TW202317630A - 抗gfral抗體及其應用 - Google Patents
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Abstract
本申請涉及新的抗GFRAL抗體及其用途,所述抗GFRAL抗體或其抗原結合部分可用於治療或預防GFRAL介導的或GFRAL-RET-GDF15信號通路介導的疾病或異常,特別是惡病質綜合征。
Description
本申請大致涉及生物製藥領域,具體而言,本申請涉及新的抗GFRAL抗體或其抗原結合片段、包含所述抗體或其抗原結合片段的藥物組合物及所述抗體或其抗原結合片段的醫藥學用途。
相關申請的引用:本申請要求於2021年6月30日遞交的中國專利申請第202110739877.2號的優先權,通過援引加入的方式將其全部內容整體併入本文,並用於所有目的。
生長分化因數15(下文稱GDF15,growth differentiation factor 15)屬於轉化生長因數β(TGF-β)超家族中的一個成員。在TGF-β超家族中存在著30個以上成員,例如:轉化生長因數β、啟動素(activin)、骨形態發生蛋白 (BMP)、生長分化因數(GDF)等。它們分別在多種器官中起著調控發育、細胞分化、組織修復等重要作用
1。
在正常的生理狀態下,GDF15在大多數組織中有著微弱的表達。當發生炎症或者組織損傷時,GDF15的表達會明顯升高。因此GDF15被認為是一種炎症標誌物,同時也參與了多個疾病的病理進程,例如腫瘤、局部缺血性疾病、代謝紊亂、神經退行性疾病等。
研究者發現在臨床前動物模型中,GDF15可以引起厭食以及體重減輕。臨床上也表明,多種晚期腫瘤病人血液中的GDF15水準明顯升高,而且它與腫瘤惡病質以及較差的生存期有著明顯相關性。2017年,多個科研小組同時發現了GDF15在腦幹神經元上的受體—GDNF家族受體樣(GFRAL,GDNF family receptor alpha-like),並證明了GFRAL-RET信號複合物介導了GDF15誘導的體重減輕
2,3,4。GFRAL特異性表達在腦幹最後區(AP,Area postrema)以及孤束核(STN,solitary tract nucleus)。研究發現,GDF15結合GFRAL並與它的共受體RET形成六元複合物後,引起RET的活化,並進一步啟動下游細胞外信號調節激酶(Erk1/2,extracellular signal-regulated kinase)、蛋白激酶B(PKB/AKT,Ak strain tranforming),以及磷脂酶γ(PLCγ: phospholipase C-gamma)信號通路
2,3,4。相關體內實驗資料表明GFRAL-RET-GDF15信號通路的啟動可通過外周交感神經誘導脂肪組織中脂質代謝相關基因的表達,導致荷瘤小鼠脂肪和肌肉品質、功能的下降。相對應地,阻斷GFRAL-RET-GDF15信號通路具有抑制癌症惡病質患者體重減輕的潛力。
惡病質綜合征(CACS,Cancer anorexia-cachexia syndrome)是一類複雜的代謝綜合征,臨床症狀表現為癌症患者不可控的體重減輕,包括厭食、肌肉量和脂肪組織減少引起的體重減輕。惡病質常發生在終末期癌症患者中,主要與癌症病人生活品質差和存活率降低有關,約占所有癌症相關死亡的四分之一。
目前尚無被全球各大藥物監管機構廣泛認可的單藥用於惡病質的治療。對於腫瘤惡病質病人,2020年的美國臨床腫瘤治療指南中僅推薦孕酮及類似物和糖皮質激素作為短期干預方案
5。
惡病質的病因病理複雜,根據相關研究,生長分化因數15(GDF15,Growth differentiation factor 15)是由癌症(包括對化學治療劑敏感性降低的癌症)和慢性疾病引起的惡病質的介體。流行病學研究表明GDF15血清水準與惡病質程度成正相關。臨床研究資料表明在組織損傷、炎症和各種疾病狀態(包括癌症、心血管疾病和腎臟疾病)中,GDF15在血液迴圈中顯著增加,並且GDF15血清水準升高和不自主的體重減輕、不良預後有關。
GFRAL-RET-GDF15信號通路是上述病症的潛在治療靶點,針對GFRAL抗體的開發和應用是本領域亟需的。
參考文獻:
1. Rochette L, Zeller M, Cottin Y, Vergely C. Insights Into Mechanisms of GDF15 and Receptor GFRAL: Therapeutic Targets. Trends Endocrinol Metab. 2020 Dec;31(12):939-951.
2. Yang, L. et al. (2017) GFRAL is the receptor for GDF15 and is required for the anti-obesity effects of the ligand. Nat. Med. 23, 1158–1166
3. Mullican, S.E. et al. (2017) GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates. Nat. Med. 23, 1150–1157
4. Hsu J-Y, Crawley S, Chen M, Ayupova DA, Lindhout DA, Higbee J, et al. Non-homeostatic body weight regulation through a brainstem-restricted receptor for GDF15. Nature. 2017;550(7675):255-9.
5. Roeland EJ, Bohlke K, Baracos VE, Bruera E, Del Fabbro E, Dixon S, et al. Management of cancer cachexia: ASCO guideline. J Clin Oncol 2020; 38: 2438– 2453.
第一方面,本申請提供了抗GFRAL抗體或其抗原結合部分,所述抗GFRAL抗體或其抗原結合部分包括重鏈可變區和/或輕鏈可變區,其中所述重鏈可變區包括重鏈CDR1(HCDR1)、重鏈CDR2(HCDR2)和重鏈CDR3(HCDR3),輕鏈可變區包括輕鏈CDR1(LCDR1)、輕鏈CDR2(LCDR2)和輕鏈CDR3(LCDR3),其中:
重鏈CDR1的序列為SEQ ID NO.75所示序列或與SEQ ID NO.75所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.76或SEQ ID NO.116所示序列或與SEQ ID NO.76或SEQ ID NO.116所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.77或SEQ ID NO.99所示序列或與SEQ ID NO.77或SEQ ID NO.99所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR1的序列為SEQ ID NO.79或SEQ ID NO.126或SEQ ID NO.128所示序列或與SEQ ID NO.79或SEQ ID NO.126或SEQ ID NO.128所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.80所示序列或與SEQ ID NO.80所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.50或SEQ ID NO.123所示序列或與SEQ ID NO.50或SEQ ID NO.123所示序列具有至少80%、85%、90%或95%同一性;或
重鏈CDR1的序列為SEQ ID NO.68所示序列或與SEQ ID NO.68所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.69或SEQ ID NO.91所示序列或與SEQ ID NO.69或SEQ ID NO.91所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.70所示序列或與SEQ ID NO.70所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR1的序列為SEQ ID NO.72或SEQ ID NO.95所示序列或與SEQ ID NO.72或SEQ ID NO.95所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.65所示序列或與SEQ ID NO.65所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.73所示序列或與SEQ ID NO.73所示序列具有至少80%、85%、90%或95%同一性;或
(3)重鏈CDR1的序列為SEQ ID NO.1所示序列或與SEQ ID NO.1所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.2所示序列或與SEQ ID NO.2所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.3所示序列或與SEQ ID NO.3所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR1的序列為SEQ ID NO.5所示序列或與SEQ ID NO.5所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.6所示序列或與SEQ ID NO.6所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.7所示序列或與SEQ ID NO.7所示序列具有至少80%、85%、90%或95%同一性;或
(4) 重鏈CDR1的序列為SEQ ID NO.9所示序列或與SEQ ID NO.9所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.10所示序列或與SEQ ID NO.10所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.11所示序列或與SEQ ID NO.11所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR1的序列為SEQ ID NO.13所示序列或與SEQ ID NO.13所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.14所示序列或與SEQ ID NO.14所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.15所示序列或與SEQ ID NO.15所示序列具有至少80%、85%、90%或95%同一性;或
(5)重鏈CDR1的序列為SEQ ID NO.17所示序列或與SEQ ID NO.17所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.18所示序列或與SEQ ID NO.18所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.19所示序列或與SEQ ID NO.19所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR1的序列為SEQ ID NO.21所示序列或與SEQ ID NO.21所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.6所示序列或與SEQ ID NO.6所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.22所示序列或與SEQ ID NO.22所示序列具有至少80%、85%、90%或95%同一性;或
(6)重鏈CDR1的序列為SEQ ID NO.24所示序列或與SEQ ID NO.24所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.25所示序列或與SEQ ID NO.25所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.26所示序列或與SEQ ID NO.26所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR1的序列為SEQ ID NO.28所示序列或與SEQ ID NO.28所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.6所示序列或與SEQ ID NO.6所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.29所示序列或與SEQ ID NO.29所示序列具有至少80%、85%、90%或95%同一性;或
(7)重鏈CDR1的序列為SEQ ID NO.31所示序列或與SEQ ID NO.31所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.32所示序列或與SEQ ID NO.32所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.33所示序列或與SEQ ID NO.33所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR1的序列為SEQ ID NO.35所示序列或與SEQ ID NO.35所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.36所示序列或與SEQ ID NO.36所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.37所示序列或與SEQ ID NO.37所示序列具有至少80%、85%、90%或95%同一性;或
(8)重鏈CDR1的序列為SEQ ID NO.39所示序列或與SEQ ID NO.39所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.40所示序列或與SEQ ID NO.40所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.41所示序列或與SEQ ID NO.41所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR1的序列為SEQ ID NO.43所示序列或與SEQ ID NO.43所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.6所示序列或與SEQ ID NO.6所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.22所示序列或與SEQ ID NO.22所示序列具有至少80%、85%、90%或95%同一性;或
(9)重鏈CDR1的序列為SEQ ID NO.45所示序列或與SEQ ID NO.45所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.46所示序列或與SEQ ID NO.46所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.47所示序列或與SEQ ID NO.47所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR1的序列為SEQ ID NO.49所示序列或與SEQ ID NO.49所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.6所示序列或與SEQ ID NO.6所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.50所示序列或與SEQ ID NO.50所示序列具有至少80%、85%、90%或95%同一性;或
(10)重鏈CDR1的序列為SEQ ID NO.31所示序列或與SEQ ID NO.31所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.53所示序列或與SEQ ID NO.53所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.54所示序列或與SEQ ID NO.54所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR1的序列為SEQ ID NO.56所示序列或與SEQ ID NO.56所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.57所示序列或與SEQ ID NO.57所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.58所示序列或與SEQ ID NO.58所示序列具有至少80%、85%、90%或95%同一性;或
(11)重鏈CDR1的序列為SEQ ID NO.60所示序列或與SEQ ID NO.60所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.61所示序列或與SEQ ID NO.61所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.62所示序列或與SEQ ID NO.62所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR1的序列為SEQ ID NO.64所示序列或與SEQ ID NO.64所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.65所示序列或與SEQ ID NO.65所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.66所示序列或與SEQ ID NO.66所示序列具有至少80%、85%、90%或95%同一性;或
(12) 重鏈CDR1的序列為SEQ ID NO.82所示序列或與SEQ ID NO.82所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.83所示序列或與SEQ ID NO.83所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.84所示序列或與SEQ ID NO.84所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR1的序列為SEQ ID NO.86所示序列或與SEQ ID NO.86示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.87所示序列或與SEQ ID NO.87所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.88所示序列或與SEQ ID NO.88所示序列具有至少80%、85%、90%或95%同一性;
其中重鏈CDR1-3和輕鏈CDR1-3的氨基酸序列根據IMGT定義。
第二方面,本申請提供了抗GFRAL抗體或其抗原結合部分,所述抗GFRAL抗體或其抗原結合部分包括重鏈可變區和輕鏈可變區,其中
重鏈可變區具有SEQ ID NO.4、12、20、27、34、42、48、52、55、63、71、78、85、90、92、93、98、100、101、102、103、104、105、106、107、108、109、110、111、112、113、114、115、117、118、119、120、121所示氨基酸序列或與SEQ ID NO.4、12、20、27、34、42、48、52、55、63、71、78、85、90、92、93、98、100、101、102、103、104、105、106、107、108、109、110、111、112、113、114、115、117、118、119、120、121所示氨基酸序列具有至少80%、至少90%、至少95%或至少99%同一性的氨基酸序列;和/或
輕鏈可變區具有SEQ ID NO.8、16、23、30、38、44、51、59、67、74、81、89、94、96、97、122、124、125、127、129、130、131、132、133、134或135所示氨基酸序列或與SEQ ID NO.8、16、23、30、38、44、51、59、67、74、81、89、94、96、97、122、124、125、127、129、130、131、132、133、134或135所示氨基酸序列具有至少80%、至少90%、至少95%或至少99%同一性的氨基酸序列。
協力廠商面,本申請提供了抗GFRAL抗體或其抗原結合部分,所述抗GFRAL抗體或其抗原結合部分包括重鏈可變區,其中所述重鏈可變區包括重鏈CDR1(HCDR1)、重鏈CDR2(HCDR2)和重鏈CDR3(HCDR3),其中:
重鏈CDR1的序列為SEQ ID NO.75所示序列或與SEQ ID NO.75所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.76或SEQ ID NO.116所示序列或與SEQ ID NO.76或SEQ ID NO.116所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.77或SEQ ID NO.99所示序列或與SEQ ID NO.77或SEQ ID NO.99所示序列具有至少80%、85%、90%或95%同一性;或
重鏈CDR1的序列為SEQ ID NO.68所示序列或與SEQ ID NO.68所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.69或SEQ ID NO.91所示序列或與SEQ ID NO.69或SEQ ID NO.91所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.70所示序列或與SEQ ID NO.70所示序列具有至少80%、85%、90%或95%同一性;或
(3)重鏈CDR1的序列為SEQ ID NO.1所示序列或與SEQ ID NO.1所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.2所示序列或與SEQ ID NO.2所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.3所示序列或與SEQ ID NO.3所示序列具有至少80%、85%、90%或95%同一性;或
(4) 重鏈CDR1的序列為SEQ ID NO.9所示序列或與SEQ ID NO.9所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.10所示序列或與SEQ ID NO.10所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.11所示序列或與SEQ ID NO.11所示序列具有至少80%、85%、90%或95%同一性;或
(5)重鏈CDR1的序列為SEQ ID NO.17所示序列或與SEQ ID NO.17所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.18所示序列或與SEQ ID NO.18所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.19所示序列或與SEQ ID NO.19所示序列具有至少80%、85%、90%或95%同一性;或
(6)重鏈CDR1的序列為SEQ ID NO.24所示序列或與SEQ ID NO.24所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.25所示序列或與SEQ ID NO.25所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.26所示序列或與SEQ ID NO.26所示序列具有至少80%、85%、90%或95%同一性;或
(7)重鏈CDR1的序列為SEQ ID NO.31所示序列或與SEQ ID NO.31所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.32所示序列或與SEQ ID NO.32所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.33所示序列或與SEQ ID NO.33所示序列具有至少80%、85%、90%或95%同一性;或
(8)重鏈CDR1的序列為SEQ ID NO.39所示序列或與SEQ ID NO.39所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.40所示序列或與SEQ ID NO.40所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.41所示序列或與SEQ ID NO.41所示序列具有至少80%、85%、90%或95%同一性;或
(9)重鏈CDR1的序列為SEQ ID NO.45所示序列或與SEQ ID NO.45所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.46所示序列或與SEQ ID NO.46所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.47所示序列或與SEQ ID NO.47所示序列具有至少80%、85%、90%或95%同一性;或
(10)重鏈CDR1的序列為SEQ ID NO.31所示序列或與SEQ ID NO.31所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.53所示序列或與SEQ ID NO.53所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.54所示序列或與SEQ ID NO.54所示序列具有至少80%、85%、90%或95%同一性;或
(11)重鏈CDR1的序列為SEQ ID NO.60所示序列或與SEQ ID NO.60所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.61所示序列或與SEQ ID NO.61所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.62所示序列或與SEQ ID NO.62所示序列具有至少80%、85%、90%或95%同一性;或
(12) 重鏈CDR1的序列為SEQ ID NO.82所示序列或與SEQ ID NO.82所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.83所示序列或與SEQ ID NO.83所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.84所示序列或與SEQ ID NO.84所示序列具有至少80%、85%、90%或95%同一性;
其中重鏈CDR1-3的氨基酸序列根據IMGT定義。
第四方面,本申請提供了抗GFRAL抗體或其抗原結合部分,所述抗GFRAL抗體或其抗原結合部分包括輕鏈可變區,其中所述輕鏈可變區包括輕鏈CDR1(HCDR1)、輕鏈CDR2(HCDR2)和輕鏈CDR3(HCDR3),其中:
輕鏈CDR1的序列為SEQ ID NO.79或SEQ ID NO.126或SEQ ID NO.128所示序列或與SEQ ID NO.79或SEQ ID NO.126或SEQ ID NO.128所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.80所示序列或與SEQ ID NO.80所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.50或SEQ ID NO.123所示序列或與SEQ ID NO.50或SEQ ID NO.123所示序列具有至少80%、85%、90%或95%同一性;或
輕鏈CDR1的序列為SEQ ID NO.72或SEQ ID NO.95所示序列或與SEQ ID NO.72或SEQ ID NO.95所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.65所示序列或與SEQ ID NO.65所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.73所示序列或與SEQ ID NO.73所示序列具有至少80%、85%、90%或95%同一性;或
(3)輕鏈CDR1的序列為SEQ ID NO.5所示序列或與SEQ ID NO.5所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.6所示序列或與SEQ ID NO.6所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.7所示序列或與SEQ ID NO.7所示序列具有至少80%、85%、90%或95%同一性;或
(4)輕鏈CDR1的序列為SEQ ID NO.13所示序列或與SEQ ID NO.13所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.14所示序列或與SEQ ID NO.14所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.15所示序列或與SEQ ID NO.15所示序列具有至少80%、85%、90%或95%同一性;或
(5)輕鏈CDR1的序列為SEQ ID NO.21所示序列或與SEQ ID NO.21所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.6所示序列或與SEQ ID NO.6所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.22所示序列或與SEQ ID NO.22所示序列具有至少80%、85%、90%或95%同一性;或
(6)輕鏈CDR1的序列為SEQ ID NO.28所示序列或與SEQ ID NO.28所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.6所示序列或與SEQ ID NO.6所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.29所示序列或與SEQ ID NO.29所示序列具有至少80%、85%、90%或95%同一性;或
(7)輕鏈CDR1的序列為SEQ ID NO.35所示序列或與SEQ ID NO.35所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.36所示序列或與SEQ ID NO.36所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.37所示序列或與SEQ ID NO.37所示序列具有至少80%、85%、90%或95%同一性;或
(8)輕鏈CDR1的序列為SEQ ID NO.43所示序列或與SEQ ID NO.43所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.6所示序列或與SEQ ID NO.6所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.22所示序列或與SEQ ID NO.22所示序列具有至少80%、85%、90%或95%同一性;或
(9)輕鏈CDR1的序列為SEQ ID NO.49所示序列或與SEQ ID NO.49所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.6所示序列或與SEQ ID NO.6所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.50所示序列或與SEQ ID NO.50所示序列具有至少80%、85%、90%或95%同一性;或
(10)輕鏈CDR1的序列為SEQ ID NO.56所示序列或與SEQ ID NO.56所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.57所示序列或與SEQ ID NO.57所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.58所示序列或與SEQ ID NO.58所示序列具有至少80%、85%、90%或95%同一性;或
(11)輕鏈CDR1的序列為SEQ ID NO.64所示序列或與SEQ ID NO.64所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.65所示序列或與SEQ ID NO.65所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.66所示序列或與SEQ ID NO.66所示序列具有至少80%、85%、90%或95%同一性;或
(12)輕鏈CDR1的序列為SEQ ID NO.86所示序列或與SEQ ID NO.86示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.87所示序列或與SEQ ID NO.87所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.88所示序列或與SEQ ID NO.88所示序列具有至少80%、85%、90%或95%同一性;
其中輕鏈CDR1-3的氨基酸序列根據IMGT定義。
第五方面,本申請提供了抗GFRAL抗體或其抗原結合部分,所述抗GFRAL抗體或其抗原結合部分包含重鏈可變區和輕鏈可變區,其中
所述重鏈可變區包含三個重鏈CDR區,其中至少一個所述重鏈CDR區的氨基酸序列選自:SEQ ID NO.1、SEQ ID NO.9、SEQ ID NO.17、SEQ ID NO.24、SEQ ID NO.31、SEQ ID NO.39、SEQ ID NO.45、SEQ ID NO.60、SEQ ID NO.68、SEQ ID NO.75、SEQ ID NO.82、SEQ ID NO.2、SEQ ID NO.10、SEQ ID NO.18、SEQ ID NO.25、SEQ ID NO.32、SEQ ID NO.40、SEQ ID NO.46、SEQ ID NO.53、SEQ ID NO.61、SEQ ID NO.69、SEQ ID NO.76、SEQ ID NO.83、 SEQ ID NO.3、SEQ ID NO.11、SEQ ID NO.19、SEQ ID NO.26、SEQ ID NO.33、SEQ ID NO.41、SEQ ID NO.47、SEQ ID NO.54、SEQ ID NO.62、SEQ ID NO.70、SEQ ID NO.77、SEQ ID NO.84、SEQ ID NO.99所示的氨基酸序列或者與其具有至少80%(優選85%、90%、95%、98%或者99%)序列同一性的序列;和/或
所述輕鏈可變區包含三個輕鏈CDR區,其中至少一個所述輕鏈CDR區的氨基酸序列具有如SEQ ID NO.5、SEQ ID NO.13、SEQ ID NO.21、SEQ ID NO.28、SEQ ID NO.35、SEQ ID NO.43、SEQ ID NO.49、SEQ ID NO.56、SEQ ID NO.64、SEQ ID NO.72、SEQ ID NO.79、SEQ ID NO.86 、SEQ ID NO.95、SEQ ID NO.126、SEQ ID NO.128、SEQ ID NO.6、SEQ ID NO.14、SEQ ID NO.36、SEQ ID NO.57、SEQ ID NO.65、SEQ ID NO.80、SEQ ID NO.87、 SEQ ID NO.7、SEQ ID NO.15、SEQ ID NO.22、SEQ ID NO.29、SEQ ID NO.37、SEQ ID NO.50、SEQ ID NO.58、SEQ ID NO.66、SEQ ID NO.73、SEQ ID NO.88、SEQ ID NO.123所示的氨基酸序列或者與其具有至少80%(優選85%、90%、95%、98%或者99%)序列同一性的序列;
其中重鏈CDR1-3和輕鏈CDR1-3的氨基酸序列根據IMGT定義。
第六方面,本申請提供了分離的核酸分子,其編碼第一至第五方面中任一實施方案所述的抗GFRAL抗體或其抗原結合部分。
第七方面,本申請提供了載體,其含有第六方面所述的核酸分子。
第八方面,本申請提供了宿主細胞,其含有第六方面所述的核酸分子或第七方面所述的載體。
第九方面,本申請提供了抗體藥物偶聯物,其包含與治療劑偶聯的第一至第五方面中任一實施方案所述的抗GFRAL抗體或其抗原結合部分。
第十方面,本申請提供了藥物組合物,其包含第一至第五方面中任一實施方案所述的抗GFRAL抗體或其抗原結合部分或第九方面所述的抗體藥物偶聯物,以及藥學可接受的載體。
第十一方面,本申請提供了第一至第五方面中任一實施方案所述的抗體或其抗原結合部分、第六方面所述的核酸分子、第七方面所述的載體、第八方面所述的宿主細胞或第九方面所述的抗體藥物偶聯物在製備用於治療或預防GFRAL介導的或GFRAL-RET-GDF15信號通路介導的疾病或異常的藥物中的用途,例如,所述疾病或異常為惡病質綜合征、腫瘤(包括癌症)、心血管疾病、腎臟疾病、局部缺血性疾病、代謝紊亂、神經退行性疾病、厭食或厭食導致的體重減輕。
第十二方面,本申請提供了治療個體中GFRAL介導的或GFRAL-RET-GDF15信號通路介導的疾病或異常的方法,所述方法包括給予所述個體治療有效量的第一至第五方面中任一實施方案所述的抗體或其抗原結合部分、第九方面所述的抗體藥物偶聯物或第十方面所述的藥物組合物,例如,所述疾病或異常為惡病質綜合征、腫瘤(包括癌症)、心血管疾病、腎臟疾病、局部缺血性疾病、代謝紊亂、神經退行性疾病、厭食或厭食導致的體重減輕。
第十三方面,本申請提供了綴合物,其包含第一至第五方面中任一實施方案所述的抗GFRAL抗體或其抗原結合部分以及可檢測標記物。
第十四方面,本申請提供了包含第一至第五方面中任一實施方案所述的抗GFRAL抗體或其抗原結合部分的融合蛋白。
定義:
除非另有定義,本文使用的所有科技術語具有本領域普通技術人員所理解的相同含義。關於本領域的定義及術語,專業人員具體可參考Current Protocols in Molecular Biology(Ausubel)。氨基酸殘基的縮寫是本領域中所用的指代20個常用L-氨基酸之一的標準3字母和/或1字母代碼。
儘管本申請的廣義範圍所示的數字範圍和參數近似值,但是具體實施例中所示的數值盡可能準確的進行記載。然而,任何數值本來就必然含有一定的誤差,其是由它們各自的測量中存在的標準差所致。另外,本文公開的所有範圍應理解為涵蓋其中包含的任何和所有子範圍。例如記載的“1至10”的範圍應認為包含最小值1和最大值10之間(包含端點)的任何和所有子範圍;也就是說,所有以最小值1或更大起始的子範圍,例如1至6.1,以及以最大值10或更小終止的子範圍,例如5.5至10。另外,任何稱為“併入本文”的參考文獻應理解為以其整體併入。
