KR102216566B1 - 종양 혈관형성을 억제하는 vegf 딥 블로커를 포함하는 암 치료용 조성물 및 이의 제조방법 - Google Patents
종양 혈관형성을 억제하는 vegf 딥 블로커를 포함하는 암 치료용 조성물 및 이의 제조방법 Download PDFInfo
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- KR102216566B1 KR102216566B1 KR1020197000553A KR20197000553A KR102216566B1 KR 102216566 B1 KR102216566 B1 KR 102216566B1 KR 1020197000553 A KR1020197000553 A KR 1020197000553A KR 20197000553 A KR20197000553 A KR 20197000553A KR 102216566 B1 KR102216566 B1 KR 102216566B1
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Abstract
본 발명은 혈관형성을 억제하는 암 치료용 조성물 및 이의 제조방법에 관한 것이다. 본 발명에 따른 혈관형성 억제제는 혈관내피 생성인자 수용체 1(VEGFR1)의 혈관내피 생성인자 결합 도메인 및 뉴로필린 1(neuropilin-1, NRP1)의 b1 도메인을 포함하는 것을 특징으로 하는 융합 단백질을 포함하는 암 치료용 조성물이다. 상기 신규한 융합 단백질은 혈관 내피 생성 인자가 세포막에서 그 수용체와 결합하는 것을 블로킹하는 혈관형성 억제제로서, 암세포 증식, 암 성장 및 전이를 억제하는 효과가 있다. 또한, 상기 융합 단백질은 항암제로 유용하게 이용될 수 있을 뿐 아니라, 종래의 혈관형성 억제제와 비교하여 보다 더 적은 용량으로 효율적인 항암작용을 나타낸다.
Description
본 발명은 암 성장 및 전이를 억제하는 신규한 혈관형성 억제 융합 단백질 및 이의 제조방법에 관한 것이다.
혈관 형성(angiogenesis)은 적절한 기관(organ)의 성장 및 손상회복에 필수적이며 매우 정교하게 조절되는 과정이다. 이러한 과정의 조절 불균형은 염증성, 심혈관성, 면역성 또는 악성 질환을 초래한다. 혈관 내피 생성 인자 A(vascular endothelial growth factor A; VEGFA)는 혈관 형성의 주요 유도체이며 암 성장 및 진행에 관여하는 것으로 알려져 있다. 여덟 개의 엑손(exon)으로 이루어진 VEGFA 유전자는 최소한 6가지 주요 VEGFA 동형 단백질(isoform)인 VEGFA-121, VEGFA-145, VEGFA-165, VEGFA-183, VEGFA-189 및 VEGFA-206을 생산한다. 주요한 세 개의 동형 단백질은 VEGFA-121, VEGFA-165, 및 VEGFA-189이고 세포에서 분비되는데, 이들의 특성, 생물학적 이용 가능성 및 분포는 서로 다르다. 하지만, 이들 중 대부분의 혈관 형성 기능은 VEGFA-165에 의해 조절되는 것으로 여겨진다.
VEGFA는 두 개의 티로신 인산화 수용체(tyrosine kinase receptor)인 VEGF 수용체 (VEGF receptor; VEGFR)1 및 VEGFR2에 결합함으로써, 신생 혈관의 발달에 관여할 뿐 아니라 내피세포 생존(vascular maintenance)할 수 있도록 세포사멸(apoptosis)로부터 보호한다. 혈관 형성 신호전달은 VEGFA가 VEGFR2(KDR) 및 공수용체(coreceptor)인 뉴로필린 1(Neurophilin-1; NRP1)에 결합함으로써 매개된다. 비록 VEGFR2가 혈관형성 및 맥관형성(vasculogenesis)에 관여하는 주요 수용체이긴 하지만, VEGFR1이 VEGFR2에 비해 VEGFA에 대한 친화도가 훨씬 높다.
