttagaag cctatatctt gttacagaat 3540
tggaattaca caaaaattct accatatttt gaaagcttag gttgttctga aaaaaacaat 3600
atattgtttt cctgggtaaa ctaaaagtcc cctcgaggaa aggcccctaa agtgaaacag 3660
tgcaaaacgt tcaaaaactg tctggcaata caagttccac tttgaccaaa acggctggca 3720
gtaaaagggt taagaagact gtcagccttg agcggtatca gctcactcaa aggcggtaat 3780
acggttatcc acagaatcag gggataacgc aggaaagaac atgtgagcaa aaggccagca 3840
aaaggccagg aaccgtaaaa aggccgcgtt gctggcgttt ttccataggc tccgcccccc 3900
tgacgagcat cacaaaaatc gacgctcaag tcagaggtgg cgaaacccga caggactata 3960
aagataccag gcgtttcccc ctggaagctc cctcgtgcgc tctcctgttc cgaccctgcc 4020
gcttaccgga tacctgtccg cctttctccc ttcgggaagc gtggcgcttt ctcatagctc 4080
acgctgtagg tatctcagtt cggtgtaggt cgttcgctcc aagctgggct gtgtgcacga 4140
accccccgtt cagcccgacc gctgcgcctt atccggtaac tatcgtcttg agtccaaccc 4200
ggtaagacac gacttatcgc cactggcagc agccactggt aacaggatta gcagagcgag 4260
gtatgtaggc ggtgctacag agttcttgaa gtggtgggct aactacggct acactagaag 4320
aacagtattt ggtatctgcg ctctgctgaa gccagttacc ttcggaaaaa gagttggtag 4380
ctcttgatcc ggcaaacaaa ccaccgctgg tagcggtggt ttttttgttt gcaagcagca 4440
gattacgcgc agaaaaaaag gatctcaaga agatcctttg atcttttcta cggggtctga 4500
cgctcagtgg aacgacgcgc gcgtaactca cgttaaggga ttttggtcat gagttagaaa 4560
aactcatcga gcatcaaatg aaactgcaat ttattcatat caggattatc aataccatat 4620
ttttgaaaaa gccgtttctg taatgaagga gaaaactcac cgaggcagtt ccataggatg 4680
gcaagatcct ggtatcggtc tgcgattccg actcgtccaa catcaataca acctattaat 4740
ttcccctcgt caaaaataag gttatcaagt gagaaatcac catgagtgac gactgaatcc 4800
ggtgagaatg gcaaaagttt atgcatttct ttccagactt gttcaacagg ccagccatta 4860
cgctcgtcat caaaatcact cgcatcaacc aaaccgttat tcattcgtga ttgcgcctga 4920
gcgaggcgaa atacgcgatc gctgttaaaa ggacaattac aaacaggaat cgagtgcaac 4980
cggcgcagga acactgccag cgcatcaaca atattttcac ctgaatcagg atattcttct 5040
aatacctgga acgctgtttt tccggggatc gcagtggtga gtaaccatgc atcatcagga 5100
gtacggataa aatgcttgat ggtcggaagt ggcataaatt ccgtcagcca gtttagtctg 5160
accatctcat ctgtaacatc attggcaacg ctacctttgc catgtttcag aaacaactct 5220
ggcgcatcgg gcttcccata caagcgatag attgtcgcac ctgattgccc gacattatcg 5280
cgagcccatt tatacccata taaatcagca tccatgttgg aatttaatcg cggcctcgac 5340
gtttcccgtt ggatatggct cattttttac ttcctcacct tgtcgtatta tactatgccg 5400
atatactatg ccgatgatta attgtcgaca ctgcgggggc tctgtgtggt aagcaggtct 5460
taaccttttt actgccaatg acgcatggga tacgtcgtgg cagtaaaagg gcttaaatgc 5520
caacgacgcg tcccatacgt tgttggcatt ttaattcttc tctctgcagc ggcagcatgt 5580
gccgccgctg cagagagttt ctagcgatga cagcccctct gggcaacgag ccgggggggc 5640
tgtctttctt tatgttttaa atgcactgac ctcccacatt ccctttttag taaaatattc 5700
agaaataatt taaatacatc attgcaatga aaataaatgt tttttattag gcagaatcca 5760
gatgctcaag gcccttcata atatccccca gtttagtagt tggacttagg gaacaaagga 5820
acctttaata gaaattggac agcaagaaag cgagtcaggc accgggcttg cgggtcatgc 5880
accaggtgcg cggtccttcg ggcacctcga cgtcggcggt gacggtgaag ccgagccgct 5940
cgtagaaggg gaggttgcgg ggcgcggatg tctccaggaa ggcgggcacc ccggcgcgct 6000
cggccgcctc cactccgggg agcacgacgg cgctgcccag acccttgccc tggtggtcgg 6060
gcgacacgcc gacggtggcc aggaaccacg cgggctcctt gggccggtgc ggcgccagga 6120
ggccttccat ctgttgctgc gcggccagcc gggaaccgct caactcggcc atgcgcgggc 6180
cgatctcggc gaacaccgcc cccgcttcga cgctctccgg cgtggtccag accgccaccg 6240
cggcgccgtc gtccgcgacc cacaccttgc cgatgtcgag cccgacgcgc gtgaggaaga 6300
gttcttgcag ctcggtgacc cgctcgatgt ggcggtccgg atcgacggtg tggcgcgtgg 6360
cggggtagtc ggcgaacgcg gcggcgaggg tgcgtacggc cctggggacg tcgtcgcggg 6420
tggcgaggcg caccgtgggc ttgtactcgg tcatggtggc ggacgaaagg cccggagatg 6480
aggaagagga gaacagcgcg gcagacgtgc gcttttgaag cgtgcagaat gccgggcctc 6540
cggaggacct tcgggcgccc gccccgcccc tgagcccgcc cctgagcccg cccccggacc 6600
caccccttcc cagcctctga gcccagaaag cgaaggagca aagctgctat tggccgctgc 6660
cccaaaggcc tacccgcttc cattgctcag cggtgctgtc catctgcacg agactagtga 6720
gtcgtgctac ttccatttgt cacgtcctgc acgacgcgag ctgcggggcg ggggggaact 6780
tcctgactag gggaggagta gaaggtggcg cgaaggggcc accaaagaac ggagccggtt 6840
ggcgcctacc ggtggatgtg gaatgtgtgc gaggccagag gccacttgtg tagcgccaag 6900
tgcccagcgg ggctgctaaa gcgcatgctc cagactgcct tgggaaaagc gcctccccta 6960
cccggtagag aaacttgatc tgtcgccgca attcaaactt cgtgaggctc cggtgcccgt 7020
cagtgacctg ctatactctg gagacgactt acggtaaatg gcccgcctgg ctgaccgccc 7080
aacgaccccc gcccattgac gtcaataatg acgtatgttc ccatagtaac gccaataggg 7140
actttccatt gacgtcaatg ggtggagtat ttacggtaaa ctgcccactt ggcagtacat 7200
caagtgtatc atatgccaag tccgccccct attgacgtca atgacggtaa atggcccgcc 7260
tggcattatg cccagtacat gaccttacgg gactttccta cttggcagta catctacgta 7320
ttagtcatcg ctattaccat gctgatgcgg ttttggcagt acaccaatgg gcgtggatag 7380
cggtttgact cacggggatt tccaagtctc caccccattg acgtcaatgg gagtttgttt 7440
tggcaccaaa atcaacggga ctttccaaaa tgtcgtaata accccgcccc gttgacgcaa 7500
atgggcggta ggcgtgtacg gtgggaggtc tatataagca gagctcgttt agtgaaccgt 7560
cagatcgcct ggagaggcca tccacgctgt tttgacctcc atagtggaca ccgggaccga 7620