本文所使用的術語“物件”或“個體”是指哺乳動物,如人類,但也可以是其它動物,如野生動物,家畜或實驗動物(如猩猩、猴子、大鼠、小鼠、兔子、豚鼠、土撥鼠、地松鼠等)。
廣義而言,“抗體”可以指能夠經由至少一個位於免疫球蛋白分子的可變區中的抗原識別位點特異性結合到靶標的免疫球蛋白分子,因此涵蓋完整抗體/全長抗體、抗體單鏈或抗體的任何抗原結合片段(也稱為“抗原結合部分”)。當“抗體”和“抗原結合片段/抗原結合部分”出現在同一語境下時,“抗體”可以理解為相對於“抗原結合片段/抗原結合部分”的完整體,二者共同對應於廣義的抗體概念。
“全長抗體”系指包含通過二硫鍵而互連的至少兩條重(H)鏈和兩條輕(L)鏈的蛋白。每條重鏈包含一重鏈可變區(縮寫為VH)和一重鏈恒定區。該重鏈恒定區包含三個域(domain),CH1、CH2和CH3。每條輕鏈包含一輕鏈可變區(縮寫為VL)和一輕鏈恒定區。該輕鏈恒定區包含一個域,CL。VH和VL區域還可再細分為具有高可變性的多個區,被稱為互補決定區(CDR),其間散佈有更為保守的被稱為框架區(FR)的多個區域。每個VH和VL均由三個CDR和四個FR構成,按照以下順序從氨基端至羧基端排布:FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4。重鏈和輕鏈的這些可變區包含與抗原相互作用的結合域。抗體的恒定區可介導免疫球蛋白與宿主的組織或因數結合,包括免疫系統的各種細胞(如效應細胞)和經典補體系統的第一成分(Clq)。全長抗體可以是任何種類的抗體,例如IgD、IgE、IgG、IgA或IgM(或上述的子類),但抗體不需要屬於任何特定的類別。根據重鏈的恒定域的抗體氨基酸序列,可以將免疫球蛋白指定為不同的類別。通常,免疫球蛋白有五種主要的類別:IgA、IgD、IgE、IgG及IgM,而且這些類別中有幾個可以再被進一步區分成子類(同型),例如IgG1、IgG2、IgG3、IgG4、IgA1及IgA2。對應於不同免疫球蛋白類別的重鏈恒定域分別稱為α、δ、ε、γ、以及μ。不同類別的免疫球蛋白的子單元結構和三維結構是公知的。嵌合或人源化抗體也涵蓋在根據本申請的抗體中。本領域技術人員公知,互補決定區(CDR,通常有CDR1、CDR2及CDR3)是可變區中對抗體的親和力和特異性影響最大的區域。VH或VL的CDR氨基酸序列有多種常見的定義方式,例如IMGT定義,Chothia定義和kabat定義等。對於給定抗體的可變區氨基酸序列,通常可以根據不同定義方式來確定VH和VL氨基酸序列中的CDR氨基酸序列。在本申請的實施方案中,利用IMGT定義CDR氨基酸序列。對於給定抗體的可變區氨基酸序列,可以通過多種方式分析可變區氨基酸序列的中CDR氨基酸序列。
術語“鼠源抗體”是指一種抗體,其來源於免疫接種過的小鼠的B細胞與骨髓瘤細胞融合,篩選出既能無限增殖又能分泌抗體的鼠雜交融合細胞,進而進行篩選、製備和純化獲得的抗體,鼠源抗體一般具有免疫原性,因此後續需要對其作人源化處理。
術語“人源化抗體”意指將源自另一哺乳動物物種,諸如小鼠種系的CDR序列嫁接到人框架序列上獲得的抗體。為了保留結合親和力,可以修飾骨架(稱為FR)區段的一些殘基。通過本領域技術人員已知的技術可以製備根據本申請的人源化抗體或其片段;
術語“嵌合抗體”系指以下抗體,其中的可變區序列來自一物種而恒定區序列來自另一物種,例如可變區序列來自小鼠抗體而恒定區序列來自人抗體的抗體。通過使用基因重組技術可以製備根據本申請的嵌合抗體或其片段。例如,所述嵌合抗體可以通過克隆重組DNA來生產,所述重組DNA包含啟動子和編碼根據本申請的非人尤其是鼠單克隆抗體可變區的序列、以及編碼人抗體恒定區的序列。由這種重組基因編碼的本申請嵌合抗體將是,例如,鼠-人嵌合體,該抗體的特異性由來源於鼠DNA的可變區確定,並且其同種型由來源於人DNA的恒定區來確定。
術語“部分人源化抗體”指含有來自人的恒定區和來自非人(如鼠)的可變區(包括CDR)的抗體。
術語“半人源化抗體”是人源化抗體的一種,是指其中一個抗體鏈包含鼠可變區,並且另一抗體鏈包含人源化可變區的抗體,即半人源化抗體。
術語“單克隆抗體”指由基本同質的抗體群體獲得的抗體,即,除了可能在少量個體中存在自然發生的突變以外,組成群體的各個抗體是相同的。
本文所使用的術語“抗原結合片段”或“抗原結合部分”可互換使用,尤其是指抗體片段如Fv、Fab、F(ab’)
2或Fab’,或者通過化學修飾或通過摻入脂質體中應能夠增加半壽期的任何片段,所述化學修飾例如添加聚(亞烷基)二醇如聚乙二醇(“聚乙二醇化,PEG化”)(被稱為Fv-PEG、scFv-PEG、Fab-PEG、F(ab’)
2-PEG或Fab’-PEG的聚乙二醇化片段)(“PEG”為聚乙二醇),所述片段具有GFRAL結合活性。優選地,所述功能片段將由其來源抗體的重鏈或輕鏈可變鏈的部分序列構成或者包含它們,所述部分序列足以保留與其來源抗體相同的結合特異性和充分的親和力,這種功能片段將包含最少5個氨基酸,優選其來源的抗體序列的10、15、25、50和100個連續氨基酸。抗原結合片段的實例包括但不限於:(1)Fab片段,其可以是具有VL-CL鏈和VH-CH1鏈的單價片段;(2)F(ab')
2片段,其可以是具有兩個Fab'片段的二價片段,該兩個Fab'片段由鉸鏈區的二硫橋(即Fab'的二聚物)連接;(3)具有抗體的單臂的VL和VH域的Fv片段。
術語“單鏈抗體(scFv)指是由VH域和VL域經由肽連接子連接的單一多肽鏈。(scFv)
2包含兩個由肽連接子連接的VH域和兩個VL域,該兩個VL域是經由二硫橋與該兩個VH域組合。
術語“Fc片段”、“Fc結構域”、“Fc部分”或類似的術語是指抗體重鏈恒定區的一部分,包括鉸鏈區(hinge)、恒定區的CH2片段和CH3片段。
如本文所用術語“特異性結合”是指兩個分子之間的非隨機結合反應,例如抗體至抗原表位的結合。
術語“多抗”又稱“多特異性抗體”,是具有針對至少2種不同抗原的結合特異性的分子,其中,僅結合2種抗原的該類分子也被稱為雙抗(即雙特異性抗體,BsAb)。
術語“雙特異性抗體”是指同時具有兩種抗原表位結合能力的抗體。兩種抗原表位可以在不同抗原上,也可是在同一抗原上。雙特異性抗體可以具有多種結構構型。例如,雙特異性抗體可以由兩個Fc片段以及分別與其融合的兩個抗原結合部分組成(與天然抗體相似,區別在於兩個臂結合不同的抗原靶標或表位元),抗原結合部分可以為單鏈抗體(scfv) 的形式或者Fab片段的形式。
通常,為了製備單克隆抗體或其功能片段,尤其是鼠源的單克隆抗體或其功能片段,可以參考尤其描述在手冊“Antibodies”中的技術(Harlow and Lane,Antibodies:A Laboratory Manual,Cold Spring Harbor Laboratory,Cold Spring Harbor NY,pp.726,1988)或者參考Kohler和Milstein描述的從雜交瘤細胞製備的技術(Nature,256:495-497,1975)。
術語“保守變體”或“保守氨基酸置換”是基本上不影響或降低蛋白的親和力例如抗體對GFRAL的親和力的那些替換。例如,特異性結合GFRAL的人抗體可包括至多約1、至多約2、至多約5、至多約10或至多約 15個保守替換,並且特異性結合GFRAL多肽。術語“保守變體”還包括使用取代的氨基酸代替未取代的親本氨基酸,只要抗體特異性結合GFRAL。非保守替換是降低活性或與GFRAL結合的那些。
術語“分離的”生物組分(例如核酸、蛋白質(包括抗體)或細胞器)已經與所述組分天然存在的環境(例如細胞)中的其他生物組分(即,其他染色體和額外染色體DNA和RNA、蛋白質和細胞器)基本分離或被純化。已經被“分離”的核酸和蛋白質包括用標準純化方法純化的核酸和蛋白質。該術語還包括通過在宿主細胞中重組表達製備的核酸和蛋白質以及化學合成的核酸。
術語“衍生序列”是指與相關序列具有至少80%(優選85%、90%、95%、98%或者99%)序列同一性且仍具有相同或相似功能的序列。
本文使用的術語“藥物組合物”其表示組合在一起以實現某種特定目的的至少一種藥物以及任選地可藥用載體或輔料的組合。在某些實施方案中,所述藥物組合物包括在時間和/或空間上分開的組合,只要其能夠共同作用以實現本申請的目的。例如,所述藥物組合物中所含的成分(例如根據本申請的抗體、核酸分子、核酸分子組合和/或綴合物)可以以整體施用於個體,或者分開施用於個體。當所述藥物組合物中所含的成分分開地施用於個體時,所述成分可以同時或依次施用於個體。優選地,所述可藥用載體是水、緩衝水溶液、等滲鹽溶液如PBS(磷酸鹽緩衝液)、葡萄糖、甘露醇、右旋葡萄糖、乳糖、澱粉、硬脂酸鎂、纖維素、碳酸鎂、0.3%甘油、透明質酸、乙醇或聚亞烷基二醇如聚丙二醇、甘油三酯等。所用可藥用載體的類型尤其依賴於根據本申請的組合物是否配製為用於口服、鼻、皮內、皮下、肌內或靜脈施用。根據本申請的組合物可包含潤濕劑、乳化劑或緩衝液物質作為添加劑。根據本申請的藥物組合物或者藥物製劑可通過任何適宜的途徑施用,例如可口服、鼻、皮內、皮下、肌內或靜脈內施用。
本文使用的術語“治療有效量”或“有效量”是指足以顯示其對於所施用個體益處的劑量。施用的實際量,以及施用的速率和時間過程會取決於所治療者的自身情況和嚴重程度。治療的處方(例如對劑量的決定等)最終是全科醫生及其它醫生的責任並依賴其做決定,通常考慮所治療的疾病、患者個體的情況、遞送部位、施用方法以及對於醫生來說已知的其它因素。
本文使用的術語“融合蛋白”在一般語境中是由至少兩個結構域組成的蛋白,各結構域不是天然狀態下相關聯的,由單獨的基因編碼,各個基因相連接,作為一個整體被轉錄和翻譯,產生單個蛋白。在本申請的技術背景下,包含抗體或抗原結合部分的“融合蛋白”指利用基因工程技術將抗體或抗原結合部分與另外的生物活性蛋白融合所得的產物,這類抗體融合蛋白兼具抗體的抗原結合能力以及與抗體融合的生物活性蛋白的獨特生物學特性。
關於氨基酸或核酸序列的術語“同一性/同源性/一致性”被定義為經過序列比對和引入空位後,氨基酸或核苷酸序列變體中相同的殘基的百分比,如果需要,達到最大百分比的同一性。用於比對的方法和電腦程式在本領域內是公知的。
基於GDF15/GFRAL/RET信號通路的阻斷或抑制作為治療癌症惡病質的一種新策略,本申請的發明人致力於找到有效的靶向GFRAL拮抗性抗體,預期阻斷GDF15/GFRAL/RET蛋白質複合物的形成或GDF15信號轉導,從而治療、預防或減輕GFRAL介導的或GFRAL-RET-GDF15信號通路介導的疾病或異常,特別是惡病質中不自主的體重損失的發生、頻率或嚴重程度,或是由GDF15蛋白誘導的或與GDF15蛋白相關的、具有對化學治療劑(例如抗腫瘤抗體曲妥珠單抗)敏感性降低的癌症,進而打破針對惡病質無批准用藥的局面,由此建立了本申請中的各項發明。
第一方面,本申請提供了抗GFRAL抗體或其抗原結合部分,所述抗GFRAL抗體或其抗原結合部分包括重鏈可變區和輕鏈可變區,其中所述重鏈可變區包括重鏈CDR1(HCDR1)、重鏈CDR2(HCDR2)和重鏈CDR3(HCDR3),輕鏈可變區包括輕鏈CDR1(LCDR1)、輕鏈CDR2(LCDR2)和輕鏈CDR3(LCDR3),其中:
(1)重鏈CDR1的序列為SEQ ID NO.75所示序列或與SEQ ID NO.75所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.76或SEQ ID NO.116所示序列或與SEQ ID NO.76或SEQ ID NO.116所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.77或SEQ ID NO.99所示序列或與SEQ ID NO.77或SEQ ID NO.99所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR1的序列為SEQ ID NO.79或SEQ ID NO.126或SEQ ID NO.128所示序列或與SEQ ID NO.79或SEQ ID NO.126或SEQ ID NO.128所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.80所示序列或與SEQ ID NO.80所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.50或SEQ ID NO.123所示序列或與SEQ ID NO.50或SEQ ID NO.123所示序列具有至少80%、85%、90%或95%同一性;或
(2)重鏈CDR1的序列為SEQ ID NO.68所示序列或與SEQ ID NO.68所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.69或SEQ ID NO.91所示序列或與SEQ ID NO.69或SEQ ID NO.91所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.70所示序列或與SEQ ID NO.70所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR1的序列為SEQ ID NO.72或SEQ ID NO.95所示序列或與SEQ ID NO.72或SEQ ID NO.95所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.65所示序列或與SEQ ID NO.65所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.73所示序列或與SEQ ID NO.73所示序列具有至少80%、85%、90%或95%同一性;或
(3)重鏈CDR1的序列為SEQ ID NO.1所示序列或與SEQ ID NO.1所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.2所示序列或與SEQ ID NO.2所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.3所示序列或與SEQ ID NO.3所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR1的序列為SEQ ID NO.5所示序列或與SEQ ID NO.5所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.6所示序列或與SEQ ID NO.6所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.7所示序列或與SEQ ID NO.7所示序列具有至少80%、85%、90%或95%同一性;或
(4) 重鏈CDR1的序列為SEQ ID NO.9所示序列或與SEQ ID NO.9所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.10所示序列或與SEQ ID NO.10所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.11所示序列或與SEQ ID NO.11所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR1的序列為SEQ ID NO.13所示序列或與SEQ ID NO.13所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.14所示序列或與SEQ ID NO.14所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.15所示序列或與SEQ ID NO.15所示序列具有至少80%、85%、90%或95%同一性;或
(5)重鏈CDR1的序列為SEQ ID NO.17所示序列或與SEQ ID NO.17所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.18所示序列或與SEQ ID NO.18所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.19所示序列或與SEQ ID NO.19所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR1的序列為SEQ ID NO.21所示序列或與SEQ ID NO.21所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.6所示序列或與SEQ ID NO.6所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.22所示序列或與SEQ ID NO.22所示序列具有至少80%、85%、90%或95%同一性;或
(6)重鏈CDR1的序列為SEQ ID NO.24所示序列或與SEQ ID NO.24所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.25所示序列或與SEQ ID NO.25所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.26所示序列或與SEQ ID NO.26所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR1的序列為SEQ ID NO.28所示序列或與SEQ ID NO.28所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.6所示序列或與SEQ ID NO.6所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.29所示序列或與SEQ ID NO.29所示序列具有至少80%、85%、90%或95%同一性;或
(7)重鏈CDR1的序列為SEQ ID NO.31所示序列或與SEQ ID NO.31所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.32所示序列或與SEQ ID NO.32所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.33所示序列或與SEQ ID NO.33所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR1的序列為SEQ ID NO.35所示序列或與SEQ ID NO.35所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.36所示序列或與SEQ ID NO.36所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.37所示序列或與SEQ ID NO.37所示序列具有至少80%、85%、90%或95%同一性;或
(8)重鏈CDR1的序列為SEQ ID NO.39所示序列或與SEQ ID NO.39所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.40所示序列或與SEQ ID NO.40所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.41所示序列或與SEQ ID NO.41所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR1的序列為SEQ ID NO.43所示序列或與SEQ ID NO.43所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.6所示序列或與SEQ ID NO.6所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.22所示序列或與SEQ ID NO.22所示序列具有至少80%、85%、90%或95%同一性;或
(9)重鏈CDR1的序列為SEQ ID NO.45所示序列或與SEQ ID NO.45所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.46所示序列或與SEQ ID NO.46所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.47所示序列或與SEQ ID NO.47所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR1的序列為SEQ ID NO.49所示序列或與SEQ ID NO.49所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.6所示序列或與SEQ ID NO.6所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.50所示序列或與SEQ ID NO.50所示序列具有至少80%、85%、90%或95%同一性;或
(10)重鏈CDR1的序列為SEQ ID NO.31所示序列或與SEQ ID NO.31所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.53所示序列或與SEQ ID NO.53所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.54所示序列或與SEQ ID NO.54所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR1的序列為SEQ ID NO.56所示序列或與SEQ ID NO.56所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.57所示序列或與SEQ ID NO.57所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.58所示序列或與SEQ ID NO.58所示序列具有至少80%、85%、90%或95%同一性;或
(11)重鏈CDR1的序列為SEQ ID NO.60所示序列或與SEQ ID NO.60所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.61所示序列或與SEQ ID NO.61所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.62所示序列或與SEQ ID NO.62所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR1的序列為SEQ ID NO.64所示序列或與SEQ ID NO.64所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.65所示序列或與SEQ ID NO.65所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.66所示序列或與SEQ ID NO.66所示序列具有至少80%、85%、90%或95%同一性;或
(12) 重鏈CDR1的序列為SEQ ID NO.82所示序列或與SEQ ID NO.82所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.83所示序列或與SEQ ID NO.83所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.84所示序列或與SEQ ID NO.84所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR1的序列為SEQ ID NO.86所示序列或與SEQ ID NO.86示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.87所示序列或與SEQ ID NO.87所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.88所示序列或與SEQ ID NO.88所示序列具有至少80%、85%、90%或95%同一性;
其中重鏈CDR1-3和輕鏈CDR1-3的氨基酸序列根據IMGT定義。
在一些實施方案中,
(1)重鏈CDR1的序列為SEQ ID NO.1所示序列,重鏈CDR2的序列為SEQ ID NO.2所示序列,重鏈CDR3的序列為SEQ ID NO.3所示序列,輕鏈CDR1的序列為SEQ ID NO.5所示序列,輕鏈CDR2的序列為SEQ ID NO.6所示序列,輕鏈CDR3的序列為SEQ ID NO.7所示序列;或
(2) 重鏈CDR1的序列為SEQ ID NO.9所示序列,重鏈CDR2的序列為SEQ ID NO.10所示序列,重鏈CDR3的序列為SEQ ID NO.11所示序列,輕鏈CDR1的序列為SEQ ID NO.13所示序列,輕鏈CDR2的序列為SEQ ID NO.14所示序列,輕鏈CDR3的序列為SEQ ID NO.15所示序列;或
(3)重鏈CDR1的序列為SEQ ID NO.17所示序列,重鏈CDR2的序列為SEQ ID NO.18所示序列,重鏈CDR3的序列為SEQ ID NO.19所示序列,輕鏈CDR1的序列為SEQ ID NO.21所示序列,輕鏈CDR2的序列為SEQ ID NO.6所示序列,輕鏈CDR3的序列為SEQ ID NO.22所示序列;或
(4)重鏈CDR1的序列為SEQ ID NO.24所示序列,重鏈CDR2的序列為SEQ ID NO.25所示序列,重鏈CDR3的序列為SEQ ID NO.26所示序列,輕鏈CDR1的序列為SEQ ID NO.28所示序列,輕鏈CDR2的序列為SEQ ID NO.6所示序列,輕鏈CDR3的序列為SEQ ID NO.29所示序列;或
(5)重鏈CDR1的序列為SEQ ID NO.31所示序列,重鏈CDR2的序列為SEQ ID NO.32所示序列,重鏈CDR3的序列為SEQ ID NO.33所示序列,輕鏈CDR1的序列為SEQ ID NO.35所示序列,輕鏈CDR2的序列為SEQ ID NO.36所示序列,輕鏈CDR3的序列為SEQ ID NO.37所示序列;或
(6)重鏈CDR1的序列為SEQ ID NO.39所示序列,重鏈CDR2的序列為SEQ ID NO.40所示序列,重鏈CDR3的序列為SEQ ID NO.41所示序列,輕鏈CDR1的序列為SEQ ID NO.43所示序列,輕鏈CDR2的序列為SEQ ID NO.6所示序列,輕鏈CDR3的序列為SEQ ID NO.22所示序列;或
(7)重鏈CDR1的序列為SEQ ID NO.45所示序列,重鏈CDR2的序列為SEQ ID NO.46所示序列,重鏈CDR3的序列為SEQ ID NO.47所示序列,輕鏈CDR1的序列為SEQ ID NO.49所示序列,輕鏈CDR2的序列為SEQ ID NO.6所示序列,輕鏈CDR3的序列為SEQ ID NO.50所示序列;或
(8)重鏈CDR1的序列為SEQ ID NO.31所示序列,重鏈CDR2的序列為SEQ ID NO.53所示序列,重鏈CDR3的序列為SEQ ID NO.54所示序列,輕鏈CDR1的序列為SEQ ID NO.56所示序列,輕鏈CDR2的序列為SEQ ID NO.57所示序列,輕鏈CDR3的序列為SEQ ID NO.58所示序列;或
(9)重鏈CDR1的序列為SEQ ID NO.60所示序列,重鏈CDR2的序列為SEQ ID NO.61所示序列,重鏈CDR3的序列為SEQ ID NO.62所示序列,輕鏈CDR1的序列為SEQ ID NO.64所示序列,輕鏈CDR2的序列為SEQ ID NO.65所示序列,輕鏈CDR3的序列為SEQ ID NO.66所示序列;或
(10)重鏈CDR1的序列為SEQ ID NO.68所示序列,重鏈CDR2的序列為SEQ ID NO.69或SEQ ID NO.91所示序列,重鏈CDR3的序列為SEQ ID NO.70所示序列,輕鏈CDR1的序列為SEQ ID NO.72或SEQ ID NO.95所示序列,輕鏈CDR2的序列為SEQ ID NO.65所示序列,輕鏈CDR3的序列為SEQ ID NO.73所示序列;或
(11)重鏈CDR1的序列為SEQ ID NO.75所示序列,重鏈CDR2的序列為SEQ ID NO.76或SEQ ID NO.116所示序列,重鏈CDR3的序列為SEQ ID NO.77或SEQ ID NO.99所示序列,輕鏈CDR1的序列為SEQ ID NO.79或SEQ ID NO.126或SEQ ID NO.128所示序列,輕鏈CDR2的序列為SEQ ID NO.80所示序列,輕鏈CDR3的序列為SEQ ID NO.50或SEQ ID NO.123所示序列;或
(12) 重鏈CDR1的序列為SEQ ID NO.82所示序列,重鏈CDR2的序列為SEQ ID NO.83所示序列,重鏈CDR3的序列為SEQ ID NO.84所示序列,輕鏈CDR1的序列為SEQ ID NO.86所示序列,輕鏈CDR2的序列為SEQ ID NO.87所示序列,輕鏈CDR3的序列為SEQ ID NO.88所示序列;
其中重鏈CDR1-3和輕鏈CDR1-3的氨基酸序列根據IMGT定義。
在一些實施方案中,重鏈可變區具有SEQ ID NO.4、12、20、27、34、42、48、52、55、63、71、78、85、90、92、93、98、100、101、102、103、104、105、106、107、108、109、110、111、112、113、114、115、117、118、119、120、121所示氨基酸序列或與SEQ ID NO.4、12、20、27、34、42、48、52、55、63、71、78、85、90、92、93、98、100、101、102、103、104、105、106、107、108、109、110、111、112、113、114、115、117、118、119、120、121所示氨基酸序列具有至少80%、至少90%、至少95%或至少99%同一性的氨基酸序列。
在一些實施方案中,輕鏈可變區具有SEQ ID NO.8、16、23、30、38、44、51、59、67、74、81、89、94、96、97、122、124、125、127、129、130、131、132、133、134或135所示氨基酸序列或與SEQ ID NO.8、16、23、30、38、44、51、59、67、74、81、89、94、96、97、122、124、125、127、129、130、131、132、133、134或135所示氨基酸序列具有至少80%、至少90%、至少95%或至少99%同一性的氨基酸序列。
在一些實施方案中:
重鏈可變區序列為SEQ ID NO.4所示序列,輕鏈可變區的序列為SEQ ID NO.8所示序列;
重鏈可變區序列為SEQ ID NO.12所示序列,輕鏈可變區的序列為SEQ ID NO.16所示序列;
重鏈可變區序列為SEQ ID NO.20所示序列,輕鏈可變區的序列為SEQ ID NO.23所示序列;
重鏈可變區序列為SEQ ID NO.27所示序列,輕鏈可變區的序列為SEQ ID NO.30所示序列;
重鏈可變區序列為SEQ ID NO.34所示序列,輕鏈可變區的序列為SEQ ID NO.38所示序列;
重鏈可變區序列為SEQ ID NO.42所示序列,輕鏈可變區的序列為SEQ ID NO.44所示序列;
重鏈可變區序列為SEQ ID NO.48所示序列,輕鏈可變區的序列為SEQ ID NO.51所示序列;
重鏈可變區序列為SEQ ID NO.52所示序列,輕鏈可變區的序列為SEQ ID NO.51所示序列;
重鏈可變區序列為SEQ ID NO.55所示序列,輕鏈可變區的序列為SEQ ID NO.59所示序列;
重鏈可變區序列為SEQ ID NO.63所示序列,輕鏈可變區的序列為SEQ ID NO.67所示序列;
重鏈可變區序列為SEQ ID NO.71所示序列,輕鏈可變區的序列為SEQ ID NO.74所示序列;
重鏈可變區序列為SEQ ID NO.78所示序列,輕鏈可變區的序列為SEQ ID NO.81所示序列;
重鏈可變區序列為SEQ ID NO.85所示序列,輕鏈可變區的序列為SEQ ID NO.89所示序列;
重鏈可變區序列為SEQ ID NO.98所示序列,輕鏈可變區的序列為SEQ ID NO.122所示序列;
重鏈可變區序列為SEQ ID NO.98所示序列,輕鏈可變區的序列為SEQ ID NO.124所示序列;
重鏈可變區序列為SEQ ID NO.100所示序列,輕鏈可變區的序列為SEQ ID NO.124所示序列;
重鏈可變區序列為SEQ ID NO.101所示序列,輕鏈可變區的序列為SEQ ID NO.124所示序列;
重鏈可變區序列為SEQ ID NO.102所示序列,輕鏈可變區的序列為SEQ ID NO.124所示序列;
重鏈可變區序列為SEQ ID NO.103所示序列,輕鏈可變區的序列為SEQ ID NO.124所示序列;
重鏈可變區序列為SEQ ID NO.104所示序列,輕鏈可變區的序列為SEQ ID NO.124所示序列;
重鏈可變區序列為SEQ ID NO.105所示序列,輕鏈可變區的序列為SEQ ID NO.124所示序列;
重鏈可變區序列為SEQ ID NO.112所示序列,輕鏈可變區的序列為SEQ ID NO.124所示序列;
重鏈可變區序列為SEQ ID NO.113所示序列,輕鏈可變區的序列為SEQ ID NO.124所示序列;
重鏈可變區序列為SEQ ID NO.105所示序列,輕鏈可變區的序列為SEQ ID NO.125所示序列;
重鏈可變區序列為SEQ ID NO.105所示序列,輕鏈可變區的序列為SEQ ID NO.127所示序列;
重鏈可變區序列為SEQ ID NO.100所示序列,輕鏈可變區的序列為SEQ ID NO.129所示序列;
重鏈可變區序列為SEQ ID NO.101所示序列,輕鏈可變區的序列為SEQ ID NO.129所示序列;
重鏈可變區序列為SEQ ID NO.105所示序列,輕鏈可變區的序列為SEQ ID NO.129所示序列;
重鏈可變區序列為SEQ ID NO.106所示序列,輕鏈可變區的序列為SEQ ID NO.129所示序列;
重鏈可變區序列為SEQ ID NO.107所示序列,輕鏈可變區的序列為SEQ ID NO.129所示序列;
重鏈可變區序列為SEQ ID NO.108所示序列,輕鏈可變區的序列為SEQ ID NO.129所示序列;
重鏈可變區序列為SEQ ID NO.109所示序列,輕鏈可變區的序列為SEQ ID NO.129所示序列;
重鏈可變區序列為SEQ ID NO.110所示序列,輕鏈可變區的序列為SEQ ID NO.129所示序列;
重鏈可變區序列為SEQ ID NO.111所示序列,輕鏈可變區的序列為SEQ ID NO.129所示序列;
重鏈可變區序列為SEQ ID NO.105所示序列,輕鏈可變區的序列為SEQ ID NO.130所示序列;
重鏈可變區序列為SEQ ID NO.105所示序列,輕鏈可變區的序列為SEQ ID NO.131所示序列;
重鏈可變區序列為SEQ ID NO.100所示序列,輕鏈可變區的序列為SEQ ID NO.132所示序列;
重鏈可變區序列為SEQ ID NO.114所示序列,輕鏈可變區的序列為SEQ ID NO.132所示序列;
重鏈可變區序列為SEQ ID NO.115所示序列,輕鏈可變區的序列為SEQ ID NO.133所示序列;
重鏈可變區序列為SEQ ID NO.117所示序列,輕鏈可變區的序列為SEQ ID NO.133所示序列;
重鏈可變區序列為SEQ ID NO.118所示序列,輕鏈可變區的序列為SEQ ID NO.133所示序列;
重鏈可變區序列為SEQ ID NO.119所示序列,輕鏈可變區的序列為SEQ ID NO.133所示序列;
重鏈可變區序列為SEQ ID NO.115所示序列,輕鏈可變區的序列為SEQ ID NO.134所示序列;
重鏈可變區序列為SEQ ID NO.117所示序列,輕鏈可變區的序列為SEQ ID NO.134所示序列;
重鏈可變區序列為SEQ ID NO.118所示序列,輕鏈可變區的序列為SEQ ID NO.134所示序列;
重鏈可變區序列為SEQ ID NO.119所示序列,輕鏈可變區的序列為SEQ ID NO.134所示序列;
重鏈可變區序列為SEQ ID NO.119所示序列,輕鏈可變區的序列為SEQ ID NO.135所示序列;
重鏈可變區序列為SEQ ID NO.120所示序列,輕鏈可變區的序列為SEQ ID NO.135所示序列;
重鏈可變區序列為SEQ ID NO.121所示序列,輕鏈可變區的序列為SEQ ID NO.135所示序列;
重鏈可變區序列為SEQ ID NO.90所示序列,輕鏈可變區的序列為SEQ ID NO.94所示序列;
重鏈可變區序列為SEQ ID NO.92所示序列,輕鏈可變區的序列為SEQ ID NO.94所示序列;
重鏈可變區序列為SEQ ID NO.90所示序列,輕鏈可變區的序列為SEQ ID NO.96所示序列;
重鏈可變區序列為SEQ ID NO.92所示序列,輕鏈可變區的序列為SEQ ID NO.96所示序列;
重鏈可變區序列為SEQ ID NO.90所示序列,輕鏈可變區的序列為SEQ ID NO.97所示序列;或
重鏈可變區序列為SEQ ID NO.93所示序列,輕鏈可變區的序列為SEQ ID NO.97所示序列。
在具體實施方案中,重鏈CDR1的序列為SEQ ID NO.75所示序列,重鏈CDR2的序列為SEQ ID NO.76所示序列,重鏈CDR3的序列為SEQ ID NO.99所示序列,輕鏈CDR1的序列為SEQ ID NO.128所示序列,輕鏈CDR2的序列為SEQ ID NO.80所示序列,輕鏈CDR3的序列為SEQ ID NO.123所示序列。在更具體的實施方案中,重鏈可變區序列為SEQ ID NO.105所示序列,輕鏈可變區的序列為SEQ ID NO.127所示序列。
第二方面,本申請提供了抗GFRAL抗體或其抗原結合部分,所述抗GFRAL抗體或其抗原結合部分包括重鏈可變區和輕鏈可變區,其中
重鏈可變區具有SEQ ID NO.4、12、20、27、34、42、48、52、55、63、71、78、85、90、92、93、98、100、101、102、103、104、105、106、107、108、109、110、111、112、113、114、115、117、118、119、120、121所示氨基酸序列或與SEQ ID NO.4、12、20、27、34、42、48、52、55、63、71、78、85、90、92、93、98、100、101、102、103、104、105、106、107、108、109、110、111、112、113、114、115、117、118、119、120、121所示氨基酸序列具有至少80%、至少90%、至少95%或至少99%同一性的氨基酸序列;和/或
輕鏈可變區具有SEQ ID NO.8、16、23、30、38、44、51、59、67、74、81、89、94、96、97、122、124、125、127、129、130、131、132、133、134或135所示氨基酸序列或與SEQ ID NO.8、16、23、30、38、44、51、59、67、74、81、89、94、96、97、122、124、125、127、129、130、131、132、133、134或135所示氨基酸序列具有至少80%、至少90%、至少95%或至少99%同一性的氨基酸序列。
協力廠商面,本申請提供了抗GFRAL抗體或其抗原結合部分,所述抗GFRAL抗體或其抗原結合部分包括重鏈可變區,其中所述重鏈可變區包括重鏈CDR1(HCDR1)、重鏈CDR2(HCDR2)和重鏈CDR3(HCDR3),其中:
重鏈CDR1的序列為SEQ ID NO.75所示序列或與SEQ ID NO.75所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.76或SEQ ID NO.116所示序列或與SEQ ID NO.76或SEQ ID NO.116所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.77或SEQ ID NO.99所示序列或與SEQ ID NO.77或SEQ ID NO.99所示序列具有至少80%、85%、90%或95%同一性;或
