KR20160123249A - 썬스크린 조성물 - Google Patents
썬스크린 조성물 Download PDFInfo
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- KR20160123249A KR20160123249A KR1020160045631A KR20160045631A KR20160123249A KR 20160123249 A KR20160123249 A KR 20160123249A KR 1020160045631 A KR1020160045631 A KR 1020160045631A KR 20160045631 A KR20160045631 A KR 20160045631A KR 20160123249 A KR20160123249 A KR 20160123249A
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- KR
- South Korea
- Prior art keywords
- leu
- ser
- val
- gly
- thr
- Prior art date
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Abstract
본 발명의 조성물은 자외선 (UV)을 흡수하기에 효과적인 양의 1차 UV-흡수제, 및 연속 실리카-함유 코팅을 포함하는 약 5% 이하의 가시광 방사선 제제를 함유하는 썬스크린 조성물을 포함한다.
Description
본 출원은 2015년 4월 15일자로 출원된 미국 가출원 제62/147676호의 이익을 주장하며, 이 미국 가출원의 개시 내용 전부가 이에 의해 모든 목적을 위하여 본 명세서에 참고로 포함된다.
본 발명은 피부에의 국소 적용에 적합한 썬스크린 조성물에 관한 것이며, 이 조성물은 자외광 (UV) 및 가시광 방사선에 의해 유발되는 피부 손상을 방지한다. 특히, 본 발명은 UV-흡수제 및 가시광 흡수제를 포함하는 썬스크린 조성물에 관한 것이다.
태양으로부터의 것과 같은 자외광 (UV) 및 가시광 방사선에 대한 장기간 노출은 광 피부병 및 홍반의 형성을 야기할 수 있을 뿐만 아니라, 흑색종과 같은 피부암의 위험을 증가시키고, 피부 탄력 상실 및 주름과 같은 피부 노화를 가속시킬 수 있다.
보다 구체적으로, 흔히 가시광으로 알려진 가시 방사선은 400 내지 760 nm의 태양 전자기 스펙트럼 범위의 부분이고, 지구 표면에 도달하는 총 태양 에너지의 대략 40%에 상당한다 (UV는 대략 3 내지 7%임). 인간 삶에 대한 그것의 주된 영향은 인간 망막의 자극, 및 적색 내지 자색 범위의 물체 색상들의 구별이다. 생물학적 응답 및 세포 배양 응답에 기초한 연구들은 가시광과 연관된 피부 손상이, UV 손상과 유사하게, 발색단에의 누적 효과로 인한 과다색소침착뿐만 아니라, 콜라겐 섬유 분해 및 새로운 섬유 합성의 억제를 초래할 수 있는 메탈로프로테이나아제 발현 및 DNA 손상으로 이어질 수 있는 활성 산소종(Reactive Oxygen Species) 형성을 유발한다는 것을 보여준다.
자외 및 가시 방사선의 해로운 영향으로부터 신체를 보호하는 다양한 능력을 가진 많은 국소 썬스크린 조성물이 구매가능하다. 그러나, 그러한 썬스크린 제형은 가시광으로부터 보호하는 데 효과적이지 않거나, 상대적으로 보다 높은 농도의 안료를 사용함으로써 착색된다. 피부를 착색시킴이 없이, UV 및 가시 방사선 둘 모두로부터의 보다 넓은 효과적인 보호를 제공하는 비-착색 썬스크린 조성물을 제공하려는 도전이 여전히 존재한다.
본 발명은, 피부를 착색시킴이 없이, 자외 (UV) 및 가시 방사선 둘 모두로부터 보호하는 데 효과적인 UV 및 가시 방사선 흡수제의 사용을 채용하는 신규한 썬스크린 조성물을 제공한다.
본 발명의 조성물은 자외 (UV) 방사선을 흡수하기에 효과적인 양의 1차 UV-흡수제 및 약 5% 이하의 가시광 흡수제를 포함하는 썬스크린 조성물을 포함한다. 가시광 흡수제는 연속 실리카-함유 코팅을 포함한다.
달리 정의되지 않으면, 본 명세서에서 사용된 모든 기술 용어 및 과학 용어는 본 발명이 속하는 기술 분야의 통상의 숙련자가 일반적으로 이해하는 것과 동일한 의미를 갖는다. 본 명세서에 사용된 바와 같이, 달리 지시되지 않으면, 모든 탄화수소 (예를 들어, 알킬, 알케닐) 기는 직쇄 또는 분지쇄 기일 수 있다. 본 명세서에 사용된 바와 같이, 달리 지시되지 않으면, 용어 "분자량"은 중량 평균 분자량 (Mw)을 말한다.
달리 정의되지 않으면, 모든 농도는 조성물의 중량 기준 농도를 말한다. 또한, 구체적으로 달리 정의되지 않으면, 한 부류의 성분들에 관한 용어 "본질적으로 부재하는"은 특정 성분이 이익 또는 특성을 제공하기에 효과적이기 위해 필요한 것보다 더 적은 농도로 특정 성분(들)이 존재함을 말하며, 이를 위해 그것은 달리, 예를 들어 약 1% 이하 또는 약 0.5% 이하로 사용될 것이다.
본 명세서에 사용된 바와 같이, "UV-흡수"는 자외 스펙트럼 (290 nm 내지 400 nm)의 일부 부분에서 방사선을 흡수하고(예컨대, 상기에 한정된 자외 스펙트럼 내의 적어도 하나의 파장에 대해, 약 1000 mol-1 cm-1 이상의 흡광 계수를 갖는 것), 반사 및/또는 굴절을 통해 UV 광 방사선으로부터의 추가의 보호를 제공하는 재료 또는 화합물, 예컨대 중합체 또는 비-중합체, 유기 또는 무기, 썬스크린제 또는 화학 모이어티(moiety)를 지칭한다.
본 명세서에 사용된 바와 같이, "가시광 흡수"는 가시 범위 (400 nm 내지 760 nm)의 일부 부분에서 방사선을 흡수하고(예컨대, 상기에 한정된 가시광 스펙트럼 내의 적어도 하나의 파장에 대해, 약 1000 mol-1 cm-1 이상의 흡광 계수를 갖는 것), 흡수, 반사 및/또는 굴절을 통해 가시광 방사선으로부터의 추가의 보호를 제공하는 재료 또는 화합물을 지칭한다. 본 명세서에 개시되고 청구되는 가시광 보호 등급 값은 하기에서 본 명세서에 기재되는 시험관내 방법을 사용하여 결정된다.
1차 UV-흡수제
본 발명의 실시 형태는 1차 UV-흡수제를 포함하는 조성물에 관한 것이다. 그러한 1차 UV-흡수제는 에틸헥실 트라이아존, 2-페닐벤즈이미다졸-5-설폰산, 비스-에틸헥실옥시페닐메톡시페닐 트라이아진, 다이소듐 페닐다이벤즈이미다졸 테트라설포네이트, 메틸렌 비스-벤조트라이아졸릴 테트라메틸부틸페놀, 다이에틸아미노 하이드록시 벤조일 헥실 벤조에이트, 및 실리카 코팅이 적용되지 않은 이산화티타늄 및/또는 산화아연을 포함할 수 있지만, 이에 제한되지 않는다. 본 발명의 소정 실시 형태에 따르면, 1차 UV-흡수제는 하기 화학식 I의 다이소듐 페닐다이벤즈이미다졸 테트라설포네이트이다:
[화학식 I]
1차 UV-흡수제는 하기에서 본 명세서에서 논의되는 UV-흡수 모이어티를 포함하고, 따라서 자외 스펙트럼 (290 nm 내지 400 nm)의 일부 부분에서 방사선을 흡수한다(예컨대, 상기에 한정된 자외 스펙트럼 내의 적어도 하나의 파장에 대해, 약 1000 mol-1 cm-1 이상, 예를 들어 10,000 또는 100,000 또는 1,000,000 mol-1 cm-1 초과의 흡광 계수를 갖는 것). 1차 UV 흡수 모이어티는 자외 스펙트럼의 주로 UVA 부분 (320 nm 내지 400 nm)에서 또는 주로 UV-B 부분 (290 nm 내지 320 nm)에서 흡수할 수 있다. 하나의 그러한 UV-흡수 모이어티는 UV-흡수 트라이아졸이다. "UV-흡수 트라이아졸"이라는 것은 2개의 탄소 원자 및 3개의 질소 원자를 갖는 5원 헤테로사이클릭 고리를 함유하는 UV-흡수 모이어티를 의미한다. 전형적인 UV-흡수 트라이아졸은 벤조트라이아졸이며, 이는 6원 호모사이클릭 방향족 고리와 융합된 전술한 5원 헤테로사이클릭 고리를 포함한다. UV-흡수제의 예에는, 예를 들어 다이소듐 페닐다이벤즈이미다졸이 포함된다.
가시광-흡수제
본 발명의 조성물은 가시광-흡수제를 포함한다. 그러한 가시광-흡수제는 무기 안료 입자, 예컨대 이산화티타늄, 산화아연, 및 소정의 다른 전이 금속 산화물을 포함한 소정의 무기 산화물을 포함한다. 본 발명의 소정 실시 형태에 따르면, 무기 안료 입자는 이산화티타늄 및 산화아연이고, 바람직하게는 이산화티타늄이다. 가시광-흡수제는 가시광 스펙트럼 (400 nm 내지 760nm)의 일부 부분에서 방사선을 흡수한다. 그러한 가시광 흡수제는 전형적으로 직경이 약 1 nm 내지 약 200 nm, 바람직하게는 약 5 내지 120 nm인 고체 입자이다.
본 발명의 조성물에 사용되는 가시광-흡수제는 실리카 필름으로 코팅된다. 하기에서 본 명세서에 나타난 바와 같이, 실리카로 코팅된 가시광-흡수 입자가 알루미나 시메티콘으로 코팅된 입자로 제조된 조성물보다 가시광의 반사가 통계적으로 상당히 더 나은 조성물을 제공한다는 것을 발견하였다. 따라서, 입자의 표면 상에 코팅된 실리카 필름에는 알루미나가 본질적으로 부재하거나, 알루미나가 부재한다. 안료 입자 상에 침착된 실리카 필름의 두께는 약 0.1 내지 약 100 nm, 바람직하게는 0.5 내지 25 nm일 수 있다. 실리카-필름-코팅된 안료 입자는 입자, 예를 들어 이산화티타늄을 수성 실리카 필름-형성 조성물에 침지시켜 이산화티타늄 입자 상에의 실리카의 침전에 의해 이산화티타늄의 표면 상에 실리카를 침착시킴으로써 형성될 수 있다. 실리카 필름은 기재 이산화티타늄과의 양호한 상용성을 갖고, 효과적인 피복 특성을 나타낸다. 실리카의 순수 무기 필름 (대략 17% 실리카)을 포함하는, 그러한 실리카-코팅된 이산화티타늄의 한 가지 예가 독일 소재의 메르크 카게아아(Merck KGaA)로부터 유솔렉스(Eusolex) T-AVO로 입수가능하다.
국소 조성물
일 실시 형태에서, 인체 (예를 들어, 피부, 모발, 입술, 또는 손발톱과 같은 케라틴성 표면), 특히 피부에 적용하기 위한 국소용/화장품 용도에 적합한 조성물이 제공된다. 조성물은 본 명세서에 기재된, 하나 이상의 1차 UV-흡수제 및 가시광-흡수 무기 안료 입자를 포함한다. 1차 UV-흡수제의 농도는, 하기에서 본 명세서에서 기재된 바와 같이, 2차 UV-흡수제의 부재하에 약 10 이상의 SPF를 제공하기에 충분하다. 따라서, 1차 UV-흡수제의 농도는 조성물의 약 1 중량% 내지 약 10 중량%, 예컨대 약 1.5 중량% 내지 약 4 중량%, 예컨대 조성물의 약 1.5 중량% 내지 약 3.0 중량%로 다양할 수 있다. 1차 UV-흡수제가 다이소듐 페닐다이벤즈이미다졸 테트라설포네이트로 본질적으로 이루어지는 소정 실시 형태에 따르면, 다이소듐 페닐다이벤즈이미다졸 테트라설포네이트의 농도는 약 1.0% 이상일 수 있다.
본 발명의 썬스크린 조성물에 함유되는 실리카-코팅된 가시광-흡수 무기 안료 입자의 농도는 효과적인 가시광 흡광도를 제공하기에 효과적인 수준으로 존재해야 하지만, 예를 들어 착색된 크림 또는 페인트에서와 같이, 조성물의 "착색"을 제공하는 데 흔히 사용되는 수준으로는 존재하지 않는다. 따라서, 농도는 약 5% 이하, 예컨대 약 0.5% 내지 약 2%, 예컨대 약 0.5% 내지 약 1%일 수 있다.
본 발명의 조성물은 2차 UV-흡수제를 추가로 포함할 수 있다. 예를 들어, 본 발명의 조성물은 약 1% 이상, 또는 약 1.5% 이상의 그러한 UV-흡수 썬스크린제를 함유할 것이다. 때때로 "단량체 유기 UV-흡수제"로 지칭되는 그러한 화합물의 예에는 메톡시신나메이트 유도체, 예컨대 옥틸 메톡시신나메이트 및 아이소아밀 메톡시신나메이트; 캄포르 유도체, 예컨대 4-메틸 벤질리덴 캄포르, 캄포르 벤잘코늄 메토설페이트, 및 테레프탈릴리덴 다이캄포르 설폰산; 살리실레이트 유도체, 예컨대 옥틸 살리실레이트, 트롤아민 살리실레이트, 및 호모살레이트; 설폰산 유도체, 예컨대, 페닐벤즈이미다졸 설폰산; 벤존 유도체, 예컨대, 다이옥시벤존, 설리소벤존, 및 옥시벤존; 벤조산 유도체, 예컨대 아미노벤조산 및 옥틸다이메틸 파라-아미노 벤조산; 옥토크릴렌 및 기타 β,β-다이페닐아크릴레이트; 다이옥틸 부타미도 트라이아존; 부틸 메톡시다이벤조일 메탄; 글리세릴 파라-아미노벤조산 (PABA); 다이갈로일 트라이올레에이트; 3,(4-5 메틸벤질리덴) 캄포르; 메틸 안트라닐레이트; 벤조페논-3; 벤조페논-4; 벤조페논-8; 시녹세이트; 옥토크릴렌; 에틸헥실 다이-메틸 파라-아미노벤조산, 드로메트라이졸 트라이실록산; 다이에틸헥실 부타미도 트라이아존; 및 폴리실리콘-15가 포함되지만, 이에 제한되지 않는다.
본 발명의 조성물은 다양한 화장품 용도에, 특히 UV 방사선 및 가시광 방사선으로부터의 피부의 보호에 사용될 수 있다. 따라서, 조성물은 매우 다양한 전달 형태로 만들어질 수 있다. 이러한 형태에는 현탁액, 분산액, 용액, 또는 수용성 또는 수불용성 기재 (예를 들어, 유기 또는 무기 분말, 섬유, 또는 필름과 같은 기재) 상의 코팅이 포함되지만, 이에 제한되지 않는다. 적합한 제품 형태에는 로션, 크림, 겔, 스틱, 스프레이, 연고, 무스, 및 콤팩트/파우더가 포함된다. 조성물은 다양한 최종 용도, 예컨대 휴양 또는 일상 용도 썬스크린, 모이스처라이저, 화장품/메이크-업, 클렌저/토너, 노화방지 제품, 또는 이들의 조합에 채용될 수 있다. 본 발명의 조성물은 화장품 제형 분야의 숙련자에 의해 잘 알려진 방법을 이용하여 제조될 수 있다.
본 발명의 조성물은 연속 수상을 포함하며, 그 안에 불연속 오일상이 실질적으로 균질하게 분포된다. UV-흡수제 및/또는 가시광 흡수제는 수상 또는 오일상 내에 함유될 수 있다. 소정 실시 형태에서, UV-흡수제는 오일상 내에, 분산되거나 현탁되는 것과는 반대로, 용해된다. 오일상은 결국 수상 내에서 안정화될 수 있다. 오일상은 이것이 약 1 마이크로미터 내지 약 1000 마이크로미터, 예컨대 약 1 마이크로미터 내지 약 100 마이크로미터의 평균 직경을 갖는 별개의 소적(droplet)들 또는 단위들로 존재하게 하는 것일 수 있다.
국소 담체
조성물 중의 하나 이상의 1차 UV-흡수제 및 가시광 흡수 무기 안료 입자는 "화장품용으로-허용가능한 국소 담체", 즉 다른 성분들이 그 안에 분산되거나 용해될 수 있고, 국소적으로 사용하는 것을 안전하게 만드는 허용가능한 특성을 보유할 수 있는 국소 사용을 위한 담체와 조합된다. 그렇기 때문에, 본 조성물은 화장품 화학 분야에 공지된 임의의 다양한 기능성 성분들, 예를 들어, 연화제 (오일 및 왁스를 포함)뿐만 아니라, 개인 케어 조성물에 일반적으로 사용되는 다른 성분들, 예를 들어, 다른 기능성 성분들 중에서도 습윤제, 증점제, 유백제, 방향제, 염료, UV-흡수 폴리에스테르를 위한 용매를 추가로 포함할 수 있다. UV-흡수 폴리에스테르를 위한 용매의 적합한 예에는 미국 펜실베이니아주 앰블러 소재의 코그니스 코포레이션(Cognis Corporation)으로부터 세티올(CETIOL) CC로 입수가능한 다이카프릴릴 카르보네이트가 포함된다.
쾌적한 심미감을 제공하기 위해, 본 발명의 소정 실시 형태에서, 조성물에는 휘발성 용매, 특히 C1-C4 알코올, 예컨대 에탄올 및 아이소프로판올이 본질적으로 부재한다. 더욱이, 본 조성물에는 조성물을 국소 사용에 부적합하게 만들 성분들이 본질적으로 부재할 수 있다. 그렇기 때문에, 본 조성물에는 용매, 예컨대 휘발성 용매가 본질적으로 부재할 수 있으며, 특히, 휘발성 유기 용매, 예컨대 케톤, 자일렌, 톨루엔 등이 부재할 수 있다.
필름-형성 중합체
본 발명의 조성물은 필름 형성 중합체를 포함한다. 필름-형성 중합체는, 하나 이상의 희석제에 용해되거나, 유화되거나, 분산된 경우, 이것을 액체 비히클과 함께 매끄러운 기재, 예를 들어, 유리 상에 펴 바르고 액체 비히클을 증발시킬 때, 연속 또는 반-연속 필름이 형성되게 할 수 있다. 그렇기 때문에, 중합체는 그것이 펴 발라진 영역 위에서 필름이 복수의 분리된 섬(island)-유사 구조를 갖기보다는 주로 연속적인 방식으로 유리 상에서 건조될 수 있다. 본 명세서에 기재된 본 발명의 실시 형태에 따라 피부 상에 조성물을 적용함으로써 형성되는 필름은 두께가 평균 약 100 마이크로미터 미만, 예컨대 약 50 마이크로미터 미만일 수 있다.
중합체 UV-흡수제 및 가시광 흡수 무기 안료 입자와는 대조적으로, 필름-형성 중합체는 일반적으로 상당한 자외광 또는 가시광 방사선을 흡수하지는 않는다. 그러나, 필름 형성을 개선함으로써, 필름-형성 중합체는 조성물의 UV- 및 가시광 보호 (UV-A, UV-B 또는 둘 모두)를 향상시킬 수 있고/있거나 조성물의 방수성 또는 내수성을 향상시킬 수 있다.
필름-형성 중합체는 알킬화 폴리비닐피롤리돈, 예컨대 비닐피롤리돈과 α-올레핀의 공중합체, 예컨대 비닐피롤리돈과 장쇄 (예를 들어, C16 내지 C30) α-올레핀의 공중합체, 예를 들어 가넥스(GANEX) V220, 가넥스 V216, 가넥스 WP660일 수 있다. 특히 주목할 만한 하나의 실시 형태에서, 필름-형성 중합체는 가넥스 V216과 같은, 20% 비닐 피롤리돈 및 80% C16 올레핀 (1-헥사데센)으로부터 형성된다. 가넥스 필름-형성 중합체는 미국 뉴저지주 웨인 소재의 아이에스피 스페셜티 케미칼스(ISP Specialty Chemicals) (현재, 애쉬랜드 스페셜티 인그래디언츠(Ashland Specialty Ingredients))로부터 구매가능하다.
본 발명의 조성물은, 다당류 또는 단백질과 같은 천연 중합체, 및 폴리에스테르, 폴리아크릴, 폴리우레탄, 비닐 중합체, 폴리설포네이트, 폴리우레아, 폴리옥사졸린 등과 같은 합성 중합체를 비롯한, 추가의 필름-형성 중합체를 포함할 수 있다. 추가의 필름-형성 중합체의 구체적인 예에는, 예를 들어 미국 펜실베이니아주 앰블러 소재의 코그니스 코포레이션으로부터 코스메디아(COSMEDIA) DC로 입수가능한 수소화 이량체 다이리놀레일/다이메틸카르보네이트 공중합체; 및 이스트만 케미칼(EASTMAN Chemical)로부터 이스트만(EASTMAN) AQ 38S로 구매가능한 것과 같은 설포폴리에스테르를 비롯한 수분산성 폴리에스테르가 포함된다.
조성물에 존재하는 필름-형성 중합체의 양은 약 0.1% 내지 약 5%, 또는 약 0.3% 내지 약 3%, 또는 약 1% 내지 약 2.5%일 수 있다.
수중유 유화제
본 발명의 조성물은 음이온성 유화제 및 비-이온성 유화제로 이루어진 군으로부터 선택되는 하나 이상의 수중유 (O/W) 유화제를 포함한다. "유화제"라는 것은, 연속 수상 중에 별개의 오일상 소적들을 유화시키기에 적합한 임의의 다양한 분자를 의미한다. "저분자량 유화제"라는 것은, 분자량이 약 2000 달톤(dalton) 이하, 예컨대 약 1000 달톤 이하인 유화제를 의미한다. O/W 유화제는, 실온에서 0.5% 이하의 O/W 유화제의 농도로 순수 탈이온수에 첨가될 때 순수 탈이온수의 표면 장력을 45 다인(dyne)/cm로 낮추는 것이 가능할 수 있다. O/W 유화제는 친수-친유 평형 (HLB)이 약 8 이상, 예컨대 약 10 이상일 수 있다.
소정 실시 형태에서, 조성물은 하나 이상의 음이온성 유화제를 포함한다. 적합한 화학적 부류의 음이온성 유화제의 예는 하기 모이어티의 알킬, 아릴 또는 알킬아릴, 또는 아실-개질된 변형(version)이다: 설페이트, 에테르 설페이트, 모노글리세릴 에테르 설페이트, 설포네이트, 설포석시네이트, 에테르 설포석시네이트, 설포석시나메이트, 아미도설포석시네이트, 카르복실레이트, 아미도에테르카르복실레이트, 석시네이트, 사르코시네이트, 아미노산, 타우레이트, 설포아세테이트, 및 포스페이트. 주목할 만한 음이온성 유화제는 인산과 세틸 알코올의 에스테르의 염, 예컨대 인산과 세틸 알코올의 에스테르의 혼합물의 포타슘 염 (예를 들어, 1-헥사데칸올, 다이하이드로겐 포스페이트, 모노포타슘 염)이다. 한 가지 주목할 만한 예는 독일 홀츠민덴 소재의 심라이즈(Symrise)로부터 에멀시포스(EMULSIPHOS)로 입수가능한, 포타슘 세틸 포스페이트, 수소화 팜 글리세라이드이다.
소정 실시 형태에서, 하나 이상의 음이온성 유화제의 농도는 약 0.5% 내지 약 6%, 예컨대 약 1% 내지 약 4%, 예컨대 약 1% 내지 약 2.5%이다.
본 발명의 다른 실시 형태에서, 조성물은 하나 이상의 비-이온성 유화제를 포함한다. 비-이온성 유화제의 예에는 지방 아미드, 모노글리세라이드; 소르비탄 에스테르; 폴리올 에스테르의 폴리옥시에틸렌 유도체; 알킬 글루코사이드 또는 폴리글루코사이드; 폴리글리세릴 에스테르; 비-가교결합된 실리콘 공중합체, 예컨대 알콕시 또는 알킬 다이메티콘 코폴리올, 펜던트 친수성 모이어티를 갖는 실리콘, 예컨대 펜던트 폴리에테르 기 또는 폴리글리세린 기를 갖는 선형 실리콘; 하나 이상의 친수성 모이어티를 포함하는 가교결합된 탄성중합체 고형 유기폴리실록산; 폴리에틸렌 글리콜, 폴리프로필렌 글리콜 또는 폴리글리세릴 에스테르가 포함된다. 일 실시 형태에 따르면, 비-이온성 유화제는 알코올 작용기를 갖지 않는다. 본 발명의 일 실시 형태에 따르면, 비-이온성 유화제는 분자량이 약 10,000 달톤 이하, 예컨대 약 7000 달톤 이하이다.
일 실시 형태에 따르면, 비-이온성 계면활성제는 지방산의 에스테르, 예컨대 다양한 포화 또는 불포화, 선형 또는 분지형 C7-C22 비에톡실화 지방족 산이다. 지방산은 14 내지 약 22개의 탄소 원자, 예컨대 약 16 내지 약 18개의 탄소 원자를 가질 수 있다. 일 실시 형태에 따르면, 비-이온성 유화제는 글리세롤의 지방산 에스테르 (예컨대, 글리세릴 스테아레이트), 폴리에틸렌 글리콜 지방산 에스테르 (예컨대, PEG-100 스테아레이트), 및 이들의 조합으로부터 선택되는 것과 같은 폴리에테르이다.
구체적으로, 25℃에서 광유와 함께 겔을 형성할 수 있는 중합체와 같은 오일-겔화 중합체는 비-이온성 계면활성제로부터 배제되는데, 예컨대 그 오일-겔화 중합체가 약 0.25 중량% 내지 2.0 중량% 사이인 오일-겔화 중합체의 농도로 광유와 혼합될 때, 생성되는 혼합물은 약 5 파스칼(Pa) 이상, 예컨대 약 10 Pa 이상, 예컨대 약 10 Pa 내지 약 1100 Pa의 항복 응력을 갖는다. 오일-겔화 중합체의 예는 아세탈 결합에 의해 함께 연결된 무수글루코스 단위들로 이루어진 장쇄 중합체를 포함하는 셀룰로오스의 에틸 에테르인, 에틸셀룰로오스와 같은, C2-C4 알킬셀룰로오스 중합체이다. 오일-겔화 중합체의 다른 예는 다이부틸 에틸헥사노일 글루타미드 및 다이부틸 라우로일 글루타미드이다.
비-이온성 유화제의 농도는 또한 약 1% 내지 약 10%, 예컨대 약 2% 내지 약 6%, 예컨대 약 2% 내지 약 4%의 범위일 수 있다.
