KR101911438B1 - 이중 특이 항원 결합 단백질 복합체 및 이중 특이 항체의 제조 방법 - Google Patents
이중 특이 항원 결합 단백질 복합체 및 이중 특이 항체의 제조 방법 Download PDFInfo
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Abstract
이중 특이 항원 결합 단백질 복합체, 이중 특이 항체, 상기 항체의 제조 방법 및 의약학적 용도에 관한 것이다. 일 구체예에 따른 단백질 복합체를 사용함으로써, 2개의 항원 또는 동일한 항원의 2개의 에피토프를 동시에 인식하는 이중 특이 항체의 효과적인 제조가 가능하다. 상기 이중 특이 항체는 세포증식 질환 또는 면역 질환과 같은 장애의 진단, 예방, 또는 치료 목적으로 사용될 수 있다.
Description
이중 특이 항원 결합 단백질 복합체, 이중 특이 항체의 제조 방법, 이중 특이 항체의 의약학적 용도에 관한 것이다.
단일 클론 항체가 신약 시장의 강자로 자리매김하면서 다양한 표적에 대한 치료제로 개발되고 있으나, 많은 경우 만족할 만한 약효를 보이지 못하거나, 항체 생산에 고비용이 드는 등 신약 개발에 있어 한계를 지니고 있다. 이러한 문제점 해결을 위한 하나의 방법으로 1980년 중반 이후 이중특이항체에 대한 연구가 꾸준히 진행되고 있으나, 많은 노력에도 불구하고 아직 주도적인 기술은 나타나지 않고 있다.
기존의 이중특이항체 제조법은 동질의 이중특이항체를 대량 생산하는데 어려움이 있거나, 낮은 효능과 부작용으로 인해 실용화에 어려움이 있었다. 최근 들어 항체 공학 기술의 발달에 힘입어 경쟁력이 있는 새로운 항체 플랫폼들이 나타나고 있으나, 아직 검증 단계에 머무르고 있는 실정이다.
따라서, 종래 기술에 의하더라도, 2 이상의 이종 항원에 대해 특이성을 갖는 새로운 항체 단백질 및 그를 제조하기 위한 방법의 개발이 요구된다.
일 구체예는 2 개의 항원 결합 부위를 포함하는 이중 특이 항원 결합 단백질 복합체를 제공한다.
다른 구체예는 상기 이중 특이 항원 결합 단백질 복합체를 코딩하는 폴리뉴클레오티드를 제공한다.
추가적인 구체예는 상기 폴리뉴클레오티드를 포함하는 재조합 벡터 및 상기 재조합 벡터로 형질전환된 숙주 세포를 사용한 이중 특이 항체의 제조 방법을 제공한다.
추가적인 구체예는 상기 이중 특이 항체를 포함하는 약제학적 조성물을 제공한다.
추가적인 구체예는 상기 이중 특이 항체를 포함하는 진단용 조성물을 제공한다.
일 양태는 N-말단에 제1 항원 결합 부위를 포함하는 제1 폴리펩티드; N-말단에 제2 항원 결합 부위를 포함하는 제2 폴리펩티드; 및 상기 제1 폴리펩티드 및 제2 폴리펩티드를 서로 연결하는 링커를 포함하는 것으로서, 상기 링커는 양 말단에 제1 태그 및 제2 태그를 포함하고, 상기 제1 태그는 상기 제1 폴리펩티드의 C-말단에, 상기 제2 태그는 상기 제2 폴리펩티드의 N-말단에 연결되며, 상기 제1 태그 및 제2 태그는 각각 절단 가능한 아미노산 서열을 포함하는 것인 이중 특이 항원 결합 단백질 복합체를 제공한다.
다른 양태는 N-말단에 제1 항원 결합 부위를 포함하는 제1 폴리펩티드; N-말단에 제2 항원 결합 부위를 포함하는 제2 폴리펩티드; 및 상기 제1 폴리펩티드 및 제2 폴리펩티드를 서로 연결하는 링커를 포함하는 것으로서, 상기 링커는 하나의 말단에 태그를 포함하고, 상기 태그는 상기 제1 폴리펩티드의 C-말단 또는 상기 제2 폴리펩티드의 N-말단에 연결되며, 절단 가능한 아미노산 서열을 포함하는 것인 이중 특이 항원 결합 단백질 복합체를 제공한다.
용어 "이중 특이(bispecific)"는 2개의 서로 다른 항원, 또는 동일한 항원이라도, 서로 다른 에피토프에 대한 결합 특이성을 갖는 것을 지칭한다. 상기 에피토프는 2가지 서로 다른 항원으로부터 기원하거나 또는 동일한 항원으로부터 기원한 것일 수 있다. 본 명세서에서, 상기 용어 "이중 특이 항원 결합 단백질 복합체" 및 "이중 특이 항체"는 전장 항체 및 항원 결합 부위를 갖는 그의 단편으로 제조된 것을 모두 포함하는 의미로 사용된다. 상기 항체는 인간 항체, 비-인간 항체, 인간화된 항체(humanized antibody) 또는 키메라 항체(chimeric antibody)일 수 있다.
용어 "항원 결합 부위(antigen binding site)"는 면역글로불린 분자 내에서 항원 또는 에피토프(epitope)가 결합하는 부위를 총칭하는 개념으로 해석되며, 상기 항원 결합 부위는 CDR(complementarity determining region)을 포함할 수 있다. CDR은 면역글로불린의 중쇄 및 경쇄의 고가변 영역(hypervariable region)의 아미노산 서열을 의미한다. 중쇄 및 경쇄는 각각 3개의 CDR을 포함할 수 있으며(CDRH1, CDRH2, CDRH3 및 CDRL1, CDRL2, CDRL3). 상기 CDR은 항체가 항원 또는 에피토프에 결합하는 데 있어서 주요한 접촉 잔기를 제공할 수 있다. 용어, "중쇄(heavy chain)"는 항원에 특이성을 부여하기 위해 충분한 가변 영역 서열을 갖는 아미노산 서열을 포함하는 가변 영역 도메인 VH 및 3 개의 불변 영역 도메인 CH1, CH2 및 CH3를 포함하는 전장 중쇄 및 이의 단편을 모두 포함하는 의미로 해석된다. 또한, 용어 "경쇄(light chain)"는 항원에 특이성을 부여하기 위한 충분한 가변영역 서열을 갖는 아미노산 서열을 포함하는 가변 영역 도메인 VL 및 불변 영역 도메인 CL을 포함하는 전장 경쇄 및 이의 단편을 모두 포함하는 의미로 해석된다.
일 구체예에 따르면, 상기 단백질 복합체 및 이중 특이 항체는 서로 다른 항원 또는 에피토프에 특이적으로 결합하는 제1 항원 결합 부위 및 제2 항원 결합 부위를 포함할 수 있다. 상기 항원 결합 부위에 결합될 수 있는 항원은 정상 상태에서는 발현되지 않거나 또는 낮은 수준으로 발현되나, 특정한 병적 상태, 예를 들면, 종양 질환 또는 면역 질환 등에서 발현이 증가하는 항원일 수 있다. 그와 같은 항원은 VEGF, EGFR, EpCAM, CCR5, CD19, HER-2 neu, HER-3, HER-4, PSMA, CEA, MUC-1(뮤신), MUC2, MUC3, MUC4, MUC5 AC, MUC5 B, MUC7, βhCG, 루이스(Lewis)-Y, CD20, CD33, CD30, 강글리오사이드(ganglioside) GD3, 9-O-아세틸-GD3, GM2, 글로보(Globo) H, 푸코실(fucosyl) GM1, 폴리 SA, GD2, 카보안하이드라제(Carboanhydrase) IX (MN/CA IX), CD44v6, Sonic Hedgehog (Shh), Wue-1, 혈장 세포 항원(Plasma Cell Antigen), (막 결합성) IgE, 멜라노마 콘드로이틴 술페이트 프로테오글리칸(Melanoma Chondroitin Sulfate Proteoglycan, MCSP), CCR8, TNF-알파 전구체, STEAP, 메소텔린(mesothelin), A33 항원, 전립선 줄기세포 항원(Prostate Stem Cell Antigen, PSCA), Ly-6; 데스모글레인(desmoglein) 4, E-카드헤린 네오에피토프(E-cadherin neoepitope), 태아 아세틸콜린 수용체(Fetal Acetylcholine Receptor), CD25, CA19-9 마커, CA-125 마커 및 뮐러 억제 물질(Muellerian Inhibitory Substance, MIS) Ⅱ형 수용체, sTn (시알화 Tn 항원; TAG-72), FAP (섬유아세포 활성화 항원), 엔도시알린(endosialin), EGFRvIII, LG, SAS 및 CD63으로 이루어진 군으로부터 선택되는 것일 수 있다.
서로 다른 항원에 결합하는 상기 단백질 복합체 및 이중 특이 항체는 일정한 생리학적 효과를 달성하기 위해, 상기 2가지 항원-항체 반응이 상승 작용을 유발하거나, 또는 일련의 연계된 작용을 수행하도록 하는 항원의 조합을 사용할 수 있다. 이와 같은 조합은, 예를 들면, 종양 세포 항원 및 성 유발 분자 항원을 표적으로 하는 BsAb, 예를 들면, 항-FcγRI/항-CD15, 항-p185HER2/FcγRIII(CD16), 항-CD3/항-악성 B-세포 (1D10), 항-CD3/항-p185HER2, 항-CD3/항-p97, 항-CD3/항-신세포암, 항-CD3/항-OVCAR-3, 항-CD3/L-D1 (항-결장암), 항-CD3/항-멜라닌구 자극 호르몬 동족체, 항-EGFR/항-CD3, 항-CD3/항-CAMA1, 항-CD3/항-CD19, 항-CD3/MoV18, 항-신경 세포 부착 분자 (NCAM)/항-CD3, 항-폴레이트 결합 단백질(FBP)/항-CD3, 항-pan 암종 관련 항원(AMOC-31)/항-CD3; 종양 항원 및 독소 항원을 표적으로 하는 BsAb, 예를 들면, 항-사포닌/항-Id-1, 항-CD22/항-사포닌, 항-CD7/항-사포닌, 항-CD38/항-사포닌, 항-CEA/항-리신 A쇄, 항-인터페론-α(IFN-α)/항-하이브리도마 이디오타입, 항-CEA/항-빈카 알칼로이드; 효소에 의해 활성화되는 프로드럭을 전환시키기 위한 BsAb, 예를 들면, 항-CD30/항-알칼리 포스파타제 (미토마이신 포스파타제 프로드럭의 미토마이신 알콜로의 전환을 촉매); 피브린분해제로서 사용되는 BsAb, 예를 들면, 항-피브린/항-조직 플라스미노겐 활성화제(tPA), 항-피브린/항-우로키나제-타입 플라스미노겐 활성화제(uPA); 세포 표면 수용체에 면역 컴플렉스를 표적하기 위한 BsAb, 예를 들어 항-저밀도 지단백질 (LDL)/항-Fc 수용체 (예: FcγRI, FcγR11 또는 FcγRIII); 감염성 질병의 치료에 사용하기 위한 BsAb, 예를 들어 항-CD3/항-헤르페스 심플렉스 바이러스(HSV), 항-T-세포 수용체:CD3 컴플렉스/항-인플루엔자, 항-FcγR/항-HIV; 시험관 내 또는 생체 내에서 종양 검출을 위한 BsAb, 예를 들어 항-CEA/항-EOTUBE, 항-CEA/항-DPTA, 항-p185HER2/항-합텐(hapten); 백신 아주반트(adjuvant)로서의 BsAb; 및 진단 수단으로의 BsAb, 예를 들어 항-래비트 IgG/항-페리틴, 항-호스 래디쉬 퍼옥시다제 (HRP)/항-호르몬, 항-소마토스타틴/항-물질 P, 항-HRP/항-FITC, 항-CEA/항-β-갈락토시다제 등을 포함할 수 있다.
일 구체예에 따르면, 상기 항원 결합 부위를 포함하는 폴리펩티드는 완전한 항체 또는 그의 단편(항원 결합 단편)일 수 있다.
완전한 항체는 2개의 전장(full length) 경쇄 및 2개의 전장 중쇄를 가지는 구조이며, 각각의 경쇄는 중쇄와 이황화 결합(disulfide bond, S-S bond)으로 연결된다. 항체의 불변 영역은 중쇄 불변 영역과 경쇄 불변 영역으로 나뉘어지며, 중쇄 불변 영역은 감마(γ), 뮤(μ), 알파(α), 델타(δ) 및 엡실론(ε) 타입을 가지고, 서브클래스로 감마1(γ1), 감마2(γ2), 감마3(γ3), 감마4(γ4), 알파1(α1) 및 알파2(α2)를 가진다. 경쇄의 불변 영역은 카파(κ) 및 람다(λ) 타입을 가진다.
용어 "항원 결합 단편(antigen binding fragment)"은, 항원 결합 부위를 포함하여 항원과 결합하는 능력을 보유하는, 완전한 항체의 일부분을 지칭한다. 본 정의에 포함되는 항원 결합 단편은 (i) 경쇄 가변 영역(VL), 경쇄 불변 영역(CL), 중쇄 가변 영역(VH) 및 중쇄의 첫 번째 불변 영역(CH1)을 갖는 Fab 단편; (ⅱ) CH1 도메인의 C-말단에 하나 이상의 시스테인 잔기를 갖는 Fab 단편인 Fab' 단편; (ⅲ) VH 및 CH1 도메인을 갖는 Fd 단편; (iv) VH 및 CH1 도메인 및 CH1 도메인의 C-말단에 하나 이상의 시스테인 잔기를 갖는 Fd' 단편; (v) 항체의 단일 암의 VL 및 VH 도메인을 갖는 최소의 항체 조각인 Fv 단편 (이중쇄 Fv(two-chain Fv)는 비공유 결합으로 중쇄 가변 영역과 경쇄 가변 영역이 연결되어 있고, 단쇄 Fv(single-chain Fv, scFv)는 일반적으로 펩타이드 링커를 통하여 중쇄의 가변 영역과 경쇄의 가변 영역이 공유 결합으로 연결되거나 또는 C-말단에서 바로 연결되어 있어서 이중쇄 Fv와 같이 다이머와 같은 구조를 이룰 수 있다); (ⅵ) VH 도메인으로 구성된 dAb 단편 (Ward et al., Nature 341, 544-546 (1989)); (ⅶ) 단리된 CDR 영역; (ⅷ) 힌지 영역에서 디설파이드 브릿지에 의해 연결된 2개의 Fab' 단편을 포함하는 이가 (bivalent) 단편인 F(ab')2 단편; (ix) 단일쇄 항체 분자 (예를 들면, 단일쇄 Fv; scFv) (Bird et al., Science 242:423-426 (1988); Huston et al., PNAS (USA) 85:5879-5883 (1988)); (x) 동일한 폴리펩티드 쇄에 경쇄 가변 도메인 (VL)에 연결된 중쇄 가변 도메인 (VH)을 포함하는, 2개의 항원 결합 부위를 갖는 "디아바디 (diabody)" (Hollinger et al., Proc. Natl. Acad. Sci. USA, 90:6444-6448 (1993)); (xi) 상보적 경쇄 폴리펩티드와 함께 한 쌍의 항원 결합 영역을 형성하는 한 쌍의 탠덤한 Fd 분절 (VH-CH1-VH-CH1)을 포함하는 "선형 항체" (Zapata et al. Protein Eng. 8(10):1057-1062 (1995)); (xii) VH, CH2 및 CH3로 구성된 중쇄만을 포함하는 "단일-도메인 항체(single-domain antibody)"를 포함할 수 있다. 상기 항원 결합 단편은 단백질 가수분해 효소를 이용해서 얻을 수 있고 (예를 들어, 전체 항체를 파파인으로 제한 절단하면 Fab를 얻을 수 있고 펩신으로 절단하면 F(ab')2 단편을 얻을 수 있다), 유전자 재조합 기술을 통하여 제작할 수 있다.
일 구체예에 따르면, 상기 항원 결합 부위를 포함하는 폴리펩티드는 단일-도메인 항체일 수 있다. 용어 "단일-도메인 항체(single-domain antibody)"는 하나의 가변 영역(VH) 모노머를 가지며, 경쇄 및 중쇄의 CH1 영역이 존재하지 않는 아미노산 110여 개로 구성된 펩티드 사슬이다. 중쇄 항체, 자연 발생 단일 도메인 항체(경쇄를 자연적으로 갖지 않는 항체), 종래의 4쇄 항체에서 유래한 단일 도메인 항체, 조작된 항체 및 항체에서 유래되지 않은 단일 도메인 스캐폴드를 포함한다. 단일 도메인 항체 분자는 IgG 분자의 약 1/10배 크기로 매우 작고, 단일 폴리펩티드로서 매우 안정하여 극한 pH 및 온도 조건에서도 안정성을 유지한다. 또한 이들은 종래의 항체와는 달리 프로테아제의 작용에 대해 내성을 가지며, 생체외 발현시 높은 수율로 대량 생산이 가능하다. 상기 단일 도메인 항체는 항원 결합 부위 및 Fc(fragment crystallizable) 부위를 포함할 수 있다. 상기 항원 결합 부위는 예를 들면, 결합 항원이 VEGF인 경우, 첨부된 서열목록의 서열번호 2 또는 3의 아미노산 서열을 가질 수 있고, 결합 항원이 EFGR인 경우 서열번호 5 내지 6의 아미노산 서열을 가질 수 있다. 상기 Fc 부위는 힌지 영역(hinge region) 및 2개의 불변 영역(CH2 및 CH3)으로 구성될 수 있으며, 예를 들면, 첨부된 서열목록 서열번호 4의 아미노산 서열을 가질 수 있다.
일 구체예에 따르면, 상기 항원 결합 부위를 포함하는 폴리펩티드는 서열번호 8 내지 서열번호 44로 이루어진 군으로부터 선택되는 아미노산 서열을 갖는 폴리펩티드로 이루어진 군으로부터 선택되는 것일 수 있다.
용어, "태그(tag)"는 상기 융합 단백질의 말단에 결합되어 있으며, 서로 다른 융합 단백질 사이를 연결하기 위한 매개가 되는 단백질 또는 폴리펩티드를 의미한다. 상기 태그는 상기 폴리펩티드의 N-말단 또는 C-말단에 연결된 것일 수 있다. 일 구체예에 따르면, 상기 태그는 인 비트로 또는 인 비보에서 절단 가능한 것일 수 있다. 상기 인 비트로 또는 인 비보에서의 절단은 프로테아제에 의한 것일 수 있다.
일 구체예에 따르면, 상기 태그는 유비퀴틴, 유비퀴틴-유사 단백질 및 TEV 절단 펩티드(TEV cleavage peptide)로 이루어진 군으로부터 선택될 수 있다.
유비퀴틴(ubiquitin, Ub)은 자연계에서 발견되는 가장 보존적인 단백질로 76개의 아미노산 서열로 이루어져 있으며, 곤충, 송어 및 인간처럼 진화적으로 다양한 종들간의 완벽한 상동성을 보이는 수용성 단백질이다. 또한, 유비퀴틴은 pH의 변화에 대해 안정하고, 고온에서도 쉽게 변성되지 않으며, 프로테아제에 대해서도 안정성이 있는 단백질로 알려져 있다.
상기 유비퀴틴 또는 유비퀴틴-유사 단백질(ubiquitin-like protein)은 야생형 유비퀴틴, 야생형 유비퀴틴-유사 단백질, 돌연변이 유비퀴틴 및 돌연변이 유비퀴틴-유사 단백질로 이루어진 군으로부터 선택되는 것일 수 있다. 일 구체예에 따르면, 상기 야생형 유비퀴틴은 서열번호 7의 아미노산 서열로 이루어진 것일 수 있다. 상기 유비퀴틴-유사 단백질은 유비퀴틴과 그 특성이 유사한 단백질로, 예를 들어, Nedd8, SUMO-1, SUMO-2, NUB1, PIC1, UBL3, UBL5 및 ISG15로 이루어진 군으로부터 선택될 수 있다. 상기 돌연변이 유비퀴틴은 야생형 유비퀴틴의 아미노산 서열을 다른 아미노산 서열로 바꾼 것을 의미하며, 예를 들면, 야생형 유비퀴틴의 Lys을 Arg으로 치환한 유비퀴틴, 야생형 유비퀴틴 C-말단 RGG를 RGA로 변경시킨 유비퀴틴을 포함한다. 일 구체예에 따르면, 상기 야생형 유비퀴틴의 Lys을 Arg으로 치환한 돌연변이형 유비퀴틴에서, 상기 치환은 야생형 유비퀴틴의 6, 11, 27, 29, 33, 48 및 63번째에 존재하는 Lys에서 이루어질 수 있으며, 치환은 상기 Lys의 위치에서 독립적으로 또는 조합하여 이루어질 수 있다.
일 구체예에 따르면, 상기 유비퀴틴 또는 유비퀴틴-유사 단백질은 인 비트로 또는 인 비보에서의 절단을 위해 C-말단에 프로테아제에 의해 절단 가능한 아미노산 서열을 포함할 수 있다. 상기 프로테아제에 의해 절단 가능한 아미노산 서열은 당업계에 공지된 검색 데이터베이스를 통해 확인할 수 있다. 예를 들어, http://www.expasy.org/tools/peptidecutter/peptidecutter_enzymes.html에서 검색되는 프로테아제 및 그의 절단 가능한 아미노산 서열을 이용할 수 있다. 상기 절단 가능한 아미노산 서열이 포함되는 경우, 상기 단백질 복합체는 인 비트로 또는 인 비보에서 상기 태그가 절단됨으로써, 상기 단백질 복합체가 이중 특이 항체로서의 3차 구조를 형성하고, 그의 기능을 수행할 수 있다.
일 구체예에 따르면, 상기 단백질 복합체는 상기 제1 폴리펩티드 및 제2 폴리펩티드를 서로 연결하는 링커를 포함할 수 있다. 상기 링커는 펩티드 링커일 수 있다. 상기 펩티드 링커는 당업계에 공지된 다양한 링커를 이용할 수 있으며, 예를 들어, 복수의 아미노산으로 이루어진 링커일 수 있다. 일 구체예에 따르면, 상기 링커는 예를 들어, 1 내지 100개 또는 2 내지 50개의 임의의 아미노산으로 이루어진 폴리펩티드일 수 있다.
상기 펩티드 링커는 상기 제1 폴리펩티드 및 제2 폴리펩티드 사이를 충분한 거리로 이격시켜 각각의 폴리펩티드가 적절한 기능을 하기 위한 적합한 이차 및 삼차 구조로 폴딩되도록 할 수 있다. 예를 들어, 상기 펩티드 링커는 Gly, Asn 및 Ser 잔기를 포함할 수 있으며, Thr 및 Ala과 같은 중성 아미노산들도 포함될 수 있다. 펩티드 링커에 적합한 아미노산 서열은 당 업계에 공지되어 있다. 한편, 상기 링커는 상기 융합 단백질의 기능에 영향을 미치지 않는 한도 내에서, 그 길이를 다양하게 결정할 수 있다.
일 구체예에 따르면, 상기 링커는 양 말단 중 적어도 하나의 말단에 태그를 포함할 수 있다. 또한, 상기 태그는 상기 폴리펩티드의 말단에 연결되며, 절단 가능한 아미노산 서열을 포함할 수 있다.
다른 구체예에서, 상기 단백질 복합체는 분비 신호 서열(signal sequence for secretion)을 추가적으로 포함할 수 있다.
분비 신호 서열은 단백질 코딩 서열의 N-말단에 연결되어 발현되는 단백질 또는 펩티드를 세포막 또는 세포 외로 분비되도록 유도하는 서열을 의미하며, 18개 내지 30개의 아미노산으로 구성된 펩티드 서열일 수 있다. 세포질 외로 수송가능한 모든 단백질은 모두 고유의 신호 서열을 가지며, 이 신호 서열은 세포막에서 시그널 펩티다아제에 의해 절단된다. 일반적으로 숙주 세포에서 자연적으로 발현되지 않는 외래 단백질의 경우, 이를 주변세포질 또는 배양액으로 분비시키기 위해 공지된 분비 신호 서열 또는 이의 변형 서열을 사용할 수 있다.
본 양태에서, 상기 단백질 복합체의 아미노산 서열은 본래 단백질의 목적 기능 또는 특성, 예를 들면, 항원 특이성을 실질적으로 변화시키지 않는 범위에서 적절하게 변형시킬 수 있다. 아미노산의 변형은 아미노산 잔기 치환체의 유사성, 예를 들면 소수성, 친수성, 전하, 크기 등에 기초하여 이루어지며, 이를 위해 아미노산의 소수성 인덱스(hodrophobic index)가 고려될 수 있다. 상기 변형은 예를 들면, 일부 아미노산의 치환, 결실, 부가 등일 수 있으며, 치환은 특히 보존적 치환일 수 있다. 용어 "보존적 치환"은 결과적인 분자의 생물학적 활성이 유의하게 변경시키지 않는 치환으로서, 치환되는 아미노산이 단백질의 3차 구조 또는 국부 전하 상태에 유의한 영향을 야기하지 않는 경우를 지칭한다. 분자 활성을 전체적으로 변경시키지 않는 아미노산 교환은 당해 분야에 공지되어 있으며, 예를 들면, 아미노산 잔기 Ala/Ser, Val/Ile, Asp/Glu, Thr/Ser, Ala/Gly, Ala/Thr, Ser/Asn, Ala/Val, Ser/Gly, Thy/Phe, Ala/Pro, Lys/Arg, Asp/Asn, Leu/Ile, Leu/Val, Ala/Glu, Asp/Gly 간의 교환을 포함할 수 있다.
다른 양태는 상기 단백질 복합체를 코딩하는 폴리뉴클레오티드를 제공한다.
용어 “폴리뉴클레오티드(polynucleotide)”는 단일가닥 또는 이중가닥 형태로 존재하는 디옥시리보뉴클레오티드 또는 리보뉴클레오티드의 중합체를 의미한다. RNA 게놈 서열, DNA(gDNA 및 cDNA) 및 이로부터 전사되는 RNA 서열을 포괄하며, 특별하게 다른 언급이 없는 한 자연의 폴리뉴클레오티드뿐만 아니라 당 또는 염기 부위가 변형된 그의 유사체(analogue)도 포함한다. 일 구체예에서, 상기 폴리뉴클레오티드는 경쇄 폴리뉴클레오티드이다.
상기 폴리뉴클레오티드는 상기 단백질 복합체의 아미노산 서열을 코딩하는 뉴클레오티드 서열뿐만 아니라, 그 서열에 상보적인(complementary) 서열도 포함한다. 상기 상보적인 서열은 완벽하게 상보적인 서열뿐만 아니라, 실질적으로 상보적인 서열도 포함하며, 이는 당업계에 공지된 엄격 조건(stringent condition) 하에서, 예를 들어, 상기 단백질 복합체의 아미노산 서열을 코딩하는 뉴클레오티드 서열의 뉴클레오티드 서열과 혼성화될 수 있는 서열을 의미한다.
또한, 상기 단백질 복합체의 아미노산 서열을 코딩하는 뉴클레오티드 서열은 변형될 수 있다. 상기 변형은 뉴클레오티드의 부가, 결실 또는 비보존적 치환 또는 보존적 치환을 포함한다. 상기 단백질 복합체의 아미노산 서열을 코딩하는 폴리뉴클레오티드는 상기 뉴클레오티드 서열에 대하여 실질적인 동일성을 나타내는 뉴클레오티드 서열도 포함하는 것으로 해석된다. 상기의 실질적인 동일성은, 상기 뉴클레오티드 서열과 임의의 다른 서열을 최대한 대응되도록 얼라인하고, 당업계에서 통상적으로 이용되는 알고리즘을 이용하여 얼라인된 서열을 분석한 경우에, 80% 이상의 상동성, 90% 이상의 상동성 또는 95% 이상의 상동성을 나타내는 서열일 수 있다.
일 구체예에 따르면, 상기 폴리뉴클레오티드는 서열번호 45 내지 서열번호 81로 이루어진 군으로부터 선택되는 염기서열을 갖는 것일 수 있다.
상기 단백질 복합체의 제조는 상기 폴리뉴클레오티드를 사용하여, 당해 기술분야에 공지된 유전자 조작 기술 및 화학적 합성을 통해 수행될 수 있다. 상기 유전자 조작 기술은 복제가능한 클로닝 벡터 또는 발현 벡터를 구축하여 상기 벡터로 숙주 세포를 형질전환시키고, 숙주 세포를 배양하여 목적 단백질을 발현시키는 방법을 포함할 수 있다.
따라서, 일 양태는 전술한 단백질 복합체를 코딩하는 폴리뉴클레오티드 서열을 삽입시킨 재조합 발현 벡터를 구축하는 단계, 상기 재조합 발현 벡터로 숙주 세포를 형질전환시키는 단계, 상기 형질전환된 숙주 세포를 배양하는 단계, 및 상기 숙주 세포에서 발현된 상기 이중 특이 항체를 회수하는 단계를 포함하는, 이중 특이 항체의 제조 방법을 제공한다.
용어 "벡터(vector)"는 숙주 세포에서 목적 유전자를 발현시키기 위한 수단으로서, 숙주 세포 내에 도입되면 독립적으로 복제되어 벡터 및 내부에 삽입된 외래 DNA 등의 카피를 생산한다. 용어 "재조합 발현 벡터(recombinant expression vector)"는 특정 단백질의 증폭을 목적으로 내부에 외래 DNA 단편을 삽입시킨 벡터로서, 본원에서 상기 외래 DNA 단편은 전술된 단백질 복합체를 코딩하는 폴리뉴클레오티드일 수 있다. 발현 또는 클로닝을 목적으로 한 벡터 시스템의 구축 방법은 공지되어 있다.
상기 벡터는 본원에 정의된 폴리뉴클레오티드 서열에 작동가능하게 연결된(operably linked) 조절 서열을 포함할 수 있다.
용어 "조절 서열"은 코딩 서열의 발현을 수행하는데 필요한 핵산 서열을 지칭하며, 조절 서열의 성질은 숙주 유기체에 따라 다르다. 원핵 생물에서, 조절 서열은 일반적으로 프로모터, 리보솜 결합 부위 및 전사/해독 터미네이터를 포함한다. 진핵 생물에서, 조절 서열은 일반적으로 프로모터, 터미네이터, 및 일부 경우, 인핸서, 트랜스활성자(transactivators) 또는 전사 인자를 포함한다. 용어 "작동가능하게 연결된(operatively linked)"은 상기 구성요소들이 의도된 방식으로 기능할 수 있도록 하는 기능적 결합 관계에 의한 병치(juxtaposition)를 의미한다. 코딩 서열에 작동가능하게 연결된 조절 서열은 코딩 서열의 발현이 조절 서열과 양립할 수 있는 조건 하에서 이루어질 수 있도록 연결된다.
상기 재조합 벡터는, 원핵 세포를 숙주로 하는 경우, 전사를 진행시킬 수 있는 강력한 프로모터 (예를 들면, tac 프로모터, lac 프로모터, lacUV5 프로모터, lpp 프로모터, pLλ프로모터, pRλ프로모터, rac5 프로모터, amp 프로모터, recA 프로모터, SP6 프로모터, trp 프로모터 및 T7 프로모터 등); 해독의 개시를 위한 라이보좀 결합 자리; 및 전사/해독 종결 서열을 포함할 수 있다. 숙주 세포로서 E. coli (예를 들면, HB101, BL21, DH5α 등)가 이용되는 경우, E. coli 트립토판 생합성 경로의 프로모터 및 오퍼레이터 부위(Yanofsky, C.(1984), J. Bacteriol., 158:1018-1024) 및 파아지 λ의 좌향 프로모터 (pLλ프로모터, Herskowitz, I. and Hagen, D.(1980), Ann. Rev. Genet., 14:399-445)가 조절 부위로서 이용될 수 있다. 진핵 세포를 숙주로 하는 경우, 포유동물 세포의 유전체로부터 유래된 프로모터(예: 메탈로티오닌 프로모터) 또는 포유동물 바이러스로부터 유래된 프로모터(예: 아데노바이러스 후기 프로모터, 백시니아 바이러스 7.5K 프로모터, SV40 프로모터 또는 사이토메갈로바이러스 프로모터 및 HSV의 tk 프로모터)가 이용될 수 있고, 전사 종결 서열로서 폴리아데닐화 서열을 가질 수 있다.
상기 재조합 발현 벡터는 조절 서열 외에, 제한 효소 절단 부위, 약물 저항성 유전자와 같은 마커 유전자, 분비 신호 서열 또는 리더(leader) 서열 등을 추가적으로 포함할 수 있다. 제한효소 절단 부위는 제한효소에 의해 특이적으로 인식되어 절단되는 특정한 염기 서열을 지칭한다. 상기 절단 부위는 예를 들면, EcoRI, BamHI, HindⅢ, kpnⅠ, NotⅠ, PstⅠ, SmaⅠ, Xho I과 같은 제한효소에 의해 특이적으로 인식되는 서열일 수 있다. 상기 마커 유전자는 선택 표지로서 기능하며, 암피실린, 게나마이신, 카베니실린, 클로람페니콜, 스트렙토마이신, 카나마이신, 게네티신, 네오마이신, 및 테트라사이클린과 같은 약물의 내성 유전자일 수 있다. 상기 분비 신호 서열 또는 리더 서열은, 합성된 단백질을 세포 구획 (예를 들면, 주변 세포질 공간(periplasmic space))으로 향하게 하거나 세포외 배지로 분비하도록 유도하는 서열로, 전술된 폴리뉴클레오티드 서열의 코딩 서열에 첨가될 수 있다. 이와 같은 서열들은 도입되는 DNA, 숙주 세포의 종류, 배양 배지의 조건 등에 따라, 당업자에 의해 적절하게 선택될 수 있다.
상기 요소들을 구비한 적절한 발현 벡터들이 공지되어 있으며, 예를 들면, 오까야마-베르그(Okayama-Berg) cDNA 발현 벡터 pcDV1(Pharmacia), pCDM8, pRc/CMV, pcDNA1, pcDNA3(Invitrogen)), pEF-DHFR, pEF-ADA 또는 pEF-neo 또는 pSPORT1(GIBCO BRL)를 포함한다.
본 양태에서, 상기 숙주 세포는 전술된 재조합 발현 벡터 또는 이중 특이 항원 결합 단백질 복합체로 숙주를 형질전환 또는 형질감염시켜 생성될 수 있다.
상기 숙주 세포는 상기 재조합 벡터를 안정화하고 연속적으로 클로닝 및 발현시킬 수 있는, 당업계에 공지된 임의의 원핵 생물 또는 진핵 세포일 수 있다. 상기 원핵 생물은 단백질의 발현을 위해 DNA 또는 RNA 분자로 형질전환될 수 있는 박테리아를 지칭한다. 예를 들면, 에스케리치아 콜라이(Escherichia coli), 바실러스 서브틸리스 및 바실러스 츄린겐시스와 같은 바실러스 속 균주, 스트렙토마이세스(Streptomyces), 슈도모나스(Pseudomonas)(예를 들면, 슈도모나스 푸티다(Pseudomonas putida)), 프로테우스 미라빌리스(Proteus mirabilis), 스타필로코쿠스(Staphylococcus) (예를 들면, 스타필로코쿠스 카르노수스(Staphylocus carnosus)), 쥐 티푸스균(S. typhimurium) 또는 영균(Serratia marcescens) 등이 있다. 진핵 세포는 효모, 고등 식물, 곤충 및 포유동물 세포를 포함한다. 일 구체예에서, 상기 숙주 세포는 포유동물 세포일 수 있다. 유용한 포유동물 세포주의 예로는 SV40으로 형질전환된 원숭이 신장 CV1 세포주 (COS-7, ATCC CRL 1651); 인간 배아 신장 세포주 (HEK-293 또는 현탁 배양으로 성장시키기 위해 서브클로닝된 hEK-293 세포, Graham 등, J. Gen Virol. 36:59 (1977)); 베이비 햄스터 신장 세포 (BHK, ATCC CCL 10); 중국 햄스터 난소 세포/-DHFR(CHO, Urlaub 등, Proc. Natl. Acad. Sci. USA 77:4216 (1980)); 마우스 세르톨리 (sertoli) 세포 (TM4, Mather, Biol. Reprod. 23:243-251 (1980)); 원숭이 신장 세포 (CV1 ATCC CCL 70); 아프리카 그린 원숭이 신장 세포 (VERO-76, ATCC CRL-1587); 인간 경부암 세포 (HELA, ATCC CCL 2); 개 신장 세포 (MDCK, ATCC CCL 34); 버팔로 래트 간 세포 (BRL 3A, ATCC CRL 1442); 인간 폐 세포 (W138, ATCC CCL 75); 인간 간 세포 (Hep G2, HB 8065); 마우스 유방 종양 (MMT 060562, ATCC CCL51); TR1 세포 (Mather 등, Annals N.Y. Acad. Sci. 383:44-68 (1982)); MRC 5 세포; FS4 세포; 및 인간 간종양 세포주 (Hep G2) 등을 포함할 수 있다.
재조합 발현 벡터의 숙주 세포로의 형질전환은 예를 들면, DEAE-덱스트란 매개 형질전환(DEAE-dextran mediated transfection), 전기천공(electroporation), 형질도입(transduction), 칼슘 포스페이트 형질전환(calcium phosphate transfection), 양이온 지질-매개 형질전환(cationic lipid-mediated transfection), 스크래프 로딩(scrape loading) 및 감염(infection) 등에 의해 수행될 수 있다.
숙주 세포의 배양은 당업계에 알려진 적절한 배지 및 배양조건을 사용하여 수행될 수 있다. 시판되는 배지, 예를 들면 Ham's F10 (Sigma), MEM (Minimal Essential Medium, Sigma), RPMI-1640 (Sigma), 및 DMEM (Dulbecco's Modified Eagle's Medium, Sigma)등이 이용될 수 있다. 필요한 경우, 호르몬 또는 기타 성장 인자, 염, 완충제, 뉴클레오티드, 항생제, 미량 원소 및 글루코오스 등이 공지된 적합한 농도로 보충될 수 있다. 배양 조건, 예를 들어 온도, pH 등은 선택된 숙주 세포에 따라 당업자에 의해 적절하게 결정될 수 있다.
숙주 세포에 의해 발현된 이중 특이 항원 결합 단백질 복합체는 분비 신호 펩티드에 의해 세포 외로 분비될 수 있으며, 이 경우 배양액 또는 배지로부터 이를 회수함으로써 수득될 수 있다. 예를 들면, 배양 상청액을 시판되는 단백질 필터를 사용하여 농축시켜 항체 단백질을 분리할 수 있다. 그러나, 분비 신호 서열이 없이 발현된 경우, 상기 단백질 복합체는 세포 내 페리플라즘 공간에 존재하므로 세포 용해물(cell lysate)로부터 직접 수득될 수 있다. 페리플라즘 공간으로 분비되는 항체를 단리시키는 공정은 공지되어 있으며, 일반적으로 미립자 파편(숙주 세포 또는 분해된 단편)을 원심분리 또는 한외여과에 의해 제거할 수 있다.
선택적으로, 이러한 배양물로부터 수득된 이중 특이 항체를 당업계에 공지된 방법에 의해 추가적으로 정제할 수 있다. 예를 들면, 회수되는 항체에 따라, 상기 이중 특이 항체는 크로마토그래피 (예를 들면, 이온 교환, 친화성, 소수성 및 크기배제), 크로마토포커싱, SDS-PAGE, 분별 용해 (예를 들면, 암모늄 술페이트 침전)와 같은, 통상의 단백질 정제 기술을 사용할 수 있다. 일 구체예에서, 상기 이중 특이 항체는 친화성 크로마토그래피에 의해 정제할 수 있다. 친화성 리간드로서 단백질 A의 적합성은 항체에 존재하는 면역글로불린 Fc 도메인의 종류 및 이소타입에 따른다. 친화성 리간드가 부착되는 매트릭스는 아가로오스일 수 있으나 이에 한정되지 않으며, 기계적으로 안정한 매트릭스(예를 들면 조절된 포어 글래스 또는 폴리(스티렌디비닐)벤젠)는 아가로오스에 비해 유속 및 프로세싱 시간을 향상시킬 수 있다.
다른 양태는, 전술된이중 특이 항체, 및 약제학적으로 허용가능한 담체, 부형제 또는 안정화제를 포함하는 약제학적 조성물에 관한 것이다.
상기 약제학적 조성물은 상기 이중 특이 항체의 항원-항체 결합 반응에 의해 유발되는 생리학적 효과가 치료 메커니즘으로 작용하거나, 상기 항원-항체 반응에 의해 병소를 표적화할 수 있는, 질환 또는 병태의 예방 및 치료에 사용될 수 있다. 일 구체예에서, 상기 질환 또는 병태는 예를 들면, 증식 질환, 종양 질환, 염증 질환, 면역 질환, 자가면역 질환, 감염 질환, 바이러스 질환, 알러지 반응, 이식편 대 숙주 질환(graft-versus-host disease) 및 숙주 대 이식편 질환(host-versus-graft disease)일 수 있다.
예를 들면, VEGF 및 EGFR에 특이적으로 결합하는 이중 특이 항체의 경우, 상기 이중 특이 항체를 포함하는 약제학적 조성물은 신생혈관생성의 억제 및 상피세포 증식의 억제 작용에 의해 개선될 수 있는 질환, 예를 들면 종양 질환의 예방 및 치료에 사용될 수 있다. 이러한 종양 질환은 편평상피세포암, 폐암 (소세포성 폐암, 비-소세포성 폐암, 폐의 선암, 및 폐의 편평상피암종을 포함), 복막암, 간세포암, 위암 (위장암을 포함), 췌장암, 교아구종, 경부암, 난소암, 간암, 방광암, 간종양, 유방암, 결장암, 대장암, 자궁내막암 또는 자궁암, 타액선암, 신장암, 전립선암, 외음암, 갑상선암, 간암종 및 다양한 유형의 두경부암; B-세포 림프종 (저등급/여포성 비-호지킨스 림프종 (NHL); 소림프구성 (SL) 비-호지킨스 림프종; 중간등급/여포성 비-호지킨스 림프종; 중간등급 확산 비-호지킨스 림프종; 고등급 면역아구성 비-호지킨스 림프종; 고등급 림프아구성 비-호지킨스 림프종; 고등급 소 비-절단세포성 비-호지킨스 림프종; 벌키 질병 비-호지킨스 림프종; 외투세포 림프종; AIDS-관련 림프종; 및 발덴스트롬 마크로글로불린혈증을 포함); 만성 림프구성 백혈병 (CLL); 급성 림프아구성 백혈병 (ALL); 유모세포 백혈병; 만성 골수아구성 백혈병; 및 이식후 림프증식성 장애 (PTLD); 모반증과 관련된 비정상적 혈관 증식, 부종 (뇌종양과 관련된 부종), 및 메이그 증후군 등일 수 있다.
일 구체예에서, 약제학적 조성물 중 이중 특이 항체는 제2 활성제(기능성 분자)와 결합된 상태로 포함될 수 있다. 상기 제2 활성제는 대상 질환에 대한 예방 또는 치료 활성을 나타내는 임의의 기능성 분자일 수 있으며, 화합물, 펩티드, 폴리펩티드, 핵산, 탄수화물, 지질 또는 무기입자를 포함할 수 있다. 상기 약제학적 조성물에서, 이중 특이 항체는 자체로서 치료 활성을 가질 수 있지만, 결합된 제2 활성제를 특이적 병소 부위로 표적화(targeting)하는 기능을 수행할 수 있다. 상기 병소 부위는 상기 이중 특이 항체가 특이적으로 결합하는 항원이 밀집되어 분포하는 기관, 조직, 세포 등일 수 있다. 병소로 표적화된 약물은 고농도로 존재하여 투여량 대비 약효를 상승시킬 수 있다. 따라서, 약제 내성이 있는 종양의 치료에 유용하며, 약물의 비특이적 분포에 기인한 부작용 및 유해반응을 감소시킬 수 있다.
상기 약제학적 조성물은 목적하는 정도의 순도를 갖는 이중 특이 항체를 약제학적으로 허용가능한 담체, 부형제 또는 안정화제와 혼합하여 제조될 수 있다. 상기 약제학적으로 허용가능한 담체, 부형제, 또는 안정화제는 사용되는 투여량 및 농도에서 수용체에 무독성일 것을 요하며, 포스페이트, 시트레이트 및 기타 유기산; 항산화제(예를 들면, 아스코르브산 및 메티오닌); 방부제(예를 들면, 옥타데실디메틸벤질 암모늄 클로라이드, 헥사메토늄 클로라이드, 벤즈알코늄 클로라이드, 벤즈에토늄 클로라이드, 페놀, 부틸 또는 벤질 알콜, 알킬 파라벤, 카테콜, 레소르시놀, 사이클로헥산올, 3-펜탄올 및 m-크레솔); 저분자량 (약 10개 잔기 미만) 폴리펩티드; 단백질, 예를 들면 혈청 알부민, 젤라틴, 또는 면역글로불린; 친수성 중합체, 예를 들면 폴리비닐피롤리돈; 아미노산 (예를 들면 글리신, 글루타민, 아스파라긴, 히스티딘, 아르기닌, 또는 리신); 단당류, 이당류 및 기타 탄수화물(예를 들면, 글루코즈, 만노즈, 또는 덱스트린을 포함); 킬레이트제(예를 들면, EDTA); 당(예를 들면, 수크로오즈, 만니톨, 트레할로즈 또는 소르비톨); 염-생성 카운터이온; 금속 착물; 및/또는 비-이온성 계면활성제(예를 들면, TWEENTM, PLURONICSTM 또는 폴리에틸렌 글리콜 (PEG) 등을 포함할 수 있다. 이 외에도 제제화 방법에 따라 통상적으로 사용되는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등이 당업자에 의해 적절하게 선택될 수 있다.
