KR20070085416A - 멜라노코르틴 수용체 결합 모방체, 조성물, 방법 및 용도 - Google Patents
멜라노코르틴 수용체 결합 모방체, 조성물, 방법 및 용도 Download PDFInfo
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Abstract
멜라노코르틴 수용체 결합 모방체 폴리펩티드가 제시된다. 이러한 폴리펩티드를 암호화하는 폴리뉴클레오티드, 이러한 폴리뉴클레오티드를 포함하거나, 모방체를 발현하는 세포 및 이들의 제조 방법과 용도 또한 제시된다.
Description
본 발명은 멜라노코르틴 수용체 결합 모방체, 이를 암호화하는 폴리뉴클레오티드, 폴리뉴클레오티드를 포함하거나 모방체를 발현하는 세포 및 이들의 제조 방법과 용도에 관한 것이다.
비만은 신체 크기와 비례하여 과도한 지방량에 의하여 나타나는 만성질환이다. 오늘날, 미국인의 삼분의 일은 과-체중(체질량 지수(BMI) >25 kg/㎡)이라고 판단되며, 이에 따라, 미국 질병 통제 및 예방 센터(CDC)는 비만이 크게 유행하고 있다고 선언하기에 이르렀다(Cummings and Schwartz, Annu. Rev. Med. 54:453- 471 ((2003)). 이러한 질환이 특히 제2형 당뇨병, 울형성심부전(congestive heart failure), 골관절염(osteoarthritis), 수면성 무호흡(sleep apnea)과 같은 질환을 발생하기 위한 근본적인 원인 또는 위험 요소라는 사실에 의하여 비만 치료의 중요성이 강조된다.
추가로, 비만은 비만 아테롬유발 이상지질혈증(atherogenic dyslipidemia), 혈압 상승 및 내인슐린성(insulin resistance)을 특징으로 한 의학적 상태인 "대사 증후군(Metabolic Syndrome)"에 연결된다. 미국에서 대사 증후군에 영향을 받는 사 람들의 수가 증가하고 있다. 중요하게는, 적당한 체중 감소도, 대사 증후군을 상당히 개선시키며, 비만-관련 질환으로의 발전 위험 요소를 감소시키는 것으로 알려진 바 있다(Wing et al. , Arch. Intern. Med. 147:1749-1753 (1987); Tuomilehto et al. , New Engl. J. Med. 344:1343-1350 (2001); Knowler et al., New Engl . J Med. 346:393-403 (2002); Franz et al., Diabetes Care 25:148-198 (2002)). 추가로, 몇몇 문화권 내에서 종종 살찐 개체에게 붙여진 사회적 오명으로, 비만의 치료는 정신 건강에도 중요할 수 있다.
멜라노코르틴 수용체는 인간 및 설치류 둘다에서, 전체적인 에너지 균형 및 비만 조절에 중요한 역할을 수행한다. 알파-멜라닌 세포 자극 호르몬(알파-MSH)은 멜라노코르틴 시스템의 중요한 성분인 13개의 아미노산 펩티드 호르몬이다. 알파-MSH는 뇌하수체에 의해 방출되는 프로오피오멜라노코르틴(proopiomelanocortin, POMC)의 단백질 가수 분해 과정에 의하여 생성된다. 알파-MSH는 멜라노코르틴 4 수용체(MC4R)에 높은 친화도로 결합하지만, 멜라노코르틴 3 수용체(MC3R) 및 멜라노코르틴 5 수용체(MC5R) 에 낮은 친화도로 결합한다. MC4R은 뇌에서 발견되는 G-커플된 단백질 수용체이며, 알파-MSH 결합에 의하여 자극될 때, 이 수용체는 식이 섭취 감소 및 지방 산화 증가를 유발한다. 궁극적으로, MC4R과 같은 멜라노코르틴 수용체의 자극은 체중 감소를 초래한다.
인간 및 설치류에서, 멜라노코르틴 시스템의 다른 성분에서 기능 상실 돌연변이는 비만 및 관련 상태에 밀접하게 관련이 있다. 마우스의 경우, POMC, 또는 MC4R 및 MC3R 내의 돌연변이는 비만, 내인슐린성 및 과식증(hyperphagia)을 나타낸 다(Goodfellow and Saunders, Curr. Topics Med. Clnem. 3: 855-883 (2003); Huszar et al., Cell 88:131-141 (1997); Yaswen et al., Nat. Med. 5: 1066-1070 (1999)). 인간의 경우, POMC 또는 MC4R 내에서의 돌연변이는 식이 섭취의 증가와 관련된 비만 발생으로 유발한다(Krude et al. , Nat. Genet. 19:155-157 (1998); Yeo et al., Nature Genetics 20:111-112 (1998); Branson et al., New Engl. J. Med. 348: 1096-1103 (2003); Vaisse et al. , J. Clin. Invest. 106) -.253-262 (2000); Ho and MacKenzie, J". Biol. Chem. 275: 35816- 35822 (1999)).
체중 감소는 멜라노코르틴 시스템 활성의 약리학적 자극에 의하여 발생될 수 있다. 설치류의 경우, HC4R과 같은 멜라노코르틴 수용체의 약리학적 자극은 식이 섭취를 감소시키고, 에너지 소비를 증가시키며, 체중을 감소시킨다(Pierroz et al., Diabetes 51: 1337-1345 (2002)). 인간의 경우, 비만이 아닌 인간의 MC4R을 자극하기 위하여, 알파-MSH의 비강내 투여로 지방 상실로 인한 체중 감소를 초래하지만, 마른 체중에서는 그렇지 않다(Fehm et al., J. Clin. Endo. Metabol. S6: 1144-1148 (2001)).
비만은 현재 몇가지 다른 전략에 의하여 치료되며, 그 성공이 제한적일 뿐이다. 이러한 전략은 일차적으로 "생활-스타일" 변화(예를 들면, 다이어트 및 운동), 작은 분자에 근거한 약제학적 치료법 또는 위의 일부분 외과적 절제를 포함한다(위 우회로 수술). 추가로, 체중 감소를 자극하는 알파-MSH와 같은 멜라노코르틴 수용체 결합 펩티드는 상기 펩티드의 매우 짧은 혈청 반감기때문에, 약제로의 이용은 제한된다. 따라서, 추가적인 비만 치료 및 특히, 알파-MSH와 같은 멜라노코르틴 수 용체 결합 펩티드의 짧은 혈청 반감기를 극복하기 위한 멜라노코르틴 수용체 결합 분자의 필요성이 존재한다.
도 1은 멜라노코르틴 수용체 결합 모방체 펩티드의 요소를 나타낸다.
도 2는 멜라노코르틴 수용체 결합 모방체의 모식도를 나타낸다.
도 3은 멜라노코르틴 수용체 결합 알파-MSH 모방체의 아미노산(서열 번호:62) 및 cDNA(서열 번호:61) 서열을 나타낸다. 개개의 모방체 요소에서 아미노 말단 부분에 밑줄을 그었다.
도 4는 경쟁적 결합 어세이에서, MC4R에 결합하는 알파-MSH 모방체를 나타낸다.
도 5는 높은 수준의 MC4R을 발현하는 세포에서 알파-MSH 모방체가 MC4R을 활성화시키는 것을 나타낸다.
도 6은 낮은 수준의 MC4R을 발현하는 세포에서 알파-MSH 모방체가 MC4R을 활성화시키는 것을 나타낸다.
도 7은 알파-MSH-매개 동물 식이 섭취의 감소를 나타낸다.
도 8은 알파-MSH-매개 동물 체중 감소를 나타낸다.
[발명의 요약]
본 발명의 일예는 하기의 화학식 (I)에 따른 폴리펩티드이다:
상기 식에서, Mp는 멜라노코르틴 수용체 결합 분자이며,
Lk는 폴리펩티드 또는 화학적 링크이고,
V2는 면역글로블린 가변 영역(variable region)의 C-말단 부분이며,
Hg는 면역글로블린 가변 힌지(hinge) 영역의 적어도 한 부분이고,
CH2는 면역글로블린 중쇄(heavy chain) CH2 불변 영역(constant region)이며,
CH3는 면역글로블린 중쇄(heavy chain) CH3 불변 영역(constant region)이고,
t는 독립적으로 1 내지 10의 정수이다.
본 발명의 다른 일예는 서열 번호: 60 또는 62를 포함하는 폴리펩티드이다.
본 발명의 다른 일예는 서열 번호: 59 또는 서열 번호: 61, 또는, 서열 번호: 59 또는 서열 번호: 61에 상보적인 폴리뉴클레오티드를 포함하는 폴리뉴클레오티드이다.
본 발명의 다른 일예는 서열 번호: 60 또는 서열 번호: 62의 폴리펩티드를 암호화하는 폴리뉴클레오티드를 포함하는 폴리뉴클레오티드이다.
본 발명의 다른 일예는 세포, 조직 또는 기관과 본 발명의 모방체 조성물을 접촉시키는 것을 포함하여, 세포, 조직 또는 기관에서, 멜라노코르틴 수용체의 생물학적 활성을 변형시키는 방법이다.
본 발명의 다른 일예는 본 발명의 모방체 조성물을 이를 필요로 하는 환자에게 투여하는 것을 포함하여, 적어도 하나의 멜라노코르틴 수용체 매개 상태를 변형시키는 방법이다.
본 명세서에서 인용한, 특허 및 특허 출원을 포함하나 이에 한정되지 않는 모든 공보 문헌은 본 발명에서 완전 개시된 참고문헌에 속한다.
본 발명은 멜라노코르틴 수용체에 결합하며, 항원 면역글로블린 분자의 다른 아이소타입을 모방하는 특성을 갖는 폴리펩티드를 제공하며, 여기서, 항원 면역글로블린은 예를 들면, IgA, IgD, IgE, IgG, 또는 IgM 및 이들의 임의의 서브클래스, 즉, IgA1, IgA2, IgG1, IgG2, IgG3 또는 IgG4, 또는 이들의 조합물이 있으며, 본 발명에서는 이하, 일반적으로, "모방체"로 언급된다. 몇몇 구체예에서, 본 발명의 모방체 폴리펩티드는 알파-멜라닌 세포 자극 호르몬(알파-MSH) 서열을 함유하며, 멜라노코르틴 수용체 결합 알파-MSH 모방체로 설계된다. 상기의 알파-MSH 모방체 폴리펩티드는 멜라노코르틴 수용체 4(MC4R)에 결합할 수 있으며, MC3R 및 MC5R 각각에 동일한 친화도 및 더 낮은 친화도로 결합할 수 있다. 상기 멜라노코르틴 수용체 결합의 한 결과는, 멜라노코르틴 수용체 활성을 자극시키거나 방해할 수 있다. 방해가 체중 증가를 유발할 수 있는 반면, 자극은 체중 감소를 유발한다.
일 구체예에서, 본 발명의 폴리펩티드는 일반식 (I)을 갖는다:
[화학식 I]
(Mp-Lk-V2-Hg-CH2-CH3)(t)
상기 식에서, Mp는 멜라노코르틴 수용체 결합 분자이며,
Lk는 폴리펩티드 또는 화학적 링크이고,
V2는 면역글로블린 가변 영역(variable region)의 C-말단 부분이며,
Hg는 면역글로블린 가변 힌지 영역의 적어도 한 부분이고,
CH2는 면역글로블린 중쇄(heavy chain) CH2 불변 영역(constant region)이며,
CH3는 면역글로블린 중쇄(heavy chain) CH3 불변 영역(constant region)이고,
t는 독립적으로 1 내지 10의 정수이다.
본 발명에서 사용된 바, "멜라노코르틴 수용체 결합 분자"는 Homo sapiens MC4R(서열 번호: 77)과 같은, 적어도 하나의 멜라노코르틴 수용체에 결합할 수 있는 분자를 의미한다. 다른 Homo sapiens 멜라노코르틴 수용체는 MCRl (서열 번호: 71) , MCR2 (서열 번호: 73), MCR3 (서열 번호: 75), 및 MCR5 (서열 번호: 79)를 포함한다. 알려진 멜라노코르틴 수용체 서열 또는 공지된 멜라노코르틴 수용체의 성숙된 형태에 적어도 85% 아미노산 서열 상동성을 갖으며, G-단백질 커플된 수용체(GPCR)로서의 기능을 수행할 수 있다면, 주어진 펩티드 사슬은 "멜라노코르틴 수용체"이다. 두개의 펩티드 사슬 사이의 퍼센트 상동성은 AlignX module of Vector NTI v.9.0 .0 (Invitrogen Corp., Carslbad, CA)의 디폴트 세팅을 이용하여 두 서열간의 정렬(pairwise alignment)에 의하여 결정될 수 있다. 바람직한 멜라노코르틴 수용체 결합 분자는 (서열 번호: 2)에 나타낸 아미노산 서열을 갖는 알파-MSH 펩티드 13개 아미노산이다. 다른 멜라노코르틴 수용체 결합 분자는 서열 번호: 2의 생물학적 활성 단편들 및 멜라노코르틴 수용체에 결합할 수 있는 다른 아미노산 서열들을 포함한다. 본 발명에서 사용된 용어 "생물학적 활성 단편"은 MC4R과 같은 멜라노코르틴 수용체에 결합할 수 있는 알파-MSH 펩티드의 한 부분을 언급한다. 펩티드 서열 HFRW (서열 번호: 81)는 알파-MSH 펩티드 서열 SYSMEHFRWGKPV (서열 번호: 2)의 바람직한 "생물학적 활성 단편"이다. HFRW 단편은 합성 멜라노코르틴 수용체를 활성화시키는 분자인 멜라노탄 II (Melanotan II, MTII)의 구조에 삽입된다.(Fan et a.1. , Nature 385: 165-168 (1997)
본 발명의 모방체 폴리펩티드에 멜라노코르틴 수용체 결합 분자가 삽입되는 것은, 멜라노코르틴 수용체에 넓은 범위의 친화도로 결합되도록 한다. 본 발명의 모방체 폴리펩티드는 약 1O-7, 10-8, 10-9, 10-10, 10-11 또는 10-12 M의 친화도(Kd)로 멜라노코르틴 수용체에 결합할 수 있다. aMSH 펩티드, MTII 펩티드 및 aMSHMMB의 IC50 수치의 범위는 각각 260-400 nM, 5-30 nM 및 200-300 nM이다. 멜라노코르틴 수용체에 대한 모방체 폴리펩티드의 친화도는 임의의 적합한 방법을 이용하여 실험적으로 결정될 수 있다. 이러한 방법들은 Biacore 또는 KinExA 기기, ELISA 또는 경쟁적 결합 어세이(competitive binding assays)를 이용할 수 있다. 바람직한 친화도로, 멜라노코르틴 수용체에 특이적으로 결합하는 모방체 폴리펩티드는 본 분야에 숙련자에게 공지된 기술에 의하여 변형체 또는 단편의 라이브러리(libraries)로부터 선택될 수 있다.
서열 번호: 2에 나타낸 아미노산 서열을 갖는 알파-MSH 펩티드는 다른 멜라노코르틴 수용체 결합 분자를 얻기 위하여 변형될 수 있다. 상기와 같은 변형은 펩티드에 C-[X]n-C 모티브가 삽입되는 것을 포함하며, 이황화 결합의 형성을 통하여 구조적으로 펩티드가 구속되도록 한다. C-[X]n-C 모티브에서, C는 시스테인 잔기, X는 아미노산 잔기 및 n은 요구되는 형태적 구속을 얻기 위하여 필요한 정수를 나타낸다 본 예로서, n은 1 잔기만큼 작을 수도, 50만큼 클 수도 있다. 바람직한 C-[X]n-C 변형된 펩티드 서열은 서열 번호: 4, 6, 8 및 10에 나타내었다.