重鏈CDR1的序列為SEQ ID NO.68所示序列或與SEQ ID NO.68所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.69或SEQ ID NO.91所示序列或與SEQ ID NO.69或SEQ ID NO.91所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.70所示序列或與SEQ ID NO.70所示序列具有至少80%、85%、90%或95%同一性;或
(3)重鏈CDR1的序列為SEQ ID NO.1所示序列或與SEQ ID NO.1所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.2所示序列或與SEQ ID NO.2所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.3所示序列或與SEQ ID NO.3所示序列具有至少80%、85%、90%或95%同一性;或
(4) 重鏈CDR1的序列為SEQ ID NO.9所示序列或與SEQ ID NO.9所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.10所示序列或與SEQ ID NO.10所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.11所示序列或與SEQ ID NO.11所示序列具有至少80%、85%、90%或95%同一性;或
(5)重鏈CDR1的序列為SEQ ID NO.17所示序列或與SEQ ID NO.17所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.18所示序列或與SEQ ID NO.18所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.19所示序列或與SEQ ID NO.19所示序列具有至少80%、85%、90%或95%同一性;或
(6)重鏈CDR1的序列為SEQ ID NO.24所示序列或與SEQ ID NO.24所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.25所示序列或與SEQ ID NO.25所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.26所示序列或與SEQ ID NO.26所示序列具有至少80%、85%、90%或95%同一性;或
(7)重鏈CDR1的序列為SEQ ID NO.31所示序列或與SEQ ID NO.31所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.32所示序列或與SEQ ID NO.32所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.33所示序列或與SEQ ID NO.33所示序列具有至少80%、85%、90%或95%同一性;或
(8)重鏈CDR1的序列為SEQ ID NO.39所示序列或與SEQ ID NO.39所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.40所示序列或與SEQ ID NO.40所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.41所示序列或與SEQ ID NO.41所示序列具有至少80%、85%、90%或95%同一性;或
(9)重鏈CDR1的序列為SEQ ID NO.45所示序列或與SEQ ID NO.45所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.46所示序列或與SEQ ID NO.46所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.47所示序列或與SEQ ID NO.47所示序列具有至少80%、85%、90%或95%同一性;或
(10)重鏈CDR1的序列為SEQ ID NO.31所示序列或與SEQ ID NO.31所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.53所示序列或與SEQ ID NO.53所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.54所示序列或與SEQ ID NO.54所示序列具有至少80%、85%、90%或95%同一性;或
(11)重鏈CDR1的序列為SEQ ID NO.60所示序列或與SEQ ID NO.60所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.61所示序列或與SEQ ID NO.61所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.62所示序列或與SEQ ID NO.62所示序列具有至少80%、85%、90%或95%同一性;或
(12) 重鏈CDR1的序列為SEQ ID NO.82所示序列或與SEQ ID NO.82所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.83所示序列或與SEQ ID NO.83所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.84所示序列或與SEQ ID NO.84所示序列具有至少80%、85%、90%或95%同一性;
其中重鏈CDR1-3的氨基酸序列根據IMGT定義。
在一些實施方案中,
(1)重鏈CDR1的序列為SEQ ID NO.1所示序列,重鏈CDR2的序列為SEQ ID NO.2所示序列,重鏈CDR3的序列為SEQ ID NO.3所示序列;或
(2) 重鏈CDR1的序列為SEQ ID NO.9所示序列,重鏈CDR2的序列為SEQ ID NO.10所示序列,重鏈CDR3的序列為SEQ ID NO.11所示序列;或
(3)重鏈CDR1的序列為SEQ ID NO.17所示序列,重鏈CDR2的序列為SEQ ID NO.18所示序列,重鏈CDR3的序列為SEQ ID NO.19所示序列;或
(4)重鏈CDR1的序列為SEQ ID NO.24所示序列,重鏈CDR2的序列為SEQ ID NO.25所示序列,重鏈CDR3的序列為SEQ ID NO.26所示序列;或
(5)重鏈CDR1的序列為SEQ ID NO.31所示序列,重鏈CDR2的序列為SEQ ID NO.32所示序列,重鏈CDR3的序列為SEQ ID NO.33所示序列;或
(6)重鏈CDR1的序列為SEQ ID NO.39所示序列,重鏈CDR2的序列為SEQ ID NO.40所示序列,重鏈CDR3的序列為SEQ ID NO.41所示序列;或
(7)重鏈CDR1的序列為SEQ ID NO.45所示序列,重鏈CDR2的序列為SEQ ID NO.46所示序列,重鏈CDR3的序列為SEQ ID NO.47所示序列;或
(8)重鏈CDR1的序列為SEQ ID NO.31所示序列,重鏈CDR2的序列為SEQ ID NO.53所示序列,重鏈CDR3的序列為SEQ ID NO.54所示序列;或
(9)重鏈CDR1的序列為SEQ ID NO.60所示序列,重鏈CDR2的序列為SEQ ID NO.61所示序列,重鏈CDR3的序列為SEQ ID NO.62所示序列;或
(10)重鏈CDR1的序列為SEQ ID NO.68所示序列,重鏈CDR2的序列為SEQ ID NO.69或SEQ ID NO.91所示序列,重鏈CDR3的序列為SEQ ID NO.70所示序列;或
(11)重鏈CDR1的序列為SEQ ID NO.75所示序列,重鏈CDR2的序列為SEQ ID NO.76或SEQ ID NO.116所示序列,重鏈CDR3的序列為SEQ ID NO.77或SEQ ID NO.99所示序列;或
(12) 重鏈CDR1的序列為SEQ ID NO.82所示序列,重鏈CDR2的序列為SEQ ID NO.83所示序列,重鏈CDR3的序列為SEQ ID NO.84所示序列;
其中重鏈CDR1-3的氨基酸序列根據IMGT定義。
協力廠商面所述抗體的一個實例是單域抗體,也稱為重鏈可變區基因抗體(Variable domain of heavy chain of heavy-chain antibody,VHH),其僅由一個重鏈可變區組成,又被稱為納米抗體。VHH抗體是最初在羊駝外周血液中發現的一種天然缺失輕鏈的抗體,該抗體只包含一個重鏈可變區(VHH)和兩個常規的CH2與CH3區。克隆並表達出來的VHH結構具有與原重鏈抗體相當的結構穩定性以及與抗原的結合活性,是已知的可結合目標抗原的最小單位。
第四方面,本申請提供了抗GFRAL抗體或其抗原結合部分,所述抗GFRAL抗體或其抗原結合部分包括輕鏈可變區,其中所述輕鏈可變區包括輕鏈CDR1(HCDR1)、輕鏈CDR2(HCDR2)和輕鏈CDR3(HCDR3),其中:
(1)輕鏈CDR1的序列為SEQ ID NO.79或SEQ ID NO.126或SEQ ID NO.128所示序列或與SEQ ID NO.79或SEQ ID NO.126或SEQ ID NO.128所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.80所示序列或與SEQ ID NO.80所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.50或SEQ ID NO.123所示序列或與SEQ ID NO.50或SEQ ID NO.123所示序列具有至少80%、85%、90%或95%同一性;或
(2)輕鏈CDR1的序列為SEQ ID NO.72或SEQ ID NO.95所示序列或與SEQ ID NO.72或SEQ ID NO.95所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.65所示序列或與SEQ ID NO.65所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.73所示序列或與SEQ ID NO.73所示序列具有至少80%、85%、90%或95%同一性;或
(3)輕鏈CDR1的序列為SEQ ID NO.5所示序列或與SEQ ID NO.5所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.6所示序列或與SEQ ID NO.6所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.7所示序列或與SEQ ID NO.7所示序列具有至少80%、85%、90%或95%同一性;或
(4)輕鏈CDR1的序列為SEQ ID NO.13所示序列或與SEQ ID NO.13所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.14所示序列或與SEQ ID NO.14所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.15所示序列或與SEQ ID NO.15所示序列具有至少80%、85%、90%或95%同一性;或
(5)輕鏈CDR1的序列為SEQ ID NO.21所示序列或與SEQ ID NO.21所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.6所示序列或與SEQ ID NO.6所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.22所示序列或與SEQ ID NO.22所示序列具有至少80%、85%、90%或95%同一性;或
(6)輕鏈CDR1的序列為SEQ ID NO.28所示序列或與SEQ ID NO.28所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.6所示序列或與SEQ ID NO.6所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.29所示序列或與SEQ ID NO.29所示序列具有至少80%、85%、90%或95%同一性;或
(7)輕鏈CDR1的序列為SEQ ID NO.35所示序列或與SEQ ID NO.35所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.36所示序列或與SEQ ID NO.36所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.37所示序列或與SEQ ID NO.37所示序列具有至少80%、85%、90%或95%同一性;或
(8)輕鏈CDR1的序列為SEQ ID NO.43所示序列或與SEQ ID NO.43所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.6所示序列或與SEQ ID NO.6所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.22所示序列或與SEQ ID NO.22所示序列具有至少80%、85%、90%或95%同一性;或
(9)輕鏈CDR1的序列為SEQ ID NO.49所示序列或與SEQ ID NO.49所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.6所示序列或與SEQ ID NO.6所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.50所示序列或與SEQ ID NO.50所示序列具有至少80%、85%、90%或95%同一性;或
(10)輕鏈CDR1的序列為SEQ ID NO.56所示序列或與SEQ ID NO.56所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.57所示序列或與SEQ ID NO.57所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.58所示序列或與SEQ ID NO.58所示序列具有至少80%、85%、90%或95%同一性;或
(11)輕鏈CDR1的序列為SEQ ID NO.64所示序列或與SEQ ID NO.64所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.65所示序列或與SEQ ID NO.65所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.66所示序列或與SEQ ID NO.66所示序列具有至少80%、85%、90%或95%同一性;或
(12)輕鏈CDR1的序列為SEQ ID NO.86所示序列或與SEQ ID NO.86示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.87所示序列或與SEQ ID NO.87所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.88所示序列或與SEQ ID NO.88所示序列具有至少80%、85%、90%或95%同一性;
其中輕鏈CDR1-3的氨基酸序列根據IMGT定義。
在一些實施方案中,
(1)輕鏈CDR1的序列為SEQ ID NO.5所示序列,輕鏈CDR2的序列為SEQ ID NO.6所示序列,輕鏈CDR3的序列為SEQ ID NO.7所示序列;或
(2)輕鏈CDR1的序列為SEQ ID NO.13所示序列,輕鏈CDR2的序列為SEQ ID NO.14所示序列,輕鏈CDR3的序列為SEQ ID NO.15所示序列;或
(3)輕鏈CDR1的序列為SEQ ID NO.21所示序列,輕鏈CDR2的序列為SEQ ID NO.6所示序列,輕鏈CDR3的序列為SEQ ID NO.22所示序列;或
(4)輕鏈CDR1的序列為SEQ ID NO.28所示序列,輕鏈CDR2的序列為SEQ ID NO.6所示序列,輕鏈CDR3的序列為SEQ ID NO.29所示序列;或
(5)輕鏈CDR1的序列為SEQ ID NO.35所示序列,輕鏈CDR2的序列為SEQ ID NO.36所示序列,輕鏈CDR3的序列為SEQ ID NO.37所示序列;或
(6)輕鏈CDR1的序列為SEQ ID NO.43所示序列,輕鏈CDR2的序列為SEQ ID NO.6所示序列,輕鏈CDR3的序列為SEQ ID NO.22所示序列;或
(7)輕鏈CDR1的序列為SEQ ID NO.49所示序列,輕鏈CDR2的序列為SEQ ID NO.6所示序列,輕鏈CDR3的序列為SEQ ID NO.50所示序列;或
(8)輕鏈CDR1的序列為SEQ ID NO.56所示序列,輕鏈CDR2的序列為SEQ ID NO.57所示序列,輕鏈CDR3的序列為SEQ ID NO.58所示序列;或
(9)輕鏈CDR1的序列為SEQ ID NO.64所示序列,輕鏈CDR2的序列為SEQ ID NO.65所示序列,輕鏈CDR3的序列為SEQ ID NO.66所示序列;或
(10)輕鏈CDR1的序列為SEQ ID NO.72或SEQ ID NO.95所示序列,輕鏈CDR2的序列為SEQ ID NO.65所示序列,輕鏈CDR3的序列為SEQ ID NO.73所示序列;或
(11)輕鏈CDR1的序列為SEQ ID NO.79或SEQ ID NO.126或SEQ ID NO.128所示序列,輕鏈CDR2的序列為SEQ ID NO.80所示序列,輕鏈CDR3的序列為SEQ ID NO.50或SEQ ID NO.123所示序列;或
(12)輕鏈CDR1的序列為SEQ ID NO.86所示序列,輕鏈CDR2的序列為SEQ ID NO.87所示序列,輕鏈CDR3的序列為SEQ ID NO.88所示序列;
其中輕鏈CDR1-3的氨基酸序列根據IMGT定義。
第五方面,本申請提供了抗GFRAL抗體或其抗原結合部分,所述抗GFRAL抗體或其抗原結合部分包含重鏈可變區和輕鏈可變區,其中
(i)所述重鏈可變區包含三個重鏈CDR區,其中至少一個所述重鏈CDR區的氨基酸序列選自:SEQ ID NO.1、SEQ ID NO.9、SEQ ID NO.17、SEQ ID NO.24、SEQ ID NO.31、SEQ ID NO.39、SEQ ID NO.45、SEQ ID NO.60、SEQ ID NO.68、SEQ ID NO.75、SEQ ID NO.82、SEQ ID NO.2、SEQ ID NO.10、SEQ ID NO.18、SEQ ID NO.25、SEQ ID NO.32、SEQ ID NO.40、SEQ ID NO.46、SEQ ID NO.53、SEQ ID NO.61、SEQ ID NO.69、SEQ ID NO.76、SEQ ID NO.83、 SEQ ID NO.3、SEQ ID NO.11、SEQ ID NO.19、SEQ ID NO.26、SEQ ID NO.33、SEQ ID NO.41、SEQ ID NO.47、SEQ ID NO.54、SEQ ID NO.62、SEQ ID NO.70、SEQ ID NO.77、SEQ ID NO.84、SEQ ID NO.99所示的氨基酸序列或者與其具有至少80%(優選85%、90%、95%、98%或者99%)序列同一性的序列;和/或
(ii)所述輕鏈可變區包含三個輕鏈CDR區,其中至少一個所述輕鏈CDR區的氨基酸序列具有如SEQ ID NO.5、SEQ ID NO.13、SEQ ID NO.21、SEQ ID NO.28、SEQ ID NO.35、SEQ ID NO.43、SEQ ID NO.49、SEQ ID NO.56、SEQ ID NO.64、SEQ ID NO.72、SEQ ID NO.79、SEQ ID NO.86 、SEQ ID NO.95、SEQ ID NO.126、SEQ ID NO.128、SEQ ID NO.6、SEQ ID NO.14、SEQ ID NO.36、SEQ ID NO.57、SEQ ID NO.65、SEQ ID NO.80、SEQ ID NO.87、 SEQ ID NO.7、SEQ ID NO.15、SEQ ID NO.22、SEQ ID NO.29、SEQ ID NO.37、SEQ ID NO.50、SEQ ID NO.58、SEQ ID NO.66、SEQ ID NO.73、SEQ ID NO.88、SEQ ID NO.123所示的氨基酸序列或者與其具有至少80%(優選85%、90%、95%、98%或者99%)序列同一性的序列;
其中重鏈CDR1-3和輕鏈CDR1-3的氨基酸序列根據IMGT定義。
在一些具體實施方案中,所述抗體包含重鏈可變區和輕鏈可變區,所述重鏈可變區和輕鏈可變區分別包括CDR1、CDR2、CDR3;其中,重鏈CDR1的序列選自:SEQ ID NO.1、SEQ ID NO.9、SEQ ID NO.17、SEQ ID NO.24、SEQ ID NO.31、SEQ ID NO.39、SEQ ID NO.45、SEQ ID NO.60、SEQ ID NO.68、SEQ ID NO.75、SEQ ID NO.82所示序列或者與其具有至少80%(優選85%、90%、95%、98%或者99%)序列同一性的序列;
重鏈CDR2的序列選自:SEQ ID NO.2、SEQ ID NO.10、SEQ ID NO.18、SEQ ID NO.25、SEQ ID NO.32、SEQ ID NO.40、SEQ ID NO.46、SEQ ID NO.53、SEQ ID NO.61、SEQ ID NO.69、SEQ ID NO.76、SEQ ID NO.83、SEQ ID NO.91、SEQ ID NO.116所示序列或者與其具有至少80%(優選85%、90%、95%、98%或者99%)序列同一性的序列;
重鏈CDR3的序列選自:SEQ ID NO.3、SEQ ID NO.11、SEQ ID NO.19、SEQ ID NO.26、SEQ ID NO.33、SEQ ID NO.41、SEQ ID NO.47、SEQ ID NO.54、SEQ ID NO.62、SEQ ID NO.70、SEQ ID NO.77、SEQ ID NO.84、SEQ ID NO.99所示序列或者與其具有至少80%(優選85%、90%、95%、98%或者99%)序列同一性的序列;
和/或其輕鏈CDR1的序列選自:SEQ ID NO.5、SEQ ID NO.13、SEQ ID NO.21、SEQ ID NO.28、SEQ ID NO.35、SEQ ID NO.43、SEQ ID NO.49、SEQ ID NO.56、SEQ ID NO.64、SEQ ID NO.72、SEQ ID NO.79、SEQ ID NO.86、SEQ ID NO.95、SEQ ID NO.126、SEQ ID NO.128所示序列或者與其具有至少80%(優選85%、90%、95%、98%或者99%)序列同一性的序列;
輕鏈CDR2的序列選自: SEQ ID NO.6、SEQ ID NO.14、SEQ ID NO.36、SEQ ID NO.57、SEQ ID NO.65、SEQ ID NO.80、SEQ ID NO.87所示序列或者與其具有至少80%(優選85%、90%、95%、98%或者99%)序列同一性的序列;
輕鏈CDR3的序列選自:SEQ ID NO.7、SEQ ID NO.15、SEQ ID NO.22、SEQ ID NO.29、SEQ ID NO.37、SEQ ID NO.50、SEQ ID NO.58、SEQ ID NO.66、SEQ ID NO.73、SEQ ID NO.88、SEQ ID NO.123所示序列或者與其具有至少80%(優選85%、90%、95%、98%或者99%)序列同一性的序列。
在一些具體實施方案中,所述抗體包含重鏈可變區和輕鏈可變區,其中
(i)所述重鏈可變區包含三個重鏈CDR區,其中:
(1)CDR1的序列為SEQ ID NO.1所示序列,CDR2的序列為SEQ ID NO.2所示序列,CDR3的序列為SEQ ID NO.3所示序列;
(2)CDR1的序列為SEQ ID NO.9所示序列,CDR2的序列為SEQ ID NO.10所示序列,CDR3的序列為SEQ ID NO.11所示序列;
(3)CDR1的序列為SEQ ID NO.17所示序列,CDR2的序列為SEQ ID NO.18所示序列,CDR3的序列為SEQ ID NO.19所示序列;
(4)CDR1的序列為SEQ ID NO.24所示序列,CDR2的序列為SEQ ID NO.25所示序列,CDR3的序列為SEQ ID NO.26所示序列;
(5)CDR1的序列為SEQ ID NO.31所示序列,CDR2的序列為SEQ ID NO.32所示序列,CDR3的序列為SEQ ID NO.33所示序列;
(6)CDR1的序列為SEQ ID NO.39所示序列,CDR2的序列為SEQ ID NO.40所示序列,CDR3的序列為SEQ ID NO.41所示序列;
(7)CDR1的序列為SEQ ID NO.45所示序列,CDR2的序列為SEQ ID NO.46所示序列,CDR3的序列為SEQ ID NO.47所示序列;
(8)CDR1的序列為SEQ ID NO.31所示序列,CDR2的序列為SEQ ID NO.53所示序列,CDR3的序列為SEQ ID NO.54所示序列;
(9)CDR1的序列為SEQ ID NO.60所示序列,CDR2的序列為SEQ ID NO.61所示序列,CDR3的序列為SEQ ID NO.62所示序列;
(10)CDR1的序列為SEQ ID NO.68所示序列,CDR2的序列為SEQ ID NO.69所示序列,CDR3的序列為SEQ ID NO.70所示序列;
(11)CDR1的序列為SEQ ID NO.75所示序列,CDR2的序列為SEQ ID NO.76所示序列,CDR3的序列為SEQ ID NO.77所示序列;
(12) CDR1的序列為SEQ ID NO.82所示序列,CDR2的序列為SEQ ID NO.83所示序列,CDR3的序列為SEQ ID NO.84所示序列;
(ii)所述輕鏈可變區包含三個輕鏈CDR區,其中:
(13)CDR1的序列為SEQ ID NO.5所示序列,CDR2的序列為SEQ ID NO.6所示序列,CDR3的序列為SEQ ID NO.7所示序列;
(14)CDR1的序列為SEQ ID NO.13所示序列,CDR2的序列為SEQ ID NO.14所示序列,CDR3的序列為SEQ ID NO.15所示序列;
(15)CDR1的序列為SEQ ID NO.21所示序列,CDR2的序列為SEQ ID NO.6所示序列,CDR3的序列為SEQ ID NO.22所示序列;
(16)CDR1的序列為SEQ ID NO.28所示序列,CDR2的序列為SEQ ID NO.6所示序列,CDR3的序列為SEQ ID NO.29所示序列;
(17)CDR1的序列為SEQ ID NO.35所示序列,CDR2的序列為SEQ ID NO.36所示序列,CDR3的序列為SEQ ID NO.37所示序列;
(18)CDR1的序列為SEQ ID NO.43所示序列,CDR2的序列為SEQ ID NO.6所示序列,CDR3的序列為SEQ ID NO.22所示序列;
(19)CDR1的序列為SEQ ID NO.49所示序列,CDR2的序列為SEQ ID NO.6所示序列,CDR3的序列為SEQ ID NO.50所示序列;
(20)CDR1的序列為SEQ ID NO.56所示序列,CDR2的序列為SEQ ID NO.57所示序列,CDR3的序列為SEQ ID NO.58所示序列;
(21)CDR1的序列為SEQ ID NO.64所示序列,CDR2的序列為SEQ ID NO.65所示序列,CDR3的序列為SEQ ID NO.66所示序列;
(22)CDR1的序列為SEQ ID NO.72所示序列,CDR2的序列為SEQ ID NO.65所示序列,CDR3的序列為SEQ ID NO.73所示序列;
(23)CDR1的序列為SEQ ID NO.79所示序列,CDR2的序列為SEQ ID NO.80所示序列,CDR3的序列為SEQ ID NO.50所示序列;
(24)CDR1的序列為SEQ ID NO.86所示序列,CDR2的序列為SEQ ID NO.87所示序列,CDR3的序列為SEQ ID NO.88所示序列。
在第一至第五方面的一些實施方案中,抗GFRAL抗體為全抗體、單鏈抗體(scFv)或雙特異性抗體。在第一至第五方面的一些實施方案中,抗GFRAL抗體的抗原結合片段為Fab、Fab’、Fv或F(ab’)2。在第一至第五方面的一些實施方案中,抗GFRAL抗體為鼠源抗體、嵌合抗體、人源化抗體或全人源抗體。在第一至第五方面的一些實施方案中,抗GFRAL抗體為單克隆抗體。在第一至第五方面的一些實施方案中,所述單克隆抗體可以是鼠源抗體,也可以是人源化抗體。在第一至第五方面的一些實施方案中,抗GFRAL抗體為雙特異性抗體。在第一至第五方面的一些實施方案中,抗GFRAL抗體為IgG1、IgG2或IgG4同種型的,即,抗體包含IgG1亞型、IgG2亞型或IgG4亞型的重鏈恒定區。在一些具體實施方案中,抗GFRAL抗體為IgG1同種型的。在具體的實施方案中,抗GFRAL抗體或其抗原結合部分包含人IgG1重鏈恒定區和人κ輕鏈恒定區。在具體的實施方案中,抗GFRAL抗體或其抗原結合部分包含人IgG4重鏈恒定區和人κ輕鏈恒定區,所述人IgG4重鏈恒定區包括野生型和突變型。在第一至第五方面的一些實施方案中,抗GFRAL抗體包含κ亞型或者λ亞型的輕鏈恒定區。在第一至第五方面的一些實施方案中,本申請的抗體或其抗原結合部分是分離的。在第一至第五方面的一些實施方案中,本申請的抗體或其抗原結合部分可以是嵌合抗體,也可以人源化抗體,人源化抗體包括半人源化抗體、部分人源化抗體或全人源抗體。在第一至第五方面的一些實施方案中,本申請的抗體或其抗原結合部分具有ADCC活性。在第一至第五方面的一些實施方案中,本申請的抗體或其抗原結合部分具有CDC活性。
第六方面,本申請提供了分離的核酸分子,其編碼第一至第五方面中任一實施方案所述的抗GFRAL抗體或其抗原結合部分。在一些實施方案中,本申請提供了分離的多核苷酸的組合,所述組合包括編碼本申請抗體或其抗原結合部分之輕鏈的多核苷酸和編碼本申請抗體或其抗原結合部分之重鏈的多核苷酸。在一些實施方案中,所述多核苷酸可操作地連接到調控序列,調控序列可以被用所述載體轉化過的宿主細胞識別。
第七方面,本申請提供了載體(例如表達載體),其含有第六方面所述的核酸分子或多核苷酸的組合。在一些實施方案中,本申請的表達載體包含本申請所述的核酸分子或者本申請所述的多核苷酸的組合,所述多核苷酸與允許其所編碼的多肽在宿主細胞或無細胞表達系統中表達的調節序列有效連接。表達載體的選擇取決於宿主細胞的選擇,並且可以選擇以便在所選宿主細胞中具有所需的表達和調控特徵。
“表達載體”是包括一個或多個表達控制序列的載體,“表達控制序列”是控制和調節另一DNA序列的轉錄和/或翻譯的DNA序列。
載體中的核酸可以與一個或多個表達控制序列可操作地連接。如本文所用,“可操作地連接”意指併入遺傳構建體中,使得表達控制序列有效地控制目標編碼序列的表達。表達控制序列的示例包括啟動子、增強子和轉錄終止區。啟動子是由DNA分子的通常在轉錄起始點上游100個核苷酸內(通常在RNA聚合酶II的起始位元點附近)的區域組成的表達控制序列。為了使編碼序列處於啟動子的控制下,必須將多肽翻譯閱讀框的翻譯起始位點定位在啟動子下游的1至約50個核苷酸之間。增強子在時間、位置和水準方面提供表達特異性。與啟動子不同,增強子可以在位於距轉錄位點的不同距離時起作用。增強子也可位於轉錄起始位點的下游。當RNA聚合酶能夠將編碼序列轉錄成mRNA,然後mRNA可以翻譯成由編碼序列所編碼的蛋白質時,編碼序列與細胞中的表達控制序列“可操作地連接”且處於表達控制序列的“控制下”。
合適的表達載體包括但不限於源自例如噬菌體、杆狀病毒、煙草花葉病毒、皰疹病毒、巨細胞病毒、逆轉錄病毒、痘苗病毒、腺病毒和腺相關病毒的質粒和病毒載體。許多載體和表達系統可從諸如Novagen(Madison,WI)、Clontech(Palo Alto,CA)、Stratagene(LaJolla,CA)和Invitrogen Life Technologies(Carlsbad,CA)等公司商購獲得。
表達載體可包括標籤序列。標籤序列通常表達為與編碼的多肽的融合體。此類標籤可以插入多肽內的任何位置,包括羧基或氨基末端。有用標籤的示例包括但不限於Fc片段、聚組氨酸、綠色螢光蛋白(GFP)、谷胱甘肽S-轉移酶(GST)、c-myc、血凝素、FlagTM 標籤(Kodak,NewHaven,CT)、麥芽糖E結合蛋白和蛋白A。在一些實施方案中,編碼GFRAL融合多肽的核酸分子存在於含有編碼Ig重鏈恒定區的一個或多個結構域的核酸的載體中,所述結構域例如,對應與人免疫球蛋白Cγ1鏈的鉸鏈區、CH 2區和CH3區的氨基酸序列(Fc片段)。
第八方面,本申請提供了宿主細胞,其含有第六方面所述的核酸分子或第七方面所述的載體。在本申請的某些實施方式中,所述宿主細胞可以為原核宿主細胞、真核宿主細胞或噬菌體。所述原核宿主細胞可以為大腸桿菌、枯草桿菌、鏈黴菌或奇異變形菌等。所述真核宿主細胞,可以為如巴斯德畢赤酵母、釀酒酵母、裂殖酵母、木黴等真菌,如草地粘蟲等昆蟲細胞,如煙草等植物細胞,如BHK細胞、CHO細胞、COS細胞、骨髓瘤細胞等哺乳動物細胞。在一些實施方案 中,本申請所述宿主細胞優選為哺乳動物細胞,更優選為BHK細胞、CHO細胞、NSO細胞或COS細胞。
第九方面,本申請提供了抗體藥物偶聯物,也稱為抗體-藥物綴合物,其包含與治療劑偶聯的第一至第五方面中任一實施方案所述的抗GFRAL抗體或其抗原結合部分。
在第九方面的一些實施方案中,治療劑為抗腫瘤藥物,例如,細胞毒性藥物、免疫增強劑或放射性同位素。
在一些實施方案中,細胞毒性藥物的類型包括微管蛋白抑制劑(例如生物鹼)、DNA拓撲異構酶抑制劑、DNA損傷劑、抗代謝藥或抗腫瘤抗生素。
在一些實施方案中,微管蛋白抑制劑包括但不限於,奧瑞斯他汀衍生物(例如MMAE(Monomethyl auristatin E)、MMAF (Monomethyl auristatin F))或美登素生物鹼衍生物(例如DM1、DM4、安絲菌素(Ansamitocin)、美登素(Mertansine)或海兔毒素肽(dolastatin)及其衍生物)。
在一些實施方案中,DNA拓撲異構酶抑制劑為喜樹堿類似物或DNA拓撲異構酶I抑制劑及其衍生物,例如,DXD、SN38、伊立替康、伊立替康鹽酸鹽、喜樹堿、9-氨基喜樹堿、9-硝基喜樹堿、10-羥基喜樹堿、9-氯-10-羥基喜樹堿、22-羥基旱蓮木堿、拓撲替康、勒托替康、貝洛替康、依喜替康、矽基高喜樹堿(homosilatecan)、6,8-二溴-2-甲基-3-[2-(D-吡喃木糖基氨基)苯基]-4(3H)-喹唑啉酮、2-氰基-3-(3,4-二羥基苯基)-N-(苯基甲基)-(2E)-2-丙烯醯胺、2-氰基-3-(3,4-二羥基苯基)-N-(3-羥基苯基丙基)-(E)-2-丙烯醯胺、12-β-D-吡喃萄萄糖基-12,13-二氫-2,10-二羥基-6-[[2-羥基-1-(羥基甲基)乙基]氨基]-5H-吲哚並[2,3-a]吡咯並[3,4-c]哢唑-5,7(6H)-二酮、N-[2-(二甲基氨基)乙基]-4-吖啶甲醯胺二鹽酸鹽、N-[2-(二甲基氨基)乙基]-4-吖啶甲醯胺。
在一些實施方案中,DNA損傷劑包括但不限於,卡奇黴素(calicheamicin)類、倍癌黴素(duocarmycin)類、安麯黴素類衍生物PBD(pyrrolobenzodiazepine,吡咯並苯並二氮雜)。
在一些實施方案中,抗代謝藥包括但不限於,甲氨蝶呤、6-巰嘌呤或5-氟尿嘧啶。
在一些實施方案中,抗腫瘤抗生素包括但不限於,多肽類抗生素(例如放線菌素D或博來黴素)或蒽醌類藥物(例如阿黴素或鹽酸米托蒽醌)。在一些實施方案中,放射性同位素包括但不限於,
211At、
131I、
125I、
90Y、
186Re、
188Re、
153Sm、
212Bi、
32P、
60Co或
177Lu。
在一些實施方案中,免疫增強劑包括但不限於,左旋咪唑(levamisole)、匹多莫德(pidotimod)、咪喹莫特(imiquimod)、異丙肌苷、聚肌胞苷酸或聚肌尿苷酸。
在一些實施方案中,本申請的抗GFRAL抗體通過接頭與藥物部分共價連接。在一些實施方案中,接頭是可切割接頭。在一些實施方案中,接頭在細胞內條件下可被切割。在一個實施方案中,接頭在小於5.5的pH下可水解。在一些實施方案中,接頭可被細胞內蛋白酶切割。在一些實施方案中,接頭是組織蛋白酶可切割接頭。在一些實施方案中,接頭包含二肽。在一些實施方案中,二肽是纈氨酸(Val)-瓜氨酸(Cit)。在一些實施方案中,抗體通過抗體的半胱氨酸巰基與接頭連接。在一個實施方案中,抗體通過抗體的氨基(特別是穀氨醯胺殘基的氨基)與接頭連接。接頭的非限制性實例包括mc-Val-Cit-pAB、mc-Val-Cit-pABC、mc-Val-Cit、NH2-(PEG)m-Val-Cit、NH2-(PEG)m-Val-Cit-pAB,其中m為1至8的整數。
第十方面,本申請提供了藥物組合物,其包含第一至第五方面中任一實施方案所述的抗GFRAL抗體或其抗原結合部分或第九方面所述的抗體藥物偶聯物,以及藥學可接受的載體。
在一些實施方案中,所述藥物組合物還可包含下述中的一種或多種:潤滑劑,如滑石粉、硬脂酸鎂和礦物油;潤濕劑;乳化劑;懸浮劑;防腐劑,如苯甲酸、山梨酸和丙酸鈣;增甜劑和/或調味劑等。在一些實施方案中,可將本申請中的藥物組合物配製為片劑、丸劑、粉劑、錠劑、酏劑、懸液、乳劑、溶液、糖漿、栓劑或膠囊等形式。
在一些實施方案中,可以利用任何生理上可接受的給藥方式遞送本申請的藥物組合物,這些給藥方式包括但不限於:口服給藥、腸胃外給藥、經鼻給藥、直腸給藥、腹膜內給藥、血管內注射、皮下給藥、經皮給藥、吸入給藥等。
在一些實施方案中,可以通過混合具有所需純度的試劑與視情況的藥學上可接受的載體、賦形劑等,以凍幹製劑或水溶液的形式配製用於治療用途的藥物組合物用於存儲。
第十一方面,本申請提供了第一至第五方面中任一實施方案所述的抗體或其抗原結合部分、第六方面所述的核酸分子、第七方面所述的載體、第八方面所述的宿主細胞或第八方面所述的抗體藥物偶聯物在製備用於治療或預防GFRAL介導的或GFRAL-RET-GDF15信號通路介導的疾病或異常的藥物中的用途,例如,所述疾病或異常為惡病質綜合征、腫瘤(包括癌症)、心血管疾病、腎臟疾病、局部缺血性疾病、代謝紊亂、神經退行性疾病、厭食或厭食導致的體重減輕。
第十二方面,本申請提供了治療個體中GFRAL介導的或GFRAL-RET-GDF15信號通路介導的疾病或異常的方法,所述方法包括給予所述個體治療有效量的第一至第五方面中任一實施方案所述的抗體或其抗原結合部分、第九方面所述的抗體藥物偶聯物或第十方面所述的藥物組合物,例如,所述疾病或異常為惡病質綜合征、腫瘤(包括癌症)、心血管疾病、腎臟疾病、局部缺血性疾病、代謝紊亂、神經退行性疾病、厭食或厭食導致的體重減輕。在一些具體實施方案中,惡病質綜合征為腫瘤(包括癌症)導致的惡病質綜合征。本申請中的腫瘤、癌症或異常增生性疾病包括(但不限於)以下:癌,包括膀胱癌、乳腺癌、結腸癌、腎癌、肝癌、肺癌、卵巢癌、胰腺癌、胃癌、宮頸癌、甲狀腺癌和皮膚癌;包括鱗狀細胞癌;淋巴譜系造血系統腫瘤,包括白血病、急性淋巴細胞性白血病、急性成淋巴細胞性白血病、B細胞淋巴瘤、T細胞淋巴瘤、伯基特淋巴瘤;髓系造血系統腫瘤,包括急性和慢性骨髓性白血病和早幼粒細胞性白血病;間充質來源的腫瘤,包括纖維肉瘤和橫紋肌肉瘤;中樞和外周神經系統腫瘤,包括星形細胞瘤、神經母細胞瘤、神經膠質瘤和神經鞘瘤;間充質來源的腫瘤,包括纖維肉瘤、橫紋肌肉瘤和骨肉瘤;和其它腫瘤,包括黑素瘤、著色性幹皮病、角化棘皮瘤、精原細胞瘤、甲狀腺濾泡狀癌以及畸胎癌。