tccagcctcc gcgtctcagg 7640
<210> 84
<211> 438
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide, MICA-Fc
<400> 84
Glu Pro His Ser Leu Arg Tyr Asn Leu Thr Val Leu Ser Trp Asp Gly
1 5 10 15
Ser Val Gln Ser Gly Phe Leu Thr Glu Val His Leu Asp Gly Gln Pro
20 25 30
Phe Leu Arg Cys Asp Arg Gln Lys Cys Arg Ala Lys Pro Gln Gly Gln
35 40 45
Trp Ala Glu Asp Val Leu Gly Asn Lys Thr Trp Asp Arg Glu Thr Arg
50 55 60
Asp Leu Thr Gly Asn Gly Lys Asp Leu Arg Met Thr Leu Ala His Ile
65 70 75 80
Lys Asp Gln Lys Glu Gly Leu His Ser Leu Gln Glu Ile Arg Val Cys
85 90 95
Glu Ile His Glu Asp Asn Ser Thr Arg Ser Ser Gln His Phe Tyr Tyr
100 105 110
Asp Gly Glu Leu Phe Leu Ser Gln Asn Leu Glu Thr Lys Glu Trp Thr
115 120 125
Met Pro Gln Ser Ser Arg Ala Gln Thr Leu Ala Met Asn Val Arg Asn
130 135 140
Phe Leu Lys Glu Asp Ala Met Lys Thr Lys Thr His Tyr His Ala Met
145 150 155 160
His Ala Asp Cys Leu Gln Glu Leu Arg Arg Tyr Leu Lys Ser Gly Val
165 170 175
Val Leu Arg Arg Thr Val Pro Pro Met Val Asn Val Thr Arg Ser Glu
180 185 190
Ala Ser Glu Gly Asn Ile Thr Val Thr Cys Arg Ala Ser Gly Phe Tyr
195 200 205
Pro Trp Asn Ile Thr Leu Ser Trp Arg Gln Asp Gly Val Ser Leu Ser
210 215 220
His Asp Thr Gln Gln Trp Gly Asp Val Leu Pro Asp Gly Asn Gly Thr
225 230 235 240
Tyr Gln Thr Trp Val Ala Thr Arg Ile Ser Gln Gly Glu Glu Gln Arg
245 250 255
Phe Thr Cys Tyr Met Glu His Ser Gly Asn His Ser Thr His Pro Val
260 265 270
Pro Ser Gly Lys Ile Glu Gly Arg Met Asp Pro Lys Ser Cys Asp Lys
275 280 285
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
290 295 300
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
305 310 315 320
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
325 330 335
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
340 345 350
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
355 360 365
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
370 375 380
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
385 390 395 400
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
405 410 415
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
420 425 430
Cys Leu Val Lys Gly Phe
435
<210> 85
<211> 513
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide, MICwed-Fc
<400> 85
Glu Pro His Ser Leu Arg Tyr Asn Leu Thr Val Leu Ser Trp Asp Gly
1 5 10 15
Ser Val Gln Ser Gly Phe Leu Thr Glu Val His Leu Asp Gly Gln Pro
20 25 30
Phe Leu Arg Cys Asp Arg Gln Lys Cys Arg Ala Lys Pro Gln Gly Gln
35 40 45
Trp Ala Glu Asp Val Leu Gly Asn Lys Thr Trp Asp Arg Glu Thr Arg
50 55 60
Asp Leu Thr Gly Trp Gly Lys Asp Leu Arg Met Thr Leu Ala His Ile
65 70 75 80
Lys Asp Gln Lys Glu Gly Leu His Ser Leu Gln Glu Ile Arg Val Cys
85 90 95
Glu Ile His Glu Asp Asn Ser Thr Arg Ser Ser Gln His Phe Tyr Tyr
100 105 110
Asp Gly Glu Leu Phe Leu Ser Gln Asn Leu Glu Thr Lys Glu Trp Thr
115 120 125
Met Pro Gln Ser Ser Arg Ala Gln Thr Leu Ala Met Asn Val Arg Asn
130 135 140
Phe Leu Lys Glu Asp Ala Met Glu Thr Asp Thr His Tyr His Ala Met
145 150 155 160
His Ala Asp Cys Leu Gln Glu Leu Arg Arg Tyr Leu Lys Ser Gly Val
165 170 175
Val Leu Arg Arg Thr Val Pro Pro Met Val Asn Val Thr Arg Ser Glu
180 185 190
Ala Ser Glu Gly Asn Ile Thr Val Thr Cys Arg Ala Ser Gly Phe Tyr
195 200 205
Pro Trp Asn Ile Thr Leu Ser Trp Arg Gln Asp Gly Val Ser Leu Ser
210 215 220
His Asp Thr Gln Gln Trp Gly Asp Val Leu Pro Asp Gly Asn Gly Thr
225 230 235 240
Tyr Gln Thr Trp Val Ala Thr Arg Ile Ser Gln Gly Glu Glu Gln Arg
245 250 255
Phe Thr Cys Tyr Met Glu His Ser Gly Asn His Ser Thr His Pro Val
260 265 270
Pro Ser Gly Lys Ile Glu Gly Arg Met Asp Pro Lys Ser Cys Asp Lys
275 280 285
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
290 295 300
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
305 310 315 320
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
325 330 335
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
340 345 350
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
355 360 365
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
370 375 380
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
385 390 395 400
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
405 410 415
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
420 425 430
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
435 440 445
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
450 455 460
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
465 470 475 480
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
485 490 495
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
500 505 510
Lys
<210> 86
<211> 513
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide, MICv25-Fc
<400> 86
Glu Pro His Ser Leu Arg Tyr Asn Leu Thr Val Leu Ser Trp Asp Gly
1 5 10 15
Ser Val Gln Ser Gly Phe Leu Thr Glu Val His Leu Asp Gly Gln Pro
20 25 30
Phe Leu Arg Cys Asp Arg Gln Lys Cys Arg Ala Lys Pro Gln Gly Gln