상기 약제학적 조성물에서 이중 특이 항체를 포함한 활성 성분은, 코아세르베이션 기술 또는 계면중합에 의해 제조된 마이크로캡슐, 예를 들면, 각각 히드록시메틸셀룰로즈 또는 젤라틴-마이크로캡슐 및 폴리-(메틸메타크릴레이트) 마이크로캡슐, 콜로이드 약물 전달 시스템 (리포좀, 알부민 마이크로스포어, 마이크로에멀젼, 나노-입자 및 나노캡슐 등) 또는 마크로에멀젼에 포획(entrapping) 시킬 수 있다.
또한, 상기 이중 특이 항체는 서방출 제제로 제제화될 수 있다. 상기 서방출 제제는 예를 들면, 항체를 포함하는 고형 소수성 중합체의 반투과성 매트릭스일 수 있다. 상기 매트릭스는 필름 또는 마이크로캡슐 등의 형태일 수 있으며, 폴리에스테르, 히드로겔 (예를 들면, 폴리(2-히드록시에틸-메타크릴레이트), 또는 폴리(비닐알콜)), 폴리락티드 (미국 등록특허 제3,773,919호), L-글루탐산과 γ 에틸-L-글루타메이트와의 공중합체, 비-분해성 에틸렌-비닐 아세테이트, 분해성 락트산-글리콜산 공중합체, 예를 들어 LUPRON DEPOTTM (락트산-글리콜산 공중합체 및 류프롤리드 아세테이트로 구성된 주사가능한 마이크로스피어), 및 폴리-D-(-)-3-히드록시부티르산 등일 수 있다. 캡슐화된 항체 단백질이 장시간 동안 체내에 머무는 경우, 항체는 37 ℃의 습기에 노출되는 결과로서 변성 또는 응집하여 생물학적 활성을 상실하고 면역원성에 변화가 생길 수 있으므로, 안정화를 위해 합리적인 방법이 고려될 수 있다. 예를 들면, 응집 기작이 티오-디술피드 교환을 통한 세포간 S-S 결합 형성인 것으로 밝혀지는 경우, 술프히드릴 잔기를 개질시키고, 산성 용액으로부터 동결건조시키고, 습기 함량을 조절하고, 적합한 첨가제를 사용하고, 특정한 중합체 매트릭스 조성을 개발하여 안정화시킬 수 있다.
또 다른 양태는, 상기 약제학적 조성물의 치료적 유효량을 개체에게 투여하는 단계를 포함하는, 증식 질환, 종양 질환, 염증 질환, 면역 질환, 자가면역 질환, 감염 질환, 바이러스 질환, 알러지 반응, 이식편 대 숙주 질환 및 숙주 대 이식편 질환으로 이루어진 군에서 선택되는 상태의 예방 또는 치료 방법에 관한 것이다.
상기 약제학적 조성물은 쥐, 생쥐, 가축, 인간 등의 포유 동물을 포함한 개체에 다양한 경로로 투여될 수 있다. 투여의 모든 방식은 예상될 수 있는데, 예를 들면, 경구, 직장 내, 또는 정맥 내, 비강 내, 복강 내, 피하 또는 국소 투여 등이 가능하다. 상기 조성물은 또한 당해 기술 분야에 공지되어 있는 다른 방법 (예를 들어 Remington's Pharmaceutical Science 최신판에 기재된 방법들)을 사용하여 투여될 수 있다.
상기 "치료적 유효량"은 의학적 치료에 적용가능한 합리적인 수혜 또는 위험 비율로 질환을 치료하기에 충분한 양을 의미한다. 치료적 유효량은 질환의 종류, 중증도, 발병 시기, 개체의 연령, 체중, 배설 속도, 반응 감응성, 건강상태, 합병증과 같은 환자측 요인, 약물의 활성, 투여 경로, 투여 기간 및 횟수, 병용 약물과 같은 약물측 요인에 따라 달라질 수 있으며, 당업자가 목적하는 치료에 따라 적절하게 선택할 수 있다. 상기 투여량은 예를 들면, 성인 체중을 기준으로, 1일당 0.001 내지 100 mg/kg 범위가 되도록, 임의로 수회 나누어서 투여할 수 있다.
또다른 양태는, 전술된 이중 특이 항체를 포함하는, 증식 질환, 종양 질환, 염증 질환, 면역 질환, 자가면역 질환, 감염 질환, 바이러스 질환, 알러지 반응, 이식편 대 숙주 질환 및 숙주 대 이식편 질환으로 이루어진 군에서 선택되는 병태의 진단용 조성물에 관한 것이다.
일 구체예에 따르면, 상기 진단용 조성물은 생물학적 시료에 적용하여, 상기 병태에서 특이적으로 발견되는 항원을 검출하는데 사용될 수 있다. 용어 "생물학적 시료"는 세포, 조직, 전혈, 혈청, 혈장, 조직 부검 시료(뇌, 피부, 림프적, 척수 등), 세포배양 상등액, 파열된 진핵세포 등을 포함할 수 있다. 상기 조성물의 적용은 채취된 생물학적 시료를 대상으로 인 비트로(in vitro)에서 수행되거나, 또는 상기 조성물을 피검 개체 내에 투여하여 인 비보(in vivo)에서 수행될 수 있다.
본 명세서에서 용어 "검출"은 상기 진단용 조성물 중 상기 이중 특이 항체를 생물학적 시료와 반응시켜 항원-항체 복합체의 형성 여부를 확인하는 것을 의미하며, 공지된 검출가능한 표지체(detectable label) 및 검출 방법에 의해 수행될 수 있다. 상기 검출 방법은 비색법(colormetric method), 전기화학법(electrochemical method), 형광법(fluorimetric method), 발광법(luminometry), 입자계수법(particle counting method), 육안측정법(visual assessment) 또는 섬광계수법(scintillation counting method) 등일 수 있다. 상기 검출가능한 표지체는 효소, 형광물질, 발광물질, 리간드, 미소입자, 또는 방사성 동위원소일 수 있다. 상기 표지체로서 사용되는 효소는 아세틸콜린에스테라제, 알칼라인 포스파타제, β-D-갈락토시다제, 호스래디쉬 퍼옥시다제 및 β-라타마제 등을 포함할 수 있고, 상기 형광물질은 플루오레세인, Eu³+, Eu³+ 킬레이트 또는 크립테이트를 포함할 수 있으며, 상기 발광물질은 아크리디늄 에스테르 및 이소루미놀 유도체를 포함할 수 있고, 상기 리간드는 바이오틴 유도체를 포함할 수 있고, 상기 미소입자는 콜로이드 금 및 착색된 라텍스를 포함할 수 있으며, 상기 방사성 동위원소는 57Co, 3H, 125I 및 125I-볼톤(Bonton) 헌터(Hunter) 시약 등을 포함할 수 있다. 일 구체예에서, 상기 항원-항체 복합체의 검출은 효소면역흡착법(Enzyme-Linked Immunosorbent Assay, ELISA)에 의해 수행된다. 또한 진단용 조성물을 개체 내에 투여하여 항원-항체 반응을 검출하는 경우, 상기 검출가능한 표지체를 이중 특이 항체에 부착 또는 결합시킨 상태로 투여할 수 있다.
추가적인 양태는, 전술된 이중 특이 항체를 포함하는 키트에 관한 것이다. 상기 키트는 전술된 조성물들과 마찬가지로, 증식 질환, 종양 질환, 염증 질환, 면역 질환, 자가면역 질환, 감염 질환, 바이러스 질환, 알러지 반응, 이식편 대 숙주 질환 및 숙주 대 이식편 질환으로 이루어진 군에서 선택되는 상태의 진단을 위한 키트, 또는 상기 상태의 치료 또는 예방을 위한 의학적 키트일 수 있다.
일 구체예에 따른 단백질 복합체를 사용함으로써, 2개의 항원 또는 동일한 항원의 2개의 에피토프를 동시에 인식하는 이중 특이 항체의 효과적인 제조가 가능하다. 상기 이중 특이 항체는 세포증식 질환 또는 면역 질환과 같은 장애의 진단, 예방, 또는 치료 목적으로 사용될 수 있다.
도 1 및 도 2는 일 구체예에 따른 이중 특이 항원 결합 단백질 복합체 및 이중 특이 항체의 개략도이다.
도 3은 일 구체예에 따른 이중 특이 항원 결합 단백질 복합체의 아미노산 서열 구조를 나타낸 것이다.
도 4는 일 구체예에 따른 이중 특이 항체의 발현 및 정제를 양이온 교환 크로마토그래피를 수행하여 확인한 결과이다.
도 5는 일 구체예에 따른 이중 특이 항체를 β-머캅토에탄올 미처리군(-), 처리군(+)으로 나누어 SDS-PAGE를 통해 확인한 결과이다.
도 6은 일 구체예에 따른 이중 특이 항체의 이중특이적 항원-항체 반응 효과를 나타낸 센소그램(sensorgram)이다.
도 3은 일 구체예에 따른 이중 특이 항원 결합 단백질 복합체의 아미노산 서열 구조를 나타낸 것이다.
도 4는 일 구체예에 따른 이중 특이 항체의 발현 및 정제를 양이온 교환 크로마토그래피를 수행하여 확인한 결과이다.
도 5는 일 구체예에 따른 이중 특이 항체를 β-머캅토에탄올 미처리군(-), 처리군(+)으로 나누어 SDS-PAGE를 통해 확인한 결과이다.
도 6은 일 구체예에 따른 이중 특이 항체의 이중특이적 항원-항체 반응 효과를 나타낸 센소그램(sensorgram)이다.
이하 하나 이상의 구체예를 실시예를 통하여 보다 상세하게 설명한다. 그러나, 이들 실시예는 하나 이상의 구체예를 예시적으로 설명하기 위한 것으로 본 발명의 범위가 이들 실시예에 한정되는 것은 아니다.
도 1 및 도 2는 일 구체예에 따른 항원 결합 부위를 포함하는 이중 특이 항원 결합 단백질 복합체 및 이중 특이 항체의 개략도이다.
도 1에서 보는 바와 같이, 제1 항원 결합 부위(101)를 포함하는 제1 폴리펩티드(100) 및 제2 항원 결합 부위(201)를 포함하는 제2 폴리펩티드 (200)는 각각 그 말단에 제1 태그(102) 및 제2 태그(202)가 연결되어 있으며, 폴리펩티드로 이루어진 링커(300)의 말단에 상기 제1 태그(102) 및 제2 태그(202)가 연결되어 있다. 상기 제1 태그(102) 및 제2 태그(202)는 유비퀴틴 또는 유비퀴틴-유사 단백질과 같은 단백질로 이루어져 있으므로, 인 비트로 또는 인 비보로 절단이 가능하다. 인 비트로 또는 인 비보 상에서 상기 제1 항원 결합 부위(101)를 포함하는 제1 폴리펩티드(100) 및 제2 항원 결합 부위(201)를 포함하는 제2 폴리펩티드(200)는 완전한 자발적 결합을 통해서 서로 결합되어 서로 다른 항원 결합 부위를 갖는 이중 특이 항체를 형성할 수 있다.
도 2는 도 1에 개시된 일 구체예에 따른 항원 결합 부위를 포함하는 2 이상의 폴리펩티드를 포함하는 단백질 복합체에서 제2 태그(201)가 없는 형태의 예를 나타낸다. 상기 설명한 바와 같이, 단백질 복합체의 인 비트로 또는 인 비보로 절단을 통해, 서로 다른 항원 결합 부위를 갖는 이중 특이 항체를 형성하게 되며, 다만, 도 2에서 개시된 단백질 복합체는 제2 태그(201)가 없기 때문에, 제2 항원 결합 부위(201)를 포함하는 제2 폴리펩티드(200)에 링커(300)가 결합된 형태로 존재하지만, 상기 링커(300)는 2 내지 50개의 짧은 아미노산 서열을 포함하므로, 상기 제2 항원 결합 부위(201)를 포함하는 제2 폴리펩티드(200)의 기능에 영향을 미치지 않게 된다.
실시예
1: 항
VEGF
-
EGFR
이중 특이 항체 발현 벡터의 제조
혈관 내피 성장인자(VEGF) 및 상피 성장인자 수용체(EGFR)에 대해 각각 특이적인 결합 부위를 포함하는 이중 특이 항체를 제조하기 위해, 상기 단백질 복합체의 발현 벡터를 GeneArt에 의뢰하여 제조하였으며, 단백질 과발현을 위한 벡터는 pCDNA 3.1 myc/his A (Invitrogen)를 사용하였다.
구체적으로, 도 3의 (A) 및 (B)에 개시된 바와 같은, 분비 신호 서열(signal sequence, ss)(서열번호 1), 혈관 내피 성장인자(VEGF) 결합 부위인 V1 또는 V2(서열번호 2 또는 3) 및 힌지(hinge)를 포함하는 Fc 도메인(서열번호 4)로 구성된 단일-도메인 항체, 상피 성장인자 수용체(EGFR) 결합 부위인 E1 또는 E2(서열번호 5 또는 6) 및 힌지(hinge)를 포함하는 Fc 도메인(서열번호 4)로 구성된 단일-도메인 항체, 적어도 하나의 유비퀴틴 태그(서열번호 7) 및 링커(Gly-Gly 또는 (Gly-Gly-Gly-Gly-Ser)n 펩티드)로 구성된 단백질 복합체의 아미노산 서열에 해당하는 단일서열 DNA(V1/V2 및 E1/E2, 링커의 길이, 유비퀴틴의 개수의 조합에 따라 총 37가지)를 합성하였다. 상기 단백질 복합체를 발현시키기 위해 플라스미드에 삽입되는 DNA 절편의 뉴클레오티드 서열을 서열번호 45 내지 서열번호 81에 나타내었다. 상기 삽입 DNA 절편은 5' 말단에 EcoRI로 절단될 수 있는 뉴클레오티드 서열을, 3' 말단에 XhoI으로 절단될 수 있는 뉴클레오티드 서열을 포함하여, pcDNA3.1 myc/his A 벡터의 EcoRI-Xho1 절단 서열에 삽입될 수 있다.
실시예
2. 항
VEGF
-
EGFR
이중 특이 항체의 발현 및 정제
실시예 1에서 얻어진 재조합 벡터 중 서열번호 78의 DNA 절편이 삽입된 재조합 벡터를 HEK-293 세포주(Human Embryonic Kidney-293 cell)(한국세포주은행)에 리포솜을 사용하여 트랜스펙션(transfection)시키고, 이로부터 항 VEGF-EGFR 이중 특이 항체를 발현시켜 분리 및 정제하였다.
500 mL Erlenmeyer 플라스크에 HEK-293 세포를 1 x 106 cells/mL의 농도로 Freestyle293 배지 100 mL를 사용하여 seeding한 후, Freestyle™ MAX를 사용하여 DNA-리포솜 혼합액을 제조하였다. DNA-리포솜 복합체를 생성시키기 위해 실온에서 10분 동안 반응시키고, 복합체 혼합액을 HEK-293 세포에 첨가하였다. 세포를 37 ℃, 8% CO2 교반 인큐베이터(shaking incubator)에서 7일 동안 배양하여 단백질 발현을 유도하였다.
상기 이중 특이 항체 발현 세포의 배양액을 0.2 ㎛ 필터를 이용하여 필터링하였다. 이 세포 배양액을 단백질 A 친화성 컬럼(Protein A affinity column, GE healthcare)을 이용하여 크로마토그래피를 수행하였다. 세포 배양액에 포함된 이중 특이 항체를 단백질 A 컬럼에 결합시킨 후, PBS (phosphate-buffered saline, pH 7.4)로 세척하고, 용출액 (100mM Glycine-HCl, pH 2.7)을 이용하여 단백질 A 컬럼으로부터 항체 단백질을 용출하였다. 용출액에 1/10 부피의 트리스 버퍼 (1M Tris-HCl, pH 9.0)를 넣어 용출액을 중화하였다. 용출액을 디설팅 컬럼(desalting column)을 이용하여 완충액(30 mM Tris-HCl, pH 9.0)으로 교환한 후, 모노S 컬럼(MonoS, GE healthcare)에 적용시켜 양이온 교환 크로마토그래피를 수행하였다. 그 결과, 도 4에 나타난 바와 같이, 상기 이중 특이 항체를 용출하였다.
얻어진 용출액 중 이중 특이 항체의 존재 여부를 SDS-PAGE를 통해 확인하였다. 겔에 로딩하기 전에, 이중 특이 항체의 모노머 형태의 분자량을 확인하기 위해 β-머캅토에탄올을 처리하였다. 그 결과, 도 5에 나타난 바와 같이, 이중 특이 항체가 분리되어, VEGF 결합 부위를 포함하는 단일 암의(one-armed) 항체 및 EGFR 결합 부위를 포함하는 단일 암의 항체가 각각 모노머의 형태로 검출된 것을 확인하였다 (도 5).
실시예
3: 항
VEGF
-
EGFR
이중 특이 항체의 항원결합력 검증
실시예 2에서 제조한 이중 특이 항체의 이중특이적 항원-항체 반응을 확인하기 위해, BiacoreT100 기기(GE Healthcare Bio-Sciences AB)를 사용하여 VEGF 및 EGFR 에 대한 항체의 결합력을 검증하였다. 인간 VEGF(R&D Systems)를 CM5 칩에 표준 아민-커플링 화학반응에 의해 약 2000 RU(response unit)로 고정화하였다. 실시예 2에서 제조된 이중 특이 항체를 10 ㎕/분의 유속으로 1분 동안 흘려주었다. 결합을 확인한 후, 인간 EGFR 세포외 도메인(human EGFR extracellular domain, Prospec)을 10 ㎕/분의 유속으로 1분 동안 흘려주었다. 결합을 확인한 후, 글리신-HCl pH 2.0 (GE Healthcare) 용액을 10 ㎕/분의 유속으로 1분 동안 흘려주어 표면을 재생시켰다.
상기 분석 결과, 이중 특이 항체는 인간 VEGF와 인간 EGFR에 대한 결합력을 동시에 갖는 것으로 확인되었다 (도 6).
100: 제1 폴리펩티드
101: 제1 항원 결합 부위
102: 제1 태그
200: 제2 폴리펩티드
201: 제2 항원 결합 부위
202: 제2 태그
300: 링커
101: 제1 항원 결합 부위
102: 제1 태그
200: 제2 폴리펩티드
201: 제2 항원 결합 부위
202: 제2 태그
300: 링커
<110> Samsung Electronics Co. Ltd
<120> Bispecific antigen binding protein complex and preparation
methods of bispecific antibodies
<130> PN094315
<160> 81
<170> KopatentIn 2.0
<210> 1
<211> 19
<212> PRT
<213> Artificial Sequence
<220>
<223> signal sequence
<400> 1
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser
<210> 2
<211> 108
<212> PRT
<213> Artificial Sequence
<220>
<223> V1(binding site of VEGF)
<400> 2
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Trp Ile Gly Pro Glu
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr His Thr Ser Ile Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Met Phe Gln Pro Arg
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Arg Arg
100 105
<210> 3
<211> 108
<212> PRT
<213> Artificial Sequence
<220>
<223> V2(binding site of VEGF)
<400> 3
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Lys Ile Phe Asn Gly
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr His Ser Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Val Leu Leu Tyr Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 4
<211> 232
<212> PRT
<213> Artificial Sequence
<220>
<223> Fc domain containing Hinge region
<400> 4
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Lys
225 230
<210> 5
<211> 108
<212> PRT
<213> Artificial Sequence
<220>
<223> E1(binding site of EGFR)
<400> 5
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Trp Ile Gly Ile Leu
20 25 30
Val Asp Trp Tyr Gln Gln Lys Pro Gly Glu Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Ala Ser Phe Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Phe Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu His Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Pro Ala Pro Leu
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 6
<211> 108
<212> PRT
<213> Artificial Sequence
<220>
<223> E2(binding site of EGFR)
<400> 6
Asp Ile Gln Met Thr Gln Ser Pro Thr Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Trp Ile Gly Asn Leu
20 25 30
Leu Asp Trp Tyr Gln Gln Lys Pro Gly Glu Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Ala Ser Phe Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Gly Gly Phe 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 Ala Asn Pro Ala Pro Leu
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 7
<211> 76
<212> PRT
<213> Artificial Sequence
<220>
<223> ubiquitin tag
<400> 7
Met Gln Ile Phe Val Lys Thr Leu Thr Gly Lys Thr Ile Thr Leu Glu
1 5 10 15
Val Glu Pro Ser Asp Thr Ile Glu Asn Val Lys Ala Lys Ile Gln Asp
20 25 30
Lys Glu Gly Ile Pro Pro Asp Gln Gln Arg Leu Ile Phe Ala Gly Lys
35 40 45
Gln Leu Glu Asp Gly Arg Thr Leu Ser Asp Tyr Asn Ile Gln Lys Glu
50 55 60
Ser Thr Leu His Leu Val Leu Arg Leu Arg Gly Gly
65 70 75
<210> 8
<211> 871
<212> PRT
<213> Artificial Sequence
<220>
<223> Protein complex comprising VEGF and EGFR specific binding
peptides #1
<400> 8
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
20 25 30
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Trp Ile
35 40 45
Gly Pro Glu Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
50 55 60
Leu Leu Ile Tyr His Thr Ser Ile Leu Gln Ser Gly Val Pro Ser Arg
65 70 75 80
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
85 90 95
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Met Phe
100 105 110
Gln Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Arg Arg Glu
115 120 125
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
130 135 140
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
145 150 155 160
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
165 170 175
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
180 185 190
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
195 200 205
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
210 215 220
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
225 230 235 240
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
245 250 255
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
260 265 270
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
275 280 285
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
290 295 300
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
305 310 315 320
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
325 330 335
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
340 345 350
Leu Ser Leu Ser Pro Gly Lys Met Gln Ile Phe Val Lys Thr Leu Thr
355 360 365
Gly Lys Thr Ile Thr Leu Glu Val Glu Pro Ser Asp Thr Ile Glu Asn
370 375 380
Val Lys Ala Lys Ile Gln Asp Lys Glu Gly Ile Pro Pro Asp Gln Gln
385 390 395 400
Arg Leu Ile Phe Ala Gly Lys Gln Leu Glu Asp Gly Arg Thr Leu Ser
405 410 415
Asp Tyr Asn Ile Gln Lys Glu Ser Thr Leu His Leu Val Leu Arg Leu
420 425 430
Arg Gly Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Met Gln Ile Phe Val Lys Thr Leu Thr
450 455 460
Gly Lys Thr Ile Thr Leu Glu Val Glu Pro Ser Asp Thr Ile Glu Asn
465 470 475 480
Val Lys Ala Lys Ile Gln Asp Lys Glu Gly Ile Pro Pro Asp Gln Gln
485 490 495
Arg Leu Ile Phe Ala Gly Lys Gln Leu Glu Asp Gly Arg Thr Leu Ser
500 505 510
Asp Tyr Asn Ile Gln Lys Glu Ser Thr Leu His Leu Val Leu Arg Leu
515 520 525
Arg Gly Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
530 535 540
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Trp Ile
545 550 555 560
Gly Ile Leu Val Asp Trp Tyr Gln Gln Lys Pro Gly Glu Ala Pro Lys
565 570 575
Leu Leu Ile Tyr Tyr Ala Ser Phe Leu Gln Ser Gly Val Pro Ser Arg
580 585 590
Phe Ser Gly Ser Gly Phe Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
595 600 605
Leu His Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Pro
610 615 620
Ala Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Glu
625 630 635 640
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
645 650 655
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
660 665 670
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
675 680 685
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
690 695 700
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
705 710 715 720
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
725 730 735
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
740 745 750
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
755 760 765
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
770 775 780
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
785 790 795 800
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
805 810 815
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
820 825 830
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
835 840 845
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
850 855 860
Leu Ser Leu Ser Pro Gly Lys
865 870
<210> 9
<211> 876
<212> PRT
<213> Artificial Sequence
<220>
<223> Protein complex comprising VEGF and EGFR specific binding
peptides #2
<400> 9
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
20 25 30
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Trp Ile
35 40 45
Gly Pro Glu Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
50 55 60
Leu Leu Ile Tyr His Thr Ser Ile Leu Gln Ser Gly Val Pro Ser Arg
65 70 75 80
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
85 90 95
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Met Phe
100 105 110
Gln Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Arg Arg Glu
115 120 125
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
130 135 140
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
145 150 155 160
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
165 170 175
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
180 185 190
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
195 200 205
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
210 215 220
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
225 230 235 240
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
245 250 255
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
260 265 270
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
275 280 285
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
290 295 300
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
305 310 315 320
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
325 330 335
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
340 345 350
Leu Ser Leu Ser Pro Gly Lys Met Gln Ile Phe Val Lys Thr Leu Thr
355 360 365
Gly Lys Thr Ile Thr Leu Glu Val Glu Pro Ser Asp Thr Ile Glu Asn
370 375 380
Val Lys Ala Lys Ile Gln Asp Lys Glu Gly Ile Pro Pro Asp Gln Gln
385 390 395 400
Arg Leu Ile Phe Ala Gly Lys Gln Leu Glu Asp Gly Arg Thr Leu Ser
405 410 415
Asp Tyr Asn Ile Gln Lys Glu Ser Thr Leu His Leu Val Leu Arg Leu
420 425 430
Arg Gly Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Met Gln Ile Phe
450 455 460
Val Lys Thr Leu Thr Gly Lys Thr Ile Thr Leu Glu Val Glu Pro Ser
465 470 475 480
Asp Thr Ile Glu Asn Val Lys Ala Lys Ile Gln Asp Lys Glu Gly Ile
485 490 495
Pro Pro Asp Gln Gln Arg Leu Ile Phe Ala Gly Lys Gln Leu Glu Asp
500 505 510
Gly Arg Thr Leu Ser Asp Tyr Asn Ile Gln Lys Glu Ser Thr Leu His
515 520 525
Leu Val Leu Arg Leu Arg Gly Gly Asp Ile Gln Met Thr Gln Ser Pro
530 535 540
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
545 550 555 560
Ala Ser Gln Trp Ile Gly Ile Leu Val Asp Trp Tyr Gln Gln Lys Pro
565 570 575
Gly Glu Ala Pro Lys Leu Leu Ile Tyr Tyr Ala Ser Phe Leu Gln Ser
580 585 590
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Phe Gly Thr Asp Phe Thr
595 600 605
Leu Thr Ile Ser Ser Leu His Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
610 615 620
Gln Gln Ala Asn Pro Ala Pro Leu Thr Phe Gly Gln Gly Thr Lys Val
625 630 635 640
Glu Ile Lys Arg Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
645 650 655
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
660 665 670
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
675 680 685
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
690 695 700
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
705 710 715 720
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
725 730 735
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
740 745 750
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
755 760 765
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
770 775 780
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
785 790 795 800
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
805 810 815
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
820 825 830
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
835 840 845
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
850 855 860
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
865 870 875
<210> 10
<211> 881
<212> PRT
<213> Artificial Sequence
<220>
<223> Protein complex comprising VEGF and EGFR specific binding
peptides #3
<400> 10
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
20 25 30
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Trp Ile
35 40 45
Gly Pro Glu Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
50 55 60
Leu Leu Ile Tyr His Thr Ser Ile Leu Gln Ser Gly Val Pro Ser Arg
65 70 75 80
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
85 90 95
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Met Phe
100 105 110
Gln Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Arg Arg Glu
115 120 125
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
130 135 140
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
145 150 155 160
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
165 170 175
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
180 185 190
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
195 200 205
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
210 215 220
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
225 230 235 240
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
245 250 255
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
260 265 270
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
275 280 285
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
290 295 300
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
305 310 315 320
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
325 330 335
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
340 345 350
Leu Ser Leu Ser Pro Gly Lys Met Gln Ile Phe Val Lys Thr Leu Thr
355 360 365
Gly Lys Thr Ile Thr Leu Glu Val Glu Pro Ser Asp Thr Ile Glu Asn
370 375 380
Val Lys Ala Lys Ile Gln Asp Lys Glu Gly Ile Pro Pro Asp Gln Gln
385 390 395 400
Arg Leu Ile Phe Ala Gly Lys Gln Leu Glu Asp Gly Arg Thr Leu Ser
405 410 415
Asp Tyr Asn Ile Gln Lys Glu Ser Thr Leu His Leu Val Leu Arg Leu
420 425 430
Arg Gly Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
450 455 460
Ser Met Gln Ile Phe Val Lys Thr Leu Thr Gly Lys Thr Ile Thr Leu
465 470 475 480
Glu Val Glu Pro Ser Asp Thr Ile Glu Asn Val Lys Ala Lys Ile Gln
485 490 495
Asp Lys Glu Gly Ile Pro Pro Asp Gln Gln Arg Leu Ile Phe Ala Gly
500 505 510
Lys Gln Leu Glu Asp Gly Arg Thr Leu Ser Asp Tyr Asn Ile Gln Lys
515 520 525
Glu Ser Thr Leu His Leu Val Leu Arg Leu Arg Gly Gly Asp Ile Gln
530 535 540
Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val
545 550 555 560
Thr Ile Thr Cys Arg Ala Ser Gln Trp Ile Gly Ile Leu Val Asp Trp
565 570 575
Tyr Gln Gln Lys Pro Gly Glu Ala Pro Lys Leu Leu Ile Tyr Tyr Ala
580 585 590
Ser Phe Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Phe
595 600 605
Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu His Pro Glu Asp Phe
610 615 620
Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Pro Ala Pro Leu Thr Phe Gly
625 630 635 640
Gln Gly Thr Lys Val Glu Ile Lys Arg Glu Pro Lys Ser Cys Asp Lys
645 650 655
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
660 665 670
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
675 680 685
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
690 695 700
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
705 710 715 720
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
725 730 735
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
740 745 750
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
755 760 765
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
770 775 780
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
785 790 795 800
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
805 810 815
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
820 825 830
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
835 840 845
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
850 855 860
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
865 870 875 880
Lys
<210> 11
<211> 886
<212> PRT
<213> Artificial Sequence
<220>
<223> Protein complex comprising VEGF and EGFR specific binding
peptides #4
<400> 11
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
20 25 30
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Trp Ile
35 40 45
Gly Pro Glu Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
50 55 60
Leu Leu Ile Tyr His Thr Ser Ile Leu Gln Ser Gly Val Pro Ser Arg
65 70 75 80
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
85 90 95
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Met Phe
100 105 110
Gln Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Arg Arg Glu
115 120 125
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
130 135 140
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
145 150 155 160
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
165 170 175
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
180 185 190
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
195 200 205
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
210 215 220
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
225 230 235 240
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
245 250 255
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
260 265 270
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
275 280 285
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
290 295 300
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
305 310 315 320
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
325 330 335
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
340 345 350
Leu Ser Leu Ser Pro Gly Lys Met Gln Ile Phe Val Lys Thr Leu Thr
355 360 365
Gly Lys Thr Ile Thr Leu Glu Val Glu Pro Ser Asp Thr Ile Glu Asn
370 375 380
Val Lys Ala Lys Ile Gln Asp Lys Glu Gly Ile Pro Pro Asp Gln Gln
385 390 395 400
Arg Leu Ile Phe Ala Gly Lys Gln Leu Glu Asp Gly Arg Thr Leu Ser
405 410 415
Asp Tyr Asn Ile Gln Lys Glu Ser Thr Leu His Leu Val Leu Arg Leu
420 425 430
Arg Gly Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
450 455 460
Ser Gly Gly Gly Gly Ser Met Gln Ile Phe Val Lys Thr Leu Thr Gly
465 470 475 480
Lys Thr Ile Thr Leu Glu Val Glu Pro Ser Asp Thr Ile Glu Asn Val
485 490 495
Lys Ala Lys Ile Gln Asp Lys Glu Gly Ile Pro Pro Asp Gln Gln Arg
500 505 510
Leu Ile Phe Ala Gly Lys Gln Leu Glu Asp Gly Arg Thr Leu Ser Asp
515 520 525
Tyr Asn Ile Gln Lys Glu Ser Thr Leu His Leu Val Leu Arg Leu Arg
530 535 540
Gly Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser
545 550 555 560
Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Trp Ile Gly
565 570 575
Ile Leu Val Asp Trp Tyr Gln Gln Lys Pro Gly Glu Ala Pro Lys Leu
580 585 590
Leu Ile Tyr Tyr Ala Ser Phe Leu Gln Ser Gly Val Pro Ser Arg Phe
595 600 605
Ser Gly Ser Gly Phe Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu
610 615 620
His Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Pro Ala
625 630 635 640
Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Glu Pro
645 650 655
Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
660 665 670
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
675 680 685
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
690 695 700
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
705 710 715 720
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
725 730 735
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
740 745 750
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
755 760 765
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
770 775 780
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
785 790 795 800
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
805 810 815
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
820 825 830
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
835 840 845
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
850 855 860
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
865 870 875 880
Ser Leu Ser Pro Gly Lys
885
<210> 12
<211> 891
<212> PRT
<213> Artificial Sequence
<220>
<223> Protein complex comprising VEGF and EGFR specific binding
peptides #5
<400> 12
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
20 25 30
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Trp Ile
35 40 45
Gly Pro Glu Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
50 55 60
Leu Leu Ile Tyr His Thr Ser Ile Leu Gln Ser Gly Val Pro Ser Arg
65 70 75 80
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
85 90 95
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Met Phe
100 105 110
Gln Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Arg Arg Glu
115 120 125
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
130 135 140
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
145 150 155 160
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
165 170 175
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
180 185 190
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
195 200 205
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
210 215 220
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
225 230 235 240
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
245 250 255
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
260 265 270
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
275 280 285
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
290 295 300
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
305 310 315 320
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
325 330 335
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
340 345 350
Leu Ser Leu Ser Pro Gly Lys Met Gln Ile Phe Val Lys Thr Leu Thr
355 360 365
Gly Lys Thr Ile Thr Leu Glu Val Glu Pro Ser Asp Thr Ile Glu Asn
370 375 380
Val Lys Ala Lys Ile Gln Asp Lys Glu Gly Ile Pro Pro Asp Gln Gln
385 390 395 400
Arg Leu Ile Phe Ala Gly Lys Gln Leu Glu Asp Gly Arg Thr Leu Ser
405 410 415
Asp Tyr Asn Ile Gln Lys Glu Ser Thr Leu His Leu Val Leu Arg Leu
420 425 430
Arg Gly Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
450 455 460
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Met Gln Ile Phe Val
465 470 475 480
Lys Thr Leu Thr Gly Lys Thr Ile Thr Leu Glu Val Glu Pro Ser Asp
485 490 495
Thr Ile Glu Asn Val Lys Ala Lys Ile Gln Asp Lys Glu Gly Ile Pro
500 505 510
Pro Asp Gln Gln Arg Leu Ile Phe Ala Gly Lys Gln Leu Glu Asp Gly
515 520 525
Arg Thr Leu Ser Asp Tyr Asn Ile Gln Lys Glu Ser Thr Leu His Leu
530 535 540
Val Leu Arg Leu Arg Gly Gly Asp Ile Gln Met Thr Gln Ser Pro Ser
545 550 555 560
Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala
565 570 575
Ser Gln Trp Ile Gly Ile Leu Val Asp Trp Tyr Gln Gln Lys Pro Gly
580 585 590
Glu Ala Pro Lys Leu Leu Ile Tyr Tyr Ala Ser Phe Leu Gln Ser Gly
595 600 605
Val Pro Ser Arg Phe Ser Gly Ser Gly Phe Gly Thr Asp Phe Thr Leu
610 615 620
Thr Ile Ser Ser Leu His Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln
625 630 635 640
Gln Ala Asn Pro Ala Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu
645 650 655
Ile Lys Arg Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro
660 665 670
Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
675 680 685
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
690 695 700
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
705 710 715 720
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
725 730 735
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
740 745 750
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
755 760 765
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
770 775 780
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
785 790 795 800
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
805 810 815
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
820 825 830
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
835 840 845
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
850 855 860
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
865 870 875 880
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
885 890
<210> 13
<211> 896
<212> PRT
<213> Artificial Sequence
<220>
<223> Protein complex comprising VEGF and EGFR specific binding
peptides #6
<400> 13
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
20 25 30
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Trp Ile
35 40 45
Gly Pro Glu Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
50 55 60
Leu Leu Ile Tyr His Thr Ser Ile Leu Gln Ser Gly Val Pro Ser Arg
65 70 75 80
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
85 90 95
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Met Phe
100 105 110
Gln Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Arg Arg Glu
115 120 125
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
130 135 140
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
145 150 155 160
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
165 170 175
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
180 185 190
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
195 200 205
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
210 215 220
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
225 230 235 240
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
245 250 255
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
260 265 270
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
275 280 285
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
290 295 300
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
305 310 315 320
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
325 330 335
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
340 345 350
Leu Ser Leu Ser Pro Gly Lys Met Gln Ile Phe Val Lys Thr Leu Thr
355 360 365
Gly Lys Thr Ile Thr Leu Glu Val Glu Pro Ser Asp Thr Ile Glu Asn
370 375 380
Val Lys Ala Lys Ile Gln Asp Lys Glu Gly Ile Pro Pro Asp Gln Gln
385 390 395 400
Arg Leu Ile Phe Ala Gly Lys Gln Leu Glu Asp Gly Arg Thr Leu Ser
405 410 415
Asp Tyr Asn Ile Gln Lys Glu Ser Thr Leu His Leu Val Leu Arg Leu
420 425 430
Arg Gly Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
450 455 460
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
465 470 475 480
Met Gln Ile Phe Val Lys Thr Leu Thr Gly Lys Thr Ile Thr Leu Glu
485 490 495
Val Glu Pro Ser Asp Thr Ile Glu Asn Val Lys Ala Lys Ile Gln Asp
500 505 510
Lys Glu Gly Ile Pro Pro Asp Gln Gln Arg Leu Ile Phe Ala Gly Lys
515 520 525
Gln Leu Glu Asp Gly Arg Thr Leu Ser Asp Tyr Asn Ile Gln Lys Glu
530 535 540
Ser Thr Leu His Leu Val Leu Arg Leu Arg Gly Gly Asp Ile Gln Met
545 550 555 560
Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr
565 570 575
Ile Thr Cys Arg Ala Ser Gln Trp Ile Gly Ile Leu Val Asp Trp Tyr
580 585 590
Gln Gln Lys Pro Gly Glu Ala Pro Lys Leu Leu Ile Tyr Tyr Ala Ser
595 600 605
Phe Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Phe Gly
610 615 620
Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu His Pro Glu Asp Phe Ala
625 630 635 640
Thr Tyr Tyr Cys Gln Gln Ala Asn Pro Ala Pro Leu Thr Phe Gly Gln
645 650 655
Gly Thr Lys Val Glu Ile Lys Arg Glu Pro Lys Ser Cys Asp Lys Thr
660 665 670
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
675 680 685
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
690 695 700
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
705 710 715 720
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
725 730 735
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
740 745 750
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
755 760 765
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
770 775 780
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
785 790 795 800
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
805 810 815
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
820 825 830
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
835 840 845
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
850 855 860
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
865 870 875 880
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
885 890 895
<210> 14
<211> 901
<212> PRT
<213> Artificial Sequence
<220>
<223> Protein complex comprising VEGF and EGFR specific binding
peptides #7
<400> 14
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
20 25 30
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Trp Ile
35 40 45
Gly Pro Glu Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
50 55 60
Leu Leu Ile Tyr His Thr Ser Ile Leu Gln Ser Gly Val Pro Ser Arg
65 70 75 80
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
85 90 95
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Met Phe
100 105 110
Gln Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Arg Arg Glu
115 120 125
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
130 135 140
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
145 150 155 160
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
165 170 175
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
180 185 190
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
195 200 205
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
210 215 220
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
225 230 235 240
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
245 250 255
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
260 265 270
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
275 280 285
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
290 295 300
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
305 310 315 320
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
325 330 335
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
340 345 350
Leu Ser Leu Ser Pro Gly Lys Met Gln Ile Phe Val Lys Thr Leu Thr
355 360 365
Gly Lys Thr Ile Thr Leu Glu Val Glu Pro Ser Asp Thr Ile Glu Asn
370 375 380
Val Lys Ala Lys Ile Gln Asp Lys Glu Gly Ile Pro Pro Asp Gln Gln
385 390 395 400
Arg Leu Ile Phe Ala Gly Lys Gln Leu Glu Asp Gly Arg Thr Leu Ser
405 410 415
Asp Tyr Asn Ile Gln Lys Glu Ser Thr Leu His Leu Val Leu Arg Leu
420 425 430
Arg Gly Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
450 455 460
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
465 470 475 480
Gly Gly Gly Gly Ser Met Gln Ile Phe Val Lys Thr Leu Thr Gly Lys
485 490 495
Thr Ile Thr Leu Glu Val Glu Pro Ser Asp Thr Ile Glu Asn Val Lys
500 505 510
Ala Lys Ile Gln Asp Lys Glu Gly Ile Pro Pro Asp Gln Gln Arg Leu
515 520 525
Ile Phe Ala Gly Lys Gln Leu Glu Asp Gly Arg Thr Leu Ser Asp Tyr
530 535 540
Asn Ile Gln Lys Glu Ser Thr Leu His Leu Val Leu Arg Leu Arg Gly
545 550 555 560
Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val
565 570 575
Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Trp Ile Gly Ile
580 585 590
Leu Val Asp Trp Tyr Gln Gln Lys Pro Gly Glu Ala Pro Lys Leu Leu
595 600 605
Ile Tyr Tyr Ala Ser Phe Leu Gln Ser Gly Val Pro Ser Arg Phe Ser
610 615 620
Gly Ser Gly Phe Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu His
625 630 635 640
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Pro Ala Pro
645 650 655
Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Glu Pro Lys
660 665 670
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu
675 680 685
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
690 695 700
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
705 710 715 720
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
725 730 735
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
740 745 750
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
755 760 765
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
770 775 780
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
785 790 795 800
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
805 810 815
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
820 825 830
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
835 840 845
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
850 855 860
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
865 870 875 880
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
885 890 895
Leu Ser Pro Gly Lys
900
<210> 15
<211> 871
<212> PRT
<213> Artificial Sequence
<220>
<223> Protein complex comprising VEGF and EGFR specific binding
peptides #8
<400> 15
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
20 25 30
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Trp Ile
35 40 45
Gly Pro Glu Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
50 55 60
Leu Leu Ile Tyr His Thr Ser Ile Leu Gln Ser Gly Val Pro Ser Arg
65 70 75 80
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
85 90 95
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Met Phe
100 105 110
Gln Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Arg Arg Glu
115 120 125
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
130 135 140
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
145 150 155 160
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
165 170 175
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
180 185 190
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
195 200 205
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
210 215 220
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
225 230 235 240
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
245 250 255
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
260 265 270
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
275 280 285
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
290 295 300
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
305 310 315 320
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
325 330 335
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
340 345 350
Leu Ser Leu Ser Pro Gly Lys Met Gln Ile Phe Val Lys Thr Leu Thr