在一些實施方案中,所述腫瘤(包括癌症)包括但不限於血液瘤或實體瘤。
在一些實施方案中,所述腫瘤(包括癌症)是血液瘤,優選淋巴瘤或白血病,包括但不限於骨髓瘤、B-細胞淋巴瘤、套細胞淋巴瘤、非霍奇金B-細胞淋巴瘤、非霍奇金淋巴瘤T-細胞淋巴瘤、皮膚淋巴瘤、間變性大細胞淋巴瘤、多發性骨髓瘤、惰性非霍奇金淋巴瘤、漿細胞瘤、慢性淋巴細胞白血病、小淋巴細胞淋巴瘤、濾泡性淋巴瘤。在一些實施方案中,血液瘤是復發或難治性的。
在一些實施方案中,所述癌症腫瘤(包括癌症)是實體瘤,包括但不限於:呼吸系統腫瘤、消化道腫瘤、泌尿系統腫瘤、男性器官腫瘤、女性器官腫瘤、皮膚癌、內皮細胞腫瘤、腦部腫瘤、神經系統腫瘤、內分泌器官腫瘤。
在一些實施方案中,所述呼吸系統腫瘤包括但不限於:肺癌和鼻咽癌以及喉癌。
在一些實施方案中,所述消化道腫瘤包括但不限於:食管癌、胃癌、大腸癌、肝癌、胰腺癌、膽管癌。
在一些實施方案中,所述泌尿系統腫瘤包括但不限於:腎癌、腎盂輸尿管癌、膀胱癌、尿道癌。
在一些實施方案中,所述男性器官腫瘤包括但不限於陰莖癌、前列腺癌或睾丸癌。
在一些實施方案中,所述女性器官腫瘤包括但不限於乳腺癌、外陰癌、陰道癌、宮頸癌、子宮體癌或卵巢癌。
在一些實施方案中,所述神經系統腫瘤包括但不限於:星形膠質細胞瘤、少突膠質細胞瘤、室管膜瘤、髓母細胞瘤、腦膜瘤。
在一些實施方案中,所述腦部腫瘤包括但不限於:膠質細胞瘤、神經細胞瘤、類胚葉間質腫瘤、間質類腫瘤、上皮類腫瘤、畸胎瘤、松果體瘤。
在一些實施方案中,所述皮膚癌包括但不限於皮膚黑色素瘤或非黑色素瘤皮膚癌。
在一些實施方案中,所述癌症是實體瘤,包括但不限於膀胱癌、腦癌、乳腺癌、宮頸癌、胸部腫瘤、子宮內膜癌、食管鱗癌、胃癌、頭部腫瘤、胰腺癌、膽管癌、結直腸癌、眼癌、頭頸鱗癌、尿路上皮癌、腎癌、肝癌、淋巴結癌、肺癌、口腔癌、頸部腫瘤、卵巢癌、前列腺癌、睾丸癌、喉癌和子宮癌、黑色素瘤、唾液腺癌、纖維肉瘤、軟組織肉瘤和骨肉瘤。在一些實施方案中,以上癌症復發或難治性的。
在一些實施方案中,所述乳腺癌包括:導管癌、小葉癌、髓性癌、膠質性癌、管狀癌、炎性乳腺癌、三陰性乳腺癌(TNBC)。
在一些實施方案中,所述卵巢癌包括:上皮卵巢腫瘤,如卵巢中的腺癌和從卵巢遷移至腹腔中的腺癌。
在一些實施方案中,所述白血病包括:急性髓性白血病(AML)、急性淋巴細胞白血病、慢性淋巴細胞白血病、慢性髓性白血病、毛細胞白血病、脊髓發育不良、骨髓增生性障礙、NK細胞白血病(例如,母細胞性漿細胞樣樹突狀細胞腫瘤)、急性骨髓性白血病(AML)、慢性骨髓性白血病(CML)、肥大細胞增多症、慢性淋巴細胞白血病(CLL)、多發性骨髓瘤(MM)和骨髓增生異常綜合征(MDS)。
在一些實施方案中,所述胰腺癌是胰腺的腺泡細胞腺癌,胰腺的導管細胞腺癌或IV期胰腺癌。
在一些實施方案中,所述肺癌包括非小細胞肺癌(NSCLC)和小細胞肺癌(SCLC);在一些實施方案中,非小細胞肺癌(NSCLC)包括但不限於:鱗狀細胞癌、腺癌、大細胞癌;在一些實施方案中,肺癌是復發性的;在一些實施方案中,肺癌是復發性鱗狀細胞肺癌或(晚期)IV期鱗狀細胞肺癌。
在一些實施方案中,所述前列腺癌是轉移性去勢抗性前列腺癌(mCRPC)。
第十三方面,本申請提供了綴合物,其包含第一至第五方面中任一實施方案所述的抗GFRAL抗體或其抗原結合部分以及可檢測標記物。所述可檢測標記物例如可檢測的螢光標記物、化學發光標記物、同位素標記物等。
第十四方面,本申請提供了包含第一至第五方面中任一實施方案所述的抗GFRAL抗體或其抗原結合部分的融合蛋白。抗體融合蛋白的實例包括Fab融合蛋白、Fc融合蛋白與單鏈抗體(scFv)融合蛋白等,根據效應蛋白(例如細胞因數)所融合的部位不同而命名。
應當理解,以上詳細描述僅為了使本領域技術人員更清楚地瞭解本申請的內容,而並非意圖在任何方面加以限制。本領域技術人員能夠對所述實施方案進行各種改動和變化。
實施例
下文將結合實施例對本申請的具體實施方案進行詳細描述,但是本領域技術人員將會理解,以下實施例僅用於說明本申請的發明,而不應視為限制本申請的範圍。
實施例中未注明具體條件者,按照常規條件或製造商建議的條件進行。所用試劑或儀器未注明生產廠商者,均為可以通過市購獲得的常規產品。
實施例1:鼠源抗體的獲得
為了獲得抗GFRAL抗體,發明人利用人GFRAL-His融合蛋白(愷佧,貨號GFL-HM401)和過表達人GFRAL蛋白的細胞免疫小鼠誘導產生抗人GFRAL的抗體。
過表達人GFRAL細胞的製備:用攜帶pLVX-IRES-嘌呤黴素-hGFRAL基因的慢病毒對HEK293細胞進行感染,72h後加入終濃度為1µg/ml的嘌呤黴素篩選獲得單克隆細胞株,並通過FACS方法篩選高表達人GFRAL的細胞株用於動物免疫。
用不含或者含有佐劑(弗氏完全佐劑、弗氏不完全佐劑)的人GFRAL-His融合蛋白或者過表達人GFRAL的細胞通過皮下或腹腔注射的方式對動物進行免疫。每2周對動物進行加強免疫持續誘導直至產生合適效價。每次加強免疫後對動物進行采血,通過ELISA和FACS方法檢測血清中抗體效價;最後一次免疫後4天,獲取合適效價動物的脾臟,並製備單細胞懸液。使用電融合將細胞與SP2/0小鼠骨髓瘤細胞進行融合。將融合的細胞重懸於含雜交瘤細胞選擇劑胸腺核苷嘧啶,次黃嘌呤和氨基喋呤(HAT)的培養基中,然後接種到96孔板中進行培養。
孵育7-10天之後,收集培養上清,通過如實施例2描述的ELISA或者FACS的方法檢測篩選出能夠結合人GFRAL以及食蟹猴GFRAL蛋白的抗體克隆,並驗證是否結合小鼠GFRAL蛋白。雜交瘤細胞在添加新鮮含有HAT的培養基之後繼續培養。2天后收集第一輪篩選出來的陽性克隆培養上清再進行如實施例3描述的GFRAL抗體拮抗功能活性檢測。之後,對篩選出的陽性克隆進行進一步的亞克隆。亞克隆成功後,用常規的抗體純化方法對這些抗體進行純化,並通過實施例3描述的GFRAL抗體拮抗功能測定法對抗體的拮抗功能進行進一步測定。同時對部分符合要求的克隆進行了抗體的可變區測序。
總共經過了5輪融合篩選,篩選了約3萬個克隆。經過ELISA和FACS篩選篩選出1千多個克隆進行了GFRAL拮抗功能檢測,從中篩選了不到100個克隆進行了亞克隆,最終獲得了本申請的抗體。
本申請中涉及的抗體相關序列如下表:
表1:鼠源抗體序列 (底線表示CDR)
名稱 | 編號(IMGT) |
61G8 | 重鏈CDR1: GYGVN SEQ ID NO.1 重鏈CDR2: MIWGDGTTDYNSALKS SEQ ID NO.2 重鏈CDR3: DPKYNYGYAMDY SEQ ID NO.3 重鏈可變區: QVQLKESGPGLVAPSQSLSITCTVSGFSLT GYGVNWVRQSPGKGLEWLG MIWGDGTTDYNSALKS RLTIRKDNSKSQVFLRMNSLQTDDTARYYCAR DPKYNYGYAMDYWGQGTSVTVSS SEQ ID NO.4 輕鏈CDR1:RASESVDNFGNSFMH SEQ ID NO.5 輕鏈CDR2:RASNLES SEQ ID NO.6 輕鏈CDR3:QQTNEEPYT SEQ ID NO.7 輕鏈可變區: DIVLTQAPGSLAVSLGQRATISC RASESVDNFGNSFMHWYQQKPGQSPKLLIY RASNLESGIPARF SGSGSRTDFTLTINPVEADDVATYYC QQTNEEPYTFGGGTKLEIE SEQ ID NO.8 |
90E1 | 重鏈CDR1: SYVIH SEQ ID NO.9 重鏈CDR2: YINPYNDDINYNEKFKG SEQ ID NO.10 重鏈CDR3: YDYDWYFDV SEQ ID NO.11 重鏈可變區: EVQLQQSGPELVKPGASVKMSCKASGYTFT SYVIHWVKQEPGQGLEWIG YINPYNDDINYNEKFKGK ATLTSDKSSSTAYMEFSSLTSEDSAVYYCAR YDYDWYFDVWGAGTAVTVSS SEQ ID NO.12 輕鏈CDR1: KSSQSLLDSDGKTYVN SEQ ID NO.13 輕鏈CDR2: LVSKLGS SEQ ID NO.14 輕鏈CDR3:WQGTHFPQT SEQ ID NO.15 輕鏈可變區: DVVMTQTPLTLSVTIGQPASISC KSSQSLLDSDGKTYVNWLLQRPGQSPKRLIF LVSKLGSGVPDRFTG SGSGTDFTLKISRVEAEDLGVYYC WQGTHFPQTFGGGTKLEIK SEQ ID NO.16 |
82G8 | 重鏈CDR1: GHGVN SEQ ID NO.17 重鏈CDR2: MIWGDGYTDYNSALKS SEQ ID NO.18 重鏈CDR3:DTYGRTYDYAMDY SEQ ID NO.19 重鏈可變區: QVQLKESGPGLVAPSQSLSITCTVSGFSLT GHGVNWVRQPPGKGLEWLG MIWGDGYTDYNSALKSRLSISKDN SKSQVFLKMNSLQTDDTATYYCAR DTYGRTYDYAMDYWGQGTSVTVSS SEQ ID NO.20 輕鏈CDR1: RASESVDNYGNSFMH SEQ ID NO.21 輕鏈CDR2: RASNLES SEQ ID NO.6 輕鏈CDR3: QQSNEDPRT SEQ ID NO.22 輕鏈可變區: DIVLTQSPASLAVSLGQRAAISC RASESVDNYGNSFMHWYQQKPGQPPKLLIY RASNLESGIPARFSGSGSRTD FTLTINPVEADDVATYYC QQSNEDPRTFGGGTKLEIK SEQ ID NO.23 |
8E10 | 重鏈CDR1: NYWMN SEQ ID NO.24 重鏈CDR2: QIYPGDDDADYNGKFQG SEQ ID NO.25 重鏈CDR3: SGRRDFDY SEQ ID NO.26 重鏈可變區: QVQLQQSGSELVRPGSSVKISCRASGYTFS NYWMNWVKQRPGQGLEWIG QIYPGDDDADYNGKFQGKATLTADKSSSTAYMQLNTLTSEDSAVYFCTR SGRRDFDYWGQGTTLTVSS SEQ ID NO.27 輕鏈CDR1: RASESIDNYGNSFMH SEQ ID NO.28 輕鏈CDR2: RASNLES SEQ ID NO.6 輕鏈CDR3: QQNNEDPYT SEQ ID NO.29 輕鏈可變區: NIVLTQSPASLAVSLGQRATISC RASESIDNYGNSFMHWYQQKPGQPPKLLIY RASNLESGVPARFSGSGS RTDFTLTIDPVEADDAATYYC QQNNEDPYTFGGGTKLEIK SEQ ID NO.30 |
174E10 | 重鏈CDR1: SYGVH SEQ ID NO.31 重鏈CDR2: VIWSGGRIDYNAAFIS SEQ ID NO.32 重鏈CDR3: KGSSYYGLYYYGMDY SEQ ID NO.33 重鏈可變區: QVQLKQSGPGLVQPSQSLSITCTVSGFSLT SYGVHWVRQSPGKGLEWLG VIWSGGRIDYNAAFISRLSIS KDNSKSQVFFKMNSLQADDTAIYYCAR KGSSYYGLYYYGMDYWGQGTSVTVSS SEQ ID NO.34 輕鏈CDR1: KSSQSLLNSGNQKNYLT SEQ ID NO.35 輕鏈CDR2: WASTRES SEQ ID NO.36 輕鏈CDR3: QNDYGYPLT SEQ ID NO.37 輕鏈可變區: DIVMTQSPSSLTVTAGEKVTMSC KSSQSLLNSGNQKNYLTWYQQKSGQTPKLLIY WASTRESGVPDRFT GSGSGTDFTLTISSVQAEDLAVYYC QNDYGYPLTFGAGTKLELK SEQ ID NO.38 |
96C12 | 重鏈CDR1: GYSVN SEQ ID NO.39 重鏈CDR2: MIWGDGSTDYNSALKS SEQ ID NO.40 重鏈CDR3: DRDYRYDGGYIMDS SEQ ID NO.41 重鏈可變區: RVQLRESGPGLVAPSQSLSITCTVSGFSLT GYSVNWVRQPPGKGLEWLG MIWGDGSTDYNSALKSRLSIS KDNSKSQVFLKMNSLQTDDTARYYCAR DRDYRYDGGYIMDSWGQGTSVTVSS SEQ ID NO.42 輕鏈CDR1: RASESVDNFGNSFLH SEQ ID NO.43 輕鏈CDR2: RASNLES SEQ ID NO.6 輕鏈CDR3: QQSNEDPRT SEQ ID NO.22 輕鏈可變區: DIVLTQSPGSLAVSLGQRATISC RASESVDNFGNSFLHWYQQKPGQPPKLLIY RASNLESGVPARFSGSGSR TDFTLTISPVEADDVATYYC QQSNEDPRTFGGGTKLEIR SEQ ID NO.44 |
36D1 | 重鏈CDR1: RNWMH SEQ ID NO.45 重鏈CDR2: EIDPSDSYTHYNQKFKG SEQ ID NO.46 重鏈CDR3: VGNYDNGKDRLYAMDY SEQ ID NO.47 重鏈可變區: QVQLQQPGTEFVKPGASVKLSCKASGYTFTRNWMHWLKQRPGQGLEWIGEIDPSDSYTHYNQKFKGKA TLTVDKSSSTAYMQLSSLTSEDSAVYYCARVGNYDNGKDRLYAMDYWGQGTSVTVSS SEQ ID NO.48 輕鏈CDR1: RASESVDNFGNTFLH SEQ ID NO.49 輕鏈CDR2: RASNLES SEQ ID NO.6 輕鏈CDR3: QQNNEDPWT SEQ ID NO.50 輕鏈可變區: DIVLTQSPASLAVSLGQRATISCRASESVDNFGNTFLHWFRQKPGQPPKLLIYRASNLESGIPARFSGSGSRTDF TLTINPVEADDVATYYCQQNNEDPWTFGGGTKLEIK SEQ ID NO.51 |
33B12 | 重鏈CDR1: RNWMH SEQ ID NO.45 重鏈CDR2: EIDPSDSYTHYNQKFKG SEQ ID NO.46 重鏈CDR3: VGNYDNGTDRLYAMDY SEQ ID NO.47 重鏈可變區: QVQLQQPGTELVKPGASVKLSCKASGYTFTRNWMHWLKQRPGQGLEWIGEIDPSDSYTHYNQKFKGKATLTV EMSSSTAYMQLRSLTSEDSAVYYCARVGNYDNGTDRLYAMDYWGQGTSVTVSS SEQ ID NO.52 輕鏈CDR1: RASESVDNFGNTFLH SEQ ID NO.49 輕鏈CDR2: RASNLES SEQ ID NO.6 輕鏈CDR3: QQNNEDPWT SEQ ID NO.50 輕鏈可變區: DIVLTQSPASLAVSLGQRATISCRASESVDNFGNTFLHWFRQKPGQPPKLLIYRASNLESGIPARFSGSGSRTDF TLTINPVEADDVATYYCQQNNEDPWTFGGGTKLEIK SEQ ID NO.51 |
174D6 | 重鏈CDR1: SYGVH SEQ ID NO.31 重鏈CDR2: VIWSGGRTDYNAAFIS SEQ ID NO.53 重鏈CDR3: KGSSYYGLYYYGMDF SEQ ID NO.54 重鏈可變區: QVQLKQSGPGLVQPSQSLSITCTVSGFSLTSYGVHWVRQSPGKGLEWLGVIWSGGRTDYNAAFISRLNISKDS SKSQVFFKMNSLQADDTAIYYCARKGSSYYGLYYYGMDFWGQGTSVTVSS SEQ ID NO.55 輕鏈CDR1: RASESVDNYGISFMN SEQ ID NO.56 輕鏈CDR2: VASNQGS SEQ ID NO.57 輕鏈CDR3: QHSKEVPRT SEQ ID NO.58 輕鏈可變區: DIVLTQSPASLTVSLGQRATISCRASESVDNYGISFMNWFQQKPGQPPKLLIYVASNQGSGVPARFSGSGSGTDFS LNIHPMEEDDTAMYFCQHSKEVPRTFGGGTKLEIK SEQ ID NO.59 |
165C5 | 重鏈CDR1: SYAMS SEQ ID NO.60 重鏈CDR2: SITTGGSTYYLDSVRG SEQ ID NO.61 重鏈CDR3: SLIITATGFDY SEQ ID NO.62 重鏈可變區: EVKLVESGGGLVKPGGSLKLSCAASGFTFSSYAMSWVRQTPEKRLEWVASITTGGSTYYLDSVRGRFTISRDNA RNILSLQMSSLRSEDTAIYYCARSLIITATGFDYWGQGTTLTVSS SEQ ID NO.63 輕鏈CDR1: RASQDVGTAVA SEQ ID NO.64 輕鏈CDR2: SASNRYT SEQ ID NO.65 輕鏈CDR3: QQYSIYYT SEQ ID NO.66 輕鏈可變區: DIVMTQSQKFMSISVGDRVNITCRASQDVGTAVAWYQQKPGQSPKLLIYSASNRYTGVPNRFTGSGSGTDFTLAI SNMQSEDLADYFCQQYSIYYTFGGGTKLEIK SEQ ID NO.67 |
2D4 | 重鏈CDR1: SFVMS SEQ ID NO.68 重鏈CDR2: SITSGGTTFYPDSVKG SEQ ID NO. 69 重鏈CDR3: GPPQFSSLSMDY SEQ ID NO.70 重鏈可變區: EVNLVESGGGLVKPGGPLKLSCAASGFTFSSFVMSWVRQTPEKRLEWVASITSGGTTFYPDSVKGRFTISRDNA RNILYLQMSNLRSGDTAMYYCARGPPQFSSLSMDYWGQGTSVTVSS SEQ ID NO.71 輕鏈CDR1: KASQNVGTAVS SEQ ID NO.72 輕鏈CDR2: SASNRYT SEQ ID NO.65 輕鏈CDR3: QQYSSLFT SEQ ID NO.73 輕鏈可變區: DIVMTQSQKFMSTSVGDRITITCKASQNVGTAVSWFQQKPGQVPKLLIYSASNRYTGVPDRFTGSGSGTEFTLTI SNIQSEDLADYFCQQYSSLFTFGSGTKLEIK SEQ ID NO.74 |
26D7 | 重鏈CDR1: GYTFTDYGMN SEQ ID NO.75 重鏈CDR2: WINTYTGEPTYADDFKD SEQ ID NO.76 重鏈CDR3: RYGYDAGIDC SEQ ID NO.77 重鏈可變區: QIQLVQSGPELKKPGETVKISCKVSGYTFTDYGMNWVKQTPGKDLKWVGWINTYTGEPTYADDFKDRFAFSLE ASASTAYLQINNLKNEDTATYFCARRYGYDAGIDCWGQGTTLTVSS SEQ ID NO.78 輕鏈CDR1: RASESVDSYGNNLMH SEQ ID NO.79 輕鏈CDR2: LASYLES SEQ ID NO.80 輕鏈CDR3: QQNNEDPWT SEQ ID NO.50 輕鏈可變區: NIVLTQSPPSLAVSLGQRATISCRASESVDSYGNNLMHWYQQKPGQPPKLLIYLASYLESGVPARFSGSGSRTD FTLTIDPVEADDAATYYCQQNNEDPWTFGGGTKLEIK SEQ ID NO.81 |
168A7 | 重鏈CDR1: TSDMGVG SEQ ID NO.82 重鏈CDR2: HIWWDDDKYYNPSLKR SEQ ID NO.83 重鏈CDR3: LYDYDDEYYFDY SEQ ID NO.84 重鏈可變區: QVTLKESGPGILKPSQTLSLTCSFSGFSLSTSDMGVGWIRQPSGKGLEWLAHIWWDDDKYYNPSLKRQLTISKDN SRNQVFLKISSVDTTDTATYYCARLYDYDDEYYFDYWGQGTTLTVSS SEQ ID NO.85 輕鏈CDR1: RASQDSNNYLN SEQ ID NO.86 輕鏈CDR2: YTSRLHS SEQ ID NO.87 輕鏈CDR3: QQGNTIPWT SEQ ID NO.88 輕鏈可變區: DIQMTQTKSSLSASLGDRVTISCRASQDSNNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSRFSGSGSGTDYSLTI SNLEHEDIATYFCQQGNTIPWTFGGGTKLEIK SEQ ID NO.89 |
實施例2:抗GFRAL抗體的篩選與選擇
通過ELISA或者FACS方法,測定了實施例1所描述的培養上清中雜交瘤產生的抗GFRAL抗體或純化抗體與人GFRAL、食蟹猴GFRAL以及小鼠GFRAL蛋白結合。
ELISA測定法流程如下:在96孔板上包被人GFRAL-His蛋白、食蟹猴GFRAL-His蛋白或鼠GFRAL-Fc蛋白,並使用PBS/1%BSA封閉孔板,將雜交瘤上清液或者純化後的抗體添加到反應孔中,在室溫下孵育1小時後,將HRP標記的抗小鼠IgG(Fab區)抗體添加到反應孔中,在室溫下再孵育1小時。先後加入底物和終止液後,讀取OD
450值,通過OD
450確認以及評價抗體與GFRAL蛋白的結合能力。
FACS篩選採用了區別於動物免疫用的過表達人GFRAL單克隆細胞株。雜交瘤上清或者純化後的抗體與過表達人GFRAL單克隆細胞在4℃孵育1小時後,將Alexa Fluor 647染料標記的抗小鼠Fc抗體添加到反應孔中,並置於4℃再孵育1小時,然後通過流式細胞儀分析細胞上的Alexa Fluor 647螢光信號,從而判斷雜交瘤上清中是否含有針對GFRAL的抗體或者評價抗體與細胞表面GFRAL蛋白的結合能力。
在ELISA測定法中,實施例1中描述的純化抗體與人GFRAL、食蟹猴GFRAL以及小鼠GFRAL蛋白的結合的代表性資料如下。
表2:抗GFRAL抗體對不同來源的GFRAL蛋白的ELISA結合實驗
ELISA EC 50(nM) | |||
克隆ID | 人GFRAL-His | 食蟹猴GFRAL-His | 小鼠GFRAL-Fc |
33B12 | 0.06 | 0.08 | >6.67 |
165C5 | 0.27 | 0.03 | 0.12 |
36D1 | 0.18 | 0.07 | >6.67 |
26D7 | 0.07 | 0.06 | 0.15 |
82G8 | 0.03 | 0.04 | >6.67 |
8E10 | 0.05 | 0.06 | >6.67 |
168A7 | 1.87 | 0.09 | >6.67 |
174D6 | 0.28 | 0.07 | 0.14 |
61G8 | 0.07 | 0.08 | >6.67 |
174E10 | 0.18 | 0.06 | 0.12 |
96C12 | 0.03 | 0.03 | >6.67 |
2D4 | 0.09 | 0.10 | 0.08 |
實施例3:GFRAL抗體拮抗功能測定
例如,基於報告基因測定法,對實施例1中描述的培養上清或者純化後的抗體進行GFRAL抗體拮抗功能測定,用於篩選或者評價抗體阻斷GDF15啟動GFRAL/RET信號通路的功能。該方法利用穩定轉染GFRAL/RET相關基因的細胞,GDF15啟動GFRAL/RET信號通路,引起ERK磷酸化,磷酸化ERK進一步導致Gal4-Elk1磷酸化並與DNA上USA啟動子區結合,隨後啟動螢光素酶報告基因轉錄的原理,通過測定螢光素酶水準來測定GDF15對GFRAL/RET信號通路的啟動以及抗體的拮抗功能。
採用如下方法構建報告基因穩定轉染細胞株。首先將兩個報告物質粒Gal4-Elk1和6XUAS-Luc轉入HEK293細胞中,通過一段時間相應抗生素篩選後獲得穩定表達目標分子的細胞株。然後進一步轉染編碼人GFRAL(hGFRAL)或者小鼠GFRAL(mGFRAL)以及人RET(hRET)或者小鼠RET(mRET)的質粒,經過抗生素篩選後獲得GFRAL/RET/Gal4-Elk1/Luc穩定轉染細胞株。
例如,採用如下方法測定GFRAL抗體的拮抗功能活性。將報告基因穩定轉染細胞按合適密度接種到96孔板中,並與雜交瘤上清或待測抗體共孵育,在37℃、5%CO
2空氣和飽和濕度的培養箱中孵育過夜。次日加入一定濃度人GDF15或小鼠GDF15刺激細胞,5-6小時後使用One-Glo(Promega)試劑盒檢測細胞中螢光素酶水準。
針對GFRAL的抗體抑制人GFRAL/RET信號轉導的代表性結果如下:
表3:GFRAL抗體的阻斷活性
鼠源 | IC 50(nM) | |
克隆ID | 人GFRAL/人RET | 小鼠GFRAL/小鼠RET |
33B12 | 7.04 | >694 |
165C5 | 55.48 | 7.22 |
36D1 | 6.89 | >694 |
26D7 | 6.35 | 0.76 |
82G8 | 5.67 | >694 |
8E10 | 3.33 | >694 |
168A7 | 3.29 | >694 |
174D6 | 104.40 | >694 |
61G8 | 11.60 | >694 |
174E10 | 37.17 | 104.90 |
96C12 | 6.42 | >694 |
2D4 | 11.64 | 2.23 |
90E1 | 81.37 | 75.50 |
實施例4:抗體親和力測定
基於Biacore親和力測定法,對168A7、8E10以及26D7三株抗體進行了結合親和力測定。通過測定純化的抗體的平衡解離常數(KD),來評估它們與人GFRAL或小鼠GFRAL的結合力。根據氨基偶聯試劑盒(貨號:BR100050,Cytiva)操作說明,將抗人Fc抗體固定在CM5晶片的流動池中。在流動池2、3和4上捕獲純化的抗體(~300RU),使用流動池1作為參考。隨後以30μL/分鐘的流動速度注入人或小鼠GFRAL蛋白 (HBS-EP緩衝液中),在25℃下評估結合動力學。結果如下(圖1A-圖1C,表4)
表4:三種鼠源抗體的結合動力學資料
結合親和性 | ||||
鼠源 | 人GFRAL | 小鼠GFRAL | ||
克隆ID | KD(M) | k off(1/s) | KD(nM) | k off(1/s) |
168A7 | 1.45E-12 | 7.06E-05 | 未測定 | 未測定 |
8E10 | 1.79E-11 | 4.04E-04 | 未測定 | 未測定 |
26D7 | 1.53E-11 | 9.37E-05 | 1.66E-10 | 2.93E-04 |
由此可見,鼠源抗體對人GFRAL具有較高的親和力,其中26D7對人GFRAL和小鼠GFRAL均有較好的結合活性,適合用於在小鼠模型上進行實驗。
實施例5:動物模型研究評估鼠源GFRAL拮抗性抗體的生物學功能
5.1 通過人纖維肉瘤HT-1080荷瘤小鼠模型評價抗GFRAL抗體在抑制腫瘤誘導的體重損失中的作用
為了確定抗GFRAL抗體是否能夠在荷瘤小鼠中改善由腫瘤引起的體重降低效應,使用6-9周齡雌性BALB/c nude小鼠(GemPharmatech Co.,Ltd)。使用體外培養好的HT1080細胞系對小鼠進行接種,當小鼠體重降低7%左右後再對接種成功的小鼠進行隨機分為2組,每組10只小鼠,分別接受每週皮下注射10mg/kg劑量的對照抗體(mIgG1,來源:Crownbio,非靶向GFRAL的陰性對照抗體)或者抗GFRAL抗體26D7。同時對另一組(n=10)非荷瘤小鼠同樣施以皮下注射10mg/kg/周的對照抗體。記錄每天的體重和食物攝取,採用Study Director
TM(version 3.1.399.19)軟體記錄測量的體重資料。資料匯總如下,資料表示為腫瘤體積、總體重以及體重改變百分比的平均值±SEM(即,體重變化相對於基線體重的百分比)。在這些實驗中,P<0.05被認為差異在統計學上是顯著的。結果(參見圖2和表5)表明抗GFRAL抗體26D7能夠逆轉荷瘤小鼠中GDF15誘導的體重損失。
表5:人纖維肉瘤HT-1080荷瘤模型中抗GFRAL抗體26D7對小鼠體重以及腫瘤大小的影響
注:資料表示為平均值±SEM;
a:體重變化= [(第i天的體重-第0天的體重)/第0天的體重] x 100%;
b:通過比較不同組從第0天到第13天的體重變化進行獨立t檢驗
組別 | 腫瘤體積 (mm 3) | 體重 (g) | 體重改變 a (%) | P b | ||
0 天 | 13 天 | 0 天 | 13 天 | 13 天 | ||
非荷瘤鼠,mIgG1 | N/A | N/A | 21.3±0.3 | 21.7±0.3 | 2.08±0.70 | 0.004 |
荷瘤鼠,mIgG1 | 0 | 1721±171 | 23.1±0.4 | 22.0±0.4 | -4.73±1.91 | - |
荷瘤鼠,26D7 | 0 | 1921±129 | 23.0±0.3 | 24.6±0.2 | 7.11±0.92 | <0.001 |
同時在該實驗終點,依照動物福利要求,對動物進行安樂死後,分離小鼠的皮下脂肪及腓腸肌進行稱重,使用one way ANOVA-檢驗進行統計分析,在實驗中,P<0.05被認為差異在統計學上是顯著的。如圖3、圖4所示,實驗結果表明抗GFRAL抗體26D7能夠逆轉荷瘤小鼠中腫瘤導致的小鼠腓腸肌及皮下脂肪重量減少。
5.2 AAV-mGDF15模型評估鼠源抗GFRAL抗體在逆轉GDF-15誘導的體重減輕中的作用。
使用12-14周齡雄性C57BL/6小鼠構建了AAV-mGDF15小鼠模型。首先構建表達GDF15的腺病毒相關病毒(rAAV),簡要流程如下:
1.設計PCR擴增片段引物,在引物5’端引入線性化克隆載體末端的同源序列,將設計引物序列進行合成。
2.將含載體質粒的菌液過夜培養,取新鮮菌液提取質粒,然後取1µg新鮮質粒,用相應的限制性內切酶進行雙酶切。在對酶切產物進行瓊脂糖凝膠電泳分析後進行膠回收,濾柱離心後測定濃度。
3.利用稀釋的引物及範本進行PCR擴增,擴增後瓊脂糖凝膠電泳分析並回收目的基因,回收方法同上。
4.測定回收載體和目的片段濃度後,利用HieffClone
TM重組反應體系,對過表達載體與目的片段在50℃條件下進行連接。將連接產物加入感受態細胞進行轉化,37℃恒溫培養過夜後,篩選克隆測序鑒定。
5.抽提高純度質粒後,使用HG transgene試劑將病毒載體及輔助包裝元件質粒共轉染進AAV-293細胞,轉染後培養48h,細胞脫落後收集細胞及上清液,對其濃縮及純化後得到高滴度病毒濃縮液。
表6:相關引物序列
引物名稱 | 引物序列(5’-3’) |
正向引物 | GCGAATTCGAAGTATACCTCGAGGCCACCATGGCCCCG |
反向引物 | GTGTCTGACTGTGTCGGATCCTCAAGCGCAGTGGCAGCCCCGG |
基於“Matched distribution” (StudyDirector
TMsoftware, version 3.1.399.19) 方法,將小鼠按照平均體重隨機分為3組,每組6只小鼠,其中組別1的小鼠無處理,組別2、3的小鼠施用以1×10
10vg表達mGDF15的rAAV的一次尾靜脈注射。rAAV注射後10天,通過皮下注射給組別1、2的小鼠施以10mg/kg劑量的對照抗體mIgG1,組別3小鼠施用相同劑量的抗GFRAL抗體26D7。一周3次監測體重,一周2次監測食物攝取。體重資料匯總如下,資料表示為總體重以及體重改變百分比的平均值±SEM(即,體重變化相對於基線體重的百分比)。
表7:AAV-mGDF15小鼠模型中抗GFRAL抗體26D7對小鼠體重減輕的改善
效果資料
注:資料表示為均值±SEM;
a.體重變化= [(第i天的體重-第0天的體重)/第0天的體重]* 100%;
b.通過比較不同組從第0天到第24天的體重變化進行獨立的t檢驗。
組別 | 0 天前預處理 | 10 天處理 (10 mg/kg) | 體重 (g) | 體重改變 a (%) | P b | |||
0 天 | 10 天 | 24 天 | 10 天 | 24 天 | ||||
1 | NA | mIgG1 | 26.5±0.8 | 28.3±0.9 | 30.1±0.9 | 6.55±2.03 | 13.30±3.26 | <0.001 |
2 | AAV- GDF15 | mIgG1 | 26.4±0.8 | 24.3±1.4 | 24.7±1.4 | -7.66±4.43 | -5.66±4.19 | - |
3 | AAV- GDF15 | 26D7 | 26.7±0.8 | 24.3±1.0 | 29.2±0.9 | -8.84±3.41 | 9.21±3.17 | <0.001 |
結合圖5和表7資料分析,實驗結果表明抗GFRAL抗體26D7能夠逆轉GDF15誘導的體重損失,能夠有效提高小鼠的體重約10%,這種體重的變化具有統計學上的顯著性。
綜合以上實驗資料表明:本申請獲得的鼠源GFRAL拮抗性抗體能夠有效阻斷GFRAL/RET信號轉導,具有優異的阻斷活性,同時通過荷瘤小鼠模型以及非荷瘤小鼠模型實驗結果證實了本申請獲得的抗GFRAL抗體能夠顯著逆轉腫瘤或者GDF15誘導的體重損失,潛在具備治療或緩解由癌症及其他原因導致的惡病質的特殊療效。
實施例6 鼠源抗體的人源化以及活性測定
選擇2D4鼠源抗體和26D7鼠源抗體進行人源化設計,簡要步驟如下:分別使用Discovery Studio和Schrödinger Antibody Modeling等軟體,先進行鼠源抗體可變區結構類比,選出最優結構模型,分析抗體可變區以及CDR結構。
通過與人 Germline 序列比對,分別篩選與鼠源抗體高度同源的人重鏈和輕鏈Germline序列。將鼠抗CDR序列轉移到人的Germline序列的相應位置,同時依據鼠抗結構模型分析結果,選擇框架區中對CDR結構形成起重要作用的氨基酸殘基單獨或者組合地替換回鼠源抗體的氨基酸序列,從而設計出不同的重鏈以及輕鏈可變區(表8、表9、表10)。
如下製備具有表8所示序列的人源化抗體。使用人IgG4恒定區和 恒定區,根據不同輕鏈和重鏈可變區組合構建出不同的人源化抗體(表11)。
採用如實施例3中的報告基因測定法,檢測人源化抗體對人GFRAL以及鼠GFRAL功能的拮抗作用,結果如表11所示。
表8:獲得的人源化抗體的序列結構