VEGFA 발현량은 상처 치유나 저산소 환경과 같은 생리적인 필요에 의해 증가되기도 하지만, 증식성 망막증(proliferative retinopathy), 관절염, 건선(psoriasis) 및 암과 같은 병리학적 상태에서도 증가된다. 더구나, VEGFA는 주변 혈관으로부터 새로운 혈관의 성장을 유도하여 암세포가 산소와 영양분을 얻고 암 전이를 용이하게 하기 때문에, 종양 맥관형성의 중요한 매개체이다.
그동안 항체 제제, 앱타머(aptamer) 및 티로신 인산화 억제제와 같은 항 VEGF 약제들이 많이 개발되어 왔지만, 최근 VEGFA에 친화도가 높은 융합 단백질인 애플리버셉트(aflibercept; VEGF-trap)이 차세대 의약품으로 각광받고 있다. 이 약제는 VEGFR1과 VEGFR2의 결합 부위로 이루어져 있다.
관련 선행 기술로는 2014년 한국공개특허 등록번호 제 1397088 호 "암세포 증식 억제와 혈관형성 억제를 위한 융합 단백질 및 이를 포함한 항암 조성물"에서 위암 또는 유방암 치료에 효과가 있는 암 특이적 항체와 혈관형성 억제제를 결합한 융합 단백질을 개시하고 있다.
관련 선행 문헌으로 황반변성에 대한 VEGF Trap-Eye(aflibercept; 상품명, Eylea®)의 3상 임상시험 분석결과를 제네론이 바이엘 헬스케어와 함께 발표하였는데, 라니비주맙 투여군과 비교하여 더 적은 투여횟수로 치료효과를 나타내었다.
Finely 등은 암 성장 속도와 VEGF 분비를 포함하여 암 특성을 연구하기 위해 인간의 암을 이식한 쥐 모델을 개발하여, VEGF-trap을 이용한 VEGF 분비 속도를 예측하고 전 임상단계에서 in vivo 암 모델로 이용할 수 있음을 시사하고 있다.
본 발명자들은 VEGF-trap보다 높은 친화도로 VEGFA에 결합하여 VEGFA 신호전달을 블로킹할 수 있도록 VEGFR1의 Ig2 도메인과 NRP1의 b1 도메인을 가지는 미끼 수용체(decoy receptor)인 혈관형성 억제제(VEGF Deep Blocker; VEEP) 융합 단백질을 제조하고 본 발명을 완성하였다
본 발명은 암 성장 및 전이를 억제하는 신규한 혈관형성 억제 융합 단백질 및 이의 제조방법을 제공하는 것을 목적으로 한다.
본 발명은 암 성장 및 전이를 억제하는 신규한 혈관형성 억제 융합 단백질을 암호화하는 재조합 DNA를 제공하는 것을 목적으로 한다.
상기한 목적을 위하여 본 발명의 제 1 의 형태는 혈관 내피 생성인자 수용체 1(VEGFR1)의 Ig2 도메인 및 뉴로필린 1(NRP1)의 b1 도메인을 포함하는 것을 특징으로 하는 융합 단백질을 제공한다. 상기 단백질을 포함하는 조성물은 암 성장 및 전이를 억제하는 암 치료용으로 이용 가능하다.
본 발명에 따른 신규한 융합 단백질은 혈관 내피 생성 인자가 세포막에서 그 수용체와 결합하는 것을 블로킹하는 혈관형성 억제제로서, 암세포 증식, 암 성장 및 전이를 억제하는 효과가 있다. 상기 융합 단백질을 포함하는 조성물은 항암제로 유용하게 이용될 수 있을 뿐 아니라, 종래의 혈관형성 억제제와 비교하여 보다 더 적은 용량으로 효율적인 항암작용 효과를 나타낸다.
도 1은 VEGFR1-NRP1-Fc 융합 단백질 모식도를 보여주는 도면이다.
도 2는 VEEP 융합 단백질의 발현을 보인다. 도 3은 LLC 쥐 모델에서 VEEP의 항암효과를 대조군 VEGF-trap과 비교분석한 것이다.
