KR20230137930A - 수술 절차에서 요관을 가시화하기 위한 방법 및 조성물 - Google Patents
수술 절차에서 요관을 가시화하기 위한 방법 및 조성물 Download PDFInfo
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Abstract
펩티드 및 형광 모이어티를 포함하는 형광 접합체를 대상체에게 투여하는 단계를 포함하는, 수술 절차 동안, 요관 및 기타 표적 조직의 형광 가시화를 포함하여 요관을 가시화하는 방법.
Description
서열 목록에 관한 성명서
이 출원과 관련된 서열 목록은 종이 사본 대신 텍스트 형식으로 제공되며, 이로써 본 명세서에 참조로 포함된다. 서열 목록을 함유하는 텍스트 파일의 명칭은 110267_405WO_SEQUENCE_LISTING.txt이다. 텍스트 파일은 142KB이며, 2022년 1월 13일에 생성되었고, EFS-Web을 통해 전자적으로 제출되고 있다.
분야
본 발명은 일반적으로 수술 중 영상화 방법, 보다 특히 수술 절차 동안 요관(ureter) 및 신경의 형광 가시화(visualizing)에 관한 것이다.
요관은 신장에서 방광으로 소변을 운반하는 한 쌍의 다층 근육관- 평균 성인의 경우, 각각 약 10 내지 12인치 길이-을 포함한다. 수송은 심박 조율기에 의해 시작된 요관 벽의 근육층의 수축으로 인해 발생하는 연동 운동에 의존한다. 벽이 리드미컬하게 조여지고 이완됨에 따라, 소변은 요관을 통해 방광으로 박동성 운동으로 유동한다.
요관은 복부에서 골반까지 연장되기 때문에, 생식선 및 자궁 혈관, 장골 동맥, 하장간막 및 S자 혈관 뿐만 아니라 자궁경부, 결장 및 직장과 같은 복부 골반강의 많은 구조에 매우 근접해 있다. 또한, 요관은 종종 붕괴된 상태로 존재하며 주변 조직과 구별하기 어려운 벽이 얇은 관이다. 그들의 위치와 신체적 특성을 감안할 때, 요관은 부인과, 비뇨기과, 결장직장 및 심혈관 수술 절차를 포함한 많은 수술에서 상당한 손상 위험이 있다. 예를 들어, 문헌(Engelsgjerd and LaGrange, 2020, StatPearls, Treasure Island (FL): StatPearls Publishing; 2020 Jul 10; Ferrara and Kann, 2019, Clin . Colon Rectal Surg. 32, 196-203; Ahn et al., 2019, Quant . Imaging Med . Surg. 9,1056-1065; Gild et al., 2018, Asian J. Urol. 5, 101-106)을 참조한다. 실제로, 요관 손상은 종종 수술 중 눈에 띄지 않아 진단이 지연되고 일부 경우에 신부전(kidney failure)과 같은 장기간 합병증(long term complications)을 유발할 수 있는 후기 치료를 초래한다(참조: Tan-Kim et al. 2015, J. Minimally Invasive Gynecol. 22, 1278-1286; Al-Awadi et al. 2005, Int . Urol . Nephrol. 37, 235-241).
결과적으로, 요관 손상은 환자 이환율과 수반되는 의료 비용에 상당한 영향을 미친다. 미국에서는, 매년 약 60만 건의 자궁절제술과 30만 건의 결장 수술이 수행되고 있으며, 요관 손상률은 각각 2.5%와 7.6%로 높다. 문헌(Gild et al. 2018, Asian J. Urol. 5, 101-106; Doll et al. 2016, JAMA Surg. 151, 876-877; Teeluckdharry et al. 2015, Obstet . Gynecol. 126, 1161-1169; Briggs and Goldberg, 2011, Clin . Colon. Rectal Surg. 30, 130-135)을 참조한다. 하복부 수술 절차에서, 의원성 요관 손상(IUI)은 암 수술의 경우 0.5 내지 1%, 복강경 부인과 수술의 경우 0.3 내지 2.5%, 부인과 종양 수술의 경우 최대 10%의 발생률을 추정하고 있다. 예를 들어, 문헌(de Valk et al. 2019, Nat. Commun. 16, 3118; Anderson et al. 2015, Surg. Endosc. 29, 1406-1412; Engel et al. 2015, Curr. Opin. Urol. 25, 331-335; Minas et al. 2014, Obstet . Gynecol. 16, 19-28; Zafar et al. 2014, JSLS. 18, e2014.00158; Silva et al. 2012, Asian J. Endosc . Surg. 5, 1050110; Delacroix and Winters, 2010, Clin . Colon Rectal Surg. 23,104-112)을 참조한다. 요관 손상의 집단적 경제적 영향은 미국에서만 평균 4일의 입원 기간과 손상 당 3만 달러를 초과하는 비용을 반영하여 10억 달러를 초과한다.
수술 중 요관 손상의 위험을 줄이는 데 도움이 되는 몇 가지 접근법이 탐색되었다. 이들은 요관에 스텐트 또는 조명 카테터를 삽입하는 것과 같은 비뇨기과 절차를 포함하지만, 이들은, 예를 들어, 비뇨기과 전문의 또는 다른 전문의와 수술 중 상담을 요구함으로써 수술의 작업 흐름을 방해하고 원치 않은 지연을 초래할 수 있다. 예를 들어, 문헌(Wood et al. 1996, J. Am. Assoc. Gynecol. Laparosc, 3, 393-397; Chahin et al. 2002, JSLS 6, 49-52)을 참조한다. 다른 접근법은 요관을 가시화하기 위해 방사성 염료 또는 형광단(또는 특정 접합체)를 투여하거나 주사하는 방법을 포함한다. 그러나, 이러한 주사 절차는 추가적인 위험과 복잡성을 나타낼 수 있으며, 일부 제제는 제한된 민감도, 강도 및 작용 기간을 갖는다. 예를 들어, 문헌(Ikeda et al., 2017, Am. J. Physiol . Renal Physiol. 312, F629-F639; Al-Taher et al., 2016, J. Laparoendosc . Adv . Surg . Tech. A. 26, 870-875; Verbeek et al., 2014, Ann. Surg . Oncol. 21, S528-S537; Hyun et al. 2012, Contrast Media Mol . Imaging 7, 516-524; Choi et al., 2011, Angew Chem . Int . Ed. Engl. 50, 6258-6263; Tanaka, et al. 2007, J. Urol. 178, 2197-2201; Cadeddu et al., 2001, J. Endourology 15, 111-116)을 참조한다.
수술 절차 중 요관의 가시화를 포함하는 바람직한 특성을 갖는 조성물을 식별하는 것이 당업계에서 여전히 요구되고 있다. 본 발명은 투여 후 민감하고 연장된 요관 가시화를 허용하고, 동시 신경 및 요관 가시화를 포함하여 신경 가시화를 추가로 뒷받침할 수 있는 펩티드 조성물, 특히 형광 펩티드 접합체를 제공함으로써 당업계에서의 이러한 요구 및 기타 요구를 충족시킨다.
수술 절차 중 요관의 형광 가시화하는 방법을 포함하여 요관을 가시화하는 방법이 본원에 개시된다.
한 측면에서, 본 개시내용은 대상체(subject)에서 요관을 가시화하는 방법에 관한 것으로서, 상기 방법은 (a) 대상체에게 유효량의 형광 접합체(fluorescent conjugate)를 투여하는 단계로서, 상기 형광 접합체가 펩티드 및 형광 모이어티(fluorescent moiety)를 포함하는, 단계, 및 (b) 투여 후 요관 내 형광 모이어티의 형광을 검출하는 단계를 포함한다. 구현예에서, 대상체는 수술 절차를 받고 있다.
다른 측면에서, 본 개시내용은 (a) 수술 절차를 받고 있는 대상체에게 유효량의 형광 접합체를 투여하는 단계로서, 상기 형광 접합체가 펩티드 및 형광 모이어티를 포함하는, 단계; 및 (b) 요관 내 형광 모이어티의 형광을 검출함으로써 대상체에서 요관을 가시화하는 단계를 포함하는 방법에 관한 것이다.
다른 측면에서, 본 개시내용은 요관 손상을 감소시키는 방법에 관한 것으로서, 상기 방법은 (a) 수술 절차 전에 요관 손상 위험에 있는 대상체를 식별하는 단계; (b) 수술 절차를 받고 있는 대상체에게 유효량의 형광 접합체를 투여하는 단계로서, 상기 형광 접합체가 펩티드 및 형광 모이어티를 포함하는, 단계; 및 (c) 요관 내 형광 모이어티의 형광을 검출하여 요관을 가시화하는 단계를 포함한다. 구현예에서, 요관 손상은 결찰, 각도, 절개, 열상, 압착, 허혈 또는 절제술로 인해 발생한다.
본 방법의 구현예에서, 펩티드는 신경 표적화 펩티드(nerve targeting peptide)일 수 있다. 임의의 방법에서, 펩티드는 국제 특허 출원 번호 PCT/US2018/045054 및 국제 특허 출원 번호 PCT/US21/61821에 제시된 것들을 포함하여 본원에 개시된 임의의 아미노산 서열로 구성되거나, 이를 포함할 수 있다. 구현예에서, 형광 접합체의 펩티드는 서열번호 1-14, 16, 18-82 및 84-748로 이루어진 그룹으로부터 선택된 아미노산 서열을 포함한다.
임의의 방법의 구현예에서, 형광 모이어티는 링커를 통해 펩티드의 N-말단, C-말단, 또는 N-말단과 C-말단 둘 모두에 직접 또는 간접적으로 접합될 수 있다. 임의의 방법의 구현예에서, 형광 모이어티는 본원에 개시된 바와 같이 형광 단백질, 형광 펩티드, 형광 염료 또는 이들의 조합으로 이루어진 그룹으로부터 선택된다.
구현예에서, 임의의 방법은 투여 후 적어도 1시간, 적어도 2시간, 적어도 3시간, 적어도 4시간, 적어도 5시간, 적어도 6시간, 적어도 7시간, 또는 적어도 8시간의 기간 내에 형광 모이어티의 형광을 검출하는 단계를 추가로 포함할 수 있다. 구현예에서, 상기 방법은 투여 후 1시간 이상, 2시간 이상, 3시간 이상, 4시간 이상, 5시간 이상, 6시간 이상, 7시간 이상 또는 8시간 이상의 기간 동안 형광 모이어티의 형광을 검출하는 단계를 추가로 포함할 수 있다.
구현예에서, 임의의 방법에서 형광 접합체는 초기 투여 후 대상체에게 추가로 투여되지 않는다. 임의의 방법에서, 요관 내 형광 모이어티의 형광을 검출하는 단계는 요관 내 소변 유동을 검출하는 단계, 보다 특히 요관 내 소변의 연동 유동(peristaltic flow)을 검출하는 단계를 포함할 수 있다. 임의의 방법 중 어느 하나에서, 형광 접합체는 정맥내로 투여될 수 있다. 임의의 방법 중 어느 하나에서, 형광 접합체는 경구 투여될 수 있다. 임의의 방법에서, 형광 접합체는 수술 절차 전에 대상체에게 투여될 수 있다.
구현예에서, 임의의 방법에서의 수술 절차는 부인과, 비뇨기과, 결장직장 또는 심혈관 수술 절차를 포함할 수 있고; 복부 또는 골반을 포함할 수 있고; 신장, 방광, 전립선, 자궁, 남성 또는 여성 생식 기관(reproductive system), 직장, 결장, 소장 또는 대장에 대해 수행될 수 있고; 개복 수술 절차, 복강경 수술 절차, 현미경 절차 또는 내시경 절차일 수 있거나; 또는 암(cancer) 수술 절차, 보다 특히 전립선암(prostate cancer) 수술 절차 또는 결장직장암(prostate cancer) 수술 절차일 수 있다.
구현예에서, 임의의 방법에서의 형광 접합체는 본원에 개시된 바와 같이 형광 단백질, 형광 펩티드, 형광 염료, 또는 이들의 조합으로 이루어진 그룹으로부터 선택된 형광 모이어티를 포함한다.
구현예에서, 임의의 방법은 약제학적으로 허용되는 부형제(excipient)를 포함할 수 있는 약제학적 조성물에서 형광 접합체를 투여하는 단계를 포함한다.
구현예에서, 형광 접합체는 대상체에서 신경 가시화뿐만 아니라 수반되는(또는 동시) 신경 및 요관 가시화를 허용할 수 있다. 구현예에서, 형광 접합체는 수술 절차 동안 상이한 시간에 대상체에서 신경 가시화 및 요관 가시화를 부여할 수 있다.
도 1: 약 2000나노몰의 형광 접합체(서열번호 747)의 정맥내 투여 후 살아있는 야생형 마우스에서 요관의 명시야 및 형광 오버레이 이미지. 이미지는 맞춤형 형광 검출 현미경을 사용하여 투여 2시간 후에 수득되었다. 왼쪽 패널: 백색 반사율 이미지. 오른쪽 패널: 형광 오버레이.
상세한 설명
펩티드 및 형광 모이어티를 포함하는 형광 접합체(이하 본원에서 "접합체"라고도 함)를 투여하여 요관을 가시화하는 방법, 보다 특히 요관을 형광 가시화하는 방법이 본원에 개시된다. 신경 표적화 펩티드를 포함하는 것을 포함하여 특정 형광 접합체의 대사 및 제거가 신장으로부터 방광으로 요관에서 통과 동안 형광의 민감하고 장기간 검출을 뒷받침하는 것으로 발견되었다. 유리하게는, 본원에서 형광 접합체의 사용은 투여 후 초기 및 후기 둘 다 요관 검출을 허용한다. 이러한 특성은 이러한 접합체의 광범위한 유용성을 강조하여 투여 후 저 짧은 기간 뿐만 아니라 더 긴 기간 동안 요관 가시화를 부여한다.
따라서, 구현예에서, 상기 방법은 소변의 요관 유동, 더욱 특히 소변의 연동 요관 유동에서 형광 모이어티를 검출함으로써 대상체에서 요관을 가시화하는 단계를 포함한다. 형광 접합체는 정맥내로 투여될 수 있으며, 수술 절차 전에 대상체에게 투여될 수 있다.
구현예에서, 형광 접합체의 펩티드는 신경 표적화 펩티드를 포함하며, 보다 특히 국제 특허 출원 번호 PCT/US2018/045054 또는 국제 특허 출원 번호 PCT/US21/61821에 개시된 신경 표적화 펩티드를 포함하며, 이들 모두는 전문이 본원에 포함된다. 따라서, 구현예에서, 본원에 개시된 형광 접합체는 요관 및 신경의 동시 검출을 허용할 수 있다.
구현예에서, 형광 접합체의 펩티드는 국제 특허 공보 번호 WO2019028281A2에 개시된 바와 같이 아미노산 서열 QVPWEEPYYVVKKSSGG(GG 링커를 갖는 HNP401-N-2, 서열번호 21)를 포함한다. 구현예에서, 형광 접합체는 5FAM-QVPWEEPYYVVKKSSGG-NH2(GG 링커를 갖는 HNP401-N-2; 서열번호 747)이다.
본 발명은 실시예를 포함한 다음의 설명을 참조함으로써 더욱 완전하게 이해될 수 있다. 달리 정의되지 않는 한, 본원에 사용된 모든 기술 및 과학 용어는 당업자에게 통상적으로 이해되는 것과 동일한 의미를 갖는다. 본원에 기재된 것들과 유사하거나 동등한 방법 및 재료가 본 발명의 실시 또는 테스트에 사용될 수 있지만, 적절한 방법 및 재료가 본원에 기재되어 있다. 또한, 재료, 방법 및 실시예는 단지 예시적이며 제한적인 것으로 의도되지 않는다.
간결성을 위해, 제한 없이, 특허, 특허 출원, 기사, 서적, 매뉴얼 및 논문을 포함하는 본 출원에서 인용된 모든 문서 또는 문서의 일부는 어떠한 목적으로든 그 전체가 명시적으로 참조로 포함된다. 그러나, 임의의 이러한 공보의 인용은 본 발명의 선행 기술임을 인정하는 것으로 해석되어서는 안 된다.
본 명세서의 섹션에서 표제 및 부제목의 사용은 단지 조직적인 목적과 참조의 편의를 위한 것이며, 명세서 전체를 참조하여 해석되어야 하는 기재된 주제를 제한하는 것으로 해석되어서는 안 된다. 예를 들어, 당업자는 본원에 기재된 본 발명의 정신 및 범위에 따라 상이한 표제 및 섹션의 다양한 측면을 적절히 조합하는 것의 유용성을 인식할 것이다.
본 문서를 읽은 후에 당업자에게 명백해지는 바와 같이, 예시된 구현예 및 그들의 다양한 대안은 예시된 예들에 국한되지 않고 구현될 수 있다.
I.
정의
본원에 사용된 용어 "a" 및 "an"은 열거된 구성 요소 중 "하나 이상"을 지칭한다. 대안(예: "또는")의 사용은 대안 중 어느 하나, 둘 또는 이들의 임의의 조합을 의미하는 것으로 이해되어야 한다. 또한, 본원에 기재된 구조 및 치환체의 다양한 조합으로부터 유래되는 개별 화합물 또는 화합물의 그룹은 각 화합물 또는 화합물의 그룹이 개별적으로 제시된 것과 동일한 정도로 본 출원에 의해 개시되는 것으로 이해되어야 한다. 따라서, 특정 구조 또는 특정 치환체의 선택은 본 개시내용의 범위 내에 있다.
본원에 사용된 용어 "약" 또는 "대략"은 당업자가 특정된 값과 합리적으로 유사한 것으로 간주할 수 있는 특정 값을 포함한 값의 범위를 의미한다. 구현예에서, "약"은 당업계에서 일반적으로 허용되는 측정을 사용하여 표준 편차 이내를 의미한다. 구현예에서, "약"은 특정된 값의 +/- 10%까지 확장되는 범위를 의미한다. 구현예에서, "약"은 특정된 값을 의미한다.
"약"이라는 용어가 명시적으로 사용되었는지 여부에 관계없이, 본원에 제공된 모든 양은 실제 제공된 값 및 이러한 제공된 값에 대한 실험 및/또는 측정 조건으로 인한 등가물 및 근사치를 포함하여 당업계의 통상의 기술에 기초하여 합리적으로 추론될 수 있는 이러한 제공된 값의 근사치를 모두 지칭하는 것으로 이해되어야 한다. 따라서, 수치 값 앞에 "약" 또는 "대략"이 붙는 본 개시내용의 임의의 구현예에 대해, 본 개시내용은 정확한 값이 인용되는 구현예를 포함한다. 반대로, 수치 값 앞에 "약" 또는 "대략"이 붙지 않는 본 개시내용의 임의의 구현예에 대해, 본 개시내용은 값 앞에 "약" 또는 "대략"이 붙는 구현예를 포함한다.
용어 "포함하는(comprising)" 및 "포함하는(including)"은 그들의 공개적이고 비제한적인 의미로 본원에서 사용된다. 이 문서에서 사용되는 기타 용어 및 문구, 및 이의 변형은 달리 명시적으로 언급되지 않는 한 제한적인 것과 대조적으로 개방형으로 해석되어야 한다. 전술한 것의 예로서: 용어 "예"는 논의 중인 항목의 예시적인 사례를 제공하기 위해 사용되며, 이의 포괄적 또는 제한적인 목록이 아니다. 형용사, 예를 들어, "통상적", "통상적", "공지된" 및 유사한 의미의 용어는 기재된 항목을 주어진 기간 또는 주어진 시간에 이용 가능한 항목으로 제한하는 것으로 해석되어서는 안 되며, 대신 현재 또는 미래의 어느 시점에 이용 가능할 수 있거나 공지될 수 있는 통상적인 또는 통상적인 기술을 포괄하는 것으로 판독되어야 한다. 마찬가지로, 본 문서가 당업자에게 명백하거나 공지된 기술을 지칭하는 경우, 이러한 기술은 현재 또는 미래의 어느 시점에 당업자에게 명백하거나 공지된 것들을 포함한다.
본원에 사용된 바와 같이, 다음 용어는 달리 명시되지 않는 한 해당 용어에 부여된 의미를 갖는다.
용어 "폴리펩티드", "펩티드" 및 "단백질"은 본원에서 아미노산 잔기의 중합체를 지칭하기 위해 상호교환적으로 사용된다. 상기 용어는 천연 아미노산 중합체 뿐만 아니라 하나 이상의 아미노산 잔기가 비천연 아미노산(예: 아미노산 유사체)인 아미노산 중합체에 적용된다. 상기 용어는 전장 단백질(즉, 신경 표적화 분자)을 포함하여 임의의 길이의 아미노산 쇄를 포함하고, 여기서 아미노산 잔기는 공유 펩티드 결합에 의해 연결된다. 본원에 사용된 용어 "펩티드"는 전형적으로 길이가 2 내지 약 50개 잔기 범위의 아미노산 잔기의 중합체를 지칭한다. 특정 구현예에서, 펩티드는 길이가 약 2, 3, 4, 5, 7, 9, 10 또는 11개 잔기 내지 약 50, 45, 40, 45, 30, 25, 20 또는 15개 잔기의 범위이다. 특정 구현예에서, 펩티드는 길이가 약 8, 9, 10, 11 또는 12개 잔기 내지 약 15, 20 또는 25개 잔기 범위이다. 아미노산 서열이 본원에 제공되는 경우, 서열의 L-, D- 또는 베타 아미노산 버전뿐만 아니라 레트로, 반전 및 레트로-반전 이소형도 고려된다. 펩티드는 또한 하나 이상의 아미노산 잔기가 상응하는 천연 아미노산의 인공 화학적 유사체인 아미노산 중합체뿐만 아니라 천연 아미노산 중합체를 포함한다. 또한, 상기 용어는 펩티드 결합 또는 기타 변형된 결합에 의해 결합된 아미노산에 적용된다(예: 펩티드 결합이 α-에스테르, /3-에스테르, 티오아미드, 포스폰아미드, 카르바메이트, 하이드록실레이트 등으로 대체된 경우(참조: 예를 들어, Spatola 1983, Chem . Biochem . Amino Acids and Proteins 7: 267-357), 아미드가 포화 아민으로 대체되는 경우(참조: 예를 들어, 본원에 참조로 포함된 Skiles et al., U.S. Pat. No. 4,496,542, 및 Kaltenbronn et al., 1990, pp. 969-970 in Proc . 1lth American Peptide Symposium, ESCOM Science Publishers, The Netherlands, 등)).
따라서, 용어 "아미노산"은 천연 및 합성 아미노산뿐만 아니라 천연 아미노산과 유사한 방식으로 기능하는 아미노산 유사체 및 아미노산 모방체를 지칭한다. 천연 아미노산은 유전자 코드에 의해 인코딩된 것들뿐만 아니라 이후 변형된 아미노산, 예를 들어, 하이드록시프롤린, γ-카르복시글루타메이트 및 O-포스포세린이다. 아미노산은 L- 또는 D-아미노산일 수 있다. 아미노산 유사체는 천연 아미노산과 동일한 기본 화학적 구조, 즉 수소, 카르복실 그룹, 아미노 그룹 및 R 그룹, 예를 들어, 호모세린, 노르류신, 메티오닌 설폭사이드에 결합된 탄소를 갖는 화합물을 지칭한다. 이러한 유사체는 변형된 R 그룹(예: 노르류신) 또는 변형된 펩티드 백본을 갖지만, 천연 아미노산과 동일한 기본 화학적 구조를 유지한다. 아미노산 모방체는 아미노산의 일반적인 화학적 구조와는 상이한 구조를 갖지만, 천연 아미노산과 유사한 방식으로 기능하는 화학적 화합물을 지칭한다.
아미노산은 본원에서 일반적으로 공지된 세 문자 기호 또는 IUP AC-IUB 생화학 명명법 위원회에 의해 권장된 한 문자 기호에 의해 참조될 수 있다. 뉴클레오티드는 마찬가지로 통상적으로 허용되는 단일 문자 코드에 의해 참조될 수 있다.
당업자는 인코딩된 서열에서 단일 아미노산 또는 작은 비율의 아미노산을 변경, 추가 또는 결실시키는 펩티드, 폴리펩티드 또는 단백질 서열에 대한 개별 치환, 결실 또는 첨가가 "보존적으로 변형된 변이체(variant)"이며, 여기서 변경은 화학적으로 유사한 아미노산으로 아미노산의 치환을 초래한다는 것을 인식할 것이다. 기능적으로 유사한 아미노산을 제공하는 보존적 치환 표는 당업자에게 익히 공지되어 있다. 이러한 보존적으로 변형된 변이체는 다형성 변이체, 종간 상동체 및 대립유전자에 추가되며, 배제하지 않는다.
다음 8개 그룹은 각각 서로에 대한 보존적 치환인 아미노산을 함유한다: 1) 알라닌(A), 글리신(G); 2) 아스파르트산(D), 글루탐산(E); 3) 아스파라긴(N), 글루타민(Q); 4) 아르기닌(R), 리신(K); 5) 이소류신(I), 류신(L), 메티오닌(M), 발린(V); 6) 페닐알라닌(F), 티로신(Y), 트립토판(W); 7) 세린(S), 트레오닌(T); 및 8) 시스테인(C), 메티오닌(M)(참조: 예를 들어, Creighton, Proteins (1984)).
본원에서 사용되는 바와 같은 "서열 동일성"(또는 "동일성")은 서열을 정렬시키고 필요한 경우 최대 퍼센트 서열 동일성을 달성하기 위해 갭을 도입한 후, 서열 동일성의 일부로서 임의의 보존적 치환을 고려하지 않고 다른 참조 폴리펩티드 서열의 아미노산 잔기와 동일한 단일 제공된 서열 내 아미노산 잔기의 백분율을 지칭한다. 본원에 사용된 바와 같이, "서열 상동성"(또는 "상동성")은 서열을 정렬시키고 필요한 경우 최대 퍼센트 서열 상동성을 달성하기 위해 갭을 도입한 후, 다른 참조 폴리펩티드 서열의 아미노산 잔기와 동일하거나 유사한 화학적 특성을 갖는 단일 제공된 서열 내 아미노산 잔기의 백분율을 지칭한다. 따라서, 서열 동일성과 대조적으로, 서열 상동성은 서열 정렬의 일부로서 임의의 보존적인 치환(본원에 기재된 바와 같음)을 고려한다. 서열 동일성 또는 서열 상동성은 문헌(Altschul et al. 1997, Nucl . Acids Res. 25, 3389-3402)에 의해 정의된 NCBI BLAST 2.0 소프트웨어와 같은 공개적으로 이용 가능한 컴퓨터 프로그램을 포함하는 익히 공지된 방법을 사용하여 결정될 수 있다. 이러한 프로그램은 제공된 서열과 참조 서열 사이에 최고 수준의 서열 동일성 또는 서열 상동성을 생성하기 위해 디폴트 갭 가중치를 사용하여 서열을 최적으로 정렬시킨다.