抗體 1 : FM1-CDR1-FM2-CDR2-FM3-CDR3-FM4 2D4-mVH EVNLVESGGGLVKPGGPLKLSCAASGFTFS SFVMSWVRQTPEKRLEWVA SITSGGTTFYPDSVKGRFTISRDNARNILYLQMSNLRSGDTAMYYCAR GPPQFSSLSMDYWGQGTSVTVSS (SEQ ID NO.71) 2D4-H6a EVQLVESGGGLVKPGGSLRLSCAASGFTFS SFVMSWVRQAPGKGLEWVA SITSGGTTFYPESVRGRFTISRDNAKNTLYLQMSSLRAEDTAVYYCAR GPPQFSSLSMDYWGQGTTVTVSS (SEQ ID NO.90) 重鏈CDR2:SITSGGTTFYPESVRG (SEQ ID NO.91) 2D4-H6b EVQLVESGGGLVKPGGSLRLSCAASGFTFS SFVMSWVRQAPGKGLEWVA SITSGGTTFYPDSVKGRFTISRDNAKNTLYLQMSSLRAEDTAVYYCAR GPPQFSSLSMDYWGQGTTVTVSS (SEQ ID NO.92) 2D4-H6c EVQLVESGGGLVKPGGSLRLSCAASGFTFS SFVMSWVRQAPGKGLEWVA SITSGGTTFYPDSVKGRFTISRDNARNILYLQMSSLRAEDTAVYYCAR GPPQFSSLSMDYWGQGTTVTVSS (SEQ ID NO.93) 2D4-mVL DIVMTQSQKFMSTSVGDRITITC KASQNVGTAVSWFQQKPGQVPKLLIY SASNRYTGVPDRFTGSGSGTEFTLTISNIQSEDLADYFC QQYSSLFTFGSGTKLEIK (SEQ ID NO.74) 2D4-L6a DIQMTQSPSSLSASVGDRVTITC RASQNVGTAVSWYQQKPGKAPKLLIY SASNRYTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC QQYSSLFTFGGGTKLEIK (SEQ ID NO.94) 輕鏈CDR1:RASQNVGTAVS(SEQ ID NO.95) 2D4-L6b DIQMTQSPSSLSASVGDRVTITC KASQNVGTAVSWFQQKPGKAPKLLIY SASNRYTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC QQYSSLFTFGGGTKLEIK (SEQ ID NO.96) 2D4-L6c DIQMTQSPSSLSASVGDRITITC KASQNVGTAVSWFQQKPGKAPKLLIY SASNRYTGVPDRFSGSGSGTDFTLTISSLQPEDFATYYC QQYSSLFTFGGGTKLEIK (SEQ ID NO.97) 抗體 2 : FM1-CDR1-FM2-CDR2-FM3-CDR3-FM4 26D7-mVH QIQLVQSGPELKKPGETVKISCKVS GYTFTDYGMNWVKQTPGKDLKWVG WINTYTGEPTYADDFKDRFAFSLEASASTAYLQINNLKNEDTATYFCAR RYGYDAGIDCWGQGTTLTVSS (SEQ ID NO.78) 26D7-H1a QVQLVQSGAEVKKPGASVKVSCKAS GYTFTDYGMNWVRQAPGQGLEWMG WINTYTGEPTYADDFKDRVTMTTDTSTSTAYMELRSLRSDDTAVYYCAR RYGYDAGIDAWGQGTLVTVSS (SEQ ID NO.98) 重鏈CDR3:RYGYDAGIDA(SEQ ID NO.99) 26D7-H1b QVQLVQSGAEVKKPGASVKVSCKAS GYTFTDYGMNWVRQAPGQGLEWMG WINTYTGEPTYADDFKDRVTFTLDASTSTAYMELRSLRSDDTAVYYCAR RYGYDAGIDAWGQGTLVTVSS (SEQ ID NO.100) 26D7-H2a QVQLVQSGAEVKKPGASVKVSCKVS GYTFTDYGMNWVRQAPGQGLEWVG WINTYTGEPTYADDFKDRFTFTLDTSTSTAYMELRSLRSDDTAVYFCAR RYGYDAGIDAWGQGTLVTVSS (SEQ ID NO.101) 26D7-H2b QVQLVQSGAEVKKPGASVKISCKAS GYTFTDYGMNWVRQAPGQGLEWMG WINTYTGEPTYADDFKDRVTFTLDTSTSTAYMELRSLRSDDTAVYYCAR RYGYDAGIDAWGQGTLVTVSS (SEQ ID NO.102) 26D7-H2c QVQLVQSGAEVKKPGASVKISCKAS GYTFTDYGMNWVRQAPGQGLEWMG WINTYTGEPTYADDFKDRVTFTLDASTSTAYMELRSLRSDDTAVYYCAR RYGYDAGIDAWGQGTLVTVSS (SEQ ID NO.103) 26D7-H2d QVQLVQSGAEVKKPGASVKISCKAS GYTFTDYGMNWVRQAPGQGLKWMG WINTYTGEPTYADDFKDRVTFTLDASTSTAYMELRSLRSDDTAVYYCAR RYGYDAGIDAWGQGTLVTVSS (SEQ ID NO.104) 26D7-H3a QVQLVQSGAEVKKPGASVKISCKVS GYTFTDYGMNWVRQTPGQGLKWVG WINTYTGEPTYADDFKDRFTFTLDASTSTAYMELRSLRSDDTAVYFCAR RYGYDAGIDAWGQGTLVTVSS (SEQ ID NO.105) 26D7-H3b QVQLVQSGAEVKKPGASVKISCKVS GYTFTDYGMNWVRQTPGQGLEWVG WINTYTGEPTYADDFKDRFTFTLDASTSTAYMELRSLRSDDTAVYFCAR RYGYDAGIDAWGQGTLVTVSS (SEQ ID NO.106) 26D7-H3c QVQLVQSGAEVKKPGASVKVSCKVS GYTFTDYGMNWVRQTPGQGLKWVG WINTYTGEPTYADDFKDRFTFTLDASTSTAYMELRSLRSDDTAVYFCAR RYGYDAGIDAWGQGTLVTVSS (SEQ ID NO.107) 26D7-H3d QVQLVQSGAEVKKPGASVKISCKVS GYTFTDYGMNWVRQAPGQGLKWVG WINTYTGEPTYADDFKDRFTFTLDASTSTAYMELRSLRSDDTAVYFCAR RYGYDAGIDAWGQGTLVTVSS (SEQ ID NO.108) 26D7-H3e QVQLVQSGAEVKKPGASVKISCKVS GYTFTDYGMNWVRQTPGQGLKWVG WINTYTGEPTYADDFKDRFTFTLDTSTSTAYMELRSLRSDDTAVYFCAR RYGYDAGIDAWGQGTLVTVSS (SEQ ID NO.109) 26D7-H3f QVQLVQSGAEVKKPGASVKVSCKVS GYTFTDYGMNWVRQAPGQGLKWVG WINTYTGEPTYADDFKDRFTFTLDASTSTAYMELRSLRSDDTAVYFCAR RYGYDAGIDAWGQGTLVTVSS (SEQ ID NO.110) 26D7-H3g QVQLVQSGAEVKKPGASVKVSCKVS GYTFTDYGMNWVRQAPGQGLEWVG WINTYTGEPTYADDFKDRFTFTLDASTSTAYMELRSLRSDDTAVYFCAR RYGYDAGIDAWGQGTLVTVSS (SEQ ID NO.111) 26D7-H3h QVQLVQSGAEVKKPGASVKISCKVS GYTFTDYGMNWVRQAPGQGLEWVG WINTYTGEPTYADDFKDRFTFTLDTSTSTAYMELRSLRSDDTAVYFCAR RYGYDAGIDAWGQGTLVTVSS (SEQ ID NO.112) 26D7-H3i QVQLVQSGAEVKKPGASVKISCKVS GYTFTDYGMNWVRQAPGQGLEWVG WINTYTGEPTYADDFKDRFTFTLDASTSTAYMELRSLRSDDTAVYFCAR RYGYDAGIDAWGQGTLVTVSS (SEQ ID NO.113) 26D7-H4a QIQLVQSGAEVKKPGASVKISCKVS GYTFTDYGMNWVRQTPGQGLKWVG WINTYTGEPTYADDFKDRFTFTLDASTSTAYLEIRSLRSDDTAVYFCAR RYGYDAGIDAWGQGTLLTVSS (SEQ ID NO.114) 26D7-H5a QVQLVQSGAEVKKPGASVKVSCKAS GYTFTDYGMNWVRQAPGQGLEWMG WINTYTGEPTYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCAR RYGYDAGIDAWGQGTTVTVSS (SEQ ID NO.115) 重鏈CDR2:WINTYTGEPTYAQKLQG (SEQ ID NO.116) 26D7-H5b QVQLVQSGAEVKKPGASVKVSCKVS GYTFTDYGMNWVRQAPGQGLEWMG WINTYTGEPTYAQKLQGRVTFTTDTSTSTAYMELRSLRSDDTAVYYCAR RYGYDAGIDAWGQGTTVTVSS (SEQ ID NO.117) 26D7-H5c QVQLVQSGAEVKKPGASVKVSCKVS GYTFTDYGMNWVRQAPGQGLEWVG WINTYTGEPTYADDFKDRVTFTTDTSTSTAYMELRSLRSDDTAVYYCAR RYGYDAGIDAWGQGTTVTVSS (SEQ ID NO.118) 26D7-H5d QIQLVQSGAEVKKPGASVKISCKVS GYTFTDYGMNWVRQAPGQGLEWVG WINTYTGEPTYADDFKDRFTFTLDTSTSTAYLEIRSLRSDDTAVYYCAR RYGYDAGIDAWGQGTTVTVSS (SEQ ID NO.119) 26D7-H5e QVQLVQSGSELKKPGASVKVSCKVS GYTFTDYGMNWVRQAPGQGLEWVG WINTYTGEPTYADDFKDRFVFSLDTSVSTAYLQISSLKAEDTAVYYCAR RYGYDAGIDAWGQGTTVTVSS (SEQ ID NO.120) 26D7-H5f QIQLVQSGSELKKPGASVKISCKVS GYTFTDYGMNWVRQAPGQGLEWVG WINTYTGEPTYADDFKDRFVFSLDASVSTAYLQISSLKAEDTAVYYCAR RYGYDAGIDAWGQGTTVTVSS (SEQ ID NO.121) 26D7-mVL NIVLTQSPPSLAVSLGQRATISC RASESVDSYGNNLMHWYQQKPGQPPKLLIY LASYLESGVPARFSGSGSRTDFTLTIDPVEADDAATYYC QQNNEDPWTFGGGTKLEIK (SEQ ID NO.81) 26D7-L1a EIVLTQSPGTLSLSPGERATLSC RASESVDSYGNNLMHWYQQKPGQAPRLLIY LASYLESGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYC QQNNESPWTFGQGTKVEIK (SEQ ID NO.122) 輕鏈CDR3:QQNNESPWT(SEQ ID NO.123) 26D7-L2a EIVLTQSPGTLSLSPGERATLSC RASESVDSYGNNLMHWYQQKPGQAPRLLIY LASYLESGVPDRFSGSGSGTDFTLTISRLEPEDFATYYC QQNNESPWTFGQGTKVEIK (SEQ ID NO.124) 26D7-L2b EIVLTQSPGTLSLSPGERATLSC RASESVDAYGNNLMHWYQQKPGQAPRLLIY LASYLESGVPDRFSGSGSGTDFTLTISRLEPEDFATYYC QQNNESPWTFGQGTKVEIK (SEQ ID NO.125) 輕鏈CDR1:RASESVDAYGNNLMH (SEQ ID NO.126) 26D7-L2c EIVLTQSPGTLSLSPGERATLSC RASESVESYGNNLMHWYQQKPGQAPRLLIY LASYLESGVPDRFSGSGSGTDFTLTISRLEPEDFATYYC QQNNESPWTFGQGTKVEIK (SEQ ID NO.127) 輕鏈CDR1:RASESVESYGNNLMH (SEQ ID NO.128) 26D7-L3a EIVLTQSPGTLSLSPGERATISC RASESVDSYGNNLMHWYQQKPGQAPRLLIY LASYLESGVPARFSGSGSRTDFTLTISRLEPEDFATYYC QQNNESPWTFGQGTKVEIK (SEQ ID NO.129) 26D7-L3b EIVLTQSPGTLSLSPGERATISC RASESVDNYGNNLMHWYQQKPGQAPRLLIY LASYLESGVPARFSGSGSRTDFTLTISRLEPEDFATYYC QQNNESPWTFGQGTKVEIK (SEQ ID NO.130) 26D7-L3c EIVLTQSPGTLSLSPGERATISC RASESVDAYGNNLMHWYQQKPGQAPRLLIY LASYLESGVPARFSGSGSRTDFTLTISRLEPEDFATYYC QQNNESPWTFGQGTKVEIK (SEQ ID NO.131) 26D7-L4a EIVLTQSPGTLSVSPGERATISC RASESVDSYGNNLMHWYQQKPGQAPRLLIY LASYLESGVPARFSGSGSRTDFTLTISRVEPEDFATYYC QQNNESPWTFGQGTKLEIK (SEQ ID NO.132) 26D7-L5a DIQMTQSPSSLSASVGDRVTITC RASESVESYGNNLMHWYQQKPGKAPKLLIY LASYLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC QQNNESPWTFGGGTKLEIK (SEQ ID NO.133) 26D7-L5b DIQLTQSPSSLSASVGDRATITC RASESVDSYGNNLMHWYQQKPGKAPKLLIY LASYLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC QQNNESPWTFGGGTKLEIK (SEQ ID NO.134) 26D7-L5c DIVLTQSPASLAVSPGQRATITC RASESVDSYGNNLMHWYQQKPGQPPKLLIY LASYLESGVPARFSGSGSGTDFTLTINPVEANDTANYYC QQNNESPWTFGGGTKLEIK (SEQ ID NO.135) 注:劃線部分為CDR區域 |
將上述人源化的重鏈和輕鏈按照下面方式組合成人源化抗體並針對其進行細胞水準IC50值檢測。
表9:26D7人源化設計方案
表10:2D4人源化設計方案
表11 人源化抗體細胞水準實驗
26D7人源化設計 | ||
克隆ID | 重鏈 | 輕鏈 |
26D7H1aL1a | H1a(SEQ ID NO.98) | L1a(SEQ ID NO.122) |
26D7H1aL2a | H1a(SEQ ID NO.98) | L2a(SEQ ID NO.124) |
26D7H1bL2a | H1b(SEQ ID NO.100) | L2a(SEQ ID NO.124) |
26D7H2aL2a | H2a(SEQ ID NO.101) | L2a(SEQ ID NO.124) |
26D7H2bL2a | H2b(SEQ ID NO.102) | L2a(SEQ ID NO.124) |
26D7H2cL2a | H2c(SEQ ID NO.103) | L2a(SEQ ID NO.124) |
26D7H2dL2a | H2d(SEQ ID NO.104) | L2a(SEQ ID NO.124) |
26D7H3aL2a | H3a(SEQ ID NO.105) | L2a(SEQ ID NO.124) |
26D7H3hL2a | H3h(SEQ ID NO.112) | L2a(SEQ ID NO.124) |
26D7H3iL2a | H3i(SEQ ID NO.113) | L2a(SEQ ID NO.124) |
26D7H3aL2b | H3a(SEQ ID NO.105) | L2b(SEQ ID NO.125) |
26D7H3aL2c | H3a(SEQ ID NO.105) | L2c(SEQ ID NO.127) |
26D7H1bL3a | H1b(SEQ ID NO.100) | L3a(SEQ ID NO.129) |
26D7H2aL3a | H2a (SEQ ID NO.101) | L3a(SEQ ID NO.129) |
26D7H3aL3a | H3a(SEQ ID NO.105) | L3a(SEQ ID NO.129) |
26D7H3bL3a | H3b(SEQ ID NO.106) | L3a(SEQ ID NO.129) |
26D7H3cL3a | H3c(SEQ ID NO.107) | L3a(SEQ ID NO.129) |
26D7H3dL3a | H3d(SEQ ID NO.108) | L3a(SEQ ID NO.129) |
26D7H3eL3a | H3e(SEQ ID NO.109) | L3a(SEQ ID NO.129) |
26D7H3fL3a | H3f(SEQ ID NO.110) | L3a(SEQ ID NO.129) |
26D7H3gL3a | H3g(SEQ ID NO.111) | L3a(SEQ ID NO.129) |
26D7H3aL3b | H3a(SEQ ID NO.105) | L3b(SEQ ID NO.130) |
26D7H3aL3c | H3a(SEQ ID NO.105) | L3c(SEQ ID NO.131) |
26D7H1bL4a | H1b(SEQ ID NO.100) | L4a(SEQ ID NO.132) |
26D7H4aL4a | H4a(SEQ ID NO.114) | L4a(SEQ ID NO.132) |
26D7H5aL5a | H5a(SEQ ID NO.115) | L5a(SEQ ID NO.133) |
26D7H5bL5a | H5b(SEQ ID NO.117) | L5a(SEQ ID NO.133) |
26D7H5cL5a | H5c(SEQ ID NO.118) | L5a(SEQ ID NO.133) |
26D7H5dL5a | H5d(SEQ ID NO.119) | L5a(SEQ ID NO.133) |
26D7H5aL5b | H5a(SEQ ID NO.115) | L5b(SEQ ID NO.134) |
26D7H5bL5b | H5b(SEQ ID NO.117) | L5b(SEQ ID NO.134) |
26D7H5cL5b | H5c(SEQ ID NO.118) | L5b(SEQ ID NO.134) |
26D7H5dL5b | H5d(SEQ ID NO.119) | L5b(SEQ ID NO.134) |
26D7H5dL5c | H5d(SEQ ID NO.119) | L5c(SEQ ID NO.135) |
26D7H5eL5c | H5e(SEQ ID NO.120) | L5c(SEQ ID NO.135) |
26D7H5fL5c | H5f(SEQ ID NO.121) | L5c(SEQ ID NO.135) |
2D4人源化設計 | ||
克隆ID | 重鏈 | 輕鏈 |
2D4H6aL6a | H6a(SEQ ID NO.90) | L6a(SEQ ID NO.94) |
2D4H6bL6a | H6b(SEQ ID NO.92) | L6a(SEQ ID NO.94) |
2D4H6aL6b | H6a(SEQ ID NO.90) | L6b(SEQ ID NO.96) |
2D4H6bL6b | H6b(SEQ ID NO.92) | L6b(SEQ ID NO.96) |
2D4H6aL6c | H6a(SEQ ID NO.90) | L6c(SEQ ID NO.97) |
2D4H6cL6c | H6c(SEQ ID NO.93) | L6c(SEQ ID NO.97) |
IC 50(nM) | ||
克隆ID | 人GFRAL/人RET | 小鼠GFRAL/小鼠RET |
26D7H1aL2a | 2.6 | 7.7 |
26D7H2aL2a | 7.6 | 1.6 |
26D7H2dL2a | 6.5 | 3.0 |
26D7H3aL2c | 8.3 | 1.9 |
26D7H4aL4a | 5.7 | 0.1 |
26D7H5bL5a | 11.8 | 0.9 |
26D7H5eL5c | 8.3 | 0.7 |
26D7H5fL5c | 8.9 | 0.4 |
26D7-mVH+mVL | 8.7 | 0.7 |
2D4H6aL6b | 24.4 | 1.4 |
2D4H6cL6c | 22.5 | 1.3 |
2D4-mVH+mVL | 23.8 | 1.4 |
如表11的細胞實驗結果所示(僅列出部分人源化抗體資料),絕大多數人源化的抗體具有與鼠源抗體相近或者更好的拮抗GFRAL功能的活性。
同時,為了驗證人源化抗GFRAL抗體的親和力水準,參考實施例4描述方法對人源化抗體26D7H3aL2c(SEQ ID NO.105+SEQ ID NO.127)和26D7H5bL5a(SEQ ID NO. 117+SEQ ID NO. 133)進行了結合親和力測定。具體方法如下:
根據氨基偶聯試劑盒(貨號:BR100050,Cytiva)操作說明,使用400mM EDC和100mM NHS以10ul/min的流速將CM5晶片表面活化,然後將鼠抗人Fc抗體固定在CM5晶片的試驗通道(Fc2)和參比通道(Fc1)中,最後晶片用1M乙醇胺以10ul/min進行封閉;然後在試驗通道(Fc2)上捕獲稀釋至5μg/ml的人源化抗體(~300RU),參比通道不需要進行配體的捕獲。隨後以30μL/分鐘的流動速度注射經2倍倍比稀釋的人、小鼠或食蟹猴GFRAL蛋白 (HBS-EP緩衝液中),在25℃下評估結合動力學。結果如下(參見表12):
表12:人源化抗體的結合動力學資料
結合親和性 | ||||||
人源化抗體 | 人GFRAL | 小鼠GFRAL | 食蟹猴GFRAL | |||
克隆ID | KD(M) | k off(1/s) | KD(nM) | k off(1/s) | KD(M) | k off(1/s) |
26D7H3aL2c | 4.65E-11 | 1.25E-04 | 1.34E-10 | 2.15E-04 | 1.31E-10 | 1.93E-04 |
26D7H5bL5a | 1.19E-10 | 2.68E-04 | 2.58E-10 | 3.14E-04 | 2.46E-10 | 2.31E-04 |
由此可見,人源化抗GFRAL抗體26D7H3aL2c和26D7H5bL5a保留了其鼠源抗體對人GFRAL和小鼠GFRAL的高度親和力,同時證明對食蟹猴GFRAL也具有較高的結合活性。
實施例7 動物模型評估人源化抗GFRAL抗體的生物學功能
7.1評估人源化抗GFRAL抗體在AAV-mGDF15模型上逆轉GDF15誘導的體重減輕。
為了進一步驗證人源化抗GFRAL抗體的動物體內藥效,參考實施例5.2描述方法研究了人源化抗體在AAV-mGDF15模型上對於GDF15誘導的小鼠(非荷瘤小鼠)體重減輕的改善作用。具體方法如下:
表13:AAV-mGDF15小鼠模型中人源化抗GFRAL抗體對小鼠體重減輕的改善效果資料
注:資料表示為均值±SEM;
a.體重變化= [(第i天的體重-第0天的體重)/第0天的體重]* 100%;
b.通過比較不同組從第0天到第33天的體重變化並進行獨立的t檢驗。
組別 | 預處理 第 0 天 | 抗體處理第 6 天 | 體重 (g) | 體重改變 a (%) | P b | |||
第 0 天 | 第 6 天 | 第 33 天 | 第 6 天 | 第 33 天 | ||||
1 | AAV8- control | hIgG4, 10mg/kg | 26.1±0.9 | 26.9±1.4 | 29.1±1.8 | 3.04±2.87 | 11.4±4.60 | <0.0001 |
2 | AAV8- mGDF15 | hIgG4, 10mg/kg | 25.9±0.7 | 24.0±0.9 | 21.2±1.3 | -7.27±2.82 | -16.89±4.98 | - |
3 | AAV8- mGDF15 | 26D7H3aL2c, 10mg/kg | 26.2±0.5 | 24.0±0.9 | 28.2±1.1 | -8.52±2.89 | 7.31±3.67 | <0.0001 |
4 | AAV8- mGDF15 | 26D7H3aL2c, 3mg/kg | 26.4±1.1 | 24.0±0.9 | 28.8±1.5 | -9.00±2.19 | 9.13±4.37 | <0.0001 |
5 | AAV8- mGDF15 | 26D7H3aL2c, 1mg/kg | 26.0±0.7 | 24.0±1.0 | 26.8±1.2 | -7.55±3.40 | 3.23±4.41 | <0.0001 |
6 | AAV8- mGDF15 | 26D7H5bL5a, 10mg/kg | 26.3±0.9 | 26.0±1.1 | 28.7±1.9 | -8.64±1.59 | 8.89±4.86 | <0.0001 |
7 | AAV8- mGDF15 | 26D7H5bL5a, 3mg/kg | 26.3±1.0 | 24.0±1.0 | 27.5±0.8 | -8.74±1.76 | 4.62±3.12 | 0.0095 |
8 | AAV8- mGDF15 | 26D7H5bL5a, 1mg/kg | 26.1±0.6 | 24.0±0.9 | 24.8±0.5 | -7.88±2.34 | -4.73±3.94 | 0.0002 |
9 | AAV8- mGDF15 | m26D7, 10mg/kg | 25.5±0.3 | 24.0±1.2 | 28.9±1.2 | -6.10±4.19 | 13.30±3.94 | <0.0001 |
如圖6-9和表13所示,實驗結果表明:與鼠源GFRAL抗體的效果類似,人源化抗GFRAL抗體能夠劑量依賴地逆轉GDF15誘導的體重下降,有效提高了小鼠的體重,同時具有增加小鼠攝食量的作用。人源化抗體26D7H3aL2c和26D7H5bL5a都實現逆轉體重的效果,26D7H3aL2c更佳。該實驗結果進一步證實人源化GFRAL抗體保留了鼠源抗體在AAV-mGDF15小鼠模型上的體內藥效,能夠有效改善由GDF-15誘導的惡病質症狀。
7.2 評估人源化抗GFRAL抗體在人源纖維肉瘤HT-1080荷瘤小鼠模型中對惡病質症狀的改善作用
為了進一步驗證人源化抗GFRAL抗體的動物體內藥效,參考實施例5.1描述方法研究了人源化抗體在人源纖維肉瘤HT-1080皮下異種移植BALB/c nude雌性小鼠模型上對於GDF15誘導的小鼠體重減輕的改善作用。具體方法如下:
收集指數生長期的HT-1080細胞用於裸鼠皮下腫瘤接種,建立小鼠皮下異種移植腫瘤模型。當腫瘤平均體積達到110.51 mm
3左右時,根據小鼠體重和腫瘤大小隨機分為4組,同時添加一組非荷瘤鼠開始給藥。實驗組分為受試品26D7H3aL2c 1 mg/kg、3 mg/kg、10 mg/kg三個劑量組,hIgG4 10 mg/kg荷瘤鼠對照組和hIgG4 10 mg/kg非荷瘤鼠對照組。每組各8只鼠,每週一次皮下注射給藥,共3周。記錄每天的體重和食物攝取,採用Study Director
TM軟體記錄測量的體重資料,總體重變化和淨體重變化的統計分析和圖形繪製在GraphPad Prism 8中進行,使用雙因素ANOVA Dunnett多重比較檢驗,p值小於0.05時被認為具有統計顯著性。
術結果(參見圖10,11和表14,15)如下:人源化抗GFRAL抗體26D7H3aL2c在1、3、10 mg/kg劑量下對人纖維肉瘤HT-1080皮下異種移植模型惡病質引起的體重減輕有顯著改善作用,且26D7H3aL2c存在劑量依賴藥效關係。
表14. 人纖維肉瘤HT-1080荷瘤模型中各組動物總體重變化情況
注:資料以“平均值 ± 標準誤”表示; 組別1、3、4、5與組別2進行比較,雙因素ANOVA Dunnett多重比較檢驗; ****p<0.0001。
表15. 人纖維肉瘤HT-1080荷瘤模型中各組動物淨體重變化情況
注:小鼠淨體重=小鼠體重-小鼠瘤重;其中小鼠瘤重預估方法[1]為1g/1000mm
3;
資料以“平均值 ± 標準誤”表示; 組別1、3、4、5與組別2進行比較,雙因素ANOVA ;
組別 | 給藥組 | 劑量(mg/kg) | 動物數 (實驗開始/實驗結束) | 平均體重/g(MEAN± SEM) | 總體重平均變化率(%)(MEAN±SEM) | PValue(相較於對照組) | |
第0天 | 第19天 | 第19天 | 第19天 | ||||
1 | 非荷瘤鼠 hIgG4 | 10 | 8/8 | 23.98 ± 0.37 | 24.73 ± 0.27 | 3.20±0.96 | 0.3618 |
2 | 荷瘤鼠 hIgG4 | 10 | 8/8 | 22.84 ± 0.69 | 22.83 ± 0.53 | 0.29±2.37 | - |
3 | 荷瘤鼠 26D7H3aL2c | 1 | 8/8 | 22.84 ± 0.65 | 24.89 ± 0.46 | 9.22±1.35 | <0.0001 |
4 | 荷瘤鼠 26D7H3aL2c | 3 | 8/8 | 22.84 ± 0.54 | 25.31 ± 0.55 | 10.92±1.30 | <0.0001 |
5 | 荷瘤鼠 26D7H3aL2c | 10 | 8/8 | 22.84 ± 0.49 | 26.13 ± 0.59 | 14.50±2.03 | <0.0001 |
組別 | 給藥組 | 劑量(mg/kg) | 動物數(實驗開始/實驗結束) | 平均體重(淨)/g(MEAN ± SEM) | 體重(淨)平均變化率(%)(MEAN±SEM) | P值(相較於對照組) | |
第0天 | 第19天 | 第19天 | 第19天 | ||||
1 | 非荷瘤鼠hIgG4 | 10 | 8/8 | 23.98 ± 0.37 | 24.73 ± 0.27 | 3.20±0.96 | <0.0001 |
2 | 荷瘤鼠hIgG4 | 10 | 8/8 | 22.73 ± 0.69 | 21.63 ± 0.55 | -4.57±﹣2.07 | - |
3 | 荷瘤鼠26D7H3aL2c | 1 | 8/8 | 22.74 ± 0.65 | 23.01 ± 0.63 | 1.39±1.67 | 0.0024 |
4 | 荷瘤鼠26D7H3aL2c | 3 | 8/8 | 22.74 ± 0.54 | 23.18 ± 0.54 | 2.03±1.26 | 0.0006 |
5 | 荷瘤鼠26D7H3aL2c | 10 | 8/8 | 22.74 ± 0.49 | 23.81 ± 0.51 | 4.76±1.14 | <0.0001 |
Dunnett多重比較檢驗; **p<0.01,***p<0.001,****p<0.0001。
無
圖1A至圖1D顯示了本申請的示例性抗體的結合動力學實驗結果,其中圖1A為168A7 hGFRAL抗體,圖1B為8E10 hGFRAL抗體,圖1C為26D7 hGFRAL抗體 圖1D為26D7 mGFRAL抗體。
圖2顯示了人纖維肉瘤HT-1080荷瘤模型中各實驗組隨治療時間的總體重百分比變化曲線。
圖3顯示了人纖維肉瘤HT-1080荷瘤模型中抗GFRAL抗體腓腸肌重量檢測實驗結果。
圖4顯示了人纖維肉瘤HT-1080荷瘤模型中抗GFRAL抗體皮下脂肪重量檢測實驗結果。
圖5顯示了AAV-GDF15模型中抗GFRAL抗體體重損失監測實驗結果。
圖6顯示了AAV-GDF15模型中人源化抗GFRAL抗體(26D7H3aL2c)體重損失監測實驗結果。
圖7顯示了AAV-GDF15模型中人源化抗GFRAL抗體(26D7H3aL2c)攝食量監測實驗結果。
圖8顯示了AAV-GDF15模型中人源化抗GFRAL抗體(26D7H5bL5a)體重損失監測實驗結果。
圖9顯示了AAV-GDF15模型中人源化抗GFRAL抗體(26D7H5bL5a)攝食量監測實驗結果。
圖10顯示了在人纖維肉瘤HT-1080荷瘤模型中各實驗組隨治療時間的總體重百分比變化曲線。
圖11顯示了在人纖維肉瘤HT-1080荷瘤模型中各實驗組隨治療時間的淨體重百分比變化曲線。
序列表 <![CDATA[<110> 上海津曼特生物科技有限公司]]> <![CDATA[<120> 抗GFRAL抗體及其應用]]> <![CDATA[<150> CN 202110739877.2]]> <![CDATA[<151> 2021-06-30]]> <![CDATA[<160> 135 ]]> <![CDATA[<170> PatentIn version 3.3]]> <![CDATA[<210> 1]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈CDR1]]> <![CDATA[<222> (1)..(5)]]> <![CDATA[<400> 1]]> Gly Tyr Gly Val Asn 1 5 <![CDATA[<210> 2]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈CDR2]]> <![CDATA[<222> (1)..(16)]]> <![CDATA[<400> 2]]> Met Ile Trp Gly Asp Gly Thr Thr Asp Tyr Asn Ser Ala Leu Lys Ser 1 5 10 15 <![CDATA[<210> 3]]> <![CDATA[<211> 12]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈CDR3]]> <![CDATA[<222> (1)..(12)]]> <![CDATA[<400> 3]]> Asp Pro Lys Tyr Asn Tyr Gly Tyr Ala Met Asp Tyr 1 5 10 <![CDATA[<210> 4]]> <![CDATA[<211> 120]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈可變區]]> <![CDATA[<222> (1)..(120)]]> <![CDATA[<400> 4]]> Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Gly Tyr 20 25 30 Gly Val Asn Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Met Ile Trp Gly Asp Gly Thr Thr Asp Tyr Asn Ser Ala Leu Lys 50 55 60 Ser Arg Leu Thr Ile Arg Lys Asp Asn Ser Lys Ser Gln Val Phe Leu 65 70 75 80 Arg Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Arg Tyr Tyr Cys Ala 85 90 95 Arg Asp Pro Lys Tyr Asn Tyr Gly Tyr Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Ser Val Thr Val Ser Ser 115 120 <![CDATA[<210> 5]]> <![CDATA[<211> 15]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 輕鏈CDR1]]> <![CDATA[<222> (1)..(15)]]> <![CDATA[<400> 5]]> Arg Ala Ser Glu Ser Val Asp Asn Phe Gly Asn Ser Phe Met His 1 5 10 15 <![CDATA[<210> 6]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 輕鏈CDR2]]> <![CDATA[<222> (1)..(7)]]> <![CDATA[<400> 6]]> Arg Ala Ser Asn Leu Glu Ser 1 5 <![CDATA[<210> 7]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 輕鏈CDR3]]> <![CDATA[<222> (1)..(9)]]> <![CDATA[<400> 7]]> Gln Gln Thr Asn Glu Glu Pro Tyr Thr 1 5 <![CDATA[<210> 8]]> <![CDATA[<211> 111]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 輕鏈可變區]]> <![CDATA[<222> (1)..(111)]]> <![CDATA[<400> 8]]> Asp Ile Val Leu Thr Gln Ala Pro Gly Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Phe 20 25 30 Gly Asn Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro 35 40 45 Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala 50 55 60 Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn 65 70 75 80 Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys Gln Gln Thr Asn 85 90 95 Glu Glu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Glu 100 105 110 <![CDATA[<210> 9]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈CDR1]]> <![CDATA[<222> (1)..(5)]]> <![CDATA[<400> 9]]> Ser Tyr Val Ile His 1 5 <![CDATA[<210> 10]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈CDR2]]> <![CDATA[<222> (1)..(17)]]> <![CDATA[<400> 10]]> Tyr Ile Asn Pro Tyr Asn Asp Asp Ile Asn Tyr Asn Glu Lys Phe Lys 1 5 10 15 Gly <![CDATA[<210> 11]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈CDR3]]> <![CDATA[<222> (1)..(9)]]> <![CDATA[<400> 11]]> Tyr Asp Tyr Asp Trp Tyr Phe Asp Val 1 5 <![CDATA[<210> 12]]> <![CDATA[<211> 118]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈可變區]]> <![CDATA[<222> (1)..(118)]]> <![CDATA[<400> 12]]> Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Val Ile His Trp Val Lys Gln Glu Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Asn Pro Tyr Asn Asp Asp Ile Asn Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ser Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Phe Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Asp Tyr Asp Trp Tyr Phe Asp Val Trp Gly Ala Gly Thr 100 105 110 Ala Val Thr Val Ser Ser 115 <![CDATA[<210> 13]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 輕鏈CDR1]]> <![CDATA[<222> (1)..(16)]]> <![CDATA[<400> 13]]> Lys Ser Ser Gln Ser Leu Leu Asp Ser Asp Gly Lys Thr Tyr Val Asn 1 5 10 15 <![CDATA[<210> 14]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 輕鏈CDR2]]> <![CDATA[<222> (1)..(7)]]> <![CDATA[<400> 14]]> Leu Val Ser Lys Leu Gly Ser 1 5 <![CDATA[<210> 15]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 輕鏈CDR3]]> <![CDATA[<222> (1)..(9)]]> <![CDATA[<400> 15]]> Trp Gln Gly Thr His Phe Pro Gln Thr 1 5 <![CDATA[<210> 16]]> <![CDATA[<211> 112]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artifici]]>al Sequence) <![CDATA[<220>]]> <![CDATA[<221> 輕鏈可變區]]> <![CDATA[<222> (1)..(112)]]> <![CDATA[<400> 16]]> Asp Val Val Met Thr Gln Thr Pro Leu Thr Leu Ser Val Thr Ile Gly 1 5 10 15 Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser 20 25 30 Asp Gly Lys Thr Tyr Val Asn Trp Leu Leu Gln Arg Pro Gly Gln Ser 35 40 45 Pro Lys Arg Leu Ile Phe Leu Val Ser Lys Leu Gly Ser Gly Val Pro 50 55 60 Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Trp Gln Gly 85 90 95 Thr His Phe Pro Gln Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 <![CDATA[<210> 17]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈CDR1]]> <![CDATA[<222> (1)..(5)]]> <![CDATA[<400> 17]]> Gly His Gly Val Asn 1 5 <![CDATA[<210> 18]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈CDR2]]> <![CDATA[<222> (1)..(16)]]> <![CDATA[<400> 18]]> Met Ile Trp Gly Asp Gly Tyr Thr Asp Tyr Asn Ser Ala Leu Lys Ser 1 5 10 15 <![CDATA[<210> 19]]> <![CDATA[<211> 13]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈CDR3]]> <![CDATA[<222> (1)..