도 4는 LLC 쥐 모델에 VEEP을 처리하고 30일 이후에 종료점 분석(endpoint analysis)한 것이다.
도 2는 VEEP 융합 단백질의 발현을 보인다. 도 3은 LLC 쥐 모델에서 VEEP의 항암효과를 대조군 VEGF-trap과 비교분석한 것이다.
도 4는 LLC 쥐 모델에 VEEP을 처리하고 30일 이후에 종료점 분석(endpoint analysis)한 것이다.
발명의 실시를 위한 최선의 형태
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시 예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 요지에 따라 본 발명의 범위가 이들 실시예에 의해 제한되지 않는다는 것은 이 발명이 속 하는 기술분야에서 통상의 지식을 가진 자에 있어서 자명할 것이다.
본 발명의 제 1 의 형태는 혈관 내피 생성인자 수용체 1(VEGFR1)의 Ig2 도메인 및 뉴로필린 1(NRP1)의 b1 도메인을 포함하는 것을 특징으로 하는 융합 단백질이다. 보다 구체적으로 상기 혈관내피 생성인자 수용체 1은 이에 제한되는 것은 아니나 서열번호 1일 수 있고, 상기 Ig2 도메인 및 뉴로필린 1(NRP1)의 b1 도메인은 다양한 형태일 수 있으나 바람직하게는 서열번호 2의 Ig2 도메인 및 뉴로필린 1(NRP1)의 b1 도메인이다. 상기 융합단백질은 면역글로블린의 Fc 도메인을 추가적으로 포함할 수 있으며, 다양한 Fc 도메인이 이용될 수 있으나, 바람직하게는 서열번호 3의 Fc 도메인을 사용할 수 있다. 상기 융합단백질은 발현을 위하여 리더단백질을 추가로 포함할 수 있으며, 다양한 리더 단백질이 이용될 수 있으나 바람직하게는 서열번호 4의 리더단백질이 이용될 수 있다. 본 발명에 따른 융합단백질은 가장 바람직하게는 서열번호 5의 단백질이다.
본 발명의 제 2 의 형태는 상기 융합단백질을 포함하는 암 치료용 조성물이다. 본 발명의 기술분야에 속하는 당업자는 다양한 형태의 약물전달물질, 부형제, 안정화제 등을 추가적으로 포함할 수 있으며, 이러한 다양한 제형은 본 발명의 요지 범위에 속한다.
본 발명의 제 3 의 형태는 상기 단백질을 암호화하는 DNA 절편이다. 본 발명이 속하는 기술분야 속하는 당업자는 유전자 코드의 퇴하에 따라 본 발명의 융합단백질을 암호화하는 다양한 서열의 DNA 서열을 제조할 수 있으며, 최종적으로 본 발멸의 단백질을 암호화내는 어떠한 형태의 DNA서열도 본 발명의 요지 범위에 든다.
본 발명의 제 4 의 형태는 상기 재조합벡터를 형질전환한 형질전환체이다. 상기 형질전환체는 다양한 세포를 사용할 수 있으며, 인간유래 세포를 사용하는 것이 바람직하며, 가장 바람직하게는 HEK293E 세포 이다.
본 발명의 제 5 의 형태는 상기 본 발명에 따른 형질전환된 세포를 배양하는 단계; 및 상기 세포의 배양액으로부터 융합 단백질을 분리하는 것을 특징으로 하는 단백질 제조방법을 제공한다.
발명의 실시를 위한 형태
실험 방법
1. VEGFR1-NRP1-Fc 융합 단백질 제조
VEGFR1 유전자의 Ig2 도메인은 합성한 DNA(이지바이오; EZbio)를 PCR하여 얻었고, NRP1의 b1 도메인은 cDNA를 한국생명공학연구원 인간 유전자 은행에서 구입하였다. 상기 두 DNA 조각을 human Fc DNA 조각에 이어 붙여서 융합 단백질을 얻었다. 클로닝한 DNA를 HEK293E 세포에서 발현하고 그 배양액을 프로틴(Protein) A 수지(resin)로 정제하였다. 정제된 단백질의 농도는 A280 흡광도를 측정함으로써 계산하였다.