본원에 사용된 용어 "표지"는 본원에 개시된 표적화 분자의 가시화 및/또는 검출을 용이하게 하는 분자를 지칭한다. 구현예에서, 표지는 형광 모이어티이다.
용어 "개체", "환자" 또는 "대상체"는 상호교환적으로 사용된다. 본원에 사용되는 바와 같이, 그들은 임의의 포유동물(즉, 분류학적 분류 동물계 내의 임의의 목(order), 과(family) 및 속(genus)의 종: 척색 동물문: 척추동물문: 포유강)을 의미한다. 구현예에서, 포유동물은 소, 말, 양, 돼지, 고양이, 개, 염소, 마우스, 래트, 토끼, 기니피그, 비인간 영장류 또는 인간이다. 구현예에서, 포유동물은 인간 대상체이며, 더욱 특히 수술 절차를 받고 있는 인간 대상체이다. 상기 용어 중 어떤 것도 의료 종사자(예: 의사, 등록 간호사, 개업 간호사, 의사 보조원, 연락병 또는 호스피스 종사자)의 감독(예: 지속적 또는 간헐적)을 특징으로 하는 상황을 요구하거나 이에 제한되지 않는다.
본원에 사용된 용어 "투여하다", "투여하는", "투여" 등은 생물학적 작용의 목적하는 부위에 제제 또는 조성물의 전달을 가능하게 하기 위해 사용될 수 있는 방법을 지칭한다. 이러한 방법은 비경구 주사(예: 정맥내, 피하, 복강내, 근육내, 혈관내, 척수강내, 유리체강내, 주입 또는 국소)를 포함하지만, 이에 제한되지 않는다. 본원에 기재된 제제 및 방법과 함께 임의로 사용되는 투여 기술은, 예를 들어, 문헌(Gennaro: Remington : The Science and Practice of Pharmacy, 21st Ed. (Lippincott Williams & Wilkins, 2005) 및 Goodman & Gilman's The Pharmacological Basis of Therapeutics (McGraw-Hill Professional, 2005))에서 논의된 것들을 포함한다. 구현예에서, 투여는 인간 환자에게 전신 정맥내 주사를 통해 이루어진다.
용어 "유효량"은 "치료적 유효량"과 상호교환 가능하며, 명시적 목적을 달성하기에, 예를 들어, 수술 중(수술 과정, 수술 절차, 수술 방법 또는 수술 중) 요관의 형광 가시화를 허용하는 것과 같이 투여되는 효과를 달성하기에 충분한 양을 의미한다. "유효량"의 예는 복부 수술 절차 중 의원성 요관 손상(IUI)과 같이 수술 또는 의료 절차로 인한 부작용의 치료, 예방 또는 감소에 기여하기에 충분한 양이다. 목적하는 효과는 1회 투여량의 투여로 발생할 수 있지만 반드시 그런 것은 아니다. 또한, 일련의 투여량의 투여 후에 발생할 수 있다. 따라서, 유효량은 하나 이상의 투여로 투여될 수 있다. 치료적 유효량의 조성물의 투여는 특히 본원의 상세한 개시내용에 비추어 당업자의 능력 범위 내에 있다. 예를 들어, 인간에 대한 투여량은 동물에서 효과적인 것으로 밝혀진 농도를 달성하도록 제형화될 수 있다. 인간의 용량은 본원에 개시된 제제 또는 조성물의 효과를 모니터링하고 용량을 상향 또는 하향 조정함으로써 조정될 수 있다. 본원에 기재된 방법 및 기타 방법에 따라 인간에서 최대 효능을 달성하기 위해 투여량을 조정하는 것은 통상의 숙련가의 능력 내에 있다.
본원에 사용된 용어 "약제학적으로 허용되는"은 본원에 기재된 제제 및 조성물의 생물학적 활성 또는 특성을 폐지하지 않고 비교적 무독성(즉, 물질의 독성이 물질의 이익을 상당히 능가한다)인 물질을 지칭한다. 일부 경우에, 약제학적으로 허용되는 물질은 유의한 바람직하지 않은 생물학적 효과를 유발하거나 그것이 함유되어 있는 조성물의 임의의 구성 요소와 유해한 방식으로 유의하게 상호 작용하지 않고 개체에게 투여될 수 있다.
본원에 사용되는 용어 "수술"은 물리적 개입에 의해 효과를 조작, 변경 또는 유발하는 데 사용될 수 있는 임의의 방법 또는 절차를 지칭한다. 수술 방법 및 절차는 개복 수술, 현미경 수술, 내시경 수술, 복강경 수술, 최소 침습 수술, 로봇 수술을 포함하지만, 이에 제한되지 않는다. 일부 경우에, 수술 대상체는 인간 대상체 또는 인간 환자이다. 수술 절차는 부인과, 비뇨기과, 결장직장 또는 심혈관 수술 절차를 포함할 수 있다. 수술 절차는 또한 복부 또는 골반 절차도 포함할 수 있지만, 이에 제한되지 않는다. 특정 경우에, 수술 절차는 신장, 방광, 전립선, 자궁, 남성 또는 여성 생식 기관, 직장, 결장, 소장 또는 대장에서 수행된다. 수술 절차는, 예를 들어, 전립선암 수술 절차 또는 결장직장 절차를 포함한 암 수술 절차일 수 있다. 본원에 기재된 조성물 및 방법은 수술 중 대상체에서 동시 신경 및 요관 가시화를 포함하여 수술 중 신경 가시화를 뒷받침할 수 있으므로, 수술 절차는 또한 요관 손상 위험을 제공하고 일부 경우에 신경에도 영향을 미칠 수 있는 절차를 포함할 수 있다.
II.
방법
본 개시내용은 형광 모이어티에 연결된 펩티드, 즉 표지된 펩티드를 포함하는 형광 접합체를 사용하여 특히 수술 중에 요관을 가시화하는 방법을 제공한다. 구현예에서, 펩티드는 신경 표적화 펩티드를 포함한다. 구현예에서, 본원에 기재된 형광 접합체(및 이의 조성물)는 수술 절차 중 요관 손상, 특히 의원성 요관 손상(IUI)의 가능성을 줄이기 위해 이러한 방법에서 수술 보조제로서 유용하다.
본원에 추가로 기재된 바와 같이, 신경 표적화 형광 접합체는 요관을 통해 통과 동안 유의하고 연장된 형광을 허용하는 조건하에서 신장 배설에 의해 제거될 수 있는 것으로 관찰되었다. 결과적으로, 요관 가시화는 요관을 통한 소변의 유동, 보다 특히 요관을 통한 소변의 연동 유동에서 형광 모이어티를 검출하여 달성될 수 있다. 요관 가시화는 특정 형광 접합체 투여 후 몇 시간 이상 지속되는 연장 기간 동안 지속될 수 있다.
따라서, 구현예에서, 본 개시내용은 본원에 기재된 임의의 분자 및 조성물을 사용하여 대상체에서 요관을 가시화하는 방법을 제공한다. 구현예에서, 대상체는 진단 절차, 의료 절차, 또는 수술 절차와 같은 절차를 받고 있다.
한 측면에서, 상기 방법은 (a) 유효량의 형광 접합체를 대상체에게 투여하는 단계로서, 상기 형광 접합체가 펩티드 및 형광 모이어티를 포함하는, 단계; 및 (b) 투여 후 대상체의 요관 내 형광 모이어티의 형광을 검출하는 단계를 포함한다.
다른 측면에서, 상기 방법은 (a) 수술 절차를 받고 있는 대상체에게 유효량의 형광 접합체를 투여하는 단계로서, 상기 형광 접합체가 펩티드 및 형광 모이어티를 포함하는, 단계; 및 (b) 요관 내 형광 모이어티의 형광을 검출함으로써 대상체에서 요관을 가시화하는 단계를 포함한다.
다른 측면에서, 상기 방법은 (a) 수술 절차 전에 요관 손상 위험에 있는 대상체를 식별하는 단계; (b) 수술 절차를 받고 있는 대상체에게 유효량의 형광 접합체를 투여하는 단계로서, 상기 형광 접합체가 펩티드 및 형광 모이어티를 포함하는, 단계; 및 (c) 요관 내 형광 모이어티의 형광을 검출하여 요관을 가시화하는 단계를 포함한다. 본원에 사용되는 바와 같이, 요관 손상 위험에 있는 대상체는 본원에 기재된 진단, 의료 또는 수술 절차가 필요한 대상체를 포함한다.
구현예에서, 형광 접합체는 수술 절차 전에 초기에 투여된다. 구현예에서, 형광 접합체는 초기 투여 후에 투여되지 않는다. 구현예에서, 형광 접합체는 수술 절차 중에 투여된다. 구현예에서, 형광 접합체는 수술 절차 전 및 수술 절차 중에 투여된다.
구현예에서, 수술 절차는 부인과, 비뇨기과, 결장직장 또는 심혈관 수술 절차를 포함한다. 구현예에서, 수술 절차는 복부 또는 골반 절차를 포함한다. 구현예에서, 수술 절차는 신장, 방광, 전립선, 자궁, 남성 또는 여성 생식 기관, 직장, 결장, 소장 또는 대장에서 수행된다. 구현예에서, 수술 절차는 개복 수술 절차, 복강경 수술 절차, 현미경 절차 또는 내시경 절차이다. 구현예에서, 수술 절차는 암 수술 절차, 더욱 특히 전립선암 수술 절차이다.
임의의 이들 방법의 구현예에서, 형광 접합체는 인간 및 포유동물(예: 마우스, 래트, 돼지, 고양이, 개 및 말)을 포함하는, 본원에 기재된 바와 같이, 대상체에게 투여된다. 구현예에서, 대상체는 포유동물이다. 구현예에서, 대상체는 영장류이다. 구현예에서, 대상체는 인간이다. 구현예에서, 인간 대상체는 소아 대상체(21세 이하), 성인 대상체(22세 내지 65세) 또는 노인 대상체(65세 이상)이다.
형광 접합체는 본원에 추가로 기재된 바와 같이 임의의 경로로 투여될 수 있다. 구현예에서, 형광 접합체는 정맥내로 투여된다. 구현예에서, 형광 접합체는 경구 투여된다. 구현예에서, 임의의 경로로 투여되는 형광 접합체는, 본원에 기재된 바와 같이, 약제학적으로 허용되는 부형제를 포함할 수 있는 약제학적 조성물로서 투여될 수 있다.
형광 접합체의 형광 모이어티는 당업계에 공지된 임의의 적합한 방법에 의해 요관에서 검출될 수 있다. 예를 들어, 형광 모이어티는 적절한 파장의 빛으로 수술장에서 형광단을 여기시키고 필터, 렌즈 및 카메라의 조합을 사용하여 생성되는 형광(및 수술장)을 검출함으로써 검출될 수 있다.
상기 방법의 구현예에서, 형광 모이어티는 형광 유도 수술(FGS)에 적합한 의료 장치에 의해 요관에서 검출된다. 이러한 적합한 장치는 개복 수술에 사용되는 휴대용 또는 장착형 장치, 복부 및 골반 절차에 사용되는 복강경 및 내시경과 같은 최소 침습 장치; 전립선 수술에 사용되는 로봇 수술 시스템; 및 수술용 확대경과 같은 기타 장치를 포함할 수 있지만, 이에 제한되지 않는다. 장치는 명시야 조명 및 형광 방출로부터 실시간 동기 정보를 제공할 수 있다. 하나 이상의 광원을 사용하여 샘플 또는 수술장을 여기시키고 조명할 수 있다. 형광 모이어티의 방출 스펙트럼에 맞춤화된 광학 필터, 이미징 렌즈 및 디지털 카메라(예: CCD 및 CMOS 검출기 시스템)를 사용하여 빛을 수집하여 최종 이미지를 생성할 수 있다. 라이브 비디오 처리를 또한 수행하여 형광 검출 동안 콘트라스트를 향상시키고, 형광 신호의 민감도를 개선시킬 수 있다.
상기 방법의 구현예에서, 형광 모이어티의 형광은 투여 후 적어도 1시간, 적어도 2시간, 적어도 3시간, 적어도 4시간, 적어도 5시간, 적어도 6시간, 적어도 7시간 또는 적어도 8시간의 기간 이내에 요관에서 검출된다.
상기 방법의 구현예에서, 형광 모이어티의 형광은 투여 후 1시간 이상, 2시간 이상, 3시간 이상, 4시간 이상, 5시간 이상, 6시간 이상, 7시간 이상 또는 8시간 이상의 기간 동안 요관에서 검출된다.
상기 방법의 구현예에서, 형광 모이어티의 형광은 투여 30분 후, 1시간 후, 2시간 후, 3시간 후, 4시간 후, 5시간 후, 6시간 후, 7시간 후 또는 8시간 이상 후에 요관에서 검출된다.
상기 방법의 구현예에서, 형광 접합체는 수반되는 신경 검출뿐만 아니라 수술 중 신경 및 요관 가시화를 포함하는 요관 가시화를 허용할 수 있다. 이러한 신경은, 예를 들어, '054 출원에 개시된 바와 같이, 인간 신경, 예를 들어, 운동 신경, 감각 신경, 교감 신경 및 부교감 신경, 말초 신경 및 자율 신경을 포함할 수 있다.
보다 일반적으로, 본원에 기재된 방법, 접합체 및 조성물은 또한 개복 수술 절차, 복강경 수술 절차, 현미경 절차 및 내시경 절차를 포함할 수 있다.
또한, 본원에 기재된 방법, 접합체 및 조성물은 또한 신경뿐만 아니라 요관의 가시화가 바람직한 수술 절차에 사용될 수 있다.
III.
형광 접합체
본 방법에서 사용하기 위한 형광 접합체는 펩티드, 더욱 특히 형광 모이어티에 연결된 신경 표적화 펩티드(또는 달리 형광 표지를 포함하는 펩티드)를 포함한다.
펩티드
구현예에서, 신경 표적화 펩티드는 본원에 전체가 포함된 국제 특허 출원 번호 PCT/US2018/045054('054 출원, WO2019028281A2로서 공개됨)에 개시된 바와 같이 임의의 결실 또는 링커 변이체를 포함하는 임의의 펩티드이다. 따라서, 이러한 펩티드는 표 1에 나열된 다음 아미노산 서열(펩티드 서열)(서열번호 1-17, 20-28 및 96-102) 중 어느 하나를 포함하거나, 이로 구성된다:
[표 1]
구현예에서, 펩티드는 임의의 서열번호 1-14, 16, 20-28 및 96-102를 포함하거나, 이로 구성된다.
또한, 펩티드는 '054 출원에 기재된 아미노산 서열의 임의의 변이체를 포함하거나 이로 구성될 수 있다. 이러한 변이체는, 제한 없이, 표 1(또는 '054 출원에 달리 개시된 바와 같이)의 아미노산 서열과 75%-99%의 동일성 또는 75%-99%의 상동성을 공유하는 아미노산 서열을 포함하거나, 이로 구성되는 펩티드를 포함할 수 있다.
구현예에서, 펩티드는 서열번호 1-14, 16, 20-28 및 96-102 중 어느 하나에 대해 적어도 75%의 동일성을 갖는 아미노산 서열을 포함하거나, 이로 구성된다. 구현예에서, 펩티드는 서열번호 1-14, 16, 20-28 및 96-102 중 어느 하나에 대해 적어도 80%의 동일성을 갖는 아미노산 서열을 포함하거나, 이로 구성된다. 구현예에서, 펩티드는 서열번호 1-14, 16, 20-28 및 96-102 중 어느 하나에 대해 적어도 85%의 동일성을 갖는 아미노산 서열을 포함하거나, 이로 구성된다. 구현예에서, 펩티드는 서열번호 1-14, 16, 20-28 및 96-102 중 어느 하나에 대해 적어도 90%의 동일성을 갖는 아미노산 서열을 포함하거나, 이로 구성된다. 구현예에서, 펩티드는 서열번호 1-14, 16, 20-28 및 96-102 중 어느 하나에 대해 적어도 95%의 동일성을 갖는 아미노산 서열을 포함하거나, 이로 구성된다. 구현예에서, 펩티드는 서열번호 1-14, 16, 20-28 및 96-102 중 어느 하나에 대해 적어도 97%의 동일성을 갖는 아미노산 서열을 포함하거나, 이로 구성된다.
구현예에서, 펩티드는 서열번호 1-14, 16, 20-28 및 96-102 중 어느 하나와 적어도 80% 상동성을 공유하는 펩티드 서열로 구성되거나, 이를 포함한다. 구현예에서, 펩티드는 서열번호 1-14, 16, 20-28 및 96-102 중 어느 하나와 적어도 80% 상동성을 공유하는 펩티드 서열로 구성되거나, 이를 포함한다. 구현예에서, 펩티드는 서열번호 1-14, 16, 20-28 및 96-102 중 어느 하나와 적어도 85% 상동성을 공유하는 아미노산 서열을 포함하거나, 이로 구성된다. 구현예에서, 펩티드는 서열번호 1-14, 16, 20-28 및 96-102 중 어느 하나와 적어도 90% 상동성을 공유하는 아미노산 서열을 포함하거나, 이로 구성된다. 구현예에서, 펩티드는 서열번호 1-14, 16, 20-28 및 96-102 중 어느 하나와 적어도 95% 상동성을 공유하는 아미노산 서열을 포함하거나, 이로 구성된다. 구현예에서, 펩티드는 서열번호 1-14, 16, 20-28 및 96-102 중 어느 하나와 적어도 99% 상동성을 공유하는 아미노산 서열을 포함하거나, 이로 구성된다.
구현예에서, 펩티드는 코어 결합 도메인, PYYVVKK(서열번호 40) 및 QVPWEE의 N-말단 서열(서열번호 41)을 포함하는 약 13개 내지 약 25개의 아미노산의 아미노산 서열을 포함하거나, 이로 구성된다.
구현예에서, 펩티드는 PYY 또는 PYYVV의 아미노산 코어 결합 도메인(서열번호 83) 및 QVPWEE의 N-말단 서열(서열번호 41)을 포함한다. 구현예에서, 펩티드는 PYY의 아미노산 코어 결합 도메인 및 QVPWEE의 N-말단 서열(서열번호 41)을 포함한다. 구현예에서, 펩티드는 PYYVV의 아미노산 코어 결합 도메인(서열번호 83) 및 QVPWEE의 N-말단 서열(서열번호 41)을 포함한다.
구현예에서, 펩티드는 QVPWEEPYYVVKKSSGG(GG 링커를 갖는 HNP401-N-2, 서열번호 21)를 포함하거나, 이로 구성된다.
구현예에서, 펩티드는 SGQVPWEEPYYVVKKSS(HNP401; 서열번호 1), WEYHYVDLNWTSQHPQ(HNP402; 서열번호 2), 및 DLPDIIWDFNWETA(HNP403; 서열번호 3)로 이루어진 그룹으로부터 선택된 아미노산 서열을 포함하거나, 이로 구성된다.
구현예에서, 펩티드는 SGQVPWEEPYYVVKKSS(HNP401; 서열번호 1), Ac-QVPWEEPYYVVKKSSGGC(GGC 링커를 갖는 HNP401-N-2; 서열번호 7), Ac-SGQVPWEEPYYVVKKGGC(GGC 링커를 갖는 HNP401-C-2; 서열번호 11), QVPWEEPYYVVKKSS(HNP401-N-2; 서열번호 20), QVPWEEPYYVVKKSSGG(GG 링커를 갖는 HNP401-N-2; 서열번호 21), 및 SGQVPWEEPYYVVKK(HNP401-C-2; 서열번호 25), 및 SGQVPWEEPYYVVKKGG(GG 링커를 갖는 HNP401-C-2; 서열번호 99)로 이루어진 그룹으로부터 선택된 아미노산 서열을 포함하거나, 이로 구성된다.
구현예에서, 펩티드는 서열번호 1, 4, 7-14, 20-28 및 96-102 중 어느 하나의 아미노 서열을 포함하거나, 이로 구성된다.
구현예에서, 펩티드는 서열번호 1, 20 및 22-24 중 어느 하나의 아미노 서열을 포함하거나, 이로 구성된다.
구현예에서, 펩티드는 서열번호 1 및 25-28 중 어느 하나의 아미노 서열을 포함하거나, 이로 구성된다.
구현예에서, 펩티드는 서열번호 4 및 7-10 중 어느 하나의 아미노 서열을 포함하거나, 이로 구성된다.
구현예에서, 펩티드는 서열번호 4 및 11-14 중 어느 하나의 아미노 서열을 포함하거나, 이로 구성된다.
구현예에서, 펩티드는 서열번호 21 및 100-102 중 어느 하나의 아미노 서열을 포함하거나, 이로 구성된다.
구현예에서, 펩티드는 서열번호 96-99 중 어느 하나의 아미노 서열을 포함하거나 구성된다.
구현예에서, 펩티드는 전체가 본원에 포함된 PCT 출원 번호 PCT/US21/61821("'821 출원")에 개시된 신경 표적화 펩티드이다. 일부 구현예에서, 이러한 펩티드는 인간 미엘린 단백질 제로(MPZ), 미엘린 염기성 단백질, 미엘린 단백질지질 단백질(미엘린 PLP) 및 니도겐-2의 4개의 상이한 신경 표적 단백질 중 하나에 대한 선택적 결합에 기초하여 파지 디스플레이 라이브러리 스크린으로부터 유래되었다. 이러한 펩티드는 표 2에 나열된 임의의 아미노산 서열(서열번호 18, 19, 29-82, 84-95 및 103-471)을 포함하거나, 이로 구성된다. 일부 구현예에서, 이들 펩티드는 라미닌 삼량체 421, 521 또는 둘 다에 대한 선택적 결합에 기초하여 파지 디스플레이 스크린으로부터 유래되었다. 이러한 펩티드는 표 3에 나열된 임의의 아미노산 서열(서열번호 472-678)을 포함하거나, 이로 구성된다. 일부 구현예에서, 이들 펩티드는 근육 추출물이 아닌 뉴런 및 신경 추출물에 대한 선택적 결합에 기초하여 파지 디스플레이 스크린으로부터 유래되었다. 이러한 펩티드는 표 4에 나열된 임의의 아미노산 서열(서열번호 679-746)을 포함하거나, 이로 구성된다.
[표 2]
[표 3]
[표 4]
따라서, 구현예에서, 펩티드는 서열번호 18, 19, 29-82, 84-95 및 103-746으로 구성되는 그룹으로부터 선택된 아미노산 서열을 포함하거나, 이로 구성된다. 구현예에서, 펩티드는 서열번호 18, 19, 29-82, 84-95 및 103-746으로 구성되는 그룹으로부터 선택된 아미노산 서열을 포함하거나, 이로 구성된다. 구현예에서, 펩티드는 서열번호 75-82, 84-95 및 103-746으로 구성되는 그룹으로부터 선택된 아미노산 서열을 포함하거나, 이로 구성된다. 구현예에서, 펩티드는 서열번호 55-74 및 188-362로 이루어진 그룹으로부터 선택된 아미노산 서열을 포함하거나, 이로 구성된다. 구현예에서, 펩티드는 서열번호 75-82, 84-95 및 103-187로 이루어진 그룹으로부터 선택된 아미노산 서열을 포함하거나, 이로 구성된다. 구현예에서, 펩티드는 서열번호 33-54 및 363-446으로 이루어진 그룹으로부터 선택된 아미노산 서열을 포함하거나, 이로 구성된다. 구현예에서, 펩티드는 서열번호 18, 19, 29-32 및 447-471로 구성되는 그룹으로부터 선택된 아미노산 서열을 포함하거나, 이로 구성된다. 구현예에서, 펩티드는 서열번호 472-678로 이루어진 그룹으로부터 선택된 아미노산 서열을 포함하거나, 이로 구성된다. 구현예에서, 펩티드는 서열번호 679-746으로 이루어진 그룹으로부터 선택된 아미노산 서열을 포함하거나, 이로 구성된다.
구현예에서, 펩티드는 국제 특허 출원 번호 PCT/US21/61821("'821 출원")에 기재된 아미노산 서열의 변이체를 포함하거나, 이로 구성된다. 따라서, 이러한 변이체는, 제한 없이, 서열번호 18, 19, 29-82, 84-95 및 103-746 중 어느 하나와 75%-99%의 동일성 또는 75%-99%의 상동성을 공유하는 아미노산 서열을 포함하거나 이로 구성되는 펩티드를 포함한다.
구현예에서, 펩티드는 서열번호 18, 19, 29-82, 84-95 및 103-746 중 어느 하나에 대해 적어도 75%의 동일성을 갖는 아미노산 서열을 포함하거나, 이로 구성된다. 구현예에서, 펩티드는 서열번호 18, 19, 29-82, 84-95 및 103-746 중 어느 하나에 대해 적어도 80%의 동일성을 갖는 아미노산 서열을 포함하거나, 이로 구성된다. 구현예에서, 펩티드는 서열번호 18, 19, 29-82, 84-95 및 103-746 중 어느 하나에 대해 적어도 85%의 동일성을 갖는 아미노산 서열을 포함하거나, 이로 구성된다. 구현예에서, 펩티드는 서열번호 18, 19, 29-82, 84-95 및 103-746 중 어느 하나에 대해 적어도 90%의 동일성을 갖는 아미노산 서열을 포함하거나, 이로 구성된다. 구현예에서, 펩티드는 서열번호 18, 19, 29-82, 84-95 및 103-746 중 어느 하나에 대해 적어도 95%의 동일성을 갖는 아미노산 서열을 포함하거나, 이로 구성된다.
구현예에서, 펩티드는 서열번호 18, 19, 29-82, 84-95 및 103-746 중 어느 하나와 적어도 80% 상동성을 공유하는 아미노산 서열로 구성되거나, 이를 포함한다. 구현예에서, 펩티드는 서열번호 18, 19, 29-82, 84-95 및 103-746 중 어느 하나와 적어도 85%의 상동성을 공유하는 아미노산 서열을 포함하거나, 이로 구성된다. 구현예에서, 펩티드는 서열번호 18, 19, 29-82, 84-95 및 103-746 중 어느 하나와 적어도 90% 상동성을 공유하는 아미노산 서열을 포함하거나, 이로 구성된다. 구현예에서, 펩티드는 서열번호 18, 19, 29-82, 84-95 및 103-746 중 어느 하나와 적어도 95% 상동성을 공유하는 아미노산 서열을 포함하거나, 이로 구성된다. 구현예에서, 펩티드는 서열번호 18, 19, 29-82, 84-95 및 103-746 중 어느 하나와 적어도 99% 상동성을 공유하는 아미노산 서열을 포함하거나, 이로 구성된다.