35 40 45
Trp Ala Glu Asp Val Leu Gly Asn Lys Thr Trp Asp Arg Glu Thr Arg
50 55 60
Asp Leu Thr Gly Trp Gly Lys Asp Leu Arg Met Thr Leu Ala His Ile
65 70 75 80
Lys Asp Gln Lys Glu Gly Leu His Ser Leu Gln Glu Ile Arg Val Cys
85 90 95
Glu Ile His Glu Asp Asn Ser Thr Arg Ser Ser Gln His Phe Tyr Tyr
100 105 110
Asp Gly Glu Leu Phe Leu Ser Gln Asn Leu Glu Thr Leu Glu Trp Thr
115 120 125
Met Pro Gln Ser Ser Arg Ala Gln Thr Leu Ala Met Asn Val Arg Asn
130 135 140
Phe Leu Lys Glu Asp Ala Met Glu Thr Asp Thr His Tyr His Ala Met
145 150 155 160
Arg Ala Asp Cys Leu Ser Glu Leu Arg Arg Tyr Leu Lys Ser Gly Val
165 170 175
Val Leu Arg Arg Thr Val Pro Pro Met Val Asn Val Thr Arg Ser Glu
180 185 190
Ala Ser Glu Gly Asn Ile Thr Val Thr Cys Arg Ala Ser Gly Phe Tyr
195 200 205
Pro Trp Asn Ile Thr Leu Ser Trp Arg Gln Asp Gly Val Ser Leu Ser
210 215 220
His Asp Thr Gln Gln Trp Gly Asp Val Leu Pro Asp Gly Asn Gly Thr
225 230 235 240
Tyr Gln Thr Trp Val Ala Thr Arg Ile Ser Gln Gly Glu Glu Gln Arg
245 250 255
Phe Thr Cys Tyr Met Glu His Ser Gly Asn His Ser Thr His Pro Val
260 265 270
Pro Ser Gly Lys Ile Glu Gly Arg Met Asp Pro Lys Ser Cys Asp Lys
275 280 285
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
290 295 300
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
305 310 315 320
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
325 330 335
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
340 345 350
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
355 360 365
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
370 375 380
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
385 390 395 400
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
405 410 415
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
420 425 430
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
435 440 445
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
450 455 460
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
465 470 475 480
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
485 490 495
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
500 505 510
Lys
<210> 87
<211> 186
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide, ULBP2 R80W
<400> 87
Ala Ala Glu Pro His Ser Leu Ser Tyr Asp Ile Thr Val Ile Pro Lys
1 5 10 15
Phe Arg Pro Gly Pro Arg Trp Cys Ala Val Gln Gly Gln Val Asp Glu
20 25 30
Lys Thr Phe Leu His Tyr Asp Cys Gly Asn Lys Thr Val Thr Pro Val
35 40 45
Ser Pro Leu Gly Lys Lys Leu Asn Val Thr Thr Ala Trp Lys Ala Gln
50 55 60
Asn Pro Val Leu Arg Glu Val Val Asp Ile Leu Thr Glu Gln Leu Trp
65 70 75 80
Asp Ile Gln Leu Glu Asn Tyr Thr Pro Lys Glu Pro Leu Thr Leu Gln
85 90 95
Ala Arg Met Ser Cys Glu Gln Lys Ala Glu Gly His Ser Ser Gly Ser
100 105 110
Trp Gln Phe Ser Phe Asp Gly Gln Ile Phe Leu Leu Phe Asp Ser Glu
115 120 125
Lys Arg Met Trp Thr Thr Val His Pro Gly Ala Arg Lys Met Lys Glu
130 135 140
Lys Trp Glu Asn Asp Lys Val Val Ala Met Ser Phe His Tyr Phe Ser
145 150 155 160
Met Gly Asp Cys Ile Gly Trp Leu Glu Asp Phe Leu Met Gly Met Asp
165 170 175
Ser Thr Leu Glu Pro Ser Ala Gly Ala Pro
180 185
<210> 88
<211> 186
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide, ULBP2 V151D
<400> 88
Ala Ala Glu Pro His Ser Leu Ser Tyr Asp Ile Thr Val Ile Pro Lys
1 5 10 15
Phe Arg Pro Gly Pro Arg Trp Cys Ala Val Gln Gly Gln Val Asp Glu
20 25 30
Lys Thr Phe Leu His Tyr Asp Cys Gly Asn Lys Thr Val Thr Pro Val
35 40 45
Ser Pro Leu Gly Lys Lys Leu Asn Val Thr Thr Ala Trp Lys Ala Gln
50 55 60
Asn Pro Val Leu Arg Glu Val Val Asp Ile Leu Thr Glu Gln Leu Arg
65 70 75 80
Asp Ile Gln Leu Glu Asn Tyr Thr Pro Lys Glu Pro Leu Thr Leu Gln
85 90 95
Ala Arg Met Ser Cys Glu Gln Lys Ala Glu Gly His Ser Ser Gly Ser
100 105 110
Trp Gln Phe Ser Phe Asp Gly Gln Ile Phe Leu Leu Phe Asp Ser Glu
115 120 125
Lys Arg Met Trp Thr Thr Val His Pro Gly Ala Arg Lys Met Lys Glu
130 135 140
Lys Trp Glu Asn Asp Lys Asp Val Ala Met Ser Phe His Tyr Phe Ser
145 150 155 160
Met Gly Asp Cys Ile Gly Trp Leu Glu Asp Phe Leu Met Gly Met Asp
165 170 175
Ser Thr Leu Glu Pro Ser Ala Gly Ala Pro
180 185
<210> 89
<211> 184
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide, ULBP3 R162G
<400> 89
Ala Ala Glu Pro His Ser Leu Trp Tyr Asn Phe Thr Ile Ile His Leu
1 5 10 15
Pro Arg His Gly Gln Gln Trp Cys Glu Val Gln Ser Gln Val Asp Gln
20 25 30
Lys Asn Phe Leu Ser Tyr Asp Cys Gly Ser Asp Lys Val Leu Ser Met
35 40 45
Gly His Leu Glu Glu Gln Leu Tyr Ala Thr Asp Ala Trp Gly Lys Gln
50 55 60
Leu Glu Met Leu Arg Glu Val Gly Gln Arg Leu Arg Leu Glu Leu Ala
65 70 75 80
Asp Thr Glu Leu Glu Asp Phe Thr Pro Ser Gly Pro Leu Thr Leu Gln
85 90 95
Val Arg Met Ser Cys Glu Ser Glu Ala Asp Gly Tyr Ile Arg Gly Ser
100 105 110
Trp Gln Phe Ser Phe Asp Gly Arg Lys Phe Leu Leu Phe Asp Ser Asn
115 120 125
Asn Arg Lys Trp Thr Val Val His Ala Gly Ala Arg Arg Met Lys Glu
130 135 140