또한, 펩티드에 Wa-[X]n-Wa 모티브가 삽입되는 변형을 포함할 수 있으며, 트립토판 지퍼(tryptophan zipper)의 형성을 통하여 펩티드를 구속하도록 할 수 있다. Wa-[X]n-Wa 모티브에서, W는 트립토판 잔기, X는 아미노산, a는 통상 2이나, 1 내지 10일 수 있는 정수, n은 요구되는 형태적 구속을 얻기 위하여 필요한 정수를 나타낸다. 본 예로서, n은 1 잔기만큼 작을 수도, 50만큼 클 수도 있다. 바람직한 Wa-[X]n-Wa 펩티드는 서열 번호: 12, 14, 16 및 18에 나타내었다. 게다가, 알파-MSH 펩티드에서 나타나는 서열 HFRW (서열 번호: 81)는 또한, 본 서열에서 임의의 잔기가 F, H, W 및 M 중 임의의 하나로 치환되는 것에 의하여 변형될 수 있다; 예를 들어, HFRW (서열 번호: 81)는 FHWM (서열 번호: 83)로 치환될 수 있다.
본 발명의 폴리펩티드에서, 링커 부분(Lk)은 모방체가 대체적인 지향성 및 결합 특성을 갖는 것을 허용함으로써 구조적 유연성을 제공한다. 바람직한 링커는 비-펩티드 화학적 링크 또는 펩티드 결합에 의해 링크된 1 내지 20 아미노산을 함유하며, 여기서, 상기 아미노산은 20개의 자연적으로 발생한 아미노산 또는 다른 아미노산들(예를 들어, D-아미노산, 비자연적으로 발생한 아미노산, 또는 드물게 자연적으로 발생하는 아미노산)로부터 선택된다. 링커 부분은 글리신, 알라닌 및 세린과 같은 입체장애를 갖지 않는(sterically unhindered) 아미노산의 대부분을 함유할 수 있으며, GS, 폴리 GS (예를 들어, GSGS (서열 번호: 20)), GGSG (서열 번호: 22), GSGGGS (서열 번호: 24), GSGGGSG (서열 번호: 26), GSSG (서열 번호: 28), 또는 GSGGGS (서열 번호: 30) 또는 GGGS (서열 번호: 85) 또는 임의의 조합물 또는 이들의 폴리머를 함유할 수 있다. 본 발명의 범위내에서, 다른 바람직한 링커들은 20 잔기보다 더 길 수 있으며, 글리신, 알라닌 및 세린을 제외한 잔기들을 함유할 수 있다.
본 발명의 폴리펩티드에서, V2는 중쇄 가변 영역과 같은 면역글로블린 가변 영역 카르복실 말단 부위의 일부분이다. 바람직한 V2 아미노산 서열은 GTLVTVSS (서열 번호: 32) 및 TLVAVSS (서열 번호: 34)이다. 본 발명의 폴리펩티드에서, Hg는 중쇄 가변 영역과 같은 면역글로블린 가변 영역의 힌지 부위의 일부분이다. 바람직한 Hg 아미노산 서열은 EPKSCDKTHTCPPCP (서열 번호: 36), EPKSADKTHTCPPCP (서열 번호: 38), ESKYGPPCPSCP (서열 번호: 40), ESKYGPPCPPCP (서열 번호: 42), CPPCP (서열 번호: 44) 및 CPSC (서열 번호: 46)를 함유한다 .
본 발명의 폴리펩티드에서, CH2는 면역글로블린 중쇄 CH2 불변 영역이다. 바람직한 CH2 아미노산 서열은: APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAK (서열 번호: 48), APEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAK (서열 번호: 50), APEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAK (서열 번호: 52) 및 APEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAK (서열 번호: 54)를 포함한다.
본 발명의 폴리펩티드에서, CH3는 면역글로블린 중쇄 CH3 불변 영역이다. 바람직한 CH3 아미노산 서열은: GQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (서열 번호: 56) 및 GQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (서열 번호: 58)를 함유한다. 본 발명의 폴리펩티드의 CH3 영역은 특정 재조합 시스템에서 발현될 때, 그것의 C-말단 아미노산이 잘려진다는 것은 종래 기술의 숙련자에게 인지될 것이다.
본 발명의 모방체 폴리펩티드 Hg, CH2 또는 CH3는 IgG1 또는 IgG4 서브클래스의 것일 수 있다. 만약, 그것이 γl 또는 γ4 중쇄로부터 각각 형성되거나 발생된 것이라면, 서열은 IgG1 또는 IgG4 서브클래스의 것이다. 만약 주어진 펩티드 사슬이 주어진 종의 알려진 γl 또는 γ4 중쇄에 대하여 적어도 80%의 상동성이 있다면, 이는 γl 또는 γ4 중쇄 사슬인 것이다. 두개의 펩티드 사슬 사이의 퍼센트 상동성은 AlignX module of Vector NTI v.9.0 .0 (Invitrogen Corp., Carslbad, CA)의 디폴트 세팅을 이용하여 두 서열간의 정렬(pairwise alignment)에 의하여 결정될 수 있다.
본 발명의 모방체 폴리펩티드 Hg, CH2 또는 CH3는 개별적으로 IgG1 또는 IgG4서브클래스의 것일 수 있다. 본 발명의 모방체는 또한 각 서브클래스로부터의 Hg, CH2 또는 CH3 요소 조합물을 포함할 수 있다. 예를 들어, CH2 및 CH3가 IgG1 서브클래스의 것인 반면, Hg는 IgG4 서브클래스의 것일 수 있다. 대체적으로, Hg, CH2 및 CH3는 모두 IgG4 또는 IgG1 서브클래스의 것일 수 있다. 폴리펩티드 EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (서열 번호: 65)는 Hg (서열 번호: 65의 잔기 1-15), CH2 (서열 번호: 65의 잔기 16-125), 및 CH3 (서열 번호: 65의 잔기 126-232)가 모두 IgG1 서브 클래스의 것인, 바람직한 폴리펩티드이다. IgG1 및 IgG4 서브클래스는 힌지 구역에서 시스테인의 수가 다르다. IgG1과 같은 대부분의 IgG 타입 항체는 두개의 동일한 중쇄(heavy (H) chain), 및 두개의 동일한 경쇄(light (L) chain), 전형적으로 단축하여 H2L2로 구성된 동종이합체(homodimeric) 분자이다. 따라서, 이러한 분자들은 일반적으로 중쇄 사이의 이황화 결합 형성 및 동일한 결합 특이성을 갖는 IgG 분자 두개의 항원 결합(Fab) 암(arm)때문에, 항체 결합에 관하여 2가이다. 반면에, IgG4 아이소타입 중쇄는 중쇄 사이(inter) 또는 중쇄 내(intra)에 이황화 결합을 형성할 능력이 있는 그들의 힌지 영역에 CPSC (서열 번호: 46) 모티브를 포함하는데, 예를 들면, CPSC 모티브의 두개 시스테인 잔기는 다른 H 사슬에서 상응하는 시스테인 잔기와 이황화 결합할 수 있으며(inter), 혹은, 주어진 CPSC 모티브 내의 두개 시스테인 잔기가 서로 이황화 결합할 수 있다(intra).
힌지 영역에서 중쇄-내의 결합과 함께, IgG4 분자들 내의 HL 쌍은 서로 공유결합적으로 회합되지 않기 때문에, 그들은 HL 모너머로 분해될 수 있으며, 그 다음, 이중특이성, 동형이합체 IgG4 분자를 형성하는 다른 IgG4 분자로부터 유래된 HL 모노머로 재조합될 수 있다. 생체내, 이성질화 효소(isomerase)는 이러한 과정을 촉진할 수 있다. 이중특이적 IgG 항체에서, 두개의 항체 분자 Fab 암(arm)은 그들이 결합하는 에피토프가 다르다. IgG4 의 힌지 구역에서 세린 잔기가 프롤린 잔기로 치환된 것은 IgG-유사 행동"을 유발하는 데, 예를 들어, 중쇄들 사이에 안정한 이황화 결합을 형성하는 분자는 더욱이, 다른 IgG4 분자와의 HL 교환을 허용하지 않는다.
본 발명의 모방체 폴리펩티드는 이황화 결합 형성에 포함되며, 모방체 폴리펩티드의 Hg-CH2-CH3 부분에서 나타나는 부위의 변형에 의하여, 더욱 IgG4-유사 또는 IgG1-유사하도록 제조할 수 있다. 상기의 부위는 제거(removal), 결실(deletion), 삽입(insertion) 또는 다른 아미노산으로의 치환(substitution)에 의하여 변형될 수 있다. 전형적으로, 이황화 결합 관련 모티브에서 나타나는 시스테인 잔기는, 제거되거나 치환된다. 이러한 부위의 제거는 모방체를 생산하는 숙주 세포에서 나타나는 다른 시스테인-함유 단백질들과의 공유결합적 이황화 결합을 피하게 할 수 있거나, IgG4-기초의 컨스트럭트에서 모방체 Hg-CH2-CH3 부위의 비공유결합적 이량체화를 허용하는 동안 중쇄내(intra) 이황화 결합을 피하도록 할 수 있다. 상기 부위의 변형은 두개의 다른 M 부분과 함께 이중특이성 모방체 폴리펩티드의 형성을 허용할 수 있거나, 상기의 이중특이성 종들의 형성을 저해할 수 있다. IgG1 및 IgG4 서브클래스는 또한 보체의존세포독성(complement dependent cytotoxicity, CDC)) 및 항체의존세포독성(antibody dependent cellular cytotoxicity, ADCC)을 매개하는 그들의 능력이 다르다. CDC는 보체의 존재하에서, 타겟 세포를 용해시킨다. 보체 활성 경로는 보체 시스템(C1q)의 첫번째 구성물 및 같은 족 항원과 복합화된 분자와의 결합에 의하여 개시된다. IgG1은 보체 캐스케이드(cascade), 및 IgG4가 보체-유도 활성을 거의 갖고 있지 않을 때 이후의 적절한 CDC 활성의 강한 유도체이다. ADCC는 ADCC (예를 들면, 자연살생세포(natural killer(NK) cell, 호중구(neutrophils), 및 대식세포(macrophages))에 포함되는 Fc 수용체(FcRs)를 발현하는 비특이적 세포독성 세포에서 세포-매개 과정이며, 이는 타겟 세포에 항원의 결합을 인지하고 그 후에 타겟 세포가 용해되도록 한다. IgG4가 상기 수용체와 매우 약하게 결합하며, ADCC 유도 능력을 거의 갖고 있지 않은 반면, IgG1 서브클래스는 ADCC에 속하는 Fc 수용체에 높은 결합력으로 결합하여, ADCC에 기여한다. ADCC와 같은 작용자(effector) 기능을 활성화시키는 데, IgG4의 상대적인 무능은, 세포 사멸없이, 모방체 폴리펩티드가 세포로 운반되는 것이 가능하도록 하기 때문에, 바람직한 것이다.
본 발명에 따른 모방체 폴리펩티드의 CDC 및 ADCC 활성은 모방체 폴리펩티드의 Hg-CH2-CH3 부분에 나타나는 CDC 및 ADCC에 속하는 부위를 바꿈으로써, 변형될 수 있다. 이러한 부위는 제거, 결실, 삽입 또는 다른 아미노산으로의 치환에 의하여 변형될 수 있다. 본 발명의 모방체에서, C1q 결합 부위와 같은 CDC에 속하는 부위는 전형적으로 제거되거나, 다른 경우에, CDC 활성을 최소화하도록 변형된다. 덧붙여, ADCC에 속하는 Fc 수용체 결합 부위는 또한 본 발명의 모방체 내에서와 유사하게 변형될 수 있다. 일반적으로, 그러한 변형은 본 발명의 모방체로부터 ADCC 활성에 속하는 Fc 수용체 결합 부위를 제거할 것이다. 본 발명 폴리펩티드의 CH2 부분에서 류신(Leu) 잔기의 알라닌(Ala) 잔기로의 치환은 본 발명의 폴리펩티드에서 ADCC 활성이 최소화되도록 할 수 있는 변형의 일예이다. CH2 아미노산 서열 APEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAK(서열 번호: 52)는 잔기 4 및 5(상기 서열에서)에서 류신 잔기가 알라닌 잔기로 치환된 바람직한 예이다. 더욱이, 펩티드의 N-말단이 이후의 신호 펩티드의 절단으로부터 자유롭도록, V1 부위는 제거될 수 있으며, 아세틸라제(acetylase)와 같은 효소에 접근하기 용이하며, 이에 의하여 변형될 수 있다.
IgG4 및 IgG1 아이소타입 둘 모두의 항체는 FcRn 구제 수용체 결합 부위(FcRn salvage receptor binding site)를 함유한다. FcRn 구제 수용체는 IgG 타입 항체를 체강 및 혈관의 내측에 정렬된 것와 같은 내피세포 층을 가로질러 순환시키거나 이송시켜, 신체에서 IgG 항체 레벨이 유지되도록 한다. FcRn 구제 수용체는 IgG에 결합하여 이를 수행하는데, 이는 비특이적 음세포작용(pinocytosis)에 의하여 내피세포에 들어가고, IgG 항체 분자가 세포의 리소좀에서 분해(degrade)되는 것을 방지하는 것이다. 상기 FcRn 수용체 활성은, 상기 부위가 결여된 다른 동일한 분자와 비교하여 FcRn 결합 부위 분자의 혈청 반감기가 길어지도록 한다.
본 발명에 따른 모방체의 Hg-CH2-CH3 부분은 CH2 및 CH3 영역의 접합부에 FcRn 결합 부위를 함유하는 것이 바람직하다. 상기와 같은 FcRn 부위는 단독 알파-MSH와 같은 멜라노코르틴 수용체 결합 분자에 관련된 다른 약동학적 특성을 향상시킬 뿐만 아니라, 본 발명의 모방체의 혈청 반감기를 증가시킬 것으로 기대된다. 본 발명의 모방체에서, FcRn 부위는 제거, 결실, 삽입 또는 아미노산으로의 치환에 의하여 변형되거나 부가된다. 전형적으로, 상기와 같은 변형은 FcRn에 주여진 부위의 결합을 향상시키는 데 이용한다. 인간 FcRn 결합 부위의 일예는 IgG4 및 IgG1 항체 둘다에서 발견되는 서열 MISRTPTVLHQHNHY (서열 번호: 69)이다. 다른 FcRn 결합 부위는 본 기술 분야의 숙련자에게 잘 알려져 있다.
IgG4 및 IgG1과 같은 다른 아이소타입을 갖는 항체는 당화 부위를 함유할 수 있다. 이러한 부위의 당화는 항체 분자의 특성 및 활성을 바꿀 수 있다. 항체 분자는 N-당화 또는 O-당화될 수 있다. 질소 원자(예를 들어, 아스파라긴)를 함유하는 항체 아미노산 잔기 곁사슬의 N-당화는 N-당화된 항체 분자에 세포용해 활성을 부여함으로써, ADCC와 같은 항체 Fc 작용자 기능을 조절할 수 있다. 세포독성과 관련된 이러한 ADCC는 상기 N-당화된 항체에 영향을 받아 세포의 용해를 유발한다. 대체적으로, 항체 분자는 산소 원자(예를 들어, 세린 또는 트레오닌)를 포함하는 아미노산 곁사슬의 변형에 의하여 O-당화될 수 있다. O-당화는 증가된 렉틴 매개로 혈청으로부터 O-당화된 항체 분자 제거를 함으로써 항체 분자의 혈청 반감기를 감소시킬 수 있다. 덧붙여, 다양한 항체 분자들 사이에 다른 정도의 O-당화때문에, O-당화는 항체 이종(heterogeneity)의 바람직하지 않은 증가를 유발할 수 있다. 마지막으로, O-당화 및 N-당화 둘다는 결합 친화도 및 면역원성(immunogenicity)과 같은, 항체 분자의 구조 의존 특성을 바꿀 수 있다.
그들이 모방하는 항체 분자와 같이, 본 발명의 모방체 폴리펩티드는 또한, N-당화 및 O-당화에 의하여 변역-후 변형된다. 대부분 예에서, 세포용해 활성의 최소화하기 위하여 본 발명의 모방체의 N-당화를 제한하는 것이 바람직하다. N-당화는 제거 또는 전형적으로 N-당화된 아스파라긴과 같은 아미노산 잔기로의 치환에 의하여 제한될 수 있다. 또한, 렉틴-매개 제거, 모방체 이종 및 결합 친화도 및 면역원성과 같은 구조 의존성 모방체 특성의 변화를 최소화하기 위하여 모방체 O-당화를 제한하는 것이 바람직하다. 본 발명의 모방체에서 O-링크된 당화를 최소화하기 위한 한가지 방법은 본 발명 폴리펩티드의 V2 부분에서, 트레오닌 잔기를 알라닌 잔기로 치환시키는 것이다. V2 아미노산 서열 TLVAVSS (서열 번호: 34)는 트레오닌을 알라닌으로 치환시킨 바람직한 예이며; 특이 V2 치환은 또한, 서열 번호: 62의 위치 47에서, 트레오닌을 알라닌으로 치환시킴으로써 얻을 수 있다. 본 분야의 숙련자는 글리코실라제 효소 활성의 조절을 포함하여 N-링크된, 그리고 O-링크된 당화를 조절할 다른 방법들을 인지할 것이다.