355 360 365
Gly Lys Thr Ile Thr Leu Glu Val Glu Pro Ser Asp Thr Ile Glu Asn
370 375 380
Val Lys Ala Lys Ile Gln Asp Lys Glu Gly Ile Pro Pro Asp Gln Gln
385 390 395 400
Arg Leu Ile Phe Ala Gly Lys Gln Leu Glu Asp Gly Arg Thr Leu Ser
405 410 415
Asp Tyr Asn Ile Gln Lys Glu Ser Thr Leu His Leu Val Leu Arg Leu
420 425 430
Arg Gly Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Met Gln Ile Phe Val Lys Thr Leu Thr
450 455 460
Gly Lys Thr Ile Thr Leu Glu Val Glu Pro Ser Asp Thr Ile Glu Asn
465 470 475 480
Val Lys Ala Lys Ile Gln Asp Lys Glu Gly Ile Pro Pro Asp Gln Gln
485 490 495
Arg Leu Ile Phe Ala Gly Lys Gln Leu Glu Asp Gly Arg Thr Leu Ser
500 505 510
Asp Tyr Asn Ile Gln Lys Glu Ser Thr Leu His Leu Val Leu Arg Leu
515 520 525
Arg Gly Gly Asp Ile Gln Met Thr Gln Ser Pro Thr Ser Leu Ser Ala
530 535 540
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Trp Ile
545 550 555 560
Gly Asn Leu Leu Asp Trp Tyr Gln Gln Lys Pro Gly Glu Ala Pro Lys
565 570 575
Leu Leu Ile Tyr Tyr Ala Ser Phe Leu Gln Ser Gly Val Pro Ser Arg
580 585 590
Phe Ser Gly Gly Gly Phe Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
595 600 605
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Pro
610 615 620
Ala Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Glu
625 630 635 640
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
645 650 655
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
660 665 670
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
675 680 685
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
690 695 700
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
705 710 715 720
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
725 730 735
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
740 745 750
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
755 760 765
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
770 775 780
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
785 790 795 800
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
805 810 815
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
820 825 830
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
835 840 845
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
850 855 860
Leu Ser Leu Ser Pro Gly Lys
865 870
<210> 16
<211> 876
<212> PRT
<213> Artificial Sequence
<220>
<223> Protein complex comprising VEGF and EGFR specific binding
peptides #9
<400> 16
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
20 25 30
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Trp Ile
35 40 45
Gly Pro Glu Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
50 55 60
Leu Leu Ile Tyr His Thr Ser Ile Leu Gln Ser Gly Val Pro Ser Arg
65 70 75 80
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
85 90 95
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Met Phe
100 105 110
Gln Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Arg Arg Glu
115 120 125
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
130 135 140
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
145 150 155 160
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
165 170 175
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
180 185 190
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
195 200 205
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
210 215 220
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
225 230 235 240
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
245 250 255
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
260 265 270
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
275 280 285
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
290 295 300
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
305 310 315 320
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
325 330 335
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
340 345 350
Leu Ser Leu Ser Pro Gly Lys Met Gln Ile Phe Val Lys Thr Leu Thr
355 360 365
Gly Lys Thr Ile Thr Leu Glu Val Glu Pro Ser Asp Thr Ile Glu Asn
370 375 380
Val Lys Ala Lys Ile Gln Asp Lys Glu Gly Ile Pro Pro Asp Gln Gln
385 390 395 400
Arg Leu Ile Phe Ala Gly Lys Gln Leu Glu Asp Gly Arg Thr Leu Ser
405 410 415
Asp Tyr Asn Ile Gln Lys Glu Ser Thr Leu His Leu Val Leu Arg Leu
420 425 430
Arg Gly Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Met Gln Ile Phe
450 455 460
Val Lys Thr Leu Thr Gly Lys Thr Ile Thr Leu Glu Val Glu Pro Ser
465 470 475 480
Asp Thr Ile Glu Asn Val Lys Ala Lys Ile Gln Asp Lys Glu Gly Ile
485 490 495
Pro Pro Asp Gln Gln Arg Leu Ile Phe Ala Gly Lys Gln Leu Glu Asp
500 505 510
Gly Arg Thr Leu Ser Asp Tyr Asn Ile Gln Lys Glu Ser Thr Leu His
515 520 525
Leu Val Leu Arg Leu Arg Gly Gly Asp Ile Gln Met Thr Gln Ser Pro
530 535 540
Thr Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
545 550 555 560
Ala Ser Gln Trp Ile Gly Asn Leu Leu Asp Trp Tyr Gln Gln Lys Pro
565 570 575
Gly Glu Ala Pro Lys Leu Leu Ile Tyr Tyr Ala Ser Phe Leu Gln Ser
580 585 590
Gly Val Pro Ser Arg Phe Ser Gly Gly Gly Phe Gly Thr Asp Phe Thr
595 600 605
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
610 615 620
Gln Gln Ala Asn Pro Ala Pro Leu Thr Phe Gly Gln Gly Thr Lys Val
625 630 635 640
Glu Ile Lys Arg Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
645 650 655
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
660 665 670
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
675 680 685
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
690 695 700
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
705 710 715 720
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
725 730 735
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
740 745 750
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
755 760 765
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
770 775 780
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
785 790 795 800
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
805 810 815
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
820 825 830
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
835 840 845
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
850 855 860
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
865 870 875
<210> 17
<211> 881
<212> PRT
<213> Artificial Sequence
<220>
<223> Protein complex comprising VEGF and EGFR specific binding
peptides #10
<400> 17
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
20 25 30
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Trp Ile
35 40 45
Gly Pro Glu Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
50 55 60
Leu Leu Ile Tyr His Thr Ser Ile Leu Gln Ser Gly Val Pro Ser Arg
65 70 75 80
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
85 90 95
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Met Phe
100 105 110
Gln Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Arg Arg Glu
115 120 125
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
130 135 140
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
145 150 155 160
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
165 170 175
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
180 185 190
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
195 200 205
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
210 215 220
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
225 230 235 240
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
245 250 255
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
260 265 270
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
275 280 285
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
290 295 300
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
305 310 315 320
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
325 330 335
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
340 345 350
Leu Ser Leu Ser Pro Gly Lys Met Gln Ile Phe Val Lys Thr Leu Thr
355 360 365
Gly Lys Thr Ile Thr Leu Glu Val Glu Pro Ser Asp Thr Ile Glu Asn
370 375 380
Val Lys Ala Lys Ile Gln Asp Lys Glu Gly Ile Pro Pro Asp Gln Gln
385 390 395 400
Arg Leu Ile Phe Ala Gly Lys Gln Leu Glu Asp Gly Arg Thr Leu Ser
405 410 415
Asp Tyr Asn Ile Gln Lys Glu Ser Thr Leu His Leu Val Leu Arg Leu
420 425 430
Arg Gly Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
450 455 460
Ser Met Gln Ile Phe Val Lys Thr Leu Thr Gly Lys Thr Ile Thr Leu
465 470 475 480
Glu Val Glu Pro Ser Asp Thr Ile Glu Asn Val Lys Ala Lys Ile Gln
485 490 495
Asp Lys Glu Gly Ile Pro Pro Asp Gln Gln Arg Leu Ile Phe Ala Gly
500 505 510
Lys Gln Leu Glu Asp Gly Arg Thr Leu Ser Asp Tyr Asn Ile Gln Lys
515 520 525
Glu Ser Thr Leu His Leu Val Leu Arg Leu Arg Gly Gly Asp Ile Gln
530 535 540
Met Thr Gln Ser Pro Thr Ser Leu Ser Ala Ser Val Gly Asp Arg Val
545 550 555 560
Thr Ile Thr Cys Arg Ala Ser Gln Trp Ile Gly Asn Leu Leu Asp Trp
565 570 575
Tyr Gln Gln Lys Pro Gly Glu Ala Pro Lys Leu Leu Ile Tyr Tyr Ala
580 585 590
Ser Phe Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Gly Gly Phe
595 600 605
Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe
610 615 620
Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Pro Ala Pro Leu Thr Phe Gly
625 630 635 640
Gln Gly Thr Lys Val Glu Ile Lys Arg Glu Pro Lys Ser Cys Asp Lys
645 650 655
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
660 665 670
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
675 680 685
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
690 695 700
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
705 710 715 720
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
725 730 735
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
740 745 750
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
755 760 765
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
770 775 780
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
785 790 795 800
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
805 810 815
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
820 825 830
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
835 840 845
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
850 855 860
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
865 870 875 880
Lys
<210> 18
<211> 886
<212> PRT
<213> Artificial Sequence
<220>
<223> Protein complex comprising VEGF and EGFR specific binding
peptides #11
<400> 18
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
20 25 30
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Trp Ile
35 40 45
Gly Pro Glu Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
50 55 60
Leu Leu Ile Tyr His Thr Ser Ile Leu Gln Ser Gly Val Pro Ser Arg
65 70 75 80
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
85 90 95
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Met Phe
100 105 110
Gln Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Arg Arg Glu
115 120 125
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
130 135 140
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
145 150 155 160
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
165 170 175
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
180 185 190
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
195 200 205
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
210 215 220
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
225 230 235 240
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
245 250 255
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
260 265 270
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
275 280 285
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
290 295 300
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
305 310 315 320
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
325 330 335
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
340 345 350
Leu Ser Leu Ser Pro Gly Lys Met Gln Ile Phe Val Lys Thr Leu Thr
355 360 365
Gly Lys Thr Ile Thr Leu Glu Val Glu Pro Ser Asp Thr Ile Glu Asn
370 375 380
Val Lys Ala Lys Ile Gln Asp Lys Glu Gly Ile Pro Pro Asp Gln Gln
385 390 395 400
Arg Leu Ile Phe Ala Gly Lys Gln Leu Glu Asp Gly Arg Thr Leu Ser
405 410 415
Asp Tyr Asn Ile Gln Lys Glu Ser Thr Leu His Leu Val Leu Arg Leu
420 425 430
Arg Gly Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
450 455 460
Ser Gly Gly Gly Gly Ser Met Gln Ile Phe Val Lys Thr Leu Thr Gly
465 470 475 480
Lys Thr Ile Thr Leu Glu Val Glu Pro Ser Asp Thr Ile Glu Asn Val
485 490 495
Lys Ala Lys Ile Gln Asp Lys Glu Gly Ile Pro Pro Asp Gln Gln Arg
500 505 510
Leu Ile Phe Ala Gly Lys Gln Leu Glu Asp Gly Arg Thr Leu Ser Asp
515 520 525
Tyr Asn Ile Gln Lys Glu Ser Thr Leu His Leu Val Leu Arg Leu Arg
530 535 540
Gly Gly Asp Ile Gln Met Thr Gln Ser Pro Thr Ser Leu Ser Ala Ser
545 550 555 560
Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Trp Ile Gly
565 570 575
Asn Leu Leu Asp Trp Tyr Gln Gln Lys Pro Gly Glu Ala Pro Lys Leu
580 585 590
Leu Ile Tyr Tyr Ala Ser Phe Leu Gln Ser Gly Val Pro Ser Arg Phe
595 600 605
Ser Gly Gly Gly Phe Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu
610 615 620
Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Pro Ala
625 630 635 640
Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Glu Pro
645 650 655
Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
660 665 670
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
675 680 685
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
690 695 700
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
705 710 715 720
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
725 730 735
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
740 745 750
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
755 760 765
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
770 775 780
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
785 790 795 800
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
805 810 815
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
820 825 830
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
835 840 845
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
850 855 860
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
865 870 875 880
Ser Leu Ser Pro Gly Lys
885
<210> 19
<211> 891
<212> PRT
<213> Artificial Sequence
<220>
<223> Protein complex comprising VEGF and EGFR specific binding
peptides #12
<400> 19
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
20 25 30
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Trp Ile
35 40 45
Gly Pro Glu Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
50 55 60
Leu Leu Ile Tyr His Thr Ser Ile Leu Gln Ser Gly Val Pro Ser Arg
65 70 75 80
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
85 90 95
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Met Phe
100 105 110
Gln Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Arg Arg Glu
115 120 125
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
130 135 140
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
145 150 155 160
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
165 170 175
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
180 185 190
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
195 200 205
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
210 215 220
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
225 230 235 240
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
245 250 255
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
260 265 270
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
275 280 285
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
290 295 300
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
305 310 315 320
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
325 330 335
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
340 345 350
Leu Ser Leu Ser Pro Gly Lys Met Gln Ile Phe Val Lys Thr Leu Thr
355 360 365
Gly Lys Thr Ile Thr Leu Glu Val Glu Pro Ser Asp Thr Ile Glu Asn
370 375 380
Val Lys Ala Lys Ile Gln Asp Lys Glu Gly Ile Pro Pro Asp Gln Gln
385 390 395 400
Arg Leu Ile Phe Ala Gly Lys Gln Leu Glu Asp Gly Arg Thr Leu Ser
405 410 415
Asp Tyr Asn Ile Gln Lys Glu Ser Thr Leu His Leu Val Leu Arg Leu
420 425 430
Arg Gly Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
450 455 460
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Met Gln Ile Phe Val
465 470 475 480
Lys Thr Leu Thr Gly Lys Thr Ile Thr Leu Glu Val Glu Pro Ser Asp
485 490 495
Thr Ile Glu Asn Val Lys Ala Lys Ile Gln Asp Lys Glu Gly Ile Pro
500 505 510
Pro Asp Gln Gln Arg Leu Ile Phe Ala Gly Lys Gln Leu Glu Asp Gly
515 520 525
Arg Thr Leu Ser Asp Tyr Asn Ile Gln Lys Glu Ser Thr Leu His Leu
530 535 540
Val Leu Arg Leu Arg Gly Gly Asp Ile Gln Met Thr Gln Ser Pro Thr
545 550 555 560
Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala
565 570 575
Ser Gln Trp Ile Gly Asn Leu Leu Asp Trp Tyr Gln Gln Lys Pro Gly
580 585 590
Glu Ala Pro Lys Leu Leu Ile Tyr Tyr Ala Ser Phe Leu Gln Ser Gly
595 600 605
Val Pro Ser Arg Phe Ser Gly Gly Gly Phe Gly Thr Asp Phe Thr Leu
610 615 620
Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln
625 630 635 640
Gln Ala Asn Pro Ala Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu
645 650 655
Ile Lys Arg Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro
660 665 670
Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
675 680 685
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
690 695 700
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
705 710 715 720
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
725 730 735
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
740 745 750
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
755 760 765
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
770 775 780
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
785 790 795 800
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
805 810 815
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
820 825 830
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
835 840 845
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
850 855 860
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
865 870 875 880
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
885 890
<210> 20
<211> 896
<212> PRT
<213> Artificial Sequence
<220>
<223> Protein complex comprising VEGF and EGFR specific binding
peptides #13
<400> 20
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
20 25 30
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Trp Ile
35 40 45
Gly Pro Glu Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
50 55 60
Leu Leu Ile Tyr His Thr Ser Ile Leu Gln Ser Gly Val Pro Ser Arg
65 70 75 80
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
85 90 95
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Met Phe
100 105 110
Gln Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Arg Arg Glu
115 120 125
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
130 135 140
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
145 150 155 160
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
165 170 175
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
180 185 190
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
195 200 205
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
210 215 220
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
225 230 235 240
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
245 250 255
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
260 265 270
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
275 280 285
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
290 295 300
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
305 310 315 320
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
325 330 335
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
340 345 350
Leu Ser Leu Ser Pro Gly Lys Met Gln Ile Phe Val Lys Thr Leu Thr
355 360 365
Gly Lys Thr Ile Thr Leu Glu Val Glu Pro Ser Asp Thr Ile Glu Asn
370 375 380
Val Lys Ala Lys Ile Gln Asp Lys Glu Gly Ile Pro Pro Asp Gln Gln
385 390 395 400
Arg Leu Ile Phe Ala Gly Lys Gln Leu Glu Asp Gly Arg Thr Leu Ser
405 410 415
Asp Tyr Asn Ile Gln Lys Glu Ser Thr Leu His Leu Val Leu Arg Leu
420 425 430
Arg Gly Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
450 455 460
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
465 470 475 480
Met Gln Ile Phe Val Lys Thr Leu Thr Gly Lys Thr Ile Thr Leu Glu
485 490 495
Val Glu Pro Ser Asp Thr Ile Glu Asn Val Lys Ala Lys Ile Gln Asp
500 505 510
Lys Glu Gly Ile Pro Pro Asp Gln Gln Arg Leu Ile Phe Ala Gly Lys
515 520 525
Gln Leu Glu Asp Gly Arg Thr Leu Ser Asp Tyr Asn Ile Gln Lys Glu
530 535 540
Ser Thr Leu His Leu Val Leu Arg Leu Arg Gly Gly Asp Ile Gln Met
545 550 555 560
Thr Gln Ser Pro Thr Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr
565 570 575
Ile Thr Cys Arg Ala Ser Gln Trp Ile Gly Asn Leu Leu Asp Trp Tyr
580 585 590
Gln Gln Lys Pro Gly Glu Ala Pro Lys Leu Leu Ile Tyr Tyr Ala Ser
595 600 605
Phe Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Gly Gly Phe Gly
610 615 620
Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala
625 630 635 640
Thr Tyr Tyr Cys Gln Gln Ala Asn Pro Ala Pro Leu Thr Phe Gly Gln
645 650 655
Gly Thr Lys Val Glu Ile Lys Arg Glu Pro Lys Ser Cys Asp Lys Thr
660 665 670
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
675 680 685
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
690 695 700
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
705 710 715 720
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
725 730 735
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
740 745 750
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
755 760 765
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
770 775 780
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
785 790 795 800
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
805 810 815
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
820 825 830
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
835 840 845
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
850 855 860
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
865 870 875 880
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
885 890 895
<210> 21
<211> 901
<212> PRT
<213> Artificial Sequence
<220>
<223> Protein complex comprising VEGF and EGFR specific binding
peptides #14
<400> 21
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
20 25 30
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Trp Ile
35 40 45
Gly Pro Glu Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
50 55 60
Leu Leu Ile Tyr His Thr Ser Ile Leu Gln Ser Gly Val Pro Ser Arg
65 70 75 80
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
85 90 95
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Met Phe
100 105 110
Gln Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Arg Arg Glu
115 120 125
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
130 135 140
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
145 150 155 160
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
165 170 175
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
180 185 190
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
195 200 205
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
210 215 220
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
225 230 235 240
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
245 250 255
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
260 265 270
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
275 280 285
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
290 295 300
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
305 310 315 320
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
325 330 335
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
340 345 350
Leu Ser Leu Ser Pro Gly Lys Met Gln Ile Phe Val Lys Thr Leu Thr
355 360 365
Gly Lys Thr Ile Thr Leu Glu Val Glu Pro Ser Asp Thr Ile Glu Asn
370 375 380
Val Lys Ala Lys Ile Gln Asp Lys Glu Gly Ile Pro Pro Asp Gln Gln
385 390 395 400
Arg Leu Ile Phe Ala Gly Lys Gln Leu Glu Asp Gly Arg Thr Leu Ser
405 410 415
Asp Tyr Asn Ile Gln Lys Glu Ser Thr Leu His Leu Val Leu Arg Leu
420 425 430
Arg Gly Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
450 455 460
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
465 470 475 480
Gly Gly Gly Gly Ser Met Gln Ile Phe Val Lys Thr Leu Thr Gly Lys
485 490 495
Thr Ile Thr Leu Glu Val Glu Pro Ser Asp Thr Ile Glu Asn Val Lys
500 505 510
Ala Lys Ile Gln Asp Lys Glu Gly Ile Pro Pro Asp Gln Gln Arg Leu
515 520 525
Ile Phe Ala Gly Lys Gln Leu Glu Asp Gly Arg Thr Leu Ser Asp Tyr
530 535 540
Asn Ile Gln Lys Glu Ser Thr Leu His Leu Val Leu Arg Leu Arg Gly
545 550 555 560
Gly Asp Ile Gln Met Thr Gln Ser Pro Thr Ser Leu Ser Ala Ser Val
565 570 575
Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Trp Ile Gly Asn
580 585 590
Leu Leu Asp Trp Tyr Gln Gln Lys Pro Gly Glu Ala Pro Lys Leu Leu
595 600 605
Ile Tyr Tyr Ala Ser Phe Leu Gln Ser Gly Val Pro Ser Arg Phe Ser
610 615 620
Gly Gly Gly Phe Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln
625 630 635 640
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Pro Ala Pro
645 650 655
Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Glu Pro Lys
660 665 670
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu
675 680 685
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
690 695 700
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
705 710 715 720
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
725 730 735
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
740 745 750
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
755 760 765
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
770 775 780
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
785 790 795 800
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
805 810 815
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
820 825 830
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
835 840 845
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
850 855 860
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
865 870 875 880
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
885 890 895
Leu Ser Pro Gly Lys
900
<210> 22
<211> 871
<212> PRT
<213> Artificial Sequence
<220>
<223> Protein complex comprising VEGF and EGFR specific binding
peptides #15
<400> 22
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
20 25 30
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Lys Ile
35 40 45
Phe Asn Gly Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
50 55 60
Leu Leu Ile Tyr His Ser Ser Thr Leu Gln Ser Gly Val Pro Ser Arg
65 70 75 80
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
85 90 95
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Val Leu Leu
100 105 110
Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Glu
115 120 125
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
130 135 140
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
145 150 155 160
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
165 170 175
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
180 185 190
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
195 200 205
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
210 215 220
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
225 230 235 240
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
245 250 255
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
260 265 270
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
275 280 285
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
290 295 300
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
305 310 315 320
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
325 330 335
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
340 345 350
Leu Ser Leu Ser Pro Gly Lys Met Gln Ile Phe Val Lys Thr Leu Thr
355 360 365
Gly Lys Thr Ile Thr Leu Glu Val Glu Pro Ser Asp Thr Ile Glu Asn
370 375 380
Val Lys Ala Lys Ile Gln Asp Lys Glu Gly Ile Pro Pro Asp Gln Gln
385 390 395 400
Arg Leu Ile Phe Ala Gly Lys Gln Leu Glu Asp Gly Arg Thr Leu Ser
405 410 415
Asp Tyr Asn Ile Gln Lys Glu Ser Thr Leu His Leu Val Leu Arg Leu
420 425 430
Arg Gly Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Met Gln Ile Phe Val Lys Thr Leu Thr
450 455 460
Gly Lys Thr Ile Thr Leu Glu Val Glu Pro Ser Asp Thr Ile Glu Asn
465 470 475 480
Val Lys Ala Lys Ile Gln Asp Lys Glu Gly Ile Pro Pro Asp Gln Gln
485 490 495
Arg Leu Ile Phe Ala Gly Lys Gln Leu Glu Asp Gly Arg Thr Leu Ser
500 505 510
Asp Tyr Asn Ile Gln Lys Glu Ser Thr Leu His Leu Val Leu Arg Leu
515 520 525
Arg Gly Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
530 535 540
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Trp Ile
545 550 555 560
Gly Ile Leu Val Asp Trp Tyr Gln Gln Lys Pro Gly Glu Ala Pro Lys
565 570 575
Leu Leu Ile Tyr Tyr Ala Ser Phe Leu Gln Ser Gly Val Pro Ser Arg
580 585 590
Phe Ser Gly Ser Gly Phe Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
595 600 605
Leu His Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Pro
610 615 620
Ala Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Glu
625 630 635 640
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
645 650 655
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
660 665 670
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
675 680 685
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
690 695 700
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
705 710 715 720
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
725 730 735
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
740 745 750
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
755 760 765
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
770 775 780
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
785 790 795 800
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
805 810 815
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
820 825 830
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
835 840 845
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
850 855 860
Leu Ser Leu Ser Pro Gly Lys
865 870
<210> 23
<211> 876
<212> PRT
<213> Artificial Sequence
<220>
<223> Protein complex comprising VEGF and EGFR specific binding
peptides #16
<400> 23
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
20 25 30
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Lys Ile
35 40 45
Phe Asn Gly Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
50 55 60
Leu Leu Ile Tyr His Ser Ser Thr Leu Gln Ser Gly Val Pro Ser Arg
65 70 75 80
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
85 90 95
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Val Leu Leu
100 105 110
Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Glu
115 120 125
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
130 135 140
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
145 150 155 160
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
165 170 175
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
180 185 190
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
195 200 205
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
210 215 220
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
225 230 235 240
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
245 250 255
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
260 265 270
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
275 280 285
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
290 295 300
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
305 310 315 320
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
325 330 335
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
340 345 350
Leu Ser Leu Ser Pro Gly Lys Met Gln Ile Phe Val Lys Thr Leu Thr
355 360 365
Gly Lys Thr Ile Thr Leu Glu Val Glu Pro Ser Asp Thr Ile Glu Asn
370 375 380
Val Lys Ala Lys Ile Gln Asp Lys Glu Gly Ile Pro Pro Asp Gln Gln
385 390 395 400
Arg Leu Ile Phe Ala Gly Lys Gln Leu Glu Asp Gly Arg Thr Leu Ser
405 410 415
Asp Tyr Asn Ile Gln Lys Glu Ser Thr Leu His Leu Val Leu Arg Leu
420 425 430
Arg Gly Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Met Gln Ile Phe
450 455 460
Val Lys Thr Leu Thr Gly Lys Thr Ile Thr Leu Glu Val Glu Pro Ser
465 470 475 480
Asp Thr Ile Glu Asn Val Lys Ala Lys Ile Gln Asp Lys Glu Gly Ile
485 490 495
Pro Pro Asp Gln Gln Arg Leu Ile Phe Ala Gly Lys Gln Leu Glu Asp
500 505 510
Gly Arg Thr Leu Ser Asp Tyr Asn Ile Gln Lys Glu Ser Thr Leu His
515 520 525
Leu Val Leu Arg Leu Arg Gly Gly Asp Ile Gln Met Thr Gln Ser Pro
530 535 540
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
545 550 555 560
Ala Ser Gln Trp Ile Gly Ile Leu Val Asp Trp Tyr Gln Gln Lys Pro
565 570 575
Gly Glu Ala Pro Lys Leu Leu Ile Tyr Tyr Ala Ser Phe Leu Gln Ser
580 585 590
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Phe Gly Thr Asp Phe Thr
595 600 605
Leu Thr Ile Ser Ser Leu His Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
610 615 620
Gln Gln Ala Asn Pro Ala Pro Leu Thr Phe Gly Gln Gly Thr Lys Val
625 630 635 640
Glu Ile Lys Arg Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
645 650 655
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
660 665 670
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
675 680 685
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
690 695 700
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
705 710 715 720
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
725 730 735
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
740 745 750
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
755 760 765
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
770 775 780
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
785 790 795 800
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
805 810 815
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
820 825 830
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
835 840 845
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
850 855 860
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
865 870 875
<210> 24
<211> 881
<212> PRT
<213> Artificial Sequence
<220>
<223> Protein complex comprising VEGF and EGFR specific binding
peptides #17
<400> 24
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
20 25 30
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Lys Ile
35 40 45
Phe Asn Gly Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
50 55 60
Leu Leu Ile Tyr His Ser Ser Thr Leu Gln Ser Gly Val Pro Ser Arg
65 70 75 80
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
85 90 95
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Val Leu Leu
100 105 110
Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Glu
115 120 125
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
130 135 140
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
145 150 155 160
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
165 170 175
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
180 185 190
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
195 200 205
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
210 215 220
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
225 230 235 240
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
245 250 255
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
260 265 270
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
275 280 285
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
290 295 300
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
305 310 315 320
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
325 330 335
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
340 345 350
Leu Ser Leu Ser Pro Gly Lys Met Gln Ile Phe Val Lys Thr Leu Thr
355 360 365
Gly Lys Thr Ile Thr Leu Glu Val Glu Pro Ser Asp Thr Ile Glu Asn
370 375 380
Val Lys Ala Lys Ile Gln Asp Lys Glu Gly Ile Pro Pro Asp Gln Gln
385 390 395 400
Arg Leu Ile Phe Ala Gly Lys Gln Leu Glu Asp Gly Arg Thr Leu Ser
405 410 415
Asp Tyr Asn Ile Gln Lys Glu Ser Thr Leu His Leu Val Leu Arg Leu
420 425 430
Arg Gly Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
450 455 460
Ser Met Gln Ile Phe Val Lys Thr Leu Thr Gly Lys Thr Ile Thr Leu
465 470 475 480
Glu Val Glu Pro Ser Asp Thr Ile Glu Asn Val Lys Ala Lys Ile Gln
485 490 495
Asp Lys Glu Gly Ile Pro Pro Asp Gln Gln Arg Leu Ile Phe Ala Gly
500 505 510
Lys Gln Leu Glu Asp Gly Arg Thr Leu Ser Asp Tyr Asn Ile Gln Lys
515 520 525
Glu Ser Thr Leu His Leu Val Leu Arg Leu Arg Gly Gly Asp Ile Gln
530 535 540
Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val
545 550 555 560
Thr Ile Thr Cys Arg Ala Ser Gln Trp Ile Gly Ile Leu Val Asp Trp
565 570 575
Tyr Gln Gln Lys Pro Gly Glu Ala Pro Lys Leu Leu Ile Tyr Tyr Ala
580 585 590
Ser Phe Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Phe
595 600 605
Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu His Pro Glu Asp Phe
610 615 620
Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Pro Ala Pro Leu Thr Phe Gly
625 630 635 640
Gln Gly Thr Lys Val Glu Ile Lys Arg Glu Pro Lys Ser Cys Asp Lys
645 650 655
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
660 665 670
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
675 680 685
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
690 695 700
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
705 710 715 720
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
725 730 735
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
740 745 750
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
755 760 765
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
770 775 780
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
785 790 795 800
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
805 810 815
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
820 825 830
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
835 840 845
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
850 855 860
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
865 870 875 880
Lys
<210> 25
<211> 886
<212> PRT
<213> Artificial Sequence
<220>
<223> Protein complex comprising VEGF and EGFR specific binding
peptides #18
<400> 25
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
20 25 30
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Lys Ile
35 40 45
Phe Asn Gly Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
50 55 60
Leu Leu Ile Tyr His Ser Ser Thr Leu Gln Ser Gly Val Pro Ser Arg
65 70 75 80
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
85 90 95
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Val Leu Leu
100 105 110
Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Glu
115 120 125
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
130 135 140
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
145 150 155 160
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
165 170 175
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
180 185 190
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
195 200 205
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
210 215 220
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
225 230 235 240
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
245 250 255
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
260 265 270
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
275 280 285
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
290 295 300
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
305 310 315 320
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
325 330 335
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
340 345 350
Leu Ser Leu Ser Pro Gly Lys Met Gln Ile Phe Val Lys Thr Leu Thr
355 360 365
Gly Lys Thr Ile Thr Leu Glu Val Glu Pro Ser Asp Thr Ile Glu Asn
370 375 380
Val Lys Ala Lys Ile Gln Asp Lys Glu Gly Ile Pro Pro Asp Gln Gln
385 390 395 400
Arg Leu Ile Phe Ala Gly Lys Gln Leu Glu Asp Gly Arg Thr Leu Ser
405 410 415
Asp Tyr Asn Ile Gln Lys Glu Ser Thr Leu His Leu Val Leu Arg Leu
420 425 430
Arg Gly Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
450 455 460
Ser Gly Gly Gly Gly Ser Met Gln Ile Phe Val Lys Thr Leu Thr Gly