본 발명의 펩티드는 본원에 포함된 바와 같이 '054 및 '821 출원에 개시된 것들을 포함하여 당업자에게 공지된 임의의 적절한 방법으로 합성된다. 예를 들어, 본 발명의 펩티드는 고상 펩티드 합성에 의해 화학적으로 합성될 수 있다. 구현예에서, 본 발명의 펩티드는 N-말단("Ac" 또는 "아세틸")에서 아세틸화되거나, C-말단("CONH2" 또는 "NH2")에서 아미드화되거나, 또는 둘 다이다. 예를 들어, 서열번호 747은 글리신아미드로 종결되는 아미드화 펩티드에 상응한다.
형광
모이어티
본원에 사용된 용어 "형광 모이어티"는 형광 단백질, 형광 펩티드, 형광단(예: 형광 염료) 또는 임의의 기타 형광 리간드 또는 마커를 포함한 임의의 형광 분자를 의미한다.
본원에 기재된 형광 모이어티의 특정 예는 단지 예시적이며 본원에 개시된 펩티드와 함께 사용하기 위한 형광 모이어티를 제한하는 것을 의미하지 않는다.
형광단(또는 형광 염료)은 가시광선 뿐만 아니라 근적외선(NIR) 영역에서 기능하는 분자를 포함한다.
형광단의 일반적인 부류는 크산텐, 예를 들어, 로다민, 로돌 및 플루오레세인, 및 그들의 유도체; 비만; 쿠마린과 그들의 유도체, 예를 들어, 움벨리페론 및 아미노메틸 쿠마린; 방향족 아민, 예를 들어, 단실; 스쿠아레이트 염료; 벤조푸란; 형광 시아닌; 카르바졸; 디시아노메틸렌 피란; 폴리메틴; 옥사벤잔트란; 피릴륨; 카르보스틸; 페릴렌; 아크리돈; 퀴나크리돈; 루브렌; 안트라센; 코로넨; 페난트레센; 피렌; 부타디엔; 스틸벤; 포르피린; 프탈로시아닌; 란탄족 금속 킬레이트 착물(complex); 희토류 금속 킬레이트 착물; 및 이들의 유도체를 포함하지만, 이에 제한되지 않는다. 형광 염료는, 예를 들어, 미국 특허 제4,452,720호; 미국 특허 제5,227,487호; 및 미국 특허 제5,543,295호에서 논의된다.
본원에 개시된 접합체와 함께 사용하기 위한 전형적인 플루오레세인 염료는 카르복시플루오레세인, 5-카르복시플루오레세인, 6-카르복시플루오레세인, 5(6)-카르복시플루오레세인, 플루오레세인 이소티오시아네이트, 플루오레세인-5-이소티오시아네이트, 플루오레세인-6-이소티오시아네이트, 5,6-디카르복시플루오레세인, 5-(및 6)-설포플루오레세인, 설폰플루오레세인, 석시닐플루오레세인, 5-(및 6)-카르복시 SNARF-1, 카르복시플루오레세인 설포네이트, 카르복시플루오레세인 쯔비터이온, 카르복시플루오레세인 4급 암모늄, 카르복시플루오레세인 포스포네이트, 카르복시플루오레세인 GABA, 카르복시플루오레세인-cys-Cy5 및 플루오레세인 글루타티온을 포함하지만, 이에 제한되지 않는다. 플루오레세인 염료의 예는 또한, 예를 들어, 미국 특허 제6,008,379호, 미국 특허 제5,750,409호, 미국 특허 제5,066,580호, 및 미국 특허 제4,439,356호에서 찾을 수 있다.
구현예에서, 형광 모이어티는 카르복시플루오레세인 분자(FAM), 즉 첨가된 카르복실 그룹을 갖는 플루오레세인 분자를 포함한다. 따라서, 용어 "FAM"은 5-위치(5-FAM) 또는 6-위치(6-FAM)에 카르복실 그룹을 갖는 플루오레세인 분자를 포함할 수 있다.
구현예에서, 형광 모이어티는 IR800CW, 시안 형광 단백질(CFP); EGFP; 5-FAM; 6-FAM; FAM; 플루오레세인; IAEDANS; EDANS; BODIPY FL; TRITC; Cy5; Cy3; YFP; LC 레드 640; Alexa Fluor 546; 테트라메틸로다민; Dabcyl; QSY 7; QSY 9; QSY 21; 및 BBQ-650 염료를 포함할 수 있다.
구현예에서, 형광 모이어티는 로다민 염료, 예를 들어, 5-(및 6)-카르복시 로다민 110, 테트라메틸로다민-6-이소티오시아네이트, 5-카르복시테트라메틸로다민, 5-카르복시 로돌 유도체, 테트라메틸 및 테트라에틸 로다민, 디페닐디메틸 및 디페닐디에틸 로다민, 디나프틸 로다민, 로다민 101 설포닐 클로라이드(TEXAS RED) 및 기타 로다민 염료을 포함한다. 기타 로다민 염료는, 예를 들어, 미국 특허 제 6,080,852호; 미국 특허 제6,025,505호; 미국 특허 제5,936,087호; 미국 특허 제5,750,409호에서 찾을 수 있다.
구현예에서, 형광 모이어티는, 예를 들어, Cy2, Cy3, Cy3B, Cy3.5, Cy5, Cy5.5, Cy 7 및 인도시아닌 그린과 같은 시아닌 염료를 포함한다.
구현예에서, 형광단은 녹색 형광(예: 494nm/519nm 또는 494/524nm), 오렌지색 형광(예: 554nm/570nm), 적색 형광(예: 590nm/617nm) 또는 원적색 형광(예: 651nm/672nm) 여기/발광 스펙트럼을 나타낸다. 구현예에서, 형광단은 약 350nm 내지 약 775nm 범위의 여기 및 방출 스펙트럼을 갖는 형광단이다. 구현예에서, 여기 및 방출 스펙트럼은 약 346nm/446nm, 약 494nm/519nm, 약 554nm/570nm, 약 555nm/572nm, 약 590nm/617nm, 약 651nm/672nm, 약 679nm/702nm 또는 약 749nm/775nm이다.
구현예에서, 형광단의 여기 및 방출 스펙트럼은 가시 스펙트럼 영역(약 380nm 내지 약 700nm)에 있다.
구현예에서, 형광단의 여기 및 방출 스펙트럼은 NIR-I 스펙트럼 영역(약 700nm 내지 약 900nm) 및 NIR-II 스펙트럼 영역(약 1000nm 내지 약 1700nm)을 포함하는 근적외선(NIR) 범위에 있다. 예를 들어, 문헌(Zhu et al. 2018, Theranostics 8, 4141-4151)을 참조한다.
구현예에서, 형광단은 AlexaFluor 3, AlexaFluor 5, AlexaFluor 350, AlexaFluor 405, AlexaFluor 430, AlexaFluor 488, AlexaFluor 500, AlexaFluor 514, AlexaFluor 532, AlexaFluor 546, AlexaFluor 555, AlexaFluor 568, AlexaFluor 594, AlexaFluor 610, AlexaFluor 633, AlexaFluor 647, AlexaFluor 660, AlexaFluor 680, AlexaFluor 700 및 AlexaFluor 750(분자 프로브 AlexaFluor 염료, Life Technologies, Inc.(USA)에서 입수가능)을 포함할 수 있지만, 이에 제한되지 않는다. 구현예에서, 형광단은 Cy2, Cy3, Cy3B, Cy3.5, Cy5, Cy5.5 및 Cy7(GE Life Sciences 또는 Lumiprobes로부터 입수가능)을 포함하는 Cy 염료를 포함할 수 있지만, 이에 제한되지 않는다. 구현예에서, 형광단은 DyLight 350, DyLight 405, DyLight 488, DyLight 550, DyLight 594, DyLight 633, DyLight 650, DyLight 680, DyLight 750 및 DyLight 800(Thermo Scientific (USA)로부터 입수가능)을 포함할 수 있지만, 이에 제한되지 않는다. 구현예에서, 형광단은 FluoProbes 390, FluoProbes 488, FluoProbes 532, FluoProbes 547H, FluoProbes 594, FluoProbes 647H, FluoProbes 682, FluoProbes 752 및 FluoProbes 782, AMCA, DEAC(7-디에틸아미노쿠마린-3-카복실산); 7-하이드록시-4-메틸쿠마린-3; 7-하이드록시쿠마린-3; MCA(7-메톡시쿠마린-4-아세트산); 7-메톡시쿠마린-3; AMF(4'-(아미노메틸)플루오레세인); 5-DTAF(5-(4,6-디클로로트리아지닐)아미노플루오레세인); 6-DTAF(6-(4,6-디클로로트리아지닐)아미노플루오레세인); FAM(카르복시플루오레세인); 6-FAM(6-카르복시플루오레세인), 5(6)-FAM 카다베린; 5-FAM 카다베린; 5(6)-FAM 에틸렌디암; 5-FAM 에틸렌디암; 5-FITC(FITC 이성체 I; 플루오레세인-5-이소티오시아네이트); 5-FITC 카다베린; 플루오레세인-5-말레이미드; 5-IAF(5-요오도아세트아미도플루오레세인); 6-JOE(6-카르복시-4',5'-디클로로-2',7'-디메톡시플루오레세인); 5-CRl l0(5-카르복시로다민 110); 6-CRl l0(6-카르복시로다민 110); 5-CR6G(5-카르복시로다민 6G); 6-CR6G(6-카르복시로다민 6G); 5(6)-카르복시로다민 6G 카다베린; 5(6)-카록시르로다민 6G 에틸렌디암; 5-ROX(5-카르복시-X-로다민); 6-ROX(6-카르복시-X-로다민); 5-TAMRA(5-카르복시테트라메틸로다민); 6-TAMRA(6-카르복시테트라메틸로다민); 5-TAMRA 카다베린; 6-TAMRA 카다베린; 5-TAMRA 에틸렌디암; 6-TAMRA 에틸렌디암; 5-TMR C6 말레이미드; 6-TMR C6 말레이미드; TR C2 말레이미드; TR 카다베린; 5-TRITC; G 이성체(테트라메틸로다민-5-이소티오시아네이트); 6-TRITC; R 이성체(테트라메틸로다민-6-이소티오시아네이트); 단실 카다베린(5-디메틸아미노나프탈렌-l-(N-(5-아미노펜틸))설폰아미드); EDANS C2 말레이미드; 플루오레스카민; NBD; 및 피로메텐 및 이의 유도체를 포함할 수 있지만, 이에 제한되지 않는다.
구현예에서, 형광 모이어티는 환경적으로 민감한 형광 염료 또는 형광단을 포함한다. 환경적으로 민감한 형광 염료 또는 형광단의 예는 5,6-카르복시-디에틸 로돌(pH 민감성), 메로시아닌(막 전위 민감성), 나일 레드 카르복실산(지질 민감성)을 포함한다.
구현예에서, 형광 모이어티는 형광 펩티드 또는 형광 단백질이다. 구현예에서, 형광 단백질은 녹색 형광 단백질(GFP)이다. 구현예에서, 형광 모이어티는, 예를 들어, 다음을 포함하는 GFP의 유도체 또는 변이체이다: EGFP, 에메랄드, 슈퍼폴더 GFP, 아자미 그린 mWasabi, TagGFP, 터보GFP, AcGFP, Zs그린, T-사파이어, EBFP, EBFP2, 아주라이트, mTagBFP, ECFP, mECFP, 세룰리안, mTurquoise, CyPet, AmCyan1, 미도리-이시 시안, TagCFP, mTFP1(청록색), EYFP, 토파즈, 비너스, mCitrine, YPet, TagYFP, PhiYFP, ZsYellow1, mBanana, Kusabira Orange, Kusbira Orange2, mOrange, mOrange2, dTomato, dTomato-Tandem, TagRFP, TagRFP-Y, DsRed, DsRed2, DsRed-익스프레스(T1), DsRed-단량체, mTangerine, mRuby, mApple, mStrawberry, AsRed2, mRFP1, JRed, mCherry, HcRed1, mRaspberry, dKeima-Tandem, HcRed-Tandem, mPlum, AQ143, mKalamal, YFP, 및 시트린.
구현예에서, 형광 모이어티는 '054 및 '821 출원에 개시된 바와 같이 형광 분자를 포함하며, 이는 전체가 본원에 포함된다.
구현예에서, 형광 모이어티는 덱스트란, PEG, 혈청 알부민 또는 폴리(아미도아민) 덴드리머를 포함하지만, 이에 제한되지 않는 수용성 중합체와 같은 고분자량 분자에 접합된다.
본원에 개시된 형광 모이어티는 펩티드의 N-말단, C-말단 또는 내부 위치(예: 내부 아미노산)에 결합될 수 있다. 구현예에서, 2개, 3개, 4개 또는 그 이상의 펩티드는 형광 모이어티에 직접 또는 간접적으로 결합된다. 구현예에서, 본원에 개시된 임의의 펩티드는 동일하거나 상이할 수 있는 둘 이상의 형광 모이어티에 결합된다.
구현예에서, 본원에 개시된 형광 모이어티는 본원에 개시된 임의의 펩티드에 직접 결합된다.
링커
구현예에서, 형광 모이어티는, 예를 들어, 링커를 통해 펩티드에 간접적으로 결합된다. 본원에 사용된 바와 같이, "링커"는 본원에 개시된 펩티드에 결합(예를 들어, 공유적으로)할 수 있는 임의의 분자이다. 링커는 직선 또는 분지쇄 탄소 함유 링커, 헤테로사이클릭 탄소 함유 링커, 아미노산 링커(예: D- 또는 L-아미노산), 친유성 잔기, 펩티드 링커, 펩티드 핵산 링커, 하이드라존 링커, SPDB 디설파이드, 설포-SPDB, 말레이미도메틸 사이클로헥산-1-카복실레이트(MCC), 아미노헥산산 링커 및 폴리에테르 링커(예: PEG)를 포함할 수 있지만, 이에 제한되지 않는다. 링커는, 예를 들어, 오하이오주 파월에 위치한 Quanta Biodesign으로부터 입수 가능한 폴리(에틸렌 글리콜) 링커를 포함한다. 이러한 링커는 임의로 아미드 결합, 설프하이드릴 결합 또는 헤테로 작용성 결합을 갖는다. 링커는 또한 본원에 포함된 바와 같이, '054 및 '821 출원에 기재된 것들을 포함하여 당업계에 개시되거나 기재된 바와 같은 다른 링커 분자를 포함한다.
구현예에서, 링커는 공유 결합에 의해 본원에 개시된 표적화 분자에 결합한다. 링커는 한 위치에서 카고 분자에 대한 공유 결합을 형성하고 다른 위치에서 펩티드에 대한 공유 결합을 형성함으로써 형광 모이어티와 같은 카고 분자를 펩티드에 연결할 수 있다. 공유 결합은 링커 상의 작용성 그룹과 펩티드 및 카고 분자 상의 작용성 그룹 사이의 반응에 의해 형성될 수 있다. 구현예에서, 공유 결합은 에테르 결합, 티오에테르 결합, 아민 결합, 아미드 결합, 탄소-탄소 결합, 탄소-질소 결합, 탄소-산소 결합 또는 탄소-황 결합을 포함한다. 예를 들어, 공유 결합은 플루오레세인의 5-위치에 있는 카르복실산 작용성 그룹과 펩티드의 N-말단, 예를 들어, 형광 접합체 5-FAM-QVPWEEPYYVVKKSSGG-NH2(GG 링커가 있는 HNP401-N-2; 서열번호 747)에 있는 1급 아민 사이의 축합 반응에 의해 형성될 수 있다.
구현예에서, 링커는 가요성이다. 구현예에서, 링커는 강성이다. 구현예에서, 링커는 가요성의 세그먼트(들)와 강성의 세그먼트(들)를 갖는다.
구현예에서, 링커는 선형 구조를 포함한다. 구현예에서, 링커는 비선형 구조를 포함한다. 구현예에서, 링커는 분지된 구조를 포함한다. 구현예에서, 링커는 사이클릭 구조를 포함한다.
구현예에서, 링커는 알킬이다. 구현예에서, 링커는 헤테로알킬이다.
구현예에서, 링커는 알킬렌이다. 구현예에서, 링커는 알케닐렌이다. 구현예에서, 링커는 알키닐렌이다. 구현예에서, 링커는 헤테로알킬렌이다.
"알킬" 그룹은 지방족 탄화수소 그룹을 지칭한다. 알킬 모이어티는 포화 알킬 또는 불포화 알킬일 수 있다. 구조에 따라, 알킬 그룹은 모노라디칼 또는 디라디칼(즉, 알킬렌 그룹)일 수 있다.
"알킬" 모이어티는 1 내지 10개의 탄소 원자를 가질 수 있다(본원에 나타날 때마다 "1 내지 10"과 같은 수치 범위는 주어진 범위의 각 정수를 지칭하고; 예를 들어, "1 내지 10개의 탄소 원자"는 알킬 그룹이 1개의 탄소 원자, 2개의 탄소 원자, 3개의 탄소 원자 등으로 구성될 수 있고, 최대 10개의 탄소 원자를 포함할 수 있지만, 본 정의는 또한 수치 범위가 지정되지 않은 용어 "알킬"의 발생을 포함한다는 것을 의미한다). 알킬 그룹은 또한 1 내지 6개의 탄소 원자를 갖는 "저급 알킬"일 수 있다. 본원에 기재된 화합물의 알킬 그룹은 "Ci-C4 알킬" 또는 유사한 명칭으로 지정될 수 있다. 단지 예로서, "C1-C4 알킬"은 알킬 쇄에 1 내지 4개의 탄소 원자가 존재한다, 즉 알킬 쇄는 메틸, 에틸, 프로필, 이소-프로필, n-부틸, 이소-부틸, sec-부틸 및 t-부틸로부터 선택된다는 것을 나타낸다. 전형적인 알킬 그룹은 메틸, 에틸, 프로필, 이소프로필, 부틸, 이소부틸, 3급 부틸, 펜틸, 헥실, 에테닐, 프로페닐, 부테닐 등을 포함하지만, 이에 제한되지 않는다.
구현예에서, 링커는 환 구조(예: 아릴)를 포함한다. 본원에 사용된 용어 "환"은 임의의 공유 폐쇄 구조를 지칭한다. 환은, 예를 들어, 카보사이클(예: 아릴 및 사이클로알킬), 헤테로사이클(예: 헤테로아릴 및 비방향족 헤테로사이클), 방향족 화합물(예: 아릴 및 헤테로아릴) 및 비방향족 화합물(예: 사이클로알킬 및 비방향족 헤테로사이클)을 포함한다. 환은 임의로 치환될 수 있다. 환은 모노사이클릭 또는 폴리사이클릭일 수 있다.
본원에 사용되는 용어 "아릴"은 환을 형성하는 각 원자가 탄소 원자인 방향족 환을 지칭한다. 아릴 환은 5개, 6개, 7개, 8개, 9개 또는 9개 이상의 탄소 원자에 의해 형성될 수 있다. 아릴 그룹은 임의로 치환될 수 있다. 아릴 그룹의 예는 페닐, 나프탈레닐, 페난트레닐, 안트라세닐, 플루오렌닐 및 인데닐을 포함하지만, 이에 제한되지 않는다. 구조에 따라, 아릴 그룹은 모노라디칼 또는 디라디칼(즉, 아릴렌 그룹)일 수 있다.
용어 "사이클로알킬"은 환을 형성하는 각 원자(즉, 골격 원자)가 탄소 원자인 모노사이클릭 또는 폴리사이클릭 비방향족 라디칼을 지칭한다. 사이클로알킬은 포화되거나 부분적으로 불포화될 수 있다. 사이클로알킬 그룹은 3 내지 10개의 환 원자를 갖는 그룹을 포함한다. 사이클로알킬은 사이클로프로필, 사이클로부틸, 사이클로펜틸, 사이클로헥실, 사이클로헵틸 및 사이클로옥틸을 포함하지만, 이에 제한되지 않는다.
구현예에서, 환은 사이클로알칸이다. 구현예에서, 환은 사이클로알켄이다.
구현예에서, 환은 방향족 환이다. 용어 "방향족"은 4n+2π 전자를 함유하는 비편재된 π 전자 시스템을 갖는 평면 환을 지칭하며, 여기서 n은 정수이다. 방향족 환은 5개, 6개, 7개, 8개, 9개 또는 9개 이상의 원자로 형성될 수 있다. 방향족은 임의로 치환될 수 있다. 용어 "방향족"은 카르보사이클릭 아릴(예: 페닐) 및 헤테로사이클릭 아릴(또는 "헤테로아릴" 또는 "헤테로방향족") 그룹(예: 피리딘)을 모두 포함한다. 상기 용어는 모노사이클릭 또는 융합 환 폴리사이클릭(즉, 인접한 탄소 원자 쌍을 공유하는 환) 그룹을 포함한다.
구현예에서, 환은 헤테로사이클이다. 용어 "헤테로사이클"은 각각 O, S 및 N으로부터 선택된 1 내지 4개의 헤테로 원자를 함유하는 헤테로방향족 및 헤테로지환식 그룹을 지칭하며, 여기서 각 헤테로사이클 그룹은 환 시스템에 4 내지 10개의 원자를 가지며, 단 상기 그룹의 환은 2개의 인접한 O 또는 S 원자를 함유하지 않는다. 비방향족 헤테로사이클릭 그룹은 환 시스템에 3개의 원자만을 갖는 그룹을 포함하지만, 방향족 헤테로사이클릭 그룹은 환 시스템에 적어도 5개의 원자를 가져야 한다. 헤테로사이클릭 그룹은 벤조 융합 환 시스템을 포함한다. 3원 헤테로사이클릭 그룹의 예는 아지리디닐이다. 4원 헤테로사이클릭 그룹의 예는 아제티디닐(아제티딘에서 유래됨)이다. 5원 헤테로사이클릭 그룹의 예는 티아졸릴이다. 6원 헤테로사이클릭 그룹의 예는 피리딜이고, 10원 헤테로사이클릭 그룹의 예는 퀴놀리닐이다. 비방향족 헤테로사이클릭 그룹의 예는 피롤리디닐, 테트라하이드로푸라닐, 디하이드로푸라닐, 테트라하이드로티에닐, 테트라하이드로피라닐, 디하이드로피라닐, 테트라하이드로티오피라닐, 피페리디노, 모르폴리노, 티오모르폴리노, 티옥산닐, 피페라지닐, 아제티디닐, 옥세타닐, 티에타닐, 호모피페리디닐, 옥세파닐, 티에파닐, 옥사제피닐, 디아제피닐, 티아제피닐, 1,2,3,6-테트라하이드로피리디닐, 2-피롤리닐, 3-피롤리닐, 인돌리닐, 2H-피라닐, 4H-피라닐, 디옥사닐, 1,3-디옥솔라닐, 피라졸리닐, 디티아닐, 디티올라닐, 디하이드로피라닐, 디하이드로티에닐, 디하이드로푸라닐, 피라졸리디닐, 이미다졸리닐, 이미다졸리디닐, 3-아자비사이클로[3.1.0]헥사닐, 3-아자비사이클로[4.1.0]헵타닐, 3H-인돌릴 및 퀴놀리지닐이다. 방향족 헤테로사이클릭 그룹의 예는 피리디닐, 이미다졸릴, 피리미디닐, 피라졸릴, 트리아졸릴, 피라지닐, 테트라졸릴, 푸릴, 티에닐, 이속사졸릴, 티아졸릴, 옥사졸릴, 이소티아졸릴, 피롤릴, 퀴놀리닐, 이소퀴놀리닐, 인돌릴, 벤즈이미다졸릴, 벤조푸라닐, 신놀리닐, 인다졸릴, 인돌리지닐, 프탈라지닐, 피리다지닐, 트리아지닐, 이소인돌릴, 프테리디닐, 퓨리닐, 옥사디아졸릴, 티아디아졸릴, 푸라자닐, 벤조푸라자닐, 벤조티오페닐, 벤조티아졸릴, 벤족사졸릴, 퀴나졸리닐, 퀴녹살리닐, 나프티리디닐 및 파로피리디닐이다. 전술한 그룹은 가능한 경우 C-부착 또는 N-부착될 수 있다. 예를 들어, 피롤로부터 유도된 그룹은 피롤-1-일(N-부착됨) 또는 피롤-3-일(C-부착됨)일 수 있다. 또한, 이미다졸로부터 유도된 그룹은 이미다졸-1-일 또는 이미다졸-3-일(모두 N-부착됨) 또는 이미다졸-2-일, 이미다졸-4-일 또는 이미다졸-5-일(모두 C-부착됨)일 수 있다. 헤테로사이클릭 그룹은 벤조 융합 환 시스템과 피롤리딘-2-온과 같이 하나 또는 두 개의 옥소(=0) 모이어티로 치환된 환 시스템을 포함한다. 구조에 따라, 헤테로사이클 그룹은 모노라디칼 또는 디라디칼(즉, 헤테로사이클렌 그룹)일 수 있다.
구현예에서, 환은 융합된다. 용어 "융합된"은 둘 이상의 환이 하나 이상의 결합을 공유하는 구조를 지칭한다. 구현예에서, 환은 이량체이다. 구현예에서, 환은 삼량체이다. 구현예에서, 환은 치환된다.
용어 "카르보사이클릭" 또는 "카르보사이클"은 환을 형성하는 각 원자가 탄소 원자인 환을 지칭한다. 카르보사이클은 아릴 및 사이클로알킬을 포함한다. 따라서, 상기 용어는 환 골격이 탄소와 상이한 적어도 하나의 원자(즉, 헤테로 원자)를 함유하는 헤테로사이클("헤테로사이클릭")과 카르보사이클을 구별한다. 헤테로사이클은 헤테로아릴 및 헤테로사이클로알킬을 포함한다. 카르보사이클 및 헤테로사이클은 임의로 치환될 수 있다.
구현예에서, 링커는 치환된다. 용어 "임의로 치환된" 또는 "치환된"은 참조된 그룹이 개별적으로 그리고 독립적으로 Ci-Ce알킬, C3-Cg사이클로알킬, 아릴, 헤테로아릴, C2-C6헤테로지환식, 하이드록시, Ci-C6알콕시, 아릴옥시, Ci-C6알킬티오, 아릴티오, Ci-C6알킬설폭사이드, 아릴설폭사이드, Ci-C6알킬설폰, 아릴설폰, 시아노, 할로, C2-C8아실, C2-C8아실옥시, 니트로, Ci-C6할로알킬, Ci-C6플루오로알킬, 및 Ci-C6알킬아미노를 포함하는 아미노 및 이들의 보호된 유도체로부터 선택된 하나 이상의 추가의 그룹(들)으로 치환될 수 있다. 예로서, 임의의 치환체는 LSRS일 수 있고, 여기서 각 L은 결합, -O-, -C(=O)-, -S-, -S(=O)-, -S(O)2-, -NH-, -NHC(O)-, -C(O)NH-, S(O)2NH-, -NHS(O)2-, -OC(O)NH-, -NHC(O)O-, -(CpC6알킬)-, 또는 -(C2-C6알케닐)-로부터 독립적으로 선택되고; 각 R은 H, (Ci-C4알킬), (C3-C8사이클로알킬), 헤테로아릴, 아릴 및 Ci-C6헤테로알킬로부터 독립적으로 선택된다. 임의로 치환된 비방향족 그룹은 하나 이상의 옥소(=0)로 치환될 수 있다. 상기 치환체의 보호 유도체를 형성할 수 있는 보호 그룹은 당업자에게 공지되어 있다.