소정 실시 형태에서, 상기에 논의된 유화제(들)에 더하여, 본 조성물은 추가의 유화제, 예컨대 양쪽성 유화제, 양이온성 유화제, 및/또는 중합체 유화제 중 하나 이상을 포함한다. 적합한 화학적 부류의 양쪽성 유화제의 예에는 알킬 베타인, 아미도알킬 베타인, 알킬암포아세테이트; 아미도알킬 설테인; 암포포스페이트; 포스포릴화 이미다졸린; 카르복시알킬 알킬 폴리아민; 알킬이미노-다이프로피오네이트; 알킬암포글리시네이트 (모노 또는 다이); 알킬암포프로프리오네이트; N-알킬 β-아미노프로프리온산; 및 알킬폴리아미노 카르복실레이트가 포함된다. 적합한 화학적 부류의 양이온성 유화제의 예에는 알킬 4차물(quaternary), 벤질 4차물, 에스테르 4차물, 에톡실화 4차물, 및 알킬 아민이 포함된다. 적합한 화학적 부류의 중합체 유화제의 예에는 아크릴아미도알킬 설폰산에 기초한 공중합체, 예컨대 클래리언트 코포레이션(Clariant Corporation)에 의한 아리스토플렉스(Aristoflex)(등록상표) AVC 및 아리스토플렉스(등록상표) HMB; 및 그랜트 인더스트리즈, 인크.(Grant Industries, Inc.)에 의한 그랜틱스(Granthix) APP가 포함된다.
소정 실시 형태에서, 본 조성물은 건조 방지 또는 완화 및 피부 보호를 위해서뿐만 아니라 UV-흡수 폴리에스테르를 가용화시키기 위해 사용되는 연화제를 포함한다. 적합한 연화제에는 광유, 바셀린, 식물유 (예를 들어, 카프릴릭/카프릭 트라이글리세라이드와 같은 트라이글리세라이드), 글리세롤의 에스테르를 포함하지만 이에 한정되지 않는 지방 에스테르들 (예를 들어, 아이소프로필 팔미테이트, 아이소프로필 미리스테이트)의 기타 혼합물 및 왁스, 및 다이메티콘과 같은 실리콘 오일이 포함된다. 소정 실시 형태에서, 트라이글리세라이드 (예를 들어, 카프릴릭/카프릭 트라이글리세라이드)와 글리콜의 에스테르 (예를 들어, 아이소프로필 미리스테이트)의 혼합물을 사용하여 UV-흡수제 및 가시광 흡수 무기 안료 입자를 가용화시킬 수 있다.
소정 실시 형태에서, 본 조성물은 색 또는 은폐력(hiding power)을 제공하기에 적합한 안료를 포함한다. 안료는 모발, 손발톱, 및/또는 피부, 특히 안면에 적용하기 위한 조성물을 포함한, 색조 화장품 제품에 사용하기에 적합한 것일 수 있다. 색조 화장품 조성물에는, 파운데이션, 컨실러, 프라이머, 블러시, 마스카라, 아이셰도우, 아이라이너, 립스틱, 매니큐어, 및 착색 모이스처라이저가 포함되지만 이로 한정되지 않는다.
색 또는 은폐력을 제공하기에 적합한 안료는, 적색 및 황색 산화철을 포함한 산화철, 이산화티타늄, 울트라마린 및 크롬 또는 수산화크롬 컬러, 및 이들의 혼합물로 구성될 수 있다. 안료는 레이크 안료, 예를 들어, 불용성 염과 같은 불활성 결합제 상에 침전된, D&C 및 FD&C 블루, 브라운, 그린, 오렌지, 레드, 옐로우 등으로 불리는, 아조, 인디고, 트라이페닐메탄, 안트라퀴논, 및 잔틴 염료와 같은 유기 염료일 수 있다. 레이크 안료의 예에는 레드 #6, 레드 #7, 옐로우 #5 및 블루 #1이 포함된다. 안료는 간섭 안료일 수 있다. 간섭 안료의 예에는 운모 기재, 비스무트 옥시클로라이드 기재, 및 실리카 기재를 함유하는 것, 예를 들어, 크로마라이트(CHROMALITE) 안료 (바스프(BASF))로 구매가능한 운모/비스무트 옥시클로라이드/산화철 안료, 운모 상에 코팅된 이산화티타늄 및/또는 산화철, 예컨대 구매가능한 플라멘코(FLAMENCO) 안료 (바스프), 구매가능한 KTZ 안료 (코보 프로덕츠(Kobo products))를 포함한 운모/이산화티타늄/산화철 안료, 셀리니(CELLINI) 펄 안료 (바스프), 및 보로실리케이트-함유 안료, 예컨대 레플렉스(REFLECKS) 안료 (바스프)가 포함된다.
본 발명의 조성물은 하나 이상의 다른 화장품용 활성제(들)를 추가로 포함할 수 있다. "화장품용 활성제"는 피부에 미용 또는 치료 효과를 나타내는 화합물, 예를 들어 주름, 여드름을 치료하는 제제 또는 피부를 미백하는 제제이다. 화장품용 활성제는 전형적으로 조성물의 약 0.001 중량% 내지 약 20 중량%, 예를 들어 조성물의 약 0.01 중량% 내지 약 10 중량%, 예컨대 약 0.1 중량% 내지 약 5 중량%의 양으로 본 발명의 조성물에 존재할 것이다.
소정의 실시 형태에서, 조성물은 약 4.0 내지 약 8.0, 예컨대 약 6.5 내지 약 7.7인 pH를 갖는다.
본 발명의 조성물은 당업자에 의해 잘 알려진 혼합 및 블렌딩 방법을 이용하여 제조될 수 있다. 본 발명의 일 실시 형태에서, 본 발명의 조성물을 제조하는 방법은 적어도 UV-흡수제 및 가시광 흡수 무기 안료 입자를 선택적인 오일-용해성 또는 오일-혼화성 성분과 혼합함으로써 오일상을 제조하는 단계; 및 물과 선택적인 수용성 또는 수-혼화성 성분을 혼합함으로써 수상을 제조하는 단계를 포함한다. 이어서, 오일상 및 수상을, 수상이 연속상이 되고 오일상이 불연속상이 되도록 수상 중에 오일상을 실질적으로 균질하게 분산시키기에 충분한 방식으로 혼합할 수 있다.
본 발명의 조성물은 포유류에 국소 투여함으로써, 예를 들어 인간의 피부 또는 모발 상에 조성물을 직접적으로 둠으로써, 와이핑함으로써 또는 펴 바름으로써 사용될 수 있다.
하기 방법을 가시광 보호 유효성의 평가 및 하기 실시예에서 사용하였다.
실시예
하기 실시예는 본 발명의 조성물의 제조 및 효능을 예시한다.
화장품용 제형에 의해 제공되는 가시광 보호 유효성의 평가 방법
샘플 제조
잔여물이 플레이트 전체에 걸쳐 관찰되지 않을 때까지 글리세린 또는 광유 0.2 mL를 플레이트 상에 펴 바름으로써 블랭크 PMMA (폴리-메틸 메타-아크릴레이트) 플레이트를 제조하였다. 칭량 전에 제형을 충분히 진탕시켰다. 적용된 때 최종 농도가 2 mg/㎠가 되게 하기에 충분한 양으로 제형을 시린지에 로딩하였다. 이어서, 제형을 균일한 소적들로서 새로운 PMMA 플레이트의 넓은 표면 위에 분배하였다. 소적들 간의 공간은 가능한 한 균일하였다. 이어서, 제형의 소적들을, 넓은 PMMA 플레이트 표면 위에서 검지를 작은 원 운동으로 움직여 10초 안에 PMMA 플레이트의 표면 전체에 걸쳐 펴 발라 연속 필름을 형성하였다. 플레이트를 90° 회전시키고, 손가락을 오른쪽 및 왼쪽으로 5초 동안 이동시켰다. 그 후에, 플레이트를 다시 90° 회전시켰다. 이러한 2단계의 회전 및 손가락 이동을 한 번 반복하여 20초의 펴 바름 및 4회의 90° 회전을 달성하였다. 각 제형의 복제물 3개를 제조하였다.
장비 설정:
이 방법을 위해, 제논 아크 램프 (솔라 라이트 컴퍼니(Solar Light Co.)에 의해 제조됨, 모델 601 - 램프 출력 300 W)를 구비한 다중포트 태양 시뮬레이터(multiport solar simulator)를 사용하였다. 가시광 및 UV광 필터를 태양 시뮬레이터로부터 제거하여, 이색성 거울만이 설치된 상태로 두었고; 적외 (IR) 방사선을 필터링할 수 있었다. 200 내지 800 nm 파장 범위에 걸쳐 정확한 스펙트럼 측정을 제공할 수 있는 분광복사기(spectroradiometer) (옵트로닉 래버러토리즈(Optronic laboratories)에 의해 제조됨, 모델 OL65A, 적분구(integrating sphere)를 구비함)를, 태양 시뮬레이터로부터의 태양 방사선 방사 조도를 측정하는 데 사용하였다. 6개의 태양 시뮬레이터 도광체 중 하나를 샘플 격실(compartment)에 연결하고, 이를 적분구에 연결하였다. 다른 5개의 도광체는 폐쇄하였다. 실험을 위한 원하는 파장 범위, 예를 들어 250 내지 800 nm를 1 nm의 증분으로 분광복사기에서 선택하였다.
판독:
글리세린을 갖는 각각의 PMMA 플레이트를 샘플 격실 내에 배치하고, 원하는 방사선 범위, 예를 들어 400 내지 760에 걸쳐 스펙트럼을 수집하였다. 샘플을 갖는 PMMA 플레이트를 샘플 격실 내에 배치하고, 원하는 방사선 범위, 예를 들어 400 내지 760 nm에 걸쳐 스펙트럼을 수집하였다. 이러한 단계를 모든 복제물에서 반복하였다. 가시 범위 (400 내지 760 nm) 내의 곡선 아래의 면적을, 글리세린을 갖는 블랭크를 포함한 모든 평가된 샘플에 대해 결정하였다. 샘플에 의해 필터링된 가시광 방사선의 수준은, 샘플에 대해 획득된 면적 평균 값을 블랭크에 대해 획득된 면적 평균 값으로 나눈 것에 상응한다.
하기 실시예는 본 발명의 소정 조성물의 가시광 흡수를 예시한다. 본 발명의 조성물 (E1 및 E2)은 1차 UV-흡수제 및 가시광 흡수 무기 안료 입자를 포함하고, 알킬화 폴리비닐피롤리돈뿐만 아니라 음이온성 또는 비-이온성 유화제를 추가로 포함한다. 이러한 본 발명의 실시예 및 비교예를 하기에 기재된 과정에 의해 제조하였다.
수상: 물, 다이소듐 EDTA, 카르보머(Carbomer) 및 아크릴레이트/C10-30 알킬 아크릴레이트 크로스폴리머(Crosspolymer)를 첨가한다. 전체 분산까지 균질화를 시작한다 (4000 RPM 내지 6000 RPM). 혼합을 시작하고 수산화나트륨을 첨가하고, 혼합하에서 페닐벤즈이미다졸 설폰산, 다이소듐 페닐 다이벤즈이미다졸 테트라설포네이트 및 글리세린을 첨가한다. 82℃ 내지 85℃까지 배치(batch)를 가열하기 시작한다.
오일상: 별개의 용기에서, 비스-에틸헥실옥시페놀 메톡시페닐 트라이아진, 부틸 메톡시다이벤조일메탄, 옥토크릴렌, 호모살레이트, 에틸헥실 트라이아존, 트라이콘타닐 PVP, 세틸 팔미테이트, 카프릴릴 메티콘, 토코페릴 아세테이트, 페녹시에탄올, 다이아이소프로필 아디페이트, 다이아이소프로필 세바케이트, 다이소듐 세테아릴 설포석시네이트, 세테아릴 알코올; 세테아릴 글루코사이드, 다이메티콘; 세테아릴 다이메티콘 크로스폴리머, 다이메티콘, 아이소노닐 아이소노나노에이트를 첨가한다. 82℃ 내지 85℃까지 배치를 가열하기 시작한다.
오일상과 수상을 혼합하고, 배치를 냉각하기 시작한다. 혼합하에서 메틸렌 비스-벤조트라이아졸릴 테트라메틸부틸페놀, 이눌린 라우릴 카르바메이트 및 하이드록시에틸 아크릴레이트/소듐 아크릴로일다이메틸 타우레이트 공중합체; 아이소헥사데칸; 폴리소르베이트 60을 첨가한다.
배치를 40℃로 냉각하고, 에틸헥실글리세린, 벤질 알코올, 글리신 소야 시드(Glycine Soya Seed) 추출물, 카프릴로일 글리신; 사르코신; 신나모뮴 제일라니쿰(Cinnamomum Zeylanicum) 추출물, 이산화티타늄; 실리카, 알루미늄 스타치 옥테닐석시네이트, 2종류의 실리카와 나일론-12를 첨가한다.
3분 동안 균질화기를 통과시킨다 (4000 RPM 내지 6000 RPM).
[표 1]
[표 2]
본 발명의 실시예 1 (E1)은 비교예 1 (C1)에 비해 가시광으로부터의 보호에 관하여 상당한 유효성을 나타내는데, 즉 E1의 경우 가시광 감소율 44% 대 비교예 (C1)의 경우 가시광 감소율 14% 이다.
[표 3]
본 발명의 실시예 1 (E1)은 비교예 2 (C2)에 비해 가시광으로부터의 보호에 관하여 필적하는 유효성을 나타내는데, 즉 E1의 경우 가시광 감소율 42.9% 대 비교예 (C2)의 경우 가시광 감소율 53.6% 이다. 비교예 2 (C2)는 착색된 제형이고, 이는 많은 양의 이산화티타늄과 무기 안료의 조합으로 인해 가시광으로부터 보호하는 것으로 인식된다. 본 발명의 실시예 1 (E1)은, 비-착색되었음에도 불구하고, 가시광 방사선으로부터의 유사한 보호를 나타낸다. 표 3에 나타낸 바와 같이, 본 발명의 실시예 1은 단지 1%의 이산화티타늄 (실리카로 코팅됨)을 함유하는 반면, 착색된 제형의 비교예 2는 20% 초과의 안료 화합물 (대략 12%의 활성 안료 함량으로 이해됨)을 함유한다. 본 발명의 실시예 1은 가시광 보호를 증가시키는 데 효과적인 것으로 보인다.
[표 4]
이산화티타늄 (실리카로 코팅됨) 및 1차 UVA 필터 다이소듐 페닐 다이벤즈이미다졸 테트라설포네이트 (DPDT)를 함유하는 본 발명의 실시예 2는, 이산화티타늄 (실리카로 코팅됨)도 UVA 필터 다이소듐 페닐 다이벤즈이미다졸 테트라설포네이트 (DPDT)도 함유하지 않는 비교예 3, 또는 단지 UVA 필터 다이소듐 페닐 다이벤즈이미다졸 테트라설포네이트 (DPDT)만을 함유하는 비교예 4에 비해 가시광 보호에 있어서 보다 상당한 개선을 나타낸다.
[표 5]
이산화티타늄 (실리카로 코팅됨) 및 UVA 필터 다이소듐 페닐 다이벤즈이미다졸 테트라설포네이트 (DPDT)를 함유하는 본 발명의 실시예 1은, 이산화티타늄 (알루미나 시메티콘으로 코팅됨)을 함유하는 비교예 5에 비해 우수한 가시광 보호를 나타낸다.
[표 6]
가시광 보호에 대한 증가 효과를 전달하는 데 관여하는 것으로 확인된 주된 핵심적인 성분은 UV-흡수제, 다이소듐 페닐 다이벤즈이미다졸 테트라설포네이트, 및 실리카로 코팅된 이산화티타늄이다.
[표 7]
[표 8]
SEQUENCE LISTING
<110> Janssen Biotech, Inc.
Jacobs, Steven
Goldberg, Shalom
Lin, Tricia
O'Neil, Karyn
<120> CYSTEINE ENGINEERED FIBRONECTIN TYPE III DOMAIN BINDING MOLECULES
<130> JBI5039WOPCT
<140> To Be Assigned
<141> 2014-10-13
<150> 61/890,539
<151> 2013-10-14
<160> 265
<170> PatentIn version 3.5
<210> 1
<211> 89
<212> PRT
<213> Artificial Sequence
<220>
<223> Tencon FN3 scaffold
<400> 1
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Leu Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Asn Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val Lys Gly Gly His Arg Ser
65 70 75 80
Asn Pro Leu Ser Ala Glu Phe Thr Thr
85
<210> 2
<211> 58
<212> DNA
<213> Artificial Sequence
<220>
<223> primer
<400> 2
ggaaacagga tctaccatgc tgccggcgcc gaaaaacctg gttgtttctg aagttacc 58
<210> 3
<211> 21
<212> DNA
<213> Artificial Sequence
<220>
<223> primer
<400> 3
aacaccgtag atagaaacgg t 21
<210> 4
<211> 131
<212> DNA
<213> Artificial Sequence
<220>
<223> primer
<400> 4
cggcggttag aacgcggcta caattaatac ataaccccat ccccctgttg acaattaatc 60
atcggctcgt ataatgtgtg gaattgtgag cggataacaa tttcacacag gaaacaggat 120
ctaccatgct g 131
<210> 5
<211> 21
<212> DNA
<213> Artificial Sequence
<220>
<223> primer
<400> 5
cggcggttag aacgcggcta c 21
<210> 6
<211> 66
<212> DNA
<213> Artificial Sequence
<220>
<223> primer
<220>
<221> misc_feature
<222> (26)..(27)
<223> n is a, c, g, or t
<220>
<221> misc_feature
<222> (29)..(30)
<223> n is a, c, g, or t
<220>
<221> misc_feature
<222> (32)..(33)
<223> n is a, c, g, or t
<220>
<221> misc_feature
<222> (35)..(36)
<223> n is a, c, g, or t
<220>
<221> misc_feature
<222> (38)..(39)
<223> n is a, c, g, or t
<220>
<221> misc_feature
<222> (41)..(42)
<223> n is a, c, g, or t
<220>
<221> misc_feature
<222> (44)..(45)
<223> n is a, c, g, or t
<400> 6
ggtggtgaat tccgcagaca gcggsnnsnn snnsnnsnns nnsnnaacac cgtagataga 60
aacggt 66
<210> 7
<211> 69
<212> DNA
<213> Artificial Sequence
<220>
<223> primer
<220>
<221> misc_feature
<222> (26)..(27)
<223> n is a, c, g, or t
<220>
<221> misc_feature
<222> (29)..(30)
<223> n is a, c, g, or t
<220>
<221> misc_feature
<222> (32)..(33)
<223> n is a, c, g, or t
<220>
<221> misc_feature
<222> (35)..(36)
<223> n is a, c, g, or t
<220>
<221> misc_feature
<222> (38)..(39)
<223> n is a, c, g, or t
<220>
<221> misc_feature
<222> (41)..(42)
<223> n is a, c, g, or t
<220>
<221> misc_feature
<222> (44)..(45)
<223> n is a, c, g, or t
<220>
<221> misc_feature
<222> (47)..(48)
<223> n is a, c, g, or t
<400> 7
ggtggtgaat tccgcagaca gcggsnnsnn snnsnnsnns nnsnnsnnaa caccgtagat 60
agaaacggt 69
<210> 8
<211> 72
<212> DNA
<213> Artificial Sequence
<220>
<223> primer
<220>
<221> misc_feature
<222> (26)..(27)
<223> n is a, c, g, or t
<220>
<221> misc_feature
<222> (29)..(30)
<223> n is a, c, g, or t
<220>
<221> misc_feature
<222> (32)..(33)
<223> n is a, c, g, or t
<220>
<221> misc_feature
<222> (35)..(36)
<223> n is a, c, g, or t
<220>
<221> misc_feature
<222> (38)..(39)
<223> n is a, c, g, or t
<220>
<221> misc_feature
<222> (41)..(42)
<223> n is a, c, g, or t
<220>
<221> misc_feature
<222> (44)..(45)
<223> n is a, c, g, or t
<220>
<221> misc_feature
<222> (47)..(48)
<223> n is a, c, g, or t
<220>
<221> misc_feature
<222> (50)..(51)
<223> n is a, c, g, or t
<400> 8
ggtggtgaat tccgcagaca gcggsnnsnn snnsnnsnns nnsnnsnnsn naacaccgta 60
gatagaaacg gt 72
<210> 9
<211> 75
<212> DNA
<213> Artificial Sequence
<220>
<223> primer
<220>
<221> misc_feature
<222> (26)..(27)
<223> n is a, c, g, or t
<220>
<221> misc_feature
<222> (29)..(30)
<223> n is a, c, g, or t
<220>
<221> misc_feature
<222> (32)..(33)
<223> n is a, c, g, or t
<220>
<221> misc_feature
<222> (35)..(36)
<223> n is a, c, g, or t
<220>
<221> misc_feature
<222> (38)..(39)
<223> n is a, c, g, or t
<220>
<221> misc_feature
<222> (41)..(42)
<223> n is a, c, g, or t
<220>
<221> misc_feature
<222> (44)..(45)
<223> n is a, c, g, or t
<220>
<221> misc_feature
<222> (47)..(48)
<223> n is a, c, g, or t
<220>
<221> misc_feature
<222> (50)..(51)
<223> n is a, c, g, or t
<220>
<221> misc_feature
<222> (53)..(54)
<223> n is a, c, g, or t
<400> 9
ggtggtgaat tccgcagaca gcggsnnsnn snnsnnsnns nnsnnsnnsn nsnnaacacc 60
gtagatagaa acggt 75
<210> 10
<211> 80
<212> DNA
<213> Artificial Sequence
<220>
<223> primer
<220>
<221> misc_feature
<222> (28)..(29)
<223> n is a, c, g, or t
<220>
<221> misc_feature
<222> (31)..(32)
<223> n is a, c, g, or t
<220>
<221> misc_feature
<222> (34)..(35)
<223> n is a, c, g, or t
<220>
<221> misc_feature
<222> (37)..(38)
<223> n is a, c, g, or t
<220>
<221> misc_feature
<222> (40)..(41)
<223> n is a, c, g, or t
<220>
<221> misc_feature
<222> (43)..(44)
<223> n is a, c, g, or t
<220>
<221> misc_feature
<222> (46)..(47)
<223> n is a, c, g, or t
<220>
<221> misc_feature
<222> (49)..(50)
<223> n is a, c, g, or t
<220>
<221> misc_feature
<222> (52)..(53)
<223> n is a, c, g, or t
<220>
<221> misc_feature
<222> (55)..(56)
<223> n is a, c, g, or t
<220>
<221> misc_feature
<222> (58)..(59)
<223> n is a, c, g, or t
<400> 10
rmggtggtga attccgcaga cagcggsnns nnsnnsnnsn nsnnsnnsnn snnsnnsnna 60
acaccgtaga tagaaacggt 80
<210> 11
<211> 81
<212> DNA
<213> Artificial Sequence
<220>
<223> primer
<220>
<221> misc_feature
<222> (26)..(27)
<223> n is a, c, g, or t
<220>
<221> misc_feature
<222> (29)..(30)
<223> n is a, c, g, or t
<220>
<221> misc_feature
<222> (32)..(33)
<223> n is a, c, g, or t
<220>
<221> misc_feature
<222> (35)..(36)
<223> n is a, c, g, or t
<220>
<221> misc_feature
<222> (38)..(39)
<223> n is a, c, g, or t
<220>
<221> misc_feature
<222> (41)..(42)
<223> n is a, c, g, or t
<220>
<221> misc_feature
<222> (44)..(45)
<223> n is a, c, g, or t
<220>
<221> misc_feature
<222> (47)..(48)
<223> n is a, c, g, or t
<220>
<221> misc_feature
<222> (50)..(51)
<223> n is a, c, g, or t
<220>
<221> misc_feature
<222> (53)..(54)
<223> n is a, c, g, or t
<220>
<221> misc_feature
<222> (56)..(57)
<223> n is a, c, g, or t
<220>
<221> misc_feature
<222> (59)..(60)
<223> n is a, c, g, or t
<400> 11
ggtggtgaat tccgcagaca gcggsnnsnn snnsnnsnns nnsnnsnnsn nsnnsnnsnn 60
aacaccgtag atagaaacgg t 81
<210> 12
<211> 81
<212> DNA
<213> Artificial Sequence
<220>
<223> primer
<400> 12
aagatcagtt gcggccgcta gactagaacc gctgccatgg tgatggtgat ggtgaccgcc 60
ggtggtgaat tccgcagaca g 81
<210> 13
<211> 30
<212> DNA
<213> Artificial Sequence
<220>
<223> primer
<400> 13
cggcggttag aacgcggcta caattaatac 30
<210> 14
<211> 22
<212> DNA
<213> Artificial Sequence
<220>
<223> primer
<400> 14
catgattacg ccaagctcag aa 22
<210> 15
<211> 65
<212> DNA
<213> Artificial Sequence
<220>
<223> primer
<400> 15
gagccgccgc caccggttta atggtgatgg tgatggtgac caccggtggt gaattccgca 60
gacag 65
<210> 16
<211> 37
<212> DNA
<213> Artificial Sequence
<220>
<223> primer
<400> 16
aagaaggaga accggtatgc tgccggcgcc gaaaaac 37
<210> 17
<211> 89
<212> DNA
<213> Artificial Sequence
<220>
<223> primer
<400> 17
tttgggaagc ttctaggtct cggcggtcac catcaccatc accatggcag cggttctagt 60
ctagcggccc caactgatct tcaccaaac 89
<210> 18
<211> 94
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain
<400> 18
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Leu Arg Leu Ser Trp Ala Asp Pro His Gly Phe Tyr Asp Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Asn Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Glu Phe Thr Thr
85 90
<210> 19
<211> 94
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain
<400> 19
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Leu Arg Leu Ser Trp Thr Tyr Asp Arg Asp Gly Tyr Asp Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Asn Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Glu Phe Thr Thr
85 90
<210> 20
<211> 94
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain
<400> 20
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Leu Arg Leu Ser Trp Gly Tyr Asn Gly Asp His Phe Asp Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Asn Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Glu Phe Thr Thr
85 90
<210> 21
<211> 94
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain
<400> 21
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Leu Arg Leu Ser Trp Asp Asp Pro Arg Gly Phe Tyr Glu Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Asn Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Glu Phe Thr Thr
85 90
<210> 22
<211> 94
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain
<400> 22
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Leu Arg Leu Ser Trp Thr Trp Pro Tyr Ala Asp Leu Asp Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Asn Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Glu Phe Thr Thr
85 90
<210> 23
<211> 94
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain
<400> 23
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Leu Arg Leu Ser Trp Gly Tyr Asn Gly Asp His Phe Asp Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Asn Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Glu Phe Thr Thr
85 90
<210> 24
<211> 95
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain
<400> 24
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Leu Arg Leu Ser Trp Asp Tyr Asp Leu Gly Val Tyr Phe Asp Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Asn Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Glu Phe Thr Thr
85 90 95
<210> 25
<211> 94
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain
<400> 25
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Leu Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Asn Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Glu Phe Thr Thr
85 90
<210> 26
<211> 94
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain
<400> 26
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Leu Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Asn Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val Leu Gly Ser Tyr Val Phe
65 70 75 80
Glu His Asp Val Met Leu Pro Leu Ser Ala Glu Phe Thr Thr
85 90
<210> 27
<211> 94
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain
<400> 27
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr
85 90
<210> 28
<211> 94
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain
<400> 28
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val Leu Gly Ser Tyr Val Phe
65 70 75 80
Glu His Asp Val Met Leu Pro Leu Ser Ala Ile Phe Thr Thr
85 90
<210> 29
<211> 94
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain
<400> 29
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Leu Arg Leu Ser Trp Thr Trp Pro Tyr Ala Asp Leu Asp Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Asn Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Glu Phe Thr Thr
85 90
<210> 30
<211> 37
<212> PRT
<213> Artificial Sequence
<220>
<223> primer
<400> 30
Ala Ala Gly Ala Ala Gly Gly Ala Gly Ala Ala Cys Cys Gly Gly Thr
1 5 10 15
Ala Thr Gly Cys Thr Gly Cys Cys Gly Gly Cys Gly Cys Cys Gly Ala
20 25 30
Ala Ala Ala Ala Cys
35
<210> 31
<211> 65
<212> PRT
<213> Artificial Sequence
<220>
<223> primer
<400> 31
Gly Ala Gly Cys Cys Gly Cys Cys Gly Cys Cys Ala Cys Cys Gly Gly
1 5 10 15
Thr Thr Thr Ala Ala Thr Gly Gly Thr Gly Ala Thr Gly Gly Thr Gly
20 25 30
Ala Thr Gly Gly Thr Gly Ala Cys Cys Ala Cys Cys Gly Gly Thr Gly
35 40 45
Gly Thr Gly Ala Ala Gly Ala Thr Cys Gly Cys Ala Gly Ala Cys Ala
50 55 60
Gly
65
<210> 32
<211> 89
<212> PRT
<213> Artificial Sequence
<220>
<223> c-Met binding FN3 domain
<400> 32
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe Trp
20 25 30
Ile Arg Tyr Asp Glu Val Val Val Gly Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Tyr Val Asn Ile Leu Gly Val Lys Gly Gly Ser Ile Ser
65 70 75 80
Val Pro Leu Ser Ala Ile Phe Thr Thr
85
<210> 33
<211> 89
<212> PRT
<213> Artificial Sequence
<220>
<223> c-Met binding FN3 domain
<400> 33
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe Phe
20 25 30
Ile Arg Tyr Asp Glu Phe Leu Arg Ser Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Trp Val Thr Ile Leu Gly Val Lys Gly Gly Leu Val Ser
65 70 75 80
Thr Pro Leu Ser Ala Ile Phe Thr Thr
85
<210> 34
<211> 89
<212> PRT
<213> Artificial Sequence
<220>
<223> c-Met binding FN3 domain
<400> 34
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe Trp
20 25 30
Ile Arg Tyr Phe Glu Phe Leu Gly Ser Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Ile Val Asn Ile Met Gly Val Lys Gly Gly Ser Ile Ser
65 70 75 80
His Pro Leu Ser Ala Ile Phe Thr Thr
85
<210> 35
<211> 89
<212> PRT
<213> Artificial Sequence
<220>
<223> c-Met binding FN3 domain
<400> 35
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe Trp
20 25 30
Ile Arg Tyr Phe Glu Phe Leu Gly Ser Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Val Val Asn Ile Leu Gly Val Lys Gly Gly Gly Leu Ser
65 70 75 80
Val Pro Leu Ser Ala Ile Phe Thr Thr
85
<210> 36
<211> 89
<212> PRT
<213> Artificial Sequence
<220>
<223> c-Met binding FN3 domain
<400> 36
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe Val
20 25 30
Ile Arg Tyr Phe Glu Phe Leu Gly Ser Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Val Val Gln Ile Leu Gly Val Lys Gly Gly Tyr Ile Ser
65 70 75 80
Ile Pro Leu Ser Ala Ile Phe Thr Thr
85
<210> 37
<211> 89
<212> PRT
<213> Artificial Sequence
<220>
<223> c-Met binding FN3 domain
<400> 37
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe Trp
20 25 30
Ile Arg Tyr Leu Glu Phe Leu Leu Gly Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Val Val Gln Ile Met Gly Val Lys Gly Gly Thr Val Ser
65 70 75 80
Pro Pro Leu Ser Ala Ile Phe Thr Thr
85
<210> 38
<211> 89
<212> PRT
<213> Artificial Sequence
<220>
<223> c-Met binding FN3 domain
<400> 38
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe Trp
20 25 30
Ile Arg Tyr Phe Glu Phe Leu Gly Ser Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Val Val Gly Ile Asn Gly Val Lys Gly Gly Tyr Ile Ser
65 70 75 80
Tyr Pro Leu Ser Ala Ile Phe Thr Thr
85
<210> 39
<211> 89
<212> PRT
<213> Artificial Sequence
<220>
<223> c-Met binding FN3 domain
<400> 39
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe Trp
20 25 30
Ile Arg Tyr Phe Glu Phe Leu Gly Ser Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Asp Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Gly Val Thr Ile Asn Gly Val Lys Gly Gly Arg Val Ser
65 70 75 80
Thr Pro Leu Ser Ala Ile Phe Thr Thr
85
<210> 40
<211> 89
<212> PRT
<213> Artificial Sequence
<220>
<223> c-Met binding FN3 domain
<400> 40
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe Trp
20 25 30
Ile Arg Tyr Phe Glu Phe Leu Gly Ser Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Val Val Gln Ile Ile Gly Val Lys Gly Gly His Ile Ser
65 70 75 80
Leu Pro Leu Ser Ala Ile Phe Thr Thr
85
<210> 41
<211> 89
<212> PRT
<213> Artificial Sequence
<220>
<223> c-Met binding FN3 domain
<400> 41
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe Trp
20 25 30
Ile Arg Tyr Phe Glu Phe Leu Gly Ser Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Val Val Asn Ile Met Gly Val Lys Gly Gly Lys Ile Ser
65 70 75 80
Pro Pro Leu Ser Ala Ile Phe Thr Thr
85
<210> 42
<211> 89
<212> PRT
<213> Artificial Sequence
<220>
<223> c-Met binding FN3 domain
<400> 42
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe Trp
20 25 30
Ile Arg Tyr Phe Glu Phe Leu Gly Ser Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Ala Val Asn Ile Met Gly Val Lys Gly Gly Arg Val Ser
65 70 75 80
Val Pro Leu Ser Ala Ile Phe Thr Thr
85
<210> 43
<211> 89
<212> PRT
<213> Artificial Sequence
<220>
<223> c-Met binding FN3 domain
<400> 43
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe Trp
20 25 30
Ile Arg Tyr Phe Glu Phe Leu Gly Ser Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Val Val Gln Ile Leu Gly Val Lys Gly Gly Ser Ile Ser
65 70 75 80
Val Pro Leu Ser Ala Ile Phe Thr Thr
85
<210> 44
<211> 89
<212> PRT
<213> Artificial Sequence
<220>
<223> c-Met binding FN3 domain
<400> 44
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe Trp
20 25 30
Ile Arg Tyr Phe Glu Phe Leu Gly Ser Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Val Val Asn Ile Met Gly Val Lys Gly Gly Ser Ile Ser
65 70 75 80
Tyr Pro Leu Ser Ala Ile Phe Thr Thr
85
<210> 45
<211> 89
<212> PRT
<213> Artificial Sequence
<220>
<223> c-Met binding FN3 domain
<400> 45
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe Trp
20 25 30
Ile Arg Tyr Phe Glu Phe Leu Gly Ser Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Val Val Gln Ile Leu Gly Val Lys Gly Gly Tyr Ile Ser
65 70 75 80
Ile Pro Leu Ser Ala Ile Phe Thr Thr
85
<210> 46
<211> 89
<212> PRT
<213> Artificial Sequence
<220>
<223> c-Met binding FN3 domain
<400> 46
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe Trp
20 25 30
Ile Arg Tyr Phe Glu Phe Leu Gly Ser Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Val Val Gln Ile Met Gly Val Lys Gly Gly Thr Val Ser
65 70 75 80
Pro Pro Leu Ser Ala Ile Phe Thr Thr
85
<210> 47
<211> 89
<212> PRT
<213> Artificial Sequence
<220>
<223> c-Met binding FN3 domain
<400> 47
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe Trp
20 25 30
Ile Arg Tyr Phe Glu Phe Thr Thr Ala Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Val Val Asn Ile Met Gly Val Lys Gly Gly Ser Ile Ser
65 70 75 80
Pro Pro Leu Ser Ala Ile Phe Thr Thr
85
<210> 48
<211> 89
<212> PRT
<213> Artificial Sequence
<220>
<223> c-Met binding FN3 domain
<400> 48
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe Trp
20 25 30
Ile Arg Tyr Phe Glu Leu Leu Ser Thr Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Val Val Asn Ile Met Gly Val Lys Gly Gly Ser Ile Ser
65 70 75 80
Pro Pro Leu Ser Ala Ile Phe Thr Thr
85
<210> 49
<211> 89
<212> PRT