465 470 475 480
Lys Thr Ile Thr Leu Glu Val Glu Pro Ser Asp Thr Ile Glu Asn Val
485 490 495
Lys Ala Lys Ile Gln Asp Lys Glu Gly Ile Pro Pro Asp Gln Gln Arg
500 505 510
Leu Ile Phe Ala Gly Lys Gln Leu Glu Asp Gly Arg Thr Leu Ser Asp
515 520 525
Tyr Asn Ile Gln Lys Glu Ser Thr Leu His Leu Val Leu Arg Leu Arg
530 535 540
Gly Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser
545 550 555 560
Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Trp Ile Gly
565 570 575
Ile Leu Val Asp Trp Tyr Gln Gln Lys Pro Gly Glu Ala Pro Lys Leu
580 585 590
Leu Ile Tyr Tyr Ala Ser Phe Leu Gln Ser Gly Val Pro Ser Arg Phe
595 600 605
Ser Gly Ser Gly Phe Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu
610 615 620
His Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Pro Ala
625 630 635 640
Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Glu Pro
645 650 655
Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
660 665 670
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
675 680 685
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
690 695 700
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
705 710 715 720
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
725 730 735
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
740 745 750
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
755 760 765
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
770 775 780
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
785 790 795 800
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
805 810 815
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
820 825 830
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
835 840 845
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
850 855 860
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
865 870 875 880
Ser Leu Ser Pro Gly Lys
885
<210> 26
<211> 891
<212> PRT
<213> Artificial Sequence
<220>
<223> Protein complex comprising VEGF and EGFR specific binding
peptides #19
<400> 26
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
20 25 30
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Lys Ile
35 40 45
Phe Asn Gly Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
50 55 60
Leu Leu Ile Tyr His Ser Ser Thr Leu Gln Ser Gly Val Pro Ser Arg
65 70 75 80
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
85 90 95
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Val Leu Leu
100 105 110
Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Glu
115 120 125
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
130 135 140
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
145 150 155 160
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
165 170 175
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
180 185 190
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
195 200 205
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
210 215 220
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
225 230 235 240
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
245 250 255
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
260 265 270
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
275 280 285
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
290 295 300
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
305 310 315 320
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
325 330 335
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
340 345 350
Leu Ser Leu Ser Pro Gly Lys Met Gln Ile Phe Val Lys Thr Leu Thr
355 360 365
Gly Lys Thr Ile Thr Leu Glu Val Glu Pro Ser Asp Thr Ile Glu Asn
370 375 380
Val Lys Ala Lys Ile Gln Asp Lys Glu Gly Ile Pro Pro Asp Gln Gln
385 390 395 400
Arg Leu Ile Phe Ala Gly Lys Gln Leu Glu Asp Gly Arg Thr Leu Ser
405 410 415
Asp Tyr Asn Ile Gln Lys Glu Ser Thr Leu His Leu Val Leu Arg Leu
420 425 430
Arg Gly Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
450 455 460
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Met Gln Ile Phe Val
465 470 475 480
Lys Thr Leu Thr Gly Lys Thr Ile Thr Leu Glu Val Glu Pro Ser Asp
485 490 495
Thr Ile Glu Asn Val Lys Ala Lys Ile Gln Asp Lys Glu Gly Ile Pro
500 505 510
Pro Asp Gln Gln Arg Leu Ile Phe Ala Gly Lys Gln Leu Glu Asp Gly
515 520 525
Arg Thr Leu Ser Asp Tyr Asn Ile Gln Lys Glu Ser Thr Leu His Leu
530 535 540
Val Leu Arg Leu Arg Gly Gly Asp Ile Gln Met Thr Gln Ser Pro Ser
545 550 555 560
Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala
565 570 575
Ser Gln Trp Ile Gly Ile Leu Val Asp Trp Tyr Gln Gln Lys Pro Gly
580 585 590
Glu Ala Pro Lys Leu Leu Ile Tyr Tyr Ala Ser Phe Leu Gln Ser Gly
595 600 605
Val Pro Ser Arg Phe Ser Gly Ser Gly Phe Gly Thr Asp Phe Thr Leu
610 615 620
Thr Ile Ser Ser Leu His Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln
625 630 635 640
Gln Ala Asn Pro Ala Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu
645 650 655
Ile Lys Arg Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro
660 665 670
Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
675 680 685
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
690 695 700
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
705 710 715 720
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
725 730 735
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
740 745 750
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
755 760 765
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
770 775 780
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
785 790 795 800
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
805 810 815
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
820 825 830
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
835 840 845
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
850 855 860
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
865 870 875 880
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
885 890
<210> 27
<211> 896
<212> PRT
<213> Artificial Sequence
<220>
<223> Protein complex comprising VEGF and EGFR specific binding
peptides #20
<400> 27
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
20 25 30
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Lys Ile
35 40 45
Phe Asn Gly Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
50 55 60
Leu Leu Ile Tyr His Ser Ser Thr Leu Gln Ser Gly Val Pro Ser Arg
65 70 75 80
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
85 90 95
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Val Leu Leu
100 105 110
Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Glu
115 120 125
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
130 135 140
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
145 150 155 160
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
165 170 175
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
180 185 190
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
195 200 205
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
210 215 220
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
225 230 235 240
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
245 250 255
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
260 265 270
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
275 280 285
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
290 295 300
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
305 310 315 320
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
325 330 335
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
340 345 350
Leu Ser Leu Ser Pro Gly Lys Met Gln Ile Phe Val Lys Thr Leu Thr
355 360 365
Gly Lys Thr Ile Thr Leu Glu Val Glu Pro Ser Asp Thr Ile Glu Asn
370 375 380
Val Lys Ala Lys Ile Gln Asp Lys Glu Gly Ile Pro Pro Asp Gln Gln
385 390 395 400
Arg Leu Ile Phe Ala Gly Lys Gln Leu Glu Asp Gly Arg Thr Leu Ser
405 410 415
Asp Tyr Asn Ile Gln Lys Glu Ser Thr Leu His Leu Val Leu Arg Leu
420 425 430
Arg Gly Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
450 455 460
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
465 470 475 480
Met Gln Ile Phe Val Lys Thr Leu Thr Gly Lys Thr Ile Thr Leu Glu
485 490 495
Val Glu Pro Ser Asp Thr Ile Glu Asn Val Lys Ala Lys Ile Gln Asp
500 505 510
Lys Glu Gly Ile Pro Pro Asp Gln Gln Arg Leu Ile Phe Ala Gly Lys
515 520 525
Gln Leu Glu Asp Gly Arg Thr Leu Ser Asp Tyr Asn Ile Gln Lys Glu
530 535 540
Ser Thr Leu His Leu Val Leu Arg Leu Arg Gly Gly Asp Ile Gln Met
545 550 555 560
Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr
565 570 575
Ile Thr Cys Arg Ala Ser Gln Trp Ile Gly Ile Leu Val Asp Trp Tyr
580 585 590
Gln Gln Lys Pro Gly Glu Ala Pro Lys Leu Leu Ile Tyr Tyr Ala Ser
595 600 605
Phe Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Phe Gly
610 615 620
Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu His Pro Glu Asp Phe Ala
625 630 635 640
Thr Tyr Tyr Cys Gln Gln Ala Asn Pro Ala Pro Leu Thr Phe Gly Gln
645 650 655
Gly Thr Lys Val Glu Ile Lys Arg Glu Pro Lys Ser Cys Asp Lys Thr
660 665 670
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
675 680 685
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
690 695 700
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
705 710 715 720
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
725 730 735
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
740 745 750
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
755 760 765
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
770 775 780
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
785 790 795 800
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
805 810 815
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
820 825 830
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
835 840 845
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
850 855 860
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
865 870 875 880
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
885 890 895
<210> 28
<211> 901
<212> PRT
<213> Artificial Sequence
<220>
<223> Protein complex comprising VEGF and EGFR specific binding
peptides #21
<400> 28
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
20 25 30
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Lys Ile
35 40 45
Phe Asn Gly Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
50 55 60
Leu Leu Ile Tyr His Ser Ser Thr Leu Gln Ser Gly Val Pro Ser Arg
65 70 75 80
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
85 90 95
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Val Leu Leu
100 105 110
Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Glu
115 120 125
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
130 135 140
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
145 150 155 160
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
165 170 175
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
180 185 190
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
195 200 205
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
210 215 220
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
225 230 235 240
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
245 250 255
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
260 265 270
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
275 280 285
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
290 295 300
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
305 310 315 320
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
325 330 335
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
340 345 350
Leu Ser Leu Ser Pro Gly Lys Met Gln Ile Phe Val Lys Thr Leu Thr
355 360 365
Gly Lys Thr Ile Thr Leu Glu Val Glu Pro Ser Asp Thr Ile Glu Asn
370 375 380
Val Lys Ala Lys Ile Gln Asp Lys Glu Gly Ile Pro Pro Asp Gln Gln
385 390 395 400
Arg Leu Ile Phe Ala Gly Lys Gln Leu Glu Asp Gly Arg Thr Leu Ser
405 410 415
Asp Tyr Asn Ile Gln Lys Glu Ser Thr Leu His Leu Val Leu Arg Leu
420 425 430
Arg Gly Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
450 455 460
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
465 470 475 480
Gly Gly Gly Gly Ser Met Gln Ile Phe Val Lys Thr Leu Thr Gly Lys
485 490 495
Thr Ile Thr Leu Glu Val Glu Pro Ser Asp Thr Ile Glu Asn Val Lys
500 505 510
Ala Lys Ile Gln Asp Lys Glu Gly Ile Pro Pro Asp Gln Gln Arg Leu
515 520 525
Ile Phe Ala Gly Lys Gln Leu Glu Asp Gly Arg Thr Leu Ser Asp Tyr
530 535 540
Asn Ile Gln Lys Glu Ser Thr Leu His Leu Val Leu Arg Leu Arg Gly
545 550 555 560
Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val
565 570 575
Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Trp Ile Gly Ile
580 585 590
Leu Val Asp Trp Tyr Gln Gln Lys Pro Gly Glu Ala Pro Lys Leu Leu
595 600 605
Ile Tyr Tyr Ala Ser Phe Leu Gln Ser Gly Val Pro Ser Arg Phe Ser
610 615 620
Gly Ser Gly Phe Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu His
625 630 635 640
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Pro Ala Pro
645 650 655
Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Glu Pro Lys
660 665 670
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu
675 680 685
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
690 695 700
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
705 710 715 720
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
725 730 735
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
740 745 750
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
755 760 765
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
770 775 780
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
785 790 795 800
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
805 810 815
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
820 825 830
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
835 840 845
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
850 855 860
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
865 870 875 880
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
885 890 895
Leu Ser Pro Gly Lys
900
<210> 29
<211> 871
<212> PRT
<213> Artificial Sequence
<220>
<223> Protein complex comprising VEGF and EGFR specific binding
peptides #22
<400> 29
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
20 25 30
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Lys Ile
35 40 45
Phe Asn Gly Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
50 55 60
Leu Leu Ile Tyr His Ser Ser Thr Leu Gln Ser Gly Val Pro Ser Arg
65 70 75 80
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
85 90 95
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Val Leu Leu
100 105 110
Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Glu
115 120 125
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
130 135 140
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
145 150 155 160
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
165 170 175
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
180 185 190
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
195 200 205
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
210 215 220
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
225 230 235 240
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
245 250 255
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
260 265 270
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
275 280 285
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
290 295 300
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
305 310 315 320
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
325 330 335
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
340 345 350
Leu Ser Leu Ser Pro Gly Lys Met Gln Ile Phe Val Lys Thr Leu Thr
355 360 365
Gly Lys Thr Ile Thr Leu Glu Val Glu Pro Ser Asp Thr Ile Glu Asn
370 375 380
Val Lys Ala Lys Ile Gln Asp Lys Glu Gly Ile Pro Pro Asp Gln Gln
385 390 395 400
Arg Leu Ile Phe Ala Gly Lys Gln Leu Glu Asp Gly Arg Thr Leu Ser
405 410 415
Asp Tyr Asn Ile Gln Lys Glu Ser Thr Leu His Leu Val Leu Arg Leu
420 425 430
Arg Gly Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Met Gln Ile Phe Val Lys Thr Leu Thr
450 455 460
Gly Lys Thr Ile Thr Leu Glu Val Glu Pro Ser Asp Thr Ile Glu Asn
465 470 475 480
Val Lys Ala Lys Ile Gln Asp Lys Glu Gly Ile Pro Pro Asp Gln Gln
485 490 495
Arg Leu Ile Phe Ala Gly Lys Gln Leu Glu Asp Gly Arg Thr Leu Ser
500 505 510
Asp Tyr Asn Ile Gln Lys Glu Ser Thr Leu His Leu Val Leu Arg Leu
515 520 525
Arg Gly Gly Asp Ile Gln Met Thr Gln Ser Pro Thr Ser Leu Ser Ala
530 535 540
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Trp Ile
545 550 555 560
Gly Asn Leu Leu Asp Trp Tyr Gln Gln Lys Pro Gly Glu Ala Pro Lys
565 570 575
Leu Leu Ile Tyr Tyr Ala Ser Phe Leu Gln Ser Gly Val Pro Ser Arg
580 585 590
Phe Ser Gly Gly Gly Phe Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
595 600 605
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Pro
610 615 620
Ala Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Glu
625 630 635 640
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
645 650 655
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
660 665 670
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
675 680 685
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
690 695 700
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
705 710 715 720
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
725 730 735
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
740 745 750
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
755 760 765
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
770 775 780
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
785 790 795 800
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
805 810 815
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
820 825 830
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
835 840 845
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
850 855 860
Leu Ser Leu Ser Pro Gly Lys
865 870
<210> 30
<211> 876
<212> PRT
<213> Artificial Sequence
<220>
<223> Protein complex comprising VEGF and EGFR specific binding
peptides #23
<400> 30
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
20 25 30
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Lys Ile
35 40 45
Phe Asn Gly Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
50 55 60
Leu Leu Ile Tyr His Ser Ser Thr Leu Gln Ser Gly Val Pro Ser Arg
65 70 75 80
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
85 90 95
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Val Leu Leu
100 105 110
Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Glu
115 120 125
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
130 135 140
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
145 150 155 160
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
165 170 175
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
180 185 190
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
195 200 205
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
210 215 220
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
225 230 235 240
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
245 250 255
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
260 265 270
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
275 280 285
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
290 295 300
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
305 310 315 320
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
325 330 335
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
340 345 350
Leu Ser Leu Ser Pro Gly Lys Met Gln Ile Phe Val Lys Thr Leu Thr
355 360 365
Gly Lys Thr Ile Thr Leu Glu Val Glu Pro Ser Asp Thr Ile Glu Asn
370 375 380
Val Lys Ala Lys Ile Gln Asp Lys Glu Gly Ile Pro Pro Asp Gln Gln
385 390 395 400
Arg Leu Ile Phe Ala Gly Lys Gln Leu Glu Asp Gly Arg Thr Leu Ser
405 410 415
Asp Tyr Asn Ile Gln Lys Glu Ser Thr Leu His Leu Val Leu Arg Leu
420 425 430
Arg Gly Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Met Gln Ile Phe
450 455 460
Val Lys Thr Leu Thr Gly Lys Thr Ile Thr Leu Glu Val Glu Pro Ser
465 470 475 480
Asp Thr Ile Glu Asn Val Lys Ala Lys Ile Gln Asp Lys Glu Gly Ile
485 490 495
Pro Pro Asp Gln Gln Arg Leu Ile Phe Ala Gly Lys Gln Leu Glu Asp
500 505 510
Gly Arg Thr Leu Ser Asp Tyr Asn Ile Gln Lys Glu Ser Thr Leu His
515 520 525
Leu Val Leu Arg Leu Arg Gly Gly Asp Ile Gln Met Thr Gln Ser Pro
530 535 540
Thr Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
545 550 555 560
Ala Ser Gln Trp Ile Gly Asn Leu Leu Asp Trp Tyr Gln Gln Lys Pro
565 570 575
Gly Glu Ala Pro Lys Leu Leu Ile Tyr Tyr Ala Ser Phe Leu Gln Ser
580 585 590
Gly Val Pro Ser Arg Phe Ser Gly Gly Gly Phe Gly Thr Asp Phe Thr
595 600 605
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
610 615 620
Gln Gln Ala Asn Pro Ala Pro Leu Thr Phe Gly Gln Gly Thr Lys Val
625 630 635 640
Glu Ile Lys Arg Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
645 650 655
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
660 665 670
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
675 680 685
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
690 695 700
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
705 710 715 720
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
725 730 735
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
740 745 750
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
755 760 765
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
770 775 780
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
785 790 795 800
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
805 810 815
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
820 825 830
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
835 840 845
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
850 855 860
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
865 870 875
<210> 31
<211> 881
<212> PRT
<213> Artificial Sequence
<220>
<223> Protein complex comprising VEGF and EGFR specific binding
peptides #24
<400> 31
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
20 25 30
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Lys Ile
35 40 45
Phe Asn Gly Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
50 55 60
Leu Leu Ile Tyr His Ser Ser Thr Leu Gln Ser Gly Val Pro Ser Arg
65 70 75 80
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
85 90 95
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Val Leu Leu
100 105 110
Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Glu
115 120 125
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
130 135 140
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
145 150 155 160
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
165 170 175
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
180 185 190
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
195 200 205
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
210 215 220
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
225 230 235 240
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
245 250 255
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
260 265 270
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
275 280 285
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
290 295 300
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
305 310 315 320
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
325 330 335
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
340 345 350
Leu Ser Leu Ser Pro Gly Lys Met Gln Ile Phe Val Lys Thr Leu Thr
355 360 365
Gly Lys Thr Ile Thr Leu Glu Val Glu Pro Ser Asp Thr Ile Glu Asn
370 375 380
Val Lys Ala Lys Ile Gln Asp Lys Glu Gly Ile Pro Pro Asp Gln Gln
385 390 395 400
Arg Leu Ile Phe Ala Gly Lys Gln Leu Glu Asp Gly Arg Thr Leu Ser
405 410 415
Asp Tyr Asn Ile Gln Lys Glu Ser Thr Leu His Leu Val Leu Arg Leu
420 425 430
Arg Gly Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
450 455 460
Ser Met Gln Ile Phe Val Lys Thr Leu Thr Gly Lys Thr Ile Thr Leu
465 470 475 480
Glu Val Glu Pro Ser Asp Thr Ile Glu Asn Val Lys Ala Lys Ile Gln
485 490 495
Asp Lys Glu Gly Ile Pro Pro Asp Gln Gln Arg Leu Ile Phe Ala Gly
500 505 510
Lys Gln Leu Glu Asp Gly Arg Thr Leu Ser Asp Tyr Asn Ile Gln Lys
515 520 525
Glu Ser Thr Leu His Leu Val Leu Arg Leu Arg Gly Gly Asp Ile Gln
530 535 540
Met Thr Gln Ser Pro Thr Ser Leu Ser Ala Ser Val Gly Asp Arg Val
545 550 555 560
Thr Ile Thr Cys Arg Ala Ser Gln Trp Ile Gly Asn Leu Leu Asp Trp
565 570 575
Tyr Gln Gln Lys Pro Gly Glu Ala Pro Lys Leu Leu Ile Tyr Tyr Ala
580 585 590
Ser Phe Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Gly Gly Phe
595 600 605
Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe
610 615 620
Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Pro Ala Pro Leu Thr Phe Gly
625 630 635 640
Gln Gly Thr Lys Val Glu Ile Lys Arg Glu Pro Lys Ser Cys Asp Lys
645 650 655
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
660 665 670
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
675 680 685
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
690 695 700
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
705 710 715 720
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
725 730 735
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
740 745 750
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
755 760 765
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
770 775 780
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
785 790 795 800
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
805 810 815
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
820 825 830
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
835 840 845
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
850 855 860
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
865 870 875 880
Lys
<210> 32
<211> 886
<212> PRT
<213> Artificial Sequence
<220>
<223> Protein complex comprising VEGF and EGFR specific binding
peptides #25
<400> 32
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
20 25 30
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Lys Ile
35 40 45
Phe Asn Gly Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
50 55 60
Leu Leu Ile Tyr His Ser Ser Thr Leu Gln Ser Gly Val Pro Ser Arg
65 70 75 80
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
85 90 95
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Val Leu Leu
100 105 110
Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Glu
115 120 125
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
130 135 140
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
145 150 155 160
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
165 170 175
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
180 185 190
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
195 200 205
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
210 215 220
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
225 230 235 240
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
245 250 255
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
260 265 270
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
275 280 285
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
290 295 300
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
305 310 315 320
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
325 330 335
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
340 345 350
Leu Ser Leu Ser Pro Gly Lys Met Gln Ile Phe Val Lys Thr Leu Thr
355 360 365
Gly Lys Thr Ile Thr Leu Glu Val Glu Pro Ser Asp Thr Ile Glu Asn
370 375 380
Val Lys Ala Lys Ile Gln Asp Lys Glu Gly Ile Pro Pro Asp Gln Gln
385 390 395 400
Arg Leu Ile Phe Ala Gly Lys Gln Leu Glu Asp Gly Arg Thr Leu Ser
405 410 415
Asp Tyr Asn Ile Gln Lys Glu Ser Thr Leu His Leu Val Leu Arg Leu
420 425 430
Arg Gly Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
450 455 460
Ser Gly Gly Gly Gly Ser Met Gln Ile Phe Val Lys Thr Leu Thr Gly
465 470 475 480
Lys Thr Ile Thr Leu Glu Val Glu Pro Ser Asp Thr Ile Glu Asn Val
485 490 495
Lys Ala Lys Ile Gln Asp Lys Glu Gly Ile Pro Pro Asp Gln Gln Arg
500 505 510
Leu Ile Phe Ala Gly Lys Gln Leu Glu Asp Gly Arg Thr Leu Ser Asp
515 520 525
Tyr Asn Ile Gln Lys Glu Ser Thr Leu His Leu Val Leu Arg Leu Arg
530 535 540
Gly Gly Asp Ile Gln Met Thr Gln Ser Pro Thr Ser Leu Ser Ala Ser
545 550 555 560
Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Trp Ile Gly
565 570 575
Asn Leu Leu Asp Trp Tyr Gln Gln Lys Pro Gly Glu Ala Pro Lys Leu
580 585 590
Leu Ile Tyr Tyr Ala Ser Phe Leu Gln Ser Gly Val Pro Ser Arg Phe
595 600 605
Ser Gly Gly Gly Phe Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu
610 615 620
Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Pro Ala
625 630 635 640
Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Glu Pro
645 650 655
Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
660 665 670
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
675 680 685
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
690 695 700
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
705 710 715 720
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
725 730 735
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
740 745 750
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
755 760 765
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
770 775 780
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
785 790 795 800
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
805 810 815
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
820 825 830
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
835 840 845
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
850 855 860
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
865 870 875 880
Ser Leu Ser Pro Gly Lys
885
<210> 33
<211> 891
<212> PRT
<213> Artificial Sequence
<220>
<223> Protein complex comprising VEGF and EGFR specific binding
peptides #26
<400> 33
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
20 25 30
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Lys Ile
35 40 45
Phe Asn Gly Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
50 55 60
Leu Leu Ile Tyr His Ser Ser Thr Leu Gln Ser Gly Val Pro Ser Arg
65 70 75 80
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
85 90 95
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Val Leu Leu
100 105 110
Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Glu
115 120 125
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
130 135 140
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
145 150 155 160
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
165 170 175
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
180 185 190
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
195 200 205
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
210 215 220
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
225 230 235 240
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
245 250 255
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
260 265 270
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
275 280 285
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
290 295 300
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
305 310 315 320
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
325 330 335
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
340 345 350
Leu Ser Leu Ser Pro Gly Lys Met Gln Ile Phe Val Lys Thr Leu Thr
355 360 365
Gly Lys Thr Ile Thr Leu Glu Val Glu Pro Ser Asp Thr Ile Glu Asn
370 375 380
Val Lys Ala Lys Ile Gln Asp Lys Glu Gly Ile Pro Pro Asp Gln Gln
385 390 395 400
Arg Leu Ile Phe Ala Gly Lys Gln Leu Glu Asp Gly Arg Thr Leu Ser
405 410 415
Asp Tyr Asn Ile Gln Lys Glu Ser Thr Leu His Leu Val Leu Arg Leu
420 425 430
Arg Gly Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
450 455 460
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Met Gln Ile Phe Val
465 470 475 480
Lys Thr Leu Thr Gly Lys Thr Ile Thr Leu Glu Val Glu Pro Ser Asp
485 490 495
Thr Ile Glu Asn Val Lys Ala Lys Ile Gln Asp Lys Glu Gly Ile Pro
500 505 510
Pro Asp Gln Gln Arg Leu Ile Phe Ala Gly Lys Gln Leu Glu Asp Gly
515 520 525
Arg Thr Leu Ser Asp Tyr Asn Ile Gln Lys Glu Ser Thr Leu His Leu
530 535 540
Val Leu Arg Leu Arg Gly Gly Asp Ile Gln Met Thr Gln Ser Pro Thr
545 550 555 560
Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala
565 570 575
Ser Gln Trp Ile Gly Asn Leu Leu Asp Trp Tyr Gln Gln Lys Pro Gly
580 585 590
Glu Ala Pro Lys Leu Leu Ile Tyr Tyr Ala Ser Phe Leu Gln Ser Gly
595 600 605
Val Pro Ser Arg Phe Ser Gly Gly Gly Phe Gly Thr Asp Phe Thr Leu
610 615 620
Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln
625 630 635 640
Gln Ala Asn Pro Ala Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu
645 650 655
Ile Lys Arg Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro
660 665 670
Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
675 680 685
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
690 695 700
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
705 710 715 720
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
725 730 735
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
740 745 750
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
755 760 765
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
770 775 780
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
785 790 795 800
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
805 810 815
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
820 825 830
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
835 840 845
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
850 855 860
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
865 870 875 880
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
885 890
<210> 34
<211> 896
<212> PRT
<213> Artificial Sequence
<220>
<223> Protein complex comprising VEGF and EGFR specific binding
peptides #27
<400> 34
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
20 25 30
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Lys Ile
35 40 45
Phe Asn Gly Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
50 55 60
Leu Leu Ile Tyr His Ser Ser Thr Leu Gln Ser Gly Val Pro Ser Arg
65 70 75 80
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
85 90 95
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Val Leu Leu
100 105 110
Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Glu
115 120 125
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
130 135 140
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
145 150 155 160
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
165 170 175
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
180 185 190
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
195 200 205
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
210 215 220
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
225 230 235 240
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
245 250 255
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
260 265 270
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
275 280 285
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
290 295 300
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
305 310 315 320
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
325 330 335
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
340 345 350
Leu Ser Leu Ser Pro Gly Lys Met Gln Ile Phe Val Lys Thr Leu Thr
355 360 365
Gly Lys Thr Ile Thr Leu Glu Val Glu Pro Ser Asp Thr Ile Glu Asn
370 375 380
Val Lys Ala Lys Ile Gln Asp Lys Glu Gly Ile Pro Pro Asp Gln Gln
385 390 395 400
Arg Leu Ile Phe Ala Gly Lys Gln Leu Glu Asp Gly Arg Thr Leu Ser
405 410 415
Asp Tyr Asn Ile Gln Lys Glu Ser Thr Leu His Leu Val Leu Arg Leu
420 425 430
Arg Gly Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
450 455 460
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
465 470 475 480
Met Gln Ile Phe Val Lys Thr Leu Thr Gly Lys Thr Ile Thr Leu Glu
485 490 495
Val Glu Pro Ser Asp Thr Ile Glu Asn Val Lys Ala Lys Ile Gln Asp
500 505 510
Lys Glu Gly Ile Pro Pro Asp Gln Gln Arg Leu Ile Phe Ala Gly Lys
515 520 525
Gln Leu Glu Asp Gly Arg Thr Leu Ser Asp Tyr Asn Ile Gln Lys Glu
530 535 540
Ser Thr Leu His Leu Val Leu Arg Leu Arg Gly Gly Asp Ile Gln Met
545 550 555 560
Thr Gln Ser Pro Thr Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr
565 570 575
Ile Thr Cys Arg Ala Ser Gln Trp Ile Gly Asn Leu Leu Asp Trp Tyr
580 585 590
Gln Gln Lys Pro Gly Glu Ala Pro Lys Leu Leu Ile Tyr Tyr Ala Ser
595 600 605
Phe Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Gly Gly Phe Gly
610 615 620
Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala
625 630 635 640
Thr Tyr Tyr Cys Gln Gln Ala Asn Pro Ala Pro Leu Thr Phe Gly Gln
645 650 655
Gly Thr Lys Val Glu Ile Lys Arg Glu Pro Lys Ser Cys Asp Lys Thr
660 665 670
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
675 680 685
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
690 695 700
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
705 710 715 720
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
725 730 735
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
740 745 750
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
755 760 765
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
770 775 780
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
785 790 795 800
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
805 810 815
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
820 825 830
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
835 840 845
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
850 855 860
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
865 870 875 880
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
885 890 895
<210> 35
<211> 901
<212> PRT
<213> Artificial Sequence
<220>
<223> Protein complex comprising VEGF and EGFR specific binding
peptides #28
<400> 35
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
20 25 30
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Lys Ile
35 40 45
Phe Asn Gly Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
50 55 60
Leu Leu Ile Tyr His Ser Ser Thr Leu Gln Ser Gly Val Pro Ser Arg
65 70 75 80
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
85 90 95
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Val Leu Leu
100 105 110
Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Glu
115 120 125
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
130 135 140
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
145 150 155 160
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
165 170 175
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
180 185 190
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
195 200 205
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
210 215 220
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
225 230 235 240
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
245 250 255
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
260 265 270
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
275 280 285
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
290 295 300
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
305 310 315 320
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
325 330 335
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
340 345 350
Leu Ser Leu Ser Pro Gly Lys Met Gln Ile Phe Val Lys Thr Leu Thr
355 360 365
Gly Lys Thr Ile Thr Leu Glu Val Glu Pro Ser Asp Thr Ile Glu Asn
370 375 380
Val Lys Ala Lys Ile Gln Asp Lys Glu Gly Ile Pro Pro Asp Gln Gln
385 390 395 400
Arg Leu Ile Phe Ala Gly Lys Gln Leu Glu Asp Gly Arg Thr Leu Ser
405 410 415
Asp Tyr Asn Ile Gln Lys Glu Ser Thr Leu His Leu Val Leu Arg Leu
420 425 430
Arg Gly Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
450 455 460
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
465 470 475 480
Gly Gly Gly Gly Ser Met Gln Ile Phe Val Lys Thr Leu Thr Gly Lys
485 490 495
Thr Ile Thr Leu Glu Val Glu Pro Ser Asp Thr Ile Glu Asn Val Lys
500 505 510
Ala Lys Ile Gln Asp Lys Glu Gly Ile Pro Pro Asp Gln Gln Arg Leu
515 520 525
Ile Phe Ala Gly Lys Gln Leu Glu Asp Gly Arg Thr Leu Ser Asp Tyr
530 535 540
Asn Ile Gln Lys Glu Ser Thr Leu His Leu Val Leu Arg Leu Arg Gly