Lys Trp Glu Lys Asp Ser Gly Leu Thr Thr Phe Phe Lys Met Val Ser
145 150 155 160
Met Gly Asp Cys Lys Ser Trp Leu Arg Asp Phe Leu Met His Arg Lys
165 170 175
Lys Arg Leu Glu Pro Thr Ala Pro
180
<210> 90
<211> 182
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide, MICA25.17
<400> 90
Glu Pro His Ser Leu Arg Tyr Asn Leu Thr Val Leu Ser Trp Asp Gly
1 5 10 15
Ser Val Gln Ser Gly Phe Leu Thr Glu Val His Leu Asp Gly Gln Pro
20 25 30
Phe Leu Arg Cys Asp Arg Gln Lys Cys Arg Ala Lys Pro Gln Gly Gln
35 40 45
Trp Ala Glu Asp Val Leu Gly Asn Lys Thr Trp Asp Arg Glu Thr Arg
50 55 60
Asp Leu Thr Gly Trp Gly Thr Thr Leu Leu Met Thr Leu Ala His Ile
65 70 75 80
Lys Asp Gln Lys Glu Gly Leu His Ser Leu Gln Glu Ile Arg Val Cys
85 90 95
Glu Ile His Glu Asp Asn Ser Thr Arg Ser Ser Gln His Phe Tyr Tyr
100 105 110
Asp Gly Glu Leu Phe Leu Ser Gln Asn Leu Glu Thr Leu Glu Trp Thr
115 120 125
Met Pro Gln Ser Ser Arg Ala Gln Thr Leu Ala Met Asn Val Arg Asn
130 135 140
Phe Leu Lys Glu Asp Ala Met Glu Thr Asp Ile Gly Tyr Arg Leu Met
145 150 155 160
Arg Ala Asp Cys Leu Ser Glu Leu Arg Arg Tyr Leu Lys Ser Gly Val
165 170 175
Val Leu Arg Arg Thr Val
180
<210> 91
<211> 182
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide, MICA25.18
<400> 91
Glu Pro His Ser Leu Arg Tyr Asn Leu Thr Val Leu Ser Trp Asp Gly
1 5 10 15
Ser Val Gln Ser Gly Phe Leu Thr Glu Val His Leu Asp Gly Gln Pro
20 25 30
Phe Leu Arg Cys Asp Arg Gln Lys Cys Arg Ala Lys Pro Gln Gly Gln
35 40 45
Trp Ala Glu Asp Val Leu Gly Asn Lys Thr Trp Asp Arg Glu Thr Arg
50 55 60
Asp Leu Thr Gly Trp Gly Thr Phe Leu Arg Met Thr Leu Ala His Ile
65 70 75 80
Lys Asp Gln Lys Glu Gly Leu His Ser Leu Gln Glu Ile Arg Val Cys
85 90 95
Glu Ile His Glu Asp Asn Ser Thr Arg Ser Ser Gln His Phe Tyr Tyr
100 105 110
Asp Gly Glu Leu Phe Leu Ser Gln Asn Leu Glu Thr Leu Glu Trp Thr
115 120 125
Met Pro Gln Ser Ser Arg Ala Gln Thr Leu Ala Met Asn Val Arg Asn
130 135 140
Phe Leu Lys Glu Asp Ala Met Glu Thr Asp Arg Ser Gly Leu Leu Met
145 150 155 160
Arg Ala Asp Cys Leu Ser Glu Leu Arg Arg Tyr Leu Lys Ser Gly Val
165 170 175
Val Leu Arg Arg Thr Val
180
<210> 92
<211> 186
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide, ULBP2.S1
<400> 92
Ala Ala Glu Pro His Ser Leu Ser Tyr Asp Ile Thr Val Ile Pro Lys
1 5 10 15
Phe Arg Pro Gly Pro Arg Trp Cys Ala Val Gln Gly Gln Val Asp Glu
20 25 30
Lys Thr Phe Leu His Tyr Asp Cys Gly Asn Lys Thr Val Thr Pro Val
35 40 45
Ser Pro Leu Gly Lys Lys Leu Asn Val Thr Thr Ala Trp Lys Ala Gln
50 55 60
Asn Pro Val Leu Arg Glu Val Val Asp Ile Leu Thr Glu Gln Leu Trp
65 70 75 80
Asp Ile Gln Leu Glu Asn Tyr Thr Pro Lys Glu Pro Leu Thr Leu Gln
85 90 95
Ala Arg Met Ser Cys Glu Gln Lys Ala Glu Gly His Ser Ser Gly Ser
100 105 110
Trp Gln Phe Ser Phe Asp Gly Gln Ile Phe Leu Leu Phe Asp Ser Glu
115 120 125
Lys Arg Met Trp Thr Thr Val His Pro Gly Ala Arg Lys Met Lys Glu
130 135 140
Lys Trp Glu Asn Asp Lys Val Val Ala Thr Thr Leu Tyr Thr Trp Ser
145 150 155 160
Met Gly Asp Cys Ile Gly Trp Leu Glu Asp Phe Leu Met Gly Met Asp
165 170 175
Ser Thr Leu Glu Pro Ser Ala Gly Ala Pro
180 185
<210> 93
<211> 186
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide, ULBP2.S2
<400> 93
Ala Ala Glu Pro His Ser Leu Ser Tyr Asp Ile Thr Val Ile Pro Lys
1 5 10 15
Phe Arg Pro Gly Pro Arg Trp Cys Ala Val Gln Gly Gln Val Asp Glu
20 25 30
Lys Thr Phe Leu His Tyr Asp Cys Gly Asn Lys Thr Val Thr Pro Val
35 40 45
Ser Pro Leu Gly Lys Lys Leu Asn Val Thr Thr Ala Trp Lys Ala Gln
50 55 60
Asn Pro Val Leu Arg Glu Val Val Asp Ile Leu Thr Glu Gln Leu Trp
65 70 75 80
Asp Ile Gln Leu Glu Asn Tyr Thr Pro Lys Glu Pro Leu Thr Leu Gln
85 90 95
Ala Arg Met Ser Cys Glu Gln Lys Ala Glu Gly His Ser Ser Gly Ser
100 105 110
Trp Gln Phe Ser Phe Asp Gly Gln Ile Phe Leu Leu Phe Asp Ser Glu
115 120 125
Lys Arg Met Trp Thr Thr Val His Pro Gly Ala Arg Lys Met Lys Glu
130 135 140
Lys Trp Glu Asn Asp Lys Val Val Ala Thr Leu Met Arg Ile Trp Ser
145 150 155 160
Met Gly Asp Cys Ile Gly Trp Leu Glu Asp Phe Leu Met Gly Met Asp
165 170 175
Ser Thr Leu Glu Pro Ser Ala Gly Ala Pro
180 185
<210> 94
<211> 186
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide, ULBP2.S3
<400> 94
Ala Ala Glu Pro His Ser Leu Ser Tyr Asp Ile Thr Val Ile Pro Lys
1 5 10 15
Phe Arg Pro Gly Pro Arg Trp Cys Ala Val Gln Gly Gln Val Asp Glu
20 25 30
Lys Thr Phe Leu His Tyr Asp Cys Gly Asn Lys Thr Val Thr Pro Val
35 40 45
Ser Pro Leu Gly Lys Lys Leu Asn Val Thr Thr Ala Trp Lys Ala Gln
50 55 60
Asn Pro Val Leu Arg Glu Val Val Asp Ile Leu Thr Glu Gln Leu Trp
65 70 75 80
Asp Ile Gln Leu Glu Asn Tyr Thr Pro Lys Glu Pro Leu Thr Leu Gln
85 90 95
Ala Arg Met Ser Cys Glu Gln Lys Ala Glu Gly His Ser Ser Gly Ser
100 105 110
Trp Gln Phe Ser Phe Asp Gly Gln Ile Phe Leu Leu Phe Asp Ser Glu
115 120 125
Lys Arg Met Trp Thr Thr Val His Pro Gly Ala Arg Lys Met Lys Glu
130 135 140
Lys Trp Glu Asn Asp Lys Val Val Ala Thr Lys Leu Tyr Leu Trp Ser