<213> Artificial Sequence
<220>
<223> c-Met binding FN3 domain
<400> 49
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe Trp
20 25 30
Ile Arg Tyr Phe Glu Phe Val Ser Lys Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Val Val Asn Ile Met Gly Val Lys Gly Gly Ser Ile Ser
65 70 75 80
Pro Pro Leu Ser Ala Ile Phe Thr Thr
85
<210> 50
<211> 205
<212> PRT
<213> Artificial Sequence
<220>
<223> bispecific EGFR/cMet binding molecule
<400> 50
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Gly
85 90 95
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
100 105 110
Gly Gly Ser Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val
115 120 125
Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe
130 135 140
Asp Ser Phe Trp Ile Arg Tyr Asp Glu Val Val Val Gly Gly Glu Ala
145 150 155 160
Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly
165 170 175
Leu Lys Pro Gly Thr Glu Tyr Tyr Val Asn Ile Leu Gly Val Lys Gly
180 185 190
Gly Ser Ile Ser Val Pro Leu Ser Ala Ile Phe Thr Thr
195 200 205
<210> 51
<211> 204
<212> PRT
<213> Artificial Sequence
<220>
<223> bispecific EGFR/cMet binding molecule
<400> 51
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Gly
85 90 95
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
100 105 110
Gly Gly Ser Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr
115 120 125
Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp
130 135 140
Ser Phe Trp Ile Arg Tyr Phe Glu Phe Leu Gly Ser Gly Glu Ala Ile
145 150 155 160
Val Leu Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu
165 170 175
Lys Pro Gly Thr Glu Tyr Val Val Asn Ile Met Gly Val Lys Gly Gly
180 185 190
Lys Ile Ser Pro Pro Leu Ser Ala Ile Phe Thr Thr
195 200
<210> 52
<211> 205
<212> PRT
<213> Artificial Sequence
<220>
<223> bispecific EGFR/cMet binding molecule
<400> 52
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Gly
85 90 95
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
100 105 110
Gly Gly Ser Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val
115 120 125
Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe
130 135 140
Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe Leu Gly Ser Gly Glu Ala
145 150 155 160
Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly
165 170 175
Leu Lys Pro Gly Thr Glu Tyr Val Val Gln Ile Ile Gly Val Lys Gly
180 185 190
Gly His Ile Ser Leu Pro Leu Ser Ala Ile Phe Thr Thr
195 200 205
<210> 53
<211> 205
<212> PRT
<213> Artificial Sequence
<220>
<223> bispecific EGFR/cMet binding molecule
<400> 53
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Gly
85 90 95
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
100 105 110
Gly Gly Ser Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val
115 120 125
Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe
130 135 140
Asp Ser Phe Phe Ile Arg Tyr Asp Glu Phe Leu Arg Ser Gly Glu Ala
145 150 155 160
Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly
165 170 175
Leu Lys Pro Gly Thr Glu Tyr Trp Val Thr Ile Leu Gly Val Lys Gly
180 185 190
Gly Leu Val Ser Thr Pro Leu Ser Ala Ile Phe Thr Thr
195 200 205
<210> 54
<211> 205
<212> PRT
<213> Artificial Sequence
<220>
<223> bispecific EGFR/cMet binding molecule
<400> 54
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Ala Asp Pro His Gly Phe Tyr Asp Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Gly
85 90 95
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
100 105 110
Gly Gly Ser Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val
115 120 125
Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe
130 135 140
Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe Leu Gly Ser Gly Glu Ala
145 150 155 160
Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly
165 170 175
Leu Lys Pro Gly Thr Glu Tyr Val Val Asn Ile Met Gly Val Lys Gly
180 185 190
Gly Lys Ile Ser Pro Pro Leu Ser Ala Ile Phe Thr Thr
195 200 205
<210> 55
<211> 205
<212> PRT
<213> Artificial Sequence
<220>
<223> bispecific EGFR/cMet binding molecule
<400> 55
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Ala Asp Pro His Gly Phe Tyr Asp Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Gly
85 90 95
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
100 105 110
Gly Gly Ser Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val
115 120 125
Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe
130 135 140
Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe Leu Gly Ser Gly Glu Ala
145 150 155 160
Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly
165 170 175
Leu Lys Pro Gly Thr Glu Tyr Val Val Gln Ile Ile Gly Val Lys Gly
180 185 190
Gly His Ile Ser Leu Pro Leu Ser Ala Ile Phe Thr Thr
195 200 205
<210> 56
<211> 205
<212> PRT
<213> Artificial Sequence
<220>
<223> bispecific EGFR/cMet binding molecule
<400> 56
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Ala Asp Pro His Gly Phe Tyr Asp Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Gly
85 90 95
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
100 105 110
Gly Gly Ser Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val
115 120 125
Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe
130 135 140
Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe Leu Gly Ser Gly Glu Ala
145 150 155 160
Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly
165 170 175
Leu Lys Pro Gly Thr Glu Tyr Val Val Gln Ile Ile Gly Val Lys Gly
180 185 190
Gly His Ile Ser Leu Pro Leu Ser Ala Ile Phe Thr Thr
195 200 205
<210> 57
<211> 194
<212> PRT
<213> Artificial Sequence
<220>
<223> bispecific EGFR/cMet binding molecule
<400> 57
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala
85 90 95
Pro Ala Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu
100 105 110
Val Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala
115 120 125
Pro Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe Leu
130 135 140
Gly Ser Gly Glu Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser
145 150 155 160
Tyr Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu Tyr Val Val Asn Ile
165 170 175
Met Gly Val Lys Gly Gly Lys Ile Ser Pro Pro Leu Ser Ala Ile Phe
180 185 190
Thr Thr
<210> 58
<211> 194
<212> PRT
<213> Artificial Sequence
<220>
<223> bispecific EGFR/cMet binding molecule
<400> 58
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala
85 90 95
Pro Ala Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu
100 105 110
Val Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala
115 120 125
Pro Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Asp Glu Val Val
130 135 140
Val Gly Gly Glu Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser
145 150 155 160
Tyr Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu Tyr Tyr Val Asn Ile
165 170 175
Leu Gly Val Lys Gly Gly Ser Ile Ser Val Pro Leu Ser Ala Ile Phe
180 185 190
Thr Thr
<210> 59
<211> 195
<212> PRT
<213> Artificial Sequence
<220>
<223> bispecific EGFR/cMet binding molecule
<400> 59
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Ala Asp Pro His Gly Phe Tyr Asp Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala
85 90 95
Pro Ala Pro Ala Pro Ala Pro Ala Pro Met Leu Pro Ala Pro Lys Asn
100 105 110
Leu Val Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr
115 120 125
Ala Pro Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe
130 135 140
Leu Gly Ser Gly Glu Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg
145 150 155 160
Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu Tyr Val Val Asn
165 170 175
Ile Met Gly Val Lys Gly Gly Lys Ile Ser Pro Pro Leu Ser Ala Ile
180 185 190
Phe Thr Thr
195
<210> 60
<211> 194
<212> PRT
<213> Artificial Sequence
<220>
<223> bispecific EGFR/cMet binding molecule
<400> 60
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Ala Asp Pro His Gly Phe Tyr Asp Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala
85 90 95
Pro Ala Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu
100 105 110
Val Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala
115 120 125
Pro Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Asp Glu Val Val
130 135 140
Val Gly Gly Glu Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser
145 150 155 160
Tyr Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu Tyr Tyr Val Asn Ile
165 170 175
Leu Gly Val Lys Gly Gly Ser Ile Ser Val Pro Leu Ser Ala Ile Phe
180 185 190
Thr Thr
<210> 61
<211> 194
<212> PRT
<213> Artificial Sequence
<220>
<223> bispecific EGFR/cMet binding molecule
<400> 61
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Ile Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala
85 90 95
Pro Ala Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu
100 105 110
Val Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala
115 120 125
Pro Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe Leu
130 135 140
Gly Ser Gly Glu Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser
145 150 155 160
Tyr Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu Tyr Val Val Asn Ile
165 170 175
Leu Gly Val Lys Gly Gly Lys Ile Ser Pro Pro Leu Ser Ala Ile Phe
180 185 190
Thr Thr
<210> 62
<211> 194
<212> PRT
<213> Artificial Sequence
<220>
<223> bispecific EGFR/cMet binding molecule
<400> 62
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Ile Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala
85 90 95
Pro Ala Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu
100 105 110
Val Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala
115 120 125
Pro Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe Val
130 135 140
Gly Ser Gly Glu Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser
145 150 155 160
Tyr Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu Tyr Val Val Asn Ile
165 170 175
Leu Gly Val Lys Gly Gly Ser Ile Ser Pro Pro Leu Ser Ala Ile Phe
180 185 190
Thr Thr
<210> 63
<211> 194
<212> PRT
<213> Artificial Sequence
<220>
<223> bispecific EGFR/cMet binding molecule
<400> 63
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Ile Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala
85 90 95
Pro Ala Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu
100 105 110
Val Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala
115 120 125
Pro Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe Val
130 135 140
Ser Lys Gly Asp Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser
145 150 155 160
Tyr Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu Tyr Val Val Asn Ile
165 170 175
Leu Gly Val Lys Gly Gly Ser Ile Ser Pro Pro Leu Ser Ala Ile Phe
180 185 190
Thr Thr
<210> 64
<211> 194
<212> PRT
<213> Artificial Sequence
<220>
<223> bispecific EGFR/cMet binding molecule
<400> 64
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Ile Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala
85 90 95
Pro Ala Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu
100 105 110
Val Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala
115 120 125
Pro Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe Leu
130 135 140
Gly Ser Gly Glu Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser
145 150 155 160
Tyr Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu Tyr Val Val Asn Ile
165 170 175
Leu Ser Val Lys Gly Gly Ser Ile Ser Pro Pro Leu Ser Ala Ile Phe
180 185 190
Thr Thr
<210> 65
<211> 194
<212> PRT
<213> Artificial Sequence
<220>
<223> bispecific EGFR/cMet binding molecule
<400> 65
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro His Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Ile Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala
85 90 95
Pro Ala Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu
100 105 110
Val Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala
115 120 125
Pro Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe Leu
130 135 140
Gly Ser Gly Glu Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser
145 150 155 160
Tyr Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu Tyr Val Val Asn Ile
165 170 175
Leu Gly Val Lys Gly Gly Lys Ile Ser Pro Pro Leu Ser Ala Ile Phe
180 185 190
Thr Thr
<210> 66
<211> 194
<212> PRT
<213> Artificial Sequence
<220>
<223> bispecific EGFR/cMet binding molecule
<400> 66
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro His Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Ile Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala
85 90 95
Pro Ala Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu
100 105 110
Val Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala
115 120 125
Pro Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe Val
130 135 140
Gly Ser Gly Glu Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser
145 150 155 160
Tyr Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu Tyr Val Val Asn Ile
165 170 175
Leu Gly Val Lys Gly Gly Ser Ile Ser Pro Pro Leu Ser Ala Ile Phe
180 185 190
Thr Thr
<210> 67
<211> 194
<212> PRT
<213> Artificial Sequence
<220>
<223> bispecific EGFR/cMet binding molecule
<400> 67
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro His Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Ile Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala
85 90 95
Pro Ala Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu
100 105 110
Val Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala
115 120 125
Pro Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe Val
130 135 140
Ser Lys Gly Asp Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser
145 150 155 160
Tyr Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu Tyr Val Val Asn Ile
165 170 175
Leu Gly Val Lys Gly Gly Ser Ile Ser Pro Pro Leu Ser Ala Ile Phe
180 185 190
Thr Thr
<210> 68
<211> 194
<212> PRT
<213> Artificial Sequence
<220>
<223> bispecific EGFR/cMet binding molecule
<400> 68
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro His Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Ile Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala
85 90 95
Pro Ala Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu
100 105 110
Val Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala
115 120 125
Pro Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe Leu
130 135 140
Gly Ser Gly Glu Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser
145 150 155 160
Tyr Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu Tyr Val Val Asn Ile
165 170 175
Leu Ser Val Lys Gly Gly Ser Ile Ser Pro Pro Leu Ser Ala Ile Phe
180 185 190
Thr Thr
<210> 69
<211> 194
<212> PRT
<213> Artificial Sequence
<220>
<223> bispecific EGFR/cMet binding molecule
<400> 69
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Ala Asp Pro His Gly Phe Tyr Asp Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Ile Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala
85 90 95
Pro Ala Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu
100 105 110
Val Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala
115 120 125
Pro Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe Leu
130 135 140
Gly Ser Gly Glu Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser
145 150 155 160
Tyr Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu Tyr Val Val Asn Ile
165 170 175
Leu Gly Val Lys Gly Gly Lys Ile Ser Pro Pro Leu Ser Ala Ile Phe
180 185 190
Thr Thr
<210> 70
<211> 194
<212> PRT
<213> Artificial Sequence
<220>
<223> bispecific EGFR/cMet binding molecule
<400> 70
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Ala Asp Pro His Gly Phe Tyr Asp Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Ile Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala
85 90 95
Pro Ala Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu
100 105 110
Val Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala
115 120 125
Pro Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe Val
130 135 140
Gly Ser Gly Glu Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser
145 150 155 160
Tyr Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu Tyr Val Val Asn Ile
165 170 175
Leu Gly Val Lys Gly Gly Ser Ile Ser Pro Pro Leu Ser Ala Ile Phe
180 185 190
Thr Thr
<210> 71
<211> 194
<212> PRT
<213> Artificial Sequence
<220>
<223> bispecific EGFR/cMet binding molecule
<400> 71
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Ala Asp Pro His Gly Phe Tyr Asp Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Ile Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala
85 90 95
Pro Ala Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu
100 105 110
Val Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala
115 120 125
Pro Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe Val
130 135 140
Ser Lys Gly Asp Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser
145 150 155 160
Tyr Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu Tyr Val Val Asn Ile
165 170 175
Leu Gly Val Lys Gly Gly Ser Ile Ser Pro Pro Leu Ser Ala Ile Phe
180 185 190
Thr Thr
<210> 72
<211> 194
<212> PRT
<213> Artificial Sequence
<220>
<223> bispecific EGFR/cMet binding molecule
<400> 72
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Ala Asp Pro His Gly Phe Tyr Asp Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Ile Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala
85 90 95
Pro Ala Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu
100 105 110
Val Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala
115 120 125
Pro Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe Leu
130 135 140
Gly Ser Gly Glu Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser
145 150 155 160
Tyr Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu Tyr Val Val Asn Ile
165 170 175
Leu Ser Val Lys Gly Gly Ser Ile Ser Pro Pro Leu Ser Ala Ile Phe
180 185 190
Thr Thr
<210> 73
<211> 1210
<212> PRT
<213> HOMO SAPIENS
<400> 73
Met Arg Pro Ser Gly Thr Ala Gly Ala Ala Leu Leu Ala Leu Leu Ala
1 5 10 15
Ala Leu Cys Pro Ala Ser Arg Ala Leu Glu Glu Lys Lys Val Cys Gln
20 25 30
Gly Thr Ser Asn Lys Leu Thr Gln Leu Gly Thr Phe Glu Asp His Phe
35 40 45
Leu Ser Leu Gln Arg Met Phe Asn Asn Cys Glu Val Val Leu Gly Asn
50 55 60
Leu Glu Ile Thr Tyr Val Gln Arg Asn Tyr Asp Leu Ser Phe Leu Lys
65 70 75 80
Thr Ile Gln Glu Val Ala Gly Tyr Val Leu Ile Ala Leu Asn Thr Val
85 90 95
Glu Arg Ile Pro Leu Glu Asn Leu Gln Ile Ile Arg Gly Asn Met Tyr
100 105 110
Tyr Glu Asn Ser Tyr Ala Leu Ala Val Leu Ser Asn Tyr Asp Ala Asn
115 120 125
Lys Thr Gly Leu Lys Glu Leu Pro Met Arg Asn Leu Gln Glu Ile Leu
130 135 140
His Gly Ala Val Arg Phe Ser Asn Asn Pro Ala Leu Cys Asn Val Glu
145 150 155 160
Ser Ile Gln Trp Arg Asp Ile Val Ser Ser Asp Phe Leu Ser Asn Met
165 170 175
Ser Met Asp Phe Gln Asn His Leu Gly Ser Cys Gln Lys Cys Asp Pro
180 185 190
Ser Cys Pro Asn Gly Ser Cys Trp Gly Ala Gly Glu Glu Asn Cys Gln
195 200 205
Lys Leu Thr Lys Ile Ile Cys Ala Gln Gln Cys Ser Gly Arg Cys Arg
210 215 220
Gly Lys Ser Pro Ser Asp Cys Cys His Asn Gln Cys Ala Ala Gly Cys
225 230 235 240
Thr Gly Pro Arg Glu Ser Asp Cys Leu Val Cys Arg Lys Phe Arg Asp
245 250 255
Glu Ala Thr Cys Lys Asp Thr Cys Pro Pro Leu Met Leu Tyr Asn Pro
260 265 270
Thr Thr Tyr Gln Met Asp Val Asn Pro Glu Gly Lys Tyr Ser Phe Gly
275 280 285
Ala Thr Cys Val Lys Lys Cys Pro Arg Asn Tyr Val Val Thr Asp His
290 295 300
Gly Ser Cys Val Arg Ala Cys Gly Ala Asp Ser Tyr Glu Met Glu Glu
305 310 315 320
Asp Gly Val Arg Lys Cys Lys Lys Cys Glu Gly Pro Cys Arg Lys Val
325 330 335
Cys Asn Gly Ile Gly Ile Gly Glu Phe Lys Asp Ser Leu Ser Ile Asn
340 345 350
Ala Thr Asn Ile Lys His Phe Lys Asn Cys Thr Ser Ile Ser Gly Asp
355 360 365
Leu His Ile Leu Pro Val Ala Phe Arg Gly Asp Ser Phe Thr His Thr
370 375 380
Pro Pro Leu Asp Pro Gln Glu Leu Asp Ile Leu Lys Thr Val Lys Glu
385 390 395 400
Ile Thr Gly Phe Leu Leu Ile Gln Ala Trp Pro Glu Asn Arg Thr Asp
405 410 415
Leu His Ala Phe Glu Asn Leu Glu Ile Ile Arg Gly Arg Thr Lys Gln
420 425 430
His Gly Gln Phe Ser Leu Ala Val Val Ser Leu Asn Ile Thr Ser Leu
435 440 445
Gly Leu Arg Ser Leu Lys Glu Ile Ser Asp Gly Asp Val Ile Ile Ser
450 455 460
Gly Asn Lys Asn Leu Cys Tyr Ala Asn Thr Ile Asn Trp Lys Lys Leu
465 470 475 480
Phe Gly Thr Ser Gly Gln Lys Thr Lys Ile Ile Ser Asn Arg Gly Glu
485 490 495
Asn Ser Cys Lys Ala Thr Gly Gln Val Cys His Ala Leu Cys Ser Pro
500 505 510
Glu Gly Cys Trp Gly Pro Glu Pro Arg Asp Cys Val Ser Cys Arg Asn
515 520 525
Val Ser Arg Gly Arg Glu Cys Val Asp Lys Cys Asn Leu Leu Glu Gly
530 535 540
Glu Pro Arg Glu Phe Val Glu Asn Ser Glu Cys Ile Gln Cys His Pro
545 550 555 560
Glu Cys Leu Pro Gln Ala Met Asn Ile Thr Cys Thr Gly Arg Gly Pro
565 570 575
Asp Asn Cys Ile Gln Cys Ala His Tyr Ile Asp Gly Pro His Cys Val
580 585 590
Lys Thr Cys Pro Ala Gly Val Met Gly Glu Asn Asn Thr Leu Val Trp
595 600 605
Lys Tyr Ala Asp Ala Gly His Val Cys His Leu Cys His Pro Asn Cys
610 615 620
Thr Tyr Gly Cys Thr Gly Pro Gly Leu Glu Gly Cys Pro Thr Asn Gly
625 630 635 640
Pro Lys Ile Pro Ser Ile Ala Thr Gly Met Val Gly Ala Leu Leu Leu
645 650 655
Leu Leu Val Val Ala Leu Gly Ile Gly Leu Phe Met Arg Arg Arg His
660 665 670
Ile Val Arg Lys Arg Thr Leu Arg Arg Leu Leu Gln Glu Arg Glu Leu
675 680 685
Val Glu Pro Leu Thr Pro Ser Gly Glu Ala Pro Asn Gln Ala Leu Leu
690 695 700
Arg Ile Leu Lys Glu Thr Glu Phe Lys Lys Ile Lys Val Leu Gly Ser
705 710 715 720
Gly Ala Phe Gly Thr Val Tyr Lys Gly Leu Trp Ile Pro Glu Gly Glu
725 730 735
Lys Val Lys Ile Pro Val Ala Ile Lys Glu Leu Arg Glu Ala Thr Ser
740 745 750
Pro Lys Ala Asn Lys Glu Ile Leu Asp Glu Ala Tyr Val Met Ala Ser
755 760 765
Val Asp Asn Pro His Val Cys Arg Leu Leu Gly Ile Cys Leu Thr Ser
770 775 780
Thr Val Gln Leu Ile Thr Gln Leu Met Pro Phe Gly Cys Leu Leu Asp
785 790 795 800
Tyr Val Arg Glu His Lys Asp Asn Ile Gly Ser Gln Tyr Leu Leu Asn
805 810 815
Trp Cys Val Gln Ile Ala Lys Gly Met Asn Tyr Leu Glu Asp Arg Arg
820 825 830
Leu Val His Arg Asp Leu Ala Ala Arg Asn Val Leu Val Lys Thr Pro
835 840 845
Gln His Val Lys Ile Thr Asp Phe Gly Leu Ala Lys Leu Leu Gly Ala
850 855 860
Glu Glu Lys Glu Tyr His Ala Glu Gly Gly Lys Val Pro Ile Lys Trp
865 870 875 880
Met Ala Leu Glu Ser Ile Leu His Arg Ile Tyr Thr His Gln Ser Asp
885 890 895
Val Trp Ser Tyr Gly Val Thr Val Trp Glu Leu Met Thr Phe Gly Ser
900 905 910
Lys Pro Tyr Asp Gly Ile Pro Ala Ser Glu Ile Ser Ser Ile Leu Glu
915 920 925
Lys Gly Glu Arg Leu Pro Gln Pro Pro Ile Cys Thr Ile Asp Val Tyr
930 935 940
Met Ile Met Val Lys Cys Trp Met Ile Asp Ala Asp Ser Arg Pro Lys
945 950 955 960
Phe Arg Glu Leu Ile Ile Glu Phe Ser Lys Met Ala Arg Asp Pro Gln
965 970 975
Arg Tyr Leu Val Ile Gln Gly Asp Glu Arg Met His Leu Pro Ser Pro
980 985 990
Thr Asp Ser Asn Phe Tyr Arg Ala Leu Met Asp Glu Glu Asp Met Asp
995 1000 1005
Asp Val Val Asp Ala Asp Glu Tyr Leu Ile Pro Gln Gln Gly Phe
1010 1015 1020
Phe Ser Ser Pro Ser Thr Ser Arg Thr Pro Leu Leu Ser Ser Leu
1025 1030 1035
Ser Ala Thr Ser Asn Asn Ser Thr Val Ala Cys Ile Asp Arg Asn
1040 1045 1050
Gly Leu Gln Ser Cys Pro Ile Lys Glu Asp Ser Phe Leu Gln Arg
1055 1060 1065
Tyr Ser Ser Asp Pro Thr Gly Ala Leu Thr Glu Asp Ser Ile Asp
1070 1075 1080
Asp Thr Phe Leu Pro Val Pro Glu Tyr Ile Asn Gln Ser Val Pro
1085 1090 1095
Lys Arg Pro Ala Gly Ser Val Gln Asn Pro Val Tyr His Asn Gln
1100 1105 1110
Pro Leu Asn Pro Ala Pro Ser Arg Asp Pro His Tyr Gln Asp Pro
1115 1120 1125
His Ser Thr Ala Val Gly Asn Pro Glu Tyr Leu Asn Thr Val Gln
1130 1135 1140
Pro Thr Cys Val Asn Ser Thr Phe Asp Ser Pro Ala His Trp Ala
1145 1150 1155
Gln Lys Gly Ser His Gln Ile Ser Leu Asp Asn Pro Asp Tyr Gln
1160 1165 1170
Gln Asp Phe Phe Pro Lys Glu Ala Lys Pro Asn Gly Ile Phe Lys
1175 1180 1185
Gly Ser Thr Ala Glu Asn Ala Glu Tyr Leu Arg Val Ala Pro Gln
1190 1195 1200
Ser Ser Glu Phe Ile Gly Ala
1205 1210
<210> 74
<211> 53
<212> PRT
<213> HOMO SAPIENS
<400> 74
Asn Ser Asp Ser Glu Cys Pro Leu Ser His Asp Gly Tyr Cys Leu His
1 5 10 15
Asp Gly Val Cys Met Tyr Ile Glu Ala Leu Asp Lys Tyr Ala Cys Asn
20 25 30
Cys Val Val Gly Tyr Ile Gly Glu Arg Cys Gln Tyr Arg Asp Leu Lys
35 40 45
Trp Trp Glu Leu Arg
50
<210> 75
<211> 2201
<212> PRT
<213> Homo sapiens
<400> 75