구현예에서, 한 분자(예: 표적화 분자) 상의 의 그룹과 반응성인 하나의 작용성 그룹과 다른 분자(예: 형광 모이어티 또는 약물) 상의 반응성인 다른 그룹을 갖는 이작용성 링커를 사용하여 목적하는 접합체를 형성한다. 대안적으로, 유도체화를 수행하여 작용성 그룹을 제공한다. 따라서, 예를 들어, 펩티드 상에 유리 설프하이드릴 그룹의 생성 절차도 또한 공지되어 있다(참조: 미국 특허 제4,659,839호). 링커는 대안적으로 표적화 분자와 상호 작용할 수 있는 헤테로사이클릭 환을 형성하는 둘 이상의 상이한 반응성 그룹을 포함하는 헤테로이작용성 가교결합제를 포함할 수 있다. 예를 들어, 시스테인과 같은 헤테로이작용성 가교결합제는 아민 반응성 그룹을 포함할 수 있고, 티올 반응성 그룹은 유도체화된 표적화 분자 상의 알데히드와 상호 작용할 수 있다. 헤테로이작용성 가교결합제에 적합한 반응성 그룹의 추가 조합은, 예를 들어, 아민- 및 설프하이드릴 반응성 그룹; 카르보닐 및 설프하이드릴 반응성 그룹; 아민 및 광반응성 그룹; 설프하이드릴 및 광반응성 그룹; 카르보닐 및 광반응성 그룹; 카르복실레이트 및 광반응성 그룹; 및 아르기닌 및 광반응성 그룹을 포함한다. 헤테로이작용성 가교결합제의 예는 N-석신이미딜 4-(2-피리딜디티오)부타노에이트(SPDB) 및 말레이미도메틸 사이클로헥산-1-카복실레이트(MCC)를 포함한다.
구현예에서, 링커는 절단 가능하다. 구현예에서, 링커는 절단 불가능하다. 링커는 세포외 환경에 대해 화학적으로 안정할 수 있고, 예를 들어, 혈류에서 화학적으로 안정할 수 있고/있거나 안정하지 않은 결합을 포함할 수 있다. 링커는 세포 내부에서 특이적으로 또는 비특이적으로 절단 및/또는 용해 또는 달리 분해되도록 설계된 결합을 포함할 수 있다. 절단 가능한 링커는 특정 부위의 효소, 예를 들어, 세포외 프로테아제에 민감할 수 있다.
절단 가능한 링커는 발린-시트룰린 펩티드, 발린-알라닌 펩티드, 페닐알라닌-리신 또는 다른 펩티드, 예를 들어, 프로테아제 인식 및 절단 부위를 형성하는 펩티드를 포함할 수 있다. 이러한 펩티드 함유 링커는 펜타플루오로페닐 그룹을 함유할 수 있다. 펩티드 함유 링커는 석신이미드 또는 말레이미드 그룹을 포함할 수 있다. 펩티드 함유 링커는 파라 아미노벤조산(PABA) 그룹을 포함할 수 있다. 펩티드 함유 링커는 아미노벤질옥시카르보닐(PABC) 그룹을 포함할 수 있다. 펩티드 함유 링커는 PABA 또는 PABC 그룹 및 펜타플루오로페닐 그룹을 포함할 수 있다. 펩티드 함유 링커는 PABA 또는 PABC 그룹 및 석신이미드 그룹을 포함할 수 있다. 펩티드 함유 링커는 PABA 또는 PABC 그룹 및 말레이미드 그룹을 포함할 수 있다.
절단 불가능한 링커는 일반적으로 프로테아제에 민감하지 않으며, 세포내 공정에 민감하지 않다. 절단 불가능한 링커는 말레이미드 그룹을 포함할 수 있다. 절단 불가능한 링커는 석신이미드 그룹을 포함할 수 있다. 절단 불가능한 링커는 말레이미도-알킬-C(O)- 링커일 수 있다. 절단 불가능한 링커는 말레이미도카프로일 링커일 수 있다. 말레이미도카프로일 링커는 N-말레이미도메틸사이클로헥산-1-카복실레이트일 수 있다. 말레이미도카프로일 링커는 석신이미드 그룹을 포함할 수 있다. 말레이미도카프로일 링커는 펜타플루오로페닐 그룹을 포함할 수 있다.
구현예에서, 하나 이상의 아미노산으로 이루어진 펩티드 링커는 표적화 분자와 형광 모이어티 또는 약물을 결합하는 데 사용된다. 일반적으로 펩티드 링커는 분자를 결합하거나 분자 사이의 일부 최소 거리 또는 다른 공간적 관계를 유지하는 것 외에는 특정 생물학적 활성을 갖지 않을 것이다. 그러나, 링커의 구성 아미노산은 접힘, 순 전하 또는 소수성과 같은 분자의 일부 특성에 영향을 미치도록 선택될 수 있다. 구현예에서, 펩티드 링커는 비교적 짧은, 전형적으로 약 10개 미만의 아미노산, 바람직하게는 약 8개 미만의 아미노산, 더욱 바람직하게는 5개 미만의 아미노산이다. 비제한적인 예시적 예는 펩티드의 C-말단에 첨가될 수 있는 글리신 및 글리신-세린 링커를 포함한다. 구현예에서, 펩티드 링커는 부위 특이적 접합을 위해 시스테인 잔기 또는 비천연 아미노산 잔기, 예를 들어, 셀레노시스테인(Sec), p-아세토페닐알라닌(pAcF), p-아지도메틸-L-페닐알라닌(pAMF) 및 아지도-리신(AzK)을 포함한다. 구현예에서, 펩티드 링커는 글리신-글리신-글리신-시스테인(GGGC)(서열번호 15) 링커, 글리신-글리신-시스테인(GGC) 링커, 글리신-글리신(GG) 링커, 또는 시스테인(C) 링커이다. 구현예에서, GGGC(서열번호 15), GGC, GG 또는 C 링커가 펩티드의 N-말단 또는 C-말단에 첨가된다.
구현예에서, 본 발명의 형광 접합체는 임의로 그들의 결합의 다원성 및 결합력을 증가시키는 고분자량 분자에 접합될 수 있다. 구현예에서, 고분자량 분자는 수용성 중합체이다. 적합한 수용성 중합체의 예는 펩티드, 당류, 폴리(비닐), 폴리(에테르), 폴리(아민), 폴리(카르복실산) 등을 포함하지만, 이에 제한되지 않는다. 구현예에서, 수용성 중합체는 덱스트란, 폴리에틸렌 글리콜(PEG), 폴리옥시알킬렌, 폴리시알산, 전분 또는 하이드록시에틸 전분이다. 임의의 적합한 방법은 펩티드를 수용성 중합체에 접합시키는 데 사용된다(참조: Hermanson G., Bioconjugate Techniques 2nd Ed., Academic Press, Inc., 2008).
구현예에서, 본 발명의 형광 접합체는 용해도를 증가시키기 위해 변형될 수 있다. 용해도를 증가시키는 펩티드 변형은 친수성 아미노산(들), PEG 모이어티 또는 둘 다의 첨가를 포함한다. 구현예에서, PEG 모이어티는 8-아미노-3,6-디옥사옥탄산(AEEA); 12-아미노-4,7,10-트리옥사도데칸산; 또는 15-아미노-4,7,10,13-테트라옥사펜타-데칸산이다. 구현예에서, 대략 1 내지 10개(예: 1, 2, 3, 4, 5, 6, 7, 8, 9, 또는 10개)의 친수성 아미노산이 펩티드의 N-말단, C-말단, 내부 위치 또는 이들의 임의의 조합에 첨가되어 용해도를 증가시킬 수 있다. 친수성 아미노산은 D, E, H, K, N, Q, R, S, T, 및 G를 포함한다. 구현예에서, 펩티드는 N-말단 또는 C-말단에 K, KK, G 또는 GG를 포함한다.
구현예에서, 형광 접합체는 5-FAM-QVPWEEPYYVVKKSSGG-NH2(GG 링커를 갖는 HNP401-N-2, 서열번호 747)를 포함하며, 본원에 기재된 임의의 방법에 사용될 수 있다.
구현예에서, 형광 접합체는 GCC 링커를 갖는 HNP401의 C-말단 시스테인에 연결된 FAM을 포함한다(Ac-SGQVPWEEPYYVVKKSSGGC-CONH2; 서열번호 748).
IV.
약제학적 조성물
특정 구현예에서, 본원에 개시된 형광 접합체를 포함하는 약제학적 조성물이 본원에 개시된다. 본원의 약제학적 조성물은 약제학적으로 사용되는 제제로 활성제의 처리를 촉진시키는 부형제 및 보조제를 포함하여 하나 이상의 생리적으로 허용되는 담체를 사용하여 제형화된다. 적절한 제형은 선택된 투여 경로에 따라 달라진다. 이러한 조성물은, 예를 들어, 문헌(Gennaro: Remington : The Science and Practice of Pharmacy, 21st Ed. (Lippincott Williams & Wilkins, 2005); Allen: Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems, 11th Ed. (Wolters Kluwer, 2018); Brunton et al.: Goodman & Gilman's The Pharmacological Basis of Therapeutics (McGraw-Hill Professional, 2005); and Rowe: Handbook of Pharmaceutical Excipients (Pharmaceutical Press, 2005)에서 발견되는 바와 같이, 당업자에게 공지된 방법 및 부형제로 제조될 수 있다.
약제학적 조성물의 구현예에서, 형광 접합체의 펩티드는 본원에 기재된 모든 변이체 및 조합을 포함하여 임의의 아미노산 서열로 구성되거나, 이를 포함할 수 있다. 구현예에서, 펩티드는 본원에 기재된 바와 같이 표 1에 나열된 임의의 아미노산 서열 또는 이의 임의의 변이체로 구성되거나, 이를 포함할 수 있다. 구현예에서, 펩티드는 임의의 서열번호 1-14, 16, 20-28 및 96-102를 포함하거나, 이로 구성된다. 구현예에서, 펩티드는 표 2-4에 나열된 임의의 아미노산 서열 또는 이의 임의의 변이체로 구성되거나, 이를 포함한다. 구현예에서, 펩티드는 서열번호 75-82, 84-95 및 103-187로부터 선택된 아미노산 서열을 포함한다. 구현예에서, 펩티드는 서열번호 55-74 및 188-362로부터 선택된 아미노산 서열을 포함한다. 구현예에서, 펩티드는 서열번호 33-54 및 363-446으로부터 선택된 아미노산 서열을 포함한다. 구현예에서, 펩티드는 서열번호 18, 19, 및 29-32 및 447-471로부터 선택된 아미노산 서열을 포함한다. 구현예에서, 펩티드는 서열번호 472-678로부터 선택된 아미노산 서열을 포함한다. 구현예에서, 펩티드는 서열번호 679-746으로부터 선택된 아미노산 서열을 포함한다. 구현예에서, 펩티드는 서열번호 21의 아미노산 서열로 구성되거나, 이를 포함한다.
구현예에서, 약제학적 조성물 내의 형광 접합체는 서열번호 747을 포함한다.
구현예에서, 본원에 개시된 약제학적 조성물은 약제학적으로 허용되는 희석제, 부형제, 담체 또는 용매를 추가로 포함한다. 적합한 수성 및 비수성 담체, 희석제, 용매 또는 비히클의 예는 물, 에탄올, 폴리올(프로필렌 글리콜, 폴리에틸렌-글리콜, 글리세롤, 크레모포어 등), 이들의 적절한 혼합물, 식물성 오일(예: 올리브 오일) 및 주사 가능한 유기 에스테르, 예를 들어, 에틸 올레에이트를 포함한다. 약제학적으로 허용되는 고체, 액체 또는 기타 투여 형태의 제조에 통상적으로 사용되는 다른 통상적으로 사용된 계면활성제, 예를 들어, 트윈(Tweens), 스팬(Spans) 및 기타 유화제 또는 생체이용률 향상제도 또한 제형화의 목적을 위해 사용될 수 있다. 생체이용률 향상제는 침투 또는 투과 향상제를 포함할 수 있다. 예를 들어, 문헌(Muheem et al., 2016, Saudi Pharm . J. 24, 413-428; Brayden et al. 2020, Adv . Drug Deliv . Rev. 2020 May 29:S0169-409X(20)30040-5; Ibrahim et al. 2020, J. Pham . Sci. 28, 403-416)을 참조한다. 일부 제형에서, 적절한 유동성은, 예를 들어, 레시틴과 같은 코팅제의 사용, 분산액의 경우 필요한 입자 크기의 유지, 및 계면활성제의 사용에 의해 유지될 수 있다.
구현예에서, 약제학적 조성물은 다른 의약 또는 약제학적 제제, 담체, 보조제, 예를 들어, 보존제, 안정화제, 습윤제 또는 유화제, 용액 촉진제, 삼투압 조절용 염 및/또는 완충제를 포함한다. 또한, 약제학적 조성물은 다른 치료적으로 유용한 물질도 또한 함유한다.
구현예에서, 본원에 개시된 펩티드 접합체는 약물 전달 비히클 또는 담체를 통해 대상체에게 전달된다. 구현예에서, 전달 비히클은 천연 또는 합성 물질 또는 둘 다로 제조된다. 구현예에서, 전달 비히클은 나노입자, 마이크로입자, 중합체 미셀, 나노캡슐, 덴드리머, 대형 PEG, 나노겔, 리포좀, 풀러렌, 나노구조화 지질 담체, 나노쉘, 양자점, 단백질 기반 나노담체(예: 알부민, 엘라스틴, 글리아딘, 레구민, 제인, 대두 단백질, 우유 단백질, 유장 기반 나노담체), 유기 나노담체(예: 젤라틴, 덱스트란, 구아 검, 키토산, 콜라겐), 다당류 기반 담체(예: 덱스트란, 키토산, 펙틴), 지질 에멀젼 또는 이들의 조합이다.
구현예에서, 본원에 개시된 약제학적 조성물은 국소, 경구, 직장내, 질내, 비강내, 흡입, 비경구(정맥내, 동맥내, 피하, 복강내, 근육내, 혈관내, 척수강내, 유리체강내, 주입) 투여를 포함하지만 이에 제한되지 않는 임의의 적절한 투여 경로로 대상체에게 투여된다. 특정 구현예에서, 본원에 개시된 약제학적 조성물은 대상체에게 국소적 또는 전신적으로 투여된다. 구현예에서, 본원에 개시된 약제학적 조성물은 정맥내로 투여된다.
근육내, 피하 또는 정맥내 주사에 적합한 제형은 생리적으로 허용되는 멸균 수용액 또는 비수성 용액, 분산액, 현탁액 또는 에멀젼, 및 멸균 주사 가능한 용액 또는 분산액으로 재구성하기 위한 멸균 분말을 포함한다. 피하 주사에 적합한 제형은 또한 당업자에게 공지된 바와 같이, 임의의 첨가제, 예를 들어, 방부제, 습윤제, 유화제 및 분산제를 함유한다. 구현예에서, 정맥내 주사에 적합한 제형은 수용액, 예를 들어, 식염수 완충액 및 당업자에게 공지된 기타 생리적으로 적합한 완충액 중에서 제조될 수 있다. 정맥내 주사의 경우, 활성제는 임의로 수용액, 바람직하게는 생리적으로 적합한 완충액, 예를 들어, 행크(Hank) 용액, 링거(Ringer) 용액 또는 생리 식염수 완충액 중에서 제형화된다.
비경구 주사는 임의로 볼러스 주사 또는 연속 주입을 포함한다. 주사용 제형은 임의로 단위 투여 형태, 예를 들어, 앰플 또는 다중 투여 용기에 첨가된 방부제와 함께 제공된다. 구현예에서, 본원에 기재된 약제학적 조성물은 유성 또는 수성 비히클에서 멸균 현탁액, 용액 또는 에멀젼으로서 비경구 주사에 적합한 형태이며, 제형화제, 예를 들어, 현탁제, 안정화제 및/또는 분산제를 함유한다. 비경구 투여용 약제학적 제형은 수용성 형태의 활성제의 수용액을 포함한다. 추가로, 현탁액은 임의로 적절한 유성 주사 현탁액으로 제조된다.
구현예에서, 본원의 약제학적 조성물은 경구 투여된다. 경구 투여에 적합한 투여 형태는 고체 또는 액체일 수 있으며, 예를 들어, 환제, 캡슐, 트로키제, 정제, 캐플릿, 겔 캐플릿(겔 캡), 시럽, 수성 현탁액 또는 용액, 저작성 형태, 삼킬 수 있는 형태, 용해 가능한 형태, 발포제, 과립 형태 및 경구 액체 용액을 포함할 수 있다. 특정 구현예에서, 투여 형태는 고체 투여 형태이며, 보다 특히 정제 또는 캡슐을 포함하거나, 본원에 개시된 바와 같은 비히클 또는 담체에 의해 경구 투여된다.
구현예에서, 본원에 기재된 약제학적 조성물은 정확한 용량의 단일 투여에 적합한 단위 투여 형태이다. 단위 투여 형태에서, 제형은 본원에 개시된 적절한 양의 활성제를 함유하는 단위 투여량으로 분할된다. 구현예에서, 단위 용량은 제형의 별개의 양을 함유하는 패키지의 형태이다. 비제한적인 예는 패키징된 정제 또는 캡슐, 및 바이알 또는 앰플 중 분말이다. 구현예에서, 수성 현탁액 조성물은 단일 투여량 재밀폐 가능하지 않은 용기에 패키징된다. 대안적으로, 다중 투여량 재밀폐 가능한 용기가 사용되며, 이 경우에 조성물에 방부제를 포함하는 것이 전형적이다. 단지 예로서, 비경구 주사용 제형은 앰플을 포함하지만 이에 제한되지 않는 단위 투여 형태로 제공되거나, 첨가된 방부제와 함께 다중 투여 용기에 제공된다.
구현예에서, 약제학적 조성물은 대상체, 특히 인간 환자, 더욱 특히 수술을 받고 있는 인간 환자에게 전신 정맥내로 투여된다.
구현예에서, 약제학적 조성물은 대상체, 특히 인간 환자, 더욱 특히 수술을 받고 있는 인간 환자에게 경구 투여된다.
실시예
1
요관 가시화에서 신경
표적화
형광 접합체의 사용
도입
파지 디스플레이 스크린은 이전에 인간 신경 균질물 또는 단리된 인간 신경 단백질에 결합하는 펩티드를 식별하기 위해 수행되었다. '054 및 '821 출원을 참조한다. 이러한 펩티드는 다양한 출원을 위한 카고 분자에 연결되거나 태깅될 수 있다. 예를 들어, 형광 모이어티로 태깅된 경우, 이러한 접합체는 형광 보조 수술 동안 신경의 생체내 표지에 잠재적으로 유용하며, 예를 들어, 활성제에 연결된 경우, 이러한 접합체는 표적화 요법으로서 잠재적으로 유용하다.
예시적인 펩티드는 형광 염료에 접합시켜 형광 접합체(여기서 접합체로서 지칭되기도 함)를 생성하고, 설치류 모델에서 평가되었고, 여기서 그들은 정맥내 투여 후 민감한 신경 검출을 나타내었다. 이러한 접합체는 리신아미드 결합을 통해 아세틸화된 NP41의 C-말단 리신에 커플링된, 형광 염료인 카르복시플루오레세인(FAM)을 포함하는 FAM-NP41(Ac-SHSNTQTLAKAPEHTGK; 서열번호 749)뿐만 아니라 GCC 링커를 갖는 아세틸화된 HNP401의 C-말단 시스테인에 접합된 FAM을 포함하는 FAM-HNP401(Ac-SGQVPWEEPYYVVKKSSGGC-CONH2; 서열번호 748)을 포함하였다. 문헌('054 출원; Hingorani et al. 2018, Theranostics 8, 4226-4237; Whitney et al. 2011, Nat. Biotechnol. 29, 352-356)을 참조한다.
추가 연구는 FAM-NP41, FAM-HNP401 및 서열번호 20, 22-24 및 25-28에 상응하는, HNP401의 N-말단 및 C-말단 결실 변이체를 포함하는 기타 접합체의 국소 투여 후 인간(및 설치류) 절제된 신경 조직의 형광 표지를 보여주었다. 문헌(Whitney et al. 2011, Nat. Biotechnol . 29, 352-356; Wu et al. 2011, Laryngoscope 121, 805-810; Hussain et al. 2015, PloS One 10, e0119600; Hingorani et al. 2018, Theranostics 8, 4226-4237)을 참조한다.
그러나, 이러한 조사는 특히 투여 후 후기 단계에서 활성, 대사 및 클리어런스와 같은 접합체 특성을 나타내지 않았다. 예를 들어, 설치류 모델에서, NP41의 혈청 반감기(혈청 형광으로 측정됨)는 약 10분으로, 이는 혈액으로부터 접합체의 신속한 클리어런스를 나타낸다. 혈액에서 유사한 짧은 반감기(15분)가 FAM-HNP401에 대해 관찰되었다. 대조적으로, NP41의 신경 형광은 약 50분의 반감기를 갖고, 조직에서 몇 시간 동안 낮은 수준으로 지속될 수 있다. 유사하게, FAM-HNP401의 형광은 정맥내 투여 후 몇 시간 후에 래트의 좌골 신경 및 전립선 신경에서 관찰되었다. 예를 들어, 문헌(Whitney et al. 2011, Nat. Biotechnol . 29, 352-356; Hingorani et al. 2018, Theranostics 8, 4226-4237)을 참조한다.
신경(또는 기타 조직)에 결합된 접합체의 클리어런스 및 후속 활성에 관한 세부 사항은 명확하지 않으며, 이러한 특성이 형광 유도 수술에서 접합체의 다른 용도를 뒷받침할 수 있는지 여부는 공지되지 않았다. 여기에 기재된 연구는 신경 표적화 접합체가 신장 배설과 함께 요관의 민감하고 연장된 형광 가시화(조명)를 부여할 수 있음을 나타낸다. 결과는 수술 부속물로서 이러한 접합체에 대한 확장된 레퍼토리를 뒷받침한다. 신경을 강조함으로써, 그들은 두경부 수술 절차와 같은 수술에서 유도제로서 유용하며, 여기서 신경 손상을 예방하는 데 도움이 될 수 있다. 그리고, 여기에 기재된 바와 같이, 요관을 강조함으로써, 그들은 요관 손상의 위험을 나타내는 많은 복부 및 골반 수술 절차와 같은 다른 수술에 유용하다.
결과
설치류 모델을 사용하여 정맥내 투여 후 5-FAM-QVPWEEPYYVVKKSSGG-NH2(GG 링커를 갖는 HNP401-N-2, 서열번호 747)의 형광 가시화의 동역학을 평가했다. 접합체는 다양한 양으로 투여되었고, 형광은 맞춤형 현미경을 사용하여 검출되었다. 예를 들어, 도 1에 도시된 바와 같이, 요관은 마우스 모델에서 약 2000나노몰(약 200 mg/kg)의 정맥내 투여 후 2시간 후 쉽게 조명된다. 약 10mg/kg 내지 약 200mg/kg의 투여량에 상응하는 100나노몰 내지 2000나노몰의 양의 범위를 탐색하는 추가 조사는 또한 마우스 모델에서 형광 접합체, 서열번호 747의 정맥내 투여 후 요관 조명을 나타내었다. 유사한 결과가 래트 모델에서 관찰되었다. 그러나, 이러한 형광 가시화는 요관의 특정 또는 직접적인 표지를 반영하지 않는다. 오히려, 그것은 신장으로부터 방광으로 요관을 따라 유동하는 소변의 형광을 반영한다. 또한, 실시간 수술 중 이미징은 소변을 농축시키고 요관의 형광 가시화를 향상시킬 수 있는 요관 맥동을 나타낸다. 추가 연구는 이 접합체의 투여 후 요관 조명의 연장된 시간 경과를 나타내었다. 예를 들어, 요관의 형광 가시화는 접합체 투여 후 1시간 미만 및 최대 적어도 6시간 이내에 관찰되었다.
설치류 모델에서 다른 조사는 추가의 펩티드 및 형광 모이어티를 포함하는 다른 접합체의 투여 후 연장된 요관 조명을 입증하였다. 이들은 FAM에 접합된 관련 HNP401 펩티드로 이루어진 분자와 다른 형광 모이어티에 접합된 관련 HNP401 펩티드로 이루어진 분자를 포함한다. 또한, 여기에 제시된 연구는 요관과 함께 신경의 동시 가시화를 허용한다.
토론:
이러한 관찰은 요관 조명에서 본원에 기재된 신경 표적화 형광 접합체의 일반적인 적용 가능성을 뒷받침한다. 따라서, 본원에 개시된 접합체는 외과의가 물리적으로 요관과 마주치고 따라서 잠재적으로 손상시키기 전에 수술 절차 중에 요관의 가시화에서 보조하기 위해 사용될 수 있다. 또한, 수술 절차 중 부주의한 손상, 즉 의원성 손상의 경우, 이러한 가시화는 손상의 보다 신속한 인식 및 조기 치료 및 개입을 허용한다.
또한, 본원에 기재된 형광 접합체의 투여는 투여 후 요관 가시화의 연장된 기간을 제공할 수 있음이 관찰되었다. 특정 메커니즘에 의해 제한되지 않고, 이 연장된 가시화 기간은 뉴런 또는 신경, 예를 들어, 말초 신경계 또는 다른 조직에서 형광 접합체의 점진적인 축적에 이어, 비뇨기계에 의한 점진적인 방출, 대사 및 배설을 반영하는 것으로 여겨진다. 따라서, 형광 염료 단독의 전신 투여 또는 형광 염료의 직접 주사와 대조적으로, 펩티드-형광 접합체를 투여하면 유리하게 요관 조명의 기간을 연장할 수 있으며, 수술을 방해하지 않는 편리한 투여에 의해 조기 및 장기 조명을 모두 제공할 수 있다. 또한, 이러한 접합체의 투여는 신경 또는 요관의 수반되는 또는 시간적으로 구별되는 검출을 제공할 수 있다.