145 150 155 160
Met Gly Asp Cys Ile Gly Trp Leu Glu Asp Phe Leu Met Gly Met Asp
165 170 175
Ser Thr Leu Glu Pro Ser Ala Gly Ala Pro
180 185
<210> 95
<211> 184
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide, ULBP3.S1
<400> 95
Ala Ala Glu Pro His Ser Leu Trp Tyr Asn Phe Thr Ile Ile His Leu
1 5 10 15
Pro Arg His Gly Gln Gln Trp Cys Glu Val Gln Ser Gln Val Asp Gln
20 25 30
Lys Asn Phe Leu Ser Tyr Asp Cys Gly Ser Asp Lys Val Leu Ser Met
35 40 45
Gly His Leu Glu Glu Gln Leu Tyr Ala Thr Asp Ala Trp Gly Lys Gln
50 55 60
Leu Glu Met Leu Arg Glu Val Gly Gln Arg Leu Arg Leu Glu Leu Ala
65 70 75 80
Asp Thr Glu Leu Glu Asp Phe Thr Pro Ser Gly Pro Leu Thr Leu Gln
85 90 95
Val Arg Met Ser Cys Glu Ser Glu Ala Asp Gly Tyr Ile Arg Gly Ser
100 105 110
Trp Gln Phe Ser Phe Asp Gly Arg Lys Phe Leu Leu Phe Asp Ser Asn
115 120 125
Asn Arg Lys Trp Thr Val Val His Ala Gly Ala Arg Arg Met Lys Glu
130 135 140
Lys Trp Glu Lys Asp Ser Gly Leu Thr Thr Asp Leu Ile Arg Arg Ser
145 150 155 160
Met Gly Asp Cys Lys Ser Trp Leu Arg Asp Phe Leu Met His Arg Lys
165 170 175
Lys Arg Leu Glu Pro Thr Ala Pro
180
<210> 96
<211> 184
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide ULBP3.S2
<400> 96
Ala Ala Glu Pro His Ser Leu Trp Tyr Asn Phe Thr Ile Ile His Leu
1 5 10 15
Pro Arg His Gly Gln Gln Trp Cys Glu Val Gln Ser Gln Val Asp Gln
20 25 30
Lys Asn Phe Leu Ser Tyr Asp Cys Gly Ser Asp Lys Val Leu Ser Met
35 40 45
Gly His Leu Glu Glu Gln Leu Tyr Ala Thr Asp Ala Trp Gly Lys Gln
50 55 60
Leu Glu Met Leu Arg Glu Val Gly Gln Arg Leu Arg Leu Glu Leu Ala
65 70 75 80
Asp Thr Glu Leu Glu Asp Phe Thr Pro Ser Gly Pro Leu Thr Leu Gln
85 90 95
Val Arg Met Ser Cys Glu Ser Glu Ala Asp Gly Tyr Ile Arg Gly Ser
100 105 110
Trp Gln Phe Ser Phe Asp Gly Arg Lys Phe Leu Leu Phe Asp Ser Asn
115 120 125
Asn Arg Lys Trp Thr Val Val His Ala Gly Ala Arg Arg Met Lys Glu
130 135 140
Lys Trp Glu Lys Asp Ser Gly Leu Thr Thr Tyr Phe Tyr Leu Arg Ser
145 150 155 160
Met Gly Asp Cys Lys Ser Trp Leu Arg Asp Phe Leu Met His Arg Lys
165 170 175
Lys Arg Leu Glu Pro Thr Ala Pro
180
<210> 97
<211> 657
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide, R3 HC25.17
<400> 97
Met Arg Pro Ile Val Leu Val Leu Leu Phe Ala Thr Ser Ala Leu Ala
1 5 10 15
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
20 25 30
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Ser Thr
35 40 45
Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
50 55 60
Gly Arg Ile Tyr Pro Thr Asn Gly Ser Thr Asn Tyr Ala Asp Ser Val
65 70 75 80
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
85 90 95
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
100 105 110
Ala Arg Thr Tyr Gly Ile Tyr Asp Leu Tyr Val Asp Tyr Thr Glu Tyr
115 120 125
Val Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala
130 135 140
Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser
145 150 155 160
Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe
165 170 175
Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly
180 185 190
Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu
195 200 205
Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr
210 215 220
Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys
225 230 235 240
Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro
245 250 255
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
260 265 270
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
275 280 285
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
290 295 300
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
305 310 315 320
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
325 330 335
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
340 345 350
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
355 360 365
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu
370 375 380
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
385 390 395 400
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
405 410 415
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
420 425 430
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
435 440 445
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
450 455 460
Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Ser Glu Pro His Ser
465 470 475 480
Leu Arg Tyr Asn Leu Thr Val Leu Ser Trp Asp Gly Ser Val Gln Ser
485 490 495
Gly Phe Leu Thr Glu Val His Leu Asp Gly Gln Pro Phe Leu Arg Cys
500 505 510
Asp Arg Gln Lys Cys Arg Ala Lys Pro Gln Gly Gln Trp Ala Glu Asp
515 520 525
Val Leu Gly Asn Lys Thr Trp Asp Arg Glu Thr Arg Asp Leu Thr Gly
530 535 540
Trp Gly Thr Thr Leu Leu Met Thr Leu Ala His Ile Lys Asp Gln Lys
545 550 555 560
Glu Gly Leu His Ser Leu Gln Glu Ile Arg Val Cys Glu Ile His Glu
565 570 575
Asp Asn Ser Thr Arg Ser Ser Gln His Phe Tyr Tyr Asp Gly Glu Leu
580 585 590
Phe Leu Ser Gln Asn Leu Glu Thr Leu Glu Trp Thr Met Pro Gln Ser