545 550 555 560
Gly Asp Ile Gln Met Thr Gln Ser Pro Thr Ser Leu Ser Ala Ser Val
565 570 575
Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Trp Ile Gly Asn
580 585 590
Leu Leu Asp Trp Tyr Gln Gln Lys Pro Gly Glu Ala Pro Lys Leu Leu
595 600 605
Ile Tyr Tyr Ala Ser Phe Leu Gln Ser Gly Val Pro Ser Arg Phe Ser
610 615 620
Gly Gly Gly Phe Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln
625 630 635 640
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Pro Ala Pro
645 650 655
Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Glu Pro Lys
660 665 670
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu
675 680 685
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
690 695 700
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
705 710 715 720
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
725 730 735
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
740 745 750
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
755 760 765
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
770 775 780
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
785 790 795 800
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
805 810 815
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
820 825 830
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
835 840 845
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
850 855 860
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
865 870 875 880
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
885 890 895
Leu Ser Pro Gly Lys
900
<210> 36
<211> 880
<212> PRT
<213> Artificial Sequence
<220>
<223> Protein complex comprising VEGF and EGFR specific binding
peptides #29
<400> 36
Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly Val
1 5 10 15
His Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser
20 25 30
Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Lys Ile Phe
35 40 45
Asn Gly Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu
50 55 60
Leu Ile Tyr His Ser Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe
65 70 75 80
Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu
85 90 95
Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Val Leu Leu Tyr
100 105 110
Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Glu Pro
115 120 125
Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
130 135 140
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
145 150 155 160
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
165 170 175
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
180 185 190
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
195 200 205
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
210 215 220
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
225 230 235 240
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
245 250 255
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
260 265 270
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
275 280 285
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
290 295 300
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
305 310 315 320
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
325 330 335
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
340 345 350
Ser Leu Ser Pro Gly Lys Met Gln Ile Phe Val Lys Thr Leu Thr Gly
355 360 365
Lys Thr Ile Thr Leu Glu Val Glu Pro Ser Asp Thr Ile Glu Asn Val
370 375 380
Lys Ala Lys Ile Gln Asp Lys Glu Gly Ile Pro Pro Asp Gln Gln Arg
385 390 395 400
Leu Ile Phe Ala Gly Lys Gln Leu Glu Asp Gly Arg Thr Leu Ser Asp
405 410 415
Tyr Asn Ile Gln Lys Glu Ser Thr Leu His Leu Val Leu Arg Leu Arg
420 425 430
Gly Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
435 440 445
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
450 455 460
Met Gln Ile Phe Val Lys Thr Leu Thr Gly Lys Thr Ile Thr Leu Glu
465 470 475 480
Val Glu Pro Ser Asp Thr Ile Glu Asn Val Lys Ala Lys Ile Gln Asp
485 490 495
Lys Glu Gly Ile Pro Pro Asp Gln Gln Arg Leu Ile Phe Ala Gly Lys
500 505 510
Gln Leu Glu Asp Gly Arg Thr Leu Ser Asp Tyr Asn Ile Gln Lys Glu
515 520 525
Ser Thr Leu His Leu Val Leu Arg Leu Arg Gly Gly Asp Ile Gln Met
530 535 540
Thr Gln Ser Pro Thr Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr
545 550 555 560
Ile Thr Cys Arg Ala Ser Gln Trp Ile Gly Asn Leu Leu Asp Trp Tyr
565 570 575
Gln Gln Lys Pro Gly Glu Ala Pro Lys Leu Leu Ile Tyr Tyr Ala Ser
580 585 590
Phe Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Gly Gly Phe Gly
595 600 605
Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala
610 615 620
Thr Tyr Tyr Cys Gln Gln Ala Asn Pro Ala Pro Leu Thr Phe Gly Gln
625 630 635 640
Gly Thr Lys Val Glu Ile Lys Arg Glu Pro Lys Ser Cys Asp Lys Thr
645 650 655
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
660 665 670
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
675 680 685
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
690 695 700
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
705 710 715 720
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
725 730 735
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
740 745 750
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
755 760 765
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
770 775 780
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
785 790 795 800
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
805 810 815
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
820 825 830
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
835 840 845
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
850 855 860
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
865 870 875 880
<210> 37
<211> 777
<212> PRT
<213> Artificial Sequence
<220>
<223> Protein complex comprising VEGF and EGFR specific binding
peptides #30
<400> 37
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
20 25 30
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Lys Ile
35 40 45
Phe Asn Gly Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
50 55 60
Leu Leu Ile Tyr His Ser Ser Thr Leu Gln Ser Gly Val Pro Ser Arg
65 70 75 80
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
85 90 95
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Val Leu Leu
100 105 110
Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Glu
115 120 125
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
130 135 140
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
145 150 155 160
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
165 170 175
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
180 185 190
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
195 200 205
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
210 215 220
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
225 230 235 240
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
245 250 255
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
260 265 270
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
275 280 285
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
290 295 300
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
305 310 315 320
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
325 330 335
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
340 345 350
Leu Ser Leu Ser Pro Gly Lys Met Gln Ile Phe Val Lys Thr Leu Thr
355 360 365
Gly Lys Thr Ile Thr Leu Glu Val Glu Pro Ser Asp Thr Ile Glu Asn
370 375 380
Val Lys Ala Lys Ile Gln Asp Lys Glu Gly Ile Pro Pro Asp Gln Gln
385 390 395 400
Arg Leu Ile Phe Ala Gly Lys Gln Leu Glu Asp Gly Arg Thr Leu Ser
405 410 415
Asp Tyr Asn Ile Gln Lys Glu Ser Thr Leu His Leu Val Leu Arg Leu
420 425 430
Arg Gly Gly Gly Gly Asp Ile Gln Met Thr Gln Ser Pro Thr Ser Leu
435 440 445
Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln
450 455 460
Trp Ile Gly Asn Leu Leu Asp Trp Tyr Gln Gln Lys Pro Gly Glu Ala
465 470 475 480
Pro Lys Leu Leu Ile Tyr Tyr Ala Ser Phe Leu Gln Ser Gly Val Pro
485 490 495
Ser Arg Phe Ser Gly Gly Gly Phe Gly Thr Asp Phe Thr Leu Thr Ile
500 505 510
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala
515 520 525
Asn Pro Ala Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
530 535 540
Arg Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro
545 550 555 560
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
565 570 575
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
580 585 590
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
595 600 605
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
610 615 620
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
625 630 635 640
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
645 650 655
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
660 665 670
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
675 680 685
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
690 695 700
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
705 710 715 720
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
725 730 735
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
740 745 750
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
755 760 765
Lys Ser Leu Ser Leu Ser Pro Gly Lys
770 775
<210> 38
<211> 886
<212> PRT
<213> Artificial Sequence
<220>
<223> Protein complex comprising VEGF and EGFR specific binding
peptides #31
<400> 38
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
20 25 30
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Lys Ile
35 40 45
Phe Asn Gly Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
50 55 60
Leu Leu Ile Tyr His Ser Ser Thr Leu Gln Ser Gly Val Pro Ser Arg
65 70 75 80
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
85 90 95
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Val Leu Leu
100 105 110
Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Glu
115 120 125
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
130 135 140
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
145 150 155 160
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
165 170 175
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
180 185 190
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
195 200 205
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
210 215 220
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
225 230 235 240
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
245 250 255
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
260 265 270
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
275 280 285
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
290 295 300
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
305 310 315 320
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
325 330 335
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
340 345 350
Leu Ser Leu Ser Pro Gly Lys Met Gln Ile Phe Val Lys Thr Leu Thr
355 360 365
Gly Lys Thr Ile Thr Leu Glu Val Glu Pro Ser Asp Thr Ile Glu Asn
370 375 380
Val Lys Ala Lys Ile Gln Asp Lys Glu Gly Ile Pro Pro Asp Gln Gln
385 390 395 400
Arg Leu Ile Phe Ala Gly Lys Gln Leu Glu Asp Gly Arg Thr Leu Ser
405 410 415
Asp Tyr Asn Ile Gln Lys Glu Ser Thr Leu His Leu Val Leu Arg Leu
420 425 430
Arg Gly Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
450 455 460
Ser Met Gln Ile Phe Val Lys Thr Leu Thr Gly Lys Thr Ile Thr Leu
465 470 475 480
Glu Val Glu Pro Ser Asp Thr Ile Glu Asn Val Lys Ala Lys Ile Gln
485 490 495
Asp Lys Glu Gly Ile Pro Pro Asp Gln Gln Arg Leu Ile Phe Ala Gly
500 505 510
Lys Gln Leu Glu Asp Gly Arg Thr Leu Ser Asp Tyr Asn Ile Gln Lys
515 520 525
Glu Ser Thr Leu His Leu Val Leu Arg Leu Arg Gly Gly Gly Gly Gly
530 535 540
Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Thr Ser Leu Ser Ala Ser
545 550 555 560
Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Trp Ile Gly
565 570 575
Asn Leu Leu Asp Trp Tyr Gln Gln Lys Pro Gly Glu Ala Pro Lys Leu
580 585 590
Leu Ile Tyr Tyr Ala Ser Phe Leu Gln Ser Gly Val Pro Ser Arg Phe
595 600 605
Ser Gly Gly Gly Phe Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu
610 615 620
Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Pro Ala
625 630 635 640
Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Glu Pro
645 650 655
Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
660 665 670
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
675 680 685
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
690 695 700
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
705 710 715 720
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
725 730 735
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
740 745 750
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
755 760 765
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
770 775 780
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
785 790 795 800
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
805 810 815
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
820 825 830
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
835 840 845
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
850 855 860
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
865 870 875 880
Ser Leu Ser Pro Gly Lys
885
<210> 39
<211> 883
<212> PRT
<213> Artificial Sequence
<220>
<223> Protein complex comprising VEGF and EGFR specific binding
peptides #32
<400> 39
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
20 25 30
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Lys Ile
35 40 45
Phe Asn Gly Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
50 55 60
Leu Leu Ile Tyr His Ser Ser Thr Leu Gln Ser Gly Val Pro Ser Arg
65 70 75 80
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
85 90 95
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Val Leu Leu
100 105 110
Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Glu
115 120 125
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
130 135 140
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
145 150 155 160
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
165 170 175
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
180 185 190
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
195 200 205
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
210 215 220
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
225 230 235 240
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
245 250 255
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
260 265 270
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
275 280 285
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
290 295 300
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
305 310 315 320
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
325 330 335
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
340 345 350
Leu Ser Leu Ser Pro Gly Lys Met Gln Ile Phe Val Lys Thr Leu Thr
355 360 365
Gly Lys Thr Ile Thr Leu Glu Val Glu Pro Ser Asp Thr Ile Glu Asn
370 375 380
Val Lys Ala Lys Ile Gln Asp Lys Glu Gly Ile Pro Pro Asp Gln Gln
385 390 395 400
Arg Leu Ile Phe Ala Gly Lys Gln Leu Glu Asp Gly Arg Thr Leu Ser
405 410 415
Asp Tyr Asn Ile Gln Lys Glu Ser Thr Leu His Leu Val Leu Arg Leu
420 425 430
Arg Gly Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
450 455 460
Ser Met Gln Ile Phe Val Lys Thr Leu Thr Gly Lys Thr Ile Thr Leu
465 470 475 480
Glu Val Glu Pro Ser Asp Thr Ile Glu Asn Val Lys Ala Lys Ile Gln
485 490 495
Asp Lys Glu Gly Ile Pro Pro Asp Gln Gln Arg Leu Ile Phe Ala Gly
500 505 510
Lys Gln Leu Glu Asp Gly Arg Thr Leu Ser Asp Tyr Asn Ile Gln Lys
515 520 525
Glu Ser Thr Leu His Leu Val Leu Arg Leu Arg Gly Gly Gly Gly Asp
530 535 540
Ile Gln Met Thr Gln Ser Pro Thr Ser Leu Ser Ala Ser Val Gly Asp
545 550 555 560
Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Trp Ile Gly Asn Leu Leu
565 570 575
Asp Trp Tyr Gln Gln Lys Pro Gly Glu Ala Pro Lys Leu Leu Ile Tyr
580 585 590
Tyr Ala Ser Phe Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Gly
595 600 605
Gly Phe Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu
610 615 620
Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Pro Ala Pro Leu Thr
625 630 635 640
Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Glu Pro Lys Ser Cys
645 650 655
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
660 665 670
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
675 680 685
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
690 695 700
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
705 710 715 720
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
725 730 735
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
740 745 750
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
755 760 765
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
770 775 780
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
785 790 795 800
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
805 810 815
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
820 825 830
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
835 840 845
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
850 855 860
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
865 870 875 880
Pro Gly Lys
<210> 40
<211> 886
<212> PRT
<213> Artificial Sequence
<220>
<223> Protein complex comprising VEGF and EGFR specific binding
peptides #33
<400> 40
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
20 25 30
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Lys Ile
35 40 45
Phe Asn Gly Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
50 55 60
Leu Leu Ile Tyr His Ser Ser Thr Leu Gln Ser Gly Val Pro Ser Arg
65 70 75 80
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
85 90 95
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Val Leu Leu
100 105 110
Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Glu
115 120 125
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
130 135 140
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
145 150 155 160
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
165 170 175
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
180 185 190
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
195 200 205
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
210 215 220
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
225 230 235 240
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
245 250 255
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
260 265 270
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
275 280 285
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
290 295 300
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
305 310 315 320
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
325 330 335
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
340 345 350
Leu Ser Leu Ser Pro Gly Lys Met Gln Ile Phe Val Lys Thr Leu Thr
355 360 365
Gly Lys Thr Ile Thr Leu Glu Val Glu Pro Ser Asp Thr Ile Glu Asn
370 375 380
Val Lys Ala Lys Ile Gln Asp Lys Glu Gly Ile Pro Pro Asp Gln Gln
385 390 395 400
Arg Leu Ile Phe Ala Gly Lys Gln Leu Glu Asp Gly Arg Thr Leu Ser
405 410 415
Asp Tyr Asn Ile Gln Lys Glu Ser Thr Leu His Leu Val Leu Arg Leu
420 425 430
Arg Gly Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
450 455 460
Ser Met Gln Ile Phe Val Lys Thr Leu Thr Gly Lys Thr Ile Thr Leu
465 470 475 480
Glu Val Glu Pro Ser Asp Thr Ile Glu Asn Val Lys Ala Lys Ile Gln
485 490 495
Asp Lys Glu Gly Ile Pro Pro Asp Gln Gln Arg Leu Ile Phe Ala Gly
500 505 510
Lys Gln Leu Glu Asp Gly Arg Thr Leu Ser Asp Tyr Asn Ile Gln Lys
515 520 525
Glu Ser Thr Leu His Leu Val Leu Arg Leu Arg Gly Gly Gly Gly Gly
530 535 540
Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Thr Ser Leu Ser Ala Ser
545 550 555 560
Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Trp Ile Gly
565 570 575
Asn Leu Leu Asp Trp Tyr Gln Gln Lys Pro Gly Glu Ala Pro Lys Leu
580 585 590
Leu Ile Tyr Tyr Ala Ser Phe Leu Gln Ser Gly Val Pro Ser Arg Phe
595 600 605
Ser Gly Gly Gly Phe Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu
610 615 620
Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Pro Ala
625 630 635 640
Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Glu Pro
645 650 655
Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
660 665 670
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
675 680 685
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
690 695 700
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
705 710 715 720
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
725 730 735
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
740 745 750
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
755 760 765
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
770 775 780
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
785 790 795 800
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
805 810 815
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
820 825 830
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
835 840 845
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
850 855 860
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
865 870 875 880
Ser Leu Ser Pro Gly Lys
885
<210> 41
<211> 777
<212> PRT
<213> Artificial Sequence
<220>
<223> Protein complex comprising VEGF and EGFR specific binding
peptides #34
<400> 41
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
20 25 30
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Lys Ile
35 40 45
Phe Asn Gly Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
50 55 60
Leu Leu Ile Tyr His Ser Ser Thr Leu Gln Ser Gly Val Pro Ser Arg
65 70 75 80
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
85 90 95
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Val Leu Leu
100 105 110
Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Glu
115 120 125
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
130 135 140
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
145 150 155 160
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
165 170 175
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
180 185 190
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
195 200 205
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
210 215 220
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
225 230 235 240
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
245 250 255
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
260 265 270
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
275 280 285
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
290 295 300
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
305 310 315 320
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
325 330 335
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
340 345 350
Leu Ser Leu Ser Pro Gly Lys Met Gln Ile Phe Val Lys Thr Leu Thr
355 360 365
Gly Lys Thr Ile Thr Leu Glu Val Glu Pro Ser Asp Thr Ile Glu Asn
370 375 380
Val Lys Ala Lys Ile Gln Asp Lys Glu Gly Ile Pro Pro Asp Gln Gln
385 390 395 400
Arg Leu Ile Phe Ala Gly Lys Gln Leu Glu Asp Gly Arg Thr Leu Ser
405 410 415
Asp Tyr Asn Ile Gln Lys Glu Ser Thr Leu His Leu Val Leu Arg Leu
420 425 430
Arg Gly Gly Gly Gly Asp Ile Gln Met Thr Gln Ser Pro Thr Ser Leu
435 440 445
Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln
450 455 460
Trp Ile Gly Asn Leu Leu Asp Trp Tyr Gln Gln Lys Pro Gly Glu Ala
465 470 475 480
Pro Lys Leu Leu Ile Tyr Tyr Ala Ser Phe Leu Gln Ser Gly Val Pro
485 490 495
Ser Arg Phe Ser Gly Gly Gly Phe Gly Thr Asp Phe Thr Leu Thr Ile
500 505 510
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala
515 520 525
Asn Pro Ala Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
530 535 540
Arg Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro
545 550 555 560
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
565 570 575
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
580 585 590
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
595 600 605
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
610 615 620
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
625 630 635 640
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
645 650 655
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
660 665 670
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
675 680 685
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
690 695 700
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
705 710 715 720
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
725 730 735
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
740 745 750
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
755 760 765
Lys Ser Leu Ser Leu Ser Pro Gly Lys
770 775
<210> 42
<211> 780
<212> PRT
<213> Artificial Sequence
<220>
<223> Protein complex comprising VEGF and EGFR specific binding
peptides #35
<400> 42
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
20 25 30
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Lys Ile
35 40 45
Phe Asn Gly Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
50 55 60
Leu Leu Ile Tyr His Ser Ser Thr Leu Gln Ser Gly Val Pro Ser Arg
65 70 75 80
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
85 90 95
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Val Leu Leu
100 105 110
Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Glu
115 120 125
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
130 135 140
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
145 150 155 160
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
165 170 175
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
180 185 190
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
195 200 205
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
210 215 220
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
225 230 235 240
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
245 250 255
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
260 265 270
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
275 280 285
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
290 295 300
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
305 310 315 320
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
325 330 335
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
340 345 350
Leu Ser Leu Ser Pro Gly Lys Met Gln Ile Phe Val Lys Thr Leu Thr
355 360 365
Gly Lys Thr Ile Thr Leu Glu Val Glu Pro Ser Asp Thr Ile Glu Asn
370 375 380
Val Lys Ala Lys Ile Gln Asp Lys Glu Gly Ile Pro Pro Asp Gln Gln
385 390 395 400
Arg Leu Ile Phe Ala Gly Lys Gln Leu Glu Asp Gly Arg Thr Leu Ser
405 410 415
Asp Tyr Asn Ile Gln Lys Glu Ser Thr Leu His Leu Val Leu Arg Leu
420 425 430
Arg Gly Gly Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
435 440 445
Thr Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
450 455 460
Ala Ser Gln Trp Ile Gly Asn Leu Leu Asp Trp Tyr Gln Gln Lys Pro
465 470 475 480
Gly Glu Ala Pro Lys Leu Leu Ile Tyr Tyr Ala Ser Phe Leu Gln Ser
485 490 495
Gly Val Pro Ser Arg Phe Ser Gly Gly Gly Phe Gly Thr Asp Phe Thr
500 505 510
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
515 520 525
Gln Gln Ala Asn Pro Ala Pro Leu Thr Phe Gly Gln Gly Thr Lys Val
530 535 540
Glu Ile Lys Arg Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
545 550 555 560
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
565 570 575
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
580 585 590
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
595 600 605
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
610 615 620
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
625 630 635 640
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
645 650 655
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
660 665 670
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
675 680 685
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
690 695 700
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
705 710 715 720
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
725 730 735
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
740 745 750
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
755 760 765
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
770 775 780
<210> 43
<211> 825
<212> PRT
<213> Artificial Sequence
<220>
<223> Protein complex comprising VEGF and EGFR specific binding
peptides #36
<400> 43
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
20 25 30
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Lys Ile
35 40 45
Phe Asn Gly Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
50 55 60
Leu Leu Ile Tyr His Ser Ser Thr Leu Gln Ser Gly Val Pro Ser Arg
65 70 75 80
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
85 90 95
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Val Leu Leu
100 105 110
Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Glu
115 120 125
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
130 135 140
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
145 150 155 160
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
165 170 175
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
180 185 190
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
195 200 205
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
210 215 220
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
225 230 235 240
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
245 250 255
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
260 265 270
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
275 280 285
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
290 295 300
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
305 310 315 320
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
325 330 335
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
340 345 350
Leu Ser Leu Ser Pro Gly Lys Gly Gly Met Lys Arg Gln Gly Lys Glu
355 360 365
Met Asp Ser Leu Arg Phe Leu Tyr Asp Gly Ile Arg Ile Gln Ala Asp
370 375 380
Gln Ala Pro Glu Asp Leu Asp Met Glu Asp Asn Asp Ile Ile Glu Ala
385 390 395 400
His Arg Glu Gln Ile Gly Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly
405 410 415
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
420 425 430
Gly Gly Gly Gly Ser Met Lys Arg Gln Gly Lys Glu Met Asp Ser Leu
435 440 445
Arg Phe Leu Tyr Asp Gly Ile Arg Ile Gln Ala Asp Gln Ala Pro Glu
450 455 460
Asp Leu Asp Met Glu Asp Asn Asp Ile Ile Glu Ala His Arg Glu Gln
465 470 475 480
Ile Gly Gly Gly Gly Asp Ile Gln Met Thr Gln Ser Pro Thr Ser Leu
485 490 495
Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln
500 505 510
Trp Ile Gly Asn Leu Leu Asp Trp Tyr Gln Gln Lys Pro Gly Glu Ala
515 520 525
Pro Lys Leu Leu Ile Tyr Tyr Ala Ser Phe Leu Gln Ser Gly Val Pro
530 535 540
Ser Arg Phe Ser Gly Gly Gly Phe Gly Thr Asp Phe Thr Leu Thr Ile
545 550 555 560
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala
565 570 575
Asn Pro Ala Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
580 585 590
Arg Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro
595 600 605
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
610 615 620
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
625 630 635 640
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
645 650 655
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
660 665 670
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
675 680 685
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
690 695 700
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
705 710 715 720
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
725 730 735
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
740 745 750
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
755 760 765
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
770 775 780
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
785 790 795 800
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
805 810 815
Lys Ser Leu Ser Leu Ser Pro Gly Lys
820 825
<210> 44
<211> 753
<212> PRT
<213> Artificial Sequence
<220>
<223> Protein complex comprising VEGF and EGFR specific binding
peptides #37
<400> 44
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
20 25 30
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Lys Ile
35 40 45
Phe Asn Gly Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
50 55 60
Leu Leu Ile Tyr His Ser Ser Thr Leu Gln Ser Gly Val Pro Ser Arg
65 70 75 80
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
85 90 95
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Val Leu Leu
100 105 110
Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Glu
115 120 125
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
130 135 140
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
145 150 155 160
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
165 170 175
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
180 185 190
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
195 200 205
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
210 215 220
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
225 230 235 240
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
245 250 255
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
260 265 270
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
275 280 285
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
290 295 300
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
305 310 315 320
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
325 330 335
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
340 345 350
Leu Ser Leu Ser Pro Gly Lys Asp Tyr Asp Ile Pro Thr Thr Glu Asn
355 360 365
Leu Tyr Phe Gln Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
370 375 380
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
385 390 395 400
Gly Gly Ser Glu Asn Leu Tyr Phe Gln Gly Ser Gly Gly Asp Ile Gln
405 410 415
Met Thr Gln Ser Pro Thr Ser Leu Ser Ala Ser Val Gly Asp Arg Val
420 425 430
Thr Ile Thr Cys Arg Ala Ser Gln Trp Ile Gly Asn Leu Leu Asp Trp
435 440 445
Tyr Gln Gln Lys Pro Gly Glu Ala Pro Lys Leu Leu Ile Tyr Tyr Ala
450 455 460
Ser Phe Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Gly Gly Phe
465 470 475 480
Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe
485 490 495
Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Pro Ala Pro Leu Thr Phe Gly
500 505 510
Gln Gly Thr Lys Val Glu Ile Lys Arg Glu Pro Lys Ser Cys Asp Lys
515 520 525
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
530 535 540
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
545 550 555 560
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
565 570 575
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
580 585 590
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
595 600 605
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
610 615 620
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
625 630 635 640
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
645 650 655
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
660 665 670
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
675 680 685
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
690 695 700
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
705 710 715 720
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
725 730 735
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
740 745 750
Lys
<210> 45
<211> 2634
<212> DNA
<213> Artificial Sequence
<220>
<223> Nucleotide sequence encoding the protein complex comprising VEGF
and EGFR specific binding peptides #1
<400> 45
gaattcgcca ccatgggctg gtcctgcatc atcctgtttc tggtggccac cgccaccggc 60
gtgcactctg atatccagat gacccagagc cccagcagcc tgtctgcctc tgtgggcgac 120
agagtgacca tcacctgtag agccagccag tggatcggcc ctgagctgag ctggtatcag 180
cagaagcccg gcaaggcccc caagctgctg atctaccaca ccagcatcct gcagagcggc 240
gtgcccagca gattttctgg cagcggcagc ggcaccgact tcaccctgac aatcagcagc 300
ctgcagcccg aggacttcgc cacctactac tgccagcagt acatgttcca gccccggacc 360
tttggccagg gcaccaaggt ggaaatcaga agagagccca agagctgcga caagacccac 420
acctgtcccc cttgtcctgc ccctgaactg ctgggaggcc ctagcgtgtt cctgttcccc 480
ccaaagccca aggacaccct gatgatcagc cggacccccg aagtgacctg cgtggtggtg 540
gatgtgtccc acgaggaccc tgaagtgaag ttcaattggt acgtggacgg cgtggaagtg 600
cacaacgcca agaccaagcc cagagaggaa cagtacaaca gcacctaccg ggtggtgtcc 660
gtgctgacag tgctgcacca ggactggctg aacggcaaag agtacaagtg caaggtgtcc 720
aacaaggccc tgcctgcccc catcgagaaa accatcagca aggccaaggg ccagcccaga 780
gaaccccagg tgtacacact gccccccagc agagaagaga tgaccaagaa ccaggtgtcc 840
ctgacctgcc tggtcaaggg cttctacccc agcgatatcg ccgtggaatg ggagagcaac 900
ggccagcctg agaacaacta caagaccacc ccccctgtgc tggacagcga cggctcattc 960
ttcctgtaca gcaagctgac cgtggacaag agccggtggc agcagggcaa cgtgttcagc 1020
tgcagcgtga tgcacgaggc cctgcacaac cactacaccc agaagtccct gagcctgagc 1080
cccggcaaga tgcagatctt cgtgaaaacc ctgaccggca agaccatcac cctggaagtg 1140
gaacccagcg acaccatcga gaacgtgaag gccaagatcc aggacaaaga gggcatcccc 1200
cccgaccagc agagactgat cttcgccggc aagcagctgg aagatggcag aaccctgagc 1260
gactacaaca tccagaaaga gtccaccctg cacctggtgc tgcggctgag aggcggaggt 1320
ggtggtggtt ctggtggcgg aggatctggc ggtggtggat ctgggggagg tggaagtatg 1380
cagatttttg tcaagacact gaccgggaaa acaatcacac tcgaagtcga gccctccgat 1440
acaattgaga atgtgaaagc caaaattcag gacaaagaag ggattcctcc tgatcagcag 1500
cggctgattt ttgccggaaa acagctcgaa gatggacgga ccctgtccga ttacaatatt 1560
cagaaagaaa gcaccctcca tctggtcctg aggctgcggg gaggcgacat tcagatgaca 1620
cagtccccca gctccctgag cgccagcgtg ggagatcgcg tgaccattac atgccgggcc 1680
tcccagtgga ttggcatcct ggtggattgg tatcagcaga aacctgggga ggctcctaaa 1740
ctgctgatct attacgccag ctttctgcag tccggcgtgc cctctagatt cagcggctct 1800
ggcttcggca cagatttcac actgaccatc tctagcctgc accctgaaga ttttgccaca 1860
tattactgtc agcaggccaa ccctgccccc ctgacattcg gccagggaac aaaggtcgag 1920
atcaagcgcg agcccaagtc ctgtgataag acacatacct gccccccctg cccagctcca 1980
gaactgctcg gaggaccttc tgtgtttctg tttccaccca agcctaagga tacactcatg 2040
atctccagaa cacctgaagt gacatgtgtg gtcgtcgacg tgtcacatga ggatccagaa 2100
gtcaagttta actggtatgt ggatggggtc gaggtgcaca atgccaaaac aaaacctcgg 2160
gaagaacagt ataattccac ctatagagtc gtgtctgtgc tcaccgtgct ccatcaggat 2220
tggctcaatg ggaaagaata caaatgtaaa gtctctaaca aagccctgcc cgctcctatc 2280
gaaaagacaa tctccaaggc caaaggacag cctcgcgagc ctcaggtcta caccctgcca 2340
ccttcccgcg aggaaatgac aaaaaatcag gtgtcactca cctgtctcgt gaaggggttt 2400
tacccctccg acattgccgt cgagtgggag tccaatggac agcccgagaa caattataag 2460
acaacacctc ccgtcctgga ctccgatgga tcattttttc tgtactccaa gctcaccgtc 2520
gataagtcca gatggcagca gggaaatgtc ttttcctgct ccgtgatgca tgaagctctc 2580
cacaatcatt acacacagaa aagcctgtcc ctgtcccccg gcaagtgact cgag 2634
<210> 46
<211> 2649
<212> DNA
<213> Artificial Sequence
<220>
<223> Nucleotide sequence encoding the protein complex comprising VEGF
and EGFR specific binding peptides #2
<400> 46
gaattcgcca ccatgggctg gtcctgcatc atcctgtttc tggtggccac cgccaccggc 60
gtgcactctg atatccagat gacccagagc cccagcagcc tgtctgcctc tgtgggcgac 120
agagtgacca tcacctgtag agccagccag tggatcggcc ctgagctgag ctggtatcag 180
cagaagcccg gcaaggcccc caagctgctg atctaccaca ccagcatcct gcagagcggc 240
gtgcccagca gattttctgg cagcggcagc ggcaccgact tcaccctgac aatcagcagc 300
ctgcagcccg aggacttcgc cacctactac tgccagcagt acatgttcca gccccggacc 360
tttggccagg gcaccaaggt ggaaatcaga agagagccca agagctgcga caagacccac 420
acctgtcccc cttgtcctgc ccctgaactg ctgggaggcc ctagcgtgtt cctgttcccc 480
ccaaagccca aggacaccct gatgatcagc cggacccccg aagtgacctg cgtggtggtg 540
gatgtgtccc acgaggaccc tgaagtgaag ttcaattggt acgtggacgg cgtggaagtg 600
cacaacgcca agaccaagcc cagagaggaa cagtacaaca gcacctaccg ggtggtgtcc 660
gtgctgacag tgctgcacca ggactggctg aacggcaaag agtacaagtg caaggtgtcc 720
aacaaggccc tgcctgcccc catcgagaaa accatcagca aggccaaggg ccagcccaga 780
gaaccccagg tgtacacact gccccccagc agagaagaga tgaccaagaa ccaggtgtcc 840
ctgacctgcc tggtcaaggg cttctacccc agcgatatcg ccgtggaatg ggagagcaac 900
ggccagcctg agaacaacta caagaccacc ccccctgtgc tggacagcga cggctcattc 960
ttcctgtaca gcaagctgac cgtggacaag agccggtggc agcagggcaa cgtgttcagc 1020
tgcagcgtga tgcacgaggc cctgcacaac cactacaccc agaagtccct gagcctgagc 1080
cccggcaaga tgcagatctt cgtgaaaacc ctgaccggca agaccatcac cctggaagtg 1140
gaacccagcg acaccatcga gaacgtgaag gccaagatcc aggacaaaga gggcatcccc 1200