본 발명의 모방체 폴리펩티드의 모노머 구조 Mp-Lk-V2-Hg-CH2-CH3는 다른 모너머 "t"에 링크될 수 있으며, 여기서 t는 1 내지 10의 정수이다. 상기의 링크는 비-공유 상호작용 또는 Cys-Cys 이황화 결합과 같은 공유 링크를 통하여 생성될 수 있다. 이와 같이, 본 발명의 폴리펩티드 다이머(dimer) 및 고도의 멀티머(multimer)와 같은 멀티머 구조는 형성될 수 있다. 본 발명에 따른 폴리펩티드의 다이머화(dimerization)는 MC4R과 같은 멜라노코르틴 수용체에 대한 이들 폴리펩티드의 친화도를 증가시킬 것으로 기대된다. 본 발명에서 사용되는 바, 용어 "멀티머"는 4차 구조를 가지며, 두개 또는 그 이상의 서브유닛의 회합에 의하여 형성되는 분자를 의미한다.
본 발명에 따른 폴리펩티드는 추가적으로 면역글로블린 가변 영역의 아미노산 말단 부분, 화학식 Ⅱ에 나타낸 바 V1으로 설계된 아미노 말단을 임의로 포함할 수 있다.
[화학식 Ⅱ]
(Vl-Mp-Lk-V2-Hg-CH2-CH3)(t)
바람직한 V1 아미노산 서열은 QIQ 및 QVQ를 포함한다.
본 발명에 따른 폴리펩티드는 또한 단백질 분비를 용이하게 하는 분비 신호 또는 세포 내에서 단백질 수송(protein trafficking)에 필요한 다른 신호들을 포함할 수 있다. 바람직한 분비 신호 서열은 MAWVWTLLFLMAAAQSIQA (서열 번호: 69)이다. 본 분야의 숙련자는 다른 분비 신호를 인지할 것이다.
일구체예에서, 본 발명의 폴리펩티드는 서열 번호: 60 또는 62를 포함한다. 서열 번호: 62는 일반식 II의 (Vl-Mp-Lk-V2-Hg-CH2-CH3)(t) 멜라노코르틴 수용체 결합 알파-MSH 폴리펩티드를 나타내며 그것의 아미노 말단에 융합된 분비 신호 MAWVWTLLFLMAAAQSIQA (서열 번호: 69)를 갖는다. 서열 번호: 60은 일반식 I의 (Mp-Lk-V2-Hg-CH2-CH3)(t) 멜라노코르틴 수용체 결합 알파-MSH 폴리펩티드를 나타낸다. 서열 번호: 60에는 분비 신호가 존재하지 않는다.
본 발명의 다른 일예는, 적어도 하나의 멜라노코르틴 수용체 결합 모방체를 암호화하는 폴리뉴클레오티드에 상보적이거나 유효성있게 상동성을 갖는 폴리뉴클레오티드를 포함하는 폴리뉴클레오티드이다. 본 발명의 다른 일예는 멜라노코르틴 수용체 결합 모방체를 암호화하는 적어도 하나의 폴리뉴클레오티드 분자를 포함하는 벡터를 함유한다. 다른 일예에서, 본 발명은 본 발명의 벡터를 포함하거나, 또는, 본 발명의 모방체 폴리펩티드를 발현하는 세포를 제공한다. 폴리뉴클레오티드, 벡터 및 세포는 본 발명의 모방체 폴리펩티드를 제조하는 데 이용할 수 있다.
일 구체예에서, 본 발명의 폴리뉴클레오티드는 서열 번호: 59 또는 서열 번호 : 61, 또는, 서열 번호: 59 또는 서열 번호: 61에 상보적인 폴리뉴클레오티드를 포함한다. 서열 번호: 59는 일반식 I의 (Mp-Lk-V2-Hg-CH2-CH3)(t) 멜라노코르틴 수용체 결합 알파-MSH 폴리펩티드를 암호화하는 cDNA이며, 이는 신호 서열이 결여된다. 서열 번호: 61은 일반식 Ⅱ의 (V1-Mp-Lk-V2-Hg-CH2-CH3)(t) 멜라노코르틴 수용체 결합 알파-MSH 펩티드를 암호화하는 cDNA이며 이는 그 아미노 말단에 융합된 분비 신호를 갖는다.
일 구체예에서, 본 발명의 폴리뉴클레오티드는 서열 번호: 60 또는 서열 번호: 62의 폴리펩티드를 암호화하는 폴리뉴클레오티드를 포함한다. 서열 번호 60 또는 서열 번호: 62에 나타낸 폴리펩티드 서열을 암호화하는 바람직한 핵산 서열은 각각 서열 번호 59 또는 서열 번호: 61에 나타냈다. 또한 제시된 폴리뉴클레오티드는 상기에서 설명한 폴리뉴클레오티드와 실질적으로 동일하다.
폴리뉴클레오티드의 문맥에서 용어 "실질적으로 동일한"은 주어진 폴리뉴클레오티드 서열이 본 발명의 폴리뉴클레오티드 서열, 또는 이의 부분과, 적어도 60%, 적어도 70%, 적어도 약 80%, 적어도 약 90%, 또는 적어도 대략 95-98% 뉴클레오티드가 동일한 것을 의미한다. 두개의 펩티드 사슬 사이의 퍼센트 상동성은 AlignX module of Vector NTI v.9.0 .0 (Invitrogen Corp., Carslbad, CA)의 디폴트 세팅을 이용하여 두 서열간의 정렬(pairwise alignment)에 의하여 결정될 수 있다.
전형적으로, 본 발명의 폴리뉴클레오티드는 본 발명의 모방체 폴리펩티드의 준비를 위한 발현 백터 내에서 이용된다. 본 발명의 범위내에서 벡터는 진핵 생물의 발현에 필요한 요소를 제공하며, CMV 프로모터 구동 벡터와 같이, 바이러스 프로모터 구동(driven) 벡터를 함유하며, 예를 들면, pcDNA3.1, pCEP4, 및 이들의 유도체, 배큘로바이러스(baculovirus) 발현 벡터, 초파리(Drosophila) 발현 벡터, 및 인간 Ig 유전자 프로모터와 같은, 포유동물 유전자 프로모터에 의하여 구동되는 발현 벡터가 있다. 다른 예들은 T7 프로모터 구동 벡터와 같이 원핵 생물 발현 벡터를 함유하며, 예를 들면, pET41, 락토오스 프로모터 구동 벡터 및 아라비노스 유전자 프로모터 구동 벡터가 있다.
본 발명은 또한 본 발명의 모방체를 발현하거나, 또는 본 발명의 벡터를 포함하는 세포에 관한 것이다. 상기와 같은 세포는 원핵 생물 또는 진핵 생물일 수 있다. 바람직한 진핵 세포는 COS-1, COS-7, HEK293, BHK21, CHO, BSC-I, HepG2, 653, SP2/0, NSO, 293, HeLa, myeloma, lymphoma 세포 또는 이들의 유도체와 같은 포유동물 세포이나, 이에 한정된 것은 아니다. 가장 바람직하게, 진핵 세포는 HEK293, NSO, SP2/0, 또는 CHO 세포이다. E. coli는 바람직한 원핵 세포이다. 본 발명에 따른 세포는 형질감염(transfection), 세포 융합(cell fusion), 불멸화(immortalization) 또는 본 분야의 숙련자에게 잘 알려진 다른 방법들에 의하여 생성될 수 있다. 세포에 형질감염된 폴리뉴클레오티드는 염색체외에 존재하거나, 세포의 염색체에 안정하게 삽입되어 존재할 수 있다.
본 발명의 모방체는 폴리펩티드의 Hg-CH2-CH3 부분을 변형함으로써, 주어진 숙주 세포에 더욱 적합하게 제조할 수 있다. 예를 들어, 본 발명의 모방체가 E.coli와 같은 박테리아 세포 내에서 재조합적으로 발현될 때, E. coli 효소 프롤린 이미노펩티다제(iminopeptidase)에 의한 분해를 방지하기 위하여, Hg 요소에서 Pro-Ala 서열이 제거될 수 있다. 유사하게, 선택된 숙주 세포에서 발현된 생성물에서, 이종(heterogeneity)을 방지하기 위하여 본 발명의 모방체에서 Hg 요소의 한 부분은 결실되거나 다른 아미노산으로 치환될 수 있다.
본 발명은 또한 본 발명의 세포를 배양하고, 본 발명의 발현된 모방체 폴리펩티드를 정제하는 단계들을 포함하여, 모방체 폴리펩티드를 제조하는 방법을 제공한다. 실험상 전사(transcription) 및 번역(translation)에서 필요한 것과 같은 세포 조성물은 또한, 본 발명의 폴리펩티드를 발현시키는 데, 이용될 수 있다. 본 발명은 두 방법 모두에 의하여 제조된 모방체를 망라한다. 발현된 모방체 폴리펩티드는 본 분야에 잘 알려진 방법에 의하여 세포 또는 세포 조성물에 근거한 시스템으로부터 수득 및 정제될 수 있으며, 상기 본 분야에 잘 알려진 방법은 단백질 A 정제, 황산암모늄(ammonium sulfate) 또는 에탄올 침전(ethanol precipitation), 산 추출(acid extraction), 음이온 또는 양이온 교환 크로마토그래피(anion or cation exchange chromatography), 인산셀룰로오즈 크로마토그래피(phosphocellulose chromatography), 소수성 상호작용 크로마토그래피(hydrophobic interaction chromatography), 친화 크로마토그래피(affinity chromatography), 히드록실앳파타이트 크로마토그래피(hydroxylatpatite chromatography) 및 렉틴 크로마토그래피(lectin chromatography)를 포함하나, 이에 한정된 것은 아니다. 고성능 액체 크로마토그래피(HPLC) 또한, 정제를 위하여 채용될 수 있다. 전형적으로, 정제는 몇몇 다른 방법들의 조합이 필요할 것이다.
본 발명의 다른 일예는 적어도 하나의 모방체 폴리펩티드의 유효량 및 약제학적으로 허용가능한 담체 또는 희석제를 포함하는 약제학적 조성물이다. 용어 "유효량"은 일반적으로 효율적인 치료, 예를 들면, 처리가 요구되는 증상 또는 질병의 부분적 또는 전체적인 완화를 위하여 필요한 모방체의 양을 언급한다. 조성물은 비만 및 다른 이하 기술된 상태의 치료에 유용한 적어도 하나의 화합물, 단백질 또는 조성물을 더 임의로 포함할 수 있다. 조성물에서 약제학적으로 허용가능한 담체 또는 희석제는, 수용액, 현탁액, 유제, 콜로이드 또는 파우더일 수 있다. 본 분야의 숙련자는 다른 약제학적으로 허용가능한 담체 및 희석제를 인지할 것이다.
본 발명의 또다른 일예는 세포, 조직 또는 기관에서 멜라노코르틴 수용체의 생물학적 활성을 변형시키는 방법이며, 이는 본 발명의 약제학적 조성물과 세포, 조직 또는 기관의 접촉되도록 하는 것을 포함한다. 상기 방법은 뇌, 뇌 조직 또는 뇌 세포에서, 멜라노코르틴 수용체 활성을 변형시키는 데 이용될 수 있다. 대체적으로, 본 발명의 방법은 위와 같은 다른 장기 또는 근육과 같은 다른 말초 세포 또는 조직에서, 멜라노코르틴 수용체 활성을 변형시키는 데 이용될 수 있다. 본 분야의 숙련자는 이용될 수 있는 세포들, 조직들, 또는 기관들을 인지할 것이다.
본 발명의 다른 일예는 적어도 하나의 멜라노코르틴 수용체-매개 상태를 조절하는 방법이며, 이는 본 발명의 약제학적 조성물을 필요로 하는 환자에게 투여하는 것을 포함한다. 본 발명의 약제학적 조성물은 임의의 적합한 경로에 의하여 투여될 수 있다. 상기 경로는 수막강내, 비강내, 말초(예를 들어, 피하 조직, 근육내, 진피내, 정맥내) 또는 본 분야에 알려진 임의의 다른 수단일 수 있다. 상기에서 설명한 바와 같이, 비정상 멜라노코르틴 수용체 활성은 비만 및 타입 2 당뇨병과 같은 많은 병리학적 상태에 내포된다. 본 발명의 모방체 폴리펩티드는 또한 남성 및 여성의 발기 부전, 염증, 울혈성 심부전(congestive heart failure), 중추신경계 질병(central nervous system disorder), 신경 손상(nerve damage), 염증성 질환, 폐질환(pulmonary disease), 피부 질환, 발열 및 통증과 같은 다른 멜라노코르틴 수용체 매개 상태를 조절하기 위하여 이용될 수 있다.
본 발명은 또한 다음 실시예에서 참조와 함께 기술된다. 이러한 실시예들은 주로 본 발명의 일면을 설명하기 위한 것이며, 본 발명을 한정하는 것이 아니다.
실시예
1
알파-
MSH
모방체
및 발현 벡터
컨스트럭트
분비 신호 서열, 알파-MSH 펩티드 서열, 링커 서열, VH 서열, 힌지 서열, 인간 IgG1 CH2 서열 및 인간 IgG1 CH3 서열을 포함하는 알파-MSH 모방체 단백질을 설계하였다(도 3 및 서열 번호: 62). 분석적 데이터, 예를 들어, 질량분석법을 이용하여, 성숙된 폴리펩티드가 생성되었음을 확인하였다(Gl/Gl 폼을 위한 61,344.6). 이러한 알파-MSH 모방체 단백질(도 3; 서열 목록: 61)을 암호화하는 핵산 서열은 표준 분자 생물학적 기술을 이용하여 생성하였다. 알파-MSH 모방체 서열을 암호화하는 핵산 서열을 p2389 발현 벡터로 서브클로닝(subclone)하여, 알파-MSH 모방체 발현 벡터를 생성하였다(서열 번호: 63).
실시예
2
알파-
MSH
모방체
발현
알파-MSH 모방체를 HEK293E 세포에서 일시적으로 발현시켰다. 표준 환경을 이용하여 세포를 배양시켰으며, Lipofectamine 2000 (Invitrogen, Carlsbad, CA)를 이용하여 제조자에 의해 지시된 대로, 알파-MSH 모방체 발현 벡터를 일시적으로 형질감염시켰다. 형질 감염 후 24시간이 경과한 세포를 혈청이 없는 배지 제제에 옮겼으며, 5일동안 배양하였다. 그 후, 배양 배지를 제거하고, 원심분리하여 불순물을 제거하였다. 불순물이 제거된 배지를 Protein A-Sepharose™ (HiTrap rProtein A FF, Amersham Biosciencies, Piscataway, NJ)와 함께 인큐베이션시켰으며, 제조자에 의해 지시된 대로, Protein A-Sepharose™ 컨쥬게이트로부터 단백질을 용출시켰다. 그 후 용출된 단백질 용액을 표준 방법에 따라, Superose™ 12 크기 배제 크로마토그래피(Superose 12 10/300 GL, Amersham Biosciencies, Piscataway, NJ)를 통하여 정제하였다. 그 후, 컬럼 용출물을 SDS-PAGE에 처리하고, 실버 및 쿠마시 블루 염색법을 이용하여 가시화하였다. 그 후, 웨스턴 블롯을 준비하고, Fc 특이 1차 항체 또는 알파-MSH 특이 1차 항체로 블롯을 프로브하였다. 웨스턴 블롯 및 SDS-PAGE 염색 결과는 함께, 두개의 폴리펩티드 사슬로 구성되는 정제된 알파-MSH 모방체가, 일시적 형질 감염된 HEK293 세포로부터 수득된 것으로 나타났다.