595 600 605
Ser Arg Ala Gln Thr Leu Ala Met Asn Val Arg Asn Phe Leu Lys Glu
610 615 620
Asp Ala Met Glu Thr Asp Ile Gly Tyr Arg Leu Met Arg Ala Asp Cys
625 630 635 640
Leu Ser Glu Leu Arg Arg Tyr Leu Lys Ser Gly Val Val Leu Arg Arg
645 650 655
Thr
<210> 98
<211> 656
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide, R3 HC.U2S3
<400> 98
Met Arg Pro Ile Val Leu Val Leu Leu Phe Ala Thr Ser Ala Leu Ala
1 5 10 15
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
20 25 30
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Ser Thr
35 40 45
Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
50 55 60
Gly Arg Ile Tyr Pro Thr Asn Gly Ser Thr Asn Tyr Ala Asp Ser Val
65 70 75 80
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
85 90 95
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
100 105 110
Ala Arg Thr Tyr Gly Ile Tyr Asp Leu Tyr Val Asp Tyr Thr Glu Tyr
115 120 125
Val Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala
130 135 140
Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser
145 150 155 160
Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe
165 170 175
Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly
180 185 190
Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu
195 200 205
Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr
210 215 220
Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys
225 230 235 240
Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro
245 250 255
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
260 265 270
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
275 280 285
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
290 295 300
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
305 310 315 320
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
325 330 335
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
340 345 350
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
355 360 365
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu
370 375 380
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
385 390 395 400
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
405 410 415
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
420 425 430
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
435 440 445
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
450 455 460
Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Ser Glu Pro His Ser
465 470 475 480
Leu Ser Tyr Asp Ile Thr Val Ile Pro Lys Phe Arg Pro Gly Pro Arg
485 490 495
Trp Cys Ala Val Gln Gly Gln Val Asp Glu Lys Thr Phe Leu His Tyr
500 505 510
Asp Cys Gly Asn Lys Thr Val Thr Pro Val Ser Pro Leu Gly Lys Lys
515 520 525
Leu Asn Val Thr Thr Ala Trp Lys Ala Gln Asn Pro Val Leu Arg Glu
530 535 540
Val Val Asp Ile Leu Thr Glu Gln Leu Trp Asp Ile Gln Leu Glu Asn
545 550 555 560
Tyr Thr Pro Lys Glu Pro Leu Thr Leu Gln Ala Arg Met Ser Cys Glu
565 570 575
Gln Lys Ala Glu Gly His Ser Ser Gly Ser Trp Gln Phe Ser Phe Asp
580 585 590
Gly Gln Ile Phe Leu Leu Phe Asp Ser Glu Lys Arg Met Trp Thr Thr
595 600 605
Val His Pro Gly Ala Arg Lys Met Lys Glu Lys Trp Glu Asn Asp Lys
610 615 620
Val Val Ala Thr Lys Leu Tyr Leu Trp Ser Met Gly Asp Cys Ile Gly
625 630 635 640
Trp Leu Glu Asp Phe Leu Met Gly Met Asp Ser Thr Leu Glu Pro Ser
645 650 655
<210> 99
<211> 171
<212> PRT
<213> Homo sapiens MICA
<400> 99
His Ser Leu Arg Tyr Asn Leu Thr Val Leu Ser Gly Asp Gly Ser Val
1 5 10 15
Gln Ser Gly Phe Leu Ala Glu Val His Leu Asp Gly Gln Pro Phe Leu
20 25 30
Arg Cys Asp Arg Gln Lys Cys Arg Ala Lys Pro Gln Gly Gln Trp Ala
35 40 45
Glu Asp Val Leu Gly Asn Lys Thr Trp Asp Arg Glu Thr Arg Asp Leu
50 55 60
Thr Gly Asn Gly Lys Asp Leu Arg Met Thr Leu Ala His Ile Lys Asp
65 70 75 80
Gln Lys Glu Gly Leu His Ser Leu Gln Glu Ile Arg Val Cys Glu Ile
85 90 95
His Glu Asp Asn Ser Thr Arg Ser Ser Gln His Phe Tyr Tyr Asp Gly
100 105 110
Glu Leu Phe Leu Ser Gln Asn Leu Glu Thr Glu Glu Trp Thr Met Pro
115 120 125
Gln Ser Ser Arg Ala Gln Thr Leu Ala Met Asn Val Arg Asn Phe Leu
130 135 140
Lys Glu Asp Ala Met Lys Thr Lys Thr His Tyr His Ala Met His Ala
145 150 155 160
Asp Cys Leu Gln Glu Leu Arg Arg Tyr Leu Lys
165 170
<210> 100
<211> 169
<212> PRT
<213> Homo sapiens ULBP1
<400> 100
His Cys Leu Cys Tyr Asp Phe Ile Ile Thr Pro Lys Ser Arg Pro Glu
1 5 10 15
Pro Gln Trp Cys Glu Val Gln Gly Leu Val Asp Glu Arg Pro Phe Leu
20 25 30
His Tyr Asp Cys Val Asn His Lys Ala Lys Ala Phe Ala Ser Leu Gly
35 40 45
Lys Lys Val Asn Val Thr Lys Thr Trp Glu Glu Gln Thr Glu Thr Leu
50 55 60
Arg Asp Val Val Asp Phe Leu Lys Gly Gln Leu Leu Asp Ile Gln Val
65 70 75 80
Glu Asn Leu Ile Pro Ile Glu Pro Leu Thr Leu Gln Ala Arg Met Ser
85 90 95
Cys Glu His Glu Ala His Gly His Gly Arg Gly Ser Trp Gln Phe Leu
100 105 110
Phe Asn Gly Gln Lys Phe Leu Leu Phe Asp Ser Asn Asn Arg Lys Trp
115 120 125
Thr Ala Leu His Pro Gly Ala Lys Lys Met Thr Glu Lys Trp Glu Lys