cccgaccagc agagactgat cttcgccggc aagcagctgg aagatggcag aaccctgagc 1260
gactacaaca tccagaaaga gtccaccctg cacctggtgc tgcggctgag aggcggaggt 1320
ggtggtggtt ctggtggcgg aggatctggc ggtggtggat ctgggggagg tggaagtggt 1380
ggcggtggta gtatgcagat ttttgtcaag acactgaccg ggaaaacaat cacactcgaa 1440
gtcgagccct ccgatacaat tgagaatgtg aaagccaaaa ttcaggacaa agaagggatt 1500
cctcctgatc agcagcggct gatttttgcc ggaaaacagc tcgaagatgg acggaccctg 1560
tccgattaca atattcagaa agaaagcacc ctccatctgg tcctgaggct gcggggaggc 1620
gacattcaga tgacacagtc ccccagctcc ctgagcgcca gcgtgggaga tcgcgtgacc 1680
attacatgcc gggcctccca gtggattggc atcctggtgg attggtatca gcagaaacct 1740
ggggaggctc ctaaactgct gatctattac gccagctttc tgcagtccgg cgtgccctct 1800
agattcagcg gctctggctt cggcacagat ttcacactga ccatctctag cctgcaccct 1860
gaagattttg ccacatatta ctgtcagcag gccaaccctg cccccctgac attcggccag 1920
ggaacaaagg tcgagatcaa gcgcgagccc aagtcctgtg ataagacaca tacctgcccc 1980
ccctgcccag ctccagaact gctcggagga ccttctgtgt ttctgtttcc acccaagcct 2040
aaggatacac tcatgatctc cagaacacct gaagtgacat gtgtggtcgt cgacgtgtca 2100
catgaggatc cagaagtcaa gtttaactgg tatgtggatg gggtcgaggt gcacaatgcc 2160
aaaacaaaac ctcgggaaga acagtataat tccacctata gagtcgtgtc tgtgctcacc 2220
gtgctccatc aggattggct caatgggaaa gaatacaaat gtaaagtctc taacaaagcc 2280
ctgcccgctc ctatcgaaaa gacaatctcc aaggccaaag gacagcctcg cgagcctcag 2340
gtctacaccc tgccaccttc ccgcgaggaa atgacaaaaa atcaggtgtc actcacctgt 2400
ctcgtgaagg ggttttaccc ctccgacatt gccgtcgagt gggagtccaa tggacagccc 2460
gagaacaatt ataagacaac acctcccgtc ctggactccg atggatcatt ttttctgtac 2520
tccaagctca ccgtcgataa gtccagatgg cagcagggaa atgtcttttc ctgctccgtg 2580
atgcatgaag ctctccacaa tcattacaca cagaaaagcc tgtccctgtc ccccggcaag 2640
tgactcgag 2649
<210> 47
<211> 2664
<212> DNA
<213> Artificial Sequence
<220>
<223> Nucleotide sequence encoding the protein complex comprising VEGF
and EGFR specific binding peptides #3
<400> 47
gaattcgcca ccatgggctg gtcctgcatc atcctgtttc tggtggccac cgccaccggc 60
gtgcactctg atatccagat gacccagagc cccagcagcc tgtctgcctc tgtgggcgac 120
agagtgacca tcacctgtag agccagccag tggatcggcc ctgagctgag ctggtatcag 180
cagaagcccg gcaaggcccc caagctgctg atctaccaca ccagcatcct gcagagcggc 240
gtgcccagca gattttctgg cagcggcagc ggcaccgact tcaccctgac aatcagcagc 300
ctgcagcccg aggacttcgc cacctactac tgccagcagt acatgttcca gccccggacc 360
tttggccagg gcaccaaggt ggaaatcaga agagagccca agagctgcga caagacccac 420
acctgtcccc cttgtcctgc ccctgaactg ctgggaggcc ctagcgtgtt cctgttcccc 480
ccaaagccca aggacaccct gatgatcagc cggacccccg aagtgacctg cgtggtggtg 540
gatgtgtccc acgaggaccc tgaagtgaag ttcaattggt acgtggacgg cgtggaagtg 600
cacaacgcca agaccaagcc cagagaggaa cagtacaaca gcacctaccg ggtggtgtcc 660
gtgctgacag tgctgcacca ggactggctg aacggcaaag agtacaagtg caaggtgtcc 720
aacaaggccc tgcctgcccc catcgagaaa accatcagca aggccaaggg ccagcccaga 780
gaaccccagg tgtacacact gccccccagc agagaagaga tgaccaagaa ccaggtgtcc 840
ctgacctgcc tggtcaaggg cttctacccc agcgatatcg ccgtggaatg ggagagcaac 900
ggccagcctg agaacaacta caagaccacc ccccctgtgc tggacagcga cggctcattc 960
ttcctgtaca gcaagctgac cgtggacaag agccggtggc agcagggcaa cgtgttcagc 1020
tgcagcgtga tgcacgaggc cctgcacaac cactacaccc agaagtccct gagcctgagc 1080
cccggcaaga tgcagatctt cgtgaaaacc ctgaccggca agaccatcac cctggaagtg 1140
gaacccagcg acaccatcga gaacgtgaag gccaagatcc aggacaaaga gggcatcccc 1200
cccgaccagc agagactgat cttcgccggc aagcagctgg aagatggcag aaccctgagc 1260
gactacaaca tccagaaaga gtccaccctg cacctggtgc tgcggctgag aggcggaggt 1320
ggtggtggtt ctggtggcgg aggatctggc ggtggtggat ctgggggagg tggaagtggt 1380
ggcggtggta gtggtggtgg cggaagcatg cagatttttg tcaagacact gaccgggaaa 1440
acaatcacac tcgaagtcga gccctccgat acaattgaga atgtgaaagc caaaattcag 1500
gacaaagaag ggattcctcc tgatcagcag cggctgattt ttgccggaaa acagctcgaa 1560
gatggacgga ccctgtccga ttacaatatt cagaaagaaa gcaccctcca tctggtcctg 1620
aggctgcggg gaggcgacat tcagatgaca cagtccccca gctccctgag cgccagcgtg 1680
ggagatcgcg tgaccattac atgccgggcc tcccagtgga ttggcatcct ggtggattgg 1740
tatcagcaga aacctgggga ggctcctaaa ctgctgatct attacgccag ctttctgcag 1800
tccggcgtgc cctctagatt cagcggctct ggcttcggca cagatttcac actgaccatc 1860
tctagcctgc accctgaaga ttttgccaca tattactgtc agcaggccaa ccctgccccc 1920
ctgacattcg gccagggaac aaaggtcgag atcaagcgcg agcccaagtc ctgtgataag 1980
acacatacct gccccccctg cccagctcca gaactgctcg gaggaccttc tgtgtttctg 2040
tttccaccca agcctaagga tacactcatg atctccagaa cacctgaagt gacatgtgtg 2100
gtcgtcgacg tgtcacatga ggatccagaa gtcaagttta actggtatgt ggatggggtc 2160
gaggtgcaca atgccaaaac aaaacctcgg gaagaacagt ataattccac ctatagagtc 2220
gtgtctgtgc tcaccgtgct ccatcaggat tggctcaatg ggaaagaata caaatgtaaa 2280
gtctctaaca aagccctgcc cgctcctatc gaaaagacaa tctccaaggc caaaggacag 2340
cctcgcgagc ctcaggtcta caccctgcca ccttcccgcg aggaaatgac aaaaaatcag 2400
gtgtcactca cctgtctcgt gaaggggttt tacccctccg acattgccgt cgagtgggag 2460
tccaatggac agcccgagaa caattataag acaacacctc ccgtcctgga ctccgatgga 2520
tcattttttc tgtactccaa gctcaccgtc gataagtcca gatggcagca gggaaatgtc 2580
ttttcctgct ccgtgatgca tgaagctctc cacaatcatt acacacagaa aagcctgtcc 2640
ctgtcccccg gcaagtgact cgag 2664
<210> 48
<211> 2679
<212> DNA
<213> Artificial Sequence
<220>
<223> Nucleotide sequence encoding the protein complex comprising VEGF
and EGFR specific binding peptides #4
<400> 48
gaattcgcca ccatgggctg gtcctgcatc atcctgtttc tggtggccac cgccaccggc 60
gtgcactctg atatccagat gacccagagc cccagcagcc tgtctgcctc tgtgggcgac 120
agagtgacca tcacctgtag agccagccag tggatcggcc ctgagctgag ctggtatcag 180
cagaagcccg gcaaggcccc caagctgctg atctaccaca ccagcatcct gcagagcggc 240
gtgcccagca gattttctgg cagcggcagc ggcaccgact tcaccctgac aatcagcagc 300
ctgcagcccg aggacttcgc cacctactac tgccagcagt acatgttcca gccccggacc 360
tttggccagg gcaccaaggt ggaaatcaga agagagccca agagctgcga caagacccac 420
acctgtcccc cttgtcctgc ccctgaactg ctgggaggcc ctagcgtgtt cctgttcccc 480
ccaaagccca aggacaccct gatgatcagc cggacccccg aagtgacctg cgtggtggtg 540
gatgtgtccc acgaggaccc tgaagtgaag ttcaattggt acgtggacgg cgtggaagtg 600
cacaacgcca agaccaagcc cagagaggaa cagtacaaca gcacctaccg ggtggtgtcc 660
gtgctgacag tgctgcacca ggactggctg aacggcaaag agtacaagtg caaggtgtcc 720
aacaaggccc tgcctgcccc catcgagaaa accatcagca aggccaaggg ccagcccaga 780
gaaccccagg tgtacacact gccccccagc agagaagaga tgaccaagaa ccaggtgtcc 840
ctgacctgcc tggtcaaggg cttctacccc agcgatatcg ccgtggaatg ggagagcaac 900
ggccagcctg agaacaacta caagaccacc ccccctgtgc tggacagcga cggctcattc 960
ttcctgtaca gcaagctgac cgtggacaag agccggtggc agcagggcaa cgtgttcagc 1020
tgcagcgtga tgcacgaggc cctgcacaac cactacaccc agaagtccct gagcctgagc 1080
cccggcaaga tgcagatctt cgtgaaaacc ctgaccggca agaccatcac cctggaagtg 1140
gaacccagcg acaccatcga gaacgtgaag gccaagatcc aggacaaaga gggcatcccc 1200
cccgaccagc agagactgat cttcgccggc aagcagctgg aagatggcag aaccctgagc 1260
gactacaaca tccagaaaga gtccaccctg cacctggtgc tgcggctgag aggcggaggt 1320
ggtggtggtt ctggtggcgg aggatctggc ggtggtggat ctgggggagg tggaagtggt 1380
ggcggtggta gtggtggtgg cggaagcgga ggcggtggat caatgcagat ttttgtcaag 1440
acactgaccg ggaaaacaat cacactcgaa gtcgagccct ccgatacaat tgagaatgtg 1500
aaagccaaaa ttcaggacaa agaagggatt cctcctgatc agcagcggct gatttttgcc 1560
ggaaaacagc tcgaagatgg acggaccctg tccgattaca atattcagaa agaaagcacc 1620
ctccatctgg tcctgaggct gcggggaggc gacattcaga tgacacagtc ccccagctcc 1680
ctgagcgcca gcgtgggaga tcgcgtgacc attacatgcc gggcctccca gtggattggc 1740
atcctggtgg attggtatca gcagaaacct ggggaggctc ctaaactgct gatctattac 1800
gccagctttc tgcagtccgg cgtgccctct agattcagcg gctctggctt cggcacagat 1860
ttcacactga ccatctctag cctgcaccct gaagattttg ccacatatta ctgtcagcag 1920
gccaaccctg cccccctgac attcggccag ggaacaaagg tcgagatcaa gcgcgagccc 1980
aagtcctgtg ataagacaca tacctgcccc ccctgcccag ctccagaact gctcggagga 2040
ccttctgtgt ttctgtttcc acccaagcct aaggatacac tcatgatctc cagaacacct 2100
gaagtgacat gtgtggtcgt cgacgtgtca catgaggatc cagaagtcaa gtttaactgg 2160
tatgtggatg gggtcgaggt gcacaatgcc aaaacaaaac ctcgggaaga acagtataat 2220
tccacctata gagtcgtgtc tgtgctcacc gtgctccatc aggattggct caatgggaaa 2280
gaatacaaat gtaaagtctc taacaaagcc ctgcccgctc ctatcgaaaa gacaatctcc 2340
aaggccaaag gacagcctcg cgagcctcag gtctacaccc tgccaccttc ccgcgaggaa 2400
atgacaaaaa atcaggtgtc actcacctgt ctcgtgaagg ggttttaccc ctccgacatt 2460
gccgtcgagt gggagtccaa tggacagccc gagaacaatt ataagacaac acctcccgtc 2520
ctggactccg atggatcatt ttttctgtac tccaagctca ccgtcgataa gtccagatgg 2580
cagcagggaa atgtcttttc ctgctccgtg atgcatgaag ctctccacaa tcattacaca 2640
cagaaaagcc tgtccctgtc ccccggcaag tgactcgag 2679
<210> 49
<211> 2694
<212> DNA
<213> Artificial Sequence
<220>
<223> Nucleotide sequence encoding the protein complex comprising VEGF
and EGFR specific binding peptides #5
<400> 49
gaattcgcca ccatgggctg gtcctgcatc atcctgtttc tggtggccac cgccaccggc 60
gtgcactctg atatccagat gacccagagc cccagcagcc tgtctgcctc tgtgggcgac 120
agagtgacca tcacctgtag agccagccag tggatcggcc ctgagctgag ctggtatcag 180
cagaagcccg gcaaggcccc caagctgctg atctaccaca ccagcatcct gcagagcggc 240
gtgcccagca gattttctgg cagcggcagc ggcaccgact tcaccctgac aatcagcagc 300
ctgcagcccg aggacttcgc cacctactac tgccagcagt acatgttcca gccccggacc 360
tttggccagg gcaccaaggt ggaaatcaga agagagccca agagctgcga caagacccac 420
acctgtcccc cttgtcctgc ccctgaactg ctgggaggcc ctagcgtgtt cctgttcccc 480
ccaaagccca aggacaccct gatgatcagc cggacccccg aagtgacctg cgtggtggtg 540
gatgtgtccc acgaggaccc tgaagtgaag ttcaattggt acgtggacgg cgtggaagtg 600
cacaacgcca agaccaagcc cagagaggaa cagtacaaca gcacctaccg ggtggtgtcc 660
gtgctgacag tgctgcacca ggactggctg aacggcaaag agtacaagtg caaggtgtcc 720
aacaaggccc tgcctgcccc catcgagaaa accatcagca aggccaaggg ccagcccaga 780
gaaccccagg tgtacacact gccccccagc agagaagaga tgaccaagaa ccaggtgtcc 840
ctgacctgcc tggtcaaggg cttctacccc agcgatatcg ccgtggaatg ggagagcaac 900
ggccagcctg agaacaacta caagaccacc ccccctgtgc tggacagcga cggctcattc 960
ttcctgtaca gcaagctgac cgtggacaag agccggtggc agcagggcaa cgtgttcagc 1020
tgcagcgtga tgcacgaggc cctgcacaac cactacaccc agaagtccct gagcctgagc 1080
cccggcaaga tgcagatctt cgtgaaaacc ctgaccggca agaccatcac cctggaagtg 1140
gaacccagcg acaccatcga gaacgtgaag gccaagatcc aggacaaaga gggcatcccc 1200
cccgaccagc agagactgat cttcgccggc aagcagctgg aagatggcag aaccctgagc 1260
gactacaaca tccagaaaga gtccaccctg cacctggtgc tgcggctgag aggcggaggt 1320
ggtggtggtt ctggtggcgg aggatctggc ggtggtggat ctgggggagg tggaagtggt 1380
ggcggtggta gtggtggtgg cggaagcgga ggcggtggat caggcggagg cggatcaatg 1440
cagatttttg tcaagacact gaccgggaaa acaatcacac tcgaagtcga gccctccgat 1500
acaattgaga atgtgaaagc caaaattcag gacaaagaag ggattcctcc tgatcagcag 1560
cggctgattt ttgccggaaa acagctcgaa gatggacgga ccctgtccga ttacaatatt 1620
cagaaagaaa gcaccctcca tctggtcctg aggctgcggg gaggcgacat tcagatgaca 1680
cagtccccca gctccctgag cgccagcgtg ggagatcgcg tgaccattac atgccgggcc 1740
tcccagtgga ttggcatcct ggtggattgg tatcagcaga aacctgggga ggctcctaaa 1800
ctgctgatct attacgccag ctttctgcag tccggcgtgc cctctagatt cagcggctct 1860
ggcttcggca cagatttcac actgaccatc tctagcctgc accctgaaga ttttgccaca 1920
tattactgtc agcaggccaa ccctgccccc ctgacattcg gccagggaac aaaggtcgag 1980
atcaagcgcg agcccaagtc ctgtgataag acacatacct gccccccctg cccagctcca 2040
gaactgctcg gaggaccttc tgtgtttctg tttccaccca agcctaagga tacactcatg 2100
atctccagaa cacctgaagt gacatgtgtg gtcgtcgacg tgtcacatga ggatccagaa 2160
gtcaagttta actggtatgt ggatggggtc gaggtgcaca atgccaaaac aaaacctcgg 2220
gaagaacagt ataattccac ctatagagtc gtgtctgtgc tcaccgtgct ccatcaggat 2280
tggctcaatg ggaaagaata caaatgtaaa gtctctaaca aagccctgcc cgctcctatc 2340
gaaaagacaa tctccaaggc caaaggacag cctcgcgagc ctcaggtcta caccctgcca 2400
ccttcccgcg aggaaatgac aaaaaatcag gtgtcactca cctgtctcgt gaaggggttt 2460
tacccctccg acattgccgt cgagtgggag tccaatggac agcccgagaa caattataag 2520
acaacacctc ccgtcctgga ctccgatgga tcattttttc tgtactccaa gctcaccgtc 2580
gataagtcca gatggcagca gggaaatgtc ttttcctgct ccgtgatgca tgaagctctc 2640
cacaatcatt acacacagaa aagcctgtcc ctgtcccccg gcaagtgact cgag 2694
<210> 50
<211> 2709
<212> DNA
<213> Artificial Sequence
<220>
<223> Nucleotide sequence encoding the protein complex comprising VEGF
and EGFR specific binding peptides #6
<400> 50
gaattcgcca ccatgggctg gtcctgcatc atcctgtttc tggtggccac cgccaccggc 60
gtgcactctg atatccagat gacccagagc cccagcagcc tgtctgcctc tgtgggcgac 120
agagtgacca tcacctgtag agccagccag tggatcggcc ctgagctgag ctggtatcag 180
cagaagcccg gcaaggcccc caagctgctg atctaccaca ccagcatcct gcagagcggc 240
gtgcccagca gattttctgg cagcggcagc ggcaccgact tcaccctgac aatcagcagc 300
ctgcagcccg aggacttcgc cacctactac tgccagcagt acatgttcca gccccggacc 360
tttggccagg gcaccaaggt ggaaatcaga agagagccca agagctgcga caagacccac 420
acctgtcccc cttgtcctgc ccctgaactg ctgggaggcc ctagcgtgtt cctgttcccc 480
ccaaagccca aggacaccct gatgatcagc cggacccccg aagtgacctg cgtggtggtg 540
gatgtgtccc acgaggaccc tgaagtgaag ttcaattggt acgtggacgg cgtggaagtg 600
cacaacgcca agaccaagcc cagagaggaa cagtacaaca gcacctaccg ggtggtgtcc 660
gtgctgacag tgctgcacca ggactggctg aacggcaaag agtacaagtg caaggtgtcc 720
aacaaggccc tgcctgcccc catcgagaaa accatcagca aggccaaggg ccagcccaga 780
gaaccccagg tgtacacact gccccccagc agagaagaga tgaccaagaa ccaggtgtcc 840
ctgacctgcc tggtcaaggg cttctacccc agcgatatcg ccgtggaatg ggagagcaac 900
ggccagcctg agaacaacta caagaccacc ccccctgtgc tggacagcga cggctcattc 960
ttcctgtaca gcaagctgac cgtggacaag agccggtggc agcagggcaa cgtgttcagc 1020
tgcagcgtga tgcacgaggc cctgcacaac cactacaccc agaagtccct gagcctgagc 1080
cccggcaaga tgcagatctt cgtgaaaacc ctgaccggca agaccatcac cctggaagtg 1140
gaacccagcg acaccatcga gaacgtgaag gccaagatcc aggacaaaga gggcatcccc 1200
cccgaccagc agagactgat cttcgccggc aagcagctgg aagatggcag aaccctgagc 1260
gactacaaca tccagaaaga gtccaccctg cacctggtgc tgcggctgag aggcggaggt 1320
ggtggtggtt ctggtggcgg aggatctggc ggtggtggat ctgggggagg tggaagtggt 1380
ggcggtggta gtggtggtgg cggaagcgga ggcggtggat caggcggagg cggatcaggt 1440
ggcgggggtt caatgcagat ttttgtcaag acactgaccg ggaaaacaat cacactcgaa 1500
gtcgagccct ccgatacaat tgagaatgtg aaagccaaaa ttcaggacaa agaagggatt 1560
cctcctgatc agcagcggct gatttttgcc ggaaaacagc tcgaagatgg acggaccctg 1620
tccgattaca atattcagaa agaaagcacc ctccatctgg tcctgaggct gcggggaggc 1680
gacattcaga tgacacagtc ccccagctcc ctgagcgcca gcgtgggaga tcgcgtgacc 1740
attacatgcc gggcctccca gtggattggc atcctggtgg attggtatca gcagaaacct 1800
ggggaggctc ctaaactgct gatctattac gccagctttc tgcagtccgg cgtgccctct 1860
agattcagcg gctctggctt cggcacagat ttcacactga ccatctctag cctgcaccct 1920
gaagattttg ccacatatta ctgtcagcag gccaaccctg cccccctgac attcggccag 1980
ggaacaaagg tcgagatcaa gcgcgagccc aagtcctgtg ataagacaca tacctgcccc 2040
ccctgcccag ctccagaact gctcggagga ccttctgtgt ttctgtttcc acccaagcct 2100
aaggatacac tcatgatctc cagaacacct gaagtgacat gtgtggtcgt cgacgtgtca 2160
catgaggatc cagaagtcaa gtttaactgg tatgtggatg gggtcgaggt gcacaatgcc 2220
aaaacaaaac ctcgggaaga acagtataat tccacctata gagtcgtgtc tgtgctcacc 2280
gtgctccatc aggattggct caatgggaaa gaatacaaat gtaaagtctc taacaaagcc 2340
ctgcccgctc ctatcgaaaa gacaatctcc aaggccaaag gacagcctcg cgagcctcag 2400
gtctacaccc tgccaccttc ccgcgaggaa atgacaaaaa atcaggtgtc actcacctgt 2460
ctcgtgaagg ggttttaccc ctccgacatt gccgtcgagt gggagtccaa tggacagccc 2520
gagaacaatt ataagacaac acctcccgtc ctggactccg atggatcatt ttttctgtac 2580
tccaagctca ccgtcgataa gtccagatgg cagcagggaa atgtcttttc ctgctccgtg 2640
atgcatgaag ctctccacaa tcattacaca cagaaaagcc tgtccctgtc ccccggcaag 2700
tgactcgag 2709
<210> 51
<211> 2724
<212> DNA
<213> Artificial Sequence
<220>
<223> Nucleotide sequence encoding the protein complex comprising VEGF
and EGFR specific binding peptides #7
<400> 51
gaattcgcca ccatgggctg gtcctgcatc atcctgtttc tggtggccac cgccaccggc 60
gtgcactctg atatccagat gacccagagc cccagcagcc tgtctgcctc tgtgggcgac 120
agagtgacca tcacctgtag agccagccag tggatcggcc ctgagctgag ctggtatcag 180
cagaagcccg gcaaggcccc caagctgctg atctaccaca ccagcatcct gcagagcggc 240
gtgcccagca gattttctgg cagcggcagc ggcaccgact tcaccctgac aatcagcagc 300
ctgcagcccg aggacttcgc cacctactac tgccagcagt acatgttcca gccccggacc 360
tttggccagg gcaccaaggt ggaaatcaga agagagccca agagctgcga caagacccac 420
acctgtcccc cttgtcctgc ccctgaactg ctgggaggcc ctagcgtgtt cctgttcccc 480
ccaaagccca aggacaccct gatgatcagc cggacccccg aagtgacctg cgtggtggtg 540
gatgtgtccc acgaggaccc tgaagtgaag ttcaattggt acgtggacgg cgtggaagtg 600
cacaacgcca agaccaagcc cagagaggaa cagtacaaca gcacctaccg ggtggtgtcc 660
gtgctgacag tgctgcacca ggactggctg aacggcaaag agtacaagtg caaggtgtcc 720
aacaaggccc tgcctgcccc catcgagaaa accatcagca aggccaaggg ccagcccaga 780
gaaccccagg tgtacacact gccccccagc agagaagaga tgaccaagaa ccaggtgtcc 840
ctgacctgcc tggtcaaggg cttctacccc agcgatatcg ccgtggaatg ggagagcaac 900
ggccagcctg agaacaacta caagaccacc ccccctgtgc tggacagcga cggctcattc 960
ttcctgtaca gcaagctgac cgtggacaag agccggtggc agcagggcaa cgtgttcagc 1020
tgcagcgtga tgcacgaggc cctgcacaac cactacaccc agaagtccct gagcctgagc 1080
cccggcaaga tgcagatctt cgtgaaaacc ctgaccggca agaccatcac cctggaagtg 1140
gaacccagcg acaccatcga gaacgtgaag gccaagatcc aggacaaaga gggcatcccc 1200
cccgaccagc agagactgat cttcgccggc aagcagctgg aagatggcag aaccctgagc 1260
gactacaaca tccagaaaga gtccaccctg cacctggtgc tgcggctgag aggcggaggt 1320
ggtggtggtt ctggtggcgg aggatctggc ggtggtggat ctgggggagg tggaagtggt 1380
ggcggtggta gtggtggtgg cggaagcgga ggcggtggat caggcggagg cggatcaggt 1440
ggcgggggtt cagggggtgg cggaagtatg cagatttttg tcaagacact gaccgggaaa 1500
acaatcacac tcgaagtcga gccctccgat acaattgaga atgtgaaagc caaaattcag 1560
gacaaagaag ggattcctcc tgatcagcag cggctgattt ttgccggaaa acagctcgaa 1620
gatggacgga ccctgtccga ttacaatatt cagaaagaaa gcaccctcca tctggtcctg 1680
aggctgcggg gaggcgacat tcagatgaca cagtccccca gctccctgag cgccagcgtg 1740
ggagatcgcg tgaccattac atgccgggcc tcccagtgga ttggcatcct ggtggattgg 1800
tatcagcaga aacctgggga ggctcctaaa ctgctgatct attacgccag ctttctgcag 1860
tccggcgtgc cctctagatt cagcggctct ggcttcggca cagatttcac actgaccatc 1920
tctagcctgc accctgaaga ttttgccaca tattactgtc agcaggccaa ccctgccccc 1980
ctgacattcg gccagggaac aaaggtcgag atcaagcgcg agcccaagtc ctgtgataag 2040
acacatacct gccccccctg cccagctcca gaactgctcg gaggaccttc tgtgtttctg 2100
tttccaccca agcctaagga tacactcatg atctccagaa cacctgaagt gacatgtgtg 2160
gtcgtcgacg tgtcacatga ggatccagaa gtcaagttta actggtatgt ggatggggtc 2220
gaggtgcaca atgccaaaac aaaacctcgg gaagaacagt ataattccac ctatagagtc 2280
gtgtctgtgc tcaccgtgct ccatcaggat tggctcaatg ggaaagaata caaatgtaaa 2340
gtctctaaca aagccctgcc cgctcctatc gaaaagacaa tctccaaggc caaaggacag 2400
cctcgcgagc ctcaggtcta caccctgcca ccttcccgcg aggaaatgac aaaaaatcag 2460
gtgtcactca cctgtctcgt gaaggggttt tacccctccg acattgccgt cgagtgggag 2520
tccaatggac agcccgagaa caattataag acaacacctc ccgtcctgga ctccgatgga 2580
tcattttttc tgtactccaa gctcaccgtc gataagtcca gatggcagca gggaaatgtc 2640
ttttcctgct ccgtgatgca tgaagctctc cacaatcatt acacacagaa aagcctgtcc 2700
ctgtcccccg gcaagtgact cgag 2724
<210> 52
<211> 2634
<212> DNA
<213> Artificial Sequence
<220>
<223> Nucleotide sequence encoding the protein complex comprising VEGF
and EGFR specific binding peptides #8
<400> 52
gaattcgcca ccatgggctg gtcctgcatc atcctgtttc tggtggccac cgccaccggc 60
gtgcactctg atatccagat gacccagagc cccagcagcc tgtctgcctc tgtgggcgac 120
agagtgacca tcacctgtag agccagccag tggatcggcc ctgagctgag ctggtatcag 180
cagaagcccg gcaaggcccc caagctgctg atctaccaca ccagcatcct gcagagcggc 240
gtgcccagca gattttctgg cagcggcagc ggcaccgact tcaccctgac aatcagcagc 300
ctgcagcccg aggacttcgc cacctactac tgccagcagt acatgttcca gccccggacc 360
tttggccagg gcaccaaggt ggaaatcaga agagagccca agagctgcga caagacccac 420
acctgtcccc cttgtcctgc ccctgaactg ctgggaggcc ctagcgtgtt cctgttcccc 480
ccaaagccca aggacaccct gatgatcagc cggacccccg aagtgacctg cgtggtggtg 540
gatgtgtccc acgaggaccc tgaagtgaag ttcaattggt acgtggacgg cgtggaagtg 600
cacaacgcca agaccaagcc cagagaggaa cagtacaaca gcacctaccg ggtggtgtcc 660
gtgctgacag tgctgcacca ggactggctg aacggcaaag agtacaagtg caaggtgtcc 720
aacaaggccc tgcctgcccc catcgagaaa accatcagca aggccaaggg ccagcccaga 780
gaaccccagg tgtacacact gccccccagc agagaagaga tgaccaagaa ccaggtgtcc 840
ctgacctgcc tggtcaaggg cttctacccc agcgatatcg ccgtggaatg ggagagcaac 900
ggccagcctg agaacaacta caagaccacc ccccctgtgc tggacagcga cggctcattc 960
ttcctgtaca gcaagctgac cgtggacaag agccggtggc agcagggcaa cgtgttcagc 1020
tgcagcgtga tgcacgaggc cctgcacaac cactacaccc agaagtccct gagcctgagc 1080
cccggcaaga tgcagatctt cgtgaaaacc ctgaccggca agaccatcac cctggaagtg 1140
gaacccagcg acaccatcga gaacgtgaag gccaagatcc aggacaaaga gggcatcccc 1200
cccgaccagc agagactgat cttcgccggc aagcagctgg aagatggcag aaccctgagc 1260
gactacaaca tccagaaaga gtccaccctg cacctggtgc tgcggctgag aggcggaggt 1320
ggtggtggtt ctggtggcgg aggatctggc ggtggtggat ctgggggagg tggaagtatg 1380
cagatttttg tcaagacact gaccgggaaa acaatcacac tcgaagtcga gccctccgat 1440
acaattgaga atgtgaaagc caaaattcag gacaaagaag ggattcctcc tgatcagcag 1500
cggctgattt ttgccggaaa acagctcgaa gatggacgga ccctgtccga ttacaatatt 1560
cagaaagaaa gcaccctcca tctggtcctg aggctgcggg gaggcgacat tcagatgaca 1620
cagtccccca cctccctgtc tgccagcgtg ggagatcgcg tgaccattac atgccgggcc 1680
tcccagtgga ttggcaacct gctggattgg tatcagcaga aacctgggga ggctcctaaa 1740
ctgctgatct attacgccag ctttctgcag tccggcgtgc cctccagatt cagcggcgga 1800
ggcttcggca cagatttcac actgaccatc tcatccctgc agcctgaaga ttttgccaca 1860
tattattgcc agcaggccaa ccctgccccc ctgacattcg gccagggaac aaaggtcgag 1920
atcaagcgcg agcccaagtc ctgtgataag acacatacct gccccccctg cccagctcca 1980
gaactgctcg gaggaccttc tgtgtttctg tttccaccca agcctaagga tacactcatg 2040
atctccagaa cacctgaagt gacatgtgtg gtcgtcgacg tgtcacatga ggatccagaa 2100
gtcaagttta actggtatgt ggatggggtc gaggtgcaca atgccaaaac aaaacctcgg 2160
gaagaacagt ataattccac ctatagagtc gtgtctgtgc tcaccgtgct ccatcaggat 2220
tggctcaatg ggaaagaata caaatgtaaa gtctctaaca aagccctgcc cgctcctatc 2280
gaaaagacaa tctccaaggc caaaggacag cctcgcgagc ctcaggtcta caccctgcca 2340
cctagccgcg aggaaatgac aaaaaatcag gtgtcactca cctgtctcgt gaaggggttt 2400
tacccctccg acattgccgt cgagtgggag tccaatggac agcccgagaa caattataag 2460
acaacacctc ccgtcctgga ctccgatgga tcattttttc tgtactccaa gctcaccgtc 2520
gataagtcca gatggcagca gggaaatgtc ttttcctgct ccgtgatgca tgaagctctc 2580
cacaatcatt acacacagaa aagcctgtcc ctgtcccccg gcaagtgact cgag 2634
<210> 53
<211> 2649
<212> DNA
<213> Artificial Sequence
<220>
<223> Nucleotide sequence encoding the protein complex comprising VEGF
and EGFR specific binding peptides #9
<400> 53
gaattcgcca ccatgggctg gtcctgcatc atcctgtttc tggtggccac cgccaccggc 60
gtgcactctg atatccagat gacccagagc cccagcagcc tgtctgcctc tgtgggcgac 120
agagtgacca tcacctgtag agccagccag tggatcggcc ctgagctgag ctggtatcag 180
cagaagcccg gcaaggcccc caagctgctg atctaccaca ccagcatcct gcagagcggc 240
gtgcccagca gattttctgg cagcggcagc ggcaccgact tcaccctgac aatcagcagc 300
ctgcagcccg aggacttcgc cacctactac tgccagcagt acatgttcca gccccggacc 360
tttggccagg gcaccaaggt ggaaatcaga agagagccca agagctgcga caagacccac 420
acctgtcccc cttgtcctgc ccctgaactg ctgggaggcc ctagcgtgtt cctgttcccc 480
ccaaagccca aggacaccct gatgatcagc cggacccccg aagtgacctg cgtggtggtg 540
gatgtgtccc acgaggaccc tgaagtgaag ttcaattggt acgtggacgg cgtggaagtg 600
cacaacgcca agaccaagcc cagagaggaa cagtacaaca gcacctaccg ggtggtgtcc 660
gtgctgacag tgctgcacca ggactggctg aacggcaaag agtacaagtg caaggtgtcc 720
aacaaggccc tgcctgcccc catcgagaaa accatcagca aggccaaggg ccagcccaga 780
gaaccccagg tgtacacact gccccccagc agagaagaga tgaccaagaa ccaggtgtcc 840
ctgacctgcc tggtcaaggg cttctacccc agcgatatcg ccgtggaatg ggagagcaac 900
ggccagcctg agaacaacta caagaccacc ccccctgtgc tggacagcga cggctcattc 960
ttcctgtaca gcaagctgac cgtggacaag agccggtggc agcagggcaa cgtgttcagc 1020
tgcagcgtga tgcacgaggc cctgcacaac cactacaccc agaagtccct gagcctgagc 1080
cccggcaaga tgcagatctt cgtgaaaacc ctgaccggca agaccatcac cctggaagtg 1140
gaacccagcg acaccatcga gaacgtgaag gccaagatcc aggacaaaga gggcatcccc 1200
cccgaccagc agagactgat cttcgccggc aagcagctgg aagatggcag aaccctgagc 1260
gactacaaca tccagaaaga gtccaccctg cacctggtgc tgcggctgag aggcggaggt 1320
ggtggtggtt ctggtggcgg aggatctggc ggtggtggat ctgggggagg tggaagtggt 1380
ggcggtggta gtatgcagat ttttgtcaag acactgaccg ggaaaacaat cacactcgaa 1440
gtcgagccct ccgatacaat tgagaatgtg aaagccaaaa ttcaggacaa agaagggatt 1500
cctcctgatc agcagcggct gatttttgcc ggaaaacagc tcgaagatgg acggaccctg 1560
tccgattaca atattcagaa agaaagcacc ctccatctgg tcctgaggct gcggggaggc 1620
gacattcaga tgacacagtc ccccacctcc ctgtctgcca gcgtgggaga tcgcgtgacc 1680
attacatgcc gggcctccca gtggattggc aacctgctgg attggtatca gcagaaacct 1740
ggggaggctc ctaaactgct gatctattac gccagctttc tgcagtccgg cgtgccctcc 1800
agattcagcg gcggaggctt cggcacagat ttcacactga ccatctcatc cctgcagcct 1860
gaagattttg ccacatatta ttgccagcag gccaaccctg cccccctgac attcggccag 1920
ggaacaaagg tcgagatcaa gcgcgagccc aagtcctgtg ataagacaca tacctgcccc 1980
ccctgcccag ctccagaact gctcggagga ccttctgtgt ttctgtttcc acccaagcct 2040
aaggatacac tcatgatctc cagaacacct gaagtgacat gtgtggtcgt cgacgtgtca 2100
catgaggatc cagaagtcaa gtttaactgg tatgtggatg gggtcgaggt gcacaatgcc 2160
aaaacaaaac ctcgggaaga acagtataat tccacctata gagtcgtgtc tgtgctcacc 2220
gtgctccatc aggattggct caatgggaaa gaatacaaat gtaaagtctc taacaaagcc 2280
ctgcccgctc ctatcgaaaa gacaatctcc aaggccaaag gacagcctcg cgagcctcag 2340
gtctacaccc tgccacctag ccgcgaggaa atgacaaaaa atcaggtgtc actcacctgt 2400
ctcgtgaagg ggttttaccc ctccgacatt gccgtcgagt gggagtccaa tggacagccc 2460
gagaacaatt ataagacaac acctcccgtc ctggactccg atggatcatt ttttctgtac 2520
tccaagctca ccgtcgataa gtccagatgg cagcagggaa atgtcttttc ctgctccgtg 2580
atgcatgaag ctctccacaa tcattacaca cagaaaagcc tgtccctgtc ccccggcaag 2640
tgactcgag 2649
<210> 54
<211> 2664
<212> DNA
<213> Artificial Sequence
<220>
<223> Nucleotide sequence encoding the protein complex comprising VEGF
and EGFR specific binding peptides #10
<400> 54
gaattcgcca ccatgggctg gtcctgcatc atcctgtttc tggtggccac cgccaccggc 60
gtgcactctg atatccagat gacccagagc cccagcagcc tgtctgcctc tgtgggcgac 120
agagtgacca tcacctgtag agccagccag tggatcggcc ctgagctgag ctggtatcag 180
cagaagcccg gcaaggcccc caagctgctg atctaccaca ccagcatcct gcagagcggc 240
gtgcccagca gattttctgg cagcggcagc ggcaccgact tcaccctgac aatcagcagc 300
ctgcagcccg aggacttcgc cacctactac tgccagcagt acatgttcca gccccggacc 360
tttggccagg gcaccaaggt ggaaatcaga agagagccca agagctgcga caagacccac 420
acctgtcccc cttgtcctgc ccctgaactg ctgggaggcc ctagcgtgtt cctgttcccc 480
ccaaagccca aggacaccct gatgatcagc cggacccccg aagtgacctg cgtggtggtg 540
gatgtgtccc acgaggaccc tgaagtgaag ttcaattggt acgtggacgg cgtggaagtg 600
cacaacgcca agaccaagcc cagagaggaa cagtacaaca gcacctaccg ggtggtgtcc 660
gtgctgacag tgctgcacca ggactggctg aacggcaaag agtacaagtg caaggtgtcc 720
aacaaggccc tgcctgcccc catcgagaaa accatcagca aggccaaggg ccagcccaga 780
gaaccccagg tgtacacact gccccccagc agagaagaga tgaccaagaa ccaggtgtcc 840
ctgacctgcc tggtcaaggg cttctacccc agcgatatcg ccgtggaatg ggagagcaac 900
ggccagcctg agaacaacta caagaccacc ccccctgtgc tggacagcga cggctcattc 960
ttcctgtaca gcaagctgac cgtggacaag agccggtggc agcagggcaa cgtgttcagc 1020
tgcagcgtga tgcacgaggc cctgcacaac cactacaccc agaagtccct gagcctgagc 1080
cccggcaaga tgcagatctt cgtgaaaacc ctgaccggca agaccatcac cctggaagtg 1140
gaacccagcg acaccatcga gaacgtgaag gccaagatcc aggacaaaga gggcatcccc 1200
cccgaccagc agagactgat cttcgccggc aagcagctgg aagatggcag aaccctgagc 1260
gactacaaca tccagaaaga gtccaccctg cacctggtgc tgcggctgag aggcggaggt 1320
ggtggtggtt ctggtggcgg aggatctggc ggtggtggat ctgggggagg tggaagtggt 1380
ggcggtggta gtggtggtgg cggaagcatg cagatttttg tcaagacact gaccgggaaa 1440
acaatcacac tcgaagtcga gccctccgat acaattgaga atgtgaaagc caaaattcag 1500
gacaaagaag ggattcctcc tgatcagcag cggctgattt ttgccggaaa acagctcgaa 1560
gatggacgga ccctgtccga ttacaatatt cagaaagaaa gcaccctcca tctggtcctg 1620
aggctgcggg gaggcgacat tcagatgaca cagtccccca cctccctgtc tgccagcgtg 1680
ggagatcgcg tgaccattac atgccgggcc tcccagtgga ttggcaacct gctggattgg 1740
tatcagcaga aacctgggga ggctcctaaa ctgctgatct attacgccag ctttctgcag 1800
tccggcgtgc cctccagatt cagcggcgga ggcttcggca cagatttcac actgaccatc 1860
tcatccctgc agcctgaaga ttttgccaca tattattgcc agcaggccaa ccctgccccc 1920
ctgacattcg gccagggaac aaaggtcgag atcaagcgcg agcccaagtc ctgtgataag 1980
acacatacct gccccccctg cccagctcca gaactgctcg gaggaccttc tgtgtttctg 2040
tttccaccca agcctaagga tacactcatg atctccagaa cacctgaagt gacatgtgtg 2100
gtcgtcgacg tgtcacatga ggatccagaa gtcaagttta actggtatgt ggatggggtc 2160
gaggtgcaca atgccaaaac aaaacctcgg gaagaacagt ataattccac ctatagagtc 2220
gtgtctgtgc tcaccgtgct ccatcaggat tggctcaatg ggaaagaata caaatgtaaa 2280
gtctctaaca aagccctgcc cgctcctatc gaaaagacaa tctccaaggc caaaggacag 2340
cctcgcgagc ctcaggtcta caccctgcca cctagccgcg aggaaatgac aaaaaatcag 2400
gtgtcactca cctgtctcgt gaaggggttt tacccctccg acattgccgt cgagtgggag 2460
tccaatggac agcccgagaa caattataag acaacacctc ccgtcctgga ctccgatgga 2520
tcattttttc tgtactccaa gctcaccgtc gataagtcca gatggcagca gggaaatgtc 2580
ttttcctgct ccgtgatgca tgaagctctc cacaatcatt acacacagaa aagcctgtcc 2640
ctgtcccccg gcaagtgact cgag 2664
<210> 55
<211> 2679
<212> DNA
<213> Artificial Sequence
<220>
<223> Nucleotide sequence encoding the protein complex comprising VEGF
and EGFR specific binding peptides #11
<400> 55
gaattcgcca ccatgggctg gtcctgcatc atcctgtttc tggtggccac cgccaccggc 60
gtgcactctg atatccagat gacccagagc cccagcagcc tgtctgcctc tgtgggcgac 120
agagtgacca tcacctgtag agccagccag tggatcggcc ctgagctgag ctggtatcag 180
cagaagcccg gcaaggcccc caagctgctg atctaccaca ccagcatcct gcagagcggc 240
gtgcccagca gattttctgg cagcggcagc ggcaccgact tcaccctgac aatcagcagc 300
ctgcagcccg aggacttcgc cacctactac tgccagcagt acatgttcca gccccggacc 360
tttggccagg gcaccaaggt ggaaatcaga agagagccca agagctgcga caagacccac 420
acctgtcccc cttgtcctgc ccctgaactg ctgggaggcc ctagcgtgtt cctgttcccc 480
ccaaagccca aggacaccct gatgatcagc cggacccccg aagtgacctg cgtggtggtg 540
gatgtgtccc acgaggaccc tgaagtgaag ttcaattggt acgtggacgg cgtggaagtg 600
cacaacgcca agaccaagcc cagagaggaa cagtacaaca gcacctaccg ggtggtgtcc 660
gtgctgacag tgctgcacca ggactggctg aacggcaaag agtacaagtg caaggtgtcc 720
aacaaggccc tgcctgcccc catcgagaaa accatcagca aggccaaggg ccagcccaga 780
gaaccccagg tgtacacact gccccccagc agagaagaga tgaccaagaa ccaggtgtcc 840
ctgacctgcc tggtcaaggg cttctacccc agcgatatcg ccgtggaatg ggagagcaac 900
ggccagcctg agaacaacta caagaccacc ccccctgtgc tggacagcga cggctcattc 960
ttcctgtaca gcaagctgac cgtggacaag agccggtggc agcagggcaa cgtgttcagc 1020
tgcagcgtga tgcacgaggc cctgcacaac cactacaccc agaagtccct gagcctgagc 1080
cccggcaaga tgcagatctt cgtgaaaacc ctgaccggca agaccatcac cctggaagtg 1140
gaacccagcg acaccatcga gaacgtgaag gccaagatcc aggacaaaga gggcatcccc 1200
cccgaccagc agagactgat cttcgccggc aagcagctgg aagatggcag aaccctgagc 1260
gactacaaca tccagaaaga gtccaccctg cacctggtgc tgcggctgag aggcggaggt 1320
ggtggtggtt ctggtggcgg aggatctggc ggtggtggat ctgggggagg tggaagtggt 1380
ggcggtggta gtggtggtgg cggaagcgga ggcggtggat caatgcagat ttttgtcaag 1440
acactgaccg ggaaaacaat cacactcgaa gtcgagccct ccgatacaat tgagaatgtg 1500
aaagccaaaa ttcaggacaa agaagggatt cctcctgatc agcagcggct gatttttgcc 1560
ggaaaacagc tcgaagatgg acggaccctg tccgattaca atattcagaa agaaagcacc 1620
ctccatctgg tcctgaggct gcggggaggc gacattcaga tgacacagtc ccccacctcc 1680
ctgtctgcca gcgtgggaga tcgcgtgacc attacatgcc gggcctccca gtggattggc 1740
aacctgctgg attggtatca gcagaaacct ggggaggctc ctaaactgct gatctattac 1800
gccagctttc tgcagtccgg cgtgccctcc agattcagcg gcggaggctt cggcacagat 1860
ttcacactga ccatctcatc cctgcagcct gaagattttg ccacatatta ttgccagcag 1920
gccaaccctg cccccctgac attcggccag ggaacaaagg tcgagatcaa gcgcgagccc 1980
aagtcctgtg ataagacaca tacctgcccc ccctgcccag ctccagaact gctcggagga 2040
ccttctgtgt ttctgtttcc acccaagcct aaggatacac tcatgatctc cagaacacct 2100
gaagtgacat gtgtggtcgt cgacgtgtca catgaggatc cagaagtcaa gtttaactgg 2160
tatgtggatg gggtcgaggt gcacaatgcc aaaacaaaac ctcgggaaga acagtataat 2220
tccacctata gagtcgtgtc tgtgctcacc gtgctccatc aggattggct caatgggaaa 2280
gaatacaaat gtaaagtctc taacaaagcc ctgcccgctc ctatcgaaaa gacaatctcc 2340
aaggccaaag gacagcctcg cgagcctcag gtctacaccc tgccacctag ccgcgaggaa 2400
atgacaaaaa atcaggtgtc actcacctgt ctcgtgaagg ggttttaccc ctccgacatt 2460
gccgtcgagt gggagtccaa tggacagccc gagaacaatt ataagacaac acctcccgtc 2520
ctggactccg atggatcatt ttttctgtac tccaagctca ccgtcgataa gtccagatgg 2580
cagcagggaa atgtcttttc ctgctccgtg atgcatgaag ctctccacaa tcattacaca 2640
cagaaaagcc tgtccctgtc ccccggcaag tgactcgag 2679
<210> 56
<211> 2694
<212> DNA
<213> Artificial Sequence
<220>
<223> Nucleotide sequence encoding the protein complex comprising VEGF
and EGFR specific binding peptides #12
<400> 56
gaattcgcca ccatgggctg gtcctgcatc atcctgtttc tggtggccac cgccaccggc 60
gtgcactctg atatccagat gacccagagc cccagcagcc tgtctgcctc tgtgggcgac 120
agagtgacca tcacctgtag agccagccag tggatcggcc ctgagctgag ctggtatcag 180
cagaagcccg gcaaggcccc caagctgctg atctaccaca ccagcatcct gcagagcggc 240
gtgcccagca gattttctgg cagcggcagc ggcaccgact tcaccctgac aatcagcagc 300
ctgcagcccg aggacttcgc cacctactac tgccagcagt acatgttcca gccccggacc 360
tttggccagg gcaccaaggt ggaaatcaga agagagccca agagctgcga caagacccac 420
acctgtcccc cttgtcctgc ccctgaactg ctgggaggcc ctagcgtgtt cctgttcccc 480
ccaaagccca aggacaccct gatgatcagc cggacccccg aagtgacctg cgtggtggtg 540
gatgtgtccc acgaggaccc tgaagtgaag ttcaattggt acgtggacgg cgtggaagtg 600
cacaacgcca agaccaagcc cagagaggaa cagtacaaca gcacctaccg ggtggtgtcc 660
gtgctgacag tgctgcacca ggactggctg aacggcaaag agtacaagtg caaggtgtcc 720
aacaaggccc tgcctgcccc catcgagaaa accatcagca aggccaaggg ccagcccaga 780
gaaccccagg tgtacacact gccccccagc agagaagaga tgaccaagaa ccaggtgtcc 840
ctgacctgcc tggtcaaggg cttctacccc agcgatatcg ccgtggaatg ggagagcaac 900
ggccagcctg agaacaacta caagaccacc ccccctgtgc tggacagcga cggctcattc 960
ttcctgtaca gcaagctgac cgtggacaag agccggtggc agcagggcaa cgtgttcagc 1020
tgcagcgtga tgcacgaggc cctgcacaac cactacaccc agaagtccct gagcctgagc 1080
cccggcaaga tgcagatctt cgtgaaaacc ctgaccggca agaccatcac cctggaagtg 1140
gaacccagcg acaccatcga gaacgtgaag gccaagatcc aggacaaaga gggcatcccc 1200
cccgaccagc agagactgat cttcgccggc aagcagctgg aagatggcag aaccctgagc 1260
gactacaaca tccagaaaga gtccaccctg cacctggtgc tgcggctgag aggcggaggt 1320
ggtggtggtt ctggtggcgg aggatctggc ggtggtggat ctgggggagg tggaagtggt 1380
ggcggtggta gtggtggtgg cggaagcgga ggcggtggat caggcggagg cggatcaatg 1440
cagatttttg tcaagacact gaccgggaaa acaatcacac tcgaagtcga gccctccgat 1500
acaattgaga atgtgaaagc caaaattcag gacaaagaag ggattcctcc tgatcagcag 1560
cggctgattt ttgccggaaa acagctcgaa gatggacgga ccctgtccga ttacaatatt 1620
cagaaagaaa gcaccctcca tctggtcctg aggctgcggg gaggcgacat tcagatgaca 1680
cagtccccca cctccctgtc tgccagcgtg ggagatcgcg tgaccattac atgccgggcc 1740
tcccagtgga ttggcaacct gctggattgg tatcagcaga aacctgggga ggctcctaaa 1800
ctgctgatct attacgccag ctttctgcag tccggcgtgc cctccagatt cagcggcgga 1860
ggcttcggca cagatttcac actgaccatc tcatccctgc agcctgaaga ttttgccaca 1920
tattattgcc agcaggccaa ccctgccccc ctgacattcg gccagggaac aaaggtcgag 1980
atcaagcgcg agcccaagtc ctgtgataag acacatacct gccccccctg cccagctcca 2040
gaactgctcg gaggaccttc tgtgtttctg tttccaccca agcctaagga tacactcatg 2100
atctccagaa cacctgaagt gacatgtgtg gtcgtcgacg tgtcacatga ggatccagaa 2160
gtcaagttta actggtatgt ggatggggtc gaggtgcaca atgccaaaac aaaacctcgg 2220
gaagaacagt ataattccac ctatagagtc gtgtctgtgc tcaccgtgct ccatcaggat 2280
tggctcaatg ggaaagaata caaatgtaaa gtctctaaca aagccctgcc cgctcctatc 2340
gaaaagacaa tctccaaggc caaaggacag cctcgcgagc ctcaggtcta caccctgcca 2400
cctagccgcg aggaaatgac aaaaaatcag gtgtcactca cctgtctcgt gaaggggttt 2460
tacccctccg acattgccgt cgagtgggag tccaatggac agcccgagaa caattataag 2520
acaacacctc ccgtcctgga ctccgatgga tcattttttc tgtactccaa gctcaccgtc 2580
gataagtcca gatggcagca gggaaatgtc ttttcctgct ccgtgatgca tgaagctctc 2640
cacaatcatt acacacagaa aagcctgtcc ctgtcccccg gcaagtgact cgag 2694
<210> 57
<211> 2709
<212> DNA
<213> Artificial Sequence
<220>
<223> Nucleotide sequence encoding the protein complex comprising VEGF
and EGFR specific binding peptides #13
<400> 57
gaattcgcca ccatgggctg gtcctgcatc atcctgtttc tggtggccac cgccaccggc 60
gtgcactctg atatccagat gacccagagc cccagcagcc tgtctgcctc tgtgggcgac 120
agagtgacca tcacctgtag agccagccag tggatcggcc ctgagctgag ctggtatcag 180
cagaagcccg gcaaggcccc caagctgctg atctaccaca ccagcatcct gcagagcggc 240
gtgcccagca gattttctgg cagcggcagc ggcaccgact tcaccctgac aatcagcagc 300
ctgcagcccg aggacttcgc cacctactac tgccagcagt acatgttcca gccccggacc 360
tttggccagg gcaccaaggt ggaaatcaga agagagccca agagctgcga caagacccac 420
acctgtcccc cttgtcctgc ccctgaactg ctgggaggcc ctagcgtgtt cctgttcccc 480
ccaaagccca aggacaccct gatgatcagc cggacccccg aagtgacctg cgtggtggtg 540
gatgtgtccc acgaggaccc tgaagtgaag ttcaattggt acgtggacgg cgtggaagtg 600
cacaacgcca agaccaagcc cagagaggaa cagtacaaca gcacctaccg ggtggtgtcc 660
gtgctgacag tgctgcacca ggactggctg aacggcaaag agtacaagtg caaggtgtcc 720
aacaaggccc tgcctgcccc catcgagaaa accatcagca aggccaaggg ccagcccaga 780
gaaccccagg tgtacacact gccccccagc agagaagaga tgaccaagaa ccaggtgtcc 840
ctgacctgcc tggtcaaggg cttctacccc agcgatatcg ccgtggaatg ggagagcaac 900
ggccagcctg agaacaacta caagaccacc ccccctgtgc tggacagcga cggctcattc 960
ttcctgtaca gcaagctgac cgtggacaag agccggtggc agcagggcaa cgtgttcagc 1020
tgcagcgtga tgcacgaggc cctgcacaac cactacaccc agaagtccct gagcctgagc 1080
cccggcaaga tgcagatctt cgtgaaaacc ctgaccggca agaccatcac cctggaagtg 1140
gaacccagcg acaccatcga gaacgtgaag gccaagatcc aggacaaaga gggcatcccc 1200
cccgaccagc agagactgat cttcgccggc aagcagctgg aagatggcag aaccctgagc 1260
gactacaaca tccagaaaga gtccaccctg cacctggtgc tgcggctgag aggcggaggt 1320
ggtggtggtt ctggtggcgg aggatctggc ggtggtggat ctgggggagg tggaagtggt 1380
ggcggtggta gtggtggtgg cggaagcgga ggcggtggat caggcggagg cggatcaggt 1440
ggcggcggaa gtatgcagat ttttgtcaag acactgaccg ggaaaacaat cacactcgaa 1500
gtcgagccct ccgatacaat tgagaatgtg aaagccaaaa ttcaggacaa agaagggatt 1560
cctcctgatc agcagcggct gatttttgcc ggaaaacagc tcgaagatgg acggaccctg 1620
tccgattaca atattcagaa agaaagcacc ctccatctgg tcctgaggct gcggggaggc 1680
gacattcaga tgacacagtc ccccacctcc ctgtctgcca gcgtgggaga tcgcgtgacc 1740
attacatgcc gggcctccca gtggattggc aacctgctgg attggtatca gcagaaacct 1800
ggggaggctc ctaaactgct gatctattac gccagctttc tgcagtccgg cgtgccctcc 1860
agattcagcg gcggaggctt cggcacagat ttcacactga ccatctcatc cctgcagcct 1920
gaagattttg ccacatatta ttgccagcag gccaaccctg cccccctgac attcggccag 1980
ggaacaaagg tcgagatcaa gcgcgagccc aagtcctgtg ataagacaca tacctgcccc 2040
ccctgcccag ctccagaact gctcggagga ccttctgtgt ttctgtttcc acccaagcct 2100
aaggatacac tcatgatctc cagaacacct gaagtgacat gtgtggtcgt cgacgtgtca 2160
catgaggatc cagaagtcaa gtttaactgg tatgtggatg gggtcgaggt gcacaatgcc 2220
aaaacaaaac ctcgggaaga acagtataat tccacctata gagtcgtgtc tgtgctcacc 2280
gtgctccatc aggattggct caatgggaaa gaatacaaat gtaaagtctc taacaaagcc 2340
ctgcccgctc ctatcgaaaa gacaatctcc aaggccaaag gacagcctcg cgagcctcag 2400
gtctacaccc tgccacctag ccgcgaggaa atgacaaaaa atcaggtgtc actcacctgt 2460
ctcgtgaagg ggttttaccc ctccgacatt gccgtcgagt gggagtccaa tggacagccc 2520
gagaacaatt ataagacaac acctcccgtc ctggactccg atggatcatt ttttctgtac 2580
tccaagctca ccgtcgataa gtccagatgg cagcagggaa atgtcttttc ctgctccgtg 2640
atgcatgaag ctctccacaa tcattacaca cagaaaagcc tgtccctgtc ccccggcaag 2700
tgactcgag 2709
<210> 58
<211> 2724
<212> DNA
<213> Artificial Sequence
<220>
<223> Nucleotide sequence encoding the protein complex comprising VEGF
and EGFR specific binding peptides #14
<400> 58
gaattcgcca ccatgggctg gtcctgcatc atcctgtttc tggtggccac cgccaccggc 60
gtgcactctg atatccagat gacccagagc cccagcagcc tgtctgcctc tgtgggcgac 120
agagtgacca tcacctgtag agccagccag tggatcggcc ctgagctgag ctggtatcag 180
cagaagcccg gcaaggcccc caagctgctg atctaccaca ccagcatcct gcagagcggc 240
gtgcccagca gattttctgg cagcggcagc ggcaccgact tcaccctgac aatcagcagc 300
ctgcagcccg aggacttcgc cacctactac tgccagcagt acatgttcca gccccggacc 360
tttggccagg gcaccaaggt ggaaatcaga agagagccca agagctgcga caagacccac 420
acctgtcccc cttgtcctgc ccctgaactg ctgggaggcc ctagcgtgtt cctgttcccc 480
ccaaagccca aggacaccct gatgatcagc cggacccccg aagtgacctg cgtggtggtg 540
gatgtgtccc acgaggaccc tgaagtgaag ttcaattggt acgtggacgg cgtggaagtg 600
cacaacgcca agaccaagcc cagagaggaa cagtacaaca gcacctaccg ggtggtgtcc 660
gtgctgacag tgctgcacca ggactggctg aacggcaaag agtacaagtg caaggtgtcc 720
aacaaggccc tgcctgcccc catcgagaaa accatcagca aggccaaggg ccagcccaga 780
gaaccccagg tgtacacact gccccccagc agagaagaga tgaccaagaa ccaggtgtcc 840
ctgacctgcc tggtcaaggg cttctacccc agcgatatcg ccgtggaatg ggagagcaac 900
ggccagcctg agaacaacta caagaccacc ccccctgtgc tggacagcga cggctcattc 960
ttcctgtaca gcaagctgac cgtggacaag agccggtggc agcagggcaa cgtgttcagc 1020