실시예
3
MC4R
에 결합하는 알파-
MSH
모방체
알파-MSH 모방체는 MC4R에 결합하며, MC4R 결합을 위하여, 방사선 표지된 [Nle(4), D-Phe(7)]-알파-MSH(NDP-알파-MSH) 경쟁자 분자와 경쟁할 수 있다(도 4). MC4R은 알파-MSH를 위한 수용체이다. HEK293 세포 막(Perkin Elmer Life and Analytical Sciences, Boston, MA)에서 재조합적으로 발현된 MC4R에 결합하는 알파-MSH를 경쟁적 결합 어세이(binding assay)에 의하여 측정시켰고, 여기서, 표지되지 않은 MC4R 작용제(양성 대조군) 및 인간 항체의 Fc 부위(음성 대조군)의 증가량을 도 4에 나타낸 대로, [125I] -NDP-알파-MSH를 포함하는 어세이 혼합물에 첨가시켰다. 표지되지 않은 MC4R 작용제는 멜라노탄 II (MTII; 알파 MSH 아날로그), 알파-MSH, 및 NDP-알파-MSH이 있다. 경쟁적 결합 어세이에 의하여 측정한 바, MC4R에 결합하는 알파-MSH 모방체는 PBS(인산 완충 용액) 중, 4℃, -20℃ 및 -80℃에서 2주 동안 보관 후에 안정한 것으로 나타났다.
경쟁적 결합 어세이는 Scintillation Proximity Assays® (Amersham Biosciences Corp, Piscataway, NJ)를 이용하여, 어세이 제조자에 의하여 지시된 대로 수행하였다. 어세이 혼합물은 EC80에서 [125I] -NDP-알파-MSH를 포함하였으며, 예를 들어, -0.5 nM, 0.1 μg of MC4R 막, 1 mM 황산마그네슘(MgSO4), 1.5 mM 염화칼슘(CaCl2), 25 mM Hepes, 0.2% BSA, 1 mM 1, 10-펜트롤린(phenthroline)를 포함하였고, 어세이 제조자는 quantity of protease inhibitor cocktail (Roche Diagnostics Corp., Indianapolis, IN) 및 SPA 비드를 추천하였다. cintillation Proximity Assay® beads로부터 방출되는 빛은 Packard Top Count NXT Instrument (Perkin Elmer Life and Analytical Sciences, Boston, MA)를 이용하여 5분 동안 측정하였다.
실시예4
MC4R
을
활성화시키는
알파-
MSH
모방체
알파-MSH 모방체는 MC4R을 발현하는 CHOK1 세포에서 cAMP 생산 증가를 위한 MC4R 신호를 활성화시킬 수 있다(도 5 및 도 6). MC4R은 7 막관통(7TM) G-단백질 커플된 수용체이다. 리간드 또는 작용제(agonist)에 의한 MC4R의 활성화는 고리 AMP 레벨(cAMP)을 증가시킨다.
MC4R 발현 벡터에 의해 안정적으로 형질 감염되고 MC4R을 발현하는 두개의 다른 클론, CHOK1 세포주를 이용하여 MC4R 수용체 활성 어세이를 수행하였다. 클론 1은 클론 2와 비교하여, 높은 레벨로 MC4R을 발현하였다. 클론 1 및 클론 2 세포들을 대략 100,000 세포/웰 밀도의 표준 배양 환경을 이용하여, 단층(monolayer)으로 성장시킨 다음, 도 5 및 도 6에 나타낸 대로, 알파-MSH, MTII 또는 알파-MSH 모방체의 증가된 양(0-100 μM)과 함께 15분 동안 인큐베이션하였다. 그 후, 세포들을 용해시켰으며, cAMP-Screeo. Direct™ Chemiluminescent Immunoassay System (Applied Biosystems, Foster City, CA)를 이용하여, 제조자에 의해 지시된 대로 cAMP 어세이를 수행하였다. 클론 1(도 5) 및 클론 2(도 6)을 이용한 cAMP 어세이로부터 얻은 EC50 수치는 표 1에 나타낸다.
클론 1 | 클론 2 | |
알파-MSH 펩티드(양성 대조군) | EC50= 3.29nM | EC50= 9.46nM |
MTII(양성 대조군) | EC50= 0.52nM | EC50= 0.52nM |
알파-MSH 모방체 | EC50= 14.36nM | EC50= 52.4nM |
실시예
5
동물의 식이 섭취와 체중을 감소시키는 알파-
MSH
모방체
투여
집쥐(Rattus norvegicus)의 뇌측실(brain ventricules)에 알파-MSH 모방체의 투여로 동물의 식이 섭취(도 7) 및 체중을 감소(도 8)시켰다. 좌측 뇌실에 외과적으로 삽입한 캐뉼라(cannula)를 통한 뇌실내 주입(intracerebroventricular injections, ICV)에 의하여, 알파-MSH 모방체를 뇌측실(brain ventricute)에 공급하였다. 캐뉼라는 250g 내지 350g 무게의 수컷 Sprague-Dawley 또는 Wistar 랫에 외과적으로 삽입하였다. 캐뉼라 위치 좌표는 다음과 같다: 정수리로부터 -0.8㎜, 복부로부터 -4.5㎜, -1.5 후전방. 동물은 수술후 7 내지 10일 동안 회복시켰다. 동물은 스트레스를 줄이기 위하여, 일간 취급 및 모의 주사 둘다로서, 시험 과정에 적응되도록 하였다. 또한 동물들을 전도된 명-암 주기에 따르도록 하였다.
앤지오텐신 II 테스트(angiotensin II test)을 이용하여, 적합한 캐뉼라 위치를 확인하였다. 캐뉼라를 통하여 랫에 10ng 앤지오텐신 II의 ICV 투여로 30분 내에 5-10㎖의 물을 마시도록 유발한다면, 상기 테스트에서 적합한 캐뉼라 위치를 확인한 것이었다. 이러한 앤지오텐신 II 테스트를 통과한 동물들만 식이 섭취 실험에 이용하였다.
동물을 18-24시간동안 금식시킨 다음, 캐뉼라를 통하여 알파-MSH 모방체, 알파-MSH(양성 대조군), 또는 PBS(음성 대조군)를 뇌측실에 9 μl/분의 주입비로 투여하였다. 각각의 치료군은 최소 7마리가 되도록 하였다. 치료 및 투약은 도 7 및 도 8에 나타낸 대로 하였다.
음식과 물을 주입후에 동물에게 제공하였다. 음식과 물의 소비량을 주입후 0, 4, 24, 48, 72시간(도 7)에 측정하였다. 주입 후 72시간째 체중을 도 6에 제시된 바와 같이 측정하였다.
본 발명은 충분하게 기술되었지만, 이는 본 분야에서 보통의 기술을 가진 자가, 청구항의 의도 또는 범위를 벗어나지 않고 수정 및 변형이 가능하다는 것이 명백할 것이다.
SEQUENCE LISTING
<110> Centocor, Inc.
<120> Melanocortin Receptor Binding Mimetibodies, Compositions, Methods and
Uses
<130> CEN5080 PCT
<140> To Be Assigned
<141> 2005-10-25
<150> 60/621,960
<151> 2004-10-25
<160> 85
<170> PatentIn version 3.2
<210> 1
<211> 39
<212> DNA
<213> Homo sapiens
<400> 1
tcctactcca tggagcactt ccgctggggc aagccggtg 39
<210> 2
<211> 13
<212> PRT
<213> Homo sapiens
<400> 2
Ser Tyr Ser Met Glu His Phe Arg Trp Gly Lys Pro Val
1 5 10
<210> 3
<211> 39
<212> DNA
<213> Artificial Sequence
<220>
<223> Constrained peptide
<400> 3
agctatagct gcgaacattt tcgctggtgc aaaccggtg 39
<210> 4
<211> 13
<212> PRT
<213> Artificial Sequence
<220>
<223> Constrained peptide
<400> 4
Ser Tyr Ser Cys Glu His Phe Arg Trp Cys Lys Pro Val
1 5 10
<210> 5
<211> 39
<212> DNA
<213> Artificial Sequence
<220>
<223> Constrained peptide
<400> 5
agctattgca tggaacattt tcgctggtgc aaaccggtg 39
<210> 6
<211> 13
<212> PRT
<213> Artificial Sequence
<220>
<223> Constrained peptide
<400> 6
Ser Tyr Cys Met Glu His Phe Arg Trp Cys Lys Pro Val
1 5 10
<210> 7
<211> 39
<212> DNA
<213> Artificial Sequence
<220>
<223> Constrained peptide
<400> 7
agctgcagca tggaacattt tcgctggtgc aaaccggtg 39
<210> 8
<211> 13
<212> PRT
<213> Artificial Sequence
<220>
<223> Constrained peptide
<400> 8
Ser Cys Ser Met Glu His Phe Arg Trp Cys Lys Pro Val
1 5 10
<210> 9
<211> 39
<212> DNA
<213> Artificial Sequence
<220>
<223> Constrained peptide
<400> 9
tgctatagca tggaacattt tcgctggggc tgcccggtg 39
<210> 10
<211> 13
<212> PRT
<213> Artificial Sequence
<220>
<223> Constrained peptide
<400> 10
Cys Tyr Ser Met Glu His Phe Arg Trp Gly Cys Pro Val
1 5 10
<210> 11
<211> 45
<212> DNA
<213> Artificial Sequence
<220>
<223> Constrained peptide
<400> 11
agctggagct gggaacattt tcgctggggc aaatggacct ggaaa 45
<210> 12
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> Constrained peptide
<400> 12
Ser Trp Ser Trp Glu His Phe Arg Trp Gly Lys Trp Thr Trp Lys
1 5 10 15
<210> 13
<211> 51
<212> DNA
<213> Artificial Sequence
<220>
<223> Constrained peptide
<400> 13
agctggagct ggggcgaaca ttttcgctgg ggcaaaggct ggacctggaa a 51
<210> 14
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Constrained peptide
<400> 14
Ser Trp Ser Trp Gly Glu His Phe Arg Trp Gly Lys Gly Trp Thr Trp
1 5 10 15
Lys
<210> 15
<211> 57
<212> DNA
<213> Artificial Sequence
<220>
<223> Constrained peptide
<400> 15
agctggagct ggggcggcga acattttcgc tggggcaaag gcggctggac ctggaaa 57
<210> 16
<211> 19
<212> PRT
<213> Artificial Sequence
<220>
<223> Constrained peptide
<400> 16
Ser Trp Ser Trp Gly Gly Glu His Phe Arg Trp Gly Lys Gly Gly Trp
1 5 10 15
Thr Trp Lys
<210> 17
<211> 57
<212> DNA
<213> Artificial Sequence
<220>
<223> Constrained peptide
<400> 17
agctggagct ggagcatgga acattttcgc tggggcaaac cggtgtggac ctggaaa 57
<210> 18
<211> 19
<212> PRT
<213> Artificial Sequence
<220>
<223> Constrained peptide
<400> 18
Ser Trp Ser Trp Ser Met Glu His Phe Arg Trp Gly Lys Pro Val Trp
1 5 10 15
Thr Trp Lys
<210> 19
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Flexible peptide
<400> 19
ggcagcggca gc 12
<210> 20
<211> 4
<212> PRT
<213> Artificial Sequence
<220>
<223> Flexible peptide
<400> 20
Gly Ser Gly Ser
1
<210> 21
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Flexible peptide
<400> 21
ggcggcagcg gc 12
<210> 22
<211> 4
<212> PRT
<213> Artificial Sequence
<220>
<223> Flexible peptide
<400> 22
Gly Gly Ser Gly
1
<210> 23
<211> 18
<212> DNA
<213> Artificial Sequence
<220>
<223> Flexible peptide
<400> 23
ggcagcggcg gcggcagc 18
<210> 24
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> Flexible peptide
<400> 24
Gly Ser Gly Gly Gly Ser
1 5
<210> 25
<211> 21
<212> DNA
<213> Artificial Sequence
<220>
<223> Flexible peptide
<400> 25
ggcagcggcg gcggcagcgg c 21
<210> 26
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Flexible peptide
<400> 26
Gly Ser Gly Gly Gly Ser Gly
1 5
<210> 27
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Flexible peptide
<400> 27
ggcagcagcg gc 12
<210> 28
<211> 4
<212> PRT
<213> Artificial Sequence
<220>
<223> Flexible peptide
<400> 28
Gly Ser Ser Gly
1
<210> 29
<211> 18
<212> DNA
<213> Artificial Sequence
<220>
<223> Flexible peptide
<400> 29
ggcagcggcg gcggcagc 18
<210> 30
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> Flexible peptide
<400> 30
Gly Ser Gly Gly Gly Ser
1 5
<210> 31
<211> 24
<212> DNA
<213> Homo sapiens
<400> 31
ggcaccctgg tgaccgtgag cagc 24
<210> 32
<211> 8
<212> PRT
<213> Homo sapiens
<400> 32
Gly Thr Leu Val Thr Val Ser Ser
1 5
<210> 33
<211> 21
<212> DNA
<213> Artificial Sequence
<220>
<223> T-->A substitution to limit O-linked glycosylation
<400> 33
accctggtgg cggtgagcag c 21
<210> 34
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> T-->A substitution to limit O-linked glycosylation
<400> 34
Thr Leu Val Ala Val Ser Ser
1 5
<210> 35
<211> 45
<212> DNA
<213> Homo sapiens
<400> 35
gaaccgaaaa gctgcgataa aacccatacc tgcccgccgt gcccg 45
<210> 36
<211> 15
<212> PRT
<213> Homo sapiens
<400> 36
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro
1 5 10 15
<210> 37
<211> 45
<212> DNA
<213> Homo sapiens
<400> 37
gaaccgaaaa gcgcggataa aacccatacc tgcccgccgt gcccg 45
<210> 38
<211> 15
<212> PRT
<213> Homo sapiens
<400> 38
Glu Pro Lys Ser Ala Asp Lys Thr His Thr Cys Pro Pro Cys Pro
1 5 10 15
<210> 39
<211> 36
<212> DNA
<213> Homo sapiens
<400> 39
gaaagcaaat atggcccgcc gtgcccgagc tgcccg 36
<210> 40
<211> 12
<212> PRT
<213> Homo sapiens
<400> 40
Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro
1 5 10
<210> 41
<211> 36
<212> DNA
<213> Homo sapiens
<400> 41
gaaagcaaat atggcccgcc gtgcccgccg tgcccg 36
<210> 42
<211> 12
<212> PRT
<213> Homo sapiens
<400> 42
Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro
1 5 10
<210> 43
<211> 15
<212> DNA
<213> Homo sapiens
<400> 43
tgcccgccgt gcccg 15
<210> 44
<211> 5
<212> PRT
<213> Homo sapiens
<400> 44
Cys Pro Pro Cys Pro
1 5
<210> 45
<211> 12
<212> DNA
<213> Homo sapiens
<400> 45
tgcccgagct gc 12
<210> 46
<211> 4
<212> PRT
<213> Homo sapiens
<400> 46
Cys Pro Ser Cys
1
<210> 47
<211> 330
<212> DNA
<213> Homo sapiens
<400> 47
gcgccggaac tgctgggcgg cccgagcgtg tttctgtttc cgccgaaacc gaaagatacc 60
ctgatgatta gccgcacccc ggaagtgacc tgcgtggtgg tggatgtgag ccatgaagat 120
ccggaagtga aatttaactg gtatgtggat ggcgtggaag tgcataacgc gaaaaccaaa 180
ccgcgcgaag aacagtataa cagcacctat cgcgtggtga gcgtgctgac cgtgctgcat 240
caggattggc tgaacggcaa agaatataaa tgcaaagtga gcaacaaagc gctgccggcg 300
ccgattgaaa aaaccattag caaagcgaaa 330
<210> 48
<211> 110
<212> PRT
<213> Homo sapiens
<400> 48
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
1 5 10 15
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
20 25 30
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
35 40 45
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
50 55 60
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
65 70 75 80
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
85 90 95
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
100 105 110
<210> 49
<211> 330
<212> DNA
<213> Homo sapiens
<400> 49
gcgccggaag cggcgggcgg cccgagcgtg tttctgtttc cgccgaaacc gaaagatacc 60
ctgatgatta gccgcacccc ggaagtgacc tgcgtggtgg tggatgtgag ccatgaagat 120
ccggaagtga aatttaactg gtatgtggat ggcgtggaag tgcataacgc gaaaaccaaa 180
ccgcgcgaag aacagtataa cagcacctat cgcgtggtga gcgtgctgac cgtgctgcat 240
caggattggc tgaacggcaa agaatataaa tgcaaagtga gcaacaaagc gctgccggcg 300
ccgattgaaa aaaccattag caaagcgaaa 330
<210> 50
<211> 110
<212> PRT
<213> Homo sapiens
<400> 50
Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
1 5 10 15
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
20 25 30
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
35 40 45
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
50 55 60
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
65 70 75 80
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
85 90 95
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
100 105 110
<210> 51
<211> 330
<212> DNA
<213> Homo sapiens
<400> 51
gcgccggaat ttctgggcgg cccgagcgtg tttctgtttc cgccgaaacc gaaagatacc 60
ctgatgatta gccgcacccc ggaagtgacc tgcgtggtgg tggatgtgag ccaggaagat 120
ccggaagtgc agtttaactg gtatgtggat ggcgtggaag tgcataacgc gaaaaccaaa 180
ccgcgcgaag aacagtttaa cagcacctat cgcgtggtga gcgtgctgac cgtgctgcat 240
caggattggc tgaacggcaa agaatataaa tgcaaagtga gcaacaaagg cctgccgagc 300
agcattgaaa aaaccattag caaagcgaaa 330
<210> 52
<211> 110
<212> PRT
<213> Homo sapiens
<400> 52
Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
1 5 10 15
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
20 25 30
Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr
35 40 45
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
50 55 60
Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
65 70 75 80
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
85 90 95
Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys
100 105 110
<210> 53
<211> 330
<212> DNA
<213> Homo sapiens
<400> 53
gcgccggaag cggcgggcgg cccgagcgtg tttctgtttc cgccgaaacc gaaagatacc 60
ctgatgatta gccgcacccc ggaagtgacc tgcgtggtgg tggatgtgag ccaggaagat 120
ccggaagtgc agtttaactg gtatgtggat ggcgtggaag tgcataacgc gaaaaccaaa 180
ccgcgcgaag aacagtttaa cagcacctat cgcgtggtga gcgtgctgac cgtgctgcat 240
caggattggc tgaacggcaa agaatataaa tgcaaagtga gcaacaaagg cctgccgagc 300
agcattgaaa aaaccattag caaagcgaaa 330
<210> 54
<211> 110
<212> PRT
<213> Homo sapiens
<400> 54
Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
1 5 10 15
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
20 25 30
Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr
35 40 45
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
50 55 60
Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
65 70 75 80
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
85 90 95
Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys
100 105 110
<210> 55
<211> 321
<212> DNA
<213> Homo sapiens
<400> 55
ggccagccgc gcgaaccgca ggtgtatacc ctgccgccga gccgcgatga actgaccaaa 60
aaccaggtga gcctgacctg cctggtgaaa ggcttttatc cgagcgatat tgcggtggaa 120
tgggaaagca acggccagcc ggaaaacaac tataaaacca ccccgccggt gctggatagc 180
gatggcagct tttttctgta tagcaaactg accgtggata aaagccgctg gcagcagggc 240
aacgtgttta gctgcagcgt gatgcatgaa gcgctgcata accattatac ccagaaaagc 300
ctgagcctga gcccgggcaa a 321
<210> 56
<211> 107
<212> PRT
<213> Homo sapiens
<400> 56
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
1 5 10 15
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
20 25 30
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
35 40 45
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
50 55 60
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
65 70 75 80
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
85 90 95
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
100 105
<210> 57
<211> 321
<212> DNA
<213> Homo sapiens
<400> 57
ggccagccgc gcgaaccgca ggtgtatacc ctgccgccga gccaggaaga aatgaccaaa 60
aaccaggtga gcctgacctg cctggtgaaa ggcttttatc cgagcgatat tgcggtggaa 120
tgggaaagca acggccagcc ggaaaacaac tataaaacca ccccgccggt gctggatagc 180
gatggcagct tttttctgta tagccgcctg accgtggata aaagccgctg gcaggaaggc 240
aacgtgttta gctgcagcgt gatgcatgaa gcgctgcata accattatac ccagaaaagc 300
ctgagcctga gcctgggcaa a 321
<210> 58
<211> 107
<212> PRT
<213> Homo sapiens
<400> 58
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu
1 5 10 15
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
20 25 30
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
35 40 45
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
50 55 60
Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly
65 70 75 80
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
85 90 95
Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
100 105
<210> 59
<211> 777
<212> DNA
<213> Artificial Sequence
<220>
<223> Melanocortin receptor binding alpha-MSH mimetibody without
<223> secretory signal.