2.
In vitro
친화도 테스트(ELISA)
VEEP 및 VEGF-trap을 VEGF가 코팅된 96-웰 플레이트(well plate)에 첨가한다. 몇 차례 씻어준 뒤, HRP가 접합된 항-인간 Fc(HRP-conjugated anti-human Fc)를 넣고, 안정화된 TMB를 첨가한 후, 450 nm에서 흡광도를 측정한다.
3. VEEP 동물실험결과 도출방법
대상질환 및 고형암 동물모델
약물의 항암효과 확인을 위한 동물모델로 6주령의 수컷 C57BL/6 마우스를 코아텍(평택시, 한국)에서 구입하여 사용하였다. 동물은 동물실험윤리 규정에 따라 1주일의 적응기간을 거친 후 진행하였다. 마우스 고형암 유도에는 LLC(Lewis lung carcinoma) 세포주를 ATCC로부터 구매하여 사용하였다.
동물 생체 내 VEEP의 항암효과 및 종료점 분석
6주령 C57BL/6 마우스의 오른쪽 측면 등쪽(Right flank region)에 1 x 106 개 LLC cell을 피하(subcutaneous, s.c) 주입하였다. 이 후 9일째부터 3일 간격으로 총 8번의 VEEP와 VEGF-trap을 각 25 mg/kg로 피하 투여하였다. 30일에 걸쳐 3-4일 간격으로 고형암의 증식을 측정하고 생존을 관찰하였다. 고형암의 크기측정은 전자 디지털 캘리퍼스(electronic digital caliper)를 이용하여 직교로 가로(긴 지름)와 세로(짧은 지름)길이를 측정하였고, 고형암의 부피는Π/6 x (가로)2 x 세로로 계산하여 산출하였다. 30일째, 마우스를 희생하여 고형암을 적출한 뒤 미세저울을 이용하여 무게를 측정하였다.
<실시예 1> 융합단백질
정제한 VEGFR1-NRP1-Fc 융합 단백질을 환원(Reducing) & 비환원(non-reducing) 조건에서 SDS-PAGE 분석으로 단량체(monomer)와 이량체(dimer)가 예상 크기 위치에 나타나는 것을 확인하였다(도 2).
<실시예 2> 친화도 분석
제조한 융합 단백질인 VEEP의 VEGFA에 대한 친화도를 특정하기 위해, ELISA 분석을 통하여 VEGF의 수용체 또는 블로커에 대한 친화도를 분석하였다. 친화도 테스트를 위해 VEGFA 동형 단백질 중 VEGF165를 사용하였다. 것이다. 대조군으로는 세포에서 자연적으로 발현되는 VEGFA 수용체들인 VEGFR1, VEGFR2, NRP1 및 NRP2를 포함하여 시판되고 있는 블로커들인 VEGF-trap, 베바시주맵(Bevacizumab) 및 라니비주맙(ranibizumab)을 사용하여 비교 분석하였다. 테스트 결과, 대조군 중에서는 VEGF-trap이 결합 친화도가 가장 높게 나타났다. 그에 비해 본 발명자들이 제조한 융합 단백질인 VEEP이 모든 대조군들과 비교하여 VEGF165에 대해 결합 친화도가 가장 높게 나타났으며, VEGF-trap보다 10배 정도 높은 결합 친화도를 보였다(표 1).