(13)]]> <![CDATA[<400> 19]]> Asp Thr Tyr Gly Arg Thr Tyr Asp Tyr Ala Met Asp Tyr 1 5 10 <![CDATA[<210> 20]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequ]]>ence) <![CDATA[<220>]]> <![CDATA[<221> 重鏈可變區]]> <![CDATA[<222> (1)..(121)]]> <![CDATA[<400> 20]]> Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Gly His 20 25 30 Gly Val Asn Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Met Ile Trp Gly Asp Gly Tyr Thr Asp Tyr Asn Ser Ala Leu Lys 50 55 60 Ser Arg Leu Ser Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Phe Leu 65 70 75 80 Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Thr Tyr Tyr Cys Ala 85 90 95 Arg Asp Thr Tyr Gly Arg Thr Tyr Asp Tyr Ala Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Ser Val Thr Val Ser Ser 115 120 <![CDATA[<210> 21]]> <![CDATA[<211> 15]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(]]>Artificial Sequence) <![CDATA[<220>]]> <![CDATA[<221> 輕鏈CDR1]]> <![CDATA[<222> (1)..(15)]]> <![CDATA[<400> 21]]> Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly Asn Ser Phe Met His 1 5 10 15 <![CDATA[<210> 22]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 輕鏈CDR3]]> <![CDATA[<222> (1)..(9)]]> <![CDATA[<400> 22]]> Gln Gln Ser Asn Glu Asp Pro Arg Thr 1 5 <![CDATA[<210> 23]]> <![CDATA[<211> 111]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 輕鏈可變區]]> <![CDATA[<222> (1)..(111)]]> <![CDATA[<400> 23]]> Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Gln Arg Ala Ala Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr 20 25 30 Gly Asn Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro 35 40 45 Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala 50 55 60 Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn 65 70 75 80 Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys Gln Gln Ser Asn 85 90 95 Glu Asp Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 <![CDATA[<210> 24]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈CDR1]]> <![CDATA[<222> (1)..(5)]]> <![CDATA[<400> 24]]> Asn Tyr Trp Met Asn 1 5 <![CDATA[<210> 25]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈CDR2]]> <![CDATA[<222> (1)..(17)]]> <![CDATA[<400> 25]]> Gln Ile Tyr Pro Gly Asp Asp Asp Ala Asp Tyr Asn Gly Lys Phe Gln 1 5 10 15 Gly <![CDATA[<210> 26]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈CDR3]]> <![CDATA[<222> (1)..(8)]]> <![CDATA[<400> 26]]> Ser Gly Arg Arg Asp Phe Asp Tyr 1 5 <![CDATA[<210> 27]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈可變區]]> <![CDATA[<222> (1)..(117)]]> <![CDATA[<400> 27]]> Gln Val Gln Leu Gln Gln Ser Gly Ser Glu Leu Val Arg Pro Gly Ser 1 5 10 15 Ser Val Lys Ile Ser Cys Arg Ala Ser Gly Tyr Thr Phe Ser Asn Tyr 20 25 30 Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Gln Ile Tyr Pro Gly Asp Asp Asp Ala Asp Tyr Asn Gly Lys Phe 50 55 60 Gln Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Asn Thr Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95 Thr Arg Ser Gly Arg Arg Asp Phe Asp Tyr Trp Gly Gln Gly Thr Thr 100 105 110 Leu Thr Val Ser Ser 115 <![CDATA[<210> 28]]> <![CDATA[<211> 15]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 輕鏈CDR1]]> <![CDATA[<222> (1)..(15)]]> <![CDATA[<400> 28]]> Arg Ala Ser Glu Ser Ile Asp Asn Tyr Gly Asn Ser Phe Met His 1 5 10 15 <![CDATA[<210> 29]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 輕鏈CDR3]]> <![CDATA[<222> (1)..(9)]]> <![CDATA[<400> 29]]> Gln Gln Asn Asn Glu Asp Pro Tyr Thr 1 5 <![CDATA[<210> 30]]> <![CDATA[<211> 111]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 輕鏈可變區]]> <![CDATA[<222> (1)..(111)]]> <![CDATA[<40]]>0> 30]]> <br/> <br/><![CDATA[Asn Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Ile Asp Asn Tyr 20 25 30 Gly Asn Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro 35 40 45 Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Val Pro Ala 50 55 60 Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asp 65 70 75 80 Pro Val Glu Ala Asp Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Asn Asn 85 90 95 Glu Asp Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 <![CDATA[<210> 31]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈CDR1]]> <![CDATA[<222> (1)..(5)]]> <![CDATA[<400> 31]]> Ser Tyr Gly Val His 1 5 <![CDATA[<210> 32]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈CDR2]]> <![CDATA[<222> (1)..(16)]]> <![CDATA[<400> 32]]> Val Ile Trp Ser Gly Gly Arg Ile Asp Tyr Asn Ala Ala Phe Ile Ser 1 5 10 15 <![CDATA[<210> 33]]> <![CDATA[<211> 15]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈CDR3]]> <![CDATA[<222> (1)..(15)]]> <![CDATA[<400> 33]]> Lys Gly Ser Ser Tyr Tyr Gly Leu Tyr Tyr Tyr Gly Met Asp Tyr 1 5 10 15 <![CDATA[<210> 34]]> <![CDATA[<211> 123]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈可變區]]> <![CDATA[<222> (1)..(123)]]> <![CDATA[<400> 34]]> Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr 20 25 30 Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Ser Gly Gly Arg Ile Asp Tyr Asn Ala Ala Phe Ile 50 55 60 Ser Arg Leu Ser Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Phe Phe 65 70 75 80 Lys Met Asn Ser Leu Gln Ala Asp Asp Thr Ala Ile Tyr Tyr Cys Ala 85 90 95 Arg Lys Gly Ser Ser Tyr Tyr Gly Leu Tyr Tyr Tyr Gly Met Asp Tyr 100 105 110 Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser 115 120 <![CDATA[<210> 35]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 輕鏈CDR1]]> <![CDATA[<222> (1)..(17)]]> <![CDATA[<400> 35]]> Lys Ser Ser Gln Ser Leu Leu Asn Ser Gly Asn Gln Lys Asn Tyr Leu 1 5 10 15 Thr <![CDATA[<210> 36]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 輕鏈CDR2]]> <![CDATA[<222> (1)..(7)]]> <![CDATA[<400> 36]]> Trp Ala Ser Thr Arg Glu Ser 1 5 <![CDATA[<210> 37]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 輕鏈CDR3]]> <![CDATA[<222> (1)..(9)]]> <![CDATA[<400> 37]]> Gln Asn Asp Tyr Gly Tyr Pro Leu Thr 1 5 <![CDATA[<210> 38]]> <![CDATA[<211> 113]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 輕鏈可變區]]> <![CDATA[<222> (1)..(113)]]> <![CDATA[<400> 38]]> Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Thr Val Thr Ala Gly 1 5 10 15 Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser 20 25 30 Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Ser Gly Gln 35 40 45 Thr Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Asn 85 90 95 Asp Tyr Gly Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu 100 105 110 Lys <![CDATA[<210> 39]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈CDR1]]> <![CDATA[<222> (1)..(5)]]> <![CDATA[<400> 39]]> Gly Tyr Ser Val Asn 1 5 <![CDATA[<210> 40]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈CDR2]]> <![CDATA[<222> (1)..(16)]]> <![CDATA[<400> 40]]> Met Ile Trp Gly Asp Gly Ser Thr Asp Tyr Asn Ser Ala Leu Lys Ser 1 5 10 15 <![CDATA[<210> 41]]> <![CDATA[<211> 14]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈CDR3]]> <![CDATA[<222> (1)..(14)]]> <![CDATA[<400> 41]]> Asp Arg Asp Tyr Arg Tyr Asp Gly Gly Tyr Ile Met Asp Ser 1 5 10 <![CDATA[<210> 42]]> <![CDATA[<211> 122]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈可變區]]> <![CDATA[<222> (1)..(122)]]> <![CDATA[<400> 42]]> Arg Val Gln Leu Arg Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Gly Tyr 20 25 30 Ser Val Asn Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Met Ile Trp Gly Asp Gly Ser Thr Asp Tyr Asn Ser Ala Leu Lys 50 55 60 Ser Arg Leu Ser Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Phe Leu 65 70 75 80 Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Arg Tyr Tyr Cys Ala 85 90 95 Arg Asp Arg Asp Tyr Arg Tyr Asp Gly Gly Tyr Ile Met Asp Ser Trp 100 105 110 Gly Gln Gly Thr Ser Val Thr Val Ser Ser 115 120 <![CDATA[<210> 43]]> <![CDATA[<211> 15]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 輕鏈CDR1]]> <![CDATA[<222> (1)..(15)]]> <![CDATA[<400> 43]]> Arg Ala Ser Glu Ser Val Asp Asn Phe Gly Asn Ser Phe Leu His 1 5 10 15 <![CDATA[<210> 44]]> <![CDATA[<211> 111]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 輕鏈可變區]]> <![CDATA[<222> (1)..(111)]]> <![CDATA[<400> 44]]> Asp Ile Val Leu Thr Gln Ser Pro Gly Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Phe 20 25 30 Gly Asn Ser Phe Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro 35 40 45 Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Val Pro Ala 50 55 60 Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser 65 70 75 80 Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys Gln Gln Ser Asn 85 90 95 Glu Asp Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Arg 100 105 110 <![CDATA[<210> 45]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈CDR1]]> <![CDATA[<222> (1)..(5)]]> <![CDATA[<400> 45]]> Arg Asn Trp Met His 1 5 <![CDATA[<210> 46]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈CDR2]]> <![CDATA[<222> (1)..(17)]]> <![CDATA[<400> 46]]> Glu Ile Asp Pro Ser Asp Ser Tyr Thr His Tyr Asn Gln Lys Phe Lys 1 5 10 15 Gly <![CDATA[<210> 47]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈CDR3]]> <![CDATA[<222> (1)..(16)]]> <![CDATA[<400> 47]]> Val Gly Asn Tyr Asp Asn Gly Lys Asp Arg Leu Tyr Ala Met Asp Tyr 1 5 10 15 <![CDATA[<210> 48]]> <![CDATA[<211> 125]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈可變區]]> <![CDATA[<222> (1)..(125)]]> <![CDATA[<400> 48]]> Gln Val Gln Leu Gln Gln Pro Gly Thr Glu Phe Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Asn 20 25 30 Trp Met His Trp Leu Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Glu Ile Asp Pro Ser Asp Ser Tyr Thr His Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Val Gly Asn Tyr Asp Asn Gly Lys Asp Arg Leu Tyr Ala Met 100 105 110 Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser 115 120 125 <![CDATA[<210> 49]]> <![CDATA[<211> 15]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 輕鏈CDR1]]> <![CDATA[<222> (1)..(15)]]> <![CDATA[<400> 49]]> Arg Ala Ser Glu Ser Val Asp Asn Phe Gly Asn Thr Phe Leu His 1 5 10 15 <![CDATA[<210> 50]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 輕鏈CDR3]]> <![CDATA[<222> (1)..(9)]]> <![CDATA[<400> 50]]> Gln Gln Asn Asn Glu Asp Pro Trp Thr 1 5 <![CDATA[<210> 51]]> <![CDATA[<211> 111]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 輕鏈可變區]]> <![CDATA[<222> (1)..(111)]]> <![CDATA[<400> 51]]> Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Phe 20 25 30 Gly Asn Thr Phe Leu His Trp Phe Arg Gln Lys Pro Gly Gln Pro Pro 35 40 45 Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala 50 55 60 Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn 65 70 75 80 Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys Gln Gln Asn Asn 85 90 95 Glu Asp Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 <![CDATA[<210> 52]]> <![CDATA[<211> 125]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈可變區]]> <![CDATA[<222> (1)..(125)]]> <![CDATA[<400> 52]]> Gln Val Gln Leu Gln Gln Pro Gly Thr Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Asn 20 25 30 Trp Met His Trp Leu Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Glu Ile Asp Pro Ser Asp Ser Tyr Thr His Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Val Glu Met Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Val Gly Asn Tyr Asp Asn Gly Thr Asp Arg Leu Tyr Ala Met 100 105 110 Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser 115 120 125 <![CDATA[<210> ]]>53 <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈CDR2]]> <![CDATA[<222> (1)..(16)]]> <![CDATA[<400> 53]]> Val Ile Trp Ser Gly Gly Arg Thr Asp Tyr Asn Ala Ala Phe Ile Ser 1 5 10 15 <![CDATA[<210> 54]]> <![CDATA[<211> 15]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈CDR3]]> <![CDATA[<222> (1)..(15)]]> <![CDATA[<400> 54]]> Lys Gly Ser Ser Tyr Tyr Gly Leu Tyr Tyr Tyr Gly Met Asp Phe 1 5 10 15 <![CDATA[<210> 55]]> <![CDATA[<211> 123]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈可變區]]> <![CDATA[<222> (1)..(123)]]> <![CDATA[<400> 55]]> Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr 20 25 30 Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Ser Gly Gly Arg Thr Asp Tyr Asn Ala Ala Phe Ile 50 55 60 Ser Arg Leu Asn Ile Ser Lys Asp Ser Ser Lys Ser Gln Val Phe Phe 65 70 75 80 Lys Met Asn Ser Leu Gln Ala Asp Asp Thr Ala Ile Tyr Tyr Cys Ala 85 90 95 Arg Lys Gly Ser Ser Tyr Tyr Gly Leu Tyr Tyr Tyr Gly Met Asp Phe 100 105 110 Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser 115 120 <![CDATA[<210> 56]]> <![CDATA[<211> 15]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 輕鏈CDR1]]> <![CDATA[<222> (1)..(15)]]> <![CDATA[<400> 56]]> Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly Ile Ser Phe Met Asn 1 5 10 15 <![CDATA[<210> 57]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 輕鏈CDR2]]> <![CDATA[<222> (1)..(7)]]> <![CDATA[<400> 57]]> Val Ala Ser Asn Gln Gly Ser 1 5 <![CDATA[<210> 58]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈CDR3]]> <![CDATA[<222> (1)..(9)]]> <![CDATA[<400> 58]]> Gln His Ser Lys Glu Val Pro Arg Thr 1 5 <![CDATA[<210> 59]]> <![CDATA[<211> 111]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<400> 59]]> Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Thr Val Ser Leu Gly 1 5 10 15 Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr 20 25 30 Gly Ile Ser Phe Met Asn Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro 35 40 45 Lys Leu Leu Ile Tyr Val Ala Ser Asn Gln Gly Ser Gly Val Pro Ala 50 55 60 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Ser Leu Asn Ile His 65 70 75 80 Pro Met Glu Glu Asp Asp Thr Ala Met Tyr Phe Cys Gln His Ser Lys 85 90 95 Glu Val Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 <![CDATA[<210> 60]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈CDR1]]> <![CDATA[<222> (1)..(5)]]> <![CDATA[<400> 60]]> Ser Tyr Ala Met Ser 1 5 <![CDATA[<210> 61]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈CDR2]]> <![CDATA[<222> (1)..(16)]]> <![CDATA[<400> 61]]> Ser Ile Thr Thr Gly Gly Ser Thr Tyr Tyr Leu Asp Ser Val Arg Gly 1 5 10 15 <![CDATA[<210> 62]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈CDR3]]> <![CDATA[<222> (1)..(11)]]> <![CDATA[<400> 62]]> Ser Leu Ile Ile Thr Ala Thr Gly Phe Asp Tyr 1 5 10 <![CDATA[<210> 63]]> <![CDATA[<211> 119]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈可變區]]> <![CDATA[<222> (1)..(119)]]> <![CDATA[<400> 63]]> Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val 35 40 45 Ala Ser Ile Thr Thr Gly Gly Ser Thr Tyr Tyr Leu Asp Ser Val Arg 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Arg Asn Ile Leu Ser Leu 65 70 75 80 Gln Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Ile Tyr Tyr Cys Ala 85 90 95 Arg Ser Leu Ile Ile Thr Ala Thr Gly Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Thr Leu Thr Val Ser Ser 115 <![CDATA[<210> 64]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 輕鏈CDR1]]> <![CDATA[<222> (1)..(11)]]> <![CDATA[<400> 64]]> Arg Ala Ser Gln Asp Val Gly Thr Ala Val Ala 1 5 10 <![CDATA[<210> 65]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 輕鏈CDR2]]> <![CDATA[<222> (1)..(7)]]> <![CDATA[<400> 65]]> Ser Ala Ser Asn Arg Tyr Thr 1 5 <![CDATA[<210> 66]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 輕鏈CDR3]]> <![CDATA[<222> (1)..(8)]]> <![CDATA[<400> 66]]> Gln Gln Tyr Ser Ile Tyr Tyr Thr 1 5 <![CDATA[<210> 67]]> <![CDATA[<211> 10]]>6 <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 輕鏈可變區]]> <![CDATA[<222> (1)..(106)]]> <![CDATA[<400> 67]]> Asp Ile Val Met Thr Gln Ser Gln Lys Phe Met Ser Ile Ser Val Gly 1 5 10 15 Asp Arg Val Asn Ile Thr Cys Arg Ala Ser Gln Asp Val Gly Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Asn Arg Tyr Thr Gly Val Pro Asn Arg Phe Thr Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Ala Ile Ser Asn Met Gln Ser 65 70 75 80 Glu Asp Leu Ala Asp Tyr Phe Cys Gln Gln Tyr Ser Ile Tyr Tyr Thr 85 90 95 Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 <![CDATA[<210> 68]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈CDR1]]> <![CDATA[<222> (1)..(5)]]> <![CDATA[<400> 68]]> Ser Phe Val Met Ser 1 5 <![CDATA[<210> 69]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈CDR2]]> <![CDATA[<222> (1)..(16)]]> <![CDATA[<400> 69]]> Ser Ile Thr Ser Gly Gly Thr Thr Phe Tyr Pro Asp Ser Val Lys Gly 1 5 10 15 <![CDATA[<210> 70]]> <![CDATA[<211> 12]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈CDR3]]> <![CDATA[<222> (1)..(12)]]> <![CDATA[<400> 70]]> Gly Pro Pro Gln Phe Ser Ser Leu Ser Met Asp Tyr 1 5 10 <![CDATA[<210> 71]]> <![CDATA[<211> 120]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈可變區]]> <![CDATA[<222> (1)..(120)]]> <![CDATA[<400> 71]]> Glu Val Asn Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Pro Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe 20 25 30 Val Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val 35 40 45 Ala Ser Ile Thr Ser Gly Gly Thr Thr Phe Tyr Pro Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Arg Asn Ile Leu Tyr Leu 65 70 75 80 Gln Met Ser Asn Leu Arg Ser Gly Asp Thr Ala Met Tyr Tyr Cys Ala 85 90 95 Arg Gly Pro Pro Gln Phe Ser Ser Leu Ser Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Ser Val Thr Val Ser Ser 115 120 <![CDATA[<210> 72]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 輕鏈CDR1]]> <![CDATA[<222> (1)..(11)]]> <![CDATA[<400> 72]]> Lys Ala Ser Gln Asn Val Gly Thr Ala Val Ser 1 5 10 <![CDATA[<210>]]> 73 <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Arti]]>ficial Sequence) <![CDATA[<220>]]> <![CDATA[<221> 輕鏈CDR3]]> <![CDATA[<222> (1)..(8)]]> <![CDATA[<400> 73]]> Gln Gln Tyr Ser Ser Leu Phe Thr 1 5 <![CDATA[<210> 74]]> <![CDATA[<211> 106]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 輕鏈可變區]]> <![CDATA[<222> (1)..