<400> 59
tcctactcca tggagcactt ccgctggggc aagccggtgg gatccggtgg aggctccggt 60
accttagtca ccgtctcctc agagcccaaa tcttgtgaca aaactcacac gtgcccaccg 120
tgcccagcac ctgaactcct ggggggaccg tcagtcttcc tcttcccccc aaaacccaag 180
gacaccctca tgatctcccg gacccctgag gtcacatgcg tggtggtgga cgtgagccac 240
gaagaccctg aggtcaagtt caactggtac gtggacggcg tggaggtgca taatgccaag 300
acaaagccgc gggaggagca gtacaacagc acgtaccggg tggtcagcgt cctcaccgtc 360
ctgcaccagg actggctgaa tggcaaggag tacaagtgca aggtctccaa caaagccctc 420
ccagccccca tcgagaaaac catctccaaa gccaaagggc agccccgaga accacaggtg 480
tacaccctgc ccccatcccg ggatgagctg accaagaacc aggtcagcct gacctgcctg 540
gtcaaaggct tctatcccag cgacatcgcc gtggagtggg agagcaatgg gcagccggag 600
aacaactaca agaccacgcc tcccgtgctg gactccgacg gctccttctt cctctacagc 660
aagctcaccg tggacaagag caggtggcag caggggaacg tcttctcatg ctccgtgatg 720
catgaggctc tgcacaacca ctacacgcag aagagcctct ccctgtctcc gggtaaa 777
<210> 60
<211> 259
<212> PRT
<213> Artificial Sequence
<220>
<223> Melanocortin receptor binding alpha-MSH mimetibody without
<223> secretory signal.
<400> 60
Ser Tyr Ser Met Glu His Phe Arg Trp Gly Lys Pro Val Gly Ser Gly
1 5 10 15
Gly Gly Ser Gly Thr Leu Val Thr Val Ser Ser Glu Pro Lys Ser Cys
20 25 30
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
35 40 45
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
50 55 60
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
65 70 75 80
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
85 90 95
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
100 105 110
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
115 120 125
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
130 135 140
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
145 150 155 160
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
165 170 175
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
180 185 190
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
195 200 205
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
210 215 220
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
225 230 235 240
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
245 250 255
Pro Gly Lys
<210> 61
<211> 843
<212> DNA
<213> Artificial Sequence
<220>
<223> Melanocortin receptor binding alpha-MSH mimetibody with secretory
<223> signal and V1.
<400> 61
atggcttggg tgtggacctt gctattcctg atggcggccg cccaaagtat acaggcccag 60
atccagtcct actccatgga gcacttccgc tggggcaagc cggtgggatc cggtggaggc 120
tccggtacct tagtcaccgt ctcctcagag cccaaatctt gtgacaaaac tcacacgtgc 180
ccaccgtgcc cagcacctga actcctgggg ggaccgtcag tcttcctctt ccccccaaaa 240
cccaaggaca ccctcatgat ctcccggacc cctgaggtca catgcgtggt ggtggacgtg 300
agccacgaag accctgaggt caagttcaac tggtacgtgg acggcgtgga ggtgcataat 360
gccaagacaa agccgcggga ggagcagtac aacagcacgt accgggtggt cagcgtcctc 420
accgtcctgc accaggactg gctgaatggc aaggagtaca agtgcaaggt ctccaacaaa 480
gccctcccag cccccatcga gaaaaccatc tccaaagcca aagggcagcc ccgagaacca 540
caggtgtaca ccctgccccc atcccgggat gagctgacca agaaccaggt cagcctgacc 600
tgcctggtca aaggcttcta tcccagcgac atcgccgtgg agtgggagag caatgggcag 660
ccggagaaca actacaagac cacgcctccc gtgctggact ccgacggctc cttcttcctc 720
tacagcaagc tcaccgtgga caagagcagg tggcagcagg ggaacgtctt ctcatgctcc 780
gtgatgcatg aggctctgca caaccactac acgcagaaga gcctctccct gtctccgggt 840
aaa 843
<210> 62
<211> 281
<212> PRT
<213> Artificial Sequence
<220>
<223> Melanocortin receptor binding alpha-MSH mimetibody with secretory
<223> signal and V1.
<400> 62
Met Ala Trp Val Trp Thr Leu Leu Phe Leu Met Ala Ala Ala Gln Ser
1 5 10 15
Ile Gln Ala Gln Ile Gln Ser Tyr Ser Met Glu His Phe Arg Trp Gly
20 25 30
Lys Pro Val Gly Ser Gly Gly Gly Ser Gly Thr Leu Val Thr Val Ser
35 40 45
Ser Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro
50 55 60
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
65 70 75 80
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
85 90 95
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
100 105 110
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
115 120 125
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
130 135 140
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
145 150 155 160
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
165 170 175
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu
180 185 190
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
195 200 205
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
210 215 220
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
225 230 235 240
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
245 250 255
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
260 265 270
Lys Ser Leu Ser Leu Ser Pro Gly Lys
275 280
<210> 63
<211> 11978
<212> DNA
<213> Artificial Sequence
<220>
<223> Expression vector.
<400> 63
gttgacattg attattgact agttattaat agtaatcaat tacggggtca ttagttcata 60
gcccatatat ggagttccgc gttacataac ttacggtaaa tggcccgcct ggctgaccgc 120
ccaacgaccc ccgcccattg acgtcaataa tgacgtatgt tcccatagta acgccaatag 180
ggactttcca ttgacgtcaa tgggtggagt atttacggta aactgcccac ttggcagtac 240
atcaagtgta tcatatgcca agtccgcccc ctattgacgt caatgacggt aaatggcccg 300
cctggcatta tgcccagtac atgaccttac gggactttcc tacttggcag tacatctacg 360
tattagtcat cgctattacc atggtgatgc ggttttggca gtacaccaat gggcgtggat 420
agcggtttga ctcacgggga tttccaagtc tccaccccat tgacgtcaat gggagtttgt 480
tttggcacca aaatcaacgg gactttccaa aatgtcgtaa taaccccgcc ccgttgacgc 540
aaatgggcgg taggcgtgta cggtgggagg tctatataag cagagctcgt ttagtgaacc 600
gtcagatcgc ctggagacgc catccacgct gttttgacct ccatagaaga caccgggacc 660
gatccagcct ccgcggccgg gaacggtgca ttggaacgcg gattccccgt gccaagagtg 720
acgtaagtac cgcctataga gtctataggc ccacctcctt ggcttcttat gcatgctata 780
ctgtttttgg cttggggtct atacaccccc gcttcctcat gttataggtg atggtatagc 840
ttagcctata ggtgtgggtt attgaccatt attgaccact cccctattgg tgacgatact 900
ttccattact aatccataac atggctcttt gccacaactc tctttattgg ctatatgcca 960
atacactgtc cttcagagac tgacacggac tctgtatttt tacaggatgg ggtctcattt 1020
attatttaca aattcacata tacaacacca ccgtccccag tgcccgcagc ttttattaaa 1080
cataacgtgg gatctccacg cgaatctcgg gtacgtgttc cggacatggg ctcttctccg 1140
gtagcggcgg agcttctaca tccgagccct gctcccatgc ctccagcgac tcatggtcgc 1200
tcggcagctc cttgctccta acagtggagg ccagacttag gcacagcacg atgcccacca 1260
ccaccagtgt gccgcacaag gccgtggcgg tagggtatgt gtctgaaaat gagctcgggg 1320
agcgggcttg caccgctgac gcatttggaa gacttaaggc agcggcagaa gaagatgcag 1380
gcagctgagt tgttgtgttc tgataagagt cagaggtaac tcccgttgcg gtgctgttaa 1440
cggtggaggg cagtgtagtc tgagcagtac tcgttgctgc cgcgcgcgcc accagacata 1500
atagctgaca gactaacaga ctgttccttt ccatgggtct tttctgcagt caccgtcctt 1560
agatctgtct agaagctggg taccagctgc tagcgccacc atggcttggg tgtggacctt 1620
gctattcctg atggcggccg cccaaagtat acaggcccag atccagtcct actccatgga 1680
gcacttccgc tggggcaagc cggtgggatc cggtggaggc tccggtacct tagtcaccgt 1740
ctcctcagag cccaaatctt gtgacaaaac tcacacgtgc ccaccgtgcc cagcacctga 1800
actcctgggg ggaccgtcag tcttcctctt ccccccaaaa cccaaggaca ccctcatgat 1860
ctcccggacc cctgaggtca catgcgtggt ggtggacgtg agccacgaag accctgaggt 1920
caagttcaac tggtacgtgg acggcgtgga ggtgcataat gccaagacaa agccgcggga 1980
ggagcagtac aacagcacgt accgggtggt cagcgtcctc accgtcctgc accaggactg 2040
gctgaatggc aaggagtaca agtgcaaggt ctccaacaaa gccctcccag cccccatcga 2100
gaaaaccatc tccaaagcca aagggcagcc ccgagaacca caggtgtaca ccctgccccc 2160
atcccgggat gagctgacca agaaccaggt cagcctgacc tgcctggtca aaggcttcta 2220
tcccagcgac atcgccgtgg agtgggagag caatgggcag ccggagaaca actacaagac 2280
cacgcctccc gtgctggact ccgacggctc cttcttcctc tacagcaagc tcaccgtgga 2340
caagagcagg tggcagcagg ggaacgtctt ctcatgctcc gtgatgcatg aggctctgca 2400
caaccactac acgcagaaga gcctctccct gtctccgggt aaatgagggc ccgtttaaac 2460
agatccagac atgataagat acattgatga gtttggacaa accacaacta gaatgcagtg 2520
aaaaaaatgc tttatttgtg aaatttgtga tgctattgct ttatttgtaa ccattataag 2580
ctgcaataaa caagttaaca acaacaattg cattcatttt atgtttcagg ttcaggggga 2640
ggtgtgggag gttttttaaa gcaagtaaaa cctctacaaa tgtggtatgg ctgattatga 2700
tccggctgcc tcgcgcgttt cggtgatgac ggtgaaaacc tctgacacat gcagctcccg 2760
gagacggtca cagcttgtct gtaagcggat gccgggagca gacaagcccg tcaggcgtca 2820
gcgggtgttg gcgggtgtcg gggcgcagcc atgaggtcga ctctagagga tcgatgcccc 2880
gccccggacg aactaaacct gactacgaca tctctgcccc ttcttcgcgg ggcagtgcat 2940
gtaatccctt cagttggttg gtacaacttg ccaactgggc cctgttccac atgtgacacg 3000
gggggggacc aaacacaaag gggttctctg actgtagttg acatccttat aaatggatgt 3060
gcacatttgc caacactgag tggctttcat cctggagcag actttgcagt ctgtggactg 3120
caacacaaca ttgcctttat gtgtaactct tggctgaagc tcttacacca atgctggggg 3180
acatgtacct cccaggggcc caggaagact acgggaggct acaccaacgt caatcagagg 3240
ggcctgtgta gctaccgata agcggaccct caagagggca ttagcaatag tgtttataag 3300
gcccccttgt taaccctaaa cgggtagcat atgcttcccg ggtagtagta tatactatcc 3360
agactaaccc taattcaata gcatatgtta cccaacggga agcatatgct atcgaattag 3420
ggttagtaaa agggtcctaa ggaacagcga tatctcccac cccatgagct gtcacggttt 3480
tatttacatg gggtcaggat tccacgaggg tagtgaacca ttttagtcac aagggcagtg 3540
gctgaagatc aaggagcggg cagtgaactc tcctgaatct tcgcctgctt cttcattctc 3600
cttcgtttag ctaatagaat aactgctgag ttgtgaacag taaggtgtat gtgaggtgct 3660
cgaaaacaag gtttcaggtg acgcccccag aataaaattt ggacgggggg ttcagtggtg 3720
gcattgtgct atgacaccaa tataaccctc acaaacccct tgggcaataa atactagtgt 3780
aggaatgaaa cattctgaat atctttaaca atagaaatcc atggggtggg gacaagccgt 3840
aaagactgga tgtccatctc acacgaattt atggctatgg gcaacacata atcctagtgc 3900
aatatgatac tggggttatt aagatgtgtc ccaggcaggg accaagacag gtgaaccatg 3960
ttgttacact ctatttgtaa caaggggaaa gagagtggac gccgacagca gcggactcca 4020
ctggttgtct ctaacacccc cgaaaattaa acggggctcc acgccaatgg ggcccataaa 4080
caaagacaag tggccactct tttttttgaa attgtggagt gggggcacgc gtcagccccc 4140
acacgccgcc ctgcggtttt ggactgtaaa ataagggtgt aataacttgg ctgattgtaa 4200
ccccgctaac cactgcggtc aaaccacttg cccacaaaac cactaatggc accccgggga 4260