tgcagcgtga tgcacgaggc cctgcacaac cactacaccc agaagtccct gagcctgagc 1080
cccggcaaga tgcagatctt cgtgaaaacc ctgaccggca agaccatcac cctggaagtg 1140
gaacccagcg acaccatcga gaacgtgaag gccaagatcc aggacaaaga gggcatcccc 1200
cccgaccagc agagactgat cttcgccggc aagcagctgg aagatggcag aaccctgagc 1260
gactacaaca tccagaaaga gtccaccctg cacctggtgc tgcggctgag aggcggaggt 1320
ggtggtggtt ctggtggcgg aggatctggc ggtggtggat ctgggggagg tggaagtggt 1380
ggcggtggta gtggtggtgg cggaagcgga ggcggtggat caggcggagg cggatcaggt 1440
ggcggcggaa gtggcggagg cggcagcatg cagatttttg tcaagacact gaccgggaaa 1500
acaatcacac tcgaagtcga gccctccgat acaattgaga atgtgaaagc caaaattcag 1560
gacaaagaag ggattcctcc tgatcagcag cggctgattt ttgccggaaa acagctcgaa 1620
gatggacgga ccctgtccga ttacaatatt cagaaagaaa gcaccctcca tctggtcctg 1680
aggctgcggg gaggcgacat tcagatgaca cagtccccca cctccctgtc tgccagcgtg 1740
ggagatcgcg tgaccattac atgccgggcc tcccagtgga ttggcaacct gctggattgg 1800
tatcagcaga aacctgggga ggctcctaaa ctgctgatct attacgccag ctttctgcag 1860
tccggcgtgc cctccagatt cagcggcgga ggcttcggca cagatttcac actgaccatc 1920
tcatccctgc agcctgaaga ttttgccaca tattattgcc agcaggccaa ccctgccccc 1980
ctgacattcg gccagggaac aaaggtcgag atcaagcgcg agcccaagtc ctgtgataag 2040
acacatacct gccccccctg cccagctcca gaactgctcg gaggaccttc tgtgtttctg 2100
tttccaccca agcctaagga tacactcatg atctccagaa cacctgaagt gacatgtgtg 2160
gtcgtcgacg tgtcacatga ggatccagaa gtcaagttta actggtatgt ggatggggtc 2220
gaggtgcaca atgccaaaac aaaacctcgg gaagaacagt ataattccac ctatagagtc 2280
gtgtctgtgc tcaccgtgct ccatcaggat tggctcaatg ggaaagaata caaatgtaaa 2340
gtctctaaca aagccctgcc cgctcctatc gaaaagacaa tctccaaggc caaaggacag 2400
cctcgcgagc ctcaggtcta caccctgcca cctagccgcg aggaaatgac aaaaaatcag 2460
gtgtcactca cctgtctcgt gaaggggttt tacccctccg acattgccgt cgagtgggag 2520
tccaatggac agcccgagaa caattataag acaacacctc ccgtcctgga ctccgatgga 2580
tcattttttc tgtactccaa gctcaccgtc gataagtcca gatggcagca gggaaatgtc 2640
ttttcctgct ccgtgatgca tgaagctctc cacaatcatt acacacagaa aagcctgtcc 2700
ctgtcccccg gcaagtgact cgag 2724
<210> 59
<211> 2634
<212> DNA
<213> Artificial Sequence
<220>
<223> Nucleotide sequence encoding the protein complex comprising VEGF
and EGFR specific binding peptides #15
<400> 59
gaattcgcca ccatgggctg gtcctgcatc atcctgtttc tggtggccac cgccaccggc 60
gtgcactctg atatccagat gacccagagc cccagcagcc tgtctgcctc tgtgggcgac 120
agagtgacca tcacctgtcg ggccagccag aagatcttca acggcctgag ctggtatcag 180
cagaagcccg gcaaggcccc caagctgctg atctaccaca gcagcaccct gcagagcggc 240
gtgccaagca gattttctgg cagcggcagc ggcaccgact tcaccctgac aatcagcagc 300
ctgcagcccg aggacttcgc cacctactac tgccagcagg tcctgctgta cccctacacc 360
tttggccagg gcaccaaggt ggaaatcaag agagagccca agagctgcga caagacccac 420
acctgtcccc cttgtcctgc ccctgaactg ctgggaggcc ctagcgtgtt cctgttcccc 480
ccaaagccca aggacaccct gatgatcagc cggacccccg aagtgacctg cgtggtggtg 540
gatgtgtccc acgaggaccc tgaagtgaag ttcaattggt acgtggacgg cgtggaagtg 600
cacaacgcca agaccaagcc cagagaggaa cagtacaaca gcacctaccg ggtggtgtcc 660
gtgctgacag tgctgcacca ggactggctg aacggcaaag agtacaagtg caaggtgtcc 720
aacaaggccc tgcctgcccc catcgagaaa accatcagca aggccaaggg ccagcccaga 780
gaaccccagg tgtacacact gccccccagc agagaagaga tgaccaagaa ccaggtgtcc 840
ctgacctgcc tggtcaaggg cttctacccc agcgatatcg ccgtggaatg ggagagcaac 900
ggccagcctg agaacaacta caagaccacc ccccctgtgc tggacagcga cggctcattc 960
ttcctgtaca gcaagctgac cgtggacaag agccggtggc agcagggcaa cgtgttcagc 1020
tgcagcgtga tgcacgaggc cctgcacaac cactacaccc agaagtccct gagcctgagc 1080
cccggcaaga tgcagatctt cgtgaaaacc ctgaccggca agaccatcac cctggaagtg 1140
gaacccagcg acaccatcga gaacgtgaag gccaagatcc aggacaaaga gggcatcccc 1200
cccgaccagc agagactgat cttcgccggc aagcagctgg aagatggcag aaccctgagc 1260
gactacaaca tccagaaaga gtccaccctg cacctggtgc tgcggctgag aggcggaggt 1320
ggtggtggtt ctggtggcgg aggatctggc ggtggtggat ctgggggagg tggaagtatg 1380
cagatttttg tcaagacact gaccgggaaa acaatcacac tcgaagtcga gccctccgat 1440
acaattgaga atgtgaaagc caaaattcag gacaaagaag ggattcctcc tgatcagcag 1500
cggctgattt ttgccggaaa acagctcgaa gatggacgga ccctgtccga ttacaatatt 1560
cagaaagaaa gcaccctcca tctggtcctg aggctgcggg gaggcgacat tcagatgaca 1620
cagtccccca gctccctgag cgccagcgtg ggagatcgcg tgaccattac ctgcagagcc 1680
tcccagtgga tcggcatcct ggtggattgg tatcagcaga aacctgggga ggctcctaaa 1740
ctgctgatct attacgccag cttcctgcag tccggcgtgc cctctagatt cagcggctct 1800
ggcttcggca cagatttcac actgaccatc tctagcctgc accctgaaga ttttgccaca 1860
tattactgtc agcaggccaa ccctgccccc ctgacatttg gacagggaac aaaggtcgag 1920
atcaagcgcg agcctaagtc ctgtgacaag acacacacat gccctccctg cccagcccca 1980
gaactgctcg gtggaccctc tgtgtttctg tttccaccca agcctaagga tacactcatg 2040
atctccagaa cacctgaagt gacatgtgtg gtcgtcgacg tgtcacatga ggatccagaa 2100
gtcaagttta actggtatgt ggatggggtc gaggtgcaca atgccaaaac aaaacctcgg 2160
gaagaacagt ataattccac ctatagagtc gtgtctgtgc tcaccgtgct ccatcaggat 2220
tggctcaatg ggaaagaata caaatgtaaa gtctctaaca aagccctgcc cgctcctatc 2280
gaaaagacaa tctccaaggc caaaggacag cctcgcgagc ctcaggtcta caccctgcca 2340
ccttcccgcg aggaaatgac aaaaaatcag gtgtcactca cctgtctcgt gaaggggttt 2400
tacccctccg acattgccgt cgagtgggag tccaatggac agcccgagaa caattataag 2460
acaacacctc ccgtcctgga ctccgatgga tcattttttc tgtactccaa gctcaccgtc 2520
gataagtcca gatggcagca gggaaatgtc ttttcctgct ccgtgatgca tgaagctctc 2580
cacaatcatt acacacagaa aagcctgtcc ctgtcccccg gcaagtgact cgag 2634
<210> 60
<211> 2649
<212> DNA
<213> Artificial Sequence
<220>
<223> Nucleotide sequence encoding the protein complex comprising VEGF
and EGFR specific binding peptides #16
<400> 60
gaattcgcca ccatgggctg gtcctgcatc atcctgtttc tggtggccac cgccaccggc 60
gtgcactctg atatccagat gacccagagc cccagcagcc tgtctgcctc tgtgggcgac 120
agagtgacca tcacctgtcg ggccagccag aagatcttca acggcctgag ctggtatcag 180
cagaagcccg gcaaggcccc caagctgctg atctaccaca gcagcaccct gcagagcggc 240
gtgccaagca gattttctgg cagcggcagc ggcaccgact tcaccctgac aatcagcagc 300
ctgcagcccg aggacttcgc cacctactac tgccagcagg tcctgctgta cccctacacc 360
tttggccagg gcaccaaggt ggaaatcaag agagagccca agagctgcga caagacccac 420
acctgtcccc cttgtcctgc ccctgaactg ctgggaggcc ctagcgtgtt cctgttcccc 480
ccaaagccca aggacaccct gatgatcagc cggacccccg aagtgacctg cgtggtggtg 540
gatgtgtccc acgaggaccc tgaagtgaag ttcaattggt acgtggacgg cgtggaagtg 600
cacaacgcca agaccaagcc cagagaggaa cagtacaaca gcacctaccg ggtggtgtcc 660
gtgctgacag tgctgcacca ggactggctg aacggcaaag agtacaagtg caaggtgtcc 720
aacaaggccc tgcctgcccc catcgagaaa accatcagca aggccaaggg ccagcccaga 780
gaaccccagg tgtacacact gccccccagc agagaagaga tgaccaagaa ccaggtgtcc 840
ctgacctgcc tggtcaaggg cttctacccc agcgatatcg ccgtggaatg ggagagcaac 900
ggccagcctg agaacaacta caagaccacc ccccctgtgc tggacagcga cggctcattc 960
ttcctgtaca gcaagctgac cgtggacaag agccggtggc agcagggcaa cgtgttcagc 1020
tgcagcgtga tgcacgaggc cctgcacaac cactacaccc agaagtccct gagcctgagc 1080
cccggcaaga tgcagatctt cgtgaaaacc ctgaccggca agaccatcac cctggaagtg 1140
gaacccagcg acaccatcga gaacgtgaag gccaagatcc aggacaaaga gggcatcccc 1200
cccgaccagc agagactgat cttcgccggc aagcagctgg aagatggcag aaccctgagc 1260
gactacaaca tccagaaaga gtccaccctg cacctggtgc tgcggctgag aggcggaggt 1320
ggtggtggtt ctggtggcgg aggatctggc ggtggtggat ctgggggagg tggaagtggt 1380
ggcggtggta gtatgcagat ttttgtcaag acactgaccg ggaaaacaat cacactcgaa 1440
gtcgagccct ccgatacaat tgagaatgtg aaagccaaaa ttcaggacaa agaagggatt 1500
cctcctgatc agcagcggct gatttttgcc ggaaaacagc tcgaagatgg acggaccctg 1560
tccgattaca atattcagaa agaaagcacc ctccatctgg tcctgaggct gcggggaggc 1620
gacattcaga tgacacagtc ccccagctcc ctgagcgcca gcgtgggaga tcgcgtgacc 1680
attacctgca gagcctccca gtggatcggc atcctggtgg attggtatca gcagaaacct 1740
ggggaggctc ctaaactgct gatctattac gccagcttcc tgcagtccgg cgtgccctct 1800
agattcagcg gctctggctt cggcacagat ttcacactga ccatctctag cctgcaccct 1860
gaagattttg ccacatatta ctgtcagcag gccaaccctg cccccctgac atttggacag 1920
ggaacaaagg tcgagatcaa gcgcgagcct aagtcctgtg acaagacaca cacatgccct 1980
ccctgcccag ccccagaact gctcggtgga ccctctgtgt ttctgtttcc acccaagcct 2040
aaggatacac tcatgatctc cagaacacct gaagtgacat gtgtggtcgt cgacgtgtca 2100
catgaggatc cagaagtcaa gtttaactgg tatgtggatg gggtcgaggt gcacaatgcc 2160
aaaacaaaac ctcgggaaga acagtataat tccacctata gagtcgtgtc tgtgctcacc 2220
gtgctccatc aggattggct caatgggaaa gaatacaaat gtaaagtctc taacaaagcc 2280
ctgcccgctc ctatcgaaaa gacaatctcc aaggccaaag gacagcctcg cgagcctcag 2340
gtctacaccc tgccaccttc ccgcgaggaa atgacaaaaa atcaggtgtc actcacctgt 2400
ctcgtgaagg ggttttaccc ctccgacatt gccgtcgagt gggagtccaa tggacagccc 2460
gagaacaatt ataagacaac acctcccgtc ctggactccg atggatcatt ttttctgtac 2520
tccaagctca ccgtcgataa gtccagatgg cagcagggaa atgtcttttc ctgctccgtg 2580
atgcatgaag ctctccacaa tcattacaca cagaaaagcc tgtccctgtc ccccggcaag 2640
tgactcgag 2649
<210> 61
<211> 2664
<212> DNA
<213> Artificial Sequence
<220>
<223> Nucleotide sequence encoding the protein complex comprising VEGF
and EGFR specific binding peptides #17
<400> 61
gaattcgcca ccatgggctg gtcctgcatc atcctgtttc tggtggccac cgccaccggc 60
gtgcactctg atatccagat gacccagagc cccagcagcc tgtctgcctc tgtgggcgac 120
agagtgacca tcacctgtcg ggccagccag aagatcttca acggcctgag ctggtatcag 180
cagaagcccg gcaaggcccc caagctgctg atctaccaca gcagcaccct gcagagcggc 240
gtgccaagca gattttctgg cagcggcagc ggcaccgact tcaccctgac aatcagcagc 300
ctgcagcccg aggacttcgc cacctactac tgccagcagg tcctgctgta cccctacacc 360
tttggccagg gcaccaaggt ggaaatcaag agagagccca agagctgcga caagacccac 420
acctgtcccc cttgtcctgc ccctgaactg ctgggaggcc ctagcgtgtt cctgttcccc 480
ccaaagccca aggacaccct gatgatcagc cggacccccg aagtgacctg cgtggtggtg 540
gatgtgtccc acgaggaccc tgaagtgaag ttcaattggt acgtggacgg cgtggaagtg 600
cacaacgcca agaccaagcc cagagaggaa cagtacaaca gcacctaccg ggtggtgtcc 660
gtgctgacag tgctgcacca ggactggctg aacggcaaag agtacaagtg caaggtgtcc 720
aacaaggccc tgcctgcccc catcgagaaa accatcagca aggccaaggg ccagcccaga 780
gaaccccagg tgtacacact gccccccagc agagaagaga tgaccaagaa ccaggtgtcc 840
ctgacctgcc tggtcaaggg cttctacccc agcgatatcg ccgtggaatg ggagagcaac 900
ggccagcctg agaacaacta caagaccacc ccccctgtgc tggacagcga cggctcattc 960
ttcctgtaca gcaagctgac cgtggacaag agccggtggc agcagggcaa cgtgttcagc 1020
tgcagcgtga tgcacgaggc cctgcacaac cactacaccc agaagtccct gagcctgagc 1080
cccggcaaga tgcagatctt cgtgaaaacc ctgaccggca agaccatcac cctggaagtg 1140
gaacccagcg acaccatcga gaacgtgaag gccaagatcc aggacaaaga gggcatcccc 1200
cccgaccagc agagactgat cttcgccggc aagcagctgg aagatggcag aaccctgagc 1260
gactacaaca tccagaaaga gtccaccctg cacctggtgc tgcggctgag aggcggaggt 1320
ggtggtggtt ctggtggcgg aggatctggc ggtggtggat ctgggggagg tggaagtggt 1380
ggcggtggta gtggtggtgg cggaagcatg cagatttttg tcaagacact gaccgggaaa 1440
acaatcacac tcgaagtcga gccctccgat acaattgaga atgtgaaagc caaaattcag 1500
gacaaagaag ggattcctcc tgatcagcag cggctgattt ttgccggaaa acagctcgaa 1560
gatggacgga ccctgtccga ttacaatatt cagaaagaaa gcaccctcca tctggtcctg 1620
aggctgcggg gaggcgacat tcagatgaca cagtccccca gctccctgag cgccagcgtg 1680
ggagatcgcg tgaccattac ctgcagagcc tcccagtgga tcggcatcct ggtggattgg 1740
tatcagcaga aacctgggga ggctcctaaa ctgctgatct attacgccag cttcctgcag 1800
tccggcgtgc cctctagatt cagcggctct ggcttcggca cagatttcac actgaccatc 1860
tctagcctgc accctgaaga ttttgccaca tattactgtc agcaggccaa ccctgccccc 1920
ctgacatttg gacagggaac aaaggtcgag atcaagcgcg agcctaagtc ctgtgacaag 1980
acacacacat gccctccctg cccagcccca gaactgctcg gtggaccctc tgtgtttctg 2040
tttccaccca agcctaagga tacactcatg atctccagaa cacctgaagt gacatgtgtg 2100
gtcgtcgacg tgtcacatga ggatccagaa gtcaagttta actggtatgt ggatggggtc 2160
gaggtgcaca atgccaaaac aaaacctcgg gaagaacagt ataattccac ctatagagtc 2220
gtgtctgtgc tcaccgtgct ccatcaggat tggctcaatg ggaaagaata caaatgtaaa 2280
gtctctaaca aagccctgcc cgctcctatc gaaaagacaa tctccaaggc caaaggacag 2340
cctcgcgagc ctcaggtcta caccctgcca ccttcccgcg aggaaatgac aaaaaatcag 2400
gtgtcactca cctgtctcgt gaaggggttt tacccctccg acattgccgt cgagtgggag 2460
tccaatggac agcccgagaa caattataag acaacacctc ccgtcctgga ctccgatgga 2520
tcattttttc tgtactccaa gctcaccgtc gataagtcca gatggcagca gggaaatgtc 2580
ttttcctgct ccgtgatgca tgaagctctc cacaatcatt acacacagaa aagcctgtcc 2640
ctgtcccccg gcaagtgact cgag 2664
<210> 62
<211> 2679
<212> DNA
<213> Artificial Sequence
<220>
<223> Nucleotide sequence encoding the protein complex comprising VEGF
and EGFR specific binding peptides #18
<400> 62
gaattcgcca ccatgggctg gtcctgcatc atcctgtttc tggtggccac cgccaccggc 60
gtgcactctg atatccagat gacccagagc cccagcagcc tgtctgcctc tgtgggcgac 120
agagtgacca tcacctgtcg ggccagccag aagatcttca acggcctgag ctggtatcag 180
cagaagcccg gcaaggcccc caagctgctg atctaccaca gcagcaccct gcagagcggc 240
gtgccaagca gattttctgg cagcggcagc ggcaccgact tcaccctgac aatcagcagc 300
ctgcagcccg aggacttcgc cacctactac tgccagcagg tcctgctgta cccctacacc 360
tttggccagg gcaccaaggt ggaaatcaag agagagccca agagctgcga caagacccac 420
acctgtcccc cttgtcctgc ccctgaactg ctgggaggcc ctagcgtgtt cctgttcccc 480
ccaaagccca aggacaccct gatgatcagc cggacccccg aagtgacctg cgtggtggtg 540
gatgtgtccc acgaggaccc tgaagtgaag ttcaattggt acgtggacgg cgtggaagtg 600
cacaacgcca agaccaagcc cagagaggaa cagtacaaca gcacctaccg ggtggtgtcc 660
gtgctgacag tgctgcacca ggactggctg aacggcaaag agtacaagtg caaggtgtcc 720
aacaaggccc tgcctgcccc catcgagaaa accatcagca aggccaaggg ccagcccaga 780
gaaccccagg tgtacacact gccccccagc agagaagaga tgaccaagaa ccaggtgtcc 840
ctgacctgcc tggtcaaggg cttctacccc agcgatatcg ccgtggaatg ggagagcaac 900
ggccagcctg agaacaacta caagaccacc ccccctgtgc tggacagcga cggctcattc 960
ttcctgtaca gcaagctgac cgtggacaag agccggtggc agcagggcaa cgtgttcagc 1020
tgcagcgtga tgcacgaggc cctgcacaac cactacaccc agaagtccct gagcctgagc 1080
cccggcaaga tgcagatctt cgtgaaaacc ctgaccggca agaccatcac cctggaagtg 1140
gaacccagcg acaccatcga gaacgtgaag gccaagatcc aggacaaaga gggcatcccc 1200
cccgaccagc agagactgat cttcgccggc aagcagctgg aagatggcag aaccctgagc 1260
gactacaaca tccagaaaga gtccaccctg cacctggtgc tgcggctgag aggcggaggt 1320
ggtggtggtt ctggtggcgg aggatctggc ggtggtggat ctgggggagg tggaagtggt 1380
ggcggtggta gtggtggtgg cggaagcgga ggcggtggat caatgcagat ttttgtcaag 1440
acactgaccg ggaaaacaat cacactcgaa gtcgagccct ccgatacaat tgagaatgtg 1500
aaagccaaaa ttcaggacaa agaagggatt cctcctgatc agcagcggct gatttttgcc 1560
ggaaaacagc tcgaagatgg acggaccctg tccgattaca atattcagaa agaaagcacc 1620
ctccatctgg tcctgaggct gcggggaggc gacattcaga tgacacagtc ccccagctcc 1680
ctgagcgcca gcgtgggaga tcgcgtgacc attacctgca gagcctccca gtggatcggc 1740
atcctggtgg attggtatca gcagaaacct ggggaggctc ctaaactgct gatctattac 1800
gccagcttcc tgcagtccgg cgtgccctct agattcagcg gctctggctt cggcacagat 1860
ttcacactga ccatctctag cctgcaccct gaagattttg ccacatatta ctgtcagcag 1920
gccaaccctg cccccctgac atttggacag ggaacaaagg tcgagatcaa gcgcgagcct 1980
aagtcctgtg acaagacaca cacatgccct ccctgcccag ccccagaact gctcggtgga 2040
ccctctgtgt ttctgtttcc acccaagcct aaggatacac tcatgatctc cagaacacct 2100
gaagtgacat gtgtggtcgt cgacgtgtca catgaggatc cagaagtcaa gtttaactgg 2160
tatgtggatg gggtcgaggt gcacaatgcc aaaacaaaac ctcgggaaga acagtataat 2220
tccacctata gagtcgtgtc tgtgctcacc gtgctccatc aggattggct caatgggaaa 2280
gaatacaaat gtaaagtctc taacaaagcc ctgcccgctc ctatcgaaaa gacaatctcc 2340
aaggccaaag gacagcctcg cgagcctcag gtctacaccc tgccaccttc ccgcgaggaa 2400
atgacaaaaa atcaggtgtc actcacctgt ctcgtgaagg ggttttaccc ctccgacatt 2460
gccgtcgagt gggagtccaa tggacagccc gagaacaatt ataagacaac acctcccgtc 2520
ctggactccg atggatcatt ttttctgtac tccaagctca ccgtcgataa gtccagatgg 2580
cagcagggaa atgtcttttc ctgctccgtg atgcatgaag ctctccacaa tcattacaca 2640
cagaaaagcc tgtccctgtc ccccggcaag tgactcgag 2679
<210> 63
<211> 2694
<212> DNA
<213> Artificial Sequence
<220>
<223> Nucleotide sequence encoding the protein complex comprising VEGF
and EGFR specific binding peptides #19
<400> 63
gaattcgcca ccatgggctg gtcctgcatc atcctgtttc tggtggccac cgccaccggc 60
gtgcactctg atatccagat gacccagagc cccagcagcc tgtctgcctc tgtgggcgac 120
agagtgacca tcacctgtcg ggccagccag aagatcttca acggcctgag ctggtatcag 180
cagaagcccg gcaaggcccc caagctgctg atctaccaca gcagcaccct gcagagcggc 240
gtgccaagca gattttctgg cagcggcagc ggcaccgact tcaccctgac aatcagcagc 300
ctgcagcccg aggacttcgc cacctactac tgccagcagg tcctgctgta cccctacacc 360
tttggccagg gcaccaaggt ggaaatcaag agagagccca agagctgcga caagacccac 420
acctgtcccc cttgtcctgc ccctgaactg ctgggaggcc ctagcgtgtt cctgttcccc 480
ccaaagccca aggacaccct gatgatcagc cggacccccg aagtgacctg cgtggtggtg 540
gatgtgtccc acgaggaccc tgaagtgaag ttcaattggt acgtggacgg cgtggaagtg 600
cacaacgcca agaccaagcc cagagaggaa cagtacaaca gcacctaccg ggtggtgtcc 660
gtgctgacag tgctgcacca ggactggctg aacggcaaag agtacaagtg caaggtgtcc 720
aacaaggccc tgcctgcccc catcgagaaa accatcagca aggccaaggg ccagcccaga 780
gaaccccagg tgtacacact gccccccagc agagaagaga tgaccaagaa ccaggtgtcc 840
ctgacctgcc tggtcaaggg cttctacccc agcgatatcg ccgtggaatg ggagagcaac 900
ggccagcctg agaacaacta caagaccacc ccccctgtgc tggacagcga cggctcattc 960
ttcctgtaca gcaagctgac cgtggacaag agccggtggc agcagggcaa cgtgttcagc 1020
tgcagcgtga tgcacgaggc cctgcacaac cactacaccc agaagtccct gagcctgagc 1080
cccggcaaga tgcagatctt cgtgaaaacc ctgaccggca agaccatcac cctggaagtg 1140
gaacccagcg acaccatcga gaacgtgaag gccaagatcc aggacaaaga gggcatcccc 1200
cccgaccagc agagactgat cttcgccggc aagcagctgg aagatggcag aaccctgagc 1260
gactacaaca tccagaaaga gtccaccctg cacctggtgc tgcggctgag aggcggaggt 1320
ggtggtggtt ctggtggcgg aggatctggc ggtggtggat ctgggggagg tggaagtggt 1380
ggcggtggta gtggtggtgg cggaagcgga ggcggtggat caggcggagg cggatcaatg 1440
cagatttttg tcaagacact gaccgggaaa acaatcacac tcgaagtcga gccctccgat 1500
acaattgaga atgtgaaagc caaaattcag gacaaagaag ggattcctcc tgatcagcag 1560
cggctgattt ttgccggaaa acagctcgaa gatggacgga ccctgtccga ttacaatatt 1620
cagaaagaaa gcaccctcca tctggtcctg aggctgcggg gaggcgacat tcagatgaca 1680
cagtccccca gctccctgag cgccagcgtg ggagatcgcg tgaccattac ctgcagagcc 1740
tcccagtgga tcggcatcct ggtggattgg tatcagcaga aacctgggga ggctcctaaa 1800
ctgctgatct attacgccag cttcctgcag tccggcgtgc cctctagatt cagcggctct 1860
ggcttcggca cagatttcac actgaccatc tctagcctgc accctgaaga ttttgccaca 1920
tattactgtc agcaggccaa ccctgccccc ctgacatttg gacagggaac aaaggtcgag 1980
atcaagcgcg agcctaagtc ctgtgacaag acacacacat gccctccctg cccagcccca 2040
gaactgctcg gtggaccctc tgtgtttctg tttccaccca agcctaagga tacactcatg 2100
atctccagaa cacctgaagt gacatgtgtg gtcgtcgacg tgtcacatga ggatccagaa 2160
gtcaagttta actggtatgt ggatggggtc gaggtgcaca atgccaaaac aaaacctcgg 2220
gaagaacagt ataattccac ctatagagtc gtgtctgtgc tcaccgtgct ccatcaggat 2280
tggctcaatg ggaaagaata caaatgtaaa gtctctaaca aagccctgcc cgctcctatc 2340
gaaaagacaa tctccaaggc caaaggacag cctcgcgagc ctcaggtcta caccctgcca 2400
ccttcccgcg aggaaatgac aaaaaatcag gtgtcactca cctgtctcgt gaaggggttt 2460
tacccctccg acattgccgt cgagtgggag tccaatggac agcccgagaa caattataag 2520
acaacacctc ccgtcctgga ctccgatgga tcattttttc tgtactccaa gctcaccgtc 2580
gataagtcca gatggcagca gggaaatgtc ttttcctgct ccgtgatgca tgaagctctc 2640
cacaatcatt acacacagaa aagcctgtcc ctgtcccccg gcaagtgact cgag 2694
<210> 64
<211> 2709
<212> DNA
<213> Artificial Sequence
<220>
<223> Nucleotide sequence encoding the protein complex comprising VEGF
and EGFR specific binding peptides #20
<400> 64
gaattcgcca ccatgggctg gtcctgcatc atcctgtttc tggtggccac cgccaccggc 60
gtgcactctg atatccagat gacccagagc cccagcagcc tgtctgcctc tgtgggcgac 120
agagtgacca tcacctgtcg ggccagccag aagatcttca acggcctgag ctggtatcag 180
cagaagcccg gcaaggcccc caagctgctg atctaccaca gcagcaccct gcagagcggc 240
gtgccaagca gattttctgg cagcggcagc ggcaccgact tcaccctgac aatcagcagc 300
ctgcagcccg aggacttcgc cacctactac tgccagcagg tcctgctgta cccctacacc 360
tttggccagg gcaccaaggt ggaaatcaag agagagccca agagctgcga caagacccac 420
acctgtcccc cttgtcctgc ccctgaactg ctgggaggcc ctagcgtgtt cctgttcccc 480
ccaaagccca aggacaccct gatgatcagc cggacccccg aagtgacctg cgtggtggtg 540
gatgtgtccc acgaggaccc tgaagtgaag ttcaattggt acgtggacgg cgtggaagtg 600
cacaacgcca agaccaagcc cagagaggaa cagtacaaca gcacctaccg ggtggtgtcc 660
gtgctgacag tgctgcacca ggactggctg aacggcaaag agtacaagtg caaggtgtcc 720
aacaaggccc tgcctgcccc catcgagaaa accatcagca aggccaaggg ccagcccaga 780
gaaccccagg tgtacacact gccccccagc agagaagaga tgaccaagaa ccaggtgtcc 840
ctgacctgcc tggtcaaggg cttctacccc agcgatatcg ccgtggaatg ggagagcaac 900
ggccagcctg agaacaacta caagaccacc ccccctgtgc tggacagcga cggctcattc 960
ttcctgtaca gcaagctgac cgtggacaag agccggtggc agcagggcaa cgtgttcagc 1020
tgcagcgtga tgcacgaggc cctgcacaac cactacaccc agaagtccct gagcctgagc 1080
cccggcaaga tgcagatctt cgtgaaaacc ctgaccggca agaccatcac cctggaagtg 1140
gaacccagcg acaccatcga gaacgtgaag gccaagatcc aggacaaaga gggcatcccc 1200
cccgaccagc agagactgat cttcgccggc aagcagctgg aagatggcag aaccctgagc 1260
gactacaaca tccagaaaga gtccaccctg cacctggtgc tgcggctgag aggcggaggt 1320
ggtggtggtt ctggtggcgg aggatctggc ggtggtggat ctgggggagg tggaagtggt 1380
ggcggtggta gtggtggtgg cggaagcgga ggcggtggat caggcggagg cggatcaggt 1440
ggcgggggtt caatgcagat ttttgtcaag acactgaccg ggaaaacaat cacactcgaa 1500
gtcgagccct ccgatacaat tgagaatgtg aaagccaaaa ttcaggacaa agaagggatt 1560
cctcctgatc agcagcggct gatttttgcc ggaaaacagc tcgaagatgg acggaccctg 1620
tccgattaca atattcagaa agaaagcacc ctccatctgg tcctgaggct gcggggaggc 1680
gacattcaga tgacacagtc ccccagctcc ctgagcgcca gcgtgggaga tcgcgtgacc 1740
attacctgca gagcctccca gtggatcggc atcctggtgg attggtatca gcagaaacct 1800
ggggaggctc ctaaactgct gatctattac gccagcttcc tgcagtccgg cgtgccctct 1860
agattcagcg gctctggctt cggcacagat ttcacactga ccatctctag cctgcaccct 1920
gaagattttg ccacatatta ctgtcagcag gccaaccctg cccccctgac atttggacag 1980
ggaacaaagg tcgagatcaa gcgcgagcct aagtcctgtg acaagacaca cacatgccct 2040
ccctgcccag ccccagaact gctcggtgga ccctctgtgt ttctgtttcc acccaagcct 2100
aaggatacac tcatgatctc cagaacacct gaagtgacat gtgtggtcgt cgacgtgtca 2160
catgaggatc cagaagtcaa gtttaactgg tatgtggatg gggtcgaggt gcacaatgcc 2220
aaaacaaaac ctcgggaaga acagtataat tccacctata gagtcgtgtc tgtgctcacc 2280
gtgctccatc aggattggct caatgggaaa gaatacaaat gtaaagtctc taacaaagcc 2340
ctgcccgctc ctatcgaaaa gacaatctcc aaggccaaag gacagcctcg cgagcctcag 2400
gtctacaccc tgccaccttc ccgcgaggaa atgacaaaaa atcaggtgtc actcacctgt 2460
ctcgtgaagg ggttttaccc ctccgacatt gccgtcgagt gggagtccaa tggacagccc 2520
gagaacaatt ataagacaac acctcccgtc ctggactccg atggatcatt ttttctgtac 2580
tccaagctca ccgtcgataa gtccagatgg cagcagggaa atgtcttttc ctgctccgtg 2640
atgcatgaag ctctccacaa tcattacaca cagaaaagcc tgtccctgtc ccccggcaag 2700
tgactcgag 2709
<210> 65
<211> 2724
<212> DNA
<213> Artificial Sequence
<220>
<223> Nucleotide sequence encoding the protein complex comprising VEGF
and EGFR specific binding peptides #21
<400> 65
gaattcgcca ccatgggctg gtcctgcatc atcctgtttc tggtggccac cgccaccggc 60
gtgcactctg atatccagat gacccagagc cccagcagcc tgtctgcctc tgtgggcgac 120
agagtgacca tcacctgtcg ggccagccag aagatcttca acggcctgag ctggtatcag 180
cagaagcccg gcaaggcccc caagctgctg atctaccaca gcagcaccct gcagagcggc 240
gtgccaagca gattttctgg cagcggcagc ggcaccgact tcaccctgac aatcagcagc 300
ctgcagcccg aggacttcgc cacctactac tgccagcagg tcctgctgta cccctacacc 360
tttggccagg gcaccaaggt ggaaatcaag agagagccca agagctgcga caagacccac 420
acctgtcccc cttgtcctgc ccctgaactg ctgggaggcc ctagcgtgtt cctgttcccc 480
ccaaagccca aggacaccct gatgatcagc cggacccccg aagtgacctg cgtggtggtg 540
gatgtgtccc acgaggaccc tgaagtgaag ttcaattggt acgtggacgg cgtggaagtg 600
cacaacgcca agaccaagcc cagagaggaa cagtacaaca gcacctaccg ggtggtgtcc 660
gtgctgacag tgctgcacca ggactggctg aacggcaaag agtacaagtg caaggtgtcc 720
aacaaggccc tgcctgcccc catcgagaaa accatcagca aggccaaggg ccagcccaga 780
gaaccccagg tgtacacact gccccccagc agagaagaga tgaccaagaa ccaggtgtcc 840
ctgacctgcc tggtcaaggg cttctacccc agcgatatcg ccgtggaatg ggagagcaac 900
ggccagcctg agaacaacta caagaccacc ccccctgtgc tggacagcga cggctcattc 960
ttcctgtaca gcaagctgac cgtggacaag agccggtggc agcagggcaa cgtgttcagc 1020
tgcagcgtga tgcacgaggc cctgcacaac cactacaccc agaagtccct gagcctgagc 1080
cccggcaaga tgcagatctt cgtgaaaacc ctgaccggca agaccatcac cctggaagtg 1140
gaacccagcg acaccatcga gaacgtgaag gccaagatcc aggacaaaga gggcatcccc 1200
cccgaccagc agagactgat cttcgccggc aagcagctgg aagatggcag aaccctgagc 1260
gactacaaca tccagaaaga gtccaccctg cacctggtgc tgcggctgag aggcggaggt 1320
ggtggtggtt ctggtggcgg aggatctggc ggtggtggat ctgggggagg tggaagtggt 1380
ggcggtggta gtggtggtgg cggaagcgga ggcggtggat caggcggagg cggatcaggt 1440
ggcgggggtt cagggggtgg cggaagtatg cagatttttg tcaagacact gaccgggaaa 1500
acaatcacac tcgaagtcga gccctccgat acaattgaga atgtgaaagc caaaattcag 1560
gacaaagaag ggattcctcc tgatcagcag cggctgattt ttgccggaaa acagctcgaa 1620
gatggacgga ccctgtccga ttacaatatt cagaaagaaa gcaccctcca tctggtcctg 1680
aggctgcggg gaggcgacat tcagatgaca cagtccccca gctccctgag cgccagcgtg 1740
ggagatcgcg tgaccattac ctgcagagcc tcccagtgga tcggcatcct ggtggattgg 1800
tatcagcaga aacctgggga ggctcctaaa ctgctgatct attacgccag cttcctgcag 1860
tccggcgtgc cctctagatt cagcggctct ggcttcggca cagatttcac actgaccatc 1920
tctagcctgc accctgaaga ttttgccaca tattactgtc agcaggccaa ccctgccccc 1980
ctgacatttg gacagggaac aaaggtcgag atcaagcgcg agcctaagtc ctgtgacaag 2040
acacacacat gccctccctg cccagcccca gaactgctcg gtggaccctc tgtgtttctg 2100
tttccaccca agcctaagga tacactcatg atctccagaa cacctgaagt gacatgtgtg 2160
gtcgtcgacg tgtcacatga ggatccagaa gtcaagttta actggtatgt ggatggggtc 2220
gaggtgcaca atgccaaaac aaaacctcgg gaagaacagt ataattccac ctatagagtc 2280
gtgtctgtgc tcaccgtgct ccatcaggat tggctcaatg ggaaagaata caaatgtaaa 2340
gtctctaaca aagccctgcc cgctcctatc gaaaagacaa tctccaaggc caaaggacag 2400
cctcgcgagc ctcaggtcta caccctgcca ccttcccgcg aggaaatgac aaaaaatcag 2460
gtgtcactca cctgtctcgt gaaggggttt tacccctccg acattgccgt cgagtgggag 2520
tccaatggac agcccgagaa caattataag acaacacctc ccgtcctgga ctccgatgga 2580
tcattttttc tgtactccaa gctcaccgtc gataagtcca gatggcagca gggaaatgtc 2640
ttttcctgct ccgtgatgca tgaagctctc cacaatcatt acacacagaa aagcctgtcc 2700
ctgtcccccg gcaagtgact cgag 2724
<210> 66
<211> 2634
<212> DNA
<213> Artificial Sequence
<220>
<223> Nucleotide sequence encoding the protein complex comprising VEGF
and EGFR specific binding peptides #22
<400> 66
gaattcgcca ccatgggctg gtcctgcatc atcctgtttc tggtggccac cgccaccggc 60
gtgcactctg atatccagat gacccagagc cccagcagcc tgtctgcctc tgtgggcgac 120
agagtgacca tcacctgtcg ggccagccag aagatcttca acggcctgag ctggtatcag 180
cagaagcccg gcaaggcccc caagctgctg atctaccaca gcagcaccct gcagagcggc 240
gtgccaagca gattttctgg cagcggcagc ggcaccgact tcaccctgac aatcagcagc 300
ctgcagcccg aggacttcgc cacctactac tgccagcagg tcctgctgta cccctacacc 360
tttggccagg gcaccaaggt ggaaatcaag agagagccca agagctgcga caagacccac 420
acctgtcccc cttgtcctgc ccctgaactg ctgggaggcc ctagcgtgtt cctgttcccc 480
ccaaagccca aggacaccct gatgatcagc cggacccccg aagtgacctg cgtggtggtg 540
gatgtgtccc acgaggaccc tgaagtgaag ttcaattggt acgtggacgg cgtggaagtg 600
cacaacgcca agaccaagcc cagagaggaa cagtacaaca gcacctaccg ggtggtgtcc 660
gtgctgacag tgctgcacca ggactggctg aacggcaaag agtacaagtg caaggtgtcc 720
aacaaggccc tgcctgcccc catcgagaaa accatcagca aggccaaggg ccagcccaga 780
gaaccccagg tgtacacact gccccccagc agagaagaga tgaccaagaa ccaggtgtcc 840
ctgacctgcc tggtcaaggg cttctacccc agcgatatcg ccgtggaatg ggagagcaac 900
ggccagcctg agaacaacta caagaccacc ccccctgtgc tggacagcga cggctcattc 960
ttcctgtaca gcaagctgac cgtggacaag agccggtggc agcagggcaa cgtgttcagc 1020
tgcagcgtga tgcacgaggc cctgcacaac cactacaccc agaagtccct gagcctgagc 1080
cccggcaaga tgcagatctt cgtgaaaacc ctgaccggca agaccatcac cctggaagtg 1140
gaacccagcg acaccatcga gaacgtgaag gccaagatcc aggacaaaga gggcatcccc 1200
cccgaccagc agagactgat cttcgccggc aagcagctgg aagatggcag aaccctgagc 1260
gactacaaca tccagaaaga gtccaccctg cacctggtgc tgcggctgag aggcggaggt 1320
ggtggtggtt ctggtggcgg aggatctggc ggtggtggat ctgggggagg tggaagtatg 1380
cagatttttg tcaagacact gaccgggaaa acaatcacac tcgaagtcga gccctccgat 1440
acaattgaga atgtgaaagc caaaattcag gacaaagaag ggattcctcc tgatcagcag 1500
cggctgattt ttgccggaaa acagctcgaa gatggacgga ccctgtccga ttacaatatt 1560
cagaaagaaa gcaccctcca tctggtcctg aggctgcggg gaggcgacat tcagatgaca 1620
cagtccccca cctccctgtc tgccagcgtg ggagatcgcg tgaccattac ctgcagagcc 1680
tcccagtgga tcggcaacct gctggattgg tatcagcaga aacctgggga ggctcctaaa 1740
ctgctgatct attacgccag cttcctgcag tccggcgtgc cctctagatt ttccggcgga 1800
ggcttcggca cagatttcac actgaccatc tcatccctgc agcctgaaga ttttgccaca 1860
tattattgcc agcaggccaa ccctgccccc ctgacatttg gacagggaac aaaggtcgag 1920
atcaagcgcg agcctaagtc ctgtgacaag acacacacat gccctccctg cccagcccca 1980
gaactgctcg gtggaccctc tgtgtttctg tttccaccca agcctaagga tacactcatg 2040
atctccagaa cacctgaagt gacatgtgtg gtcgtcgacg tgtcacatga ggatccagaa 2100
gtcaagttta actggtatgt ggatggggtc gaggtgcaca atgccaaaac aaaacctcgg 2160
gaagaacagt ataattccac ctatagagtc gtgtctgtgc tcaccgtgct ccatcaggat 2220
tggctcaatg ggaaagaata caaatgtaaa gtctctaaca aagccctgcc cgctcctatc 2280
gaaaagacaa tctccaaggc caaaggacag cctcgcgagc ctcaggtcta caccctgcca 2340
ccttcccgcg aggaaatgac aaaaaatcag gtgtcactca cctgtctcgt gaaggggttt 2400
tacccctccg acattgccgt cgagtgggag tccaatggac agcccgagaa caattataag 2460
acaacacctc ccgtcctgga ctccgatgga tcattttttc tgtactccaa gctcaccgtc 2520
gataagtcca gatggcagca gggaaatgtc ttttcctgct ccgtgatgca tgaagctctc 2580
cacaatcatt acacacagaa aagcctgtcc ctgtcccccg gcaagtgact cgag 2634
<210> 67
<211> 2649
<212> DNA
<213> Artificial Sequence
<220>
<223> Nucleotide sequence encoding the protein complex comprising VEGF
and EGFR specific binding peptides #23
<400> 67
gaattcgcca ccatgggctg gtcctgcatc atcctgtttc tggtggccac cgccaccggc 60
gtgcactctg atatccagat gacccagagc cccagcagcc tgtctgcctc tgtgggcgac 120
agagtgacca tcacctgtcg ggccagccag aagatcttca acggcctgag ctggtatcag 180
cagaagcccg gcaaggcccc caagctgctg atctaccaca gcagcaccct gcagagcggc 240
gtgccaagca gattttctgg cagcggcagc ggcaccgact tcaccctgac aatcagcagc 300
ctgcagcccg aggacttcgc cacctactac tgccagcagg tcctgctgta cccctacacc 360
tttggccagg gcaccaaggt ggaaatcaag agagagccca agagctgcga caagacccac 420
acctgtcccc cttgtcctgc ccctgaactg ctgggaggcc ctagcgtgtt cctgttcccc 480
ccaaagccca aggacaccct gatgatcagc cggacccccg aagtgacctg cgtggtggtg 540
gatgtgtccc acgaggaccc tgaagtgaag ttcaattggt acgtggacgg cgtggaagtg 600
cacaacgcca agaccaagcc cagagaggaa cagtacaaca gcacctaccg ggtggtgtcc 660
gtgctgacag tgctgcacca ggactggctg aacggcaaag agtacaagtg caaggtgtcc 720
aacaaggccc tgcctgcccc catcgagaaa accatcagca aggccaaggg ccagcccaga 780
gaaccccagg tgtacacact gccccccagc agagaagaga tgaccaagaa ccaggtgtcc 840
ctgacctgcc tggtcaaggg cttctacccc agcgatatcg ccgtggaatg ggagagcaac 900
ggccagcctg agaacaacta caagaccacc ccccctgtgc tggacagcga cggctcattc 960
ttcctgtaca gcaagctgac cgtggacaag agccggtggc agcagggcaa cgtgttcagc 1020
tgcagcgtga tgcacgaggc cctgcacaac cactacaccc agaagtccct gagcctgagc 1080
cccggcaaga tgcagatctt cgtgaaaacc ctgaccggca agaccatcac cctggaagtg 1140
gaacccagcg acaccatcga gaacgtgaag gccaagatcc aggacaaaga gggcatcccc 1200
cccgaccagc agagactgat cttcgccggc aagcagctgg aagatggcag aaccctgagc 1260
gactacaaca tccagaaaga gtccaccctg cacctggtgc tgcggctgag aggcggaggt 1320
ggtggtggtt ctggtggcgg aggatctggc ggtggtggat ctgggggagg tggaagtggt 1380
ggcggtggta gtatgcagat ttttgtcaag acactgaccg ggaaaacaat cacactcgaa 1440
gtcgagccct ccgatacaat tgagaatgtg aaagccaaaa ttcaggacaa agaagggatt 1500
cctcctgatc agcagcggct gatttttgcc ggaaaacagc tcgaagatgg acggaccctg 1560
tccgattaca atattcagaa agaaagcacc ctccatctgg tcctgaggct gcggggaggc 1620
gacattcaga tgacacagtc ccccacctcc ctgtctgcca gcgtgggaga tcgcgtgacc 1680
attacctgca gagcctccca gtggatcggc aacctgctgg attggtatca gcagaaacct 1740
ggggaggctc ctaaactgct gatctattac gccagcttcc tgcagtccgg cgtgccctct 1800
agattttccg gcggaggctt cggcacagat ttcacactga ccatctcatc cctgcagcct 1860
gaagattttg ccacatatta ttgccagcag gccaaccctg cccccctgac atttggacag 1920
ggaacaaagg tcgagatcaa gcgcgagcct aagtcctgtg acaagacaca cacatgccct 1980
ccctgcccag ccccagaact gctcggtgga ccctctgtgt ttctgtttcc acccaagcct 2040
aaggatacac tcatgatctc cagaacacct gaagtgacat gtgtggtcgt cgacgtgtca 2100
catgaggatc cagaagtcaa gtttaactgg tatgtggatg gggtcgaggt gcacaatgcc 2160
aaaacaaaac ctcgggaaga acagtataat tccacctata gagtcgtgtc tgtgctcacc 2220
gtgctccatc aggattggct caatgggaaa gaatacaaat gtaaagtctc taacaaagcc 2280
ctgcccgctc ctatcgaaaa gacaatctcc aaggccaaag gacagcctcg cgagcctcag 2340
gtctacaccc tgccaccttc ccgcgaggaa atgacaaaaa atcaggtgtc actcacctgt 2400
ctcgtgaagg ggttttaccc ctccgacatt gccgtcgagt gggagtccaa tggacagccc 2460
gagaacaatt ataagacaac acctcccgtc ctggactccg atggatcatt ttttctgtac 2520
tccaagctca ccgtcgataa gtccagatgg cagcagggaa atgtcttttc ctgctccgtg 2580
atgcatgaag ctctccacaa tcattacaca cagaaaagcc tgtccctgtc ccccggcaag 2640
tgactcgag 2649
<210> 68
<211> 2664
<212> DNA
<213> Artificial Sequence
<220>
<223> Nucleotide sequence encoding the protein complex comprising VEGF
and EGFR specific binding peptides #24
<400> 68
gaattcgcca ccatgggctg gtcctgcatc atcctgtttc tggtggccac cgccaccggc 60
gtgcactctg atatccagat gacccagagc cccagcagcc tgtctgcctc tgtgggcgac 120
agagtgacca tcacctgtcg ggccagccag aagatcttca acggcctgag ctggtatcag 180
cagaagcccg gcaaggcccc caagctgctg atctaccaca gcagcaccct gcagagcggc 240
gtgccaagca gattttctgg cagcggcagc ggcaccgact tcaccctgac aatcagcagc 300
ctgcagcccg aggacttcgc cacctactac tgccagcagg tcctgctgta cccctacacc 360
tttggccagg gcaccaaggt ggaaatcaag agagagccca agagctgcga caagacccac 420
acctgtcccc cttgtcctgc ccctgaactg ctgggaggcc ctagcgtgtt cctgttcccc 480
ccaaagccca aggacaccct gatgatcagc cggacccccg aagtgacctg cgtggtggtg 540
gatgtgtccc acgaggaccc tgaagtgaag ttcaattggt acgtggacgg cgtggaagtg 600
cacaacgcca agaccaagcc cagagaggaa cagtacaaca gcacctaccg ggtggtgtcc 660
gtgctgacag tgctgcacca ggactggctg aacggcaaag agtacaagtg caaggtgtcc 720
aacaaggccc tgcctgcccc catcgagaaa accatcagca aggccaaggg ccagcccaga 780
gaaccccagg tgtacacact gccccccagc agagaagaga tgaccaagaa ccaggtgtcc 840
ctgacctgcc tggtcaaggg cttctacccc agcgatatcg ccgtggaatg ggagagcaac 900
ggccagcctg agaacaacta caagaccacc ccccctgtgc tggacagcga cggctcattc 960
ttcctgtaca gcaagctgac cgtggacaag agccggtggc agcagggcaa cgtgttcagc 1020
tgcagcgtga tgcacgaggc cctgcacaac cactacaccc agaagtccct gagcctgagc 1080
cccggcaaga tgcagatctt cgtgaaaacc ctgaccggca agaccatcac cctggaagtg 1140
gaacccagcg acaccatcga gaacgtgaag gccaagatcc aggacaaaga gggcatcccc 1200
cccgaccagc agagactgat cttcgccggc aagcagctgg aagatggcag aaccctgagc 1260
gactacaaca tccagaaaga gtccaccctg cacctggtgc tgcggctgag aggcggaggt 1320
ggtggtggtt ctggtggcgg aggatctggc ggtggtggat ctgggggagg tggaagtggt 1380
ggcggtggta gtggtggtgg cggaagcatg cagatttttg tcaagacact gaccgggaaa 1440
acaatcacac tcgaagtcga gccctccgat acaattgaga atgtgaaagc caaaattcag 1500
gacaaagaag ggattcctcc tgatcagcag cggctgattt ttgccggaaa acagctcgaa 1560
gatggacgga ccctgtccga ttacaatatt cagaaagaaa gcaccctcca tctggtcctg 1620
aggctgcggg gaggcgacat tcagatgaca cagtccccca cctccctgtc tgccagcgtg 1680
ggagatcgcg tgaccattac ctgcagagcc tcccagtgga tcggcaacct gctggattgg 1740
tatcagcaga aacctgggga ggctcctaaa ctgctgatct attacgccag cttcctgcag 1800
tccggcgtgc cctctagatt ttccggcgga ggcttcggca cagatttcac actgaccatc 1860
tcatccctgc agcctgaaga ttttgccaca tattattgcc agcaggccaa ccctgccccc 1920
ctgacatttg gacagggaac aaaggtcgag atcaagcgcg agcctaagtc ctgtgacaag 1980
acacacacat gccctccctg cccagcccca gaactgctcg gtggaccctc tgtgtttctg 2040
tttccaccca agcctaagga tacactcatg atctccagaa cacctgaagt gacatgtgtg 2100
gtcgtcgacg tgtcacatga ggatccagaa gtcaagttta actggtatgt ggatggggtc 2160
gaggtgcaca atgccaaaac aaaacctcgg gaagaacagt ataattccac ctatagagtc 2220
gtgtctgtgc tcaccgtgct ccatcaggat tggctcaatg ggaaagaata caaatgtaaa 2280
gtctctaaca aagccctgcc cgctcctatc gaaaagacaa tctccaaggc caaaggacag 2340
cctcgcgagc ctcaggtcta caccctgcca ccttcccgcg aggaaatgac aaaaaatcag 2400
gtgtcactca cctgtctcgt gaaggggttt tacccctccg acattgccgt cgagtgggag 2460
tccaatggac agcccgagaa caattataag acaacacctc ccgtcctgga ctccgatgga 2520
tcattttttc tgtactccaa gctcaccgtc gataagtcca gatggcagca gggaaatgtc 2580
ttttcctgct ccgtgatgca tgaagctctc cacaatcatt acacacagaa aagcctgtcc 2640
ctgtcccccg gcaagtgact cgag 2664
<210> 69
<211> 2679
<212> DNA
<213> Artificial Sequence
<220>
<223> Nucleotide sequence encoding the protein complex comprising VEGF
and EGFR specific binding peptides #25
<400> 69
gaattcgcca ccatgggctg gtcctgcatc atcctgtttc tggtggccac cgccaccggc 60
gtgcactctg atatccagat gacccagagc cccagcagcc tgtctgcctc tgtgggcgac 120
agagtgacca tcacctgtcg ggccagccag aagatcttca acggcctgag ctggtatcag 180
cagaagcccg gcaaggcccc caagctgctg atctaccaca gcagcaccct gcagagcggc 240
gtgccaagca gattttctgg cagcggcagc ggcaccgact tcaccctgac aatcagcagc 300
ctgcagcccg aggacttcgc cacctactac tgccagcagg tcctgctgta cccctacacc 360
tttggccagg gcaccaaggt ggaaatcaag agagagccca agagctgcga caagacccac 420
acctgtcccc cttgtcctgc ccctgaactg ctgggaggcc ctagcgtgtt cctgttcccc 480
ccaaagccca aggacaccct gatgatcagc cggacccccg aagtgacctg cgtggtggtg 540
gatgtgtccc acgaggaccc tgaagtgaag ttcaattggt acgtggacgg cgtggaagtg 600
cacaacgcca agaccaagcc cagagaggaa cagtacaaca gcacctaccg ggtggtgtcc 660
gtgctgacag tgctgcacca ggactggctg aacggcaaag agtacaagtg caaggtgtcc 720
aacaaggccc tgcctgcccc catcgagaaa accatcagca aggccaaggg ccagcccaga 780
gaaccccagg tgtacacact gccccccagc agagaagaga tgaccaagaa ccaggtgtcc 840
ctgacctgcc tggtcaaggg cttctacccc agcgatatcg ccgtggaatg ggagagcaac 900
ggccagcctg agaacaacta caagaccacc ccccctgtgc tggacagcga cggctcattc 960
ttcctgtaca gcaagctgac cgtggacaag agccggtggc agcagggcaa cgtgttcagc 1020
tgcagcgtga tgcacgaggc cctgcacaac cactacaccc agaagtccct gagcctgagc 1080
cccggcaaga tgcagatctt cgtgaaaacc ctgaccggca agaccatcac cctggaagtg 1140
gaacccagcg acaccatcga gaacgtgaag gccaagatcc aggacaaaga gggcatcccc 1200
cccgaccagc agagactgat cttcgccggc aagcagctgg aagatggcag aaccctgagc 1260
gactacaaca tccagaaaga gtccaccctg cacctggtgc tgcggctgag aggcggaggt 1320
ggtggtggtt ctggtggcgg aggatctggc ggtggtggat ctgggggagg tggaagtggt 1380
ggcggtggta gtggtggtgg cggaagcgga ggcggtggat caatgcagat ttttgtcaag 1440
acactgaccg ggaaaacaat cacactcgaa gtcgagccct ccgatacaat tgagaatgtg 1500
aaagccaaaa ttcaggacaa agaagggatt cctcctgatc agcagcggct gatttttgcc 1560
ggaaaacagc tcgaagatgg acggaccctg tccgattaca atattcagaa agaaagcacc 1620
ctccatctgg tcctgaggct gcggggaggc gacattcaga tgacacagtc ccccacctcc 1680
ctgtctgcca gcgtgggaga tcgcgtgacc attacctgca gagcctccca gtggatcggc 1740
aacctgctgg attggtatca gcagaaacct ggggaggctc ctaaactgct gatctattac 1800
gccagcttcc tgcagtccgg cgtgccctct agattttccg gcggaggctt cggcacagat 1860
ttcacactga ccatctcatc cctgcagcct gaagattttg ccacatatta ttgccagcag 1920
gccaaccctg cccccctgac atttggacag ggaacaaagg tcgagatcaa gcgcgagcct 1980
aagtcctgtg acaagacaca cacatgccct ccctgcccag ccccagaact gctcggtgga 2040
ccctctgtgt ttctgtttcc acccaagcct aaggatacac tcatgatctc cagaacacct 2100
gaagtgacat gtgtggtcgt cgacgtgtca catgaggatc cagaagtcaa gtttaactgg 2160
tatgtggatg gggtcgaggt gcacaatgcc aaaacaaaac ctcgggaaga acagtataat 2220
tccacctata gagtcgtgtc tgtgctcacc gtgctccatc aggattggct caatgggaaa 2280
gaatacaaat gtaaagtctc taacaaagcc ctgcccgctc ctatcgaaaa gacaatctcc 2340
aaggccaaag gacagcctcg cgagcctcag gtctacaccc tgccaccttc ccgcgaggaa 2400
atgacaaaaa atcaggtgtc actcacctgt ctcgtgaagg ggttttaccc ctccgacatt 2460
gccgtcgagt gggagtccaa tggacagccc gagaacaatt ataagacaac acctcccgtc 2520
ctggactccg atggatcatt ttttctgtac tccaagctca ccgtcgataa gtccagatgg 2580
cagcagggaa atgtcttttc ctgctccgtg atgcatgaag ctctccacaa tcattacaca 2640
cagaaaagcc tgtccctgtc ccccggcaag tgactcgag 2679
<210> 70
<211> 2694
<212> DNA
<213> Artificial Sequence
<220>
<223> Nucleotide sequence encoding the protein complex comprising VEGF
and EGFR specific binding peptides #26
<400> 70
gaattcgcca ccatgggctg gtcctgcatc atcctgtttc tggtggccac cgccaccggc 60
gtgcactctg atatccagat gacccagagc cccagcagcc tgtctgcctc tgtgggcgac 120
agagtgacca tcacctgtcg ggccagccag aagatcttca acggcctgag ctggtatcag 180
cagaagcccg gcaaggcccc caagctgctg atctaccaca gcagcaccct gcagagcggc 240
gtgccaagca gattttctgg cagcggcagc ggcaccgact tcaccctgac aatcagcagc 300
ctgcagcccg aggacttcgc cacctactac tgccagcagg tcctgctgta cccctacacc 360
tttggccagg gcaccaaggt ggaaatcaag agagagccca agagctgcga caagacccac 420
acctgtcccc cttgtcctgc ccctgaactg ctgggaggcc ctagcgtgtt cctgttcccc 480
ccaaagccca aggacaccct gatgatcagc cggacccccg aagtgacctg cgtggtggtg 540
gatgtgtccc acgaggaccc tgaagtgaag ttcaattggt acgtggacgg cgtggaagtg 600
cacaacgcca agaccaagcc cagagaggaa cagtacaaca gcacctaccg ggtggtgtcc 660
gtgctgacag tgctgcacca ggactggctg aacggcaaag agtacaagtg caaggtgtcc 720
aacaaggccc tgcctgcccc catcgagaaa accatcagca aggccaaggg ccagcccaga 780
gaaccccagg tgtacacact gccccccagc agagaagaga tgaccaagaa ccaggtgtcc 840