<실시예 3> 항암효과 분석
본 발명에 따라 제조하고 정제한 VEEP 융합 단백질의 항암 효과를 측정하기 위해 LLC 쥐 모델을 이용하여 고형암의 증식을 측정하고 생존을 관찰하였다. LLC 쥐의 고형암 증식을 측정한 결과, 블로커를 처리하지 않은 대조군은 암의 크기가 13105 mm3로 측정되었다. VEGF-trap을 처리한 경우 크기가 9479 mm3로 감소되었으나, 쥐 모델 개체간에 그 효과의 편차가 크게 나타났다. 이에 반해, VEEP을 처리한 쥐의 고형암 크기는 5872 mm3로 측정되었으며, 이는 블로커를 처리하지 않은 대조군과 비교하여 항암 효과가 유의적으로 감소되었음을 관찰하였다(도 3). 또한, VEGF-trap의 항암 효과보다 우수한 결과를 보였다. 생존율에서도 VEEP 융합 단백질은 80%로 측정되었는데, 이는 VEGF-trap 처리한 대조군(80%)이나 블로커를 처리하지 않은 대조군(0%)에 비해 월등한 결과이다. 따라서, 본 발명에서 제조한 VEEP 융합 단백질을 VEGF-trap으로 치료할 수 없는 환자의 경우에 사용할 수 있다고 여겨진다.
<실시예 4> 종료점 분석
LLC 쥐 모델에서 LLC 쥐에 VEEP을 처리하고 30일 째, 암의 무게와 크기를 측정한 결과, 고형암의 무게는 VEGF-trap을 처리한 대조군(7.49g)에 비해 VEEP 융합 단백질을 처리한 쥐(5.15g)에서 유의적으로 감소되었음을 확인하였다(도 3). 종양의 크기를 보면, VEGF-trap을 처리한 쥐의 경우 개체 별로 크기의 편차가 크게 나타남을 확인할 수 있었지만 VEEP를 처리한 쥐는 암 크기가 평균적으로 더 작았으며 개체간에 유사한 수준으로 감소되었음을 확인할 수 있다(도 4). 따라서, 상기 항암 효과 분석의 결과에서와 동일하게, 본 발명의 VEEP 블로커는 VEGF-trap으로 치료 효과가 없었던 환자의 경우에 사용할 수 있다고 여겨진다.
참고문헌
1. Arcondeguy, T., et al. (2013). VEGF-A mRNA processing, stability and translation: a paradigm for intricate regulation of gene expression at the post-transcriptional level. Nucleic Acids Res 41, 7997-8010.
2. Carmeliet,P. (2005) Angiogenesis in life, disease and medicine. Nature 438, 932-936.
3. Ferrara,N. (2005) The role of VEGF in the regulation of physiological and pathological angiogenesis. EXS 209-231.
4. Bhagat, N., et al. (2009)Diabetic macular edema: pathogenesis and treatment. Surv. Ophthalmol. 54(1), 1-32.
5. Houck,K.A., et al. (1991) The vascular endothelial growth factor family: identification of a fourth molecular species and characterization of alternative splicing of RNA. Mol. Endocrinol. 5, 1806.1814.
6. Vempati,P., Popel,A.S. and Mac Gabhann,F. (2011) Formation of VEGF isoform-specific spatial distributions governing angiogenesis: computational analysis. BMC Syst. Biol. 5, 59.
7. Houck, K.A., et al. (1992) Dual regulation of vascular endothelial growth factor bioavailability by genetic and proteolytic mechanisms. J. Biol. Chem. 267, 26031-26037.
8. Carmeliet,P. (2005) VEGF as a key mediator of angiogenesis in cancer. Oncology 69(Suppl. 3), 4-10.
9. Ferrara,N., Gerber,H.P. and LeCouter,J. (2003) The biology of VEGF and its receptors. Nat. Med. 9, 669-676.
10. Ferrara,N. (1999) Role of vascular endothelial growth factor in the regulation of angiogenesis. Kidney Int. 56, 794-814.
11. Ferrara,N. (2002) VEGF and the quest for tumour angiogenesis factors. Nat. Rev. Cancer 2, 795-803.
12. Folkman,J. (1995) Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat. Med. 1, 27-31.
13. Stewart, M.W. (2012). Aflibercept (VEGF Trap-eye): the newest anti-VEGF drug. Br J Ophthalmol 96, 1157-1158.
14. Finley, S.D., Dhar, M., and Popel, A.S. (2013). Compartment model predicts VEGF secretion and investigates the effects of VEGF trap in tumor-bearing mice. Front Oncol 3, 196.