atacctgcat aagtaggtgg gcgggccaag ataggggcgc gattgctgcg atctggagga 4320
caaattacac acacttgcgc ctgagcgcca agcacagggt tgttggtcct catattcacg 4380
aggtcgctga gagcacggtg ggctaatgtt gccatgggta gcatatacta cccaaatatc 4440
tggatagcat atgctatcct aatctatatc tgggtagcat aggctatcct aatctatatc 4500
tgggtagcat atgctatcct aatctatatc tgggtagtat atgctatcct aatttatatc 4560
tgggtagcat aggctatcct aatctatatc tgggtagcat atgctatcct aatctatatc 4620
tgggtagtat atgctatcct aatctgtatc cgggtagcat atgctatcct aatagagatt 4680
agggtagtat atgctatcct aatttatatc tgggtagcat atactaccca aatatctgga 4740
tagcatatgc tatcctaatc tatatctggg tagcatatgc tatcctaatc tatatctggg 4800
tagcataggc tatcctaatc tatatctggg tagcatatgc tatcctaatc tatatctggg 4860
tagtatatgc tatcctaatt tatatctggg tagcataggc tatcctaatc tatatctggg 4920
tagcatatgc tatcctaatc tatatctggg tagtatatgc tatcctaatc tgtatccggg 4980
tagcatatgc tatcctcatg catatacagt cagcatatga tacccagtag tagagtggga 5040
gtgctatcct ttgcatatgc cgccacctcc caagggggcg tgaattttcg ctgcttgtcc 5100
ttttcctgct ggttgctccc attcttaggt gaatttaagg aggccaggct aaagccgtcg 5160
catgtctgat tgctcaccag gtaaatgtcg ctaatgtttt ccaacgcgag aaggtgttga 5220
gcgcggagct gagtgacgtg acaacatggg tatgcccaat tgccccatgt tgggaggacg 5280
aaaatggtga caagacagat ggccagaaat acaccaacag cacgcatgat gtctactggg 5340
gatttattct ttagtgcggg ggaatacacg gcttttaata cgattgaggg cgtctcctaa 5400
caagttacat cactcctgcc cttcctcacc ctcatctcca tcacctcctt catctccgtc 5460
atctccgtca tcaccctccg cggcagcccc ttccaccata ggtggaaacc agggaggcaa 5520
atctactcca tcgtcaaagc tgcacacagt caccctgata ttgcaggtag gagcgggctt 5580
tgtcataaca aggtccttaa tcgcatcctt caaaacctca gcaaatatat gagtttgtaa 5640
aaagaccatg aaataacaga caatggactc ccttagcggg ccaggttgtg ggccgggtcc 5700
aggggccatt ccaaagggga gacgactcaa tggtgtaaga cgacattgtg gaatagcaag 5760
ggcagttcct cgccttaggt tgtaaaggga ggtcttacta cctccatata cgaacacacc 5820
ggcgacccaa gttccttcgt cggtagtcct ttctacgtga ctcctagcca ggagagctct 5880
taaaccttct gcaatgttct caaatttcgg gttggaacct ccttgaccac gatgcttttc 5940
caaaccaccc tccttttttg cgccctgcct ccatcaccct gaccccgggg tccagtgctt 6000
gggccttctc ctgggtcatc tgcggggccc tgctctatcg ctcccggggg cacgtcaggc 6060
tcaccatctg ggccaccttc ttggtggtat tcaaaataat cggcttcccc tacagggtgg 6120
aaaaatggcc ttctacctgg agggggcctg cgcggtggag acccggatga tgatgactga 6180
ctactgggac tcctgggcct cttttctcca cgtccacgac ctctccccct ggctctttca 6240
cgacttcccc ccctggctct ttcacgtcct ctaccccggc ggcctccact acctcctcga 6300
ccccggcctc cactacctcc tcgaccccgg cctccactgc ctcctcgacc ccggcctcca 6360
cctcctgctc ctgcccctcc tgctcctgcc cctcctcctg ctcctgcccc tcctgcccct 6420
cctgctcctg cccctcctgc ccctcctgct cctgcccctc ctgcccctcc tgctcctgcc 6480
cctcctgccc ctcctcctgc tcctgcccct cctgcccctc ctcctgctcc tgcccctcct 6540
gcccctcctg ctcctgcccc tcctgcccct cctgctcctg cccctcctgc ccctcctgct 6600
cctgcccctc ctgctcctgc ccctcctgct cctgcccctc ctgctcctgc ccctcctgcc 6660
cctcctgccc ctcctcctgc tcctgcccct cctgctcctg cccctcctgc ccctcctgcc 6720
cctcctgctc ctgcccctcc tcctgctcct gcccctcctg cccctcctgc ccctcctcct 6780
gctcctgccc ctcctgcccc tcctcctgct cctgcccctc ctcctgctcc tgcccctcct 6840
gcccctcctg cccctcctcc tgctcctgcc cctcctgccc ctcctcctgc tcctgcccct 6900
cctcctgctc ctgcccctcc tgcccctcct gcccctcctc ctgctcctgc ccctcctcct 6960
gctcctgccc ctcctgcccc tcctgcccct cctgcccctc ctcctgctcc tgcccctcct 7020
cctgctcctg cccctcctgc tcctgcccct cccgctcctg ctcctgctcc tgttccaccg 7080
tgggtccctt tgcagccaat gcaacttgga cgtttttggg gtctccggac accatctcta 7140
tgtcttggcc ctgatcctga gccgcccggg gctcctggtc ttccgcctcc tcgtcctcgt 7200
cctcttcccc gtcctcgtcc atggttatca ccccctcttc tttgaggtcc actgccgccg 7260
gagccttctg gtccagatgt gtctcccttc tctcctaggc catttccagg tcctgtacct 7320
ggcccctcgt cagacatgat tcacactaaa agagatcaat agacatcttt attagacgac 7380
gctcagtgaa tacagggagt gcagactcct gccccctcca acagcccccc caccctcatc 7440
cccttcatgg tcgctgtcag acagatccag gtctgaaaat tccccatcct ccgaaccatc 7500
ctcgtcctca tcaccaatta ctcgcagccc ggaaaactcc cgctgaacat cctcaagatt 7560
tgcgtcctga gcctcaagcc aggcctcaaa ttcctcgtcc ccctttttgc tggacggtag 7620
ggatggggat tctcgggacc cctcctcttc ctcttcaagg tcaccagaca gagatgctac 7680
tggggcaacg gaagaaaagc tgggtgcggc ctgtgaggat cagcttatcg atgataagct 7740
gtcaaacatg agaattcttg aagacgaaag ggcctcgtga tacgcctatt tttataggtt 7800
aatgtcatga taataatggt ttcttagacg tcaggtggca cttttcgggg aaatgtgcgc 7860
ggaaccccta tttgtttatt tttctaaata cattcaaata tgtatccgct catgagacaa 7920
taaccctgat aaatgcttca ataatattga aaaaggaaga gtatgagtat tcaacatttc 7980
cgtgtcgccc ttattccctt ttttgcggca ttttgccttc ctgtttttgc tcacccagaa 8040
acgctggtga aagtaaaaga tgctgaagat cagttgggtg cacgagtggg ttacatcgaa 8100
ctggatctca acagcggtaa gatccttgag agttttcgcc ccgaagaacg ttttccaatg 8160
atgagcactt ttaaagttct gctatgtggc gcggtattat cccgtgttga cgccgggcaa 8220
gagcaactcg gtcgccgcat acactattct cagaatgact tggttgagta ctcaccagtc 8280
acagaaaagc atcttacgga tggcatgaca gtaagagaat tatgcagtgc tgccataacc 8340
atgagtgata acactgcggc caacttactt ctgacaacga tcggaggacc gaaggagcta 8400
accgcttttt tgcacaacat gggggatcat gtaactcgcc ttgatcgttg ggaaccggag 8460
ctgaatgaag ccataccaaa cgacgagcgt gacaccacga tgcctgcagc aatggcaaca 8520
acgttgcgca aactattaac tggcgaacta cttactctag cttcccggca acaattaata 8580
gactggatgg aggcggataa agttgcagga ccacttctgc gctcggccct tccggctggc 8640
tggtttattg ctgataaatc tggagccggt gagcgtgggt ctcgcggtat cattgcagca 8700
ctggggccag atggtaagcc ctcccgtatc gtagttatct acacgacggg gagtcaggca 8760
actatggatg aacgaaatag acagatcgct gagataggtg cctcactgat taagcattgg 8820
taactgtcag accaagttta ctcatatata ctttagattg atttaaaact tcatttttaa 8880
tttaaaagga tctaggtgaa gatccttttt gataatctca tgaccaaaat cccttaacgt 8940
gagttttcgt tccactgagc gtcagacccc gtagaaaaga tcaaaggatc ttcttgagat 9000
cctttttttc tgcgcgtaat ctgctgcttg caaacaaaaa aaccaccgct accagcggtg 9060
gtttgtttgc cggatcaaga gctaccaact ctttttccga aggtaactgg cttcagcaga 9120
gcgcagatac caaatactgt ccttctagtg tagccgtagt taggccacca cttcaagaac 9180
tctgtagcac cgcctacata cctcgctctg ctaatcctgt taccagtggc tgctgccagt 9240
ggcgataagt cgtgtcttac cgggttggac tcaagacgat agttaccgga taaggcgcag 9300
cggtcgggct gaacgggggg ttcgtgcaca cagcccagct tggagcgaac gacctacacc 9360
gaactgagat acctacagcg tgagctatga gaaagcgcca cgcttcccga agggagaaag 9420
gcggacaggt atccggtaag cggcagggtc ggaacaggag agcgcacgag ggagcttcca 9480
gggggaaacg cctggtatct ttatagtcct gtcgggtttc gccacctctg acttgagcgt 9540
cgatttttgt gatgctcgtc aggggggcgg agcctatgga aaaacgccag caacgcggcc 9600
tttttacggt tcctggcctt ttgctggcct tgaagctgtc cctgatggtc gtcatctacc 9660
tgcctggaca gcatggcctg caacgcgggc atcccgatgc cgccggaagc gagaagaatc 9720
ataatgggga aggccatcca gcctcgcgtc gcgaacgcca gcaagacgta gcccagcgcg 9780
tcggccccga gatgcgccgc gtgcggctgc tggagatggc ggacgcgatg gatatgttct 9840
gccaagggtt ggtttgcgca ttcacagttc tccgcaagaa ttgattggct ccaattcttg 9900
gagtggtgaa tccgttagcg aggtgccgcc ctgcttcatc cccgtggccc gttgctcgcg 9960
tttgctggcg gtgtccccgg aagaaatata tttgcatgtc tttagttcta tgatgacaca 10020
aaccccgccc agcgtcttgt cattggcgaa ttcgaacacg cagatgcagt cggggcggcg 10080
cggtccgagg tccacttcgc atattaaggt gacgcgtgtg gcctcgaaca ccgagcgacc 10140
ctgcagcgac ccgcttaaca gcgtcaacag cgtgccgcag atcccggggg gcaatgagat 10200
atgaaaaagc ctgaactcac cgcgacgtct gtcgagaagt ttctgatcga aaagttcgac 10260
agcgtctccg acctgatgca gctctcggag ggcgaagaat ctcgtgcttt cagcttcgat 10320
gtaggagggc gtggatatgt cctgcgggta aatagctgcg ccgatggttt ctacaaagat 10380
cgttatgttt atcggcactt tgcatcggcc gcgctcccga ttccggaagt gcttgacatt 10440
ggggaattca gcgagagcct gacctattgc atctcccgcc gtgcacaggg tgtcacgttg 10500
caagacctgc ctgaaaccga actgcccgct gttctgcagc cggtcgcgga ggccatggat 10560
gcgatcgctg cggccgatct tagccagacg agcgggttcg gcccattcgg accgcaagga 10620
atcggtcaat acactacatg gcgtgatttc atatgcgcga ttgctgatcc ccatgtgtat 10680
cactggcaaa ctgtgatgga cgacaccgtc agtgcgtccg tcgcgcaggc tctcgatgag 10740
ctgatgcttt gggccgagga ctgccccgaa gtccggcacc tcgtgcacgc ggatttcggc 10800
tccaacaatg tcctgacgga caatggccgc ataacagcgg tcattgactg gagcgaggcg 10860
atgttcgggg attcccaata cgaggtcgcc aacatcttct tctggaggcc gtggttggct 10920
tgtatggagc agcagacgcg ctacttcgag cggaggcatc cggagcttgc aggatcgccg 10980
cggctccggg cgtatatgct ccgcattggt cttgaccaac tctatcagag cttggttgac 11040
ggcaatttcg atgatgcagc ttgggcgcag ggtcgatgcg acgcaatcgt ccgatccgga 11100
gccgggactg tcgggcgtac acaaatcgcc cgcagaagcg cggccgtctg gaccgatggc 11160
tgtgtagaag tactcgccga tagtggaaac cgacgcccca gcactcgtcc ggatcgggag 11220
atgggggagg ctaactgaaa cacggaagga gacaataccg gaaggaaccc gcgctatgac 11280
ggcaataaaa agacagaata aaacgcacgg gtgttgggtc gtttgttcat aaacgcgggg 11340
ttcggtccca gggctggcac tctgtcgata ccccaccgag accccattgg ggccaatacg 11400
cccgcgtttc ttccttttcc ccaccccacc ccccaagttc gggtgaaggc ccagggctcg 11460
cagccaacgt cggggcggca ggccctgcca tagccactgg ccccgtgggt tagggacggg 11520
gtcccccatg gggaatggtt tatggttcgt gggggttatt attttgggcg ttgcgtgggg 11580
tcaggtccac gactggactg agcagacaga cccatggttt ttggatggcc tgggcatgga 11640
ccgcatgtac tggcgcgaca cgaacaccgg gcgtctgtgg ctgccaaaca cccccgaccc 11700
ccaaaaacca ccgcgcggat ttctggcgtg ccaagctagt cgaccaattc tcatgtttga 11760
cagcttatca tcgcagatcc gggcaacgtt gttgccattg ctgcaggcgc agaactggta 11820
ggtatggaag atctatacat tgaatcaata ttggcaatta gccatattag tcattggtta 11880
tatagcataa atcaatattg gctattggcc attgcatacg ttgtatctat atcataatat 11940
gtacatttat attggctcat gtccaatatg accgccat 11978
<210> 64
<211> 696
<212> DNA
<213> Homo sapiens
<400> 64
gaaccgaaaa gctgcgataa aacccatacc tgcccgccgt gcccggcgcc ggaactgctg 60
ggcggcccga gcgtgtttct gtttccgccg aaaccgaaag ataccctgat gattagccgc 120
accccggaag tgacctgcgt ggtggtggat gtgagccatg aagatccgga agtgaaattt 180
aactggtatg tggatggcgt ggaagtgcat aacgcgaaaa ccaaaccgcg cgaagaacag 240
tataacagca cctatcgcgt ggtgagcgtg ctgaccgtgc tgcatcagga ttggctgaac 300
ggcaaagaat ataaatgcaa agtgagcaac aaagcgctgc cggcgccgat tgaaaaaacc 360
attagcaaag cgaaaggcca gccgcgcgaa ccgcaggtgt ataccctgcc gccgagccgc 420