Met Gly Ala Met Thr Gln Leu Leu Ala Gly Val Phe Leu Ala Phe Leu
1 5 10 15
Ala Leu Ala Thr Glu Gly Gly Val Leu Lys Lys Val Ile Arg His Lys
20 25 30
Arg Gln Ser Gly Val Asn Ala Thr Leu Pro Glu Glu Asn Gln Pro Val
35 40 45
Val Phe Asn His Val Tyr Asn Ile Lys Leu Pro Val Gly Ser Gln Cys
50 55 60
Ser Val Asp Leu Glu Ser Ala Ser Gly Glu Lys Asp Leu Ala Pro Pro
65 70 75 80
Ser Glu Pro Ser Glu Ser Phe Gln Glu His Thr Val Asp Gly Glu Asn
85 90 95
Gln Ile Val Phe Thr His Arg Ile Asn Ile Pro Arg Arg Ala Cys Gly
100 105 110
Cys Ala Ala Ala Pro Asp Val Lys Glu Leu Leu Ser Arg Leu Glu Glu
115 120 125
Leu Glu Asn Leu Val Ser Ser Leu Arg Glu Gln Cys Thr Ala Gly Ala
130 135 140
Gly Cys Cys Leu Gln Pro Ala Thr Gly Arg Leu Asp Thr Arg Pro Phe
145 150 155 160
Cys Ser Gly Arg Gly Asn Phe Ser Thr Glu Gly Cys Gly Cys Val Cys
165 170 175
Glu Pro Gly Trp Lys Gly Pro Asn Cys Ser Glu Pro Glu Cys Pro Gly
180 185 190
Asn Cys His Leu Arg Gly Arg Cys Ile Asp Gly Gln Cys Ile Cys Asp
195 200 205
Asp Gly Phe Thr Gly Glu Asp Cys Ser Gln Leu Ala Cys Pro Ser Asp
210 215 220
Cys Asn Asp Gln Gly Lys Cys Val Asn Gly Val Cys Ile Cys Phe Glu
225 230 235 240
Gly Tyr Ala Gly Ala Asp Cys Ser Arg Glu Ile Cys Pro Val Pro Cys
245 250 255
Ser Glu Glu His Gly Thr Cys Val Asp Gly Leu Cys Val Cys His Asp
260 265 270
Gly Phe Ala Gly Asp Asp Cys Asn Lys Pro Leu Cys Leu Asn Asn Cys
275 280 285
Tyr Asn Arg Gly Arg Cys Val Glu Asn Glu Cys Val Cys Asp Glu Gly
290 295 300
Phe Thr Gly Glu Asp Cys Ser Glu Leu Ile Cys Pro Asn Asp Cys Phe
305 310 315 320
Asp Arg Gly Arg Cys Ile Asn Gly Thr Cys Tyr Cys Glu Glu Gly Phe
325 330 335
Thr Gly Glu Asp Cys Gly Lys Pro Thr Cys Pro His Ala Cys His Thr
340 345 350
Gln Gly Arg Cys Glu Glu Gly Gln Cys Val Cys Asp Glu Gly Phe Ala
355 360 365
Gly Val Asp Cys Ser Glu Lys Arg Cys Pro Ala Asp Cys His Asn Arg
370 375 380
Gly Arg Cys Val Asp Gly Arg Cys Glu Cys Asp Asp Gly Phe Thr Gly
385 390 395 400
Ala Asp Cys Gly Glu Leu Lys Cys Pro Asn Gly Cys Ser Gly His Gly
405 410 415
Arg Cys Val Asn Gly Gln Cys Val Cys Asp Glu Gly Tyr Thr Gly Glu
420 425 430
Asp Cys Ser Gln Leu Arg Cys Pro Asn Asp Cys His Ser Arg Gly Arg
435 440 445
Cys Val Glu Gly Lys Cys Val Cys Glu Gln Gly Phe Lys Gly Tyr Asp
450 455 460
Cys Ser Asp Met Ser Cys Pro Asn Asp Cys His Gln His Gly Arg Cys
465 470 475 480
Val Asn Gly Met Cys Val Cys Asp Asp Gly Tyr Thr Gly Glu Asp Cys
485 490 495
Arg Asp Arg Gln Cys Pro Arg Asp Cys Ser Asn Arg Gly Leu Cys Val
500 505 510
Asp Gly Gln Cys Val Cys Glu Asp Gly Phe Thr Gly Pro Asp Cys Ala
515 520 525
Glu Leu Ser Cys Pro Asn Asp Cys His Gly Gln Gly Arg Cys Val Asn
530 535 540
Gly Gln Cys Val Cys His Glu Gly Phe Met Gly Lys Asp Cys Lys Glu
545 550 555 560
Gln Arg Cys Pro Ser Asp Cys His Gly Gln Gly Arg Cys Val Asp Gly
565 570 575
Gln Cys Ile Cys His Glu Gly Phe Thr Gly Leu Asp Cys Gly Gln His
580 585 590
Ser Cys Pro Ser Asp Cys Asn Asn Leu Gly Gln Cys Val Ser Gly Arg
595 600 605
Cys Ile Cys Asn Glu Gly Tyr Ser Gly Glu Asp Cys Ser Glu Val Ser
610 615 620
Pro Pro Lys Asp Leu Val Val Thr Glu Val Thr Glu Glu Thr Val Asn
625 630 635 640
Leu Ala Trp Asp Asn Glu Met Arg Val Thr Glu Tyr Leu Val Val Tyr
645 650 655
Thr Pro Thr His Glu Gly Gly Leu Glu Met Gln Phe Arg Val Pro Gly
660 665 670
Asp Gln Thr Ser Thr Ile Ile Gln Glu Leu Glu Pro Gly Val Glu Tyr
675 680 685
Phe Ile Arg Val Phe Ala Ile Leu Glu Asn Lys Lys Ser Ile Pro Val
690 695 700
Ser Ala Arg Val Ala Thr Tyr Leu Pro Ala Pro Glu Gly Leu Lys Phe
705 710 715 720
Lys Ser Ile Lys Glu Thr Ser Val Glu Val Glu Trp Asp Pro Leu Asp
725 730 735
Ile Ala Phe Glu Thr Trp Glu Ile Ile Phe Arg Asn Met Asn Lys Glu
740 745 750
Asp Glu Gly Glu Ile Thr Lys Ser Leu Arg Arg Pro Glu Thr Ser Tyr
755 760 765
Arg Gln Thr Gly Leu Ala Pro Gly Gln Glu Tyr Glu Ile Ser Leu His
770 775 780
Ile Val Lys Asn Asn Thr Arg Gly Pro Gly Leu Lys Arg Val Thr Thr
785 790 795 800
Thr Arg Leu Asp Ala Pro Ser Gln Ile Glu Val Lys Asp Val Thr Asp
805 810 815
Thr Thr Ala Leu Ile Thr Trp Phe Lys Pro Leu Ala Glu Ile Asp Gly
820 825 830
Ile Glu Leu Thr Tyr Gly Ile Lys Asp Val Pro Gly Asp Arg Thr Thr
835 840 845
Ile Asp Leu Thr Glu Asp Glu Asn Gln Tyr Ser Ile Gly Asn Leu Lys
850 855 860
Pro Asp Thr Glu Tyr Glu Val Ser Leu Ile Ser Arg Arg Gly Asp Met
865 870 875 880
Ser Ser Asn Pro Ala Lys Glu Thr Phe Thr Thr Gly Leu Asp Ala Pro
885 890 895
Arg Asn Leu Arg Arg Val Ser Gln Thr Asp Asn Ser Ile Thr Leu Glu
900 905 910
Trp Arg Asn Gly Lys Ala Ala Ile Asp Ser Tyr Arg Ile Lys Tyr Ala
915 920 925
Pro Ile Ser Gly Gly Asp His Ala Glu Val Asp Val Pro Lys Ser Gln
930 935 940
Gln Ala Thr Thr Lys Thr Thr Leu Thr Gly Leu Arg Pro Gly Thr Glu
945 950 955 960
Tyr Gly Ile Gly Val Ser Ala Val Lys Glu Asp Lys Glu Ser Asn Pro
965 970 975
Ala Thr Ile Asn Ala Ala Thr Glu Leu Asp Thr Pro Lys Asp Leu Gln
980 985 990
Val Ser Glu Thr Ala Glu Thr Ser Leu Thr Leu Leu Trp Lys Thr Pro
995 1000 1005
Leu Ala Lys Phe Asp Arg Tyr Arg Leu Asn Tyr Ser Leu Pro Thr
1010 1015 1020
Gly Gln Trp Val Gly Val Gln Leu Pro Arg Asn Thr Thr Ser Tyr
1025 1030 1035
Val Leu Arg Gly Leu Glu Pro Gly Gln Glu Tyr Asn Val Leu Leu
1040 1045 1050
Thr Ala Glu Lys Gly Arg His Lys Ser Lys Pro Ala Arg Val Lys
1055 1060 1065
Ala Ser Thr Glu Gln Ala Pro Glu Leu Glu Asn Leu Thr Val Thr
1070 1075 1080
Glu Val Gly Trp Asp Gly Leu Arg Leu Asn Trp Thr Ala Ala Asp
1085 1090 1095
Gln Ala Tyr Glu His Phe Ile Ile Gln Val Gln Glu Ala Asn Lys
1100 1105 1110
Val Glu Ala Ala Arg Asn Leu Thr Val Pro Gly Ser Leu Arg Ala
1115 1120 1125
Val Asp Ile Pro Gly Leu Lys Ala Ala Thr Pro Tyr Thr Val Ser
1130 1135 1140
Ile Tyr Gly Val Ile Gln Gly Tyr Arg Thr Pro Val Leu Ser Ala
1145 1150 1155
Glu Ala Ser Thr Gly Glu Thr Pro Asn Leu Gly Glu Val Val Val
1160 1165 1170
Ala Glu Val Gly Trp Asp Ala Leu Lys Leu Asn Trp Thr Ala Pro
1175 1180 1185
Glu Gly Ala Tyr Glu Tyr Phe Phe Ile Gln Val Gln Glu Ala Asp
1190 1195 1200
Thr Val Glu Ala Ala Gln Asn Leu Thr Val Pro Gly Gly Leu Arg
1205 1210 1215
Ser Thr Asp Leu Pro Gly Leu Lys Ala Ala Thr His Tyr Thr Ile
1220 1225 1230
Thr Ile Arg Gly Val Thr Gln Asp Phe Ser Thr Thr Pro Leu Ser
1235 1240 1245
Val Glu Val Leu Thr Glu Glu Val Pro Asp Met Gly Asn Leu Thr
1250 1255 1260
Val Thr Glu Val Ser Trp Asp Ala Leu Arg Leu Asn Trp Thr Thr
1265 1270 1275
Pro Asp Gly Thr Tyr Asp Gln Phe Thr Ile Gln Val Gln Glu Ala
1280 1285 1290
Asp Gln Val Glu Glu Ala His Asn Leu Thr Val Pro Gly Ser Leu
1295 1300 1305
Arg Ser Met Glu Ile Pro Gly Leu Arg Ala Gly Thr Pro Tyr Thr
1310 1315 1320
Val Thr Leu His Gly Glu Val Arg Gly His Ser Thr Arg Pro Leu
1325 1330 1335
Ala Val Glu Val Val Thr Glu Asp Leu Pro Gln Leu Gly Asp Leu
1340 1345 1350
Ala Val Ser Glu Val Gly Trp Asp Gly Leu Arg Leu Asn Trp Thr
1355 1360 1365
Ala Ala Asp Asn Ala Tyr Glu His Phe Val Ile Gln Val Gln Glu
1370 1375 1380
Val Asn Lys Val Glu Ala Ala Gln Asn Leu Thr Leu Pro Gly Ser
1385 1390 1395
Leu Arg Ala Val Asp Ile Pro Gly Leu Glu Ala Ala Thr Pro Tyr
1400 1405 1410
Arg Val Ser Ile Tyr Gly Val Ile Arg Gly Tyr Arg Thr Pro Val
1415 1420 1425
Leu Ser Ala Glu Ala Ser Thr Ala Lys Glu Pro Glu Ile Gly Asn
1430 1435 1440
Leu Asn Val Ser Asp Ile Thr Pro Glu Ser Phe Asn Leu Ser Trp
1445 1450 1455
Met Ala Thr Asp Gly Ile Phe Glu Thr Phe Thr Ile Glu Ile Ile
1460 1465 1470
Asp Ser Asn Arg Leu Leu Glu Thr Val Glu Tyr Asn Ile Ser Gly
1475 1480 1485
Ala Glu Arg Thr Ala His Ile Ser Gly Leu Pro Pro Ser Thr Asp
1490 1495 1500
Phe Ile Val Tyr Leu Ser Gly Leu Ala Pro Ser Ile Arg Thr Lys
1505 1510 1515
Thr Ile Ser Ala Thr Ala Thr Thr Glu Ala Leu Pro Leu Leu Glu
1520 1525 1530
Asn Leu Thr Ile Ser Asp Ile Asn Pro Tyr Gly Phe Thr Val Ser
1535 1540 1545
Trp Met Ala Ser Glu Asn Ala Phe Asp Ser Phe Leu Val Thr Val
1550 1555 1560
Val Asp Ser Gly Lys Leu Leu Asp Pro Gln Glu Phe Thr Leu Ser
1565 1570 1575
Gly Thr Gln Arg Lys Leu Glu Leu Arg Gly Leu Ile Thr Gly Ile
1580 1585 1590
Gly Tyr Glu Val Met Val Ser Gly Phe Thr Gln Gly His Gln Thr
1595 1600 1605
Lys Pro Leu Arg Ala Glu Ile Val Thr Glu Ala Glu Pro Glu Val
1610 1615 1620
Asp Asn Leu Leu Val Ser Asp Ala Thr Pro Asp Gly Phe Arg Leu
1625 1630 1635
Ser Trp Thr Ala Asp Glu Gly Val Phe Asp Asn Phe Val Leu Lys
1640 1645 1650
Ile Arg Asp Thr Lys Lys Gln Ser Glu Pro Leu Glu Ile Thr Leu
1655 1660 1665
Leu Ala Pro Glu Arg Thr Arg Asp Ile Thr Gly Leu Arg Glu Ala
1670 1675 1680
Thr Glu Tyr Glu Ile Glu Leu Tyr Gly Ile Ser Lys Gly Arg Arg
1685 1690 1695
Ser Gln Thr Val Ser Ala Ile Ala Thr Thr Ala Met Gly Ser Pro
1700 1705 1710
Lys Glu Val Ile Phe Ser Asp Ile Thr Glu Asn Ser Ala Thr Val
1715 1720 1725
Ser Trp Arg Ala Pro Thr Ala Gln Val Glu Ser Phe Arg Ile Thr
1730 1735 1740
Tyr Val Pro Ile Thr Gly Gly Thr Pro Ser Met Val Thr Val Asp
1745 1750 1755
Gly Thr Lys Thr Gln Thr Arg Leu Val Lys Leu Ile Pro Gly Val
1760 1765 1770
Glu Tyr Leu Val Ser Ile Ile Ala Met Lys Gly Phe Glu Glu Ser
1775 1780 1785
Glu Pro Val Ser Gly Ser Phe Thr Thr Ala Leu Asp Gly Pro Ser
1790 1795 1800
Gly Leu Val Thr Ala Asn Ile Thr Asp Ser Glu Ala Leu Ala Arg
1805 1810 1815
Trp Gln Pro Ala Ile Ala Thr Val Asp Ser Tyr Val Ile Ser Tyr
1820 1825 1830
Thr Gly Glu Lys Val Pro Glu Ile Thr Arg Thr Val Ser Gly Asn
1835 1840 1845
Thr Val Glu Tyr Ala Leu Thr Asp Leu Glu Pro Ala Thr Glu Tyr
1850 1855 1860
Thr Leu Arg Ile Phe Ala Glu Lys Gly Pro Gln Lys Ser Ser Thr
1865 1870 1875
Ile Thr Ala Lys Phe Thr Thr Asp Leu Asp Ser Pro Arg Asp Leu
1880 1885 1890
Thr Ala Thr Glu Val Gln Ser Glu Thr Ala Leu Leu Thr Trp Arg
1895 1900 1905
Pro Pro Arg Ala Ser Val Thr Gly Tyr Leu Leu Val Tyr Glu Ser
1910 1915 1920
Val Asp Gly Thr Val Lys Glu Val Ile Val Gly Pro Asp Thr Thr
1925 1930 1935
Ser Tyr Ser Leu Ala Asp Leu Ser Pro Ser Thr His Tyr Thr Ala
1940 1945 1950
Lys Ile Gln Ala Leu Asn Gly Pro Leu Arg Ser Asn Met Ile Gln
1955 1960 1965
Thr Ile Phe Thr Thr Ile Gly Leu Leu Tyr Pro Phe Pro Lys Asp
1970 1975 1980
Cys Ser Gln Ala Met Leu Asn Gly Asp Thr Thr Ser Gly Leu Tyr
1985 1990 1995
Thr Ile Tyr Leu Asn Gly Asp Lys Ala Glu Ala Leu Glu Val Phe
2000 2005 2010
Cys Asp Met Thr Ser Asp Gly Gly Gly Trp Ile Val Phe Leu Arg
2015 2020 2025
Arg Lys Asn Gly Arg Glu Asn Phe Tyr Gln Asn Trp Lys Ala Tyr
2030 2035 2040
Ala Ala Gly Phe Gly Asp Arg Arg Glu Glu Phe Trp Leu Gly Leu
2045 2050 2055
Asp Asn Leu Asn Lys Ile Thr Ala Gln Gly Gln Tyr Glu Leu Arg
2060 2065 2070
Val Asp Leu Arg Asp His Gly Glu Thr Ala Phe Ala Val Tyr Asp
2075 2080 2085
Lys Phe Ser Val Gly Asp Ala Lys Thr Arg Tyr Lys Leu Lys Val
2090 2095 2100
Glu Gly Tyr Ser Gly Thr Ala Gly Asp Ser Met Ala Tyr His Asn
2105 2110 2115
Gly Arg Ser Phe Ser Thr Phe Asp Lys Asp Thr Asp Ser Ala Ile
2120 2125 2130
Thr Asn Cys Ala Leu Ser Tyr Lys Gly Ala Phe Trp Tyr Arg Asn
2135 2140 2145
Cys His Arg Val Asn Leu Met Gly Arg Tyr Gly Asp Asn Asn His
2150 2155 2160
Ser Gln Gly Val Asn Trp Phe His Trp Lys Gly His Glu His Ser
2165 2170 2175
Ile Gln Phe Ala Glu Met Lys Leu Arg Pro Ser Asn Phe Arg Asn
2180 2185 2190
Leu Glu Gly Arg Arg Lys Arg Ala
2195 2200
<210> 76
<211> 89
<212> PRT
<213> Artificial Sequence
<220>
<223> Fibcon FN3 domain
<400> 76
Leu Asp Ala Pro Thr Asp Leu Gln Val Thr Asn Val Thr Asp Thr Ser
1 5 10 15
Ile Thr Val Ser Trp Thr Pro Pro Ser Ala Thr Ile Thr Gly Tyr Arg
20 25 30
Ile Thr Tyr Thr Pro Ser Asn Gly Pro Gly Glu Pro Lys Glu Leu Thr
35 40 45
Val Pro Pro Ser Ser Thr Ser Val Thr Ile Thr Gly Leu Thr Pro Gly
50 55 60
Val Glu Tyr Val Val Ser Leu Tyr Ala Leu Lys Asp Asn Gln Glu Ser
65 70 75 80
Pro Pro Leu Val Gly Thr Gln Thr Thr
85
<210> 77
<211> 94
<212> PRT
<213> Homo sapiens
<400> 77
Val Ser Asp Val Pro Arg Asp Leu Glu Val Val Ala Ala Thr Pro Thr
1 5 10 15
Ser Leu Leu Ile Ser Trp Asp Ala Pro Ala Val Thr Val Arg Tyr Tyr
20 25 30
Arg Ile Thr Tyr Gly Glu Thr Gly Gly Asn Ser Pro Val Gln Glu Phe
35 40 45
Thr Val Pro Gly Ser Lys Ser Thr Ala Thr Ile Ser Gly Leu Lys Pro
50 55 60
Gly Val Asp Tyr Thr Ile Thr Val Tyr Ala Val Thr Gly Arg Gly Asp
65 70 75 80
Ser Pro Ala Ser Ser Lys Pro Ile Ser Ile Asn Tyr Arg Thr
85 90
<210> 78
<211> 4
<212> PRT
<213> Artificial Sequence
<220>
<223> linker
<400> 78
Gly Ser Gly Ser
1
<210> 79
<211> 25
<212> PRT
<213> Artificial Sequence
<220>
<223> linker
<400> 79
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Gly Gly Gly Ser Gly Gly Gly Gly Ser
20 25
<210> 80
<211> 4
<212> PRT
<213> Artificial Sequence
<220>
<223> linker
<400> 80
Ala Pro Ala Pro
1
<210> 81
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> linker
<400> 81
Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro
1 5 10
<210> 82
<211> 20
<212> PRT
<213> Artificial Sequence
<220>
<223> linker
<400> 82
Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro
1 5 10 15
Ala Pro Ala Pro
20
<210> 83
<211> 40
<212> PRT
<213> Artificial Sequence
<220>
<223> linker
<400> 83
Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro
1 5 10 15
Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro
20 25 30
Ala Pro Ala Pro Ala Pro Ala Pro
35 40
<210> 84
<211> 29
<212> PRT
<213> Artificial Sequence
<220>
<223> linker
<400> 84
Ala Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys
1 5 10 15
Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Ala Ala Ala
20 25
<210> 85
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> tencon BC loop
<400> 85
Thr Ala Pro Asp Ala Ala Phe Asp
1 5
<210> 86
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> tencon FG loop
<400> 86
Lys Gly Gly His Arg Ser Asn
1 5
<210> 87
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain BC loop
<400> 87
Ala Asp Pro His Gly Phe Tyr Asp
1 5
<210> 88
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain BC loop
<400> 88
Thr Tyr Asp Arg Asp Gly Tyr Asp
1 5
<210> 89
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain BC loop
<400> 89
Trp Asp Pro Phe Ser Phe Tyr Asp
1 5
<210> 90
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain BC loop
<400> 90
Asp Asp Pro Arg Gly Phe Tyr Glu
1 5
<210> 91
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain BC loop
<400> 91
Thr Trp Pro Tyr Ala Asp Leu Asp
1 5
<210> 92
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain BC loop
<400> 92
Gly Tyr Asn Gly Asp His Phe Asp
1 5
<210> 93
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain BC loop
<400> 93
Asp Tyr Asp Leu Gly Val Tyr Asp
1 5
<210> 94
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain BC loop
<400> 94
Asp Asp Pro Trp Asp Phe Tyr Glu
1 5
<210> 95
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain FG loop
<400> 95
His Asn Val Tyr Lys Asp Thr Asn Met Arg Gly Leu
1 5 10
<210> 96
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain FG loop
<400> 96
Leu Gly Ser Tyr Val Phe Glu His Asp Val Met
1 5 10
<210> 97
<211> 285
<212> DNA
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain from ECB97; P54AR4-83V22
<400> 97
atgttgccag cgccgaagaa cctggtagtt agcgaggtta ctgaggacag cgcgcgtctg 60
agctgggacg atccgtgggc gttctacgag agctttctga tccagtatca agagagcgag 120
aaagtcggtg aagcgattgt gctgaccgtc ccgggctccg agcgttccta cgacctgacc 180
ggtttgaagc cgggtaccga gtatacggtg agcatctacg gtgttcacaa tgtctataag 240
gacactaata tccgcggtct gcctctgagc gccattttca ccacc 285
<210> 98
<211> 285
<212> DNA
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain from ECB15; P54AR4-83V2
<400> 98
atgctgccag cccctaagaa tctggtcgtg agcgaagtaa ccgaggacag cgcccgcctg 60
agctgggacg acccgtgggc gttctatgag tctttcctga ttcagtatca agaaagcgaa 120
aaagttggcg aagcgatcgt cctgaccgtc ccgggtagcg agcgctccta cgatctgacc 180
ggcctgaaac cgggtacgga gtacacggtg tccatttacg gtgttcacaa tgtgtataaa 240
gacaccaaca tgcgtggcct gccgctgtcg gcgattttca ccacc 285
<210> 99
<211> 89
<212> PRT
<213> Artificial Sequence
<220>
<223> tencon27 FN3 domain
<400> 99
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val Lys Gly Gly His Arg Ser
65 70 75 80
Asn Pro Leu Ser Ala Ile Phe Thr Thr
85
<210> 100
<211> 89
<212> PRT
<213> Artificial Sequence
<220>
<223> TCL14 library
<220>
<221> MISC_FEATURE
<222> (32)..(32)
<223> Xaa is any amino acid
<220>
<221> MISC_FEATURE
<222> (34)..(34)
<223> Xaa is any amino acid
<220>
<221> MISC_FEATURE
<222> (36)..(36)
<223> Xaa is any amino acid
<220>
<221> MISC_FEATURE
<222> (38)..(38)
<223> Xaa is any amino acid
<220>
<221> MISC_FEATURE
<222> (39)..(39)
<223> Xaa is any amino acid
<220>
<221> MISC_FEATURE
<222> (40)..(40)
<223> Xaa is any amino acid
<220>
<221> MISC_FEATURE
<222> (41)..(41)
<223> Xaa is any amino acid
<220>
<221> MISC_FEATURE
<222> (68)..(68)
<223> Xaa is any amino acid
<220>
<221> MISC_FEATURE
<222> (70)..(70)
<223> Xaa is any amino acid
<220>
<221> MISC_FEATURE
<222> (72)..(72)
<223> Xaa is any amino acid
<220>
<221> MISC_FEATURE
<222> (78)..(78)
<223> Xaa is any amino acid
<220>
<221> MISC_FEATURE
<222> (79)..(79)
<223> Xaa is any amino acid
<220>
<221> MISC_FEATURE
<222> (81)..(81)
<223> Xaa is any amino acid
<400> 100
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe Xaa
20 25 30
Ile Xaa Tyr Xaa Glu Xaa Xaa Xaa Xaa Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Xaa Val Xaa Ile Xaa Gly Val Lys Gly Gly Xaa Xaa Ser
65 70 75 80
Xaa Pro Leu Ser Ala Ile Phe Thr Thr
85
<210> 101
<211> 1408
<212> PRT
<213> HOMO SAPIENS
<400> 101
Met Lys Ala Pro Ala Val Leu Ala Pro Gly Ile Leu Val Leu Leu Phe
1 5 10 15
Thr Leu Val Gln Arg Ser Asn Gly Glu Cys Lys Glu Ala Leu Ala Lys
20 25 30
Ser Glu Met Asn Val Asn Met Lys Tyr Gln Leu Pro Asn Phe Thr Ala
35 40 45
Glu Thr Pro Ile Gln Asn Val Ile Leu His Glu His His Ile Phe Leu
50 55 60
Gly Ala Thr Asn Tyr Ile Tyr Val Leu Asn Glu Glu Asp Leu Gln Lys
65 70 75 80
Val Ala Glu Tyr Lys Thr Gly Pro Val Leu Glu His Pro Asp Cys Phe
85 90 95
Pro Cys Gln Asp Cys Ser Ser Lys Ala Asn Leu Ser Gly Gly Val Trp
100 105 110
Lys Asp Asn Ile Asn Met Ala Leu Val Val Asp Thr Tyr Tyr Asp Asp
115 120 125
Gln Leu Ile Ser Cys Gly Ser Val Asn Arg Gly Thr Cys Gln Arg His
130 135 140
Val Phe Pro His Asn His Thr Ala Asp Ile Gln Ser Glu Val His Cys
145 150 155 160
Ile Phe Ser Pro Gln Ile Glu Glu Pro Ser Gln Cys Pro Asp Cys Val
165 170 175
Val Ser Ala Leu Gly Ala Lys Val Leu Ser Ser Val Lys Asp Arg Phe
180 185 190
Ile Asn Phe Phe Val Gly Asn Thr Ile Asn Ser Ser Tyr Phe Pro Asp
195 200 205
His Pro Leu His Ser Ile Ser Val Arg Arg Leu Lys Glu Thr Lys Asp
210 215 220
Gly Phe Met Phe Leu Thr Asp Gln Ser Tyr Ile Asp Val Leu Pro Glu
225 230 235 240
Phe Arg Asp Ser Tyr Pro Ile Lys Tyr Val His Ala Phe Glu Ser Asn
245 250 255
Asn Phe Ile Tyr Phe Leu Thr Val Gln Arg Glu Thr Leu Asp Ala Gln
260 265 270
Thr Phe His Thr Arg Ile Ile Arg Phe Cys Ser Ile Asn Ser Gly Leu
275 280 285
His Ser Tyr Met Glu Met Pro Leu Glu Cys Ile Leu Thr Glu Lys Arg
290 295 300
Lys Lys Arg Ser Thr Lys Lys Glu Val Phe Asn Ile Leu Gln Ala Ala
305 310 315 320
Tyr Val Ser Lys Pro Gly Ala Gln Leu Ala Arg Gln Ile Gly Ala Ser
325 330 335
Leu Asn Asp Asp Ile Leu Phe Gly Val Phe Ala Gln Ser Lys Pro Asp
340 345 350
Ser Ala Glu Pro Met Asp Arg Ser Ala Met Cys Ala Phe Pro Ile Lys
355 360 365
Tyr Val Asn Asp Phe Phe Asn Lys Ile Val Asn Lys Asn Asn Val Arg
370 375 380
Cys Leu Gln His Phe Tyr Gly Pro Asn His Glu His Cys Phe Asn Arg
385 390 395 400
Thr Leu Leu Arg Asn Ser Ser Gly Cys Glu Ala Arg Arg Asp Glu Tyr
405 410 415
Arg Thr Glu Phe Thr Thr Ala Leu Gln Arg Val Asp Leu Phe Met Gly
420 425 430
Gln Phe Ser Glu Val Leu Leu Thr Ser Ile Ser Thr Phe Ile Lys Gly
435 440 445
Asp Leu Thr Ile Ala Asn Leu Gly Thr Ser Glu Gly Arg Phe Met Gln
450 455 460
Val Val Val Ser Arg Ser Gly Pro Ser Thr Pro His Val Asn Phe Leu
465 470 475 480
Leu Asp Ser His Pro Val Ser Pro Glu Val Ile Val Glu His Thr Leu
485 490 495
Asn Gln Asn Gly Tyr Thr Leu Val Ile Thr Gly Lys Lys Ile Thr Lys
500 505 510
Ile Pro Leu Asn Gly Leu Gly Cys Arg His Phe Gln Ser Cys Ser Gln
515 520 525
Cys Leu Ser Ala Pro Pro Phe Val Gln Cys Gly Trp Cys His Asp Lys
530 535 540
Cys Val Arg Ser Glu Glu Cys Leu Ser Gly Thr Trp Thr Gln Gln Ile
545 550 555 560
Cys Leu Pro Ala Ile Tyr Lys Val Phe Pro Asn Ser Ala Pro Leu Glu
565 570 575
Gly Gly Thr Arg Leu Thr Ile Cys Gly Trp Asp Phe Gly Phe Arg Arg
580 585 590
Asn Asn Lys Phe Asp Leu Lys Lys Thr Arg Val Leu Leu Gly Asn Glu
595 600 605
Ser Cys Thr Leu Thr Leu Ser Glu Ser Thr Met Asn Thr Leu Lys Cys
610 615 620
Thr Val Gly Pro Ala Met Asn Lys His Phe Asn Met Ser Ile Ile Ile
625 630 635 640
Ser Asn Gly His Gly Thr Thr Gln Tyr Ser Thr Phe Ser Tyr Val Asp
645 650 655
Pro Val Ile Thr Ser Ile Ser Pro Lys Tyr Gly Pro Met Ala Gly Gly
660 665 670
Thr Leu Leu Thr Leu Thr Gly Asn Tyr Leu Asn Ser Gly Asn Ser Arg
675 680 685
His Ile Ser Ile Gly Gly Lys Thr Cys Thr Leu Lys Ser Val Ser Asn
690 695 700
Ser Ile Leu Glu Cys Tyr Thr Pro Ala Gln Thr Ile Ser Thr Glu Phe
705 710 715 720
Ala Val Lys Leu Lys Ile Asp Leu Ala Asn Arg Glu Thr Ser Ile Phe
725 730 735
Ser Tyr Arg Glu Asp Pro Ile Val Tyr Glu Ile His Pro Thr Lys Ser
740 745 750
Phe Ile Ser Thr Trp Trp Lys Glu Pro Leu Asn Ile Val Ser Phe Leu
755 760 765
Phe Cys Phe Ala Ser Gly Gly Ser Thr Ile Thr Gly Val Gly Lys Asn
770 775 780
Leu Asn Ser Val Ser Val Pro Arg Met Val Ile Asn Val His Glu Ala
785 790 795 800
Gly Arg Asn Phe Thr Val Ala Cys Gln His Arg Ser Asn Ser Glu Ile
805 810 815
Ile Cys Cys Thr Thr Pro Ser Leu Gln Gln Leu Asn Leu Gln Leu Pro
820 825 830
Leu Lys Thr Lys Ala Phe Phe Met Leu Asp Gly Ile Leu Ser Lys Tyr
835 840 845
Phe Asp Leu Ile Tyr Val His Asn Pro Val Phe Lys Pro Phe Glu Lys
850 855 860
Pro Val Met Ile Ser Met Gly Asn Glu Asn Val Leu Glu Ile Lys Gly
865 870 875 880
Asn Asp Ile Asp Pro Glu Ala Val Lys Gly Glu Val Leu Lys Val Gly
885 890 895
Asn Lys Ser Cys Glu Asn Ile His Leu His Ser Glu Ala Val Leu Cys
900 905 910
Thr Val Pro Asn Asp Leu Leu Lys Leu Asn Ser Glu Leu Asn Ile Glu
915 920 925
Trp Lys Gln Ala Ile Ser Ser Thr Val Leu Gly Lys Val Ile Val Gln
930 935 940
Pro Asp Gln Asn Phe Thr Gly Leu Ile Ala Gly Val Val Ser Ile Ser
945 950 955 960
Thr Ala Leu Leu Leu Leu Leu Gly Phe Phe Leu Trp Leu Lys Lys Arg
965 970 975
Lys Gln Ile Lys Asp Leu Gly Ser Glu Leu Val Arg Tyr Asp Ala Arg
980 985 990
Val His Thr Pro His Leu Asp Arg Leu Val Ser Ala Arg Ser Val Ser
995 1000 1005
Pro Thr Thr Glu Met Val Ser Asn Glu Ser Val Asp Tyr Arg Ala
1010 1015 1020
Thr Phe Pro Glu Asp Gln Phe Pro Asn Ser Ser Gln Asn Gly Ser
1025 1030 1035
Cys Arg Gln Val Gln Tyr Pro Leu Thr Asp Met Ser Pro Ile Leu
1040 1045 1050
Thr Ser Gly Asp Ser Asp Ile Ser Ser Pro Leu Leu Gln Asn Thr
1055 1060 1065
Val His Ile Asp Leu Ser Ala Leu Asn Pro Glu Leu Val Gln Ala
1070 1075 1080
Val Gln His Val Val Ile Gly Pro Ser Ser Leu Ile Val His Phe
1085 1090 1095
Asn Glu Val Ile Gly Arg Gly His Phe Gly Cys Val Tyr His Gly
1100 1105 1110
Thr Leu Leu Asp Asn Asp Gly Lys Lys Ile His Cys Ala Val Lys
1115 1120 1125
Ser Leu Asn Arg Ile Thr Asp Ile Gly Glu Val Ser Gln Phe Leu
1130 1135 1140
Thr Glu Gly Ile Ile Met Lys Asp Phe Ser His Pro Asn Val Leu
1145 1150 1155
Ser Leu Leu Gly Ile Cys Leu Arg Ser Glu Gly Ser Pro Leu Val
1160 1165 1170
Val Leu Pro Tyr Met Lys His Gly Asp Leu Arg Asn Phe Ile Arg
1175 1180 1185
Asn Glu Thr His Asn Pro Thr Val Lys Asp Leu Ile Gly Phe Gly
1190 1195 1200
Leu Gln Val Ala Lys Gly Met Lys Tyr Leu Ala Ser Lys Lys Phe
1205 1210 1215
Val His Arg Asp Leu Ala Ala Arg Asn Cys Met Leu Asp Glu Lys
1220 1225 1230
Phe Thr Val Lys Val Ala Asp Phe Gly Leu Ala Arg Asp Met Tyr
1235 1240 1245
Asp Lys Glu Tyr Tyr Ser Val His Asn Lys Thr Gly Ala Lys Leu
1250 1255 1260
Pro Val Lys Trp Met Ala Leu Glu Ser Leu Gln Thr Gln Lys Phe
1265 1270 1275
Thr Thr Lys Ser Asp Val Trp Ser Phe Gly Val Leu Leu Trp Glu
1280 1285 1290
Leu Met Thr Arg Gly Ala Pro Pro Tyr Pro Asp Val Asn Thr Phe
1295 1300 1305
Asp Ile Thr Val Tyr Leu Leu Gln Gly Arg Arg Leu Leu Gln Pro
1310 1315 1320
Glu Tyr Cys Pro Asp Pro Leu Tyr Glu Val Met Leu Lys Cys Trp
1325 1330 1335
His Pro Lys Ala Glu Met Arg Pro Ser Phe Ser Glu Leu Val Ser
1340 1345 1350
Arg Ile Ser Ala Ile Phe Ser Thr Phe Ile Gly Glu His Tyr Val
1355 1360 1365
His Val Asn Ala Thr Tyr Val Asn Val Lys Cys Val Ala Pro Tyr
1370 1375 1380
Pro Ser Leu Leu Ser Ser Glu Asp Asn Ala Asp Asp Glu Val Asp
1385 1390 1395
Thr Arg Pro Ala Ser Phe Trp Glu Thr Ser
1400 1405
<210> 102