서열목록 1 VEGFR1 부분서열
VSDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDSRKGFIISNATYKEIGLLTCEATVNGHLYKTNYLTHRQTNT (VEGFR1)
서열목록 2 Nrp1 부분 서열
SaiakegfSanysvLQSsvsedfkcmealgmesgeihsdqitassqystnwsaersrlnypengwtpgedsyrewiqvdlgllrfvtavgtqgaisketkkkyyvktykidvssngedwitikegnkpvlfqgntnptdvvvavfpkplitrfvrikpatwetgismrfevygckit
서열목록 3 면역글로블린 Fc 도메인
DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
서열목록 4 리더 서열
MYLGLNYVFIVFLLNGVQS
서열목록 5 전장서열
MYLGLNYVFIVFLLNGVQSVSDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDSRKGFIISNATYKEIGLLTCEATVNGHLYKTNYLTHRQTNTSaiakegfSanysvLQSsvsedfkcmealgmesgeihsdqitassqystnwsaersrlnypengwtpgedsyrewiqvdlgllrfvtavgtqgaisketkkkyyvktykidvssngedwitikegnkpvlfqgntnptdvvvavfpkplitrfvrikpatwetgismrfevygckitDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
VSDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDSRKGFIISNATYKEIGLLTCEATVNGHLYKTNYLTHRQTNT (VEGFR1)
서열목록 2 Nrp1 부분 서열
SaiakegfSanysvLQSsvsedfkcmealgmesgeihsdqitassqystnwsaersrlnypengwtpgedsyrewiqvdlgllrfvtavgtqgaisketkkkyyvktykidvssngedwitikegnkpvlfqgntnptdvvvavfpkplitrfvrikpatwetgismrfevygckit
서열목록 3 면역글로블린 Fc 도메인
DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
서열목록 4 리더 서열
MYLGLNYVFIVFLLNGVQS
서열목록 5 전장서열
MYLGLNYVFIVFLLNGVQSVSDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDSRKGFIISNATYKEIGLLTCEATVNGHLYKTNYLTHRQTNTSaiakegfSanysvLQSsvsedfkcmealgmesgeihsdqitassqystnwsaersrlnypengwtpgedsyrewiqvdlgllrfvtavgtqgaisketkkkyyvktykidvssngedwitikegnkpvlfqgntnptdvvvavfpkplitrfvrikpatwetgismrfevygckitDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
<110> IBENTRUS, Inc.
<120> Anticancer composition comprising VEGF Deep Blocker (Veep)
suppressing tumor angiogenesis and methods of preparation thereof
<130> PP160001
<160> 5
<170> KopatentIn 2.0
<210> 1
<211> 101
<212> PRT
<213> Homo sapiens partial VEGFR1
<400> 1
Val Ser Asp Thr Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro
1 5 10 15
Glu Ile Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg
20 25 30
Val Thr Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp
35 40 45
Thr Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys Gly
50 55 60
Phe Ile Ile Ser Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr Cys
65 70 75 80
Glu Ala Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr His
85 90 95
Arg Gln Thr Asn Thr
100
<210> 2
<211> 177
<212> PRT
<213> Homo sapiens partial Nrp1 sequence
<400> 2
Ser Ala Ile Ala Lys Glu Gly Phe Ser Ala Asn Tyr Ser Val Leu Gln
1 5 10 15
Ser Ser Val Ser Glu Asp Phe Lys Cys Met Glu Ala Leu Gly Met Glu
20 25 30
Ser Gly Glu Ile His Ser Asp Gln Ile Thr Ala Ser Ser Gln Tyr Ser
35 40 45
Thr Asn Trp Ser Ala Glu Arg Ser Arg Leu Asn Tyr Pro Glu Asn Gly
50 55 60
Trp Thr Pro Gly Glu Asp Ser Tyr Arg Glu Trp Ile Gln Val Asp Leu
65 70 75 80
Gly Leu Leu Arg Phe Val Thr Ala Val Gly Thr Gln Gly Ala Ile Ser
85 90 95
Lys Glu Thr Lys Lys Lys Tyr Tyr Val Lys Thr Tyr Lys Ile Asp Val
100 105 110
Ser Ser Asn Gly Glu Asp Trp Ile Thr Ile Lys Glu Gly Asn Lys Pro
115 120 125
Val Leu Phe Gln Gly Asn Thr Asn Pro Thr Asp Val Val Val Ala Val
130 135 140
Phe Pro Lys Pro Leu Ile Thr Arg Phe Val Arg Ile Lys Pro Ala Thr
145 150 155 160
Trp Glu Thr Gly Ile Ser Met Arg Phe Glu Val Tyr Gly Cys Lys Ile
165 170 175
Thr
<210> 3
<211> 227
<212> PRT
<213> Homo spiens immunoglobulin Fc domain
<400> 3
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
130 135 140
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
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Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