gatgaactga ccaaaaacca ggtgagcctg acctgcctgg tgaaaggctt ttatccgagc 480
gatattgcgg tggaatggga aagcaacggc cagccggaaa acaactataa aaccaccccg 540
ccggtgctgg atagcgatgg cagctttttt ctgtatagca aactgaccgt ggataaaagc 600
cgctggcagc agggcaacgt gtttagctgc agcgtgatgc atgaagcgct gcataaccat 660
tatacccaga aaagcctgag cctgagcccg ggcaaa 696
<210> 65
<211> 232
<212> PRT
<213> Homo sapiens
<400> 65
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Lys
225 230
<210> 66
<211> 45
<212> DNA
<213> Homo sapiens
<400> 66
atgattagcc gcaccccgac cgtgctgcat cagcataacc attat 45
<210> 67
<211> 15
<212> PRT
<213> Homo sapiens
<400> 67
Met Ile Ser Arg Thr Pro Thr Val Leu His Gln His Asn His Tyr
1 5 10 15
<210> 68
<211> 57
<212> DNA
<213> Homo sapiens
<400> 68
atggcttggg tgtggacctt gctattcctg atggcggccg cccaaagtat acaggcc 57
<210> 69
<211> 19
<212> PRT
<213> Homo sapiens
<400> 69
Met Ala Trp Val Trp Thr Leu Leu Phe Leu Met Ala Ala Ala Gln Ser
1 5 10 15
Ile Gln Ala
<210> 70
<211> 951
<212> DNA
<213> Homo sapiens
<400> 70
atggctgtgc agggatccca gagaagactt ctgggctccc tcaactccac ccccacagcc 60
atcccccagc tggggctggc tgccaaccag acaggagccc ggtgcctgga ggtgtccatc 120
tctgacgggc tcttcctcag cctggggctg gtgagcttgg tggagaacgc gctggtggtg 180
gccaccatcg ccaagaaccg gaacctgcac tcacccatgt actgcttcat ctgctgcctg 240
gccttgtcgg acctgctggt gagcgggagc aacgtgctgg agacggccgt catcctcctg 300
ctggaggccg gtgcactggt ggcccgggct gcggtgctgc agcagctgga caatgtcatt 360
gacgtgatca cctgcagctc catgctgtcc agcctctgct tcctgggcgc catcgccgtg 420
gaccgctaca tctccatctt ctacgcactg cgctaccaca gcaccgtgac cctgccgcgg 480
gcgcggcgag ccgttgcggc catctgggtg gccagtgtcg tcttcagcac gctcttcatc 540
gcctactacg accacgtggc cgtcctgctg tgcctcgtgg tcttcttcct ggctatgctg 600
gtgctcatgg ccgtgctgta cgtccacatg ctggcccggg cctgccagca cgcccagggc 660
atcgcccggc tccacaagag gcagcgcccg gtccaccagg gctttggcct taaaggcgct 720
gtcaccctca ccatcctgct gggcattttc ttcctctgct ggggcccctt cttcctgcat 780
ctcacactca tcgtcctctg ccccgagcac cccacgtgcg gctgcatctt caagaacttc 840
aacctctttc tcgccctcat catctgcaat gccatcatcg accccctcat ctacgccttc 900
cacagccagg agctccgcag gacgctcaag gaggtgctga cgtgctcctg g 951
<210> 71
<211> 317
<212> PRT
<213> Homo sapiens
<400> 71
Met Ala Val Gln Gly Ser Gln Arg Arg Leu Leu Gly Ser Leu Asn Ser
1 5 10 15
Thr Pro Thr Ala Ile Pro Gln Leu Gly Leu Ala Ala Asn Gln Thr Gly
20 25 30
Ala Arg Cys Leu Glu Val Ser Ile Ser Asp Gly Leu Phe Leu Ser Leu
35 40 45
Gly Leu Val Ser Leu Val Glu Asn Ala Leu Val Val Ala Thr Ile Ala
50 55 60
Lys Asn Arg Asn Leu His Ser Pro Met Tyr Cys Phe Ile Cys Cys Leu
65 70 75 80
Ala Leu Ser Asp Leu Leu Val Ser Gly Ser Asn Val Leu Glu Thr Ala
85 90 95
Val Ile Leu Leu Leu Glu Ala Gly Ala Leu Val Ala Arg Ala Ala Val
100 105 110
Leu Gln Gln Leu Asp Asn Val Ile Asp Val Ile Thr Cys Ser Ser Met
115 120 125
Leu Ser Ser Leu Cys Phe Leu Gly Ala Ile Ala Val Asp Arg Tyr Ile
130 135 140
Ser Ile Phe Tyr Ala Leu Arg Tyr His Ser Thr Val Thr Leu Pro Arg
145 150 155 160
Ala Arg Arg Ala Val Ala Ala Ile Trp Val Ala Ser Val Val Phe Ser
165 170 175
Thr Leu Phe Ile Ala Tyr Tyr Asp His Val Ala Val Leu Leu Cys Leu
180 185 190
Val Val Phe Phe Leu Ala Met Leu Val Leu Met Ala Val Leu Tyr Val
195 200 205
His Met Leu Ala Arg Ala Cys Gln His Ala Gln Gly Ile Ala Arg Leu
210 215 220
His Lys Arg Gln Arg Pro Val His Gln Gly Phe Gly Leu Lys Gly Ala
225 230 235 240
Val Thr Leu Thr Ile Leu Leu Gly Ile Phe Phe Leu Cys Trp Gly Pro
245 250 255
Phe Phe Leu His Leu Thr Leu Ile Val Leu Cys Pro Glu His Pro Thr
260 265 270
Cys Gly Cys Ile Phe Lys Asn Phe Asn Leu Phe Leu Ala Leu Ile Ile
275 280 285
Cys Asn Ala Ile Ile Asp Pro Leu Ile Tyr Ala Phe His Ser Gln Glu
290 295 300
Leu Arg Arg Thr Leu Lys Glu Val Leu Thr Cys Ser Trp
305 310 315
<210> 72
<211> 891
<212> DNA
<213> Homo sapiens
<400> 72
atgaagcaca ttatcaactc gtatgaaaac atcaacaaca cagcaagaaa taattccgac 60
tgtcctcgtg tggttttgcc ggaggagata tttttcacaa tttccattgt tggagttttg 120
gagaatctga tcgtcctgct ggctgtgttc aagaataaga atctccaggc acccatgtac 180
tttttcatct gtagcttggc catatctgat atgctgggca gcctatataa gatcttggaa 240
aatatcctga tcatattgag aaacatgggc tatctcaagc cacgtggcag ttttgaaacc 300
acagccgatg acatcatcga ctccctgttt gtcctctccc tgcttggctc catcttcagc 360
ctgtctgtga ttgctgcgga ccgctacatc accatcttcc acgcactgcg gtaccacagc 420
atcgtgacca tgcgccgcac tgtggtggtg cttacggtca tctggacgtt ctgcacgggg 480
actggcatca ccatggtgat cttctcccat catgtgccca cagtgatcac cttcacgtcg 540
ctgttcccgc tgatgctggt cttcatcctg tgcctctatg tgcacatgtt cctgctggct 600
cgatcccaca ccaggaagat ctccaccctc cccagagcca acatgaaagg ggccatcaca 660
ctgaccatcc tgctcggggt cttcatcttc tgctgggccc cctttgtgct tcatgtcctc 720
ttgatgacat tctgcccaag taacccctac tgcgcctgct acatgtctct cttccaggtg 780
aacggcatgt tgatcatgtg caatgccgtc attgacccct tcatatatgc cttccggagc 840
ccagagctca gggacgcatt caaaaagatg atcttctgca gcaggtactg g 891
<210> 73
<211> 297
<212> PRT
<213> Homo sapiens
<400> 73
Met Lys His Ile Ile Asn Ser Tyr Glu Asn Ile Asn Asn Thr Ala Arg
1 5 10 15
Asn Asn Ser Asp Cys Pro Arg Val Val Leu Pro Glu Glu Ile Phe Phe
20 25 30
Thr Ile Ser Ile Val Gly Val Leu Glu Asn Leu Ile Val Leu Leu Ala
35 40 45
Val Phe Lys Asn Lys Asn Leu Gln Ala Pro Met Tyr Phe Phe Ile Cys
50 55 60
Ser Leu Ala Ile Ser Asp Met Leu Gly Ser Leu Tyr Lys Ile Leu Glu
65 70 75 80
Asn Ile Leu Ile Ile Leu Arg Asn Met Gly Tyr Leu Lys Pro Arg Gly
85 90 95
Ser Phe Glu Thr Thr Ala Asp Asp Ile Ile Asp Ser Leu Phe Val Leu
100 105 110
Ser Leu Leu Gly Ser Ile Phe Ser Leu Ser Val Ile Ala Ala Asp Arg
115 120 125
Tyr Ile Thr Ile Phe His Ala Leu Arg Tyr His Ser Ile Val Thr Met
130 135 140
Arg Arg Thr Val Val Val Leu Thr Val Ile Trp Thr Phe Cys Thr Gly
145 150 155 160
Thr Gly Ile Thr Met Val Ile Phe Ser His His Val Pro Thr Val Ile
165 170 175
Thr Phe Thr Ser Leu Phe Pro Leu Met Leu Val Phe Ile Leu Cys Leu
180 185 190
Tyr Val His Met Phe Leu Leu Ala Arg Ser His Thr Arg Lys Ile Ser
195 200 205
Thr Leu Pro Arg Ala Asn Met Lys Gly Ala Ile Thr Leu Thr Ile Leu
210 215 220
Leu Gly Val Phe Ile Phe Cys Trp Ala Pro Phe Val Leu His Val Leu
225 230 235 240
Leu Met Thr Phe Cys Pro Ser Asn Pro Tyr Cys Ala Cys Tyr Met Ser
245 250 255
Leu Phe Gln Val Asn Gly Met Leu Ile Met Cys Asn Ala Val Ile Asp
260 265 270
Pro Phe Ile Tyr Ala Phe Arg Ser Pro Glu Leu Arg Asp Ala Phe Lys
275 280 285
Lys Met Ile Phe Cys Ser Arg Tyr Trp
290 295
<210> 74
<211> 1080
<212> DNA
<213> Homo sapiens
<400> 74
atgagcatcc aaaagacgta tctggaggga gattttgtct ttcctgtgag cagcagcagc 60
ttcctacgga ccctgctgga gccccagctc ggatcagccc ttctgacagc aatgaatgct 120
tcgtgctgcc tgccctctgt tcagccaaca ctgcctaatg gctcggagca cctccaagcc 180
cctttcttca gcaaccagag cagcagcgcc ttctgtgagc aggtcttcat caagcccgag 240
gttttcctgt ctctgggcat cgtcagtctg ctggaaaaca tcctggttat cctggccgtg 300
gtcaggaacg gcaacctgca ctccccgatg tacttctttc tctgcagcct ggcggtggcc 360
gacatgctgg taagtgtgtc caatgccctg gagaccatca tgatcgccat cgtccacagc 420
gactacctga ccttcgagga ccagtttatc cagcacatgg acaacatctt cgactccatg 480
atctgcatct ccctggtggc ctccatctgc aacctcctgg ccatcgccgt cgacaggtac 540
gtcaccatct tttacgcgct ccgctaccac agcatcatga ccgtgaggaa ggccctcacc 600
ttgatcgtgg ccatctgggt ctgctgcggc gtctgtggcg tggtgttcat cgtctactcg 660
gagagcaaaa tggtcattgt gtgcctcatc accatgttct tcgccatgat gctcctcatg 720
ggcaccctct acgtgcacat gttcctcttt gcgcggctgc acgtcaagcg catagcagca 780
ctgccacctg ccgacggggt ggccccacag caacactcat gcatgaaggg ggcagtcacc 840
atcaccattc tcctgggcgt gttcatcttc tgctgggccc ccttcttcct ccacctggtc 900
ctcatcatca cctgccccac caacccctac tgcatctgct acactgccca cttcaacacc 960
tacctggtcc tcatcatgtg caactccgtc atcgacccac tcatctacgc tttccggagc 1020
ctggaattgc gcaacacctt tagggagatt ctctgtggct gcaacggcat gaacttggga 1080
<210> 75
<211> 360
<212> PRT
<213> Homo sapiens
<400> 75
Met Ser Ile Gln Lys Thr Tyr Leu Glu Gly Asp Phe Val Phe Pro Val
1 5 10 15
Ser Ser Ser Ser Phe Leu Arg Thr Leu Leu Glu Pro Gln Leu Gly Ser
20 25 30
Ala Leu Leu Thr Ala Met Asn Ala Ser Cys Cys Leu Pro Ser Val Gln
35 40 45
Pro Thr Leu Pro Asn Gly Ser Glu His Leu Gln Ala Pro Phe Phe Ser
50 55 60
Asn Gln Ser Ser Ser Ala Phe Cys Glu Gln Val Phe Ile Lys Pro Glu
65 70 75 80
Val Phe Leu Ser Leu Gly Ile Val Ser Leu Leu Glu Asn Ile Leu Val
85 90 95
Ile Leu Ala Val Val Arg Asn Gly Asn Leu His Ser Pro Met Tyr Phe
100 105 110
Phe Leu Cys Ser Leu Ala Val Ala Asp Met Leu Val Ser Val Ser Asn
115 120 125
Ala Leu Glu Thr Ile Met Ile Ala Ile Val His Ser Asp Tyr Leu Thr
130 135 140
Phe Glu Asp Gln Phe Ile Gln His Met Asp Asn Ile Phe Asp Ser Met
145 150 155 160
Ile Cys Ile Ser Leu Val Ala Ser Ile Cys Asn Leu Leu Ala Ile Ala
165 170 175
Val Asp Arg Tyr Val Thr Ile Phe Tyr Ala Leu Arg Tyr His Ser Ile
180 185 190
Met Thr Val Arg Lys Ala Leu Thr Leu Ile Val Ala Ile Trp Val Cys
195 200 205
Cys Gly Val Cys Gly Val Val Phe Ile Val Tyr Ser Glu Ser Lys Met
210 215 220
Val Ile Val Cys Leu Ile Thr Met Phe Phe Ala Met Met Leu Leu Met
225 230 235 240
Gly Thr Leu Tyr Val His Met Phe Leu Phe Ala Arg Leu His Val Lys
245 250 255
Arg Ile Ala Ala Leu Pro Pro Ala Asp Gly Val Ala Pro Gln Gln His
260 265 270
Ser Cys Met Lys Gly Ala Val Thr Ile Thr Ile Leu Leu Gly Val Phe
275 280 285
Ile Phe Cys Trp Ala Pro Phe Phe Leu His Leu Val Leu Ile Ile Thr
290 295 300
Cys Pro Thr Asn Pro Tyr Cys Ile Cys Tyr Thr Ala His Phe Asn Thr
305 310 315 320
Tyr Leu Val Leu Ile Met Cys Asn Ser Val Ile Asp Pro Leu Ile Tyr
325 330 335
Ala Phe Arg Ser Leu Glu Leu Arg Asn Thr Phe Arg Glu Ile Leu Cys
340 345 350
Gly Cys Asn Gly Met Asn Leu Gly
355 360
<210> 76
<211> 999
<212> DNA
<213> Homo sapiens
<400> 76
atggtgaact ccacccaccg tgggatgcac acttctctgc acctctggaa ccgcagcagt 60
tacagactgc acagcaatgc cagtgagtcc cttggaaaag gctactctga tggagggtgc 120
tacgagcaac tttttgtctc tcctgaggtg tttgtgactc tgggtgtcat cagcttgttg 180
gagaatatct tagtgattgt ggcaatagcc aagaacaaga atctgcattc acccatgtac 240
tttttcatct gcagcttggc tgtggctgat atgctggtga gcgtttcaaa tggatcagaa 300