<211> 697
<212> PRT
<213> HOMO SAPIENS
<400> 102
Gln Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys Lys Ser Ala Lys
1 5 10 15
Thr Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile Lys Thr Lys Lys
20 25 30
Val Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr Arg Asn Lys Gly
35 40 45
Leu Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys Ala Arg Lys Gln
50 55 60
Cys Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly Val Lys Lys Glu
65 70 75 80
Phe Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Asp Tyr Ile Arg Asn
85 90 95
Cys Ile Ile Gly Lys Gly Arg Ser Tyr Lys Gly Thr Val Ser Ile Thr
100 105 110
Lys Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met Ile Pro His Glu
115 120 125
His Ser Phe Leu Pro Ser Ser Tyr Arg Gly Lys Asp Leu Gln Glu Asn
130 135 140
Tyr Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro Trp Cys Phe Thr
145 150 155 160
Ser Asn Pro Glu Val Arg Tyr Glu Val Cys Asp Ile Pro Gln Cys Ser
165 170 175
Glu Val Glu Cys Met Thr Cys Asn Gly Glu Ser Tyr Arg Gly Leu Met
180 185 190
Asp His Thr Glu Ser Gly Lys Ile Cys Gln Arg Trp Asp His Gln Thr
195 200 205
Pro His Arg His Lys Phe Leu Pro Glu Arg Tyr Pro Asp Lys Gly Phe
210 215 220
Asp Asp Asn Tyr Cys Arg Asn Pro Asp Gly Gln Pro Arg Pro Trp Cys
225 230 235 240
Tyr Thr Leu Asp Pro His Thr Arg Trp Glu Tyr Cys Ala Ile Lys Thr
245 250 255
Cys Ala Asp Asn Thr Met Asn Asp Thr Asp Val Pro Leu Glu Thr Thr
260 265 270
Glu Cys Ile Gln Gly Gln Gly Glu Gly Tyr Arg Gly Thr Val Asn Thr
275 280 285
Ile Trp Asn Gly Ile Pro Cys Gln Arg Trp Asp Ser Gln Tyr Pro His
290 295 300
Glu His Asp Met Thr Pro Glu Asn Phe Lys Cys Lys Asp Leu Arg Glu
305 310 315 320
Asn Tyr Cys Arg Asn Pro Asp Gly Ser Glu Ser Pro Trp Cys Phe Thr
325 330 335
Thr Asp Pro Asn Ile Arg Val Gly Tyr Cys Ser Gln Ile Pro Asn Cys
340 345 350
Asp Met Ser His Gly Gln Asp Cys Tyr Arg Gly Asn Gly Lys Asn Tyr
355 360 365
Met Gly Asn Leu Ser Gln Thr Arg Ser Gly Leu Thr Cys Ser Met Trp
370 375 380
Asp Lys Asn Met Glu Asp Leu His Arg His Ile Phe Trp Glu Pro Asp
385 390 395 400
Ala Ser Lys Leu Asn Glu Asn Tyr Cys Arg Asn Pro Asp Asp Asp Ala
405 410 415
His Gly Pro Trp Cys Tyr Thr Gly Asn Pro Leu Ile Pro Trp Asp Tyr
420 425 430
Cys Pro Ile Ser Arg Cys Glu Gly Asp Thr Thr Pro Thr Ile Val Asn
435 440 445
Leu Asp His Pro Val Ile Ser Cys Ala Lys Thr Lys Gln Leu Arg Val
450 455 460
Val Asn Gly Ile Pro Thr Arg Thr Asn Ile Gly Trp Met Val Ser Leu
465 470 475 480
Arg Tyr Arg Asn Lys His Ile Cys Gly Gly Ser Leu Ile Lys Glu Ser
485 490 495
Trp Val Leu Thr Ala Arg Gln Cys Phe Pro Ser Arg Asp Leu Lys Asp
500 505 510
Tyr Glu Ala Trp Leu Gly Ile His Asp Val His Gly Arg Gly Asp Glu
515 520 525
Lys Cys Lys Gln Val Leu Asn Val Ser Gln Leu Val Tyr Gly Pro Glu
530 535 540
Gly Ser Asp Leu Val Leu Met Lys Leu Ala Arg Pro Ala Val Leu Asp
545 550 555 560
Asp Phe Val Ser Thr Ile Asp Leu Pro Asn Tyr Gly Cys Thr Ile Pro
565 570 575
Glu Lys Thr Ser Cys Ser Val Tyr Gly Trp Gly Tyr Thr Gly Leu Ile
580 585 590
Asn Tyr Asp Gly Leu Leu Arg Val Ala His Leu Tyr Ile Met Gly Asn
595 600 605
Glu Lys Cys Ser Gln His His Arg Gly Lys Val Thr Leu Asn Glu Ser
610 615 620
Glu Ile Cys Ala Gly Ala Glu Lys Ile Gly Ser Gly Pro Cys Glu Gly
625 630 635 640
Asp Tyr Gly Gly Pro Leu Val Cys Glu Gln His Lys Met Arg Met Val
645 650 655
Leu Gly Val Ile Val Pro Gly Arg Gly Cys Ala Ile Pro Asn Arg Pro
660 665 670
Gly Ile Phe Val Arg Val Ala Tyr Tyr Ala Lys Trp Ile His Lys Ile
675 680 685
Ile Leu Thr Tyr Lys Val Pro Gln Ser
690 695
<210> 103
<211> 276
<212> DNA
<213> Artificial Sequence
<220>
<223> c-Met binding FN3 domain
<400> 103
ctgccggctc cgaagaactt ggtggtgagc cgtgttaccg aagatagcgc acgcctgagc 60
tggacggcac cggatgcggc gttcgatagc ttctggattc gctattttga gtttctgggt 120
agcggtgagg caattgttct gacggtgccg ggctctgaac gctcctacga tttgaccggt 180
ctgaaaccgg gcaccgagta tgtggtgaac attctgagcg ttaagggcgg tagcatcagc 240
ccaccgctga gcgcgatctt cacgactggt ggttgc 276
<210> 104
<211> 267
<212> DNA
<213> Artificial Sequence
<220>
<223> c-Met binding FN3 domain
<400> 104
ctgccggcac cgaagaacct ggttgtcagc cgtgtgaccg aggatagcgc acgtttgagc 60
tggaccgctc cggatgcagc ctttgacagc ttctggattc gttactttga atttctgggt 120
agcggtgagg cgatcgttct gacggtgccg ggctctgaac gcagctatga tttgacgggc 180
ctgaagccgg gtactgagta cgtggttaac atcatgggcg ttaagggtgg taaaatcagc 240
ccgccattgt ccgcgatctt taccacg 267
<210> 105
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> linker
<400> 105
Gly Gly Gly Gly Ser
1 5
<210> 106
<211> 194
<212> PRT
<213> Artificial Sequence
<220>
<223> Bispecific EGFR/c-Met binding molecule
<400> 106
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Ile Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala
85 90 95
Pro Ala Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu
100 105 110
Val Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala
115 120 125
Pro Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe Leu
130 135 140
Gly Ser Gly Glu Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser
145 150 155 160
Tyr Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu Tyr Val Val Asn Ile
165 170 175
Leu Ser Val Lys Gly Gly Ser Ile Ser Pro Pro Leu Ser Ala Ile Phe
180 185 190
Thr Thr
<210> 107
<211> 94
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain
<400> 107
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Ala Asp Pro His Gly Phe Tyr Asp Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr
85 90
<210> 108
<211> 94
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain
<400> 108
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Ile Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr
85 90
<210> 109
<211> 94
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain
<400> 109
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Asp Asp Pro His Ala Phe Tyr Glu Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Ile Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr
85 90
<210> 110
<211> 94
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain
<400> 110
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Ala Asp Pro His Gly Phe Tyr Asp Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Ile Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr
85 90
<210> 111
<211> 89
<212> PRT
<213> Artificial Sequence
<220>
<223> c-Met binding FN3 domain
<400> 111
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe Trp
20 25 30
Ile Arg Tyr Phe Glu Phe Leu Gly Ser Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Val Val Asn Ile Leu Gly Val Lys Gly Gly Lys Ile Ser
65 70 75 80
Pro Pro Leu Ser Ala Ile Phe Thr Thr
85
<210> 112
<211> 89
<212> PRT
<213> Artificial Sequence
<220>
<223> c-Met binding FN3 domain
<400> 112
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe Trp
20 25 30
Ile Arg Tyr Phe Glu Phe Val Gly Ser Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Val Val Asn Ile Leu Gly Val Lys Gly Gly Ser Ile Ser
65 70 75 80
Pro Pro Leu Ser Ala Ile Phe Thr Thr
85
<210> 113
<211> 89
<212> PRT
<213> Artificial Sequence
<220>
<223> c-Met binding FN3 domain
<400> 113
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe Trp
20 25 30
Ile Arg Tyr Phe Glu Phe Val Ser Lys Gly Asp Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Val Val Asn Ile Leu Gly Val Lys Gly Gly Ser Ile Ser
65 70 75 80
Pro Pro Leu Ser Ala Ile Phe Thr Thr
85
<210> 114
<211> 89
<212> PRT
<213> Artificial Sequence
<220>
<223> c-Met binding FN3 domain
<400> 114
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe Trp
20 25 30
Ile Arg Tyr Phe Glu Phe Leu Gly Ser Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Val Val Asn Ile Leu Ser Val Lys Gly Gly Ser Ile Ser
65 70 75 80
Pro Pro Leu Ser Ala Ile Phe Thr Thr
85
<210> 115
<211> 591
<212> DNA
<213> Artificial Sequence
<220>
<223> Bispecific EGFR/c-Met binding molecule
<400> 115
atgttgccag cgccgaagaa cctggtagtt agcgaggtta ctgaggacag cgcgcgtctg 60
agctgggacg atccgtgggc gttctacgag agctttctga tccagtatca agagagcgag 120
aaagtcggtg aagcgattgt gctgaccgtc ccgggctccg agcgttccta cgacctgacc 180
ggtttgaagc cgggtaccga gtatacggtg agcatctacg gtgttcacaa tgtctataag 240
gacactaata tccgcggtct gcctctgagc gccattttca ccaccgcacc ggcaccggct 300
ccggctcctg ccccgctgcc ggctccgaag aacttggtgg tgagccgtgt taccgaagat 360
agcgcacgcc tgagctggac ggcaccggat gcggcgttcg atagcttctg gattcgctat 420
tttgagtttc tgggtagcgg tgaggcaatt gttctgacgg tgccgggctc tgaacgctcc 480
tacgatttga ccggtctgaa accgggcacc gagtatgtgg tgaacattct gagcgttaag 540
ggcggtagca tcagcccacc gctgagcgcg atcttcacga ctggtggttg c 591
<210> 116
<211> 582
<212> DNA
<213> Artificial Sequence
<220>
<223> Bispecific EGFR/c-Met binding molecule
<400> 116
atgctgccag cccctaagaa tctggtcgtg agcgaagtaa ccgaggacag cgcccgcctg 60
agctgggacg acccgtgggc gttctatgag tctttcctga ttcagtatca agaaagcgaa 120
aaagttggcg aagcgatcgt cctgaccgtc ccgggtagcg agcgctccta cgatctgacc 180
ggcctgaaac cgggtacgga gtacacggtg tccatttacg gtgttcacaa tgtgtataaa 240
gacaccaaca tgcgtggcct gccgctgtcg gcgattttca ccaccgcgcc tgcgccagcg 300
cctgcaccgg ctccgctgcc ggcaccgaag aacctggttg tcagccgtgt gaccgaggat 360
agcgcacgtt tgagctggac cgctccggat gcagcctttg acagcttctg gattcgttac 420
tttgaatttc tgggtagcgg tgaggcgatc gttctgacgg tgccgggctc tgaacgcagc 480
tatgatttga cgggcctgaa gccgggtact gagtacgtgg ttaacatcat gggcgttaag 540
ggtggtaaaa tcagcccgcc attgtccgcg atctttacca cg 582
<210> 117
<211> 51
<212> PRT
<213> Artificial Sequence
<220>
<223> albumin binding domain
<400> 117
Thr Ile Asp Glu Trp Leu Leu Lys Glu Ala Lys Glu Lys Ala Ile Glu
1 5 10 15
Glu Leu Lys Lys Ala Gly Ile Thr Ser Asp Tyr Tyr Phe Asp Leu Ile
20 25 30
Asn Lys Ala Lys Thr Val Glu Gly Val Asn Ala Leu Lys Asp Glu Ile
35 40 45
Leu Lys Ala
50
<210> 118
<211> 250
<212> PRT
<213> Artificial Sequence
<220>
<223> Bispecific EGFR/c-Met binding molecule
<400> 118
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala
85 90 95
Pro Ala Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu
100 105 110
Val Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala
115 120 125
Pro Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Asp Glu Val Val
130 135 140
Val Gly Gly Glu Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser
145 150 155 160
Tyr Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu Tyr Tyr Val Asn Ile
165 170 175
Leu Gly Val Lys Gly Gly Ser Ile Ser Val Pro Leu Ser Ala Ile Phe
180 185 190
Thr Thr Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Leu Ala Glu Ala
195 200 205
Lys Val Leu Ala Asn Arg Glu Leu Asp Lys Tyr Gly Val Ser Asp Tyr
210 215 220
Tyr Lys Asn Leu Ile Asn Asn Ala Lys Thr Val Glu Gly Val Lys Ala
225 230 235 240
Leu Leu Asp Glu Ile Leu Ala Ala Leu Pro
245 250
<210> 119
<211> 250
<212> PRT
<213> Artificial Sequence
<220>
<223> Bispecific EGFR/c-Met binding molecule
<400> 119
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Ala Asp Pro His Gly Phe Tyr Asp Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala
85 90 95
Pro Ala Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu
100 105 110
Val Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala
115 120 125
Pro Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Asp Glu Val Val
130 135 140
Val Gly Gly Glu Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser
145 150 155 160
Tyr Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu Tyr Tyr Val Asn Ile
165 170 175
Leu Gly Val Lys Gly Gly Ser Ile Ser Val Pro Leu Ser Ala Ile Phe
180 185 190
Thr Thr Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Leu Ala Glu Ala
195 200 205
Lys Val Leu Ala Asn Arg Glu Leu Asp Lys Tyr Gly Val Ser Asp Tyr
210 215 220
Tyr Lys Asn Leu Ile Asn Asn Ala Lys Thr Val Glu Gly Val Lys Ala
225 230 235 240
Leu Leu Asp Glu Ile Leu Ala Ala Leu Pro
245 250
<210> 120
<211> 250
<212> PRT
<213> Artificial Sequence
<220>
<223> Bispecific EGFR/c-Met binding molecule
<400> 120
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala
85 90 95
Pro Ala Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu
100 105 110
Val Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala
115 120 125
Pro Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe Leu
130 135 140
Gly Ser Gly Glu Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser
145 150 155 160
Tyr Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu Tyr Val Val Asn Ile
165 170 175
Met Gly Val Lys Gly Gly Lys Ile Ser Pro Pro Leu Ser Ala Ile Phe
180 185 190
Thr Thr Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Leu Ala Glu Ala
195 200 205
Lys Val Leu Ala Asn Arg Glu Leu Asp Lys Tyr Gly Val Ser Asp Tyr
210 215 220
Tyr Lys Asn Leu Ile Asn Asn Ala Lys Thr Val Glu Gly Val Lys Ala
225 230 235 240
Leu Leu Asp Glu Ile Leu Ala Ala Leu Pro
245 250
<210> 121
<211> 250
<212> PRT
<213> Artificial Sequence
<220>
<223> Bispecific EGFR/c-Met binding molecule
<400> 121
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Ala Asp Pro His Gly Phe Tyr Asp Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala
85 90 95
Pro Ala Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu
100 105 110
Val Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala
115 120 125
Pro Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe Leu
130 135 140
Gly Ser Gly Glu Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser
145 150 155 160
Tyr Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu Tyr Val Val Asn Ile
165 170 175
Met Gly Val Lys Gly Gly Lys Ile Ser Pro Pro Leu Ser Ala Ile Phe
180 185 190
Thr Thr Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Leu Ala Glu Ala
195 200 205
Lys Val Leu Ala Asn Arg Glu Leu Asp Lys Tyr Gly Val Ser Asp Tyr
210 215 220
Tyr Lys Asn Leu Ile Asn Asn Ala Lys Thr Val Glu Gly Val Lys Ala
225 230 235 240
Leu Leu Asp Glu Ile Leu Ala Ala Leu Pro
245 250
<210> 122
<211> 95
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain
<400> 122
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Leu Arg Leu Ser Trp Ala Asp Pro His Gly Phe Tyr Asp Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Asn Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Glu Phe Thr Thr
85 90 95
<210> 123
<211> 95
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain
<400> 123
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Leu Arg Leu Ser Trp Thr Tyr Asp Arg Asp Gly Tyr Asp Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Asn Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Glu Phe Thr Thr
85 90 95
<210> 124
<211> 95
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain
<400> 124
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Leu Arg Leu Ser Trp Gly Tyr Asn Gly Asp His Phe Asp Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Asn Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Glu Phe Thr Thr
85 90 95
<210> 125
<211> 95
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain
<400> 125
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Leu Arg Leu Ser Trp Asp Asp Pro Arg Gly Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Asn Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Glu Phe Thr Thr
85 90 95
<210> 126
<211> 95
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain
<400> 126
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Leu Arg Leu Ser Trp Thr Trp Pro Tyr Ala Asp Leu Asp Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Asn Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Glu Phe Thr Thr
85 90 95
<210> 127
<211> 95
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain
<400> 127
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Leu Arg Leu Ser Trp Gly Tyr Asn Gly Asp His Phe Asp Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Asn Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Glu Phe Thr Thr
85 90 95
<210> 128
<211> 96
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain
<400> 128
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Leu Arg Leu Ser Trp Asp Tyr Asp Leu Gly Val Tyr Phe Asp Ser
20 25 30
Phe Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Asn
35 40 45
Leu Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys
50 55 60
Pro Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr
65 70 75 80
Lys Asp Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Glu Phe Thr Thr
85 90 95
<210> 129
<211> 95
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain
<400> 129
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Leu Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Asn Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Glu Phe Thr Thr
85 90 95
<210> 130
<211> 95
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain
<400> 130
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Leu Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Asn Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val Leu Gly Ser Tyr Val
65 70 75 80
Phe Glu His Asp Val Met Leu Pro Leu Ser Ala Glu Phe Thr Thr
85 90 95
<210> 131
<211> 95
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain
<400> 131
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr
85 90 95
<210> 132
<211> 95
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain
<400> 132
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val Leu Gly Ser Tyr Val
65 70 75 80
Phe Glu His Asp Val Met Leu Pro Leu Ser Ala Ile Phe Thr Thr
85 90 95
<210> 133
<211> 95
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain
<400> 133
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Leu Arg Leu Ser Trp Thr Trp Pro Tyr Ala Asp Leu Asp Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Asn Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Glu Phe Thr Thr
85 90 95
<210> 134
<211> 95
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain
<400> 134
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Ala Asp Pro His Gly Phe Tyr Asp Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr
85 90 95
<210> 135
<211> 95
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain
<400> 135
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Ile Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr
85 90 95
<210> 136
<211> 95
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain
<400> 136
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro His Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Ile Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr
85 90 95
<210> 137
<211> 95
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain
<400> 137
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Ala Asp Pro His Gly Phe Tyr Asp Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Ile Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr
85 90 95
<210> 138
<211> 204
<212> PRT
<213> Artificial Sequence
<220>
<223> Bispecific EGFR/c-Met binding domain
<400> 138
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Gly Gly
85 90 95
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
100 105 110
Gly Ser Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr
115 120 125
Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp
130 135 140
Ser Phe Trp Ile Arg Tyr Asp Glu Val Val Val Gly Gly Glu Ala Ile
145 150 155 160
Val Leu Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu
165 170 175
Lys Pro Gly Thr Glu Tyr Tyr Val Asn Ile Leu Gly Val Lys Gly Gly
180 185 190
Ser Ile Ser Val Pro Leu Ser Ala Ile Phe Thr Thr
195 200
<210> 139
<211> 203
<212> PRT
<213> Artificial Sequence
<220>
<223> Bispecific EGFR/c-Met binding domain
<400> 139
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Gly Gly
85 90 95
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
100 105 110
Gly Ser Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu
115 120 125
Asp Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser
130 135 140
Phe Trp Ile Arg Tyr Phe Glu Phe Leu Gly Ser Gly Glu Ala Ile Val
145 150 155 160
Leu Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys
165 170 175
Pro Gly Thr Glu Tyr Val Val Asn Ile Met Gly Val Lys Gly Gly Lys
180 185 190
Ile Ser Pro Pro Leu Ser Ala Ile Phe Thr Thr
195 200
<210> 140
<211> 204
<212> PRT
<213> Artificial Sequence
<220>
<223> Bispecific EGFR/c-Met binding domain
<400> 140
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Gly Gly
85 90 95
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
100 105 110
Gly Ser Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr
115 120 125
Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp
130 135 140
Ser Phe Trp Ile Arg Tyr Phe Glu Phe Leu Gly Ser Gly Glu Ala Ile
145 150 155 160
Val Leu Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu
165 170 175
Lys Pro Gly Thr Glu Tyr Val Val Gln Ile Ile Gly Val Lys Gly Gly
180 185 190
His Ile Ser Leu Pro Leu Ser Ala Ile Phe Thr Thr
195 200
<210> 141
<211> 204
<212> PRT
<213> Artificial Sequence
<220>
<223> Bispecific EGFR/c-Met binding domain
<400> 141
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Gly Gly
85 90 95
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
100 105 110
Gly Ser Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr
115 120 125
Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp
130 135 140
Ser Phe Phe Ile Arg Tyr Asp Glu Phe Leu Arg Ser Gly Glu Ala Ile
145 150 155 160
Val Leu Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu
165 170 175
Lys Pro Gly Thr Glu Tyr Trp Val Thr Ile Leu Gly Val Lys Gly Gly
180 185 190
Leu Val Ser Thr Pro Leu Ser Ala Ile Phe Thr Thr
195 200
<210> 142
<211> 204
<212> PRT
<213> Artificial Sequence
<220>
<223> Bispecific EGFR/c-Met binding domain
<400> 142
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Ala Asp Pro His Gly Phe Tyr Asp Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Gly Gly
85 90 95
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
100 105 110
Gly Ser Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr
115 120 125
Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp
130 135 140
Ser Phe Trp Ile Arg Tyr Phe Glu Phe Leu Gly Ser Gly Glu Ala Ile
145 150 155 160
Val Leu Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu
165 170 175
Lys Pro Gly Thr Glu Tyr Val Val Asn Ile Met Gly Val Lys Gly Gly
180 185 190
Lys Ile Ser Pro Pro Leu Ser Ala Ile Phe Thr Thr
195 200
<210> 143
<211> 204
<212> PRT
<213> Artificial Sequence
<220>
<223> Bispecific EGFR/c-Met binding domain
<400> 143
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Ala Asp Pro His Gly Phe Tyr Asp Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Gly Gly
85 90 95
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
100 105 110
Gly Ser Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr
115 120 125
Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp
130 135 140
Ser Phe Trp Ile Arg Tyr Phe Glu Phe Leu Gly Ser Gly Glu Ala Ile
145 150 155 160
Val Leu Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu
165 170 175
Lys Pro Gly Thr Glu Tyr Val Val Gln Ile Ile Gly Val Lys Gly Gly
180 185 190
His Ile Ser Leu Pro Leu Ser Ala Ile Phe Thr Thr
195 200
<210> 144
<211> 204
<212> PRT
<213> Artificial Sequence
<220>
<223> Bispecific EGFR/c-Met binding domain
<400> 144
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Ala Asp Pro His Gly Phe Tyr Asp Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Gly Gly
85 90 95
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
100 105 110
Gly Ser Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr
115 120 125
Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp
130 135 140
Ser Phe Trp Ile Arg Tyr Phe Glu Phe Leu Gly Ser Gly Glu Ala Ile
145 150 155 160
Val Leu Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu
165 170 175
Lys Pro Gly Thr Glu Tyr Val Val Gln Ile Ile Gly Val Lys Gly Gly
180 185 190
His Ile Ser Leu Pro Leu Ser Ala Ile Phe Thr Thr
195 200
<210> 145
<211> 193
<212> PRT
<213> Artificial Sequence
<220>
<223> Bispecific EGFR/c-Met binding domain
<400> 145
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala Pro
85 90 95
Ala Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu Val
100 105 110
Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala Pro
115 120 125
Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe Leu Gly