ctgacctgcc tggtcaaggg cttctacccc agcgatatcg ccgtggaatg ggagagcaac 900
ggccagcctg agaacaacta caagaccacc ccccctgtgc tggacagcga cggctcattc 960
ttcctgtaca gcaagctgac cgtggacaag agccggtggc agcagggcaa cgtgttcagc 1020
tgcagcgtga tgcacgaggc cctgcacaac cactacaccc agaagtccct gagcctgagc 1080
cccggcaaga tgcagatctt cgtgaaaacc ctgaccggca agaccatcac cctggaagtg 1140
gaacccagcg acaccatcga gaacgtgaag gccaagatcc aggacaaaga gggcatcccc 1200
cccgaccagc agagactgat cttcgccggc aagcagctgg aagatggcag aaccctgagc 1260
gactacaaca tccagaaaga gtccaccctg cacctggtgc tgcggctgag aggcggaggt 1320
ggtggtggtt ctggtggcgg aggatctggc ggtggtggat ctgggggagg tggaagtggt 1380
ggcggtggta gtggtggtgg cggaagcgga ggcggtggat caggcggagg cggatcaatg 1440
cagatttttg tcaagacact gaccgggaaa acaatcacac tcgaagtcga gccctccgat 1500
acaattgaga atgtgaaagc caaaattcag gacaaagaag ggattcctcc tgatcagcag 1560
cggctgattt ttgccggaaa acagctcgaa gatggacgga ccctgtccga ttacaatatt 1620
cagaaagaaa gcaccctcca tctggtcctg aggctgcggg gaggcgacat tcagatgaca 1680
cagtccccca cctccctgtc tgccagcgtg ggagatcgcg tgaccattac ctgcagagcc 1740
tcccagtgga tcggcaacct gctggattgg tatcagcaga aacctgggga ggctcctaaa 1800
ctgctgatct attacgccag cttcctgcag tccggcgtgc cctctagatt ttccggcgga 1860
ggcttcggca cagatttcac actgaccatc tcatccctgc agcctgaaga ttttgccaca 1920
tattattgcc agcaggccaa ccctgccccc ctgacatttg gacagggaac aaaggtcgag 1980
atcaagcgcg agcctaagtc ctgtgacaag acacacacat gccctccctg cccagcccca 2040
gaactgctcg gtggaccctc tgtgtttctg tttccaccca agcctaagga tacactcatg 2100
atctccagaa cacctgaagt gacatgtgtg gtcgtcgacg tgtcacatga ggatccagaa 2160
gtcaagttta actggtatgt ggatggggtc gaggtgcaca atgccaaaac aaaacctcgg 2220
gaagaacagt ataattccac ctatagagtc gtgtctgtgc tcaccgtgct ccatcaggat 2280
tggctcaatg ggaaagaata caaatgtaaa gtctctaaca aagccctgcc cgctcctatc 2340
gaaaagacaa tctccaaggc caaaggacag cctcgcgagc ctcaggtcta caccctgcca 2400
ccttcccgcg aggaaatgac aaaaaatcag gtgtcactca cctgtctcgt gaaggggttt 2460
tacccctccg acattgccgt cgagtgggag tccaatggac agcccgagaa caattataag 2520
acaacacctc ccgtcctgga ctccgatgga tcattttttc tgtactccaa gctcaccgtc 2580
gataagtcca gatggcagca gggaaatgtc ttttcctgct ccgtgatgca tgaagctctc 2640
cacaatcatt acacacagaa aagcctgtcc ctgtcccccg gcaagtgact cgag 2694
<210> 71
<211> 2709
<212> DNA
<213> Artificial Sequence
<220>
<223> Nucleotide sequence encoding the protein complex comprising VEGF
and EGFR specific binding peptides #27
<400> 71
gaattcgcca ccatgggctg gtcctgcatc atcctgtttc tggtggccac cgccaccggc 60
gtgcactctg atatccagat gacccagagc cccagcagcc tgtctgcctc tgtgggcgac 120
agagtgacca tcacctgtcg ggccagccag aagatcttca acggcctgag ctggtatcag 180
cagaagcccg gcaaggcccc caagctgctg atctaccaca gcagcaccct gcagagcggc 240
gtgccaagca gattttctgg cagcggcagc ggcaccgact tcaccctgac aatcagcagc 300
ctgcagcccg aggacttcgc cacctactac tgccagcagg tcctgctgta cccctacacc 360
tttggccagg gcaccaaggt ggaaatcaag agagagccca agagctgcga caagacccac 420
acctgtcccc cttgtcctgc ccctgaactg ctgggaggcc ctagcgtgtt cctgttcccc 480
ccaaagccca aggacaccct gatgatcagc cggacccccg aagtgacctg cgtggtggtg 540
gatgtgtccc acgaggaccc tgaagtgaag ttcaattggt acgtggacgg cgtggaagtg 600
cacaacgcca agaccaagcc cagagaggaa cagtacaaca gcacctaccg ggtggtgtcc 660
gtgctgacag tgctgcacca ggactggctg aacggcaaag agtacaagtg caaggtgtcc 720
aacaaggccc tgcctgcccc catcgagaaa accatcagca aggccaaggg ccagcccaga 780
gaaccccagg tgtacacact gccccccagc agagaagaga tgaccaagaa ccaggtgtcc 840
ctgacctgcc tggtcaaggg cttctacccc agcgatatcg ccgtggaatg ggagagcaac 900
ggccagcctg agaacaacta caagaccacc ccccctgtgc tggacagcga cggctcattc 960
ttcctgtaca gcaagctgac cgtggacaag agccggtggc agcagggcaa cgtgttcagc 1020
tgcagcgtga tgcacgaggc cctgcacaac cactacaccc agaagtccct gagcctgagc 1080
cccggcaaga tgcagatctt cgtgaaaacc ctgaccggca agaccatcac cctggaagtg 1140
gaacccagcg acaccatcga gaacgtgaag gccaagatcc aggacaaaga gggcatcccc 1200
cccgaccagc agagactgat cttcgccggc aagcagctgg aagatggcag aaccctgagc 1260
gactacaaca tccagaaaga gtccaccctg cacctggtgc tgcggctgag aggcggaggt 1320
ggtggtggtt ctggtggcgg aggatctggc ggtggtggat ctgggggagg tggaagtggt 1380
ggcggtggta gtggtggtgg cggaagcgga ggcggtggat caggcggagg cggatcaggt 1440
ggcgggggtt caatgcagat ttttgtcaag acactgaccg ggaaaacaat cacactcgaa 1500
gtcgagccct ccgatacaat tgagaatgtg aaagccaaaa ttcaggacaa agaagggatt 1560
cctcctgatc agcagcggct gatttttgcc ggaaaacagc tcgaagatgg acggaccctg 1620
tccgattaca atattcagaa agaaagcacc ctccatctgg tcctgaggct gcggggaggc 1680
gacattcaga tgacacagtc ccccacctcc ctgtctgcca gcgtgggaga tcgcgtgacc 1740
attacctgca gagcctccca gtggatcggc aacctgctgg attggtatca gcagaaacct 1800
ggggaggctc ctaaactgct gatctattac gccagcttcc tgcagtccgg cgtgccctct 1860
agattttccg gcggaggctt cggcacagat ttcacactga ccatctcatc cctgcagcct 1920
gaagattttg ccacatatta ttgccagcag gccaaccctg cccccctgac atttggacag 1980
ggaacaaagg tcgagatcaa gcgcgagcct aagtcctgtg acaagacaca cacatgccct 2040
ccctgcccag ccccagaact gctcggtgga ccctctgtgt ttctgtttcc acccaagcct 2100
aaggatacac tcatgatctc cagaacacct gaagtgacat gtgtggtcgt cgacgtgtca 2160
catgaggatc cagaagtcaa gtttaactgg tatgtggatg gggtcgaggt gcacaatgcc 2220
aaaacaaaac ctcgggaaga acagtataat tccacctata gagtcgtgtc tgtgctcacc 2280
gtgctccatc aggattggct caatgggaaa gaatacaaat gtaaagtctc taacaaagcc 2340
ctgcccgctc ctatcgaaaa gacaatctcc aaggccaaag gacagcctcg cgagcctcag 2400
gtctacaccc tgccaccttc ccgcgaggaa atgacaaaaa atcaggtgtc actcacctgt 2460
ctcgtgaagg ggttttaccc ctccgacatt gccgtcgagt gggagtccaa tggacagccc 2520
gagaacaatt ataagacaac acctcccgtc ctggactccg atggatcatt ttttctgtac 2580
tccaagctca ccgtcgataa gtccagatgg cagcagggaa atgtcttttc ctgctccgtg 2640
atgcatgaag ctctccacaa tcattacaca cagaaaagcc tgtccctgtc ccccggcaag 2700
tgactcgag 2709
<210> 72
<211> 2724
<212> DNA
<213> Artificial Sequence
<220>
<223> Nucleotide sequence encoding the protein complex comprising VEGF
and EGFR specific binding peptides #28
<400> 72
gaattcgcca ccatgggctg gtcctgcatc atcctgtttc tggtggccac cgccaccggc 60
gtgcactctg atatccagat gacccagagc cccagcagcc tgtctgcctc tgtgggcgac 120
agagtgacca tcacctgtcg ggccagccag aagatcttca acggcctgag ctggtatcag 180
cagaagcccg gcaaggcccc caagctgctg atctaccaca gcagcaccct gcagagcggc 240
gtgccaagca gattttctgg cagcggcagc ggcaccgact tcaccctgac aatcagcagc 300
ctgcagcccg aggacttcgc cacctactac tgccagcagg tcctgctgta cccctacacc 360
tttggccagg gcaccaaggt ggaaatcaag agagagccca agagctgcga caagacccac 420
acctgtcccc cttgtcctgc ccctgaactg ctgggaggcc ctagcgtgtt cctgttcccc 480
ccaaagccca aggacaccct gatgatcagc cggacccccg aagtgacctg cgtggtggtg 540
gatgtgtccc acgaggaccc tgaagtgaag ttcaattggt acgtggacgg cgtggaagtg 600
cacaacgcca agaccaagcc cagagaggaa cagtacaaca gcacctaccg ggtggtgtcc 660
gtgctgacag tgctgcacca ggactggctg aacggcaaag agtacaagtg caaggtgtcc 720
aacaaggccc tgcctgcccc catcgagaaa accatcagca aggccaaggg ccagcccaga 780
gaaccccagg tgtacacact gccccccagc agagaagaga tgaccaagaa ccaggtgtcc 840
ctgacctgcc tggtcaaggg cttctacccc agcgatatcg ccgtggaatg ggagagcaac 900
ggccagcctg agaacaacta caagaccacc ccccctgtgc tggacagcga cggctcattc 960
ttcctgtaca gcaagctgac cgtggacaag agccggtggc agcagggcaa cgtgttcagc 1020
tgcagcgtga tgcacgaggc cctgcacaac cactacaccc agaagtccct gagcctgagc 1080
cccggcaaga tgcagatctt cgtgaaaacc ctgaccggca agaccatcac cctggaagtg 1140
gaacccagcg acaccatcga gaacgtgaag gccaagatcc aggacaaaga gggcatcccc 1200
cccgaccagc agagactgat cttcgccggc aagcagctgg aagatggcag aaccctgagc 1260
gactacaaca tccagaaaga gtccaccctg cacctggtgc tgcggctgag aggcggaggt 1320
ggtggtggtt ctggtggcgg aggatctggc ggtggtggat ctgggggagg tggaagtggt 1380
ggcggtggta gtggtggtgg cggaagcgga ggcggtggat caggcggagg cggatcaggt 1440
ggcgggggtt cagggggtgg cggaagtatg cagatttttg tcaagacact gaccgggaaa 1500
acaatcacac tcgaagtcga gccctccgat acaattgaga atgtgaaagc caaaattcag 1560
gacaaagaag ggattcctcc tgatcagcag cggctgattt ttgccggaaa acagctcgaa 1620
gatggacgga ccctgtccga ttacaatatt cagaaagaaa gcaccctcca tctggtcctg 1680
aggctgcggg gaggcgacat tcagatgaca cagtccccca cctccctgtc tgccagcgtg 1740
ggagatcgcg tgaccattac ctgcagagcc tcccagtgga tcggcaacct gctggattgg 1800
tatcagcaga aacctgggga ggctcctaaa ctgctgatct attacgccag cttcctgcag 1860
tccggcgtgc cctctagatt ttccggcgga ggcttcggca cagatttcac actgaccatc 1920
tcatccctgc agcctgaaga ttttgccaca tattattgcc agcaggccaa ccctgccccc 1980
ctgacatttg gacagggaac aaaggtcgag atcaagcgcg agcctaagtc ctgtgacaag 2040
acacacacat gccctccctg cccagcccca gaactgctcg gtggaccctc tgtgtttctg 2100
tttccaccca agcctaagga tacactcatg atctccagaa cacctgaagt gacatgtgtg 2160
gtcgtcgacg tgtcacatga ggatccagaa gtcaagttta actggtatgt ggatggggtc 2220
gaggtgcaca atgccaaaac aaaacctcgg gaagaacagt ataattccac ctatagagtc 2280
gtgtctgtgc tcaccgtgct ccatcaggat tggctcaatg ggaaagaata caaatgtaaa 2340
gtctctaaca aagccctgcc cgctcctatc gaaaagacaa tctccaaggc caaaggacag 2400
cctcgcgagc ctcaggtcta caccctgcca ccttcccgcg aggaaatgac aaaaaatcag 2460
gtgtcactca cctgtctcgt gaaggggttt tacccctccg acattgccgt cgagtgggag 2520
tccaatggac agcccgagaa caattataag acaacacctc ccgtcctgga ctccgatgga 2580
tcattttttc tgtactccaa gctcaccgtc gataagtcca gatggcagca gggaaatgtc 2640
ttttcctgct ccgtgatgca tgaagctctc cacaatcatt acacacagaa aagcctgtcc 2700
ctgtcccccg gcaagtgact cgag 2724
<210> 73
<211> 2664
<212> DNA
<213> Artificial Sequence
<220>
<223> Nucleotide sequence encoding the protein complex comprising VEGF
and EGFR specific binding peptides #29
<400> 73
gaattcgcca ccatgggctg gtcctgcatc atcctgtttc tggtggccac cgccaccggc 60
gtgcactctg atatccagat gacccagagc cccagcagcc tgtctgcctc tgtgggcgac 120
agagtgacca tcacctgtcg ggccagccag aagatcttca acggcctgag ctggtatcag 180
cagaagcccg gcaaggcccc caagctgctg atctaccaca gcagcaccct gcagagcggc 240
gtgccaagca gattttctgg cagcggcagc ggcaccgact tcaccctgac aatcagcagc 300
ctgcagcccg aggacttcgc cacctactac tgccagcagg tcctgctgta cccctacacc 360
tttggccagg gcaccaaggt ggaaatcaag agagagccca agagctgcga caagacccac 420
acctgtcccc cttgtcctgc ccctgaactg ctgggaggcc ctagcgtgtt cctgttcccc 480
ccaaagccca aggacaccct gatgatcagc cggacccccg aagtgacctg cgtggtggtg 540
gatgtgtccc acgaggaccc tgaagtgaag ttcaattggt acgtggacgg cgtggaagtg 600
cacaacgcca agaccaagcc cagagaggaa cagtacaaca gcacctaccg ggtggtgtcc 660
gtgctgacag tgctgcacca ggactggctg aacggcaaag agtacaagtg caaggtgtcc 720
aacaaggccc tgcctgcccc catcgagaaa accatcagca aggccaaggg ccagcccaga 780
gaaccccagg tgtacacact gccccccagc agagaagaga tgaccaagaa ccaggtgtcc 840
ctgacctgcc tggtcaaggg cttctacccc agcgatatcg ccgtggaatg ggagagcaac 900
ggccagcctg agaacaacta caagaccacc ccccctgtgc tggacagcga cggctcattc 960
ttcctgtaca gcaagctgac cgtggacaag agccggtggc agcagggcaa cgtgttcagc 1020
tgcagcgtga tgcacgaggc cctgcacaac cactacaccc agaagtccct gagcctgagc 1080
cccggcaaga tgcagatctt cgtgaaaacc ctgaccggca agaccatcac cctggaagtg 1140
gaacccagcg acaccatcga gaacgtgaag gccaagatcc aggacaaaga gggcatcccc 1200
cccgaccagc agagactgat cttcgccggc aagcagctgg aagatggcag aaccctgagc 1260
gactacaaca tccagaaaga gtccaccctg cacctggtgc tgcggctgag aggcggaggt 1320
ggtggtggtt ctggtggcgg aggatctggc ggtggtggat ctgggggagg tggaagtggt 1380
ggcggtggta gtggtggtgg cggaagcatg cagatttttg tcaagacact gaccgggaaa 1440
acaatcacac tcgaagtcga gccctccgat acaattgaga atgtgaaagc caaaattcag 1500
gacaaagaag ggattcctcc tgatcagcag cggctgattt ttgccggaaa acagctcgaa 1560
gatggacgga ccctgtccga ttacaatatt cagaaagaaa gcaccctcca tctggtcctg 1620
aggctgcggg gaggcgacat tcagatgaca cagtccccca cctccctgtc tgccagcgtg 1680
ggagatcgcg tgaccattac ctgcagagcc tcccagtgga tcggcaacct gctggattgg 1740
tatcagcaga aacctgggga ggctcctaaa ctgctgatct attacgccag cttcctgcag 1800
tccggcgtgc cctctagatt ttccggcgga ggcttcggca cagatttcac actgaccatc 1860
tcatccctgc agcctgaaga ttttgccaca tattattgcc agcaggccaa ccctgccccc 1920
ctgacatttg gacagggaac aaaggtcgag atcaagcgcg agcctaagtc ctgtgacaag 1980
acacacacat gccctccctg cccagcccca gaactgctcg gtggaccctc tgtgtttctg 2040
tttccaccca agcctaagga tacactcatg atctccagaa cacctgaagt gacatgtgtg 2100
gtcgtcgacg tgtcacatga ggatccagaa gtcaagttta actggtatgt ggatggggtc 2160
gaggtgcaca atgccaaaac aaaacctcgg gaagaacagt ataattccac ctatagagtc 2220
gtgtctgtgc tcaccgtgct ccatcaggat tggctcaatg ggaaagaata caaatgtaaa 2280
gtctctaaca aagccctgcc cgctcctatc gaaaagacaa tctccaaggc caaaggacag 2340
cctcgcgagc ctcaggtcta caccctgcca ccttcccgcg aggaaatgac aaaaaatcag 2400
gtgtcactca cctgtctcgt gaaggggttt tacccctccg acattgccgt cgagtgggag 2460
tccaatggac agcccgagaa caattataag acaacacctc ccgtcctgga ctccgatgga 2520
tcattttttc tgtactccaa gctcaccgtc gataagtcca gatggcagca gggaaatgtc 2580
ttttcctgct ccgtgatgca tgaagctctc cacaatcatt acacacagaa aagcctgtcc 2640
ctgtcccccg gcaagtgact cgag 2664
<210> 74
<211> 2352
<212> DNA
<213> Artificial Sequence
<220>
<223> Nucleotide sequence encoding the protein complex comprising VEGF
and EGFR specific binding peptides #30
<400> 74
gaattcgcca ccatgggctg gtcctgcatc atcctgtttc tggtggccac cgccaccggc 60
gtgcactctg atatccagat gacccagagc cccagcagcc tgtctgcctc tgtgggcgac 120
agagtgacca tcacctgtcg ggccagccag aagatcttca acggcctgag ctggtatcag 180
cagaagcccg gcaaggcccc caagctgctg atctaccaca gcagcaccct gcagagcggc 240
gtgccaagca gattttctgg cagcggcagc ggcaccgact tcaccctgac aatcagcagc 300
ctgcagcccg aggacttcgc cacctactac tgccagcagg tcctgctgta cccctacacc 360
tttggccagg gcaccaaggt ggaaatcaag agagagccca agagctgcga caagacccac 420
acctgtcccc cttgtcctgc ccctgaactg ctgggaggcc ctagcgtgtt cctgttcccc 480
ccaaagccca aggacaccct gatgatcagc cggacccccg aagtgacctg cgtggtggtg 540
gatgtgtccc acgaggaccc tgaagtgaag ttcaattggt acgtggacgg cgtggaagtg 600
cacaacgcca agaccaagcc cagagaggaa cagtacaaca gcacctaccg ggtggtgtcc 660
gtgctgacag tgctgcacca ggactggctg aacggcaaag agtacaagtg caaggtgtcc 720
aacaaggccc tgcctgcccc catcgagaaa accatcagca aggccaaggg ccagcccaga 780
gaaccccagg tgtacacact gccccccagc agagaagaga tgaccaagaa ccaggtgtcc 840
ctgacctgcc tggtcaaggg cttctacccc agcgatatcg ccgtggaatg ggagagcaac 900
ggccagcctg agaacaacta caagaccacc ccccctgtgc tggacagcga cggctcattc 960
ttcctgtaca gcaagctgac cgtggacaag agccggtggc agcagggcaa cgtgttcagc 1020
tgcagcgtga tgcacgaggc cctgcacaac cactacaccc agaagtccct gagcctgagc 1080
cccggcaaga tgcagatctt cgtgaaaacc ctgaccggca agaccatcac cctggaagtg 1140
gaacccagcg acaccatcga gaacgtgaag gccaagatcc aggacaaaga gggcatcccc 1200
cccgaccagc agagactgat cttcgccggc aagcagctgg aagatggcag aaccctgagc 1260
gactacaaca tccagaaaga gtccaccctg cacctggtgc tgcggctgag aggcggaggt 1320
ggtgacattc agatgacaca gtcccccacc tccctgtctg ccagcgtggg agatcgcgtg 1380
accattacct gcagagcctc ccagtggatc ggcaacctgc tggattggta tcagcagaaa 1440
cctggggagg ctcctaaact gctgatctat tacgccagct tcctgcagtc cggcgtgccc 1500
tctagatttt ccggcggagg cttcggcaca gatttcacac tgaccatctc atccctgcag 1560
cctgaagatt ttgccacata ttattgccag caggccaacc ctgcccccct gacatttgga 1620
cagggaacaa aggtcgagat caagcgcgag cctaagtcct gtgacaagac acacacatgc 1680
cctccctgcc cagccccaga actgctcggt ggaccctctg tgtttctgtt tccacccaag 1740
cctaaggata cactcatgat ctccagaaca cctgaagtga catgtgtggt cgtcgacgtg 1800
tcacatgagg atccagaagt caagtttaac tggtatgtgg atggggtcga ggtgcacaat 1860
gccaaaacaa aacctcggga agaacagtat aattccacct atagagtcgt gtctgtgctc 1920
accgtgctcc atcaggattg gctcaatggg aaagaataca aatgtaaagt ctctaacaaa 1980
gccctgcccg ctcctatcga aaagacaatc tccaaggcca aaggacagcc tcgcgagcct 2040
caggtctaca ccctgccacc ttcccgcgag gaaatgacaa aaaatcaggt gtcactcacc 2100
tgtctcgtga aggggtttta cccctccgac attgccgtcg agtgggagtc caatggacag 2160
cccgagaaca attataagac aacacctccc gtcctggact ccgatggatc attttttctg 2220
tactccaagc tcaccgtcga taagtccaga tggcagcagg gaaatgtctt ttcctgctcc 2280
gtgatgcatg aagctctcca caatcattac acacagaaaa gcctgtccct gtcccccggc 2340
aagtgactcg ag 2352
<210> 75
<211> 2679
<212> DNA
<213> Artificial Sequence
<220>
<223> Nucleotide sequence encoding the protein complex comprising VEGF
and EGFR specific binding peptides #31
<400> 75
gaattcgcca ccatgggctg gtcctgcatc atcctgtttc tggtggccac cgccaccggc 60
gtgcactctg atatccagat gacccagagc cccagcagcc tgtctgcctc tgtgggcgac 120
agagtgacca tcacctgtcg ggccagccag aagatcttca acggcctgag ctggtatcag 180
cagaagcccg gcaaggcccc caagctgctg atctaccaca gcagcaccct gcagagcggc 240
gtgccaagca gattttctgg cagcggcagc ggcaccgact tcaccctgac aatcagcagc 300
ctgcagcccg aggacttcgc cacctactac tgccagcagg tcctgctgta cccctacacc 360
tttggccagg gcaccaaggt ggaaatcaag agagagccca agagctgcga caagacccac 420
acctgtcccc cttgtcctgc ccctgaactg ctgggaggcc ctagcgtgtt cctgttcccc 480
ccaaagccca aggacaccct gatgatcagc cggacccccg aagtgacctg cgtggtggtg 540
gatgtgtccc acgaggaccc tgaagtgaag ttcaattggt acgtggacgg cgtggaagtg 600
cacaacgcca agaccaagcc cagagaggaa cagtacaaca gcacctaccg ggtggtgtcc 660
gtgctgacag tgctgcacca ggactggctg aacggcaaag agtacaagtg caaggtgtcc 720
aacaaggccc tgcctgcccc catcgagaaa accatcagca aggccaaggg ccagcccaga 780
gaaccccagg tgtacacact gccccccagc agagaagaga tgaccaagaa ccaggtgtcc 840
ctgacctgcc tggtcaaggg cttctacccc agcgatatcg ccgtggaatg ggagagcaac 900
ggccagcctg agaacaacta caagaccacc ccccctgtgc tggacagcga cggctcattc 960
ttcctgtaca gcaagctgac cgtggacaag agccggtggc agcagggcaa cgtgttcagc 1020
tgcagcgtga tgcacgaggc cctgcacaac cactacaccc agaagtccct gagcctgagc 1080
cccggcaaga tgcagatctt cgtgaaaacc ctgaccggca agaccatcac cctggaagtg 1140
gaacccagcg acaccatcga gaacgtgaag gccaagatcc aggacaaaga gggcatcccc 1200
cccgaccagc agagactgat cttcgccggc aagcagctgg aagatggcag aaccctgagc 1260
gactacaaca tccagaaaga gtccaccctg cacctggtgc tgcggctgag aggcggaggt 1320
ggtggtggtt ctggtggcgg aggatctggc ggtggtggat ctgggggagg tggaagtggt 1380
ggcggtggta gtggtggtgg cggaagcatg cagatttttg tcaagacact gaccgggaaa 1440
acaatcacac tcgaagtcga gccctccgat acaattgaga atgtgaaagc caaaattcag 1500
gacaaagaag ggattcctcc tgatcagcag cggctgattt ttgccggaaa acagctcgaa 1560
gatggacgga ccctgtccga ttacaatatt cagaaagaaa gcaccctcca tctggtcctg 1620
aggctgcggg gaggcggcgg cggcggcagc gacattcaga tgacacagtc ccccacctcc 1680
ctgtctgcca gcgtgggaga tcgcgtgacc attacctgca gagcctccca gtggatcggc 1740
aacctgctgg attggtatca gcagaaacct ggggaggctc ctaaactgct gatctattac 1800
gccagcttcc tgcagtccgg cgtgccctct agattttccg gcggaggctt cggcacagat 1860
ttcacactga ccatctcatc cctgcagcct gaagattttg ccacatatta ttgccagcag 1920
gccaaccctg cccccctgac atttggacag ggaacaaagg tcgagatcaa gcgcgagcct 1980
aagtcctgtg acaagacaca cacatgccct ccctgcccag ccccagaact gctcggtgga 2040
ccctctgtgt ttctgtttcc acccaagcct aaggatacac tcatgatctc cagaacacct 2100
gaagtgacat gtgtggtcgt cgacgtgtca catgaggatc cagaagtcaa gtttaactgg 2160
tatgtggatg gggtcgaggt gcacaatgcc aaaacaaaac ctcgggaaga acagtataat 2220
tccacctata gagtcgtgtc tgtgctcacc gtgctccatc aggattggct caatgggaaa 2280
gaatacaaat gtaaagtctc taacaaagcc ctgcccgctc ctatcgaaaa gacaatctcc 2340
aaggccaaag gacagcctcg cgagcctcag gtctacaccc tgccaccttc ccgcgaggaa 2400
atgacaaaaa atcaggtgtc actcacctgt ctcgtgaagg ggttttaccc ctccgacatt 2460
gccgtcgagt gggagtccaa tggacagccc gagaacaatt ataagacaac acctcccgtc 2520
ctggactccg atggatcatt ttttctgtac tccaagctca ccgtcgataa gtccagatgg 2580
cagcagggaa atgtcttttc ctgctccgtg atgcatgaag ctctccacaa tcattacaca 2640
cagaaaagcc tgtccctgtc ccccggcaag tgactcgag 2679
<210> 76
<211> 2670
<212> DNA
<213> Artificial Sequence
<220>
<223> Nucleotide sequence encoding the protein complex comprising VEGF
and EGFR specific binding peptides #32
<400> 76
gaattcgcca ccatgggctg gtcctgcatc atcctgtttc tggtggccac cgccaccggc 60
gtgcactctg atatccagat gacccagagc cccagcagcc tgtctgcctc tgtgggcgac 120
agagtgacca tcacctgtcg ggccagccag aagatcttca acggcctgag ctggtatcag 180
cagaagcccg gcaaggcccc caagctgctg atctaccaca gcagcaccct gcagagcggc 240
gtgccaagca gattttctgg cagcggcagc ggcaccgact tcaccctgac aatcagcagc 300
ctgcagcccg aggacttcgc cacctactac tgccagcagg tcctgctgta cccctacacc 360
tttggccagg gcaccaaggt ggaaatcaag agagagccca agagctgcga caagacccac 420
acctgtcccc cttgtcctgc ccctgaactg ctgggaggcc ctagcgtgtt cctgttcccc 480
ccaaagccca aggacaccct gatgatcagc cggacccccg aagtgacctg cgtggtggtg 540
gatgtgtccc acgaggaccc tgaagtgaag ttcaattggt acgtggacgg cgtggaagtg 600
cacaacgcca agaccaagcc cagagaggaa cagtacaaca gcacctaccg ggtggtgtcc 660
gtgctgacag tgctgcacca ggactggctg aacggcaaag agtacaagtg caaggtgtcc 720
aacaaggccc tgcctgcccc catcgagaaa accatcagca aggccaaggg ccagcccaga 780
gaaccccagg tgtacacact gccccccagc agagaagaga tgaccaagaa ccaggtgtcc 840
ctgacctgcc tggtcaaggg cttctacccc agcgatatcg ccgtggaatg ggagagcaac 900
ggccagcctg agaacaacta caagaccacc ccccctgtgc tggacagcga cggctcattc 960
ttcctgtaca gcaagctgac cgtggacaag agccggtggc agcagggcaa cgtgttcagc 1020
tgcagcgtga tgcacgaggc cctgcacaac cactacaccc agaagtccct gagcctgagc 1080
cccggcaaga tgcagatctt cgtgaaaacc ctgaccggca agaccatcac cctggaagtg 1140
gaacccagcg acaccatcga gaacgtgaag gccaagatcc aggacaaaga gggcatcccc 1200
cccgaccagc agagactgat cttcgccggc aagcagctgg aagatggcag aaccctgagc 1260
gactacaaca tccagaaaga gtccaccctg cacctggtgc tgcggctgag aggcggaggt 1320
ggtggtggtt ctggtggcgg aggatctggc ggtggtggat ctgggggagg tggaagtggt 1380
ggcggtggta gtggtggtgg cggaagcatg cagatttttg tcaagacact gaccgggaaa 1440
acaatcacac tcgaagtcga gccctccgat acaattgaga atgtgaaagc caaaattcag 1500
gacaaagaag ggattcctcc tgatcagcag cggctgattt ttgccggaaa acagctcgaa 1560
gatggacgga ccctgtccga ttacaatatt cagaaagaaa gcaccctcca tctggtcctg 1620
aggctgcggg gaggcggcgg cgacattcag atgacacagt cccccacctc cctgtctgcc 1680
agcgtgggag atcgcgtgac cattacctgc agagcctccc agtggatcgg caacctgctg 1740
gattggtatc agcagaaacc tggggaggct cctaaactgc tgatctatta cgccagcttc 1800
ctgcagtccg gcgtgccctc tagattttcc ggcggaggct tcggcacaga tttcacactg 1860
accatctcat ccctgcagcc tgaagatttt gccacatatt attgccagca ggccaaccct 1920
gcccccctga catttggaca gggaacaaag gtcgagatca agcgcgagcc taagtcctgt 1980
gacaagacac acacatgccc tccctgccca gccccagaac tgctcggtgg accctctgtg 2040
tttctgtttc cacccaagcc taaggataca ctcatgatct ccagaacacc tgaagtgaca 2100
tgtgtggtcg tcgacgtgtc acatgaggat ccagaagtca agtttaactg gtatgtggat 2160
ggggtcgagg tgcacaatgc caaaacaaaa cctcgggaag aacagtataa ttccacctat 2220
agagtcgtgt ctgtgctcac cgtgctccat caggattggc tcaatgggaa agaatacaaa 2280
tgtaaagtct ctaacaaagc cctgcccgct cctatcgaaa agacaatctc caaggccaaa 2340
ggacagcctc gcgagcctca ggtctacacc ctgccacctt cccgcgagga aatgacaaaa 2400
aatcaggtgt cactcacctg tctcgtgaag gggttttacc cctccgacat tgccgtcgag 2460
tgggagtcca atggacagcc cgagaacaat tataagacaa cacctcccgt cctggactcc 2520
gatggatcat tttttctgta ctccaagctc accgtcgata agtccagatg gcagcaggga 2580
aatgtctttt cctgctccgt gatgcatgaa gctctccaca atcattacac acagaaaagc 2640
ctgtccctgt cccccggcaa gtgactcgag 2670
<210> 77
<211> 2679
<212> DNA
<213> Artificial Sequence
<220>
<223> Nucleotide sequence encoding the protein complex comprising VEGF
and EGFR specific binding peptides #33
<400> 77
gaattcgcca ccatgggctg gtcctgcatc atcctgtttc tggtggccac cgccaccggc 60
gtgcactctg atatccagat gacccagagc cccagcagcc tgtctgcctc tgtgggcgac 120
agagtgacca tcacctgtcg ggccagccag aagatcttca acggcctgag ctggtatcag 180
cagaagcccg gcaaggcccc caagctgctg atctaccaca gcagcaccct gcagagcggc 240
gtgccaagca gattttctgg cagcggcagc ggcaccgact tcaccctgac aatcagcagc 300
ctgcagcccg aggacttcgc cacctactac tgccagcagg tcctgctgta cccctacacc 360
tttggccagg gcaccaaggt ggaaatcaag agagagccca agagctgcga caagacccac 420
acctgtcccc cttgtcctgc ccctgaactg ctgggaggcc ctagcgtgtt cctgttcccc 480
ccaaagccca aggacaccct gatgatcagc cggacccccg aagtgacctg cgtggtggtg 540
gatgtgtccc acgaggaccc tgaagtgaag ttcaattggt acgtggacgg cgtggaagtg 600
cacaacgcca agaccaagcc cagagaggaa cagtacaaca gcacctaccg ggtggtgtcc 660
gtgctgacag tgctgcacca ggactggctg aacggcaaag agtacaagtg caaggtgtcc 720
aacaaggccc tgcctgcccc catcgagaaa accatcagca aggccaaggg ccagcccaga 780
gaaccccagg tgtacacact gccccccagc agagaagaga tgaccaagaa ccaggtgtcc 840
ctgacctgcc tggtcaaggg cttctacccc agcgatatcg ccgtggaatg ggagagcaac 900
ggccagcctg agaacaacta caagaccacc ccccctgtgc tggacagcga cggctcattc 960
ttcctgtaca gcaagctgac cgtggacaag agccggtggc agcagggcaa cgtgttcagc 1020
tgcagcgtga tgcacgaggc cctgcacaac cactacaccc agaagtccct gagcctgagc 1080
cccggcaaga tgcagatctt cgtgaaaacc ctgaccggca agaccatcac cctggaagtg 1140
gaacccagcg acaccatcga gaacgtgaag gccaagatcc aggacaaaga gggcatcccc 1200
cccgaccagc agagactgat cttcgccggc aagcagctgg aagatggcag aaccctgagc 1260
gactacaaca tccagaaaga gtccaccctg cacctggtgc tgcggctgag aggcggaggt 1320
ggtggtggtt ctggtggcgg aggatctggc ggtggtggat ctgggggagg tggaagtggt 1380
ggcggtggta gtggtggtgg cggaagcatg cagatttttg tcaagacact gaccgggaaa 1440
acaatcacac tcgaagtcga gccctccgat acaattgaga atgtgaaagc caaaattcag 1500
gacaaagaag ggattcctcc tgatcagcag cggctgattt ttgccggaaa acagctcgaa 1560
gatggacgga ccctgtccga ttacaatatt cagaaagaaa gcaccctcca tctggtcctg 1620
aggctgcggg gaggcggcgg cggcggcagc gacattcaga tgacacagtc ccccacctcc 1680
ctgtctgcca gcgtgggaga tcgcgtgacc attacctgca gagcctccca gtggatcggc 1740
aacctgctgg attggtatca gcagaaacct ggggaggctc ctaaactgct gatctattac 1800
gccagcttcc tgcagtccgg cgtgccctct agattttccg gcggaggctt cggcacagat 1860
ttcacactga ccatctcatc cctgcagcct gaagattttg ccacatatta ttgccagcag 1920
gccaaccctg cccccctgac atttggacag ggaacaaagg tcgagatcaa gcgcgagcct 1980
aagtcctgtg acaagacaca cacatgccct ccctgcccag ccccagaact gctcggtgga 2040
ccctctgtgt ttctgtttcc acccaagcct aaggatacac tcatgatctc cagaacacct 2100
gaagtgacat gtgtggtcgt cgacgtgtca catgaggatc cagaagtcaa gtttaactgg 2160
tatgtggatg gggtcgaggt gcacaatgcc aaaacaaaac ctcgggaaga acagtataat 2220
tccacctata gagtcgtgtc tgtgctcacc gtgctccatc aggattggct caatgggaaa 2280
gaatacaaat gtaaagtctc taacaaagcc ctgcccgctc ctatcgaaaa gacaatctcc 2340
aaggccaaag gacagcctcg cgagcctcag gtctacaccc tgccaccttc ccgcgaggaa 2400
atgacaaaaa atcaggtgtc actcacctgt ctcgtgaagg ggttttaccc ctccgacatt 2460
gccgtcgagt gggagtccaa tggacagccc gagaacaatt ataagacaac acctcccgtc 2520
ctggactccg atggatcatt ttttctgtac tccaagctca ccgtcgataa gtccagatgg 2580
cagcagggaa atgtcttttc ctgctccgtg atgcatgaag ctctccacaa tcattacaca 2640
cagaaaagcc tgtccctgtc ccccggcaag tgactcgag 2679
<210> 78
<211> 2352
<212> DNA
<213> Artificial Sequence
<220>
<223> Nucleotide sequence encoding the protein complex comprising VEGF
and EGFR specific binding peptides #34
<400> 78
gaattcgcca ccatgggctg gtcctgcatc atcctgtttc tggtggccac cgccaccggc 60
gtgcactctg atatccagat gacccagagc cccagcagcc tgtctgcctc tgtgggcgac 120
agagtgacca tcacctgtcg ggccagccag aagatcttca acggcctgag ctggtatcag 180
cagaagcccg gcaaggcccc caagctgctg atctaccaca gcagcaccct gcagagcggc 240
gtgccaagca gattttctgg cagcggcagc ggcaccgact tcaccctgac aatcagcagc 300
ctgcagcccg aggacttcgc cacctactac tgccagcagg tcctgctgta cccctacacc 360
tttggccagg gcaccaaggt ggaaatcaag agagagccca agagctgcga caagacccac 420
acctgtcccc cttgtcctgc ccctgaactg ctgggaggcc ctagcgtgtt cctgttcccc 480
ccaaagccca aggacaccct gatgatcagc cggacccccg aagtgacctg cgtggtggtg 540
gatgtgtccc acgaggaccc tgaagtgaag ttcaattggt acgtggacgg cgtggaagtg 600
cacaacgcca agaccaagcc cagagaggaa cagtacaaca gcacctaccg ggtggtgtcc 660
gtgctgacag tgctgcacca ggactggctg aacggcaaag agtacaagtg caaggtgtcc 720
aacaaggccc tgcctgcccc catcgagaaa accatcagca aggccaaggg ccagcccaga 780
gaaccccagg tgtacacact gccccccagc agagaagaga tgaccaagaa ccaggtgtcc 840
ctgacctgcc tggtcaaggg cttctacccc agcgatatcg ccgtggaatg ggagagcaac 900
ggccagcctg agaacaacta caagaccacc ccccctgtgc tggacagcga cggctcattc 960
ttcctgtaca gcaagctgac cgtggacaag agccggtggc agcagggcaa cgtgttcagc 1020
tgcagcgtga tgcacgaggc cctgcacaac cactacaccc agaagtccct gagcctgagc 1080
cccggcaaga tgcagatctt cgtgaaaacc ctgaccggca agaccatcac cctggaagtg 1140
gaacccagcg acaccatcga gaacgtgaag gccaagatcc aggacaaaga gggcatcccc 1200
cccgaccagc agagactgat cttcgccggc aagcagctgg aagatggcag aaccctgagc 1260
gactacaaca tccagaaaga gtccaccctg cacctggtgc tgcggctgag aggcggaggt 1320
ggtgacattc agatgacaca gtcccccacc tccctgtctg ccagcgtggg agatcgcgtg 1380
accattacct gcagagcctc ccagtggatc ggcaacctgc tggattggta tcagcagaaa 1440
cctggggagg ctcctaaact gctgatctat tacgccagct tcctgcagtc cggcgtgccc 1500
tctagatttt ccggcggagg cttcggcaca gatttcacac tgaccatctc atccctgcag 1560
cctgaagatt ttgccacata ttattgccag caggccaacc ctgcccccct gacatttgga 1620
cagggaacaa aggtcgagat caagcgcgag cctaagtcct gtgacaagac acacacatgc 1680
cctccctgcc cagccccaga actgctcggt ggaccctctg tgtttctgtt tccacccaag 1740
cctaaggata cactcatgat ctccagaaca cctgaagtga catgtgtggt cgtcgacgtg 1800
tcacatgagg atccagaagt caagtttaac tggtatgtgg atggggtcga ggtgcacaat 1860
gccaaaacaa aacctcggga agaacagtat aattccacct atagagtcgt gtctgtgctc 1920
accgtgctcc atcaggattg gctcaatggg aaagaataca aatgtaaagt ctctaacaaa 1980
gccctgcccg ctcctatcga aaagacaatc tccaaggcca aaggacagcc tcgcgagcct 2040
caggtctaca ccctgccacc ttcccgcgag gaaatgacaa aaaatcaggt gtcactcacc 2100
tgtctcgtga aggggtttta cccctccgac attgccgtcg agtgggagtc caatggacag 2160
cccgagaaca attataagac aacacctccc gtcctggact ccgatggatc attttttctg 2220
tactccaagc tcaccgtcga taagtccaga tggcagcagg gaaatgtctt ttcctgctcc 2280
gtgatgcatg aagctctcca caatcattac acacagaaaa gcctgtccct gtcccccggc 2340
aagtgactcg ag 2352
<210> 79
<211> 2361
<212> DNA
<213> Artificial Sequence
<220>
<223> Nucleotide sequence encoding the protein complex comprising VEGF
and EGFR specific binding peptides #35
<400> 79
gaattcgcca ccatgggctg gtcctgcatc atcctgtttc tggtggccac cgccaccggc 60
gtgcactctg atatccagat gacccagagc cccagcagcc tgtctgcctc tgtgggcgac 120
agagtgacca tcacctgtcg ggccagccag aagatcttca acggcctgag ctggtatcag 180
cagaagcccg gcaaggcccc caagctgctg atctaccaca gcagcaccct gcagagcggc 240
gtgccaagca gattttctgg cagcggcagc ggcaccgact tcaccctgac aatcagcagc 300
ctgcagcccg aggacttcgc cacctactac tgccagcagg tcctgctgta cccctacacc 360
tttggccagg gcaccaaggt ggaaatcaag agagagccca agagctgcga caagacccac 420
acctgtcccc cttgtcctgc ccctgaactg ctgggaggcc ctagcgtgtt cctgttcccc 480
ccaaagccca aggacaccct gatgatcagc cggacccccg aagtgacctg cgtggtggtg 540
gatgtgtccc acgaggaccc tgaagtgaag ttcaattggt acgtggacgg cgtggaagtg 600
cacaacgcca agaccaagcc cagagaggaa cagtacaaca gcacctaccg ggtggtgtcc 660
gtgctgacag tgctgcacca ggactggctg aacggcaaag agtacaagtg caaggtgtcc 720
aacaaggccc tgcctgcccc catcgagaaa accatcagca aggccaaggg ccagcccaga 780
gaaccccagg tgtacacact gccccccagc agagaagaga tgaccaagaa ccaggtgtcc 840
ctgacctgcc tggtcaaggg cttctacccc agcgatatcg ccgtggaatg ggagagcaac 900
ggccagcctg agaacaacta caagaccacc ccccctgtgc tggacagcga cggctcattc 960
ttcctgtaca gcaagctgac cgtggacaag agccggtggc agcagggcaa cgtgttcagc 1020
tgcagcgtga tgcacgaggc cctgcacaac cactacaccc agaagtccct gagcctgagc 1080
cccggcaaga tgcagatctt cgtgaaaacc ctgaccggca agaccatcac cctggaagtg 1140
gaacccagcg acaccatcga gaacgtgaag gccaagatcc aggacaaaga gggcatcccc 1200
cccgaccagc agagactgat cttcgccggc aagcagctgg aagatggcag aaccctgagc 1260
gactacaaca tccagaaaga gtccaccctg cacctggtgc tgcggctgag aggcggaggt 1320
ggtggtggtt ctgacattca gatgacacag tcccccacct ccctgtctgc cagcgtggga 1380
gatcgcgtga ccattacctg cagagcctcc cagtggatcg gcaacctgct ggattggtat 1440
cagcagaaac ctggggaggc tcctaaactg ctgatctatt acgccagctt cctgcagtcc 1500
ggcgtgccct ctagattttc cggcggaggc ttcggcacag atttcacact gaccatctca 1560
tccctgcagc ctgaagattt tgccacatat tattgccagc aggccaaccc tgcccccctg 1620
acatttggac agggaacaaa ggtcgagatc aagcgcgagc ctaagtcctg tgacaagaca 1680
cacacatgcc ctccctgccc agccccagaa ctgctcggtg gaccctctgt gtttctgttt 1740
ccacccaagc ctaaggatac actcatgatc tccagaacac ctgaagtgac atgtgtggtc 1800
gtcgacgtgt cacatgagga tccagaagtc aagtttaact ggtatgtgga tggggtcgag 1860
gtgcacaatg ccaaaacaaa acctcgggaa gaacagtata attccaccta tagagtcgtg 1920
tctgtgctca ccgtgctcca tcaggattgg ctcaatggga aagaatacaa atgtaaagtc 1980
tctaacaaag ccctgcccgc tcctatcgaa aagacaatct ccaaggccaa aggacagcct 2040
cgcgagcctc aggtctacac cctgccacct tcccgcgagg aaatgacaaa aaatcaggtg 2100
tcactcacct gtctcgtgaa ggggttttac ccctccgaca ttgccgtcga gtgggagtcc 2160
aatggacagc ccgagaacaa ttataagaca acacctcccg tcctggactc cgatggatca 2220
ttttttctgt actccaagct caccgtcgat aagtccagat ggcagcaggg aaatgtcttt 2280
tcctgctccg tgatgcatga agctctccac aatcattaca cacagaaaag cctgtccctg 2340
tcccccggca agtgactcga g 2361
<210> 80
<211> 2496
<212> DNA
<213> Artificial Sequence
<220>
<223> Nucleotide sequence encoding the protein complex comprising VEGF
and EGFR specific binding peptides #36
<400> 80
gaattcgcca ccatgggctg gtcctgcatc atcctgtttc tggtggccac cgccaccggc 60
gtgcactctg atatccagat gacccagagc cccagcagcc tgtctgcctc tgtgggcgac 120
agagtgacca tcacctgtcg ggccagccag aagatcttca acggcctgag ctggtatcag 180
cagaagcccg gcaaggcccc caagctgctg atctaccaca gcagcaccct gcagagcggc 240
gtgccaagca gattttctgg cagcggcagc ggcaccgact tcaccctgac aatcagcagc 300
ctgcagcccg aggacttcgc cacctactac tgccagcagg tcctgctgta cccctacacc 360
tttggccagg gcaccaaggt ggaaatcaag agagagccca agagctgcga caagacccac 420
acctgtcccc cttgtcctgc ccctgaactg ctgggaggcc ctagcgtgtt cctgttcccc 480
ccaaagccca aggacaccct gatgatcagc cggacccccg aagtgacctg cgtggtggtg 540
gatgtgtccc acgaggaccc tgaagtgaag ttcaattggt acgtggacgg cgtggaagtg 600
cacaacgcca agaccaagcc cagagaggaa cagtacaaca gcacctaccg ggtggtgtcc 660
gtgctgacag tgctgcacca ggactggctg aacggcaaag agtacaagtg caaggtgtcc 720
aacaaggccc tgcctgcccc catcgagaaa accatcagca aggccaaggg ccagcccaga 780
gaaccccagg tgtacacact gccccccagc agagaagaga tgaccaagaa ccaggtgtcc 840
ctgacctgcc tggtcaaggg cttctacccc agcgatatcg ccgtggaatg ggagagcaac 900
ggccagcctg agaacaacta caagaccacc ccccctgtgc tggacagcga cggctcattc 960
ttcctgtaca gcaagctgac cgtggacaag agccggtggc agcagggcaa cgtgttcagc 1020
tgcagcgtga tgcacgaggc cctgcacaac cactacaccc agaagtccct gagcctgagc 1080
cccggcaagg gcggcatgaa gcgccagggc aaggagatgg acagcctgcg cttcctgtac 1140
gacggcatcc gcatccaggc cgaccaggcc cccgaggacc tggacatgga ggacaacgac 1200
atcatcgagg cccaccgcga gcagatcggc ggcggtggtg gtggttctgg tggcggagga 1260
tctggcggtg gtggatctgg gggaggtgga agtggtggcg gtggtagtgg tggtggcgga 1320
agcatgaagc gccagggcaa ggagatggac agcctgcgct tcctgtacga cggcatccgc 1380
atccaggccg accaggcccc cgaggacctg gacatggagg acaacgacat catcgaggcc 1440
caccgcgagc agatcggcgg cggcggcgac attcagatga cacagtcccc cacctccctg 1500
tctgccagcg tgggagatcg cgtgaccatt acctgcagag cctcccagtg gatcggcaac 1560
ctgctggatt ggtatcagca gaaacctggg gaggctccta aactgctgat ctattacgcc 1620
agcttcctgc agtccggcgt gccctctaga ttttccggcg gaggcttcgg cacagatttc 1680
acactgacca tctcatccct gcagcctgaa gattttgcca catattattg ccagcaggcc 1740
aaccctgccc ccctgacatt tggacaggga acaaaggtcg agatcaagcg cgagcctaag 1800
tcctgtgaca agacacacac atgccctccc tgcccagccc cagaactgct cggtggaccc 1860
tctgtgtttc tgtttccacc caagcctaag gatacactca tgatctccag aacacctgaa 1920
gtgacatgtg tggtcgtcga cgtgtcacat gaggatccag aagtcaagtt taactggtat 1980
gtggatgggg tcgaggtgca caatgccaaa acaaaacctc gggaagaaca gtataattcc 2040
acctatagag tcgtgtctgt gctcaccgtg ctccatcagg attggctcaa tgggaaagaa 2100
tacaaatgta aagtctctaa caaagccctg cccgctccta tcgaaaagac aatctccaag 2160
gccaaaggac agcctcgcga gcctcaggtc tacaccctgc caccttcccg cgaggaaatg 2220
acaaaaaatc aggtgtcact cacctgtctc gtgaaggggt tttacccctc cgacattgcc 2280
gtcgagtggg agtccaatgg acagcccgag aacaattata agacaacacc tcccgtcctg 2340
gactccgatg gatcattttt tctgtactcc aagctcaccg tcgataagtc cagatggcag 2400
cagggaaatg tcttttcctg ctccgtgatg catgaagctc tccacaatca ttacacacag 2460
aaaagcctgt ccctgtcccc cggcaagtga ctcgag 2496
<210> 81
<211> 2280
<212> DNA
<213> Artificial Sequence
<220>
<223> Nucleotide sequence encoding the protein complex comprising VEGF
and EGFR specific binding peptides #37
<400> 81
gaattcgcca ccatgggctg gtcctgcatc atcctgtttc tggtggccac cgccaccggc 60
gtgcactctg atatccagat gacccagagc cccagcagcc tgtctgcctc tgtgggcgac 120
agagtgacca tcacctgtcg ggccagccag aagatcttca acggcctgag ctggtatcag 180
cagaagcccg gcaaggcccc caagctgctg atctaccaca gcagcaccct gcagagcggc 240
gtgccaagca gattttctgg cagcggcagc ggcaccgact tcaccctgac aatcagcagc 300
ctgcagcccg aggacttcgc cacctactac tgccagcagg tcctgctgta cccctacacc 360
tttggccagg gcaccaaggt ggaaatcaag agagagccca agagctgcga caagacccac 420
acctgtcccc cttgtcctgc ccctgaactg ctgggaggcc ctagcgtgtt cctgttcccc 480
ccaaagccca aggacaccct gatgatcagc cggacccccg aagtgacctg cgtggtggtg 540
gatgtgtccc acgaggaccc tgaagtgaag ttcaattggt acgtggacgg cgtggaagtg 600
cacaacgcca agaccaagcc cagagaggaa cagtacaaca gcacctaccg ggtggtgtcc 660
gtgctgacag tgctgcacca ggactggctg aacggcaaag agtacaagtg caaggtgtcc 720
aacaaggccc tgcctgcccc catcgagaaa accatcagca aggccaaggg ccagcccaga 780
gaaccccagg tgtacacact gccccccagc agagaagaga tgaccaagaa ccaggtgtcc 840
ctgacctgcc tggtcaaggg cttctacccc agcgatatcg ccgtggaatg ggagagcaac 900
ggccagcctg agaacaacta caagaccacc ccccctgtgc tggacagcga cggctcattc 960
ttcctgtaca gcaagctgac cgtggacaag agccggtggc agcagggcaa cgtgttcagc 1020
tgcagcgtga tgcacgaggc cctgcacaac cactacaccc agaagtccct gagcctgagc 1080
cccggcaagg actacgacat ccccaccacc gagaacctgt acttccaggg cggtggtggt 1140
ggttctggtg gcggaggatc tggcggtggt ggatctgggg gaggtggaag tggtggcggt 1200
ggtagtggtg gtggcggaag cgagaacctg tacttccagg gctctggcgg cgacattcag 1260
atgacacagt cccccacctc cctgtctgcc agcgtgggag atcgcgtgac cattacctgc 1320
agagcctccc agtggatcgg caacctgctg gattggtatc agcagaaacc tggggaggct 1380
cctaaactgc tgatctatta cgccagcttc ctgcagtccg gcgtgccctc tagattttcc 1440
ggcggaggct tcggcacaga tttcacactg accatctcat ccctgcagcc tgaagatttt 1500
gccacatatt attgccagca ggccaaccct gcccccctga catttggaca gggaacaaag 1560
gtcgagatca agcgcgagcc taagtcctgt gacaagacac acacatgccc tccctgccca 1620
gccccagaac tgctcggtgg accctctgtg tttctgtttc cacccaagcc taaggataca 1680
ctcatgatct ccagaacacc tgaagtgaca tgtgtggtcg tcgacgtgtc acatgaggat 1740
ccagaagtca agtttaactg gtatgtggat ggggtcgagg tgcacaatgc caaaacaaaa 1800
cctcgggaag aacagtataa ttccacctat agagtcgtgt ctgtgctcac cgtgctccat 1860
caggattggc tcaatgggaa agaatacaaa tgtaaagtct ctaacaaagc cctgcccgct 1920
cctatcgaaa agacaatctc caaggccaaa ggacagcctc gcgagcctca ggtctacacc 1980
ctgccacctt cccgcgagga aatgacaaaa aatcaggtgt cactcacctg tctcgtgaag 2040
gggttttacc cctccgacat tgccgtcgag tgggagtcca atggacagcc cgagaacaat 2100
tataagacaa cacctcccgt cctggactcc gatggatcat tttttctgta ctccaagctc 2160
accgtcgata agtccagatg gcagcaggga aatgtctttt cctgctccgt gatgcatgaa 2220
gctctccaca atcattacac acagaaaagc ctgtccctgt cccccggcaa gtgactcgag 2280
2280
Claims (14)
- N-말단으로부터 제1 항원 결합 부위 및 제1 Fc(fragment crystallizable) 부위를 포함하는 제1 폴리펩티드;
N-말단으로부터 제2 항원 결합 부위 및 제2 Fc 부위를 포함하는 제2 폴리펩티드; 및
상기 제1 폴리펩티드 및 제2 폴리펩티드를 서로 연결하는 링커를 포함하는 것으로서,
상기 링커는 양 말단에 제1 태그 및 제2 태그를 포함하고,
상기 제1 태그는 상기 제1 폴리펩티드 제1 Fc 부위의 C-말단에, 상기 제2 태그는 상기 제2 폴리펩티드의 N-말단에 연결되며,
상기 제1 태그 및 제2 태그는 각각 절단 가능한 아미노산 서열을 포함하는 것인 이중 특이 항원 결합 단백질. - N-말단으로부터 제1 항원 결합 부위 및 제1 Fc 부위를 포함하는 제1 폴리펩티드;
N-말단으로부터 제2 항원 결합 부위 및 제2 Fc 부위를 포함하는 제2 폴리펩티드; 및
상기 제1 폴리펩티드 및 제2 폴리펩티드를 서로 연결하는 링커를 포함하는 것으로서,
상기 링커는 하나의 말단에 태그를 포함하고,
상기 태그는 상기 제1 폴리펩티드 제1 Fc 부위의 C-말단 또는 상기 제2 폴리펩티드의 N-말단에 연결되며, 절단 가능한 아미노산 서열을 포함하는 것인 이중 특이 항원 결합 단백질. - 청구항 1 또는 2에 있어서, 상기 항원 결합 부위를 포함하는 폴리펩티드는 Fab, Fab', Fv 및 scFv로 이루어진 군으로부터 선택되는 항체 단편의 중쇄(heavy chain) 또는 경쇄(light chain) 또는 단일-도메인 항체(single-domain antibody)인 것인 단백질.
- 청구항 1 또는 2에 있어서, 상기 태그는 유비퀴틴, 유비퀴틴-유사 단백질 및 TEV 절단 펩티드(TEV cleavage peptide)로 이루어진 군으로부터 선택되는 것인 단백질.
- 청구항 1 또는 2에 있어서, 상기 제1 항원 결합 부위 및 제2 항원 결합 부위는 서로 독립적으로, EpCAM, CCR5, CD19, HER-2 neu, HER-3, HER-4, EGFR, PSMA, CEA, MUC-1(뮤신), MUC2, MUC3, MUC4, MUC5 AC, MUC5 B, MUC7, βhCG, 루이스(Lewis)-Y, CD20, CD33, CD30, 강글리오사이드(ganglioside) GD3, 9-O-아세틸-GD3, GM2, 글로보(Globo) H, 푸코실(fucosyl) GM1, 폴리 SA, GD2, 카보안하이드라제(Carboanhydrase) IX (MN/CA IX), CD44v6, Sonic Hedgehog (Shh), Wue-1, 혈장 세포 항원(Plasma Cell Antigen), (막 결합) IgE, 멜라노마 콘드로이틴 술페이트 프로테오글리칸(Melanoma Chondroitin Sulfate Proteoglycan, MCSP), CCR8, TNF-알파 전구체, STEAP, 메소텔린(mesothelin), A33 항원, 전립선 줄기세포 항원(Prostate Stem Cell Antigen, PSCA), Ly-6; 데스모글레인(desmoglein) 4, E-카드헤린 네오에피토프(E-cadherin neoepitope), 태아 아세틸콜린 수용체(Fetal Acetylcholine Receptor), CD25, CA19-9 마커, CA-125 마커 및 뮐러 억제 물질(Muellerian Inhibitory Substance, MIS) Ⅱ형 수용체, sTn (시알화 Tn 항원; TAG-72), FAP (섬유아세포 활성화 항원), 엔도시알린(endosialin), EGFRvIII, LG, SAS 및 CD63으로 이루어진 군으로부터 선택되는 표적 항원에 특이적으로 결합되는 부위를 갖는 것인 단백질.
- 삭제
- 청구항 1 또는 2에 있어서, 상기 이중 특이 항원 결합 단백질은 서열번호 8 내지 서열번호 44로 이루어진 군으로부터 선택되는 아미노산 서열을 갖는 것인 단백질.
- 청구항 1 또는 2의 단백질을 코딩하는 폴리뉴클레오티드.
- 청구항 8에 있어서, 상기 폴리뉴클레오티드는 서열번호 45 내지 서열번호 81로 이루어진 군으로부터 선택되는 염기서열을 갖는 것인 폴리뉴클레오티드.
- 청구항 8의 폴리뉴클레오티드를 삽입시킨 재조합 발현 벡터를 구축하는 단계;
상기 재조합 발현 벡터로 숙주 세포를 형질전환시키는 단계;
상기 형질전환된 숙주 세포를 배양하는 단계; 및
상기 숙주 세포에서 발현된 이중 특이 항체를 회수하는 단계를 포함하는 이중 특이 항체의 제조 방법. - 삭제
- 삭제
- 삭제
- 삭제
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EP13190818.8A EP2727940A1 (en) | 2012-10-31 | 2013-10-30 | Bispecific antigen binding protein complex and preparation methods of bispecific antibodies |
JP2013225872A JP2014090721A (ja) | 2012-10-31 | 2013-10-30 | 二重特異性(bispecific)抗原結合蛋白質複合体及び二重特異性抗体の製造方法 |
CN201310529748.6A CN103788212A (zh) | 2012-10-31 | 2013-10-31 | 双特异性抗原结合蛋白复合物以及制备双特异性抗体的方法 |
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