이러한 형광 매개 보조는 요관 손상, 특히 수술 절차 중 의원성 요관 손상(IUI)의 유의한 위험을 제공하는 수술 절차 중에 특히 중요하다. 요관은 복부에서 골반으로 확장되기 때문에, 이 위험은 광범위한 수술 절차에 적용될 수 있다. 요관 조명의 혜택을 받을 수 있는 적용 가능한 절차는 부인과, 비뇨기과 및 결장직장 수술 절차와 같은 복잡한 복부 및 골반 수술뿐만 아니라 심혈관 수술 절차를 포함한다. 그들은 또한 요관 근처의 장기 및 시스템, 예를 들어, 신장, 방광, 전립선, 자궁, 남성 또는 여성 생식 기관, 직장, 결장, 소장 또는 대장에 대해 수행되는 수술 절차를 포함한다. 그들은 또한 암 수술 절차, 예를 들어, 전립선암 수술 절차 또는 결장직장암 절차, 또는 요관 및 신경의 향상된 가시화가 바람직한 절차도 포함할 수 있다.
실시예
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수술 환자의 소변에서 형광 접합체의 생물 분석
소변 샘플은 500mg의 부모 시험 약물(형광 접합 펩티드에 상응, 서열번호 747)의 정맥내 투여 30분 전, 두경부 수술 전 주입 30분 후, 및 22시간 후에 수집하였다. 온전한 부모 시험 약물의 농도는 적격한 생물 분석 방법을 사용하여 탠덤 질량 분석법(LC-MS/MS)을 사용한 액체 크로마토그래피로 결정되었다. 또한, 형광 모이어티에 접합된 부모 펩티드의 단축 버전에 상응하는 대사산물 M3-M8(시험관내 연구에서 처음 식별됨)의 존재도 평가했다. 결과는 표 5에 제시되어 있다.
[표 5]
30분 시점에, 정량화 가능한 수준의 시험 약물(또는 형광 대사산물 M4, M6 및 M7)이 평가된 5명의 대상체 중 4명에서 검출되었다. 22시간 시점에, 형광 대사산물 M4와 M6이 평가된 두 대상체에서 검출되었다. 예상된 바와 같이, 시험 약물 및 형광 대사산물은 임의의 투여 전 샘플에서 검출되지 않았다.
이러한 데이터는 설치류 모델에서의 투여 및 요관 이미징 실험과 일치하며, 시험 약물의 단일 투여가 소변에서 형광 분자의 즉시(예: 30분) 및 연장된 축적(예: 22시간)을 유발할 수 있음을 나타낸다. 또한, 이는 수술 절차의 초기 및 후기 단계에서 연장된 요관 가시화를 부여할 수 있을뿐만 아니라 수술 절차 또는 기타 적용에서 신경 및 요관의 동시 또는 별개의 가시화를 뒷받침할 수 있다.
실시예
3
수술 중 요관 및 신경 조명
본 개시내용의 형광 접합체의 요관(및 신경)을 영상화하는 능력은 위장/비뇨생식기(GI/GU) 수술을 받고 있는 환자에 대해 아래에 기재된 것과 같이 적절하게 설계된 임상 연구를 사용하여 평가될 수 있다.
이 예언적 예에서, 임상 시험은 GI/GU 수술을 받고 있는 80명의 대상체에서 시험 약물(형광 접합된 펩티드에 상응, 서열번호 747)의 투여를 평가하는 개방 표지, 다기관 연구를 포함한다. 연구에 등록하기 위한 포함 기준은 대상체가 신경(및 요관)이 잠재적으로 손상 위험이 있는 GI/GU 영역에서의 수술 절차를 받고 있다는 요건을 포함한다. 예를 들어, 이러한 절차는 결장직장 또는 전립선 수술을 포함할 수 있다.
등록된 대상체는 수술 2 내지 5시간 전에 정맥내 주입에 의해 단일 투여량의 시험 약물(500mg)을 투여받는다. 시험 약물의 형광은 복강경을 통한 실시간 백색광 반사율(WLR) 및 형광(FL) 이미징으로 평가된다.
다중 종점을 사용하여 1차 및 2차 효능 목표를 평가한다.
신경 검출과 관련하여, 종점은 WLR 단독 대 쌍(FL 오버레이를 갖는 WLR)을 사용하여 신경의 콘트라스트 향상, 분지 묘사 및 길이를 개선하는 데 있어 시험 약물의 효능을 측정하는 가시화 점수 시스템을 포함한다. 그들은 또한 WLR 대 FL을 사용하여 신경 가시화를 개선하는 데 있어 시험 약물의 효능을 측정하기 위한 신경(및 인접한 비신경) 조직의 여러 영역에 대한 신호 대 배경 비율의 계산을 포함한다.
요관 검출과 관련하여, 종점은 WLR 단독 대 FL 오버레이를 갖는 WLR을 사용하여 요관의 콘스트라스 증강을 개선하는 데 있어 시험 약물의 효능을 측정하기 위한 가시화 점수 시스템을 포함한다. 그들은 또한 WLR 대 FL을 사용하여 요관 가시화를 개선하는 데 있어 시험 약물의 효능을 측정하기 위한 요관(및 인접한 비요관) 조직의 여러 영역에 대한 신호 대 배경 비율의 계산을 포함한다.
시험 약물을 사용한 신경 및 요관 검출 효능의 유의한 개선이 여러 종점으로 제시된다. 개선은 수술 절차의 초기 및 후기 시점에 관찰된다. 따라서, 본 개시내용의 형광 접합체는 신경, 요관 또는 둘 다의 향상된 가시화를 포함하여 형광 유도 GI/GU 수술 절차에 유용할 수 있다. 이러한 향상된 가시화의 이점은 수술 절차에서 요관 및 신경을 식별하는 데 있어 외과의 신뢰도의 유의한 개선뿐만 아니라 이러한 수술 절차의 기간의 유의한 감소를 포함할 수 있다.
상기 제시된 실시예는 당업자에게 본 개시내용의 조성물 및 방법의 구현예를 제조하고 사용하는 방법에 대한 완전한 개시내용 및 설명을 제공하기 위해 제공된 것이며, 발명자들이 그들의 개시내용으로 간주하는 범위를 제한하려는 의도는 아니다. 당업자에게 명백한 본 개시내용을 수행하기 위한 상기 기재된 방식의 변형은 다음 청구범위의 범위 내에 있는 것으로 의도된다. 본 명세서에 언급된 모든 특허 및 공보는 본 개시내용이 관련된 당업자의 기술 수준을 나타낸다. 본 개시내용에 인용된 모든 참고문헌은 각 참고문헌이 그 전체가 개별적으로 참조로 포함된 것과 동일한 정도로 참조로 포함된다.
본 출원의 많은 변형 및 변동이 당업자에게 명백한 바와 같이 이의 정신 및 범위로부터 벗어나지 않고 이루어질 수 있다. 본원에 기재된 특정 구현예 및 실시예는 단지 예로서 제공되며, 본 출원은 청구범위가 자격이 부여되는 등가물의 전체 범위와 함께 첨부된 청구범위의 조건에 의해서만 제한되어야 한다.
또한, 본 개시내용의 특정 세부 사항은 첨부된 청구범위에 의해 정의된 본 발명의 완전한 이해를 전달하기 위해 제공되지만, 특정 구현예는 이러한 세부 사항 없이 실시될 수 있음이 당업자에게 명백할 것이다. 또한, 특정 예에서, 익히 공지된 방법, 절차 또는 다른 특정 세부 사항은 첨부된 청구범위에 의해 정의된 본 발명의 측면을 불필요하게 모호하게 하는 것을 피하기 위해 기재되지 않았다.
본 출원은 2021년 1월 14일에 출원된 미국 가출원 제63/137,621호에 대한 우선권의 이익을 주장하며, 이 출원은 그 전체가 본원에 참조로 포함된다.
SEQUENCE LISTING
<110> Alume Biosciences, Inc.
<120> METHODS AND COMPOSITIONS FOR VISUALIZING A URETER IN A SURGICAL
PROCEDURE
<130> 110267.405WO
<150> US 63/137621
<151> 2021-01-14
<160> 749
<170> PatentIn version 3.5
<210> 1
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> HNP401
<400> 1
Ser Gly Gln Val Pro Trp Glu Glu Pro Tyr Tyr Val Val Lys Lys Ser
1 5 10 15
Ser
<210> 2
<211> 16
<212> PRT
<213> Artificial Sequence
<220>
<223> HNP402
<400> 2
Trp Glu Tyr His Tyr Val Asp Leu Asn Trp Thr Ser Gln His Pro Gln
1 5 10 15
<210> 3
<211> 14
<212> PRT
<213> Artificial Sequence
<220>
<223> HNP403
<400> 3
Asp Leu Pro Asp Ile Ile Trp Asp Phe Asn Trp Glu Thr Ala
1 5 10
<210> 4
<211> 20
<212> PRT
<213> Artificial Sequence
<220>
<223> HNP401 with GGC linker
<220>
<221> MOD_RES
<222> (1)..(1)
<223> Ac
<400> 4
Ser Gly Gln Val Pro Trp Glu Glu Pro Tyr Tyr Val Val Lys Lys Ser
1 5 10 15
Ser Gly Gly Cys
20
<210> 5
<211> 19
<212> PRT
<213> Artificial Sequence
<220>
<223> HNP402 with GGC linker
<220>
<221> MOD_RES
<222> (1)..(1)
<223> Ac
<400> 5
Trp Glu Tyr His Tyr Val Asp Leu Asn Trp Thr Ser Gln His Pro Gln
1 5 10 15
Gly Gly Cys
<210> 6
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> HNP403 with GGC linker
<220>
<221> MOD_RES
<222> (1)..(1)
<223> Ac
<400> 6
Asp Leu Pro Asp Ile Ile Trp Asp Phe Asn Trp Glu Thr Ala Gly Gly
1 5 10 15
Cys
<210> 7
<211> 18
<212> PRT
<213> Artificial Sequence
<220>
<223> HNP401-N-2 with GGC linker
<220>
<221> MOD_RES
<222> (1)..(1)
<223> Ac
<400> 7
Gln Val Pro Trp Glu Glu Pro Tyr Tyr Val Val Lys Lys Ser Ser Gly
1 5 10 15
Gly Cys
<210> 8
<211> 16
<212> PRT
<213> Artificial Sequence
<220>
<223> HNP401-N-4 with GGC linker
<220>
<221> MOD_RES
<222> (1)..(1)
<223> Ac
<400> 8
Pro Trp Glu Glu Pro Tyr Tyr Val Val Lys Lys Ser Ser Gly Gly Cys
1 5 10 15
<210> 9
<211> 14
<212> PRT
<213> Artificial Sequence
<220>
<223> HNP401-N-6 with GGC linker
<220>
<221> MOD_RES
<222> (1)..(1)
<223> Ac
<400> 9
Glu Glu Pro Tyr Tyr Val Val Lys Lys Ser Ser Gly Gly Cys
1 5 10
<210> 10
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> HNP401-N-8 with GGC linker
<220>
<221> MOD_RES
<222> (1)..(1)
<223> Ac
<400> 10
Pro Tyr Tyr Val Val Lys Lys Ser Ser Gly Gly Cys
1 5 10
<210> 11
<211> 18
<212> PRT
<213> Artificial Sequence
<220>
<223> HNP401-C-2 with GGC linker
<220>
<221> MOD_RES
<222> (1)..(1)
<223> Ac
<400> 11
Ser Gly Gln Val Pro Trp Glu Glu Pro Tyr Tyr Val Val Lys Lys Gly
1 5 10 15
Gly Cys
<210> 12
<211> 16
<212> PRT
<213> Artificial Sequence
<220>
<223> HNP401-C-4 with GGC linker
<220>
<221> MOD_RES
<222> (1)..(1)
<223> Ac
<400> 12
Ser Gly Gln Val Pro Trp Glu Glu Pro Tyr Tyr Val Val Gly Gly Cys
1 5 10 15
<210> 13
<211> 14
<212> PRT
<213> Artificial Sequence
<220>
<223> HNP401-C-6 with GGC linker
<220>
<221> MOD_RES
<222> (1)..(1)
<223> Ac
<400> 13
Ser Gly Gln Val Pro Trp Glu Glu Pro Tyr Tyr Gly Gly Cys
1 5 10
<210> 14
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> HNP401-C-8 with GGC linker
<220>
<221> MOD_RES
<222> (1)..(1)
<223> Ac
<400> 14
Ser Gly Gln Val Pro Trp Glu Glu Pro Gly Gly Cys
1 5 10
<210> 15
<211> 4
<212> PRT
<213> Artificial Sequence
<220>
<223> linker
<400> 15
Gly Gly Gly Cys
1
<210> 16
<211> 16
<212> PRT
<213> Artificial Sequence
<220>
<223> HNP404
<400> 16
Asp Thr His Ala His Ala Lys Pro Arg Val Pro Ala Phe Lys Ser Val
1 5 10 15
<210> 17
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> NP41
<220>
<221> MOD_RES
<222> (1)..(1)
<223> Ac
<400> 17
Ser His Ser Asn Thr Gln Thr Leu Ala Lys Ala Pro Glu His Thr Gly
1 5 10 15
Cys
<210> 18
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Nidogen-2
<400> 18
Lys Ala Ile His Pro Met Arg Gly
1 5
<210> 19
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Nidogen-2
<400> 19
Gly Tyr Trp Arg Asn Ala Leu
1 5
<210> 20
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> HNP401-N-2
<400> 20
Gln Val Pro Trp Glu Glu Pro Tyr Tyr Val Val Lys Lys Ser Ser
1 5 10 15
<210> 21
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> HNP401-N-2 with GG linker
<400> 21
Gln Val Pro Trp Glu Glu Pro Tyr Tyr Val Val Lys Lys Ser Ser Gly
1 5 10 15
Gly
<210> 22
<211> 13
<212> PRT
<213> Artificial Sequence
<220>
<223> HNP401-N-4
<400> 22
Pro Trp Glu Glu Pro Tyr Tyr Val Val Lys Lys Ser Ser
1 5 10
<210> 23
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> HNP401-N-6
<400> 23
Glu Glu Pro Tyr Tyr Val Val Lys Lys Ser Ser
1 5 10
<210> 24
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> HNP401-N-8
<400> 24
Pro Tyr Tyr Val Val Lys Lys Ser Ser
1 5
<210> 25
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> HNP401-C-2
<400> 25
Ser Gly Gln Val Pro Trp Glu Glu Pro Tyr Tyr Val Val Lys Lys
1 5 10 15
<210> 26
<211> 13
<212> PRT
<213> Artificial Sequence
<220>
<223> HNP401-C-4
<400> 26
Ser Gly Gln Val Pro Trp Glu Glu Pro Tyr Tyr Val Val
1 5 10
<210> 27
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> HNP401-C-6
<400> 27
Ser Gly Gln Val Pro Trp Glu Glu Pro Tyr Tyr
1 5 10
<210> 28
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> HNP401-C-8
<400> 28
Ser Gly Gln Val Pro Trp Glu Glu Pro
1 5
<210> 29
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Nidogen-2
<400> 29
Ala Cys Thr Val His Lys Trp Asp Asn Cys
1 5 10
<210> 30
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Nidogen-2
<400> 30
Ala Cys Glu Pro Arg Ser Leu Ala Asn Cys
1 5 10
<210> 31
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Nidogen-2
<400> 31
Ala Cys Pro Glu Asn Lys Ser Lys His Cys
1 5 10
<210> 32
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Nidogen-2
<400> 32
Ala Cys Gly Glu Gly Glu Ala Asp Val Cys
1 5 10
<210> 33
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 33
Glu Lys Pro Ser Trp Thr Arg
1 5
<210> 34
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 34
Asp Thr Ser Arg Thr Met Glu
1 5
<210> 35
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 35
Ser Met Trp Ser Gln Phe Arg
1 5
<210> 36
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 36
Asn Pro Asn Trp Arg Thr Ile
1 5
<210> 37
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 37
Phe Lys Met Pro Ile Pro Thr
1 5
<210> 38
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 38
Tyr Pro Lys Leu Trp Thr Tyr
1 5
<210> 39
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 39
Asn Pro Ser His His Pro Arg
1 5
<210> 40
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> core binding domain
<400> 40
Pro Tyr Tyr Val Val Lys Lys
1 5
<210> 41
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> N-terminal sequence
<400> 41
Gln Val Pro Trp Glu Glu
1 5
<210> 42
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 42
Leu Thr His His Phe Ala Pro
1 5
<210> 43
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 43
Arg His Asn Val Glu Phe Ser
1 5
<210> 44
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 44
Phe Pro Val Val Thr Arg Asn
1 5
<210> 45
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 45
Leu Arg Phe Gln Ile Pro Pro
1 5
<210> 46
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 46
Leu Ala Leu Tyr Ala Arg Met
1 5
<210> 47
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 47
Gly Pro Phe Leu Phe Thr Val
1 5
<210> 48
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 48
Tyr Thr Pro Met Gly Thr Gly
1 5
<210> 49
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 49
Arg Phe Glu Leu Pro Ala Pro
1 5
<210> 50
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 50
His Gln Gly Ser Arg Thr Tyr
1 5
<210> 51
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 51
Thr Asn Pro Trp Lys Pro His
1 5
<210> 52
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 52
Met Thr Pro His Thr Ser Cys
1 5
<210> 53
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 53
Gly Leu Ile Arg His Tyr Thr
1 5
<210> 54
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 54
Ala Thr Leu Lys Pro Tyr Arg
1 5
<210> 55
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 55
His Arg Leu Pro Trp His His
1 5
<210> 56
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 56
Asp Gly Lys Asn Thr Ser Asn
1 5
<210> 57
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 57
Ala Gly Phe Pro Pro Asn Thr
1 5
<210> 58
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 58
Gln Asn Thr Gly Leu Lys Trp
1 5
<210> 59
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 59
Gln Ile Gly Val Leu Pro Ser
1 5
<210> 60
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 60
Asp Pro Trp Val Met Leu Arg
1 5
<210> 61
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 61
Ser Pro Asp Arg Thr Ser Leu
1 5
<210> 62
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 62
Met Gln Thr Gln Gly Arg Val
1 5
<210> 63
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 63
Leu Arg Pro Ile Ser His Glu
1 5
<210> 64
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 64
Ala Trp Ser Thr Ser Ser Val
1 5
<210> 65
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 65
Ala Gly Gln Leu Met Arg Cys Ala Asn Cys
1 5 10
<210> 66
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 66
Trp Thr Met Lys Pro Asn Tyr
1 5
<210> 67
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 67
Ile Leu Leu Pro Ser Leu Asn
1 5
<210> 68
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 68
Ser Lys Ser Asp Ala Trp Arg
1 5
<210> 69
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 69
Ala Ile Thr Ser Arg Asn Ala
1 5
<210> 70
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 70
Ser Val Leu Arg Met Leu Asn
1 5
<210> 71
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 71
Leu Pro Met Arg Ile Leu Thr
1 5
<210> 72
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 72
Glu His Gly Tyr Tyr Lys Val
1 5
<210> 73
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 73
His Pro Ser Thr Trp His Lys
1 5
<210> 74
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 74
Asn Asp Thr Lys Thr Pro Ser
1 5
<210> 75
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 75
Gly Asp Glu Arg Ile Val Arg Thr Leu Ser His Asn
1 5 10
<210> 76
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 76
Gly Leu Thr Pro Lys Leu Phe
1 5
<210> 77
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 77
Arg Val Pro His Ser Arg Thr
1 5
<210> 78
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 78
Thr Glu Ser Leu Phe Pro His
1 5
<210> 79
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 79
Gly Pro Leu Arg Met Ala Thr
1 5
<210> 80
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 80
Asp Arg Asn Ser Val Phe Trp
1 5
<210> 81
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 81
Ser Ala His Ala Lys His His
1 5
<210> 82
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 82
Lys Met Ala Gly His Thr Val
1 5
<210> 83
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> core binding domain
<400> 83
Pro Tyr Tyr Val Val
1 5
<210> 84
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 84
Thr Met Ala Ser Pro Ala Lys
1 5
<210> 85
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 85
Val Leu Thr Lys Pro Met Pro
1 5
<210> 86
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 86
Leu Ser Ser Pro Leu Ser Leu
1 5
<210> 87
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 87
Trp Pro Ser Ile Ser Arg Pro
1 5
<210> 88
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 88
Ser His Ser Pro Gly Asn Lys
1 5
<210> 89
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 89
Glu Thr Thr Arg Asn Tyr Gly
1 5
<210> 90
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 90
Ile Lys Pro Pro Tyr Thr His
1 5
<210> 91
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 91
Val Leu Lys Asn Asn Pro Thr
1 5
<210> 92
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 92
Asp Pro Ile Thr Arg Leu Lys
1 5
<210> 93
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 93
Ser His Leu Ala Ser Arg Pro
1 5
<210> 94
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 94
Thr Ser Pro Trp Glu Leu Arg
1 5
<210> 95
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 95
Ala Leu Pro Leu Ser Ala Ser
1 5
<210> 96
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> HNP401-C-8 (with GG linker)
<400> 96
Ser Gly Gln Val Pro Trp Glu Glu Pro Gly Gly
1 5 10
<210> 97
<211> 13
<212> PRT
<213> Artificial Sequence
<220>
<223> HNP401-C-6 (with GG linker)
<400> 97
Ser Gly Gln Val Pro Trp Glu Glu Pro Tyr Tyr Gly Gly
1 5 10
<210> 98
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> HNP401-C-4 (with GG linker)
<400> 98
Ser Gly Gln Val Pro Trp Glu Glu Pro Tyr Tyr Val Val Gly Gly
1 5 10 15
<210> 99
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> HNP401-C-2 (with GG linker)
<400> 99
Ser Gly Gln Val Pro Trp Glu Glu Pro Tyr Tyr Val Val Lys Lys Gly
1 5 10 15
Gly
<210> 100
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> HNP401-N-8 (with GG linker)
<400> 100
Pro Tyr Tyr Val Val Lys Lys Ser Ser Gly Gly
1 5 10
<210> 101
<211> 13
<212> PRT
<213> Artificial Sequence
<220>
<223> HNP401-N-6 (with GG linker)
<400> 101
Glu Glu Pro Tyr Tyr Val Val Lys Lys Ser Ser Gly Gly
1 5 10
<210> 102
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> HNP401-N-4 (with GG linker)
<400> 102
Pro Trp Glu Glu Pro Tyr Tyr Val Val Lys Lys Ser Ser Gly Gly
1 5 10 15
<210> 103
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 103
Cys Leu Lys Gln Gln Thr Gly Asp Cys
1 5
<210> 104
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 104
Glu Gly His Val Trp Ser Glu Tyr Thr Trp Gly Thr
1 5 10
<210> 105
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 105
Phe Met Ser Asp Val Asp His
1 5
<210> 106
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 106
Ile Ser Ser Val Thr Val Val
1 5
<210> 107
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 107
Lys Gln Pro Ala Met Phe Asn
1 5
<210> 108
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 108
Leu Ile Ser Pro Thr Ala Arg
1 5
<210> 109
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 109
Leu Val Leu Gln Thr Thr Pro
1 5
<210> 110
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 110
Asn Pro Thr Ser Glu Gly Ala
1 5
<210> 111
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 111
Thr His Ser Thr Asp Leu Ser
1 5
<210> 112
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 112
Thr Thr Asn Val Thr Glu Ile Glu Arg Glu Ser Tyr
1 5 10
<210> 113
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 113
Tyr Ala Pro Trp Arg Val Phe
1 5
<210> 114
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 114
Tyr Gly Gln Ser Ile Thr Glu
1 5
<210> 115
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 115
Cys Asp Ile Lys Asp Ala Asn Ser Cys
1 5
<210> 116
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 116
Cys Ile Lys Gly Glu Asp Asn Gln Cys
1 5
<210> 117
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 117
His Asn Gln Leu Leu Tyr Thr
1 5
<210> 118
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 118
Ile Glu Gln Val Gly Trp Arg
1 5
<210> 119
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 119
Lys Thr Pro Ile Leu Ala Ser
1 5
<210> 120
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 120
Leu Trp Ala Lys Arg Asp Ala
1 5
<210> 121
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 121
Asn Pro Ile Ser Pro Arg Asn
1 5
<210> 122
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 122
Asn Thr Ala Ser Met Thr Thr
1 5
<210> 123
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 123
Ser Ala His Ser Val Val Glu
1 5
<210> 124
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 124
Tyr Ser Ser Leu Thr Ser Asn
1 5
<210> 125
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 125
Ala Trp Thr Met Arg Ala Ser
1 5
<210> 126
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 126
Cys Glu Arg Ile Gly Pro Arg Glu Cys
1 5
<210> 127
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 127
Cys Gln Lys Trp Phe Thr Phe Ala Cys
1 5
<210> 128
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 128
Cys Ser Asn Ala Leu Asn Lys Ala Cys
1 5
<210> 129
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 129
Phe Ser Pro Arg Asp Val Ser
1 5
<210> 130
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 130
Phe Ser Thr Thr Gly Arg Gly
1 5
<210> 131
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 131
His His Pro Leu Phe Ile Asp
1 5
<210> 132
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 132
Leu Val Asn Pro Phe Pro Glu
1 5
<210> 133
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 133
Tyr Glu Gly Glu Arg Gly Ala
1 5
<210> 134
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 134
Cys Glu Asp Arg Gln Arg Ser Met Cys
1 5
<210> 135
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 135
Cys Gly Glu Lys Ile Met Ser Leu Cys
1 5
<210> 136
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 136
Asp Arg Tyr Leu Leu Asn Gln
1 5
<210> 137
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 137
Phe Pro Ser Tyr Thr Ile Ser
1 5
<210> 138
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 138
Gly Gly Ser Lys Val Trp Gly
1 5
<210> 139
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 139
Gly Leu Trp Arg His Thr Met
1 5
<210> 140
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 140
Lys Arg Asn Leu Trp Asp Ile
1 5
<210> 141
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 141
Ser Pro Asn Thr Asn Ser His
1 5
<210> 142
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 142
Thr Leu Leu His Tyr Ser Ala
1 5
<210> 143
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 143
Val Pro Leu Ala Tyr Leu Arg
1 5
<210> 144
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 144
Val Val Pro Leu Lys Trp Ile
1 5
<210> 145
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 145
Cys Arg Val Gly Val Thr Ser Ala Cys
1 5
<210> 146
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 146
Phe Ala Leu Pro Ala Gly Leu
1 5
<210> 147
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 147
Phe Arg Val Thr Gln Thr Ala
1 5
<210> 148
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 148
His Pro Leu Met Val Pro Ser
1 5
<210> 149
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 149
Leu Pro Asn Ala Asn Asn Leu
1 5
<210> 150
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 150
Met Ile His Thr Arg Gln Thr
1 5
<210> 151
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 151
Ser Glu Thr Glu Ser Tyr Met
1 5
<210> 152
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 152
Ser Asn Ala Leu Ser Tyr Phe
1 5
<210> 153
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 153
Ser Tyr Leu Pro Pro Phe Ile
1 5
<210> 154
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 154
Val His Thr Pro Tyr Arg Ser
1 5
<210> 155
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 155
Trp Pro Arg Pro Ile Gln Ile
1 5
<210> 156
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 156
Trp Thr Ser Val Ala Thr Ala
1 5
<210> 157
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 157
Ala Leu Pro Ile Ser Tyr Leu
1 5
<210> 158
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 158
Phe Glu His Met Ala Val Thr
1 5
<210> 159
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 159
Asn Ala Ser Val Pro Pro Lys
1 5
<210> 160
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 160
Ser Gly His Gly Ala Phe Arg
1 5
<210> 161
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 161
Thr Thr Leu Val Val Thr Ala
1 5
<210> 162
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 162
Cys Pro Asp Ala Ala Arg Asn Ser Cys
1 5
<210> 163
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 163
Cys Tyr Ser Ser Val Ala Asp Met Cys
1 5
<210> 164
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 164
Leu Ser Pro Pro Arg Ile Met
1 5
<210> 165
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 165
Trp Met Thr Asn Leu Asp Pro
1 5
<210> 166
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 166
Lys Leu Pro Thr Leu Ser Val
1 5
<210> 167
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 167
Ala Met Ser Asn Leu Ser Tyr
1 5
<210> 168
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 168
His Pro Phe Pro Arg Phe Asp
1 5
<210> 169
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 169
Leu Pro Ala Glu Ser His Trp
1 5
<210> 170
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 170
Ser Thr His Glu Trp Arg Thr
1 5
<210> 171
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 171
Thr Thr Trp Pro Asn Thr Ala
1 5
<210> 172
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 172
Tyr Met Lys His Ser Pro Gly
1 5
<210> 173
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 173
Ala Tyr Leu Glu Asp Trp Arg Ser Met Ser Thr Arg
1 5 10
<210> 174
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 174
Gly Pro Val Val Ser Gly Met
1 5
<210> 175
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 175
His Leu Asp Ser Arg Arg His
1 5
<210> 176
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 176
Leu Val Leu Ser Asn Pro Arg
1 5
<210> 177
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 177
Asn Met Ser His Ser Asn Arg
1 5
<210> 178
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 178
Ser Val Ala Tyr Val Pro Val
1 5
<210> 179
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 179
Tyr Pro Gln Ala Arg Thr Ser
1 5
<210> 180