130 135 140
Ser Gly Glu Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser Tyr
145 150 155 160
Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu Tyr Val Val Asn Ile Met
165 170 175
Gly Val Lys Gly Gly Lys Ile Ser Pro Pro Leu Ser Ala Ile Phe Thr
180 185 190
Thr
<210> 146
<211> 193
<212> PRT
<213> Artificial Sequence
<220>
<223> Bispecific EGFR/c-Met binding domain
<400> 146
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala Pro
85 90 95
Ala Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu Val
100 105 110
Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala Pro
115 120 125
Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Asp Glu Val Val Val
130 135 140
Gly Gly Glu Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser Tyr
145 150 155 160
Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu Tyr Tyr Val Asn Ile Leu
165 170 175
Gly Val Lys Gly Gly Ser Ile Ser Val Pro Leu Ser Ala Ile Phe Thr
180 185 190
Thr
<210> 147
<211> 194
<212> PRT
<213> Artificial Sequence
<220>
<223> Bispecific EGFR/c-Met binding domain
<400> 147
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Ala Asp Pro His Gly Phe Tyr Asp Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala Pro
85 90 95
Ala Pro Ala Pro Ala Pro Ala Pro Met Leu Pro Ala Pro Lys Asn Leu
100 105 110
Val Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala
115 120 125
Pro Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe Leu
130 135 140
Gly Ser Gly Glu Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser
145 150 155 160
Tyr Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu Tyr Val Val Asn Ile
165 170 175
Met Gly Val Lys Gly Gly Lys Ile Ser Pro Pro Leu Ser Ala Ile Phe
180 185 190
Thr Thr
<210> 148
<211> 193
<212> PRT
<213> Artificial Sequence
<220>
<223> Bispecific EGFR/c-Met binding domain
<400> 148
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Ala Asp Pro His Gly Phe Tyr Asp Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala Pro
85 90 95
Ala Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu Val
100 105 110
Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala Pro
115 120 125
Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Asp Glu Val Val Val
130 135 140
Gly Gly Glu Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser Tyr
145 150 155 160
Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu Tyr Tyr Val Asn Ile Leu
165 170 175
Gly Val Lys Gly Gly Ser Ile Ser Val Pro Leu Ser Ala Ile Phe Thr
180 185 190
Thr
<210> 149
<211> 193
<212> PRT
<213> Artificial Sequence
<220>
<223> Bispecific EGFR/c-Met binding domain
<400> 149
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Ile Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala Pro
85 90 95
Ala Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu Val
100 105 110
Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala Pro
115 120 125
Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe Leu Gly
130 135 140
Ser Gly Glu Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser Tyr
145 150 155 160
Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu Tyr Val Val Asn Ile Leu
165 170 175
Gly Val Lys Gly Gly Lys Ile Ser Pro Pro Leu Ser Ala Ile Phe Thr
180 185 190
Thr
<210> 150
<211> 193
<212> PRT
<213> Artificial Sequence
<220>
<223> Bispecific EGFR/c-Met binding domain
<400> 150
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Ile Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala Pro
85 90 95
Ala Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu Val
100 105 110
Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala Pro
115 120 125
Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe Val Gly
130 135 140
Ser Gly Glu Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser Tyr
145 150 155 160
Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu Tyr Val Val Asn Ile Leu
165 170 175
Gly Val Lys Gly Gly Ser Ile Ser Pro Pro Leu Ser Ala Ile Phe Thr
180 185 190
Thr
<210> 151
<211> 193
<212> PRT
<213> Artificial Sequence
<220>
<223> Bispecific EGFR/c-Met binding domain
<400> 151
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Ile Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala Pro
85 90 95
Ala Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu Val
100 105 110
Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala Pro
115 120 125
Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe Val Ser
130 135 140
Lys Gly Asp Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser Tyr
145 150 155 160
Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu Tyr Val Val Asn Ile Leu
165 170 175
Gly Val Lys Gly Gly Ser Ile Ser Pro Pro Leu Ser Ala Ile Phe Thr
180 185 190
Thr
<210> 152
<211> 193
<212> PRT
<213> Artificial Sequence
<220>
<223> Bispecific EGFR/c-Met binding domain
<400> 152
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Ile Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala Pro
85 90 95
Ala Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu Val
100 105 110
Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala Pro
115 120 125
Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe Leu Gly
130 135 140
Ser Gly Glu Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser Tyr
145 150 155 160
Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu Tyr Val Val Asn Ile Leu
165 170 175
Ser Val Lys Gly Gly Ser Ile Ser Pro Pro Leu Ser Ala Ile Phe Thr
180 185 190
Thr
<210> 153
<211> 193
<212> PRT
<213> Artificial Sequence
<220>
<223> Bispecific EGFR/c-Met binding domain
<400> 153
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Asp Asp Pro His Ala Phe Tyr Glu Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Ile Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala Pro
85 90 95
Ala Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu Val
100 105 110
Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala Pro
115 120 125
Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe Leu Gly
130 135 140
Ser Gly Glu Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser Tyr
145 150 155 160
Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu Tyr Val Val Asn Ile Leu
165 170 175
Gly Val Lys Gly Gly Lys Ile Ser Pro Pro Leu Ser Ala Ile Phe Thr
180 185 190
Thr
<210> 154
<211> 193
<212> PRT
<213> Artificial Sequence
<220>
<223> Bispecific EGFR/c-Met binding domain
<400> 154
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Asp Asp Pro His Ala Phe Tyr Glu Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Ile Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala Pro
85 90 95
Ala Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu Val
100 105 110
Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala Pro
115 120 125
Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe Val Gly
130 135 140
Ser Gly Glu Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser Tyr
145 150 155 160
Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu Tyr Val Val Asn Ile Leu
165 170 175
Gly Val Lys Gly Gly Ser Ile Ser Pro Pro Leu Ser Ala Ile Phe Thr
180 185 190
Thr
<210> 155
<211> 193
<212> PRT
<213> Artificial Sequence
<220>
<223> Bispecific EGFR/c-Met binding domain
<400> 155
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Asp Asp Pro His Ala Phe Tyr Glu Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Ile Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala Pro
85 90 95
Ala Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu Val
100 105 110
Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala Pro
115 120 125
Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe Val Ser
130 135 140
Lys Gly Asp Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser Tyr
145 150 155 160
Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu Tyr Val Val Asn Ile Leu
165 170 175
Gly Val Lys Gly Gly Ser Ile Ser Pro Pro Leu Ser Ala Ile Phe Thr
180 185 190
Thr
<210> 156
<211> 193
<212> PRT
<213> Artificial Sequence
<220>
<223> Bispecific EGFR/c-Met binding domain
<400> 156
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Asp Asp Pro His Ala Phe Tyr Glu Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Ile Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala Pro
85 90 95
Ala Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu Val
100 105 110
Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala Pro
115 120 125
Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe Leu Gly
130 135 140
Ser Gly Glu Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser Tyr
145 150 155 160
Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu Tyr Val Val Asn Ile Leu
165 170 175
Ser Val Lys Gly Gly Ser Ile Ser Pro Pro Leu Ser Ala Ile Phe Thr
180 185 190
Thr
<210> 157
<211> 193
<212> PRT
<213> Artificial Sequence
<220>
<223> Bispecific EGFR/c-Met binding domain
<400> 157
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Ala Asp Pro His Gly Phe Tyr Asp Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Ile Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala Pro
85 90 95
Ala Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu Val
100 105 110
Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala Pro
115 120 125
Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe Leu Gly
130 135 140
Ser Gly Glu Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser Tyr
145 150 155 160
Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu Tyr Val Val Asn Ile Leu
165 170 175
Gly Val Lys Gly Gly Lys Ile Ser Pro Pro Leu Ser Ala Ile Phe Thr
180 185 190
Thr
<210> 158
<211> 193
<212> PRT
<213> Artificial Sequence
<220>
<223> Bispecific EGFR/c-Met binding domain
<400> 158
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Ala Asp Pro His Gly Phe Tyr Asp Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Ile Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala Pro
85 90 95
Ala Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu Val
100 105 110
Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala Pro
115 120 125
Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe Val Gly
130 135 140
Ser Gly Glu Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser Tyr
145 150 155 160
Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu Tyr Val Val Asn Ile Leu
165 170 175
Gly Val Lys Gly Gly Ser Ile Ser Pro Pro Leu Ser Ala Ile Phe Thr
180 185 190
Thr
<210> 159
<211> 193
<212> PRT
<213> Artificial Sequence
<220>
<223> Bispecific EGFR/c-Met binding domain
<400> 159
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Ala Asp Pro His Gly Phe Tyr Asp Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Ile Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala Pro
85 90 95
Ala Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu Val
100 105 110
Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala Pro
115 120 125
Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe Val Ser
130 135 140
Lys Gly Asp Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser Tyr
145 150 155 160
Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu Tyr Val Val Asn Ile Leu
165 170 175
Gly Val Lys Gly Gly Ser Ile Ser Pro Pro Leu Ser Ala Ile Phe Thr
180 185 190
Thr
<210> 160
<211> 193
<212> PRT
<213> Artificial Sequence
<220>
<223> Bispecific EGFR/c-Met binding domain
<400> 160
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Ala Asp Pro His Gly Phe Tyr Asp Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Ile Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala Pro
85 90 95
Ala Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu Val
100 105 110
Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala Pro
115 120 125
Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe Leu Gly
130 135 140
Ser Gly Glu Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser Tyr
145 150 155 160
Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu Tyr Val Val Asn Ile Leu
165 170 175
Ser Val Lys Gly Gly Ser Ile Ser Pro Pro Leu Ser Ala Ile Phe Thr
180 185 190
Thr
<210> 161
<211> 193
<212> PRT
<213> Artificial Sequence
<220>
<223> Bispecific EGFR/c-Met binding domain
<400> 161
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Ile Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala Pro
85 90 95
Ala Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu Val
100 105 110
Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala Pro
115 120 125
Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe Leu Gly
130 135 140
Ser Gly Glu Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser Tyr
145 150 155 160
Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu Tyr Val Val Asn Ile Leu
165 170 175
Ser Val Lys Gly Gly Ser Ile Ser Pro Pro Leu Ser Ala Ile Phe Thr
180 185 190
Thr
<210> 162
<211> 249
<212> PRT
<213> Artificial Sequence
<220>
<223> Bispecific EGFR/c-Met binding domain
<400> 162
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala Pro
85 90 95
Ala Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu Val
100 105 110
Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala Pro
115 120 125
Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Asp Glu Val Val Val
130 135 140
Gly Gly Glu Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser Tyr
145 150 155 160
Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu Tyr Tyr Val Asn Ile Leu
165 170 175
Gly Val Lys Gly Gly Ser Ile Ser Val Pro Leu Ser Ala Ile Phe Thr
180 185 190
Thr Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Leu Ala Glu Ala Lys
195 200 205
Val Leu Ala Asn Arg Glu Leu Asp Lys Tyr Gly Val Ser Asp Tyr Tyr
210 215 220
Lys Asn Leu Ile Asn Asn Ala Lys Thr Val Glu Gly Val Lys Ala Leu
225 230 235 240
Leu Asp Glu Ile Leu Ala Ala Leu Pro
245
<210> 163
<211> 249
<212> PRT
<213> Artificial Sequence
<220>
<223> Bispecific EGFR/c-Met binding domain
<400> 163
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Ala Asp Pro His Gly Phe Tyr Asp Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala Pro
85 90 95
Ala Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu Val
100 105 110
Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala Pro
115 120 125
Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Asp Glu Val Val Val
130 135 140
Gly Gly Glu Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser Tyr
145 150 155 160
Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu Tyr Tyr Val Asn Ile Leu
165 170 175
Gly Val Lys Gly Gly Ser Ile Ser Val Pro Leu Ser Ala Ile Phe Thr
180 185 190
Thr Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Leu Ala Glu Ala Lys
195 200 205
Val Leu Ala Asn Arg Glu Leu Asp Lys Tyr Gly Val Ser Asp Tyr Tyr
210 215 220
Lys Asn Leu Ile Asn Asn Ala Lys Thr Val Glu Gly Val Lys Ala Leu
225 230 235 240
Leu Asp Glu Ile Leu Ala Ala Leu Pro
245
<210> 164
<211> 249
<212> PRT
<213> Artificial Sequence
<220>
<223> Bispecific EGFR/c-Met binding domain
<400> 164
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala Pro
85 90 95
Ala Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu Val
100 105 110
Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala Pro
115 120 125
Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe Leu Gly
130 135 140
Ser Gly Glu Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser Tyr
145 150 155 160
Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu Tyr Val Val Asn Ile Met
165 170 175
Gly Val Lys Gly Gly Lys Ile Ser Pro Pro Leu Ser Ala Ile Phe Thr
180 185 190
Thr Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Leu Ala Glu Ala Lys
195 200 205
Val Leu Ala Asn Arg Glu Leu Asp Lys Tyr Gly Val Ser Asp Tyr Tyr
210 215 220
Lys Asn Leu Ile Asn Asn Ala Lys Thr Val Glu Gly Val Lys Ala Leu
225 230 235 240
Leu Asp Glu Ile Leu Ala Ala Leu Pro
245
<210> 165
<211> 249
<212> PRT
<213> Artificial Sequence
<220>
<223> Bispecific EGFR/c-Met binding domain
<400> 165
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Ala Asp Pro His Gly Phe Tyr Asp Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala Pro
85 90 95
Ala Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu Val
100 105 110
Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala Pro
115 120 125
Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe Leu Gly
130 135 140
Ser Gly Glu Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser Tyr
145 150 155 160
Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu Tyr Val Val Asn Ile Met
165 170 175
Gly Val Lys Gly Gly Lys Ile Ser Pro Pro Leu Ser Ala Ile Phe Thr
180 185 190
Thr Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Leu Ala Glu Ala Lys
195 200 205
Val Leu Ala Asn Arg Glu Leu Asp Lys Tyr Gly Val Ser Asp Tyr Tyr
210 215 220
Lys Asn Leu Ile Asn Asn Ala Lys Thr Val Glu Gly Val Lys Ala Leu
225 230 235 240
Leu Asp Glu Ile Leu Ala Ala Leu Pro
245
<210> 166
<211> 588
<212> DNA
<213> Artificial Sequence
<220>
<223> Bispecific EGFR/c-Met binding domain
<400> 166
ttgccagcgc cgaagaacct ggtagttagc gaggttactg aggacagcgc gcgtctgagc 60
tgggacgatc cgtgggcgtt ctacgagagc tttctgatcc agtatcaaga gagcgagaaa 120
gtcggtgaag cgattgtgct gaccgtcccg ggctccgagc gttcctacga cctgaccggt 180
ttgaagccgg gtaccgagta tacggtgagc atctacggtg ttcacaatgt ctataaggac 240
actaatatcc gcggtctgcc tctgagcgcc attttcacca ccgcaccggc accggctccg 300
gctcctgccc cgctgccggc tccgaagaac ttggtggtga gccgtgttac cgaagatagc 360
gcacgcctga gctggacggc accggatgcg gcgttcgata gcttctggat tcgctatttt 420
gagtttctgg gtagcggtga ggcaattgtt ctgacggtgc cgggctctga acgctcctac 480
gatttgaccg gtctgaaacc gggcaccgag tatgtggtga acattctgag cgttaagggc 540
ggtagcatca gcccaccgct gagcgcgatc ttcacgactg gtggttgc 588
<210> 167
<211> 579
<212> DNA
<213> Artificial Sequence
<220>
<223> Bispecific EGFR/c-Met binding domain
<400> 167
ctgccagccc ctaagaatct ggtcgtgagc gaagtaaccg aggacagcgc ccgcctgagc 60
tgggacgacc cgtgggcgtt ctatgagtct ttcctgattc agtatcaaga aagcgaaaaa 120
gttggcgaag cgatcgtcct gaccgtcccg ggtagcgagc gctcctacga tctgaccggc 180
ctgaaaccgg gtacggagta cacggtgtcc atttacggtg ttcacaatgt gtataaagac 240
accaacatgc gtggcctgcc gctgtcggcg attttcacca ccgcgcctgc gccagcgcct 300
gcaccggctc cgctgccggc accgaagaac ctggttgtca gccgtgtgac cgaggatagc 360
gcacgtttga gctggaccgc tccggatgca gcctttgaca gcttctggat tcgttacttt 420
gaatttctgg gtagcggtga ggcgatcgtt ctgacggtgc cgggctctga acgcagctat 480
gatttgacgg gcctgaagcc gggtactgag tacgtggtta acatcatggg cgttaagggt 540
ggtaaaatca gcccgccatt gtccgcgatc tttaccacg 579
<210> 168
<211> 282
<212> DNA
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain from ECB97
<400> 168
ttgccagcgc cgaagaacct ggtagttagc gaggttactg aggacagcgc gcgtctgagc 60
tgggacgatc cgtgggcgtt ctacgagagc tttctgatcc agtatcaaga gagcgagaaa 120
gtcggtgaag cgattgtgct gaccgtcccg ggctccgagc gttcctacga cctgaccggt 180
ttgaagccgg gtaccgagta tacggtgagc atctacggtg ttcacaatgt ctataaggac 240
actaatatcc gcggtctgcc tctgagcgcc attttcacca cc 282
<210> 169
<211> 282
<212> DNA
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain from ECB15
<400> 169
ctgccagccc ctaagaatct ggtcgtgagc gaagtaaccg aggacagcgc ccgcctgagc 60
tgggacgacc cgtgggcgtt ctatgagtct ttcctgattc agtatcaaga aagcgaaaaa 120
gttggcgaag cgatcgtcct gaccgtcccg ggtagcgagc gctcctacga tctgaccggc 180
ctgaaaccgg gtacggagta cacggtgtcc atttacggtg ttcacaatgt gtataaagac 240
accaacatgc gtggcctgcc gctgtcggcg attttcacca cc 282
<210> 170
<211> 195
<212> PRT
<213> Artificial Sequence
<220>
<223> Bispecific EGFR/c-Met binding molecule
<400> 170
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Ile Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala
85 90 95
Pro Ala Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu
100 105 110
Val Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala
115 120 125
Pro Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe Leu
130 135 140
Gly Ser Gly Glu Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser
145 150 155 160
Tyr Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu Tyr Val Val Asn Ile
165 170 175
Leu Gly Val Lys Gly Gly Lys Ile Ser Pro Pro Leu Ser Ala Ile Phe
180 185 190
Thr Thr Cys
195
<210> 171
<211> 195
<212> PRT
<213> Artificial Sequence
<220>
<223> Bispecific EGFR/c-Met binding molecule
<400> 171
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Ile Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala
85 90 95
Pro Ala Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu
100 105 110
Val Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala
115 120 125
Pro Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe Val
130 135 140
Gly Ser Gly Glu Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser
145 150 155 160
Tyr Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu Tyr Val Val Asn Ile
165 170 175
Leu Gly Val Lys Gly Gly Ser Ile Ser Pro Pro Leu Ser Ala Ile Phe
180 185 190
Thr Thr Cys
195
<210> 172
<211> 195
<212> PRT
<213> Artificial Sequence
<220>
<223> Bispecific EGFR/c-Met binding molecule
<400> 172
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Ile Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala
85 90 95
Pro Ala Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu
100 105 110
Val Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala
115 120 125
Pro Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe Val
130 135 140
Ser Lys Gly Asp Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser
145 150 155 160
Tyr Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu Tyr Val Val Asn Ile
165 170 175
Leu Gly Val Lys Gly Gly Ser Ile Ser Pro Pro Leu Ser Ala Ile Phe
180 185 190
Thr Thr Cys
195
<210> 173
<211> 195
<212> PRT
<213> Artificial Sequence
<220>
<223> Bispecific EGFR/c-Met binding molecule
<400> 173
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Ile Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala
85 90 95
Pro Ala Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu
100 105 110
Val Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala
115 120 125
Pro Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe Leu
130 135 140
Gly Ser Gly Glu Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser
145 150 155 160
Tyr Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu Tyr Val Val Asn Ile
165 170 175
Leu Ser Val Lys Gly Gly Ser Ile Ser Pro Pro Leu Ser Ala Ile Phe
180 185 190
Thr Thr Cys
195
<210> 174
<211> 195
<212> PRT
<213> Artificial Sequence
<220>
<223> Bispecific EGFR/c-Met binding molecule
<400> 174
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro His Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Ile Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala
85 90 95
Pro Ala Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu
100 105 110
Val Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala
115 120 125
Pro Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe Leu
130 135 140
Gly Ser Gly Glu Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser
145 150 155 160
Tyr Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu Tyr Val Val Asn Ile
165 170 175
Leu Gly Val Lys Gly Gly Lys Ile Ser Pro Pro Leu Ser Ala Ile Phe
180 185 190
Thr Thr Cys
195
<210> 175
<211> 195
<212> PRT
<213> Artificial Sequence
<220>
<223> Bispecific EGFR/c-Met binding molecule
<400> 175
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro His Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Ile Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala
85 90 95
Pro Ala Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu
100 105 110
Val Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala
115 120 125
Pro Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe Val
130 135 140
Gly Ser Gly Glu Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser
145 150 155 160
Tyr Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu Tyr Val Val Asn Ile
165 170 175
Leu Gly Val Lys Gly Gly Ser Ile Ser Pro Pro Leu Ser Ala Ile Phe
180 185 190
Thr Thr Cys
195
<210> 176
<211> 195
<212> PRT
<213> Artificial Sequence
<220>
<223> Bispecific EGFR/c-Met binding molecule
<400> 176
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro His Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Ile Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala
85 90 95
Pro Ala Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu
100 105 110
Val Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala
115 120 125
Pro Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe Val
130 135 140
Ser Lys Gly Asp Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser
145 150 155 160
Tyr Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu Tyr Val Val Asn Ile
165 170 175
Leu Gly Val Lys Gly Gly Ser Ile Ser Pro Pro Leu Ser Ala Ile Phe
180 185 190
Thr Thr Cys
195
<210> 177
<211> 195
<212> PRT
<213> Artificial Sequence
<220>
<223> Bispecific EGFR/c-Met binding molecule
<400> 177
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro His Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Ile Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala
85 90 95
Pro Ala Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu
100 105 110
Val Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala
115 120 125
Pro Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe Leu
130 135 140
Gly Ser Gly Glu Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser
145 150 155 160
Tyr Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu Tyr Val Val Asn Ile
165 170 175
Leu Ser Val Lys Gly Gly Ser Ile Ser Pro Pro Leu Ser Ala Ile Phe
180 185 190
Thr Thr Cys
195
<210> 178
<211> 195
<212> PRT
<213> Artificial Sequence
<220>
<223> Bispecific EGFR/c-Met binding molecule
<400> 178
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Ile Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala
85 90 95
Pro Ala Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu
100 105 110
Val Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala
115 120 125
Pro Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe Leu
130 135 140
Gly Ser Gly Glu Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser
145 150 155 160
Tyr Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu Tyr Val Val Asn Ile
165 170 175
Leu Ser Val Lys Gly Gly Ser Ile Ser Pro Pro Leu Ser Ala Ile Phe
180 185 190
Thr Thr Cys
195
<210> 179
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Consensus FG loop of EGFR bindiing FN3 domain
<220>
<221> VARIANT
<222> (9)..(9)
<223> Xaa may be Met or Ile
<400> 179
His Asn Val Tyr Lys Asp Thr Asn Xaa Arg Gly Leu
1 5 10
<210> 180
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> GF loop of EGFR binding FN3 domain
<400> 180
Leu Gly Ser Tyr Val Phe Glu His Asp Val Met Leu
1 5 10
<210> 181
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Consensus BC loop of EGFR binding FN3 domain
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa may be Ala, Thr, Gly or Asp
<220>
<221> VARIANT
<222> (2)..(2)
<223> Xaa may be Ala, Asp, Tyr or Trp
<220>
<221> VARIANT
<222> (3)..(3)
<223> Xaa may be Pro, Asp or Asn
<220>
<221> VARIANT
<222> (4)..(4)
<223> Xaa may be Leu or absent
<220>
<221> VARIANT
<222> (5)..(5)
<223> Xaa may be Asp, His, Arg, Gly, Tyr or Trp
<220>
<221> VARIANT
<222> (6)..(6)
<223> Xaa may be Glu, Asp or Ala
<220>
<221> VARIANT
<222> (7)..(7)
<223> Xaa may be Ala, Phe, Gly, His or Asp
<220>
<221> VARIANT
<222> (8)..(8)
<223> Xaa may be Tyr, Phe or Leu
<400> 181
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
1 5
<210> 182
<211> 95
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain consensus sequence
<220>
<221> VARIANT
<222> (22)..(22)
<223> Xaa may be Ala, Thr, Gly or Asp
<220>
<221> VARIANT
<222> (23)..(23)
<223> Xaa may be Ala, Asp, Tyr or Trp
<220>
<221> VARIANT
<222> (24)..(24)
<223> Xaa may be Pro, Asp or Asn
<220>
<221> VARIANT
<222> (25)..(25)
<223> Xaa may be Leu or absent
<220>
<221> VARIANT
<222> (26)..(26)
<223> Xaa may be Asp, His, Arg, Gly, Tyr or Trp
<220>
<221> VARIANT
<222> (27)..(27)
<223> Xaa may be Gly, Asp or Ala
<220>
<221> VARIANT
<222> (28)..(28)
<223> Xaa may be Ala, Phe, Gly, His or Asp
<220>
<221> VARIANT
<222> (29)..(29)
<223> Xaa may be Tyr, Phe or Leu
<220>
<221> VARIANT
<222> (84)..(84)
<223> Xaa may be Met or Ile
<400> 182
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Leu Arg Leu Ser Trp Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Asp Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Asn Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Xaa Arg Gly Leu Pro Leu Ser Ala Glu Phe Thr Thr
85 90 95
<210> 183
<211> 95
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain consensus sequence
<220>
<221> VARIANT
<222> (22)..(22)
<223> Xaa may be Ala, Thr, Gly or Asp
<220>
<221> VARIANT
<222> (23)..(23)
<223> Xaa may be Ala, Asp, Tyr or Trp
<220>
<221> VARIANT
<222> (24)..(24)
<223> Xaa may be Pro, Asp or Asn
<220>
<221> VARIANT
<222> (25)..(25)
<223> Xaa may be Leu or absent
<220>
<221> VARIANT
<222> (26)..(26)
<223> Xaa may be Asp, His, Arg, Gly, Tyr or Trp
<220>
<221> VARIANT
<222> (27)..(27)
<223> Xaa may be Gly, Asp or Ala
<220>
<221> VARIANT
<222> (28)..(28)
<223> Xaa may be Ala, Phe, Gly, His or Asp
<220>
<221> VARIANT
<222> (29)..(29)
<223> Xaa may be Tyr, Phe or Leu
<400> 183
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Leu Arg Leu Ser Trp Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Asp Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Asn Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val Leu Gly Ser Tyr Val
65 70 75 80
Phe Glu His Asp Val Met Leu Pro Leu Ser Ala Glu Phe Thr Thr
85 90 95
<210> 184
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> c-Met binding FN3 domain C strand and CD loop consensus sequence
<220>
<221> VARIANT
<222> (4)..(4)
<223> Xaa is Trp, Phe or Val
<220>
<221> VARIANT
<222> (8)..(8)
<223> Xaa is Asp, Phe or Leu
<220>
<221> VARIANT
<222> (10)..(10)
<223> Xaa is Val, Phe or Leu
<220>
<221> VARIANT
<222> (11)..(11)
<223> Xaa is Val, Leu or Thr
<220>
<221> VARIANT
<222> (12)..(12)
<223> Xaa is Val, Arg, Gly, Leu, Thr or Ser
<220>
<221> VARIANT
<222> (13)..(13)
<223> Xaa is Gly, Ser, Ala, Thr or Lys
<220>
<221> VARIANT
<222> (15)..(15)
<223> Xaa is Glu or Asp
<400> 184
Asp Ser Phe Xaa Ile Arg Tyr Xaa Glu Xaa Xaa Xaa Xaa Gly Xaa
1 5 10 15
<210> 185
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> c-Met binding FN3 domain F strand and FG loop consensus sequence
<220>
<221> VARIANT
<222> (4)..(4)
<223> Xaa is Tyr, Trp, Ile, Val, Gly or Ala
<220>
<221> VARIANT
<222> (6)..(6)
<223> Xaa is Asn, Thr, Qln or Gly
<220>
<221> VARIANT
<222> (8)..(8)
<223> Xaa is Leu, Met, Asn or Ile
<220>
<221> VARIANT
<222> (9)..(9)
<223> Xaa is Gly or Ser
<220>
<221> VARIANT
<222> (14)..(14)
<223> Xaa is Ser, Leu, Gly, Tyr, Thr, Arg, His or Lys
<220>
<221> VARIANT
<222> (15)..(15)
<223> Xaa is Ile, Val or Leu
<220>
<221> VARIANT
<222> (17)..(17)
<223> Xaa is Val, Thr, His, Ile, Pro, Tyr or Leu
<400> 185
Thr Glu Tyr Xaa Val Xaa Ile Xaa Xaa Val Lys Gly Gly Xaa Xaa Ser
1 5 10 15
Xaa
<210> 186
<211> 89
<212> PRT
<213> Artificial Sequence
<220>
<223> c-Met binding FN3 domain consensus sequence
<220>
<221> VARIANT
<222> (32)..(32)
<223> Xaa is Trp, Phe or Val
<220>
<221> VARIANT
<222> (36)..(36)
<223> Xaa is Asp, Phe or Leu
<220>
<221> VARIANT
<222> (38)..(38)
<223> Xaa is Val, Phe or Leu
<220>
<221> VARIANT
<222> (39)..(39)
<223> Xaa is Val, Leu or Thr
<220>
<221> VARIANT
<222> (40)..(40)
<223> Xaa is Val, Arg, Gly, Leu, Thr or Ser
<220>
<221> VARIANT
<222> (41)..(41)
<223> Xaa is Gly, Ser, Ala, Thr or Lys
<220>
<221> VARIANT
<222> (43)..(43)
<223> Xaa is Glu or Asp
<220>
<221> VARIANT
<222> (68)..(68)
<223> Xaa is Tyr, Trp, Ile, Val, Gly or Ala
<220>
<221> VARIANT
<222> (70)..(70)
<223> Xaa is Asn, Thr, Qln or Gly
<220>
<221> VARIANT
<222> (72)..(72)
<223> Xaa is Leu, Met, Asn or Ile
<220>
<221> VARIANT
<222> (73)..(73)
<223> Xaa is Gly or Ser
<220>
<221> VARIANT
<222> (78)..(78)
<223> Xaa is Ser, Leu, Gly, Tyr, Thr, Arg, His or Lys
<220>
<221> VARIANT
<222> (79)..(79)
<223> Xaa is Ile, Val or Leu
<220>
<221> VARIANT
<222> (81)..(81)
<223> Xaa is Val, Thr, His, Ile, Pro, Tyr or Leu
<400> 186
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe Xaa
20 25 30
Ile Arg Tyr Xaa Glu Xaa Xaa Xaa Xaa Gly Xaa Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Xaa Val Xaa Ile Xaa Xaa Val Lys Gly Gly Xaa Xaa Ser
65 70 75 80
Xaa Pro Leu Ser Ala Glu Phe Thr Thr
85
<210> 187
<211> 94
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR consensus FN3 domain of bispecific EGFR/c-Met molecule
<220>
<221> VARIANT
<222> (11)..(11)
<223> Xaa is Glu, Asn or Arg
<220>
<221> VARIANT
<222> (14)..(14)
<223> Xaa is Glu or Pro
<220>
<221> VARIANT
<222> (17)..(17)
<223> Xaa is Leu or Ala
<220>
<221> VARIANT
<222> (25)..(25)
<223> Xaa is His or Trp
<220>
<221> VARIANT
<222> (29)..(29)
<223> Xaa is Glu or Asp
<220>
<221> VARIANT
<222> (37)..(37)
<223> Xaa is Glu or Pro
<220>
<221> VARIANT
<222> (46)..(46)
<223> Xaa is Asn or Val
<220>
<221> VARIANT
<222> (73)..(73)
<223> Xaa is Gly or Tyr
<220>
<221> VARIANT
<222> (83)..(83)
<223> Xaa is Met or Ile
<220>
<221> VARIANT
<222> (91)..(91)
<223> Xaa is Glu or Ile
<400> 187
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Xaa Val Thr Xaa Asp Ser
1 5 10 15
Xaa Arg Leu Ser Trp Asp Asp Pro Xaa Ala Phe Tyr Xaa Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Xaa Ser Glu Lys Val Gly Glu Ala Ile Xaa Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Xaa Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Xaa Arg Gly Leu Pro Leu Ser Ala Xaa Phe Thr Thr
85 90
<210> 188
<211> 89
<212> PRT
<213> Artificial Sequence
<220>
<223> c-Met consensus FN3 domain of bispecific EGFR/c-Met molecule
<220>
<221> VARIANT
<222> (11)..(11)
<223> Xaa is Glu, Asn or Arg
<220>
<221> VARIANT
<222> (14)..(14)
<223> Xaa is Glu or Pro
<220>
<221> VARIANT
<222> (17)..(17)
<223> Xaa is Leu or Ala
<220>
<221> VARIANT
<222> (37)..(37)
<223> Xaa is Glu or Pro
<220>
<221> VARIANT
<222> (39)..(39)
<223> Xaa is Val or Leu
<220>
<221> VARIANT
<222> (40)..(40)
<223> Xaa is Gly or Ser
<220>
<221> VARIANT
<222> (41)..(41)
<223> Xaa is Ser or Lys
<220>
<221> VARIANT
<222> (43)..(43)
<223> Xaa is Glu or Asp
<220>
<221> VARIANT
<222> (46)..(46)
<223> Xaa is Asn or Val
<220>
<221> VARIANT
<222> (72)..(72)
<223> Xaa is Leu or Met
<220>
<221> VARIANT
<222> (73)..(73)
<223> Xaa is Gly or Ser
<220>
<221> VARIANT
<222> (78)..(78)
<223> Xaa is Ser or Lys
<220>
<221> VARIANT
<222> (86)..(86)
<223> Xaa is Glu or Ile
<400> 188
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Xaa Val Thr Xaa Asp Ser
1 5 10 15
Xaa Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe Trp
20 25 30
Ile Arg Tyr Phe Xaa Phe Xaa Xaa Xaa Gly Xaa Ala Ile Xaa Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Val Val Asn Ile Xaa Xaa Val Lys Gly Gly Xaa Ile Ser
65 70 75 80
Pro Pro Leu Ser Ala Xaa Phe Thr Thr
85
<210> 189
<211> 95
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain
<400> 189
Met Leu Pro Ala Pro Lys Asn Leu Cys Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr
85 90 95
<210> 190
<211> 95
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain
<400> 190
Met Leu Pro Ala Pro Lys Asn Leu Val Val Cys Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr
85 90 95
<210> 191
<211> 95
<212> PRT
<213> Artificial sequence
<220>
<223> EGFR binding FN3 domain
<400> 191
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Cys Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr
85 90 95
<210> 192
<211> 95
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain
<400> 192
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Cys Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr
85 90 95
<210> 193
<211> 95
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain
<400> 193
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Cys
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr
85 90 95
<210> 194
<211> 95
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain
<400> 194
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Cys Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr
85 90 95
<210> 195
<211> 95
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain
<400> 195
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Cys Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr
85 90 95
<210> 196
<211> 95
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain
<400> 196
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Cys Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr
85 90 95
<210> 197
<211> 95
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain
<400> 197
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Cys Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr
85 90 95
<210> 198
<211> 95
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain
<400> 198
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Cys Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr
85 90 95
<210> 199
<211> 95
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain
<400> 199
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Cys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr
85 90 95
<210> 200
<211> 95
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain
<400> 200
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Cys Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr
85 90 95
<210> 201
<211> 95
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain
<400> 201
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Cys Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr
85 90 95
<210> 202
<211> 95
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain
<400> 202
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Cys
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr
85 90 95
<210> 203
<211> 95
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain
<400> 203
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Cys Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr
85 90 95
<210> 204
<211> 95
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain
<400> 204
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Cys Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr
85 90 95
<210> 205
<211> 95
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain
<400> 205
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Cys Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr
85 90 95
<210> 206
<211> 95
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain
<400> 206
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Cys Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr
85 90 95
<210> 207
<211> 95
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain
<400> 207
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Cys Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr
85 90 95
<210> 208
<211> 95
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain
<400> 208
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Cys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr
85 90 95
<210> 209
<211> 95
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain
<400> 209
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Cys Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr
85 90 95
<210> 210
<211> 95
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain
<400> 210
Met Leu Pro Ala Pro Lys Cys Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr
85 90 95
<210> 211
<211> 95
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain
<400> 211
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Cys Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr
85 90 95
<210> 212
<211> 95
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain
<400> 212
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Met Arg Gly Leu Pro Cys Ser Ala Ile Phe Thr Thr
85 90 95
<210> 213
<211> 95
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain
<400> 213
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Met Arg Gly Leu Pro Leu Cys Ala Ile Phe Thr Thr
85 90 95
<210> 214
<211> 95
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain
<400> 214
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Met Arg Gly Leu Pro Leu Ser Cys Ile Phe Thr Thr
85 90 95
<210> 215
<211> 95
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain
<400> 215
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Cys Phe Thr Thr
85 90 95
<210> 216
<211> 95
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain
<400> 216
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Cys Thr
85 90 95
<210> 217
<211> 104
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR binding FN3 domain
<400> 217
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Gly
85 90 95
Gly His His His His His His Cys
100
<210> 218
<211> 250
<212> PRT
<213> Artificial Sequence
<220>
<223> bispecific anti-EGFR/c-Met binding FN3 domain
<400> 218
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala
85 90 95
Pro Ala Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu
100 105 110
Val Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala
115 120 125
Pro Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe Leu
130 135 140
Gly Ser Gly Glu Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser
145 150 155 160
Tyr Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu Tyr Val Val Asn Ile
165 170 175
Met Ser Val Lys Gly Gly Ser Ile Ser Pro Pro Leu Ser Ala Ile Phe
180 185 190
Thr Thr Ala Pro Ser Pro Ala Pro Ala Pro Ala Pro Leu Ala Glu Ala
195 200 205
Lys Val Leu Ala Asn Arg Glu Leu Asp Lys Tyr Gly Val Ser Asp Tyr
210 215 220
Tyr Lys Asn Leu Ile Asn Asn Ala Lys Thr Val Glu Gly Val Lys Ala
225 230 235 240
Leu Leu Asp Glu Ile Leu Ala Ala Leu Pro
245 250
<210> 219
<211> 250
<212> PRT
<213> Artificial Sequence
<220>
<223> bispecific anti-EGFR/c-Met binding FN3 domain
<400> 219
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala
85 90 95
Pro Cys Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu
100 105 110
Val Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala
115 120 125
Pro Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe Leu
130 135 140
Gly Ser Gly Glu Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser
145 150 155 160
Tyr Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu Tyr Val Val Asn Ile
165 170 175
Met Ser Val Lys Gly Gly Ser Ile Ser Pro Pro Leu Ser Ala Ile Phe
180 185 190
Thr Thr Ala Pro Ser Pro Ala Pro Ala Pro Ala Pro Leu Ala Glu Ala
195 200 205
Lys Val Leu Ala Asn Arg Glu Leu Asp Lys Tyr Gly Val Ser Asp Tyr
210 215 220
Tyr Lys Asn Leu Ile Asn Asn Ala Lys Thr Val Glu Gly Val Lys Ala
225 230 235 240
Leu Leu Asp Glu Ile Leu Ala Ala Leu Pro
245 250
<210> 220
<211> 250
<212> PRT
<213> Artificial Sequence
<220>
<223> bispecific anti-EGFR/c-Met binding FN3 domain
<400> 220
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala
85 90 95
Pro Ala Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu
100 105 110
Val Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala
115 120 125
Pro Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe Leu
130 135 140
Gly Ser Gly Glu Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser
145 150 155 160
Tyr Asp Leu Thr Gly Leu Cys Pro Gly Thr Glu Tyr Val Val Asn Ile
165 170 175
Met Ser Val Lys Gly Gly Ser Ile Ser Pro Pro Leu Ser Ala Ile Phe
180 185 190
Thr Thr Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Leu Ala Glu Ala
195 200 205
Lys Val Leu Ala Asn Arg Glu Leu Asp Lys Tyr Gly Val Ser Asp Tyr
210 215 220
Tyr Lys Asn Leu Ile Asn Asn Ala Lys Thr Val Glu Gly Val Lys Ala
225 230 235 240
Leu Leu Asp Glu Ile Leu Ala Ala Leu Pro
245 250
<210> 221
<211> 250
<212> PRT
<213> Artificial Sequence
<220>
<223> bispecific anti-EGFR/c-Met binding FN3 domain
<400> 221
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Cys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala
85 90 95
Pro Cys Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu
100 105 110
Val Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala
115 120 125
Pro Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe Leu
130 135 140
Gly Ser Gly Glu Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser
145 150 155 160
Tyr Asp Leu Thr Gly Leu Cys Pro Gly Thr Glu Tyr Val Val Asn Ile
165 170 175
Met Ser Val Lys Gly Gly Ser Ile Ser Pro Pro Leu Ser Ala Ile Phe
180 185 190
Thr Thr Ala Pro Cys Pro Ala Pro Ala Pro Ala Pro Leu Ala Glu Ala
195 200 205
Lys Val Leu Ala Asn Arg Glu Leu Asp Lys Tyr Gly Val Ser Asp Tyr
210 215 220
Tyr Lys Asn Leu Ile Asn Asn Ala Lys Thr Val Glu Gly Val Lys Ala
225 230 235 240
Leu Leu Asp Glu Ile Leu Ala Ala Leu Pro
245 250
<210> 222
<211> 250
<212> PRT
<213> Artificial Sequence
<220>
<223> bispecific anti-EGFR/c-Met binding FN3 domain
<400> 222
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala
85 90 95
Pro Ala Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu
100 105 110
Val Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala
115 120 125
Pro Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe Leu
130 135 140
Gly Ser Gly Glu Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser
145 150 155 160
Tyr Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu Tyr Val Val Asn Ile
165 170 175
Met Ser Val Lys Gly Gly Ser Ile Ser Pro Pro Leu Ser Ala Ile Phe
180 185 190
Thr Thr Ala Pro Cys Pro Ala Pro Ala Pro Ala Pro Leu Ala Glu Ala
195 200 205
Lys Val Leu Ala Asn Arg Glu Leu Asp Lys Tyr Gly Val Ser Asp Tyr
210 215 220
Tyr Lys Asn Leu Ile Asn Asn Ala Lys Thr Val Glu Gly Val Lys Ala
225 230 235 240
Leu Leu Asp Glu Ile Leu Ala Ala Leu Pro
245 250
<210> 223
<211> 250
<212> PRT
<213> Artificial Sequence
<220>
<223> bispecific anti-EGFR/c-Met binding FN3 domain
<400> 223
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Cys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala
85 90 95
Pro Ala Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu
100 105 110
Val Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala
115 120 125
Pro Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe Leu
130 135 140
Gly Ser Gly Glu Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser
145 150 155 160
Tyr Asp Leu Thr Gly Leu Cys Pro Gly Thr Glu Tyr Val Val Asn Ile
165 170 175
Met Ser Val Lys Gly Gly Ser Ile Ser Pro Pro Leu Ser Ala Ile Phe
180 185 190
Thr Thr Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Leu Ala Glu Ala
195 200 205
Lys Val Leu Ala Asn Arg Glu Leu Asp Lys Tyr Gly Val Ser Asp Tyr
210 215 220
Tyr Lys Asn Leu Ile Asn Asn Ala Lys Thr Val Glu Gly Val Lys Ala
225 230 235 240
Leu Leu Asp Glu Ile Leu Ala Ala Leu Pro
245 250
<210> 224
<211> 250
<212> PRT
<213> Artificial Sequence
<220>
<223> bispecific anti-EGFR/c-Met binding FN3 domain
<400> 224
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Cys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala
85 90 95
Pro Ala Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu
100 105 110
Val Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala
115 120 125
Pro Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe Leu
130 135 140
Gly Ser Gly Glu Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser
145 150 155 160
Tyr Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu Tyr Val Val Asn Ile
165 170 175
Met Ser Val Lys Gly Gly Ser Ile Ser Pro Pro Leu Ser Ala Ile Phe
180 185 190
Thr Thr Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Leu Ala Glu Ala
195 200 205
Lys Val Leu Ala Asn Arg Glu Leu Asp Lys Tyr Gly Val Ser Asp Tyr
210 215 220
Tyr Lys Asn Leu Ile Asn Asn Ala Lys Thr Val Glu Gly Val Lys Ala
225 230 235 240
Leu Leu Asp Glu Ile Leu Ala Ala Leu Pro
245 250
<210> 225
<211> 250
<212> PRT
<213> Artificial Sequence
<220>
<223> bispecific anti-EGFR/c-Met binding FN3 domain
<400> 225
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala
85 90 95
Pro Cys Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu
100 105 110
Val Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala
115 120 125
Pro Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe Leu
130 135 140
Gly Ser Gly Glu Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser
145 150 155 160
Tyr Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu Tyr Val Val Asn Ile
165 170 175
Met Ser Val Lys Gly Gly Ser Ile Ser Pro Pro Leu Ser Ala Ile Phe
180 185 190
Thr Thr Ala Pro Cys Pro Ala Pro Ala Pro Ala Pro Leu Ala Glu Ala
195 200 205
Lys Val Leu Ala Asn Arg Glu Leu Asp Lys Tyr Gly Val Ser Asp Tyr
210 215 220
Tyr Lys Asn Leu Ile Asn Asn Ala Lys Thr Val Glu Gly Val Lys Ala
225 230 235 240
Leu Leu Asp Glu Ile Leu Ala Ala Leu Pro
245 250
<210> 226
<211> 264
<212> PRT
<213> Artificial Sequence
<220>
<223> bispecific anti-EGFR/c-Met binding FN3 domain
<400> 226
Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp
1 5 10 15
Ser Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe
20 25 30
Leu Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu
35 40 45
Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro
50 55 60
Gly Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys
65 70 75 80
Asp Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala
85 90 95
Pro Ala Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu
100 105 110
Val Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala
115 120 125
Pro Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe Leu
130 135 140
Gly Ser Gly Glu Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser
145 150 155 160
Tyr Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu Tyr Val Val Asn Ile
165 170 175
Met Gly Val Lys Gly Gly Lys Ile Ser Pro Pro Leu Ser Ala Ile Phe
180 185 190
Thr Thr Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Thr Ile Asp Glu
195 200 205
Trp Leu Leu Lys Glu Ala Lys Glu Lys Ala Ile Glu Glu Leu Lys Lys
210 215 220
Ala Gly Ile Thr Ser Asp Tyr Tyr Phe Asp Leu Ile Asn Lys Ala Lys
225 230 235 240
Thr Val Glu Gly Val Asn Ala Leu Lys Asp Glu Ile Leu Lys Ala Gly
245 250 255
Gly His His His His His His Cys
260
<210> 227
<211> 94
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR-binding FN3 domain
<400> 227
Leu Pro Ala Pro Lys Asn Leu Cys Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr
85 90
<210> 228
<211> 94
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR-binding FN3 domain
<400> 228
Leu Pro Ala Pro Lys Asn Leu Val Val Cys Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr
85 90
<210> 229
<211> 94
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR-binding FN3 domain
<400> 229
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Cys Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr
85 90
<210> 230
<211> 94
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR-binding FN3 domain
<400> 230
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Cys Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr
85 90
<210> 231
<211> 94
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR-binding FN3 domain
<400> 231
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Cys Ser
1 5 10 15
Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr
85 90
<210> 232
<211> 94
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR-binding FN3 domain
<400> 232
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Cys
1 5 10 15
Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr
85 90
<210> 233
<211> 94
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR-binding FN3 domain
<400> 233
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Cys Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr
85 90
<210> 234
<211> 94
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR-binding FN3 domain
<400> 234
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Cys Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr
85 90
<210> 235
<211> 94
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR-binding FN3 domain
<400> 235
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe Leu
20 25 30
Ile Cys Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr
85 90
<210> 236
<211> 94
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR-binding FN3 domain
<400> 236
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Cys Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr
85 90
<210> 237
<211> 94
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR-binding FN3 domain
<400> 237
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Cys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr
85 90
<210> 238
<211> 94
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR-binding FN3 domain
<400> 238
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Cys Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr
85 90
<210> 239
<211> 94
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR-binding FN3 domain
<400> 239
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Cys Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr
85 90
<210> 240
<211> 94
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR-binding FN3 domain
<400> 240
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Cys Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr
85 90
<210> 241
<211> 94
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR-binding FN3 domain
<400> 241
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Cys
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr
85 90
<210> 242
<211> 94
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR-binding FN3 domain
<400> 242
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Cys Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr
85 90
<210> 243
<211> 94
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR-binding FN3 domain
<400> 243
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Cys Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr
85 90
<210> 244
<211> 94
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR-binding FN3 domain
<400> 244
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Cys Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr
85 90
<210> 245
<211> 94
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR-binding FN3 domain
<400> 245
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Cys Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr
85 90
<210> 246
<211> 94
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR-binding FN3 domain
<400> 246
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Cys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr
85 90
<210> 247
<211> 94
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR-binding FN3 domain
<400> 247
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Cys
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr
85 90
<210> 248
<211> 94
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR-binding FN3 domain
<400> 248
Leu Pro Ala Pro Lys Cys Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr
85 90
<210> 249
<211> 94
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR-binding FN3 domain
<400> 249
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Cys Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr
85 90
<210> 250
<211> 94
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR-binding FN3 domain
<400> 250
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Met Arg Gly Leu Pro Cys Ser Ala Ile Phe Thr Thr
85 90
<210> 251
<211> 94
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR-binding FN3 domain
<400> 251
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Met Arg Gly Leu Pro Leu Cys Ala Ile Phe Thr Thr
85 90
<210> 252
<211> 94
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR-binding FN3 domain
<400> 252
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Met Arg Gly Leu Pro Leu Ser Cys Ile Phe Thr Thr
85 90
<210> 253
<211> 94
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR-binding FN3 domain
<400> 253
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Cys Phe Thr Thr
85 90
<210> 254
<211> 94
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR-binding FN3 domain
<400> 254
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Cys Thr
85 90
<210> 255
<211> 103
<212> PRT
<213> Artificial Sequence
<220>
<223> EGFR-binding FN3 domain
<400> 255
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Gly Gly
85 90 95
His His His His His His Cys
100
<210> 256
<211> 249
<212> PRT
<213> Artificial Sequence
<220>
<223> bispecific anti-EGFR/c-Met binding FN3 domain
<400> 256
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala Pro
85 90 95
Ala Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu Val
100 105 110
Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala Pro
115 120 125
Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe Leu Gly
130 135 140
Ser Gly Glu Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser Tyr
145 150 155 160
Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu Tyr Val Val Asn Ile Met
165 170 175
Ser Val Lys Gly Gly Ser Ile Ser Pro Pro Leu Ser Ala Ile Phe Thr
180 185 190
Thr Ala Pro Ser Pro Ala Pro Ala Pro Ala Pro Leu Ala Glu Ala Lys
195 200 205
Val Leu Ala Asn Arg Glu Leu Asp Lys Tyr Gly Val Ser Asp Tyr Tyr
210 215 220
Lys Asn Leu Ile Asn Asn Ala Lys Thr Val Glu Gly Val Lys Ala Leu
225 230 235 240
Leu Asp Glu Ile Leu Ala Ala Leu Pro
245
<210> 257
<211> 249
<212> PRT
<213> Artificial Sequence
<220>
<223> bispecific anti-EGFR/c-Met binding FN3 domain
<400> 257
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala Pro
85 90 95
Cys Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu Val
100 105 110
Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala Pro
115 120 125
Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe Leu Gly
130 135 140
Ser Gly Glu Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser Tyr
145 150 155 160
Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu Tyr Val Val Asn Ile Met
165 170 175
Ser Val Lys Gly Gly Ser Ile Ser Pro Pro Leu Ser Ala Ile Phe Thr
180 185 190
Thr Ala Pro Ser Pro Ala Pro Ala Pro Ala Pro Leu Ala Glu Ala Lys
195 200 205
Val Leu Ala Asn Arg Glu Leu Asp Lys Tyr Gly Val Ser Asp Tyr Tyr
210 215 220
Lys Asn Leu Ile Asn Asn Ala Lys Thr Val Glu Gly Val Lys Ala Leu
225 230 235 240
Leu Asp Glu Ile Leu Ala Ala Leu Pro
245
<210> 258
<211> 249
<212> PRT
<213> Artificial Sequence
<220>
<223> bispecific anti-EGFR/c-Met binding FN3 domain
<400> 258
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala Pro
85 90 95
Ala Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu Val
100 105 110
Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala Pro
115 120 125
Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe Leu Gly
130 135 140
Ser Gly Glu Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser Tyr
145 150 155 160
Asp Leu Thr Gly Leu Cys Pro Gly Thr Glu Tyr Val Val Asn Ile Met
165 170 175
Ser Val Lys Gly Gly Ser Ile Ser Pro Pro Leu Ser Ala Ile Phe Thr
180 185 190
Thr Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Leu Ala Glu Ala Lys
195 200 205
Val Leu Ala Asn Arg Glu Leu Asp Lys Tyr Gly Val Ser Asp Tyr Tyr
210 215 220
Lys Asn Leu Ile Asn Asn Ala Lys Thr Val Glu Gly Val Lys Ala Leu
225 230 235 240
Leu Asp Glu Ile Leu Ala Ala Leu Pro
245
<210> 259
<211> 249
<212> PRT
<213> Artificial Sequence
<220>
<223> bispecific anti-EGFR/c-Met binding FN3 domain
<400> 259
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Cys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala Pro
85 90 95
Cys Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu Val
100 105 110
Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala Pro
115 120 125
Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe Leu Gly
130 135 140
Ser Gly Glu Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser Tyr
145 150 155 160
Asp Leu Thr Gly Leu Cys Pro Gly Thr Glu Tyr Val Val Asn Ile Met
165 170 175
Ser Val Lys Gly Gly Ser Ile Ser Pro Pro Leu Ser Ala Ile Phe Thr
180 185 190
Thr Ala Pro Cys Pro Ala Pro Ala Pro Ala Pro Leu Ala Glu Ala Lys
195 200 205
Val Leu Ala Asn Arg Glu Leu Asp Lys Tyr Gly Val Ser Asp Tyr Tyr
210 215 220
Lys Asn Leu Ile Asn Asn Ala Lys Thr Val Glu Gly Val Lys Ala Leu
225 230 235 240
Leu Asp Glu Ile Leu Ala Ala Leu Pro
245
<210> 260
<211> 249
<212> PRT
<213> Artificial Sequence
<220>
<223> bispecific anti-EGFR/c-Met binding FN3 domain
<400> 260
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala Pro
85 90 95
Ala Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu Val
100 105 110
Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala Pro
115 120 125
Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe Leu Gly
130 135 140
Ser Gly Glu Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser Tyr
145 150 155 160
Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu Tyr Val Val Asn Ile Met
165 170 175
Ser Val Lys Gly Gly Ser Ile Ser Pro Pro Leu Ser Ala Ile Phe Thr
180 185 190
Thr Ala Pro Cys Pro Ala Pro Ala Pro Ala Pro Leu Ala Glu Ala Lys
195 200 205
Val Leu Ala Asn Arg Glu Leu Asp Lys Tyr Gly Val Ser Asp Tyr Tyr
210 215 220
Lys Asn Leu Ile Asn Asn Ala Lys Thr Val Glu Gly Val Lys Ala Leu
225 230 235 240
Leu Asp Glu Ile Leu Ala Ala Leu Pro
245
<210> 261
<211> 249
<212> PRT
<213> Artificial Sequence
<220>
<223> bispecific anti-EGFR/c-Met binding FN3 domain
<400> 261
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Cys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala Pro
85 90 95
Ala Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu Val
100 105 110
Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala Pro
115 120 125
Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe Leu Gly
130 135 140
Ser Gly Glu Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser Tyr
145 150 155 160
Asp Leu Thr Gly Leu Cys Pro Gly Thr Glu Tyr Val Val Asn Ile Met
165 170 175
Ser Val Lys Gly Gly Ser Ile Ser Pro Pro Leu Ser Ala Ile Phe Thr
180 185 190
Thr Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Leu Ala Glu Ala Lys
195 200 205
Val Leu Ala Asn Arg Glu Leu Asp Lys Tyr Gly Val Ser Asp Tyr Tyr
210 215 220
Lys Asn Leu Ile Asn Asn Ala Lys Thr Val Glu Gly Val Lys Ala Leu
225 230 235 240
Leu Asp Glu Ile Leu Ala Ala Leu Pro
245
<210> 262
<211> 249
<212> PRT
<213> Artificial Sequence
<220>
<223> bispecific anti-EGFR/c-Met binding FN3 domain
<400> 262
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Cys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala Pro
85 90 95
Ala Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu Val
100 105 110
Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala Pro
115 120 125
Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe Leu Gly
130 135 140
Ser Gly Glu Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser Tyr
145 150 155 160
Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu Tyr Val Val Asn Ile Met
165 170 175
Ser Val Lys Gly Gly Ser Ile Ser Pro Pro Leu Ser Ala Ile Phe Thr
180 185 190
Thr Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Leu Ala Glu Ala Lys
195 200 205
Val Leu Ala Asn Arg Glu Leu Asp Lys Tyr Gly Val Ser Asp Tyr Tyr
210 215 220
Lys Asn Leu Ile Asn Asn Ala Lys Thr Val Glu Gly Val Lys Ala Leu
225 230 235 240
Leu Asp Glu Ile Leu Ala Ala Leu Pro
245
<210> 263
<211> 249
<212> PRT
<213> Artificial Sequence
<220>
<223> bispecific anti-EGFR/c-Met binding FN3 domain
<400> 263
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala Pro
85 90 95
Cys Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu Val
100 105 110
Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala Pro
115 120 125
Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe Leu Gly
130 135 140
Ser Gly Glu Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser Tyr
145 150 155 160
Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu Tyr Val Val Asn Ile Met
165 170 175
Ser Val Lys Gly Gly Ser Ile Ser Pro Pro Leu Ser Ala Ile Phe Thr
180 185 190
Thr Ala Pro Cys Pro Ala Pro Ala Pro Ala Pro Leu Ala Glu Ala Lys
195 200 205
Val Leu Ala Asn Arg Glu Leu Asp Lys Tyr Gly Val Ser Asp Tyr Tyr
210 215 220
Lys Asn Leu Ile Asn Asn Ala Lys Thr Val Glu Gly Val Lys Ala Leu
225 230 235 240
Leu Asp Glu Ile Leu Ala Ala Leu Pro
245
<210> 264
<211> 263
<212> PRT
<213> Artificial Sequence
<220>
<223> bispecific anti-EGFR/c-Met binding FN3 domain
<400> 264
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Ala Arg Leu Ser Trp Asp Asp Pro Trp Ala Phe Tyr Glu Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val His Asn Val Tyr Lys Asp
65 70 75 80
Thr Asn Met Arg Gly Leu Pro Leu Ser Ala Ile Phe Thr Thr Ala Pro
85 90 95
Ala Pro Ala Pro Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu Val
100 105 110
Val Ser Arg Val Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala Pro
115 120 125
Asp Ala Ala Phe Asp Ser Phe Trp Ile Arg Tyr Phe Glu Phe Leu Gly
130 135 140
Ser Gly Glu Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser Tyr
145 150 155 160
Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu Tyr Val Val Asn Ile Met
165 170 175
Gly Val Lys Gly Gly Lys Ile Ser Pro Pro Leu Ser Ala Ile Phe Thr
180 185 190
Thr Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Thr Ile Asp Glu Trp
195 200 205
Leu Leu Lys Glu Ala Lys Glu Lys Ala Ile Glu Glu Leu Lys Lys Ala
210 215 220
Gly Ile Thr Ser Asp Tyr Tyr Phe Asp Leu Ile Asn Lys Ala Lys Thr
225 230 235 240
Val Glu Gly Val Asn Ala Leu Lys Asp Glu Ile Leu Lys Ala Gly Gly
245 250 255
His His His His His His Cys
260
<210> 265
<211> 98
<212> PRT
<213> Artificial Sequence
<220>
<223> Tencon FN3 scaffold
<400> 265
Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser
1 5 10 15
Leu Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe Leu
20 25 30
Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Asn Leu Thr
35 40 45
Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly
50 55 60
Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val Lys Gly Gly His Arg Ser
65 70 75 80
Asn Pro Leu Ser Ala Glu Phe Thr Thr Gly Gly His His His His His
85 90 95
His Cys
Claims (10)
- 썬스크린 조성물로서,
자외광을 흡수하기에 효과적인 양의 1차 UV-흡수제; 및
약 5% 이하의 가시광 흡수제
를 포함하며, 상기 가시광 흡수제는 실리카-함유 코팅을 포함하는, 썬스크린 조성물. - 제1항에 있어서, 상기 1차 UV-흡수제는 에틸헥실 트라이아존, 2-페닐벤즈이미다졸-5-설폰산, 비스-에틸헥실옥시페닐메톡시페닐 트라이아진, 다이소듐 페닐다이벤즈이미다졸 테트라설포네이트, 메틸렌 비스-벤조트라이아졸릴 테트라메틸부틸페놀, 다이에틸아미노 하이드록시 벤조일 헥실 벤조에이트, 실리카 코팅이 적용되지 않은 이산화티타늄, 및 실리카 코팅이 적용되지 않은 산화아연으로 이루어진 군으로부터 선택되는, 썬스크린 조성물.
- 제2항에 있어서, 상기 1차 UV-흡수제 중 적어도 하나는 다이소듐 페닐다이벤즈이미다졸 테트라설포네이트인, 썬스크린 조성물.
- 제1항에 있어서, 상기 가시광 흡수제는 무기 산화물 및 다른 전이 금속 산화물로 이루어진 군으로부터 선택되는, 썬스크린 조성물.
- 제1항에 있어서, 상기 실리카-함유 코팅은 필름인, 썬스크린 조성물.
- 제5항에 있어서, 상기 실리카-함유 필름에는 알루미나가 본질적으로 부재하는, 썬스크린 조성물.
- 제5항에 있어서, 상기 가시광 흡수제 상의 상기 필름의 두께는 약 0.1 내지 약 100 nm인, 썬스크린 조성물.
- 제4항에 있어서, 상기 가시광 흡수제는 이산화티타늄인, 썬스크린 조성물.
- 제1항에 있어서, 상기 실리카-함유 코팅은 연속적인 것인, 썬스크린 조성물.
- 제1항에 있어서, 2차 UV-흡수제를 추가로 포함하는, 썬스크린 조성물.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201562147676P | 2015-04-15 | 2015-04-15 | |
| US62/147,676 | 2015-04-15 |
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| Publication Number | Publication Date |
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| KR20160123249A true KR20160123249A (ko) | 2016-10-25 |
| KR102656734B1 KR102656734B1 (ko) | 2024-04-15 |
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| US (2) | US20160303020A1 (ko) |
| EP (1) | EP3081206B1 (ko) |
| KR (1) | KR102656734B1 (ko) |
| CN (1) | CN106038347A (ko) |
| AU (2) | AU2016202321A1 (ko) |
| BR (1) | BR102016008214B8 (ko) |
| CA (1) | CA2927048C (ko) |
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| KR20190063213A (ko) * | 2017-11-29 | 2019-06-07 | 주식회사 케미랜드 | 유무기 자외선 차단제가 혼합된 자외선 차단용 분산물과 이를 유효성분으로 포함하는 화장료 조성물 및 그 제조방법 |
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| EP3166574B1 (en) * | 2014-07-11 | 2021-03-31 | Mary Kay, Inc. | Cosmetic composition based on color particles, stearalkonium hectorite, polyhydroxystearic acid, polyglyceryl-1-pentaisostearate and a polar activator |
| US10590278B2 (en) | 2017-04-10 | 2020-03-17 | Nanophase Technologies Corporation | Coated powders having high photostability |
| WO2020163928A1 (en) * | 2019-02-13 | 2020-08-20 | L'oreal | Sunscreen composition, use of the sunscreen composition and process of manufacturing the sunscreen composition |
| CN111137917A (zh) * | 2019-12-20 | 2020-05-12 | 成都理工大学 | 一种微晶白云母负载纳米TiO2复合抗紫外剂及其制备技术 |
| CN110974715B (zh) * | 2019-12-26 | 2023-08-01 | 常州纳欧新材料科技有限公司 | 一种apg改性mbbt复合材料及其水性浆料的制备方法 |
| JP2023533146A (ja) * | 2020-06-02 | 2023-08-02 | ユニリーバー・アイピー・ホールディングス・ベスローテン・ヴェンノーツハップ | 高ｓｐｆ皮膚クレンジング組成物 |
| WO2022160021A1 (en) * | 2021-01-29 | 2022-08-04 | L'oreal | Cosmetic composition for providing dark color shades, use of a cosmetic composition for providing dark color shades and processes for manufacturing a cosmetic composition for providing dark color shades |
| BR112023014058A2 (pt) * | 2021-04-23 | 2023-10-31 | Oreal | Composição cosmética de proteção solar, uso de uma composição cosmética de proteção solar e processo para fabricar uma composição cosmética de proteção solar |
| US20230080141A1 (en) * | 2021-09-08 | 2023-03-16 | Doc Martin's Of Maui | Sunscreen composition and methods of protection from ultraviolet and visible light |
| EP4176936A1 (en) | 2021-11-08 | 2023-05-10 | Martiderm, SL | Cosmetic composition for protecting the skin and hair against solar radiation |
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| FR2718638B1 (fr) * | 1994-04-19 | 1996-05-24 | Oreal | Compositions cosmétiques filtrantes contenant un agent hydrophile acide et utilisation. |
| DE10155963A1 (de) * | 2001-11-09 | 2003-05-22 | Beiersdorf Ag | Kosmetische und dermatologische Lichtschutzformulierungen mit einem Gehalt an Hydroxybenzophenonen, Triazin- und/oder Benzotriazol-Derivaten |
| DE102005007482A1 (de) * | 2005-02-17 | 2006-09-14 | Merck Patent Gmbh | Zubereitung enthaltend nanopartikuläres UV-Schutzmittel |
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2016
- 2016-04-04 US US15/089,997 patent/US20160303020A1/en not_active Abandoned
- 2016-04-12 RU RU2016113835A patent/RU2709537C2/ru active
- 2016-04-13 BR BR102016008214A patent/BR102016008214B8/pt active IP Right Grant
- 2016-04-13 AU AU2016202321A patent/AU2016202321A1/en not_active Abandoned
- 2016-04-14 CA CA2927048A patent/CA2927048C/en active Active
- 2016-04-14 KR KR1020160045631A patent/KR102656734B1/ko active IP Right Grant
- 2016-04-14 EP EP16165370.4A patent/EP3081206B1/en active Active
- 2016-04-14 ES ES16165370T patent/ES2786264T3/es active Active
- 2016-04-15 CN CN201610236915.1A patent/CN106038347A/zh active Pending
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2018
- 2018-06-20 US US16/012,988 patent/US20180296455A1/en not_active Abandoned
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2021
- 2021-04-26 AU AU2021202557A patent/AU2021202557B2/en active Active
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| US20140023770A1 (en) * | 2012-07-17 | 2014-01-23 | Symrise Ag | Use Of Defined Cyclohexenones As Agents For The Superadditive Enhancement Of An Olfactory Impression And Fragrance And/Or Flavor Material Composition |
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| Appl. Chem. Eng., 2013, Vol.24, No.3, pp.231-238. 1부.* * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20190063213A (ko) * | 2017-11-29 | 2019-06-07 | 주식회사 케미랜드 | 유무기 자외선 차단제가 혼합된 자외선 차단용 분산물과 이를 유효성분으로 포함하는 화장료 조성물 및 그 제조방법 |
Also Published As
| Publication number | Publication date |
|---|---|
| CA2927048A1 (en) | 2016-10-15 |
| BR102016008214A2 (pt) | 2016-10-18 |
| CA2927048C (en) | 2023-09-19 |
| US20160303020A1 (en) | 2016-10-20 |
| EP3081206B1 (en) | 2020-02-19 |
| AU2021202557A1 (en) | 2021-05-27 |
| AU2021202557B2 (en) | 2022-11-17 |
| KR102656734B1 (ko) | 2024-04-15 |
| RU2709537C2 (ru) | 2019-12-18 |
| BR102016008214B1 (pt) | 2021-05-04 |
| EP3081206A1 (en) | 2016-10-19 |
| RU2016113835A (ru) | 2017-10-17 |
| BR102016008214B8 (pt) | 2022-08-16 |
| ES2786264T3 (es) | 2020-10-09 |
| AU2016202321A1 (en) | 2016-11-03 |
| US20180296455A1 (en) | 2018-10-18 |
| RU2016113835A3 (ko) | 2019-07-17 |
| CN106038347A (zh) | 2016-10-26 |
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