130 135 140
Asn Arg Asp Val Thr Met Phe Phe Gln Lys Ile Ser Leu Gly Asp Cys
145 150 155 160
Lys Met Trp Leu Glu Glu Phe Leu Met
165
<210> 101
<211> 169
<212> PRT
<213> Homo sapiens ULBP2
<400> 101
His Ser Leu Cys Tyr Asp Ile Thr Val Ile Pro Lys Phe Arg Pro Gly
1 5 10 15
Pro Arg Trp Cys Ala Val Gln Gly Gln Val Asp Glu Lys Thr Phe Leu
20 25 30
His Tyr Asp Cys Gly Asn Lys Thr Val Thr Pro Val Ser Pro Leu Gly
35 40 45
Lys Lys Leu Asn Val Thr Thr Ala Trp Lys Ala Gln Asn Pro Val Leu
50 55 60
Arg Glu Val Val Asp Ile Leu Thr Glu Gln Leu Arg Asp Ile Gln Leu
65 70 75 80
Glu Asn Tyr Thr Pro Lys Glu Pro Leu Thr Leu Gln Ala Arg Met Ser
85 90 95
Cys Glu Gln Lys Ala Glu Gly His Ser Ser Gly Ser Trp Gln Phe Ser
100 105 110
Phe Asp Gly Gln Ile Phe Leu Leu Phe Asp Ser Glu Lys Arg Met Trp
115 120 125
Thr Thr Val His Pro Gly Ala Arg Lys Met Lys Glu Lys Trp Glu Asn
130 135 140
Asp Lys Val Val Ala Met Ser Phe His Tyr Phe Ser Met Gly Asp Cys
145 150 155 160
Ile Gly Trp Leu Glu Asp Phe Leu Met
165
<210> 102
<211> 169
<212> PRT
<213> Homo sapiens ULBP3
<400> 102
His Ser Leu Trp Tyr Asn Phe Thr Ile Ile His Leu Pro Arg His Gly
1 5 10 15
Gln Gln Trp Cys Glu Val Gln Ser Gln Val Asp Gln Lys Asn Phe Leu
20 25 30
Ser Tyr Asp Cys Gly Ser Asp Lys Val Leu Ser Met Gly His Leu Glu
35 40 45
Glu Gln Leu Tyr Ala Thr Asp Ala Trp Gly Lys Gln Leu Glu Met Leu
50 55 60
Arg Glu Val Gly Gln Arg Leu Arg Leu Glu Leu Ala Asp Thr Glu Leu
65 70 75 80
Glu Asp Phe Thr Pro Ser Gly Pro Leu Thr Leu Gln Val Arg Met Ser
85 90 95
Cys Glu Cys Glu Ala Asp Gly Tyr Ile Arg Gly Ser Trp Gln Phe Ser
100 105 110
Phe Asp Gly Arg Lys Phe Leu Leu Phe Asp Ser Asn Asn Arg Lys Trp
115 120 125
Thr Val Val His Ala Gly Ala Arg Arg Met Lys Glu Lys Trp Glu Lys
130 135 140
Asp Ser Gly Leu Thr Thr Phe Phe Lys Met Val Ser Met Arg Asp Cys
145 150 155 160
Lys Ser Trp Leu Arg Asp Phe Leu Met
165
<210> 103
<211> 168
<212> PRT
<213> Homo sapiens ULBP4
<400> 103
His Ser Leu Cys Phe Asn Phe Thr Ile Lys Ser Leu Ser Arg Pro Gly
1 5 10 15
Gln Pro Trp Cys Glu Ala Gln Val Phe Leu Asn Lys Asn Leu Phe Leu
20 25 30
Gln Tyr Asn Ser Asp Asn Asn Met Val Lys Pro Leu Gly Leu Leu Gly
35 40 45
Lys Lys Val Tyr Ala Thr Ser Thr Trp Gly Glu Leu Thr Gln Thr Leu
50 55 60
Gly Glu Val Gly Arg Asp Leu Arg Met Leu Leu Cys Asp Ile Lys Pro
65 70 75 80
Gln Ile Lys Thr Ser Asp Pro Ser Thr Leu Gln Val Glu Met Phe Cys
85 90 95
Gln Arg Glu Ala Glu Arg Cys Thr Gly Ala Ser Trp Gln Phe Ala Thr
100 105 110
Asn Gly Glu Lys Ser Leu Leu Phe Asp Ala Met Asn Met Thr Trp Thr
115 120 125
Val Ile Asn His Glu Ala Ser Lys Ile Lys Glu Thr Trp Lys Lys Asp
130 135 140
Arg Gly Leu Glu Lys Tyr Phe Arg Lys Leu Ser Lys Gly Asp Cys Asp
145 150 155 160
His Trp Leu Arg Glu Phe Leu Gly
165
<210> 104
<211> 169
<212> PRT
<213> Homo sapiens ULBP5
<400> 104
His Ser Leu Cys Tyr Asp Ile Thr Val Ile Pro Lys Phe Arg Pro Gly
1 5 10 15
Pro Arg Trp Cys Ala Val Gln Gly Gln Val Asp Glu Lys Thr Phe Leu
20 25 30
His Tyr Asp Cys Gly Ser Lys Thr Val Thr Pro Val Ser Pro Leu Gly
35 40 45
Lys Lys Leu Asn Val Thr Thr Ala Trp Lys Ala Gln Asn Pro Val Leu
50 55 60
Arg Glu Val Val Asp Ile Leu Thr Glu Gln Leu Leu Asp Ile Gln Leu
65 70 75 80
Glu Asn Tyr Ile Pro Lys Glu Pro Leu Thr Leu Gln Ala Arg Met Ser
85 90 95
Cys Glu Gln Lys Ala Glu Gly His Gly Ser Gly Ser Trp Gln Leu Ser
100 105 110
Phe Asp Gly Gln Ile Phe Leu Leu Phe Asp Ser Glu Asn Arg Met Trp
115 120 125
Thr Thr Val His Pro Gly Ala Arg Lys Met Lys Glu Lys Trp Glu Asn
130 135 140
Asp Lys Asp Met Thr Met Ser Phe His Tyr Ile Ser Met Gly Asp Cys
145 150 155 160
Thr Gly Trp Leu Glu Asp Phe Leu Met
165
<210> 105
<211> 169
<212> PRT
<213> Homo sapiens ULBP6
<400> 105
His Ser Leu Cys Tyr Asp Ile Thr Val Ile Pro Lys Phe Arg Pro Gly
1 5 10 15
Pro Arg Trp Cys Ala Val Gln Gly Gln Val Asp Glu Lys Thr Phe Leu
20 25 30
His Tyr Asp Cys Gly Asn Lys Thr Val Thr Pro Val Ser Pro Leu Gly
35 40 45
Lys Lys Leu Asn Val Thr Thr Ala Trp Lys Ala Gln Asn Pro Val Leu
50 55 60
Arg Glu Val Val Asp Ile Leu Thr Glu Gln Leu Leu Asp Ile Gln Leu
65 70 75 80
Glu Asn Tyr Thr Pro Lys Glu Pro Leu Thr Leu Gln Ala Arg Met Ser
85 90 95
Cys Glu Gln Lys Ala Glu Gly His Ser Ser Gly Ser Trp Gln Phe Ser
100 105 110
Ile Asp Gly Gln Thr Phe Leu Leu Phe Asp Ser Glu Lys Arg Met Trp
115 120 125
Thr Thr Val His Pro Gly Ala Arg Lys Met Lys Glu Lys Trp Glu Asn
130 135 140
Asp Lys Asp Val Ala Met Ser Phe His Tyr Ile Ser Met Gly Asp Cys
145 150 155 160
Ile Gly Trp Leu Glu Asp Phe Leu Met
165
Claims (20)
- 천연 α1-α2 도메인에 대하여 80% 이상의 동일성을 포함하는 천연 NKG2D 리간드 분자의 비-천연의 개질된 α1-α2 도메인으로서, 여기서 상기 개질된 α1-α2 도메인은 천연 α1-α2 도메인에서 대체된 하나 이상의 아미노산을 갖고, 상기 개질은 비-천연 NKG2D 수용체 엑토도메인에 대한 결합 친화성을 증가시키고, 비-천연 NKG2D 수용체의 엑토도메인의 천연 NKG2D 리간드에 대한 친화성은 천연 NKG2D 수용체 엑토도메인의 천연 NKG2D 리간드에 대한 친화성보다 더 적은, 비-천연의 개질된 α1-α2 도메인.
- 제 1 항에 있어서, 천연 NKG2D 리간드가 SEQ ID NO: 36, 43 및 49 내지 54 중 임의의 하나인, 비-천연의 개질된 α1-α2 도메인.