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His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
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<210> 4
<211> 19
<212> PRT
<213> Homo sapiens leader sequence
<400> 4
Met Tyr Leu Gly Leu Asn Tyr Val Phe Ile Val Phe Leu Leu Asn Gly
1 5 10 15
Val Gln Ser
<210> 5
<211> 524
<212> PRT
<213> Artificial Sequence
<220>
<223> Fusion protein VEEP6
<400> 5
Met Tyr Leu Gly Leu Asn Tyr Val Phe Ile Val Phe Leu Leu Asn Gly
1 5 10 15
Val Gln Ser Val Ser Asp Thr Gly Arg Pro Phe Val Glu Met Tyr Ser
20 25 30
Glu Ile Pro Glu Ile Ile His Met Thr Glu Gly Arg Glu Leu Val Ile
35 40 45
Pro Cys Arg Val Thr Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe
50 55 60
Pro Leu Asp Thr Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser
65 70 75 80
Arg Lys Gly Phe Ile Ile Ser Asn Ala Thr Tyr Lys Glu Ile Gly Leu
85 90 95
Leu Thr Cys Glu Ala Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr
100 105 110
Leu Thr His Arg Gln Thr Asn Thr Ser Ala Ile Ala Lys Glu Gly Phe
115 120 125
Ser Ala Asn Tyr Ser Val Leu Gln Ser Ser Val Ser Glu Asp Phe Lys
130 135 140
Cys Met Glu Ala Leu Gly Met Glu Ser Gly Glu Ile His Ser Asp Gln
145 150 155 160
Ile Thr Ala Ser Ser Gln Tyr Ser Thr Asn Trp Ser Ala Glu Arg Ser
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Arg Leu Asn Tyr Pro Glu Asn Gly Trp Thr Pro Gly Glu Asp Ser Tyr
180 185 190
Arg Glu Trp Ile Gln Val Asp Leu Gly Leu Leu Arg Phe Val Thr Ala
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Val Gly Thr Gln Gly Ala Ile Ser Lys Glu Thr Lys Lys Lys Tyr Tyr
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Val Lys Thr Tyr Lys Ile Asp Val Ser Ser Asn Gly Glu Asp Trp Ile
225 230 235 240
Thr Ile Lys Glu Gly Asn Lys Pro Val Leu Phe Gln Gly Asn Thr Asn
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Pro Thr Asp Val Val Val Ala Val Phe Pro Lys Pro Leu Ile Thr Arg
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Phe Val Arg Ile Lys Pro Ala Thr Trp Glu Thr Gly Ile Ser Met Arg
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Phe Glu Val Tyr Gly Cys Lys Ile Thr Asp Lys Thr His Thr Cys Pro
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Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
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Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
325 330 335
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
340 345 350
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
355 360 365
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
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Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
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Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
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Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
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Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
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Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
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Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
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Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
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Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
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Claims (12)
- 혈관 내피 생성인자 수용체 1(VEGFR1)의 Ig2 도메인 및 뉴로필린 1(NRP1)의 b1 도메인을 포함하는 것을 특징으로 하는 융합 단백질.