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 180
Met Tyr His Asp Ser Val Ser
1 5
<210> 181
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 181
Ala Asp Asn Val Leu Arg Arg Ala Leu Glu Asn Ile
1 5 10
<210> 182
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 182
Gln Ile Ala His Leu Glu Tyr
1 5
<210> 183
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 183
Gly Met Val Ser Pro His His Ser Val Tyr Arg His
1 5 10
<210> 184
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 184
Gly Ser Trp Ser Ser Gly Phe
1 5
<210> 185
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 185
Asn Gly Ala Tyr Ser Leu Ala Ile Arg Tyr Thr Ser
1 5 10
<210> 186
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 186
Tyr Thr Pro Asn Trp His Phe Arg Trp Met Pro Ala
1 5 10
<210> 187
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Human MPZ
<400> 187
Gly Glu Trp Arg Ala Arg Ile Asp Gln Asp Val Ser
1 5 10
<210> 188
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 188
Ala Gly Ser Leu Leu Ser Leu
1 5
<210> 189
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 189
Ala Ile Pro Pro Arg Lys Leu
1 5
<210> 190
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 190
Ala Ile Ser Trp Lys Gly Phe
1 5
<210> 191
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 191
Ala Lys Phe Thr Met Trp Val
1 5
<210> 192
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 192
Ala Leu Arg Asp Thr Arg Val
1 5
<210> 193
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 193
Ala Leu Tyr Asn Gln Met Thr
1 5
<210> 194
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 194
Ala Gln Phe Leu Thr Ile Tyr
1 5
<210> 195
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 195
Ala Gln Leu Gly Ala Phe Arg
1 5
<210> 196
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 196
Ala Arg Val Pro Asn Pro Leu
1 5
<210> 197
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 197
Cys Thr Met Thr Asn Gln Tyr Asp Cys
1 5
<210> 198
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 198
Asp Ser Gln Glu Lys Ser Val
1 5
<210> 199
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 199
Asp Val Arg Ile Trp Thr Leu
1 5
<210> 200
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 200
Glu Leu Lys Ser Leu Arg Phe
1 5
<210> 201
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 201
Glu Ser Lys Ser Pro Arg Glu
1 5
<210> 202
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 202
Glu Thr His Tyr Lys Ile Ala
1 5
<210> 203
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 203
Phe Asp Leu Leu Ala Arg Lys
1 5
<210> 204
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 204
Phe Gln Leu Ser Tyr Glu Thr
1 5
<210> 205
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 205
Gly Glu Pro Ala Leu Val Thr
1 5
<210> 206
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 206
Gly Pro Arg Val Thr Pro His
1 5
<210> 207
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 207
Gly Gln Trp Trp Lys Met Leu
1 5
<210> 208
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 208
Gly Arg His Thr Asp Val Val
1 5
<210> 209
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 209
Gly Ser Pro Tyr Gly Trp Gly
1 5
<210> 210
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 210
Gly Val Ala Glu Val Gly Leu
1 5
<210> 211
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 211
His Ala His Trp Ala Arg Leu
1 5
<210> 212
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 212
His Phe Thr Phe Phe Pro Ile
1 5
<210> 213
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 213
His Pro Trp Ser His Pro Asn
1 5
<210> 214
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 214
His Gln Met Arg Thr Met Leu
1 5
<210> 215
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 215
His Gln Pro Leu Phe Pro Arg
1 5
<210> 216
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 216
His Arg Thr His Leu His Gln
1 5
<210> 217
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 217
His Ser Gly Pro Leu Leu Pro
1 5
<210> 218
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 218
His Ser Ser Ala Thr Met Ser
1 5
<210> 219
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 219
Ile Gly Thr Arg Trp His Gln
1 5
<210> 220
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 220
Ile Asn Phe Pro Phe Ala Val
1 5
<210> 221
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 221
Ile Pro Ile Pro Tyr Arg Thr
1 5
<210> 222
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 222
Ile Pro Tyr Ser Gln Met Pro
1 5
<210> 223
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 223
Lys Ile Ile Thr Thr Lys Ser
1 5
<210> 224
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 224
Lys Met Ser Leu Ala Pro Pro
1 5
<210> 225
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 225
Lys Val His His Leu Ala Arg
1 5
<210> 226
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 226
Leu Glu Leu His Gln Asn Val
1 5
<210> 227
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 227
Leu Ile Thr His Pro Gln Leu
1 5
<210> 228
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 228
Leu Met Leu Pro Gln Leu Glu
1 5
<210> 229
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 229
Leu Val Pro Pro Val Asn His
1 5
<210> 230
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 230
Met Asn Ser Pro Leu Ala Gln
1 5
<210> 231
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 231
Met Gln Arg Leu Gly Ala Asp
1 5
<210> 232
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 232
Asn Gly Pro Asn Ser Leu Gln
1 5
<210> 233
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 233
Asn Gly Val Ser Ser Ser Leu
1 5
<210> 234
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 234
Asn Leu Thr Tyr Leu Arg Phe
1 5
<210> 235
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 235
Gln Gly Ala Tyr Val Arg Pro
1 5
<210> 236
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 236
Gln Lys Ala Leu Pro Gln Thr
1 5
<210> 237
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 237
Gln Thr Ser Ile Met Ser Gly
1 5
<210> 238
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 238
Gln Tyr Trp Asp Ile Leu Gly
1 5
<210> 239
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 239
Arg Gly His Pro Ser Gln Leu
1 5
<210> 240
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 240
Arg Ser Arg Lys His Arg Pro
1 5
<210> 241
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 241
Arg Thr Thr Asp Trp Trp Thr
1 5
<210> 242
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 242
Arg Val Ile Pro Ser Thr Thr
1 5
<210> 243
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 243
Ser Ala Val Leu Met Pro Pro
1 5
<210> 244
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 244
Ser Glu Gly Leu Thr Leu Leu
1 5
<210> 245
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 245
Ser Gly Pro Phe Pro Leu Val
1 5
<210> 246
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 246
Ser Ile Gln Thr Ser Ala Met
1 5
<210> 247
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 247
Ser Lys Leu Ala Gly Phe Pro
1 5
<210> 248
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 248
Ser Lys Pro His Ala Ser His
1 5
<210> 249
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 249
Ser Leu Asp His Leu Arg Leu
1 5
<210> 250
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 250
Ser Leu Lys Thr Thr Asn Pro
1 5
<210> 251
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 251
Ser Leu Trp Gln Thr Leu Arg
1 5
<210> 252
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 252
Ser Leu Trp Thr His Arg Thr
1 5
<210> 253
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 253
Ser Asn Ala His Thr Leu Pro
1 5
<210> 254
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 254
Ser Pro Lys Pro Asp Ile Pro
1 5
<210> 255
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 255
Ser Arg His Leu Pro Pro Leu
1 5
<210> 256
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 256
Ser Ser Phe Tyr Val Ala Tyr
1 5
<210> 257
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 257
Ser Ser Met Arg Tyr Asn Ser
1 5
<210> 258
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 258
Ser Val Gly Leu Pro Thr Lys
1 5
<210> 259
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 259
Ser Tyr Arg Ser Met Ala Pro
1 5
<210> 260
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 260
Ser Tyr Val Thr Val Phe Arg
1 5
<210> 261
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 261
Thr Gly Pro Ser Ser Ala Val
1 5
<210> 262
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 262
Thr Gly Ser Val Ser Lys Gln
1 5
<210> 263
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 263
Thr His Lys His Met Met Thr
1 5
<210> 264
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 264
Thr Ile Arg Val Ala His Thr
1 5
<210> 265
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 265
Thr Pro Gly Arg Ala Thr Leu
1 5
<210> 266
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 266
Thr Pro Val Leu Trp Leu Pro
1 5
<210> 267
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 267
Thr Pro Val Arg Leu Asn Thr
1 5
<210> 268
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 268
Thr Arg Ile Pro Ile Leu Leu
1 5
<210> 269
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 269
Thr Thr Thr Gln Gly His Pro
1 5
<210> 270
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 270
Val Gly Thr Phe Trp Thr Arg
1 5
<210> 271
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 271
Val Ile Arg Thr Ala Ala Met
1 5
<210> 272
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 272
Val Leu Ser Pro Tyr His Asn
1 5
<210> 273
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 273
Val Arg Gly Thr Pro Asn His
1 5
<210> 274
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 274
Trp Asp Leu Pro Gln Asn Arg
1 5
<210> 275
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 275
Trp Asp Leu Arg His Ser Lys
1 5
<210> 276
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 276
Trp Thr Tyr His Pro Thr Thr
1 5
<210> 277
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 277
Trp Val Pro Asp Arg Ser Leu
1 5
<210> 278
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 278
Tyr Pro Thr Tyr Leu Ser Tyr
1 5
<210> 279
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 279
Tyr Pro Tyr Val Pro Ile Tyr
1 5
<210> 280
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 280
Tyr Ser Ser Arg Leu Asn Asp
1 5
<210> 281
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 281
Tyr Thr Ala Ser Pro Arg Trp
1 5
<210> 282
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 282
Tyr Val Asn Arg Val Lys Gln
1 5
<210> 283
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 283
Ala Ala Gly Gln Arg Ser Phe
1 5
<210> 284
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 284
Ala Ile Leu Thr Arg Pro Pro
1 5
<210> 285
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 285
Ala Leu Gly Thr Arg Pro Leu
1 5
<210> 286
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 286
Ala Ser Asn Thr Ser Lys Gly
1 5
<210> 287
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 287
Ala Val Arg Gln Thr Thr Met
1 5
<210> 288
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 288
Cys Glu Asp Ser Asp Lys Ser Val Cys
1 5
<210> 289
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 289
Cys Asn Arg Val Pro Phe Lys Gln Cys
1 5
<210> 290
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 290
Cys Pro Arg Met Asn Asn Pro Leu Cys
1 5
<210> 291
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 291
Asp Val Val Lys Asp Val Ile
1 5
<210> 292
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 292
Glu Ser Pro Tyr Pro His Ser
1 5
<210> 293
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 293
Phe Lys Leu Pro Trp Ala Ser
1 5
<210> 294
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 294
Phe Leu Asn Gln Ala Pro Thr
1 5
<210> 295
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 295
Phe Ser Ala Gly Val Gly Lys
1 5
<210> 296
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 296
Gly His Ser His Tyr Ile Leu Gly Lys Pro Thr Ala
1 5 10
<210> 297
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 297
Gly Pro Ile Thr His Ala Ile
1 5
<210> 298
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 298
His Phe Leu Arg Pro Ser Asp
1 5
<210> 299
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 299
His Leu Leu Lys Thr His Ser
1 5
<210> 300
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 300
His Met Ala Gly Val Asn Gln
1 5
<210> 301
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 301
His Pro Asp Thr Leu Pro Gln
1 5
<210> 302
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 302
His Pro Thr Gly Thr Pro Thr
1 5
<210> 303
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 303
His Thr Gly Leu Arg Ser Leu
1 5
<210> 304
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 304
Lys Gly Gln Pro Leu Phe Arg
1 5
<210> 305
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 305
Lys Tyr Arg His Gly Ala Glu
1 5
<210> 306
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 306
Leu Phe Arg Arg Val Thr Glu
1 5
<210> 307
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 307
Leu Thr Lys Ser Leu Asn His
1 5
<210> 308
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 308
Met Pro Leu Leu Glu Leu Pro
1 5
<210> 309
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 309
Met Thr Asn His Gly Asn Ala
1 5
<210> 310
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 310
Asn Leu Lys Leu Trp Thr Arg
1 5
<210> 311
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 311
Asn Leu Leu Gln Gly Val Met
1 5
<210> 312
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 312
Asn Met Tyr Pro Arg Val Thr
1 5
<210> 313
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 313
Asn Ser Ser Pro His Gln Ile
1 5
<210> 314
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 314
Gln Gly Thr Leu Phe Asp Thr
1 5
<210> 315
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 315
Gln Pro Ile Asp Ser Thr Ser
1 5
<210> 316
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 316
Ser Glu Pro Gly Thr Val Arg
1 5
<210> 317
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 317
Ser Gly Asn Leu Lys Lys Ala
1 5
<210> 318
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 318
Ser Ile Ala Glu Val Leu Gly Leu Trp Arg Asn Val
1 5 10
<210> 319
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 319
Ser Ile Arg Met Thr Glu Ile
1 5
<210> 320
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 320
Ser Ile Ser Lys Ile Arg Thr
1 5
<210> 321
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 321
Ser Leu Arg Ser Val Gly Ala
1 5
<210> 322
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 322
Ser Ser Gly Met Leu Ser Lys
1 5
<210> 323
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 323
Ser Tyr Thr Leu Ser Arg Ser
1 5
<210> 324
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 324
Thr Leu Leu Thr Ala Leu Thr
1 5
<210> 325
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 325
Thr Pro Leu Tyr Leu Ser Ser
1 5
<210> 326
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 326
Val Ser Phe Thr Leu Glu Pro
1 5
<210> 327
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 327
Val Val Asp Met Ser Thr Tyr
1 5
<210> 328
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 328
Trp Pro Asp Leu Arg Ile Leu
1 5
<210> 329
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 329
Trp Ser Leu Pro Leu Leu Ser
1 5
<210> 330
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 330
Trp Ser Pro Arg Trp Pro Ser
1 5
<210> 331
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 331
Tyr Leu Pro Pro Pro Leu Pro
1 5
<210> 332
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 332
Asp Ser Tyr Leu Leu Ser Ala
1 5
<210> 333
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 333
Phe Val Leu Pro Asn Lys Asn
1 5
<210> 334
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 334
Ile Ile Leu Pro Ser Ala Gln
1 5
<210> 335
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 335
Lys Asn Ser Ile Ala Pro Arg
1 5
<210> 336
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 336
Leu Pro Pro Gln Ile Ser Arg
1 5
<210> 337
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 337
Met Pro Ser Leu Lys His Gln
1 5
<210> 338
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 338
Asn Pro Thr Asp Thr Asn Lys
1 5
<210> 339
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 339
Asn Thr Ser Leu Ser Phe Lys
1 5
<210> 340
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 340
Gln Asn Ser Tyr Leu Ser Asn
1 5
<210> 341
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 341
Gln Gln Ala His Leu Gln Ser
1 5
<210> 342
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 342
Ser Pro Pro Arg Phe Ile Pro
1 5
<210> 343
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 343
Ser Trp Phe Glu Ser His Asn
1 5
<210> 344
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 344
Thr Pro Gln Val Met Leu Lys
1 5
<210> 345
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 345
Thr Ser Pro Pro Leu Ala His
1 5
<210> 346
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 346
Thr Ser Arg Leu Val Ser Thr
1 5
<210> 347
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 347
Val Ala His Gln Arg Val Ser
1 5
<210> 348
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 348
Val Pro Thr Leu Arg Ile Pro
1 5
<210> 349
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 349
Tyr Ala Thr Ala Thr Pro Ser
1 5
<210> 350
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 350
Ala Asn Leu Ser Arg Ser Val
1 5
<210> 351
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 351
Phe Ser Ala Arg Thr Asn Thr
1 5
<210> 352
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 352
His Phe Tyr Gly Pro Gly Pro
1 5
<210> 353
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 353
His Pro Trp Leu Gly Asn Arg
1 5
<210> 354
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 354
His Tyr Ser Pro Asn Val Met
1 5
<210> 355
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 355
Asn Phe Ala Gln His Met Gln
1 5
<210> 356
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 356
Ser Asn Ala Glu Arg Trp Arg
1 5
<210> 357
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 357
Ser Arg Pro Thr Arg Val Pro
1 5
<210> 358
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 358
Ser Val Glu Tyr Gly Gln Leu
1 5
<210> 359
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 359
Thr Gly Asn Leu Arg Leu Tyr
1 5
<210> 360
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 360
Met Asp Leu Ser Leu Lys Pro
1 5
<210> 361
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 361
Asn Thr Pro Lys Val Leu Ala
1 5
<210> 362
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin Basic Protein
<400> 362
Thr Gln Met Thr Met Asp Ser
1 5
<210> 363
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 363
Ala Ser Leu Thr Leu Ala Leu
1 5
<210> 364
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 364
Asp Arg His Glu Gly His Arg
1 5
<210> 365
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 365
Phe Arg Ile Asp Lys Ser Met
1 5
<210> 366
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 366
Gly His Leu Gln Ser Leu Phe
1 5
<210> 367
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 367
Gly Leu Trp Gly Pro Ser Leu
1 5
<210> 368
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 368
Lys Pro Ser Ala Ser Ile Tyr
1 5
<210> 369
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 369
Leu Pro Ser His Ala Ser Ile
1 5
<210> 370
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 370
Leu Pro Val Lys Asn Leu Leu
1 5
<210> 371
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 371
Met Lys Ile Met Pro Met Asp
1 5
<210> 372
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 372
Ser Ala Gln Ser Arg Ser Phe
1 5
<210> 373
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 373
Ser Leu Pro Ser Leu Leu Pro
1 5
<210> 374
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 374
Ser Val Val Tyr Gln Asn Ser
1 5
<210> 375
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 375
Thr Thr Thr Ile Ala Asp Met
1 5
<210> 376
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 376
Val Thr Gly Pro Gly Thr Pro
1 5
<210> 377
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 377
Val Thr Pro Asn Lys Ala Arg
1 5
<210> 378
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 378
Trp His Tyr Thr Pro Ser Met
1 5
<210> 379
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 379
Trp Ser Arg Ile Ser Val Asp
1 5
<210> 380
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 380
Ala Leu Phe Gln Glu Arg Lys
1 5
<210> 381
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 381
Ala Gln Ala Ser Ser Ala Arg
1 5
<210> 382
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 382
Glu Val Leu Tyr Pro Asn Asn
1 5
<210> 383
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 383
His Leu His Thr Arg Pro Thr
1 5
<210> 384
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 384
Ile Arg Pro Thr His Asn Gly
1 5
<210> 385
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 385
Lys Gly Val Ile Pro Ala Thr
1 5
<210> 386
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 386
Leu His Gln Thr Tyr Arg Pro
1 5
<210> 387
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 387
Leu Pro His Arg Leu Asn Pro
1 5
<210> 388
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 388
Thr Gly Ile Ser Ser Thr Pro
1 5
<210> 389
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 389
Thr Met Pro Ile Lys Ala Met
1 5
<210> 390
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 390
Val Pro Gly His Ile Ser Gly
1 5
<210> 391
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 391
Val Ser Ala Ser Trp Met Pro
1 5
<210> 392
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 392
Trp Ser Pro His Gly Tyr Lys
1 5
<210> 393
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 393
Tyr Ser Gln Ala Ile Ser Ala
1 5
<210> 394
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 394
Ala Val Val Ala Met Asn Lys
1 5
<210> 395
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 395
Gly Ile Pro Ser Ser Lys Asn
1 5
<210> 396
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 396
Asn Asp Ala Ser Thr Val Ser
1 5
<210> 397
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 397
Gln Leu Pro Arg Asn Asn Leu
1 5
<210> 398
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 398
Ser Leu Asn Arg Gly Gly Ala
1 5
<210> 399
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 399
Ser Leu Pro Gly Tyr Arg His
1 5
<210> 400
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 400
Ser Val Leu Pro Asp Lys Leu
1 5
<210> 401
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 401
Thr Leu Trp Ala Gln Lys Thr
1 5
<210> 402
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 402
Thr Gln Pro Arg Tyr Pro Ser
1 5
<210> 403
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 403
Val Phe Pro Glu Arg Arg Val
1 5
<210> 404
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 404
Val Gly Tyr Arg Ser Ala Ser
1 5
<210> 405
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 405
Val Arg Thr Ser Met Asn His
1 5
<210> 406
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 406
Tyr Thr Trp Thr Pro Ser Arg
1 5
<210> 407
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 407
Phe Ser Leu Asp Arg Asp Gly
1 5
<210> 408
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 408
Phe Ser Thr Pro Thr Asn Val
1 5
<210> 409
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 409
Gly Pro Ala Ala Val Ile Ile
1 5
<210> 410
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 410
Gly Trp Ser Thr Ala Ile Arg
1 5
<210> 411
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 411
His Lys Ala Pro Leu Gly Thr
1 5
<210> 412
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 412
Ile Asp Arg Val Arg Gly Leu
1 5
<210> 413
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 413
Leu Met Gln Lys Pro Ser Ile
1 5
<210> 414
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 414
Ser Val Met Trp Met Thr Pro
1 5
<210> 415
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 415
Thr Lys Ile Thr Pro His Arg
1 5
<210> 416
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 416
Tyr Ser Ser Arg Leu Thr Ala
1 5
<210> 417
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 417
Ala Arg Phe Val Pro Leu Thr
1 5
<210> 418