- 제 1 항에 있어서, 천연 α1-α2 도메인에서 대체된 아미노산이 SEQ ID NO: 36 또는 43 의 위치 69, 71, 72, 74, 125, 152, 154, 155, 156, 157, 158, 159 및 161 중 셋 이상에 존재하는, 비-천연의 개질된 α1-α2 도메인.
- 제 3 항에 있어서, SEQ ID NO.: 90 또는 91 의 아미노산 서열을 포함하는, 비-천연의 개질된 α1-α2 도메인.
- 제 1 항에 있어서, 천연 α1-α2 도메인에서 대체된 아미노산이 SEQ ID NO.: 16 의 위치 8, 80, 151, 154, 155, 156, 157, 158 및 159 중 셋 이상에 존재하는, 비-천연의 개질된 α1-α2 도메인.
- 제 1 항에 있어서, 천연 α1-α2 도메인에서 대체된 아미노산이 SEQ ID NO.: 17 의 위치 103, 155, 156, 157, 158, 159, 162 및 165 중 셋 이상에 존재하는, 비-천연의 개질된 α1-α2 도메인.
- 제 5 항에 있어서, SEQ ID NO.: 92, 93 또는 94 의 아미노산 서열을 포함하는, 비-천연의 개질된 α1-α2 도메인.
- 제 6 항에 있어서, SEQ ID NO.: 95 또는 96 의 아미노산 서열을 포함하는, 비-천연의 개질된 α1-α2 도메인.
- 제 1 항에 있어서, 비-천연 NKG2D 수용체 엑토도메인이 SEQ ID NO: 75 의 아미노산 서열을 포함하지만, SEQ ID NO: 75 의 위치 73 에서의 타이로신이 또다른 아미노산으로 대체되어 있는, 비-천연의 개질된 α1-α2 도메인.
- 제 9 항에 있어서, 타이로신을 대체하는 아미노산이 알라닌인, 비-천연의 개질된 α1-α2 도메인.
- 제 1 항에 있어서, 부착되는 표적화 이종성 분자를 추가로 포함함으로써, 이중특이적 분자를 조성하게 되는, 비-천연의 개질된 α1-α2 도메인.
- 제 11 항에 있어서, 표적화 이종성 분자가 펩티드 또는 폴리펩티드인, 비-천연의 개질된 α1-α2 도메인.
- 제 12 항에 있어서, 폴리펩티드가 항체 또는 항체 절편인, 비-천연의 개질된 α1-α2 도메인.
- 포유류 세포에 부착되어 있는 제 1 항의 비-천연 NKG2D 수용체 엑토도메인.
- 제 14 항에 있어서, 포유류 세포가 림프구인, 비-천연 NKG2D 수용체 엑토도메인.
- 제 15 항에 있어서, 림프구가 인간 림프구인, 비-천연 NKG2D 수용체 엑토도메인.
- 제 11 항에 있어서, 표적화 이종성 분자가 그에 부착된 비-천연 NKG2D 수용체 엑토도메인을 가진 포유류 세포에 전달되는, 비-천연의 개질된 α1-α2 도메인.
- 제 17 항에 있어서, 비-천연 NKG2D 수용체 엑토도메인을 발현하는 세포의 강화된 활성화를 나타내어, 세포에 전달되는 천연 또는 본연의 α1-α2 도메인을 가진 천연 NKG2D 리간드 또는 이중특이적 분자보다 더 큰 표적 세포 살해 효능을 나타내는 세포를 유도하는, 비-천연의 개질된 α1-α2 도메인.
- 제 18 항에 있어서, 천연 NKG2D 수용체 엑토도메인을 발현하는 세포의 활성화보다 더 큰, 비-천연 NKG2D 수용체 엑토도메인을 발현하는 세포의 활성화를 나타내어, 천연 NKG2D 수용체 엑토도메인을 발현하는 세포보다 더 큰 표적 세포 살해 효능을 나타내는 비-천연 NKG2D 수용체 엑토도메인을 발현하는 세포를 유도하는, 비-천연의 개질된 α1-α2 도메인.
- 제 18 항에 있어서, 천연 NKG2D 수용체 엑토도메인을 발현하는 세포의 활성화보다 더 큰, 비-천연 NKG2D 수용체 엑토도메인을 발현하는 세포의 활성화를 나타내어, 천연 NKG2D 수용체 엑토도메인을 발현하는 세포보다 더 적은 독성을 나타내는 비-천연 NKG2D 수용체 엑토도메인을 발현하는 세포를 유도하는, 비-천연의 개질된 α1-α2 도메인.
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HUE058851T2 (hu) * | 2014-12-05 | 2022-09-28 | Xyphos Biosciences Inc | Inzertálható variábilis antitestfragmentumok és az NKG2D ligandumok módosított A1-A2 doménjei |
US11117969B2 (en) * | 2014-12-05 | 2021-09-14 | Xyphos Biosciences Inc. | Insertable variable fragments of antibodies and modified α1-α2 domains of NKG2D ligands |
CA2977350C (en) | 2015-02-20 | 2022-08-23 | Ohio State Innovation Foundation | Bivalent antibody directed against nkg2d and tumor associated antigens |
AU2016410294A1 (en) * | 2016-06-24 | 2019-01-03 | Xyphos Biosciences Inc. | Insertable variable fragments of antibodies and modified a1-a2 domains of NKG2D ligands |
JP7270253B2 (ja) | 2017-03-27 | 2023-05-10 | ナショナル ユニヴァーシティ オブ シンガポール | ナチュラルキラー細胞のエクスビボ拡大及び活性化のための刺激細胞株 |
KR102660336B1 (ko) * | 2017-03-27 | 2024-04-26 | 내셔널 유니버시티 오브 싱가포르 | 절단된 nkg2d 키메라 수용체 및 자연 살해 세포 면역요법에서의 그의 용도 |
US20210171907A1 (en) * | 2017-12-05 | 2021-06-10 | Celyad S.A. | Compositions and methods for improving persistence of cells for adoptive transfer |
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EP3828200A4 (en) * | 2018-07-09 | 2022-05-18 | National University Corporation Kumamoto University | CYCLIC SINGLE CHAIN ANTIBODIES |
US20210275589A1 (en) | 2018-07-13 | 2021-09-09 | Nanjing Legend Biotech Co. Ltd. | Co-receptor systems for treating infectious diseases |
US11957714B2 (en) * | 2018-11-05 | 2024-04-16 | Xyphos Biosciences Inc. | Non-natural NKG2D receptors that do not directly signal the cells to which they are attached |
CN109627342B (zh) * | 2018-12-10 | 2022-12-06 | 苏州近岸蛋白质科技股份有限公司 | 应用于nk细胞培养的蛋白质、培养基配方组合及制备方法 |
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AU2020226493A1 (en) * | 2019-02-18 | 2021-10-14 | Courier Therapeutics Inc. | Bispecific fusion protein using orthopoxvirus major histocompatibility complex (MHC) class l-like protein (OMCP) and tumor-specific binding partner |
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