- 제1항에 있어서, 면역글로블린의 Fc 도메인을 추가적으로 포함하는 것인, 융합 단백질.
- 제2항에 있어서, 상기 Ig2 도메인, 상기 b1 도메인, 및 상기 Fc 도메인이 순차적으로 연결된 것인, 융합 단백질.
- 제2항에 있어서, 상기 Ig2 도메인은 서열번호 1의 아미노산 서열로 이루어지고, 상기 b1 도메인은 서열번호 2의 아미노산 서열로 이루어지며, 상기 Fc 도메인은 서열번호 3의 아미노산 서열로 이루어진 것인, 융합 단백질.
- 제4항에 있어서, 상기 융합 단백질은 서열번호 4의 아미노산 서열을 추가적으로 포함하는 것인, 융합 단백질.
- 제5항에 있어서, 상기 융합 단백질은 서열번호 5의 아미노산 서열로 표현되는 것인, 융합 단백질.
- 제1항 내지 제6항 중 어느 한 항에 따른 융합 단백질을 포함하는 암 치료용 조성물.
- 제1항 내지 제6항 중 어느 한 항에 따른 융합 단백질을 암호화하는 DNA 절편.
- 제8항에 따른 DNA 절편을 포함하는 것을 특징으로 하는 재조합 벡터.
- 제9항에 따른 재조합 벡터로 형질전환된 세포.
- 제10항에 있어서, 상기 세포는 HEK293E인 것을 특징으로 하는 세포.
- (a) 제10항에 따른 형질전환된 세포를 배양하는 단계; 및
(b) 상기 세포의 배양액으로부터 융합 단백질을 분리하는 단계
를 포함하는, 암치료용 단백질 제조방법.
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| AU2009224955B2 (en) * | 2008-03-14 | 2012-08-09 | Transgene S.A. | Antibody against the CSF-1 R |
| US8470977B2 (en) | 2008-03-14 | 2013-06-25 | Transgene S.A. | Antibody against the CSF-1R |
| CN101838329A (zh) * | 2009-03-18 | 2010-09-22 | 嘉和生物药业有限公司 | 抗血管新生融合蛋白 |
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2016
- 2016-07-05 CN CN201680087472.2A patent/CN109476719A/zh active Pending
- 2016-07-05 AU AU2016413999A patent/AU2016413999B2/en active Active
- 2016-07-05 US US16/311,822 patent/US10787497B2/en active Active
- 2016-07-05 CA CA3029752A patent/CA3029752C/en active Active
- 2016-07-05 WO PCT/KR2016/007231 patent/WO2018008772A1/ko unknown
- 2016-07-05 KR KR1020197000553A patent/KR102216566B1/ko active Active
- 2016-07-05 JP JP2019521359A patent/JP6876126B2/ja active Active
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| US20110243912A1 (en) | 2004-03-05 | 2011-10-06 | Vegenics Limited | Growth Factor Binding Constructs Materials and Methods |
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| CA3029752A1 (en) | 2018-01-11 |
| JP6876126B2 (ja) | 2021-05-26 |
| JP2019524153A (ja) | 2019-09-05 |
| CN109476719A (zh) | 2019-03-15 |
| AU2016413999A1 (en) | 2019-01-24 |
| KR20190016085A (ko) | 2019-02-15 |
| US20190375821A1 (en) | 2019-12-12 |
| AU2016413999B2 (en) | 2020-05-14 |
| WO2018008772A1 (ko) | 2018-01-11 |
| CA3029752C (en) | 2022-03-15 |
| EP3486254A4 (en) | 2019-12-18 |
| EP3486254A1 (en) | 2019-05-22 |
| US10787497B2 (en) | 2020-09-29 |
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