(106)]]> <![CDATA[<400> 74]]> Asp Ile Val Met Thr Gln Ser Gln Lys Phe Met Ser Thr Ser Val Gly 1 5 10 15 Asp Arg Ile Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Ala 20 25 30 Val Ser Trp Phe Gln Gln Lys Pro Gly Gln Val Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Asn Ile Gln Ser 65 70 75 80 Glu Asp Leu Ala Asp Tyr Phe Cys Gln Gln Tyr Ser Ser Leu Phe Thr 85 90 95 Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys 100 105 <![CDATA[<210> 75]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈CDR1]]> <![CDATA[<222> (1)..(10)]]> <![CDATA[<400> 75]]> Gly Tyr Thr Phe Thr Asp Tyr Gly Met Asn 1 5 10 <![CDATA[<210> 76]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈CDR2]]> <![CDATA[<222> (1)..(17)]]> <![CDATA[<400> 76]]> Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe Lys 1 5 10 15 Asp <![CDATA[<210> 77]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈CDR3]]> <![CDATA[<222> (1)..(10)]]> <![CDATA[<400> 77]]> Arg Tyr Gly Tyr Asp Ala Gly Ile Asp Cys 1 5 10 <![CDATA[<210> 78]]> <![CDATA[<211> 119]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈可變區]]> <![CDATA[<222> (1)..(119)]]> <![CDATA[<400> 78]]> Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu 1 5 10 15 Thr Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Gly Met Asn Trp Val Lys Gln Thr Pro Gly Lys Asp Leu Lys Trp Val 35 40 45 Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe 50 55 60 Lys Asp Arg Phe Ala Phe Ser Leu Glu Ala Ser Ala Ser Thr Ala Tyr 65 70 75 80 Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys 85 90 95 Ala Arg Arg Tyr Gly Tyr Asp Ala Gly Ile Asp Cys Trp Gly Gln Gly 100 105 110 Thr Thr Leu Thr Val Ser Ser 115 <![CDATA[<210> 79]]> <![CDATA[<211> 15]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 輕鏈CDR1]]> <![CDATA[<222> (1)..(15)]]> <![CDATA[<400> 79]]> Arg Ala Ser Glu Ser Val Asp Ser Tyr Gly Asn Asn Leu Met His 1 5 10 15 <![CDATA[<210> 80]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 輕鏈CDR2]]> <![CDATA[<222> (1)..(7)]]> <![CDATA[<400> 80]]> Leu Ala Ser Tyr Leu Glu Ser 1 5 <![CDATA[<210> 81]]> <![CDATA[<211> 111]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 輕鏈可變區]]> <![CDATA[<222> (1)..(111)]]> <![CDATA[<400> 81]]> Asn Ile Val Leu Thr Gln Ser Pro Pro Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Ser Tyr 20 25 30 Gly Asn Asn Leu Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro 35 40 45 Lys Leu Leu Ile Tyr Leu Ala Ser Tyr Leu Glu Ser Gly Val Pro Ala 50 55 60 Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asp 65 70 75 80 Pro Val Glu Ala Asp Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Asn Asn 85 90 95 Glu Asp Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 <![CDATA[<210> 82]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈CDR1]]> <![CDATA[<222> (1)..(7)]]> <![CDATA[<400> 82]]> Thr Ser Asp Met Gly Val Gly 1 5 <![CDATA[<210> 83]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈CDR2]]> <![CDATA[<222> (1)..(16)]]> <![CDATA[<400> 83]]> His Ile Trp Trp Asp Asp Asp Lys Tyr Tyr Asn Pro Ser Leu Lys Arg 1 5 10 15 <![CDATA[<210> 84]]> <![CDATA[<211> 12]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈CDR3]]> <![CDATA[<222> (1)..(12)]]> <![CDATA[<400> 84]]> Leu Tyr Asp Tyr Asp Asp Glu Tyr Tyr Phe Asp Tyr 1 5 10 <![CDATA[<210> 85]]> <![CDATA[<211> 122]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈可變區]]> <![CDATA[<222> (1)..(122)]]> <![CDATA[<400> 85]]> Gln Val Thr Leu Lys Glu Ser Gly Pro Gly Ile Leu Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Ser Phe Ser Gly Phe Ser Leu Ser Thr Ser 20 25 30 Asp Met Gly Val Gly Trp Ile Arg Gln Pro Ser Gly Lys Gly Leu Glu 35 40 45 Trp Leu Ala His Ile Trp Trp Asp Asp Asp Lys Tyr Tyr Asn Pro Ser 50 55 60 Leu Lys Arg Gln Leu Thr Ile Ser Lys Asp Asn Ser Arg Asn Gln Val 65 70 75 80 Phe Leu Lys Ile Ser Ser Val Asp Thr Thr Asp Thr Ala Thr Tyr Tyr 85 90 95 Cys Ala Arg Leu Tyr Asp Tyr Asp Asp Glu Tyr Tyr Phe Asp Tyr Trp 100 105 110 Gly Gln Gly Thr Thr Leu Thr Val Ser Ser 115 120 <![CDATA[<210> 86]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 輕鏈CDR1]]> <![CDATA[<222> (1)..(11)]]> <![CDATA[<400> 86]]> Arg Ala Ser Gln Asp Ser Asn Asn Tyr Leu Asn 1 5 10 <![CDATA[<210> 87]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 輕鏈CDR2]]> <![CDATA[<222> (1)..(7)]]> <![CDATA[<400> 87]]> Tyr Thr Ser Arg Leu His Ser 1 5 <![CDATA[<210> 88]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 輕鏈CDR3]]> <![CDATA[<222> (1)..(9)]]> <![CDATA[<400> 88]]> Gln Gln Gly Asn Thr Ile Pro Trp Thr 1 5 <![CDATA[<210> 89]]> <![CDATA[<211> 107]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 輕鏈可變區]]> <![CDATA[<222> (1)..(107)]]> <![CDATA[<400> 89]]> Asp Ile Gln Met Thr Gln Thr Lys Ser Ser Leu Ser Ala Ser Leu Gly 1 5 10 15 Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ser Asn Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile 35 40 45 Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu His 65 70 75 80 Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Ile Pro Trp 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 <![CDATA[<210> 90]]> <![CDATA[<211> 120]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈可變區]]> <![CDATA[<222> (1)..(120)]]> <![CDATA[<400> 90]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe 20 25 30 Val Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Ser Ile Thr Ser Gly Gly Thr Thr Phe Tyr Pro Glu Ser Val Arg 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Gly Pro Pro Gln Phe Ser Ser Leu Ser Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Thr Val Thr Val Ser Ser 115 120 <![CDATA[<210> 91]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈CDR2]]> <![CDATA[<222> (1)..(16)]]> <![CDATA[<400> 91]]> Ser Ile Thr Ser Gly Gly Thr Thr Phe Tyr Pro Glu Ser Val Arg Gly 1 5 10 15 <![CDATA[<210> 92]]> <![CDATA[<211> 120]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈可變區]]> <![CDATA[<222> (1)..(120)]]> <![CDATA[<400> 92]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe 20 25 30 Val Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Ser Ile Thr Ser Gly Gly Thr Thr Phe Tyr Pro Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Gly Pro Pro Gln Phe Ser Ser Leu Ser Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Thr Val Thr Val Ser Ser 115 120 <![CDATA[<210> 93]]> <![CDATA[<211> 120]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈可變區]]> <![CDATA[<222> (1)..(120)]]> <![CDATA[<400> 93]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe 20 25 30 Val Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Ser Ile Thr Ser Gly Gly Thr Thr Phe Tyr Pro Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Arg Asn Ile Leu Tyr Leu 65 70 75 80 Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Gly Pro Pro Gln Phe Ser Ser Leu Ser Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Thr Val Thr Val Ser Ser 115 120 <![CDATA[<210> 94]]> <![CDATA[<211> 106]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 輕鏈可變區]]> <![CDATA[<222> (1)..(106)]]> <![CDATA[<400> 94]]> Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asn Val Gly Thr Ala 20 25 30 Val Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Asn Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Ser Leu Phe Thr 85 90 95 Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 <![CDATA[<210> 95]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 輕鏈CDR1]]> <![CDATA[<222> (1)..(11)]]> <![CDATA[<400> 95]]> Arg Ala Ser Gln Asn Val Gly Thr Ala Val Ser 1 5 10 <![CDATA[<210> 96]]> <![CDATA[<211> 106]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 輕鏈可變區]]> <![CDATA[<222> (1)..(106)]]> <![CDATA[<400> 96]]> Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Ala 20 25 30 Val Ser Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Asn Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Ser Leu Phe Thr 85 90 95 Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 <![CDATA[<210> 97]]> <![CDATA[<211> 106]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 輕鏈可變區]]> <![CDATA[<222> (1)..(106)]]> <![CDATA[<400> 97]]> Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Ile Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Ala 20 25 30 Val Ser Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Ser Leu Phe Thr 85 90 95 Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 <![CDATA[<210> 98]]> <![CDATA[<211> 119]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈可變區]]> <![CDATA[<222> (1)..(119)]]> <![CDATA[<400> 98]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe 50 55 60 Lys Asp Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Tyr Gly Tyr Asp Ala Gly Ile Asp Ala Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <![CDATA[<210> 99]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈CDR3]]> <![CDATA[<222> (1)..(10)]]> <![CDATA[<400> 99]]> Arg Tyr Gly Tyr Asp Ala Gly Ile Asp Ala 1 5 10 <![CDATA[<210> 100]]> <![CDATA[<211> 119]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈可變區]]> <![CDATA[<222> (1)..(119)]]> <![CDATA[<400> 100]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe 50 55 60 Lys Asp Arg Val Thr Phe Thr Leu Asp Ala Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Tyr Gly Tyr Asp Ala Gly Ile Asp Ala Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <![CDATA[<210> 101]]> <![CDATA[<211> 119]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈可變區]]> <![CDATA[<222> (1)..(119)]]> <![CDATA[<400> 101]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Val 35 40 45 Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe 50 55 60 Lys Asp Arg Phe Thr Phe Thr Leu Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Arg Arg Tyr Gly Tyr Asp Ala Gly Ile Asp Ala Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <![CDATA[<210> 102]]> <![CDATA[<211> 119]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈可變區]]> <![CDATA[<222> (1)..(119)]]> <![CDATA[<400> 102]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe 50 55 60 Lys Asp Arg Val Thr Phe Thr Leu Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Tyr Gly Tyr Asp Ala Gly Ile Asp Ala Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <![CDATA[<210> 103]]> <![CDATA[<211> 119]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈可變區]]> <![CDATA[<222> (1)..(119)]]> <![CDATA[<400> 103]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe 50 55 60 Lys Asp Arg Val Thr Phe Thr Leu Asp Ala Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Tyr Gly Tyr Asp Ala Gly Ile Asp Ala Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <![CDATA[<210> 104]]> <![CDATA[<211> 119]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈可變區]]> <![CDATA[<222> (1)..(119)]]> <![CDATA[<400> 104]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Lys Trp Met 35 40 45 Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe 50 55 60 Lys Asp Arg Val Thr Phe Thr Leu Asp Ala Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Tyr Gly Tyr Asp Ala Gly Ile Asp Ala Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <![CDATA[<210> 105]]> <![CDATA[<211> 119]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈可變區]]> <![CDATA[<222> (1)..(119)]]> <![CDATA[<400> 105]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Gly Met Asn Trp Val Arg Gln Thr Pro Gly Gln Gly Leu Lys Trp Val 35 40 45 Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe 50 55 60 Lys Asp Arg Phe Thr Phe Thr Leu Asp Ala Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Arg Arg Tyr Gly Tyr Asp Ala Gly Ile Asp Ala Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <![CDATA[<210> 106]]> <![CDATA[<211> 119]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈可變區]]> <![CDATA[<222> (1)..(119)]]> <![CDATA[<400> 106]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Gly Met Asn Trp Val Arg Gln Thr Pro Gly Gln Gly Leu Glu Trp Val 35 40 45 Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe 50 55 60 Lys Asp Arg Phe Thr Phe Thr Leu Asp Ala Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Arg Arg Tyr Gly Tyr Asp Ala Gly Ile Asp Ala Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <![CDATA[<210> 107]]> <![CDATA[<211> 119]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈可變區]]> <![CDATA[<222> (1)..(119)]]> <![CDATA[<400> 107]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Gly Met Asn Trp Val Arg Gln Thr Pro Gly Gln Gly Leu Lys Trp Val 35 40 45 Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe 50 55 60 Lys Asp Arg Phe Thr Phe Thr Leu Asp Ala Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Arg Arg Tyr Gly Tyr Asp Ala Gly Ile Asp Ala Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <![CDATA[<210> 108]]> <![CDATA[<211> 119]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈可變區]]> <![CDATA[<222> (1)..(119)]]> <![CDATA[<400> 108]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Lys Trp Val 35 40 45 Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe 50 55 60 Lys Asp Arg Phe Thr Phe Thr Leu Asp Ala Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Arg Arg Tyr Gly Tyr Asp Ala Gly Ile Asp Ala Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <![CDATA[<210> 109]]> <![CDATA[<211> 119]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈可變區]]> <![CDATA[<222> (1)..(119)]]> <![CDATA[<400> 109]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Gly Met Asn Trp Val Arg Gln Thr Pro Gly Gln Gly Leu Lys Trp Val 35 40 45 Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe 50 55 60 Lys Asp Arg Phe Thr Phe Thr Leu Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Arg Arg Tyr Gly Tyr Asp Ala Gly Ile Asp Ala Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <![CDATA[<210> 110]]> <![CDATA[<211> 119]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈可變區]]> <![CDATA[<222> (1)..(119)]]> <![CDATA[<400> 110]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Lys Trp Val 35 40 45 Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe 50 55 60 Lys Asp Arg Phe Thr Phe Thr Leu Asp Ala Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Arg Arg Tyr Gly Tyr Asp Ala Gly Ile Asp Ala Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <![CDATA[<210> 111]]> <![CDATA[<211> 119]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈可變區]]> <![CDATA[<222> (1)..(119)]]> <![CDATA[<400> 111]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Val 35 40 45 Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe 50 55 60 Lys Asp Arg Phe Thr Phe Thr Leu Asp Ala Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Arg Arg Tyr Gly Tyr Asp Ala Gly Ile Asp Ala Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <![CDATA[<210> 112]]> <![CDATA[<211>]]> 119 <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈可變區]]> <![CDATA[<222> (1)..(119)]]> <![CDATA[<400> 112]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Val 35 40 45 Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe 50 55 60 Lys Asp Arg Phe Thr Phe Thr Leu Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Arg Arg Tyr Gly Tyr Asp Ala Gly Ile Asp Ala Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <![CDATA[<210> 113]]> <![CDATA[<211> 119]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈可變區]]> <![CDATA[<222> (1)..(119)]]> <![CDATA[<400> 113]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Val 35 40 45 Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe 50 55 60 Lys Asp Arg Phe Thr Phe Thr Leu Asp Ala Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Arg Arg Tyr Gly Tyr Asp Ala Gly Ile Asp Ala Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <![CDATA[<210> 114]]> <![CDATA[<211> 119]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈可變區]]> <![CDATA[<222> (1)..(119)]]> <![CDATA[<400> 114]]> Gln Ile Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Gly Met Asn Trp Val Arg Gln Thr Pro Gly Gln Gly Leu Lys Trp Val 35 40 45 Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe 50 55 60 Lys Asp Arg Phe Thr Phe Thr Leu Asp Ala Ser Thr Ser Thr Ala Tyr 65 70 75 80 Leu Glu Ile Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Arg Arg Tyr Gly Tyr Asp Ala Gly Ile Asp Ala Trp Gly Gln Gly 100 105 110 Thr Leu Leu Thr Val Ser Ser 115 <![CDATA[<210> 115]]> <![CDATA[<211> 119]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<22]]>0>]]> <br/><![CDATA[<221> 重鏈可變區]]> <br/><![CDATA[<222> (1)..(119)]]> <br/> <br/><![CDATA[<400> 115]]> <br/> <br/><![CDATA[Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Gln Lys Leu 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Tyr Gly Tyr Asp Ala Gly Ile Asp Ala Trp Gly Gln Gly 100 105 110 Thr Thr Val Thr Val Ser Ser 115 <![CDATA[<210> 116]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈CDR2]]> <![CDATA[<222> (1)..(17)]]> <![CDATA[<400> 116]]> Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Gln Lys Leu Gln 1 5 10 15 Gly <![CDATA[<210> 117]]> <![CDATA[<211> 119]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈可變區]]> <![CDATA[<222> (1)..(]]>119) <![CDATA[<400> 117]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Gln Lys Leu 50 55 60 Gln Gly Arg Val Thr Phe Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Tyr Gly Tyr Asp Ala Gly Ile Asp Ala Trp Gly Gln Gly 100 105 110 Thr Thr Val Thr Val Ser Ser 115 <![CDATA[<210> 118]]> <![CDATA[<211> 119]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈柯斌去]]> <![CDATA[<222> (1)..(119)]]> <![CDATA[<400> 118]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Val 35 40 45 Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe 50 55 60 Lys Asp Arg Val Thr Phe Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Tyr Gly Tyr Asp Ala Gly Ile Asp Ala Trp Gly Gln Gly 100 105 110 Thr Thr Val Thr Val Ser Ser 115 <![CDATA[<210> 119]]> <![CDATA[<211> 119]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈可變區]]> <![CDATA[<222> (1)..