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 418
Asp Gly Ser Arg Asp Leu Val
1 5
<210> 419
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 419
Glu Lys Ser Thr Thr Val Ala
1 5
<210> 420
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 420
Tyr Ser Asp Thr Tyr Lys His
1 5
<210> 421
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 421
Glu Pro Ser Ser Phe Thr Phe
1 5
<210> 422
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 422
Gly Lys Ser Tyr Ser Gln Ile
1 5
<210> 423
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 423
Gly Asn Val Phe Gln Thr Ser
1 5
<210> 424
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 424
Ile Ile Pro Pro Thr Ser Val
1 5
<210> 425
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 425
Leu Pro Leu Arg Leu His Ala
1 5
<210> 426
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 426
Asn Val Phe Ser Ala Thr Pro
1 5
<210> 427
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 427
Gln Arg Arg Ser Val Ile Leu
1 5
<210> 428
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 428
Ser Gly Val Ala Thr Tyr Thr
1 5
<210> 429
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 429
Ser Trp Asp Val Leu Glu Leu
1 5
<210> 430
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 430
Thr Phe Pro Glu Arg Leu Arg
1 5
<210> 431
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 431
Trp Ser Pro His Arg Ser Phe
1 5
<210> 432
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 432
Ile His His Leu Glu Ser Ser
1 5
<210> 433
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 433
Leu Asn Gly Ile Ser Ala Leu
1 5
<210> 434
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 434
Ser Ala Leu Ile Ser Thr Arg
1 5
<210> 435
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 435
Ser Gly Leu His Tyr Ala Leu
1 5
<210> 436
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 436
Thr Arg Ala Ser Tyr Pro Gln
1 5
<210> 437
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 437
Asn Ile Pro Ser Ser Ile Leu
1 5
<210> 438
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 438
Gln Pro Asn Met Leu Lys Pro
1 5
<210> 439
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 439
Arg Leu Gln Pro Glu Pro Thr
1 5
<210> 440
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 440
Ser Val Glu Lys Tyr Ser Lys
1 5
<210> 441
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 441
Val Ser Ser Gln Glu Gln Ala
1 5
<210> 442
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 442
Trp Asn Thr Ala Asp Arg Leu
1 5
<210> 443
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 443
Met Pro His Ala Pro Val Gln
1 5
<210> 444
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 444
Thr Asp Val Glu Met Val Pro
1 5
<210> 445
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 445
Ala His Gln Ser Ser Val Thr
1 5
<210> 446
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Myelin PLP
<400> 446
Gly Ser Ala Trp Lys Lys His
1 5
<210> 447
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Nidogen-2
<400> 447
Cys Ile His His Lys Gly Val Leu Cys
1 5
<210> 448
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Nidogen-2
<400> 448
Cys Lys Asp Gly His Ile Arg His Cys
1 5
<210> 449
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Nidogen-2
<400> 449
Cys Asn Leu Ala Thr Ser Leu Gln Cys
1 5
<210> 450
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Nidogen-2
<400> 450
Cys Arg Ser Pro His Glu Pro Met Cys
1 5
<210> 451
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Nidogen-2
<400> 451
Cys Val Asp Lys Met Ala Ser Val Cys
1 5
<210> 452
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Nidogen-2
<400> 452
Cys Tyr Ser Ala Pro Thr Lys Ser Cys
1 5
<210> 453
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Nidogen-2
<400> 453
Glu Ala Met Met His Arg Asn
1 5
<210> 454
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Nidogen-2
<400> 454
Leu His Ile Thr Pro Glu Val
1 5
<210> 455
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Nidogen-2
<400> 455
Leu Ser Ile Arg Gly Leu Thr
1 5
<210> 456
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Nidogen-2
<400> 456
Asn Ile Leu Ser Gln Val Asn
1 5
<210> 457
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Nidogen-2
<400> 457
Gln Leu Leu Glu Ser Arg Thr
1 5
<210> 458
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Nidogen-2
<400> 458
Gln Met Asp Ala Lys His Met
1 5
<210> 459
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Nidogen-2
<400> 459
Gln Thr Leu Arg Pro Lys Gln
1 5
<210> 460
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Nidogen-2
<400> 460
Thr Ile Ala Ser Leu Leu Val
1 5
<210> 461
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Nidogen-2
<400> 461
Trp Leu Ala Ala Gly Ser Gln
1 5
<210> 462
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Nidogen-2
<400> 462
Ala Leu Tyr Leu Pro Gly Arg
1 5
<210> 463
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Nidogen-2
<400> 463
Ala Arg Met Ala Phe Ser Leu
1 5
<210> 464
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Nidogen-2
<400> 464
Ala Thr Tyr Asn Met Ser Gln
1 5
<210> 465
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Nidogen-2
<400> 465
Gly Leu Arg Thr Met Glu Pro
1 5
<210> 466
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Nidogen-2
<400> 466
Thr Pro Trp Leu Pro Thr Ile
1 5
<210> 467
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Nidogen-2
<400> 467
Tyr Asn His Thr Met Met Tyr
1 5
<210> 468
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Nidogen-2
<400> 468
Cys Ser Phe Lys Met Asn Gln Lys Cys
1 5
<210> 469
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Nidogen-2
<400> 469
Leu Val His Pro Phe His Gly
1 5
<210> 470
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Nidogen-2
<400> 470
Cys Ser Ser Ser Ala Pro Arg Ile Cys
1 5
<210> 471
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> R3 Nidogen-2
<400> 471
His Ser Arg Leu Pro Thr Pro
1 5
<210> 472
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 472
Cys Lys Ser Pro Ile Lys Gly Thr Cys
1 5
<210> 473
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 473
Cys Leu Gln Lys Asn His Lys Phe Cys
1 5
<210> 474
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 474
Cys Val Leu Lys Cys Glu Asp Gln Lys Tyr Arg Gly
1 5 10
<210> 475
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 475
Asp Gly Ala Asn Met Phe Asn Ile Ala Pro Ala Asn
1 5 10
<210> 476
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 476
Asp Arg Met Tyr Ser Thr Val Pro Ala Glu Gly Leu
1 5 10
<210> 477
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 477
Glu Ala Val Ser Thr Gln Ile
1 5
<210> 478
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 478
Gly Ile Asn Leu Arg Ala Leu Asp Leu His Ala Asn
1 5 10
<210> 479
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 479
His Gln Ser Val Thr Gly Val Arg Ser His Phe His
1 5 10
<210> 480
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 480
Ser Val Val Gly Trp Ala Ala Pro Arg Thr Ala Gln
1 5 10
<210> 481
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 481
Thr Ile Leu Lys Pro Ala Ala Gln Gly Phe Ala Asp
1 5 10
<210> 482
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 482
Thr Ser Ala Val Ser Leu Arg
1 5
<210> 483
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 483
Thr Thr Leu Trp Leu Asp Arg Asp Glu Ala Leu Lys
1 5 10
<210> 484
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 484
Val Ile Ala Asp Gln Ser Lys Ser Ala Val Ala Val
1 5 10
<210> 485
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 485
Ala Gln Asn Leu Arg Val His Ala Trp Ala Ser Leu
1 5 10
<210> 486
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 486
Cys Pro Met His Gln Ser Lys Thr Cys
1 5
<210> 487
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 487
Cys Thr Asp Gly Arg Asn Phe Val Cys
1 5
<210> 488
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 488
Cys Thr Gly Glu Thr Leu Leu Thr Cys
1 5
<210> 489
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 489
Cys Thr Ser Ser Ser His Gln Thr Cys
1 5
<210> 490
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 490
Glu Thr Gly Gly Leu Ala Tyr Gly Ser Gly Gln Lys
1 5 10
<210> 491
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 491
Gly Ile Val Pro Ser Arg His Thr Thr Gly Leu Gly
1 5 10
<210> 492
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 492
Gly Trp Thr Ser Asp Leu Ser Arg Asn Val Arg Gly
1 5 10
<210> 493
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 493
His Thr Gln Ile His Arg Leu
1 5
<210> 494
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 494
Lys Phe Ala Asp Thr Lys Leu Thr Ser Leu Arg Tyr
1 5 10
<210> 495
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 495
Gln Leu Gln His Val His Leu
1 5
<210> 496
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 496
Gln Pro Thr Pro Ser Gln Ile Lys Phe Thr Arg Thr
1 5 10
<210> 497
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 497
Arg Ala Leu Asp Arg Tyr Leu Pro Trp Ser Pro His
1 5 10
<210> 498
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 498
Ser Leu Pro Tyr Ala Ala Ser Leu Asn Ser Val Glu
1 5 10
<210> 499
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 499
Ser Thr Asn Val Gln Arg Ala
1 5
<210> 500
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 500
Ser Val Leu Ser Thr Gly Thr Ala Asn Gln Arg His
1 5 10
<210> 501
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 501
Ser Val Gln Thr Pro Met Trp Arg Ser Leu Val Gly
1 5 10
<210> 502
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 502
Ser Trp His Phe Thr Gly Thr Pro Phe Met Asn Arg
1 5 10
<210> 503
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 503
Ser Tyr Thr Ala Thr Trp Ser Glu Met Ser Arg Ser
1 5 10
<210> 504
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 504
Thr Ala Leu Ser His Arg His Glu Ala Met Arg Trp
1 5 10
<210> 505
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 505
Thr Lys Gly Ile Ala Pro Lys
1 5
<210> 506
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 506
Thr Val Ala Arg Ser Thr Ala Gln Glu Arg Ser Ile
1 5 10
<210> 507
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 507
Ala Val Arg Pro Leu Gly Leu Pro Asp Asn His Arg
1 5 10
<210> 508
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 508
Cys Ile Gly Gly Pro His Arg Asn Cys
1 5
<210> 509
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 509
Cys Lys Ser Pro Ala Ile Lys Gly Cys
1 5
<210> 510
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 510
Cys Asn Ser Trp Lys Ala Ala Lys Cys
1 5
<210> 511
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 511
Asp Ser Leu Tyr Arg Gly Met His Gln Pro Arg Ile
1 5 10
<210> 512
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 512
Glu Asp Arg Met Met Thr Tyr Arg Tyr Thr Ser Thr
1 5 10
<210> 513
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 513
Glu Val Glu Arg Ile Leu Thr Pro His Val Asn Asn
1 5 10
<210> 514
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 514
Phe Asn Ser Asp Ser Arg Ser Thr His Gln Glu Asp
1 5 10
<210> 515
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 515
His Pro Ala Trp Ala Asp Phe Phe Thr Met Ser Ser
1 5 10
<210> 516
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 516
Ile Asp Leu Ser Leu Arg Ser
1 5
<210> 517
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 517
Ile Asp Gln Ser Gly Leu Gln Lys Ser Gly Met Lys
1 5 10
<210> 518
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 518
Leu Gly Ser Ser Arg Ser Pro Ser Ser Phe Leu Gly
1 5 10
<210> 519
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 519
Asn Gly His Glu Val Gln Ser Arg Ala Ala Asn Arg
1 5 10
<210> 520
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 520
Gln Gly Trp Lys Asp Arg Leu Pro Ile Trp Arg Tyr
1 5 10
<210> 521
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 521
Ser His Asp Val Ala Asn Gly Thr Ser Val Arg Thr
1 5 10
<210> 522
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 522
Ser Pro Asp Arg Thr Asn Trp Gly Trp Gln Thr Asn
1 5 10
<210> 523
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 523
Ser Val Glu Ser Asn Ser Lys Leu Thr Met Pro Arg
1 5 10
<210> 524
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 524
Trp Pro Met Met Gln Thr Arg
1 5
<210> 525
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 525
Cys Lys Ser Glu Arg Gly Pro Glu Cys
1 5
<210> 526
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 526
Cys Gln Gly Trp Pro Arg Pro Met Cys
1 5
<210> 527
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 527
Cys Ser Arg Ala Gly Leu Ser Ala Cys
1 5
<210> 528
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 528
Cys Thr Trp Lys His Arg Asp Asn Cys
1 5
<210> 529
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 529
Gly Leu Leu Asp Trp Gly Ser Leu Gln Gly Gly Asn
1 5 10
<210> 530
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 530
Gly Pro Leu Leu Phe Arg Gly
1 5
<210> 531
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 531
Gly Ser Pro Glu Lys Arg Thr
1 5
<210> 532
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 532
Lys Ala Ser Ile Ala Tyr Asp
1 5
<210> 533
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 533
Leu Gly Tyr Gly Gln Gly Thr Pro His Arg Ser Asn
1 5 10
<210> 534
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 534
Gln Gly Trp Glu Phe Gln Val Pro Ala Arg His Ser
1 5 10
<210> 535
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 535
Gln Thr Phe Gly Tyr Ser Met Phe Asn Val Arg Thr
1 5 10
<210> 536
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 536
Arg Asn Leu His Tyr Pro Leu Asn His Pro Phe Met
1 5 10
<210> 537
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 537
Thr Ala Pro Arg Trp Thr Gln
1 5
<210> 538
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 538
Val Pro Ser Tyr Ile Leu Arg
1 5
<210> 539
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 539
Trp Arg Ser Pro Leu Thr Thr
1 5
<210> 540
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 540
Cys Gln Thr Ser Gly His His Gln Cys
1 5
<210> 541
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 541
Cys Ser Ser Gln Ala Lys Arg Ser Cys
1 5
<210> 542
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 542
Cys Thr Ala Trp Thr Arg Gln Glu Cys
1 5
<210> 543
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 543
Glu Tyr Val Lys Phe Ser His Ser Pro Arg Thr Tyr
1 5 10
<210> 544
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 544
Gly Gly Trp Gln Ser Leu Trp Asp Lys Pro Glu His
1 5 10
<210> 545
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 545
Gly Pro Met Leu Lys Asn Leu Ser Asp Ala Val Thr
1 5 10
<210> 546
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 546
Asn His Asp Gln Gly Ser Leu Thr Arg Trp Arg Ser
1 5 10
<210> 547
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 547
Ser Leu Leu Ser Val Val Asn Thr Ser Ser Lys Ser
1 5 10
<210> 548
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 548
Val Val Pro Ser Trp Pro Ser Val His Arg Pro Pro
1 5 10
<210> 549
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 549
Trp Gly Trp Asn Gly Ala Asn Met Ser Pro Arg Gly
1 5 10
<210> 550
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 550
Cys His Asn Ala Asp Asn Asn Gly Cys
1 5
<210> 551
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 551
Leu Pro Met Leu Arg His Ser
1 5
<210> 552
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 552
Asn Asp Thr Gly Arg His Ala Ser Gly Ile Ser Lys
1 5 10
<210> 553
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 553
Gln Ala Leu Arg Thr Asn Tyr Ser Pro Leu Asn Ser
1 5 10
<210> 554
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 554
Thr Leu Lys Ala Gly Thr Arg Ala Asn Asp Gly Val
1 5 10
<210> 555
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 555
Cys Gly Glu Thr Thr Ala Gly Lys Cys
1 5
<210> 556
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 556
His Ser Thr Tyr Ala Pro Gly
1 5
<210> 557
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 557
Gln Ile Asn Trp Lys Gln Ala Asp Lys Asn Ala Asp
1 5 10
<210> 558
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 558
Ala Leu Pro Trp Gln Ser Gly Val His Gly Thr Lys
1 5 10
<210> 559
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 559
Thr Phe Gly Ser Gly Arg Ser Met Pro Ile Gln Tyr
1 5 10
<210> 560
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 560
Val Tyr Arg Asn Gly Gly Gly Leu Pro Leu Thr Ala
1 5 10
<210> 561
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 561
Ala Leu Lys Ile Gly Pro Glu Thr Thr Ile Tyr Met
1 5 10
<210> 562
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 562
Asp Trp Thr Gln Val Arg Val Thr Asn Trp Phe Leu
1 5 10
<210> 563
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 563
Leu Gly His Gln Asn Gly Gly Arg Ala Asp Met Trp
1 5 10
<210> 564
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 564
Met Thr Asn Ser Gly Ala Lys
1 5
<210> 565
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 565
Trp Ala Tyr Thr Asp Tyr Met
1 5
<210> 566
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 566
Ala His Ala Ala Gly Arg Asp Met Arg Gln Gly Thr
1 5 10
<210> 567
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 567
Asp Val Ile His Ser Ser Arg Gly Ala Tyr Phe Glu
1 5 10
<210> 568
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 568
Asn Trp Thr His Leu Gly Val Ala Arg Leu Gln Pro
1 5 10
<210> 569
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 569
Ser Tyr Asp Gly Thr Met Leu Lys Gln Val Arg Leu
1 5 10
<210> 570
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 570
Trp Gln Trp Arg Ser Thr Glu Leu Gly Tyr Arg Tyr
1 5 10
<210> 571
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 571
Trp Ser Pro Ala Asn Gly Trp Arg His Gln Thr Ile
1 5 10
<210> 572
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 572
Cys Leu His Asn Gly Gln Arg Ser Cys
1 5
<210> 573
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 573
Cys Thr Pro Arg Ser Ala Thr Leu Cys
1 5
<210> 574
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 574
Asp Ile Met Lys Ser Pro Arg Ser Asn Leu Arg Ser
1 5 10
<210> 575
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 575
Gln Thr Phe His Glu Tyr Leu Asn Pro Ala Arg Gly
1 5 10
<210> 576
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 576
Ser Leu Asn Thr Thr Trp Val Ser Pro Met Met Lys
1 5 10
<210> 577
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 577
Ala Gln Arg Met Asn Gln Ala
1 5
<210> 578
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 578
Gly Asp Ala Gln Ile Leu Met
1 5
<210> 579
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 579
Gly His Arg Thr Leu Val Thr Ser Glu Arg Tyr Leu
1 5 10
<210> 580
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 580
Leu Gly Pro Ser Thr Gln Gly Ala Gly Gln Thr Arg
1 5 10
<210> 581
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 581
Thr Phe Ala Ala Ala Gln Ala Glu Leu Ile Met Val
1 5 10
<210> 582
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 582
Trp Glu Glu His Arg Val Glu Ile Leu Pro Asp Val
1 5 10
<210> 583
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 583
Ala Gly Ala Tyr Thr Ser Arg His Ala Phe Asp Glu
1 5 10
<210> 584
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 584
Cys Gly Leu Ala Thr Asn Lys Ser Cys
1 5
<210> 585
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 585
Gly Asp Val Ile Thr Ala Tyr Ile Asn Pro Trp Pro
1 5 10
<210> 586
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 586
Gly Tyr Asp Leu Ser Arg Leu Trp Gly Met Ala Ser
1 5 10
<210> 587
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 587
Ala Asn Arg Tyr Leu Ala Ser
1 5
<210> 588
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 588
Cys Lys Trp Thr Gln Leu Trp Gly Cys
1 5
<210> 589
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 589
Cys Leu Lys Asp Thr His Leu Asn Cys
1 5
<210> 590
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 590
Gly Gln Pro Arg Asn Ile His Leu Pro Gly Thr His
1 5 10
<210> 591
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 591
Gly Ser Thr Thr His Pro His Phe Gly Leu Pro Gly
1 5 10
<210> 592
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 592
Gly Trp Ile Gln Asp Thr Phe Val Leu Gly Arg Ser
1 5 10
<210> 593
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 593
Gln Gly His Pro Phe Ile Tyr
1 5
<210> 594
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 594
Ser Asn Pro Lys His Val Ser Ser Leu Gly Gln Met
1 5 10
<210> 595
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 595
Trp Gly Ala Asn Thr Thr Gly Arg Thr His Gly Gly
1 5 10
<210> 596
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 596
Ala Gln Gly Val Trp Trp Ser Glu Trp Phe Ala Pro
1 5 10
<210> 597
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 597
Cys Phe Gln Pro Lys Met Asn Ser Cys
1 5
<210> 598
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 598
Cys Trp Ser Gly Asn Ser Arg Ser Cys
1 5
<210> 599
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 599
Phe Pro Leu Lys Ile Arg Thr
1 5
<210> 600
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 600
Leu Ala Arg Ser Ser Ile Met Ala Ala Asn Asn Val
1 5 10
<210> 601
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 601
Ala Lys Thr Gln Ala Pro Ser Asn Trp Ser Gly Val
1 5 10
<210> 602
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 602
Cys Ser Val Trp Asn Ser Gly Asn Cys
1 5
<210> 603
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 603
Cys Thr Gly Arg Ile Ser Lys His Cys
1 5
<210> 604
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 604
Gly Ala Met Met Asn Ser Asn Asn Leu Val Ala Arg
1 5 10
<210> 605
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 605
Gly Gly Gly Tyr His Ile Phe Gly Pro Leu Val Thr
1 5 10
<210> 606
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 606
His Ser Phe Leu Gly Ala Arg
1 5
<210> 607
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 607
Leu Leu Ala Gly Pro Phe Arg
1 5
<210> 608
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 608
Gln Thr Leu Gln Thr Arg His
1 5
<210> 609
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 609
Ala Leu Gly Gly Glu Pro Arg Lys Ala Tyr Gln Arg
1 5 10
<210> 610
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 610
Cys Asn His Leu Thr Gln Lys Leu Cys
1 5
<210> 611
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 611
Cys Thr Ser Lys Leu Ala Arg His Cys
1 5
<210> 612
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 612
Ala Val Tyr Pro Leu Asp Leu Gly Ala Gly Met Arg
1 5 10
<210> 613
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 613
Cys His Arg Thr Tyr Asn Ser Thr Cys
1 5
<210> 614
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 614
Leu Asp Arg Asn Ala Asp Ser Val Arg Ala Val Leu
1 5 10
<210> 615
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 615
Thr Thr Asn Gly Val Pro Gly His Asp Arg Ser Pro
1 5 10
<210> 616
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 616
Ala Asp Met Pro Gln Met Thr Leu Lys Tyr Gly Val
1 5 10
<210> 617
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 617
Ala Trp Asn Gly Asn Arg Ser
1 5
<210> 618
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 618
Gly Asp Leu Leu Leu Lys Arg
1 5
<210> 619
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 619
Val Pro Gln Ile Arg Ile Lys
1 5
<210> 620
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 620
Ser Trp Gln Met Arg Ser Tyr
1 5
<210> 621
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 621
Tyr His Leu Gly Pro Asn Gln Lys Met Arg Thr Ser
1 5 10
<210> 622
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 622
Ala Ser His Ser Arg Pro Leu Met Asn Tyr Ala Pro
1 5 10
<210> 623
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 623
Gln Thr Arg Trp Asp Asp Gly Ser Tyr Gln Ile Ser
1 5 10
<210> 624
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 624
Ser Leu Ala Val Ala Asn Thr Arg Phe Met Ile Arg
1 5 10
<210> 625
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 625
Glu Gly His Val Trp Ser Glu Tyr Thr Trp Gly Thr
1 5 10
<210> 626
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 626
Glu Thr Tyr Lys Val Thr Arg Val Ile Ser Pro Trp
1 5 10
<210> 627
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 627
Gly His Pro Trp Thr Glu Ile Asp Phe Met Ser Ser
1 5 10
<210> 628
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 628
Lys Gln Glu Leu Ser Asp Asn Leu Ala Ser His Arg
1 5 10
<210> 629