accattatca tcaccctatt aaacagtaca gatacggatg cacagagttt cacagtgaat 360
attgataatg tcattgactc ggtgatctgt agctccttgc ttgcatccat ttgcagcctg 420
ctttcaattg cagtggacag gtactttact atcttctatg ctctccagta ccataacatt 480
atgacagtta agcgggttgg gatcatcata agttgtatct gggcagcttg cacggtttca 540
ggcattttgt tcatcattta ctcagatagt agtgctgtca tcatctgcct catcaccatg 600
ttcttcacca tgctggctct catggcttct ctctatgtcc acatgttcct gatggccagg 660
cttcacatta agaggattgc tgtcctcccc ggcactggtg ccatccgcca aggtgccaat 720
atgaagggag cgattacctt gaccatcctg attggcgtct ttgttgtctg ctgggcccca 780
ttcttcctcc acttaatatt ctacatctct tgtcctcaga atccatattg tgtgtgcttc 840
atgtctcact ttaacttgta tctcatactg atcatgtgta attcaatcat cgatcctctg 900
atttatgcac tccggagtca agaactgagg aaaaccttca aagagatcat ctgttgctat 960
cccctgggag gcctttgtga cttgtctagc agatattaa 999
<210> 77
<211> 332
<212> PRT
<213> Homo sapiens
<400> 77
Met Val Asn Ser Thr His Arg Gly Met His Thr Ser Leu His Leu Trp
1 5 10 15
Asn Arg Ser Ser Tyr Arg Leu His Ser Asn Ala Ser Glu Ser Leu Gly
20 25 30
Lys Gly Tyr Ser Asp Gly Gly Cys Tyr Glu Gln Leu Phe Val Ser Pro
35 40 45
Glu Val Phe Val Thr Leu Gly Val Ile Ser Leu Leu Glu Asn Ile Leu
50 55 60
Val Ile Val Ala Ile Ala Lys Asn Lys Asn Leu His Ser Pro Met Tyr
65 70 75 80
Phe Phe Ile Cys Ser Leu Ala Val Ala Asp Met Leu Val Ser Val Ser
85 90 95
Asn Gly Ser Glu Thr Ile Ile Ile Thr Leu Leu Asn Ser Thr Asp Thr
100 105 110
Asp Ala Gln Ser Phe Thr Val Asn Ile Asp Asn Val Ile Asp Ser Val
115 120 125
Ile Cys Ser Ser Leu Leu Ala Ser Ile Cys Ser Leu Leu Ser Ile Ala
130 135 140
Val Asp Arg Tyr Phe Thr Ile Phe Tyr Ala Leu Gln Tyr His Asn Ile
145 150 155 160
Met Thr Val Lys Arg Val Gly Ile Ile Ile Ser Cys Ile Trp Ala Ala
165 170 175
Cys Thr Val Ser Gly Ile Leu Phe Ile Ile Tyr Ser Asp Ser Ser Ala
180 185 190
Val Ile Ile Cys Leu Ile Thr Met Phe Phe Thr Met Leu Ala Leu Met
195 200 205
Ala Ser Leu Tyr Val His Met Phe Leu Met Ala Arg Leu His Ile Lys
210 215 220
Arg Ile Ala Val Leu Pro Gly Thr Gly Ala Ile Arg Gln Gly Ala Asn
225 230 235 240
Met Lys Gly Ala Ile Thr Leu Thr Ile Leu Ile Gly Val Phe Val Val
245 250 255
Cys Trp Ala Pro Phe Phe Leu His Leu Ile Phe Tyr Ile Ser Cys Pro
260 265 270
Gln Asn Pro Tyr Cys Val Cys Phe Met Ser His Phe Asn Leu Tyr Leu
275 280 285
Ile Leu Ile Met Cys Asn Ser Ile Ile Asp Pro Leu Ile Tyr Ala Leu
290 295 300
Arg Ser Gln Glu Leu Arg Lys Thr Phe Lys Glu Ile Ile Cys Cys Tyr
305 310 315 320
Pro Leu Gly Gly Leu Cys Asp Leu Ser Ser Arg Tyr
325 330
<210> 78
<211> 975
<212> DNA
<213> Homo sapiens
<400> 78
atgaattcct catttcacct gcatttcttg gatctcaacc tgaatgccac agagggcaac 60
ctttcaggac ccaatgtcaa aaacaagtct tcaccatgtg aagacatggg cattgctgtg 120
gaggtgtttc tcactctggg tgtcatcagc ctcttggaga acatcttggt cataggggcc 180
atagtgaaga acaaaaacct gcactccccc atgtacttct tcgtgtgcag cctggcagtg 240
gcggacatgc tggtgagcat gtccagtgcc tgggagacca tcaccatcta cctactcaac 300
aacaagcacc tagtgatagc agacgccttt gtgcgccaca ttgacaatgt gtttgactcc 360
atgatctgca tttccgtggt ggcatccatg tgcagcttac tggccattgc agtggatagg 420
tacgtcacca tcttctacgc cctgcgctac caccacatca tgacggcgag gcgctcaggg 480
gccatcatcg ccggcatctg ggctttctgc acgggctgcg gcattgtctt catcctgtac 540
tcagaatcca cctacgtcat cctgtgcctc atctccatgt tcttcgctat gctgttcctc 600
ctggtgtctc tgtacataca catgttcctc ctggcgcgga ctcacgtcaa gcggatcgcg 660
gctctgcccg gggccagctc tgcgcggcag aggaccagca tgcagggcgc ggtcaccgtc 720
accatgctgc tgggcgtgtt taccgtgtgc tgggccccgt tcttccttca tctcacttta 780
atgctttctt gccctcagaa cctctactgc tctcgcttca tgtctcactt caatatgtac 840
ctcatactca tcatgtgtaa ttccgtgatg gaccctctca tatatgcctt ccgcagccaa 900
gagatgcgga agacctttaa ggagattatt tgctgccgtg gtttcaggat cgcctgcagc 960
tttcccagaa gggat 975
<210> 79
<211> 325
<212> PRT
<213> Homo sapiens
<400> 79
Met Asn Ser Ser Phe His Leu His Phe Leu Asp Leu Asn Leu Asn Ala
1 5 10 15
Thr Glu Gly Asn Leu Ser Gly Pro Asn Val Lys Asn Lys Ser Ser Pro
20 25 30
Cys Glu Asp Met Gly Ile Ala Val Glu Val Phe Leu Thr Leu Gly Val
35 40 45
Ile Ser Leu Leu Glu Asn Ile Leu Val Ile Gly Ala Ile Val Lys Asn
50 55 60
Lys Asn Leu His Ser Pro Met Tyr Phe Phe Val Cys Ser Leu Ala Val
65 70 75 80
Ala Asp Met Leu Val Ser Met Ser Ser Ala Trp Glu Thr Ile Thr Ile
85 90 95
Tyr Leu Leu Asn Asn Lys His Leu Val Ile Ala Asp Ala Phe Val Arg
100 105 110
His Ile Asp Asn Val Phe Asp Ser Met Ile Cys Ile Ser Val Val Ala
115 120 125
Ser Met Cys Ser Leu Leu Ala Ile Ala Val Asp Arg Tyr Val Thr Ile
130 135 140
Phe Tyr Ala Leu Arg Tyr His His Ile Met Thr Ala Arg Arg Ser Gly
145 150 155 160
Ala Ile Ile Ala Gly Ile Trp Ala Phe Cys Thr Gly Cys Gly Ile Val
165 170 175
Phe Ile Leu Tyr Ser Glu Ser Thr Tyr Val Ile Leu Cys Leu Ile Ser
180 185 190
Met Phe Phe Ala Met Leu Phe Leu Leu Val Ser Leu Tyr Ile His Met
195 200 205
Phe Leu Leu Ala Arg Thr His Val Lys Arg Ile Ala Ala Leu Pro Gly
210 215 220
Ala Ser Ser Ala Arg Gln Arg Thr Ser Met Gln Gly Ala Val Thr Val
225 230 235 240
Thr Met Leu Leu Gly Val Phe Thr Val Cys Trp Ala Pro Phe Phe Leu
245 250 255
His Leu Thr Leu Met Leu Ser Cys Pro Gln Asn Leu Tyr Cys Ser Arg
260 265 270
Phe Met Ser His Phe Asn Met Tyr Leu Ile Leu Ile Met Cys Asn Ser
275 280 285
Val Met Asp Pro Leu Ile Tyr Ala Phe Arg Ser Gln Glu Met Arg Lys
290 295 300
Thr Phe Lys Glu Ile Ile Cys Cys Arg Gly Phe Arg Ile Ala Cys Ser
305 310 315 320
Phe Pro Arg Arg Asp
325
<210> 80
<211> 12
<212> DNA
<213> Homo sapiens
<400> 80
cattttcgct gg 12
<210> 81
<211> 4
<212> PRT
<213> Homo sapiens
<400> 81
His Phe Arg Trp
1
<210> 82
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Modification of alpha-MSH HFRW core.
<400> 82
tttcattgga tg 12
<210> 83
<211> 4
<212> PRT
<213> Artificial Sequence
<220>
<223> Modification of alpha-MSH HFRW core.
<400> 83
Phe His Trp Met
1
<210> 84
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Flexible peptide
<400> 84
ggcggcggca gc 12
<210> 85
<211> 4
<212> PRT
<213> Artificial Sequence
<220>
<223> Flexible peptide
<400> 85
Gly Gly Gly Ser
1
Claims (19)
- 화학식 I에 따른 폴리펩티드:[화학식 I](Mp-Lk-V2-Hg-CH2-CH3)(t)상기 식에서, Mp는 멜라노코르틴 수용체 결합 분자이며,Lk는 폴리펩티드 또는 화학적 링크이고,V2는 면역글로블린 가변 영역 C-말단의 일부분이며,Hg는 적어도 하나의 면역글로블린 가변 힌지(hinge) 영역의 한부분이고,CH2는 면역글로블린 중쇄(heavy chain) CH2 불변 영역이며,CH3는 면역글로블린 중쇄(heavy chain) CH3 불변 영역이고,t는 독립적으로 1 내지 10의 정수이다.
- 제 1항에 있어서,상기 M은 서열 번호: 2, 4, 6, 8, 10, 12, 14, 16, 또는 18의 생물학적 활성 단편인 폴리펩티드.
- 제 1항에 있어서,상기 M은 서열 번호: 2, 4, 6, 8, 10, 12, 14, 16, 또는 18에 나타낸 아미노 산 서열을 갖는 폴리펩티드.
- 제 1항에 있어서,상기 폴리펩티드는 적어도 하나의 멜라노코르틴 수용체에 결합하는 폴리펩티드.
- 제 4항에 있어서,상기 멜라노코르틴 수용체는 멜라노코르틴 4 수용체인 폴리펩티드.
- 서열 번호: 60 또는 62를 포함하는 폴리펩티드.
- 제 1항 내지 제 6항 중 어느 한 항에 따른 폴리펩티드를 암호화하는 폴리뉴클레오티드.
- 서열 번호: 59 또는 서열 번호: 61을 포함하거나, 서열 번호: 59 또는 서열 번호: 61에 상보적인 폴리뉴클레오티드를 포함하는 폴리뉴클레오티드.
- 서열 번호: 60 또는 서열 번호: 62의 폴리펩티드를 암호화하는 폴리뉴클레오티드를 포함하는 폴리뉴클레오티드.
- 제 8항 또는 제 9항의 폴리뉴클레오티드를 포함하는 벡터.
- 제 10항에 있어서,서열 번호: 63을 포함하는 벡터.
- 제1항 내지 제 6항 중 어느 한 항에 따른 폴리펩티드를 발현하는 세포.
- 제 10항의 벡터를 포함하는 세포.
- 제 13항에 있어서,HEK293 유래 세포인 세포.
- 제 12항의 세포를 배양하고 발현된 폴리펩티드를 정제하는 단계들을 포함하여 폴리펩티드를 제조하는 방법.
- 제 1항 내지 제 6항 중 어느 한 항에 따른 적어도 하나의 폴리펩티드 유효량 및 약제학적으로 허용가능한 담체 또는 희석제를 포함하는 약제학적 조성물.
- 제 16항의 약제학적 조성물과 세포, 조직 또는 기관을 접촉시키는 것을 포함하여, 세포, 조직 또는 기관에서 멜라노코르틴 수용체의 생물학적 활성을 변형시키 는 방법.
- 제 16항의 약제학적 조성물을 필요로 하는 환자에게 투여하는 것을 포함하여, 적어도 하나의 멜라노코르틴 수용체 매개 상태를 조절하는 방법.
- 제 18항에 있어서,상기 멜라노코르틴 수용체 매개 상태는 비만인 방법.
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US62196004P | 2004-10-25 | 2004-10-25 | |
US60/621,960 | 2004-10-25 | ||
PCT/US2005/038431 WO2006047535A2 (en) | 2004-10-25 | 2005-10-25 | Melanocortin receptor binding mimetibodies, compositions, methods and uses |
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US (1) | US20060105951A1 (ko) |
EP (1) | EP1812046B1 (ko) |
JP (1) | JP2008517605A (ko) |
KR (1) | KR101255140B1 (ko) |
CN (1) | CN101437540B (ko) |
AT (1) | ATE501731T1 (ko) |
AU (1) | AU2005299440B2 (ko) |
BR (1) | BRPI0518411A2 (ko) |
CA (1) | CA2585287A1 (ko) |
CY (1) | CY1111486T1 (ko) |
DE (1) | DE602005026970D1 (ko) |
DK (1) | DK1812046T3 (ko) |
EA (1) | EA200700944A1 (ko) |
EC (1) | ECSP077416A (ko) |
ES (1) | ES2363023T3 (ko) |
HK (1) | HK1106445A1 (ko) |
HR (1) | HRP20110405T1 (ko) |
IL (1) | IL182683A0 (ko) |
MA (1) | MA28943B1 (ko) |
ME (1) | ME01234B (ko) |
MX (1) | MX2007004974A (ko) |
NO (1) | NO20072499L (ko) |
PL (1) | PL1812046T3 (ko) |
PT (1) | PT1812046E (ko) |
RS (1) | RS51789B (ko) |
SI (1) | SI1812046T1 (ko) |
TN (1) | TNSN07157A1 (ko) |
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US7910101B2 (en) | 2004-10-25 | 2011-03-22 | Centocor, Inc. | Melanocortin receptor binding mimetibodies, compositions, methods and uses |
US7790671B2 (en) * | 2005-10-07 | 2010-09-07 | Codman & Shurtleff, Inc. | Implantable pump for protein delivery for obesity control by drug infusion into the brain |
US20090305960A1 (en) * | 2008-06-09 | 2009-12-10 | Palatin Technologies, Inc | Melanocortin Receptor-Specific Peptides for Treatment of Obesity / 669 |
NZ590254A (en) * | 2008-06-09 | 2012-07-27 | Palatin Technologies Inc | Melanocortin receptor-specific cyclic peptides for treatment of sexual dysfunction |
US8614185B2 (en) * | 2009-05-04 | 2013-12-24 | Centocor Ortho Biotech Inc. | Fusion proteins of alpha-MSH derivatives and Fc |
CN105037502A (zh) | 2009-06-08 | 2015-11-11 | 帕拉丁科技公司 | 黑皮质素受体特异性肽 |
UY32690A (es) * | 2009-06-08 | 2011-01-31 | Astrazeneca Ab | Péptidos específicos para receptores de melanocortina |
EP2440572B1 (en) | 2009-06-08 | 2017-04-05 | Palatin Technologies, Inc. | Lactam-bridged melanocortin receptor-specific peptides |
CN102725305B (zh) | 2009-11-23 | 2016-08-24 | 帕拉丁科技公司 | 黑皮质素-1受体特异性环肽 |
EP2504351A4 (en) | 2009-11-23 | 2013-10-30 | Palatin Technologies Inc | MELANOCORTIN-1 RECEPTOR-SPECIFIC LINEAR PEPTIDE |
JP2020141710A (ja) * | 2011-07-06 | 2020-09-10 | ゲンマブ エー/エス | 抗体重鎖のc末端の修飾による補体依存性細胞傷害の調節 |
CN113272330A (zh) * | 2019-03-02 | 2021-08-17 | 上海一宸医药科技有限公司 | 一种双特异抗体 |
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