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 629
Ser Phe Arg Asn Leu Glu Lys Leu Ser Leu Trp Ser
1 5 10
<210> 630
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 630
Gly Asp Leu Trp Asn Val Pro
1 5
<210> 631
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 631
Gly Pro Lys Asn His His Gln
1 5
<210> 632
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 632
Gly Ser Gly Phe Arg Asn Glu Glu His Ser Ala His
1 5 10
<210> 633
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 633
Asn Asn Asn Ala Ala Met Gln Asn His Gly Val Arg
1 5 10
<210> 634
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 634
Arg Ala Gln Ala His Gln Val
1 5
<210> 635
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 635
Cys Ser Leu Ala Asn Pro Ala Thr Cys
1 5
<210> 636
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 636
Gly Glu Pro Leu Thr Arg Phe Pro Asn Ser Asp Ser
1 5 10
<210> 637
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 637
Lys Pro Ile Leu Trp Asn Arg Ser Leu Asn Ala Leu
1 5 10
<210> 638
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 638
Gly Phe Ala Asp Val Ile His Arg Lys Trp Ser Ser
1 5 10
<210> 639
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 639
His Gln Ser Leu Ala Gly Val Pro Trp Ser Arg His
1 5 10
<210> 640
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 640
Val Pro Val Phe Leu Asp Gln Ala Arg Val Met Lys
1 5 10
<210> 641
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 641
Asp Asp Leu Leu Thr Ala Pro Arg Leu Gly Val Trp
1 5 10
<210> 642
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 642
Ser Asp Arg Gly Lys Thr Val Leu His Gly Gln Ile
1 5 10
<210> 643
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 643
Cys Gly Ile Thr Gln Thr Thr Thr Cys
1 5
<210> 644
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 644
Cys His Gln Arg Gln Gln Thr Tyr Cys
1 5
<210> 645
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 645
Glu Tyr Trp His Gln Arg Gly Ser Trp Phe His Arg
1 5 10
<210> 646
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 646
Tyr Thr Pro Arg Asn Gln Leu
1 5
<210> 647
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 647
Cys Thr Lys Ser Pro Ser Asn Ser Cys
1 5
<210> 648
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 648
Trp Ala Phe Lys Ala Pro Gln
1 5
<210> 649
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 649
Gly Ser Leu Asp Met Gly Asn Asn Lys Gln Pro Val
1 5 10
<210> 650
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 650
Ala Val Val Ser Gln Asn Gln Met Ser Gln Gln Lys
1 5 10
<210> 651
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 651
Cys Leu Asn Gln Lys Trp Glu Ala Cys
1 5
<210> 652
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 652
Trp Pro Val Arg Asn Leu Leu
1 5
<210> 653
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 653
Gly Tyr Arg Ser Phe Ile His Glu Asn Trp Ser Ile
1 5 10
<210> 654
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 654
Ser Gly Trp Glu Gly Lys Thr His Gln Gly Val Arg
1 5 10
<210> 655
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 655
Leu Gln Ser Asn Ala Ala Asp His His Gln Gly Met
1 5 10
<210> 656
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 656
Ala Thr Ser Lys Tyr Pro Asn Ser Trp Ala Gln Thr
1 5 10
<210> 657
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 657
Asp Arg Leu Thr Pro Ile Thr Trp Asp Trp Ser Arg
1 5 10
<210> 658
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 658
Trp Thr Lys His Asn Thr Pro Ala His His Leu Ser
1 5 10
<210> 659
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 659
Trp Asn Ala Asn Tyr Gly Thr Met Thr Arg His Ala
1 5 10
<210> 660
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 660
His Ala Ser Asn Gln Arg Val
1 5
<210> 661
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 661
Gly Arg Thr Ile His Ser Met
1 5
<210> 662
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 662
Arg Leu Val Thr Ala Ser Met Val Ser Pro Ser Phe
1 5 10
<210> 663
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 663
Asp Gly Gln Val Ser Asp His Ser Tyr Val Gln Trp
1 5 10
<210> 664
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 664
Lys Ile Ser Met Asn Arg Leu His Ala Asn Phe Thr
1 5 10
<210> 665
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 665
Trp Asp Leu Pro Thr Leu Arg Lys Thr Lys Gln Ala
1 5 10
<210> 666
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 666
Trp Val Ala Ala Glu Arg Arg
1 5
<210> 667
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 667
Met Thr His Ser Ala His Asn Ser Gln Lys Thr Asn
1 5 10
<210> 668
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 668
Trp Gly Leu Lys Leu Pro His
1 5
<210> 669
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 669
Gln Gly Trp Phe Arg His Ser
1 5
<210> 670
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 670
Ile Pro Val Gly Glu Arg Lys
1 5
<210> 671
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 671
Cys Met Asn Lys Ile Gln Arg Asp Cys
1 5
<210> 672
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 672
Lys Ala Leu Gly Tyr Ser Leu Val Gly Gly Glu Trp
1 5 10
<210> 673
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 673
Ala Pro Lys Val Thr Asn Ala Arg Pro Thr Gln Leu
1 5 10
<210> 674
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 674
Ala Trp Val Glu Ala Gln Asn Ala Ser Asn Pro Ser
1 5 10
<210> 675
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 675
Cys Ser Lys His Asn His Ser Arg Cys
1 5
<210> 676
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 676
Gly Lys Pro Asp His Arg Leu Val Ser Leu Trp Arg
1 5 10
<210> 677
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 677
Cys Ser His His Lys Leu Lys Gln Cys
1 5
<210> 678
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Laminin 421/521
<400> 678
Gly Gly Tyr Asp Leu Pro Trp Ala Asn Trp Gln Asn
1 5 10
<210> 679
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 679
Gly Trp Gln Met Phe Pro Pro Met Gln Asn Thr Arg
1 5 10
<210> 680
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 680
Ser Ser Leu Tyr Met Asn Gly Trp Ser Arg Asp Gln
1 5 10
<210> 681
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 681
Tyr Ala Gly Gln Asn Gly Trp Met Arg Ser Asp Leu
1 5 10
<210> 682
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 682
Val Glu Arg Leu Asn Trp Pro Lys Arg Met Gln Ser
1 5 10
<210> 683
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 683
Trp Asp Val Ala Trp Leu Glu Arg Arg Ala Leu His
1 5 10
<210> 684
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 684
Val Arg Leu Pro Met Leu Ala Ser Met Gly His Gln
1 5 10
<210> 685
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 685
Asp Arg Gly Leu Thr Ile Leu Thr Asp Asp Leu Arg
1 5 10
<210> 686
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 686
Gly Trp Asn Glu Ala Thr Asn Ser Ala Arg His Thr
1 5 10
<210> 687
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 687
Glu Phe Ala Arg Phe Arg Val Phe Gly Val Ala Glu
1 5 10
<210> 688
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 688
Asn Arg Ile Gly His Gly Thr Ala Thr Gly Thr Leu
1 5 10
<210> 689
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 689
Val Thr Asp Met Leu Gly Ile Pro Lys Leu His Ala
1 5 10
<210> 690
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 690
Asp Glu Leu Val Gly Gly Ala Pro Trp Tyr Lys Ser
1 5 10
<210> 691
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 691
Gly Leu Leu Arg Glu Pro Asp Glu Leu Met Phe Leu
1 5 10
<210> 692
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 692
Gln Asn Ile Val Glu Asn Phe Ile Asp Asn Glu Arg
1 5 10
<210> 693
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 693
Ser Gly Glu Tyr Asn Leu Ile Lys Pro Asn Leu Leu
1 5 10
<210> 694
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 694
Glu Glu Ser Asn Ala Lys Leu Glu Leu Leu Ser Arg
1 5 10
<210> 695
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 695
Gly Trp Ala Asn Ser Ile Thr Tyr Arg Asn Leu Tyr
1 5 10
<210> 696
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 696
Asn Tyr Ala Val Gly Asp Arg Ile Thr Lys Asn Ile
1 5 10
<210> 697
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 697
His Gly Ile Val Phe Ser Lys Arg Pro Phe Ser Asn
1 5 10
<210> 698
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 698
Phe Asp Pro Leu Ser Arg Asn Val Pro His Lys Thr
1 5 10
<210> 699
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 699
Asn Ala Val His Arg Pro Asp Leu Asn Leu Leu Ala
1 5 10
<210> 700
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 700
Gly Met Arg Thr Gly Asp Asp Ser Pro Lys Tyr Pro
1 5 10
<210> 701
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 701
Ile Pro Gly Gln Thr Pro Arg Met Pro His Ser Lys
1 5 10
<210> 702
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 702
Lys Thr Thr Ser Met Thr Ala Leu Thr Met Gly Leu
1 5 10
<210> 703
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 703
Val Asn Tyr Gln Thr Pro Trp Asn Lys His Trp Tyr
1 5 10
<210> 704
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 704
Val Glu Ser Gly His Ala Tyr Ser Val Ser Ser Trp
1 5 10
<210> 705
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 705
Val Arg Ser Asp Met Val Ser Gly Gly Leu Gln Lys
1 5 10
<210> 706
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 706
Tyr Ala Asn Gly Ile Glu Ala Lys Asp Ser Ser Arg
1 5 10
<210> 707
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 707
Tyr Ala Trp Asp Thr Val Ala Ser Arg Asn Tyr Lys
1 5 10
<210> 708
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 708
Leu Gln Thr His Ser Ile Thr Tyr Arg His Glu Arg
1 5 10
<210> 709
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 709
Ser Leu Gly Ser Ser Phe Val Gln Gly Gly Glu Leu
1 5 10
<210> 710
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 710
Trp Glu Lys His Thr Gly Pro Leu Ser Arg Tyr Leu
1 5 10
<210> 711
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 711
Ala Phe Arg Phe Glu Phe Gln Val Pro Asp Ser His
1 5 10
<210> 712
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 712
Gly His Ala His Ser Leu Thr Gln Asn Pro Leu Phe
1 5 10
<210> 713
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 713
Gly Leu Thr Ile Met Ser Ser Arg His Ser Leu Gln
1 5 10
<210> 714
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 714
Asn Gly Met Asn Trp Leu Gln Val His Gln Leu Ser
1 5 10
<210> 715
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 715
Trp Ser Gly Gly Met Glu Asp Asn Ser Asn Arg Leu
1 5 10
<210> 716
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 716
Ala Ile Met Ser Tyr Asn Ser Pro Trp Ile Gln Gly
1 5 10
<210> 717
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 717
Asp Val Met Gln Met Phe His Gln Val His Phe Tyr
1 5 10
<210> 718
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 718
Gln Ala Asn Leu Tyr Tyr Trp Asp Pro Ser Asp Leu
1 5 10
<210> 719
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 719
Gln Arg Ala Thr Asn Asp Ile Leu Ile Arg Gly Trp
1 5 10
<210> 720
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 720
Ser Pro Met Ala Asn Val Trp Phe Asn Arg Leu Ser
1 5 10
<210> 721
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 721
Tyr Ser Ala Asn Ser Asn Pro Lys Lys Ser Leu Met
1 5 10
<210> 722
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 722
Ala Leu Asn His Asn Gly Pro Val Lys Thr Gly Leu
1 5 10
<210> 723
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 723
Asp Ala Ser Gln Tyr Pro Leu Val Ser Gly Leu Trp
1 5 10
<210> 724
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 724
Glu Pro Trp Gln Ser Arg Asp Lys Val Ile Glu Glu
1 5 10
<210> 725
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 725
Gly Leu Trp Asp Gly Lys Gly Arg Ile Val Glu Val
1 5 10
<210> 726
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 726
Gly Thr Val Ser Tyr Met Val Lys Met Asp Asn Asn
1 5 10
<210> 727
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 727
Ser Leu Gln Leu Trp Asn Ser Glu Lys Val Thr Thr
1 5 10
<210> 728
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 728
Trp Val Gly Pro Asp Ile Ile Ala Gln Met Arg Ile
1 5 10
<210> 729
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 729
Glu Ile Ile Val Met Ser Gly Ser Asn Val Thr Asn
1 5 10
<210> 730
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 730
His Ser Gly Ala Tyr Thr Ile Gln Ala Ser Tyr Lys
1 5 10
<210> 731
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 731
Met Leu Lys Met Glu Arg Pro Gly Arg Met Ala Tyr
1 5 10
<210> 732
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 732
Ser Asp His Thr Phe Lys Arg Val Met Phe Arg Trp
1 5 10
<210> 733
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 733
Glu Met Val Pro Met Lys Phe Leu Met Met Ala Lys
1 5 10
<210> 734
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 734
Asn Thr Glu Tyr Ser Arg Tyr Thr Ser Ile Trp Lys
1 5 10
<210> 735
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 735
Thr Asp Asn Gly Ser Phe Leu Gly Lys Leu Thr Ser
1 5 10
<210> 736
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 736
Thr Glu Trp Met Val Arg Ala Ser Ser Ile Gly Glu
1 5 10
<210> 737
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 737
Val Pro Val Pro Lys Lys Met Ser Leu Asp Pro Thr
1 5 10
<210> 738
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 738
Trp Pro Leu Lys Arg Phe Glu Gln Leu Pro Leu Lys
1 5 10
<210> 739
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 739
Met Leu Arg His Val Asp Leu Thr Glu Pro Asn Ala
1 5 10
<210> 740
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 740
Gln Ser Thr Leu Gly Val His Met Leu Arg Val Ser
1 5 10
<210> 741
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 741
Arg Thr Val Ile Thr Asn Glu Met Leu Leu Leu Val
1 5 10
<210> 742
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 742
Ser Glu Pro Ile Glu Lys Gly Ser Arg Thr Ile Val
1 5 10
<210> 743
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 743
Thr Leu Asn Ala Arg Asp Gln Leu Ser Ile Asn Gly
1 5 10
<210> 744
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 744
Gly Thr Ala Leu Asn Leu Gln Lys Asp Ile Asn Lys
1 5 10
<210> 745
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 745
Ser Gly Trp His Leu Val Met Ser Met Ser Ile Gly
1 5 10
<210> 746
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> nerve-binding peptide
<400> 746
Thr Ser Ala His His Asp Arg Thr Leu Ala Gly Ser
1 5 10
<210> 747
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> HNP401-N-2 with GG linker
<220>
<221> MOD_RES
<222> (1)..(1)
<223> 5FAM
<220>
<221> MOD_RES
<222> (17)..(17)
<223> NH2
<400> 747
Gln Val Pro Trp Glu Glu Pro Tyr Tyr Val Val Lys Lys Ser Ser Gly
1 5 10 15
Gly
<210> 748
<211> 20
<212> PRT
<213> Artificial Sequence
<220>
<223> HNP401with GCC linker
<220>
<221> MOD_RES
<222> (1)..(1)
<223> Ac
<220>
<221> MOD_RES
<222> (20)..(20)
<223> CONH2
<400> 748
Ser Gly Gln Val Pro Trp Glu Glu Pro Tyr Tyr Val Val Lys Lys Ser
1 5 10 15
Ser Gly Gly Cys
20
<210> 749
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> NP41
<220>
<221> MOD_RES
<222> (1)..(1)
<223> Ac
<400> 749
Ser His Ser Asn Thr Gln Thr Leu Ala Lys Ala Pro Glu His Thr Gly
1 5 10 15
Lys
Claims (63)
- 대상체(subject)에서 요관(ureter)을 가시화(visualizing)하는 방법으로서, 상기 방법이
(a) 대상체에게 유효량의 형광 접합체(fluorescent conjugate)를 투여하는 단계로서, 상기 형광 접합체가 펩티드 및 형광 모이어티(fluorescent moiety)를 포함하는, 단계; 및
(b) 투여 후 요관 내 형광 모이어티의 형광을 검출하는 단계를 포함하고;
상기 형광 접합체의 펩티드가 서열번호 1-14, 16, 18-82 및 84-748로 이루어진 그룹으로부터 선택된 아미노산 서열을 포함하는, 방법. - 제1항에 있어서, 상기 대상체가 수술 절차를 받고 있는, 방법.
- 제2항에 있어서, 상기 형광 접합체가 수술 절차 전에 초기에 투여되는, 방법.
- 제3항에 있어서, 상기 형광 접합체가 초기 투여 후 대상체에게 추가로 투여되지 않는, 방법.
- 제2항 내지 제4항 중 어느 한 항에 있어서, 상기 수술 절차가 부인과, 비뇨기과, 결장직장 또는 심혈관 수술 절차를 포함하는, 방법.
- 제2항 내지 제4항 중 어느 한 항에 있어서, 상기 수술 절차가 복부 또는 골반 절차를 포함하는, 방법.
- 제2항 내지 제4항 중 어느 한 항에 있어서, 상기 수술 절차가 신장, 방광, 전립선, 자궁, 남성 또는 여성 생식 기관, 직장, 결장, 소장 또는 대장에 대해 수행되는, 방법.
- 제2항 내지 제4항 중 어느 한 항에 있어서, 상기 수술 절차가 개복 수술 절차, 복강경 수술 절차, 현미경 절차 또는 내시경 절차인, 방법.
- 제2항 내지 제4항 중 어느 한 항에 있어서, 상기 수술 절차가 암(cancer) 수술 절차, 더욱 특히 전립선암(prostate cancer) 수술 절차 또는 결장직장암(colorectal cancer) 수술 절차인, 방법.
- (a) 수술 절차를 받고 있는 대상체에게 유효량의 형광 접합체를 투여하는 단계로서, 상기 형광 접합체가 펩티드 및 형광 모이어티를 포함하는, 단계; 및
(b) 요관 내 형광 모이어티의 형광을 검출함으로써 대상체에서 요관을 가시화하는 단계를 포함하는 방법으로서,
상기 형광 접합체의 펩티드가 서열번호 1-14, 16, 18-82 및 84-748로 이루어진 그룹으로부터 선택된 아미노산 서열을 포함하는, 방법. - 제10항에 있어서, 상기 형광 접합체가 수술 절차 전에 초기에 투여되는, 방법.
- 제11항에 있어서, 상기 형광 접합체가 초기 투여 후 대상체에게 추가로 투여되지 않는, 방법.
- 제10항 내지 제12항 중 어느 한 항에 있어서, 상기 수술 절차가 부인과, 비뇨기과, 결장직장 또는 심혈관 수술 절차를 포함하는, 방법.
- 제10항 내지 제12항 중 어느 한 항에 있어서, 상기 수술 절차가 복부 또는 골반 절차를 포함하는, 방법.
- 제10항 내지 제12항 중 어느 한 항에 있어서, 상기 수술 절차가 신장, 방광, 전립선, 자궁, 남성 또는 여성 생식 기관(reproductive system), 직장, 결장, 소장 또는 대장에 대해 수행되는, 방법.
- 제10항 내지 제12항 중 어느 한 항에 있어서, 상기 수술 절차가 개복 수술 절차, 복강경 수술 절차, 현미경 절차 또는 내시경 절차인, 방법.
- 제10항 내지 제12항 중 어느 한 항에 있어서, 상기 수술 절차가 암 수술 절차, 더욱 특히 전립선암 수술 절차 또는 결장직장암 수술 절차인, 방법.
- 요관의 손상을 감소시키는 방법으로서, 상기 방법이
(a) 수술 절차 전에 요관 손상 위험이 있는 대상체를 식별하는 단계;
(b) 수술 절차를 받고 있는 대상체에게 유효량의 형광 접합체를 투여하는 단계로서, 상기 형광 접합체가 펩티드 및 형광 모이어티를 포함하는, 단계; 및
(c) 요관 내 형광 모이어티의 형광을 검출하여 요관을 가시화하는 단계를 포함하고;
상기 형광 접합체의 펩티드가 서열번호 1-14, 16, 18-82 및 84-748로 이루어진 그룹으로부터 선택된 아미노산 서열을 포함하는, 방법. - 제18항에 있어서, 상기 형광 접합체가 수술 절차 전에 초기에 투여되는, 방법.
- 제19항에 있어서, 상기 형광 접합체가 초기 투여 후 대상체에게 추가로 투여되지 않는, 방법.
- 제18항 내지 제20항 중 어느 한 항에 있어서, 상기 요관 손상이 결찰, 각도, 절개, 열상, 압착, 허혈 또는 절제술로 인해 발생하는, 방법.
- 제18항 내지 제21항 중 어느 한 항에 있어서, 상기 수술 절차가 부인과, 비뇨기과, 결장직장 또는 심혈관 수술 절차를 포함하는, 방법.
- 제18항 내지 제21항 중 어느 한 항에 있어서, 상기 수술 절차가 복부 또는 골반 절차를 포함하는, 방법.
- 제18항 내지 제21항 중 어느 한 항에 있어서, 상기 수술 절차가 신장, 방광, 전립선, 자궁, 남성 또는 여성 생식 기관, 직장, 결장, 소장 또는 대장에 대해 수행되는, 방법.
- 제18항 내지 제21항 중 어느 한 항에 있어서, 상기 수술 절차가 개복 수술 절차, 복강경 수술 절차, 현미경 절차 또는 내시경 절차인, 방법.
- 제18항 내지 제21항 중 어느 한 항에 있어서, 상기 수술 절차가 암 수술 절차, 보다 특히 전립선암 수술 절차 또는 결장직장암 수술 절차인, 방법.
- 제1항 내지 제26항 중 어느 한 항에 있어서, 상기 펩티드가 신경 표적화 펩티드(nerve targeting peptide)인, 방법.
- 제1항 내지 제27항 중 어느 한 항에 있어서, 상기 형광 모이어티가 펩티드의 N-말단, C-말단, 또는 N-말단과 C-말단 둘 모두에 접합되는, 방법.
- 제1항 내지 제28항 중 어느 한 항에 있어서, 투여 후 적어도 1시간, 적어도 2시간, 적어도 3시간, 적어도 4시간, 적어도 5시간, 적어도 6시간, 적어도 7시간 또는 적어도 8시간의 기간 이내에 형광 모이어티의 형광을 검출하는 단계를 추가로 포함하는, 방법.
- 제1항 내지 제29항 중 어느 한 항에 있어서, 투여 후 1시간 이상, 2시간 이상, 3시간 이상, 4시간 이상, 5시간 이상, 6시간 이상, 7시간 이상 또는 8시간 이상의 기간 동안; 또는 투여 후 30분, 1시간, 2시간, 3시간, 4시간, 5시간, 6시간, 7시간 후 또는 8시간 이상 후에 형광 모이어티의 형광을 검출하는 단계를 추가로 포함하는, 방법.
- 제1항 내지 제30항 중 어느 한 항에 있어서, 요관 내 형광 모이어티의 형광을 검출하는 단계가 요관 내 소변 유동에서 형광 모이어티를 검출하는 단계, 더욱 특히 요관 내 소변의 연동 유동(peristaltic flow)에서 형광 모이어티를 검출하는 단계를 포함하는, 방법.
- 제1항 내지 제31항 중 어느 한 항에 있어서, 상기 펩티드가 서열번호 1, 서열번호 2, 및 서열번호 3으로 이루어진 그룹으로부터 선택된 아미노산 서열을 포함하는, 방법.
- 제1항 내지 제31항 중 어느 한 항에 있어서, 상기 펩티드가 서열번호 1-14, 16, 20-28 및 96-102로 이루어진 그룹으로부터 선택된 아미노산 서열을 포함하는, 방법.
- 제1항 내지 제31항 중 어느 한 항에 있어서, 상기 펩티드가 서열번호 1, 4, 7-14, 20-28 및 96-102로 이루어진 그룹으로부터 선택된 아미노산 서열을 포함하는, 방법.
- 제1항 내지 제31항 중 어느 한 항에 있어서, 상기 펩티드가 서열번호 18, 19, 29-82, 84-95 및 103-746으로 이루어진 그룹으로부터 선택된 아미노산 서열을 포함하는, 방법.
- 제1항 내지 제31항 중 어느 한 항에 있어서, 상기 펩티드가 서열번호 75-82, 84-95, 및 103-187로 이루어진 그룹으로부터 선택된 아미노산 서열을 포함하는, 방법.
- 제1항 내지 제31항 중 어느 한 항에 있어서, 상기 펩티드가 서열번호 55-74 및 188-362로 이루어진 그룹으로부터 선택된 아미노산 서열을 포함하는, 방법.
- 제1항 내지 제31항 중 어느 한 항에 있어서, 상기 펩티드가 서열번호 33-54 및 363-446으로 이루어진 그룹으로부터 선택된 아미노산 서열을 포함하는, 방법.
- 제1항 내지 제31항 중 어느 한 항에 있어서, 상기 펩티드가 서열번호 18, 19, 29-32 및 447-471로 이루어진 그룹으로부터 선택된 아미노산 서열을 포함하는, 방법.
- 제1항 내지 제31항 중 어느 한 항에 있어서, 상기 펩티드가 서열번호 472-678로 이루어진 그룹으로부터 선택된 아미노산 서열을 포함하는, 방법.
- 제1항 내지 제31항 중 어느 한 항에 있어서, 상기 펩티드가 서열번호 679-746으로 이루어진 그룹으로부터 선택된 아미노산 서열을 포함하는, 방법.
- 제1항 내지 제31항 중 어느 한 항에 있어서, 상기 펩티드가 서열번호 1, 서열번호 7, 서열번호 11, 서열번호 20, 서열번호 21, 서열번호 25, 및 서열번호 99로 이루어진 그룹으로부터 선택된 아미노산 서열을 포함하는, 방법.
- 제42항에 있어서, 상기 펩티드가 서열번호 21의 아미노산 서열을 포함하는, 방법.
- 제42항에 있어서, 상기 펩티드가 서열번호 1의 아미노산 서열, 또는 N-말단 또는 C-말단으로부터 결실된 2 내지 8개의 아미노산을 갖는 이의 변이체(variant)를 포함하는, 방법.
- 제44항에 있어서, 상기 펩티드가 서열번호 1, 서열번호 20, 서열번호 22, 서열번호 23, 서열번호 24, 서열번호 25, 서열번호 26, 서열번호 27 또는 서열번호 28의 아미노산 서열을 포함하는, 방법.
- 제45항에 있어서, 상기 아미노산 서열이 C-말단에 GC, GG 또는 GGC 아미노산 서열을 추가로 포함하는, 방법.
- 제46항에 있어서, 상기 아미노산 서열이 서열번호 4, 서열번호 7, 서열번호 8, 서열번호 9, 서열번호 10, 서열번호 11, 서열번호 12, 서열번호 13, 서열번호 14, 서열번호 21, 서열번호 102, 서열번호 101, 서열번호 100, 서열번호 99, 서열번호 98, 서열번호 97, 및 서열번호 96으로 이루어진 그룹으로부터 선택되는, 방법.
- 제1항 내지 제47항 중 어느 한 항에 있어서, 상기 형광 모이어티가 형광 단백질, 형광 펩티드, 형광 염료 및 이들의 조합으로 이루어진 그룹으로부터 선택되는, 방법.
- 제1항 내지 제48항 중 어느 한 항에 있어서, 상기 형광 모이어티가 크산텐; 비만; 쿠마린; 방향족 아민; 벤조푸란; 형광 시아닌; 카르바졸; 디시아노메틸렌 피란; 폴리메틴; 옥사벤잔트란; 피릴륨; 카르보스틸; 페릴렌; 아크리돈; 퀴나크리돈; 루브렌; 안트라센; 코로넨; 페난트레센; 피렌; 부타디엔; 스틸벤; 포르피린; 프탈로시아닌; 란탄족 금속 킬레이트 착물(complex); 희토류 금속 킬레이트 착물; 또는 이들의 유도체를 포함하는, 방법.
- 제1항 내지 제48항 중 어느 하나에 있어서, 상기 형광 모이어티가 카르복시플루오레세인, 5-카르복시플루오레세인, 6-카르복시플루오레세인, 5(6)-카르복시플루오레세인, 플루오레세인 이소티오시아네이트, 플루오레세인-5-이소티오시아네이트, 플루오레세인-6-이소티오시아네이트, 5,6-디카르복시플루오레세인, 5-설포플루오레세인, 6-설포플루오레세인, 설폰플루오레세인, 석시닐플루오레세인, 5-카르복시 SNARF-1, 6-카르복시 SNARF-1, 카르복시플루오레세인 설포네이트, 카르복시플루오레세인 쯔비터이온, 카르복시플루오레세인 4급 암모늄, 카르복시플루오레세인 포스포네이트, 카르복시플루오레세인 GABA, 카르복시플루오레세인-cys-Cy5 또는 플루오레세인 글루타티온을 포함하는, 방법.
- 제1항 내지 제48항 중 어느 한 항에 있어서, 상기 형광 모이어티가 카르복시플루오레세인(FAM)을 포함하는, 방법.
- 제1항 내지 제48항 중 어느 한 항에 있어서, 상기 형광 모이어티가 5-카르복시 로다민 110, 6-카르복시 로다민 110, 테트라메틸로다민-6-이소티오시아네이트, 5-카르복시테트라메틸로다민, 5-카르복시 로돌 유도체, 테트라메틸 및 테트라에틸 로다민, 디페닐디메틸 및 디페닐디에틸 로다민, 디나프틸 로다민, 로다민 101 설포닐 클로라이드 또는 기타 로다민 염료를 포함하는, 방법.
- 제1항 내지 제48항 중 어느 한 항에 있어서, 상기 형광 모이어티가 Cy2, Cy3, Cy3B, Cy3.5, Cy5, Cy5.5, Cy7 또는 인도시아닌 그린을 포함하는, 방법.
- 제1항 내지 제48항 중 어느 한 항에 있어서, 상기 형광 모이어티가 IR800CW, 시안 형광 단백질(CFP), EGFP, 5-FAM, 6-FAM, FAM, 플루오레세인, IAEDANS, EDANS, BODIPY FL, TRITC, Cy5, Cy3, YFP, LC 레드 640, Alexa Fluor 546, 테트라메틸로다민, Dabcyl, QSY 7, QSY 9, QSY 21, 또는 BBQ-650 염료를 포함하는, 방법.
- 제1항 내지 제31항 중 어느 한 항에 있어서, 상기 형광 접합체가 서열번호 747을 포함하는, 방법.
- 제1항 내지 제31항 중 어느 한 항에 있어서, 상기 펩티드가 서열번호 20을 포함하고, 상기 형광 모이어티가 FAM을 포함하는, 방법.
- 제1항 내지 제31항 중 어느 한 항에 있어서, 상기 펩티드가 서열번호 21을 포함하고, 상기 형광 모이어티가 FAM을 포함하는, 방법.
- 제1항 내지 제57항 중 어느 한 항에 있어서, 상기 형광 접합체가 정맥내로 투여되는, 방법.
- 제1항 내지 제57항 중 어느 한 항에 있어서, 상기 형광 접합체가 경구 투여되는, 방법.
- 제1항 내지 제59항 중 어느 한 항에 있어서, 상기 형광 접합체를 약제학적으로 허용되는 부형제(excipient)를 포함하는 약제학적 조성물에 투여하는 단계를 추가로 포함하는, 방법.
- 제1항 내지 제60항 중 어느 한 항에 있어서, 상기 형광 접합체의 형광 검출에 의해 대상체에서 신경을 가시화하는 단계를 추가로 포함하는, 방법.
- 제61항에 있어서, 상기 신경 및 요관의 가시화가 수술 중 대상체에서 동시에 검출되는, 방법.
- 제61항에 있어서, 상기 신경 및 요관의 가시화가 수술 중 대상체에서 상이한 시간에 검출되는, 방법.
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| US4452720A (en) | 1980-06-04 | 1984-06-05 | Teijin Limited | Fluorescent composition having the ability to change wavelengths of light, shaped article of said composition as a light wavelength converting element and device for converting optical energy to electrical energy using said element |
| US4439356A (en) | 1981-03-03 | 1984-03-27 | Syva Company | Unsymmetrical fluorescein derivatives |
| US4496542A (en) | 1981-03-30 | 1985-01-29 | Usv Pharmaceutical Corporation | N-substituted-amido-amino acids |
| US4659839A (en) | 1984-10-10 | 1987-04-21 | Mallinckrodt, Inc. | Coupling agents for radiolabeled antibody fragments |
| US5330900A (en) | 1987-12-31 | 1994-07-19 | Tropix, Inc. | Chemiluminescent 3-(substituted adamant-2'-ylidene) 1,2-dioxetanes |
| US5066580A (en) | 1988-08-31 | 1991-11-19 | Becton Dickinson And Company | Xanthene dyes that emit to the red of fluorescein |
| US5227487A (en) | 1990-04-16 | 1993-07-13 | Molecular Probes, Inc. | Certain tricyclic and pentacyclic-hetero nitrogen rhodol dyes |
| US5750409A (en) | 1991-11-18 | 1998-05-12 | Boehringer Mannheim Gmbh | Pentacyclic compounds and their use as absorption or fluorescent dyes |
| US5847162A (en) | 1996-06-27 | 1998-12-08 | The Perkin Elmer Corporation | 4, 7-Dichlororhodamine dyes |
| US6080852A (en) | 1996-06-27 | 2000-06-27 | The Perkin-Elmer Corporation | 4,7-dichlororhodamine dyes |
| US6008379A (en) | 1997-10-01 | 1999-12-28 | The Perkin-Elmer Corporation | Aromatic-substituted xanthene dyes |
| US5936087A (en) | 1997-11-25 | 1999-08-10 | The Perkin-Elmer Corporation | Dibenzorhodamine dyes |
| US20180043037A1 (en) * | 2016-08-12 | 2018-02-15 | Invuity, Inc. | Tissue specific markers for preoperative and intraoperative localization and visualization of tissue |
| EP3661539B1 (en) | 2017-08-02 | 2024-10-09 | The Regents of The University of California | Optimized peptides for targeting human nerves and their use in image guided surgery, diagnostics and therapeutic delivery |
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| WO2022155385A1 (en) | 2022-07-21 |
| CA3202831A1 (en) | 2022-07-21 |
| CN116916971A (zh) | 2023-10-20 |
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