(119)]]> <![CDATA[<400> 119]]> Gln Ile Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Val 35 40 45 Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe 50 55 60 Lys Asp Arg Phe Thr Phe Thr Leu Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Leu Glu Ile Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Tyr Gly Tyr Asp Ala Gly Ile Asp Ala Trp Gly Gln Gly 100 105 110 Thr Thr Val Thr Val Ser Ser 115 <![CDATA[<210> 120]]> <![CDATA[<211> 119]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈可變區]]> <![CDATA[<222> (1)..(119)]]> <![CDATA[<400> 120]]> Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Val 35 40 45 Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe 50 55 60 Lys Asp Arg Phe Val Phe Ser Leu Asp Thr Ser Val Ser Thr Ala Tyr 65 70 75 80 Leu Gln Ile Ser Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Tyr Gly Tyr Asp Ala Gly Ile Asp Ala Trp Gly Gln Gly 100 105 110 Thr Thr Val Thr Val Ser Ser 115 <![CDATA[<210> 121]]> <![CDATA[<211> 119]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 重鏈可變區]]> <![CDATA[<222> (1)..(119)]]> <![CDATA[<400> 121]]> Gln Ile Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Val 35 40 45 Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe 50 55 60 Lys Asp Arg Phe Val Phe Ser Leu Asp Ala Ser Val Ser Thr Ala Tyr 65 70 75 80 Leu Gln Ile Ser Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Tyr Gly Tyr Asp Ala Gly Ile Asp Ala Trp Gly Gln Gly 100 105 110 Thr Thr Val Thr Val Ser Ser 115 <![CDATA[<210> 122]]> <![CDATA[<211> 111]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 輕鏈可變區]]> <![CDATA[<222> (1)..(111)]]> <![CDATA[<400> 122]]> Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Glu Ser Val Asp Ser Tyr 20 25 30 Gly Asn Asn Leu Met His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro 35 40 45 Arg Leu Leu Ile Tyr Leu Ala Ser Tyr Leu Glu Ser Gly Ile Pro Asp 50 55 60 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser 65 70 75 80 Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Asn Asn 85 90 95 Glu Ser Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 110 <![CDATA[<210> 123]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 輕鏈CDR3]]> <![CDATA[<222> (1)..(9)]]> <![CDATA[<400> 123]]> Gln Gln Asn Asn Glu Ser Pro Trp Thr 1 5 <![CDATA[<210> 124]]> <![CDATA[<211> 111]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 輕鏈可變區]]> <![CDATA[<222> (1)..(111)]]> <![CDATA[<400> 124]]> Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Glu Ser Val Asp Ser Tyr 20 25 30 Gly Asn Asn Leu Met His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro 35 40 45 Arg Leu Leu Ile Tyr Leu Ala Ser Tyr Leu Glu Ser Gly Val Pro Asp 50 55 60 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser 65 70 75 80 Arg Leu Glu Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Asn Asn 85 90 95 Glu Ser Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 110 <![CDATA[<210> 125]]> <![CDATA[<211> 111]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 輕鏈可變區]]> <![CDATA[<222> (1)..(111)]]> <![CDATA[<400> 125]]> Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Glu Ser Val Asp Ala Tyr 20 25 30 Gly Asn Asn Leu Met His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro 35 40 45 Arg Leu Leu Ile Tyr Leu Ala Ser Tyr Leu Glu Ser Gly Val Pro Asp 50 55 60 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser 65 70 75 80 Arg Leu Glu Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Asn Asn 85 90 95 Glu Ser Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 110 <![CDATA[<210> 126]]> <![CDATA[<211> 15]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 輕鏈CDR1]]> <![CDATA[<222> (1)..(15)]]> <![CDATA[<400> 126]]> Arg Ala Ser Glu Ser Val Asp Ala Tyr Gly Asn Asn Leu Met His 1 5 10 15 <![CDATA[<210> 127]]> <![CDATA[<211> 111]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 輕鏈可變區]]> <![CDATA[<222> (1)..(111)]]> <![CDATA[<400> 127]]> Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Glu Ser Val Glu Ser Tyr 20 25 30 Gly Asn Asn Leu Met His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro 35 40 45 Arg Leu Leu Ile Tyr Leu Ala Ser Tyr Leu Glu Ser Gly Val Pro Asp 50 55 60 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser 65 70 75 80 Arg Leu Glu Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Asn Asn 85 90 95 Glu Ser Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 110 <![CDATA[<210> 128]]> <![CDATA[<211> 15]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 輕鏈CDR1]]> <![CDATA[<222> (1)..(15)]]> <![CDATA[<400> 128]]> Arg Ala Ser Glu Ser Val Glu Ser Tyr Gly Asn Asn Leu Met His 1 5 10 15 <![CDATA[<210> 129]]> <![CDATA[<211> 111]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 輕鏈可變區]]> <![CDATA[<222> (1)..(111)]]> <![CDATA[<400> 129]]> Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Ser Tyr 20 25 30 Gly Asn Asn Leu Met His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro 35 40 45 Arg Leu Leu Ile Tyr Leu Ala Ser Tyr Leu Glu Ser Gly Val Pro Ala 50 55 60 Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser 65 70 75 80 Arg Leu Glu Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Asn Asn 85 90 95 Glu Ser Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 110 <![CDATA[<210> 130]]> <![CDATA[<211> 111]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 輕鏈可變區]]> <![CDATA[<222> (1)..(111)]]> <![CDATA[<400> 130]]> Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr 20 25 30 Gly Asn Asn Leu Met His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro 35 40 45 Arg Leu Leu Ile Tyr Leu Ala Ser Tyr Leu Glu Ser Gly Val Pro Ala 50 55 60 Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser 65 70 75 80 Arg Leu Glu Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Asn Asn 85 90 95 Glu Ser Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 110 <![CDATA[<210> 131]]> <![CDATA[<211> 111]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<400> 131]]> Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Ala Tyr 20 25 30 Gly Asn Asn Leu Met His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro 35 40 45 Arg Leu Leu Ile Tyr Leu Ala Ser Tyr Leu Glu Ser Gly Val Pro Ala 50 55 60 Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser 65 70 75 80 Arg Leu Glu Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Asn Asn 85 90 95 Glu Ser Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 110 <![CDATA[<210> 132]]> <![CDATA[<211> 111]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 輕鏈可變區]]> <![CDATA[<222> (1)..(111)]]> <![CDATA[<400> 132]]> Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Ser Tyr 20 25 30 Gly Asn Asn Leu Met His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro 35 40 45 Arg Leu Leu Ile Tyr Leu Ala Ser Tyr Leu Glu Ser Gly Val Pro Ala 50 55 60 Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser 65 70 75 80 Arg Val Glu Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Asn Asn 85 90 95 Glu Ser Pro Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 110 <![CDATA[<210> 133]]> <![CDATA[<211> 111]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 輕鏈可變區]]> <![CDATA[<222> (1)..(111)]]> <![CDATA[<400> 133]]> Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Glu Ser Tyr 20 25 30 Gly Asn Asn Leu Met His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro 35 40 45 Lys Leu Leu Ile Tyr Leu Ala Ser Tyr Leu Glu Ser Gly Val Pro Ser 50 55 60 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser 65 70 75 80 Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Asn Asn 85 90 95 Glu Ser Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 <![CDATA[<210> 134]]> <![CDATA[<211> 111]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 輕鏈可變區]]> <![CDATA[<222> (1)..(111)]]> <![CDATA[<400> 134]]> Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Ala Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Asp Ser Tyr 20 25 30 Gly Asn Asn Leu Met His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro 35 40 45 Lys Leu Leu Ile Tyr Leu Ala Ser Tyr Leu Glu Ser Gly Val Pro Ser 50 55 60 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser 65 70 75 80 Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Asn Asn 85 90 95 Glu Ser Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 <![CDATA[<210> 135]]> <![CDATA[<211> 111]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<221> 輕鏈可變區]]> <![CDATA[<222> (1)..(111)]]> <![CDATA[<400> 135]]> Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Pro Gly 1 5 10 15 Gln Arg Ala Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Asp Ser Tyr 20 25 30 Gly Asn Asn Leu Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro 35 40 45 Lys Leu Leu Ile Tyr Leu Ala Ser Tyr Leu Glu Ser Gly Val Pro Ala 50 55 60 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn 65 70 75 80 Pro Val Glu Ala Asn Asp Thr Ala Asn Tyr Tyr Cys Gln Gln Asn Asn 85 90 95 Glu Ser Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110
Claims (24)
- 一種抗GFRAL抗體或其抗原結合部分,所述抗GFRAL抗體或其抗原結合部分包括重鏈可變區和輕鏈可變區,其中所述重鏈可變區包括重鏈CDR1(HCDR1)、重鏈CDR2(HCDR2)和重鏈CDR3(HCDR3),輕鏈可變區包括輕鏈CDR1(LCDR1)、輕鏈CDR2(LCDR2)和輕鏈CDR3(LCDR3),其中: (1)重鏈CDR1的序列為SEQ ID NO.75所示序列或與SEQ ID NO.75所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.76或SEQ ID NO.116所示序列或與SEQ ID NO.76或SEQ ID NO.116所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.77或SEQ ID NO.99所示序列或與SEQ ID NO.77或SEQ ID NO.99所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR1的序列為SEQ ID NO.79或SEQ ID NO.126或SEQ ID NO.128所示序列或與SEQ ID NO.79或SEQ ID NO.126或SEQ ID NO.128所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.80所示序列或與SEQ ID NO.80所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.50或SEQ ID NO.123所示序列或與SEQ ID NO.50或SEQ ID NO.123所示序列具有至少80%、85%、90%或95%同一性;或 (2)重鏈CDR1的序列為SEQ ID NO.68所示序列或與SEQ ID NO.68所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.69或SEQ ID NO.91所示序列或與SEQ ID NO.69或SEQ ID NO.91所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.70所示序列或與SEQ ID NO.70所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR1的序列為SEQ ID NO.72或SEQ ID NO.95所示序列或與SEQ ID NO.72或SEQ ID NO.95所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.65所示序列或與SEQ ID NO.65所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.73所示序列或與SEQ ID NO.73所示序列具有至少80%、85%、90%或95%同一性;或 (3)重鏈CDR1的序列為SEQ ID NO.1所示序列或與SEQ ID NO.1所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.2所示序列或與SEQ ID NO.2所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.3所示序列或與SEQ ID NO.3所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR1的序列為SEQ ID NO.5所示序列或與SEQ ID NO.5所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.6所示序列或與SEQ ID NO.6所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.7所示序列或與SEQ ID NO.7所示序列具有至少80%、85%、90%或95%同一性;或 (4) 重鏈CDR1的序列為SEQ ID NO.9所示序列或與SEQ ID NO.9所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.10所示序列或與SEQ ID NO.10所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.11所示序列或與SEQ ID NO.11所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR1的序列為SEQ ID NO.13所示序列或與SEQ ID NO.13所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.14所示序列或與SEQ ID NO.14所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.15所示序列或與SEQ ID NO.15所示序列具有至少80%、85%、90%或95%同一性;或 (5)重鏈CDR1的序列為SEQ ID NO.17所示序列或與SEQ ID NO.17所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.18所示序列或與SEQ ID NO.18所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.19所示序列或與SEQ ID NO.19所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR1的序列為SEQ ID NO.21所示序列或與SEQ ID NO.21所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.6所示序列或與SEQ ID NO.6所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.22所示序列或與SEQ ID NO.22所示序列具有至少80%、85%、90%或95%同一性;或 (6)重鏈CDR1的序列為SEQ ID NO.24所示序列或與SEQ ID NO.24所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.25所示序列或與SEQ ID NO.25所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.26所示序列或與SEQ ID NO.26所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR1的序列為SEQ ID NO.28所示序列或與SEQ ID NO.28所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.6所示序列或與SEQ ID NO.6所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.29所示序列或與SEQ ID NO.29所示序列具有至少80%、85%、90%或95%同一性;或 (7)重鏈CDR1的序列為SEQ ID NO.31所示序列或與SEQ ID NO.31所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.32所示序列或與SEQ ID NO.32所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.33所示序列或與SEQ ID NO.33所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR1的序列為SEQ ID NO.35所示序列或與SEQ ID NO.35所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.36所示序列或與SEQ ID NO.36所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.37所示序列或與SEQ ID NO.37所示序列具有至少80%、85%、90%或95%同一性;或 (8)重鏈CDR1的序列為SEQ ID NO.39所示序列或與SEQ ID NO.39所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.40所示序列或與SEQ ID NO.40所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.41所示序列或與SEQ ID NO.41所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR1的序列為SEQ ID NO.43所示序列或與SEQ ID NO.43所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.6所示序列或與SEQ ID NO.6所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.22所示序列或與SEQ ID NO.22所示序列具有至少80%、85%、90%或95%同一性;或 (9)重鏈CDR1的序列為SEQ ID NO.45所示序列或與SEQ ID NO.45所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.46所示序列或與SEQ ID NO.46所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.47所示序列或與SEQ ID NO.47所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR1的序列為SEQ ID NO.49所示序列或與SEQ ID NO.49所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.6所示序列或與SEQ ID NO.6所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.50所示序列或與SEQ ID NO.50所示序列具有至少80%、85%、90%或95%同一性;或 (10)重鏈CDR1的序列為SEQ ID NO.31所示序列或與SEQ ID NO.31所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.53所示序列或與SEQ ID NO.53所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.54所示序列或與SEQ ID NO.54所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR1的序列為SEQ ID NO.56所示序列或與SEQ ID NO.56所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.57所示序列或與SEQ ID NO.57所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.58所示序列或與SEQ ID NO.58所示序列具有至少80%、85%、90%或95%同一性;或 (11)重鏈CDR1的序列為SEQ ID NO.60所示序列或與SEQ ID NO.60所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.61所示序列或與SEQ ID NO.61所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.62所示序列或與SEQ ID NO.62所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR1的序列為SEQ ID NO.64所示序列或與SEQ ID NO.64所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.65所示序列或與SEQ ID NO.65所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.66所示序列或與SEQ ID NO.66所示序列具有至少80%、85%、90%或95%同一性;或 (12) 重鏈CDR1的序列為SEQ ID NO.82所示序列或與SEQ ID NO.82所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.83所示序列或與SEQ ID NO.83所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.84所示序列或與SEQ ID NO.84所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR1的序列為SEQ ID NO.86所示序列或與SEQ ID NO.86示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.87所示序列或與SEQ ID NO.87所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.88所示序列或與SEQ ID NO.88所示序列具有至少80%、85%、90%或95%同一性; 其中重鏈CDR1-3和輕鏈CDR1-3的氨基酸序列根據IMGT定義。
- 如請求項1所述的抗GFRAL抗體或其抗原結合部分,其中重鏈可變區具有SEQ ID NO.4、12、20、27、34、42、48、52、55、63、71、78、85、90、92、93、98、100、101、102、103、104、105、106、107、108、109、110、111、112、113、114、115、117、118、119、120、121所示氨基酸序列或與SEQ ID NO.4、12、20、27、34、42、48、52、55、63、71、78、85、90、92、93、98、100、101、102、103、104、105、106、107、108、109、110、111、112、113、114、115、117、118、119、120、121所示氨基酸序列具有至少80%、至少90%、至少95%或至少99%同一性的氨基酸序列。
- 如請求項1或2所述的抗GFRAL抗體或其抗原結合部分,其中輕鏈可變區具有SEQ ID NO.8、16、23、30、38、44、51、59、67、74、81、89、94、96、97、122、124、125、127、129、130、131、132、133、134或135所示氨基酸序列或與SEQ ID NO.8、16、23、30、38、44、51、59、67、74、81、89、94、96、97、122、124、125、127、129、130、131、132、133、134或135所示氨基酸序列具有至少80%、至少90%、至少95%或至少99%同一性的氨基酸序列。
- 如請求項1-3任一項所述的抗GFRAL抗體或其抗原結合部分,其中: (1)重鏈可變區序列為SEQ ID NO.4所示序列,輕鏈可變區的序列為SEQ ID NO.8所示序列; (2)重鏈可變區序列為SEQ ID NO.12所示序列,輕鏈可變區的序列為SEQ ID NO.16所示序列; (3)重鏈可變區序列為SEQ ID NO.20所示序列,輕鏈可變區的序列為SEQ ID NO.23所示序列; (4)重鏈可變區序列為SEQ ID NO.27所示序列,輕鏈可變區的序列為SEQ ID NO.30所示序列; (5)重鏈可變區序列為SEQ ID NO.34所示序列,輕鏈可變區的序列為SEQ ID NO.38所示序列; (6)重鏈可變區序列為SEQ ID NO.42所示序列,輕鏈可變區的序列為SEQ ID NO.44所示序列; (7)重鏈可變區序列為SEQ ID NO.48所示序列,輕鏈可變區的序列為SEQ ID NO.51所示序列; (8)重鏈可變區序列為SEQ ID NO.52所示序列,輕鏈可變區的序列為SEQ ID NO.51所示序列; (9)重鏈可變區序列為SEQ ID NO.55所示序列,輕鏈可變區的序列為SEQ ID NO.59所示序列; (10)重鏈可變區序列為SEQ ID NO.63所示序列,輕鏈可變區的序列為SEQ ID NO.67所示序列; (11)重鏈可變區序列為SEQ ID NO.71所示序列,輕鏈可變區的序列為SEQ ID NO.74所示序列; (12)重鏈可變區序列為SEQ ID NO.78所示序列,輕鏈可變區的序列為SEQ ID NO.81所示序列; (13)重鏈可變區序列為SEQ ID NO.85所示序列,輕鏈可變區的序列為SEQ ID NO.89所示序列; (14)重鏈可變區序列為SEQ ID NO.98所示序列,輕鏈可變區的序列為SEQ ID NO.122所示序列; (15)重鏈可變區序列為SEQ ID NO.98所示序列,輕鏈可變區的序列為SEQ ID NO.124所示序列; (16)重鏈可變區序列為SEQ ID NO.100所示序列,輕鏈可變區的序列為SEQ ID NO.124所示序列; (17)重鏈可變區序列為SEQ ID NO.101所示序列,輕鏈可變區的序列為SEQ ID NO.124所示序列; (18)重鏈可變區序列為SEQ ID NO.102所示序列,輕鏈可變區的序列為SEQ ID NO.124所示序列; (19)重鏈可變區序列為SEQ ID NO.103所示序列,輕鏈可變區的序列為SEQ ID NO.124所示序列; (20)重鏈可變區序列為SEQ ID NO.104所示序列,輕鏈可變區的序列為SEQ ID NO.124所示序列; (21)重鏈可變區序列為SEQ ID NO.105所示序列,輕鏈可變區的序列為SEQ ID NO.124所示序列; (22)重鏈可變區序列為SEQ ID NO.112所示序列,輕鏈可變區的序列為SEQ ID NO.124所示序列; (23)重鏈可變區序列為SEQ ID NO.113所示序列,輕鏈可變區的序列為SEQ ID NO.124所示序列; (24)重鏈可變區序列為SEQ ID NO.105所示序列,輕鏈可變區的序列為SEQ ID NO.125所示序列; (25)重鏈可變區序列為SEQ ID NO.105所示序列,輕鏈可變區的序列為SEQ ID NO.127所示序列; (26)重鏈可變區序列為SEQ ID NO.100所示序列,輕鏈可變區的序列為SEQ ID NO.129所示序列; (27)重鏈可變區序列為SEQ ID NO.101所示序列,輕鏈可變區的序列為SEQ ID NO.129所示序列; (28)重鏈可變區序列為SEQ ID NO.105所示序列,輕鏈可變區的序列為SEQ ID NO.129所示序列; (29)重鏈可變區序列為SEQ ID NO.106所示序列,輕鏈可變區的序列為SEQ ID NO.129所示序列; (30)重鏈可變區序列為SEQ ID NO.107所示序列,輕鏈可變區的序列為SEQ ID NO.129所示序列; (31)重鏈可變區序列為SEQ ID NO.108所示序列,輕鏈可變區的序列為SEQ ID NO.129所示序列; (32)重鏈可變區序列為SEQ ID NO.109所示序列,輕鏈可變區的序列為SEQ ID NO.129所示序列; (33)重鏈可變區序列為SEQ ID NO.110所示序列,輕鏈可變區的序列為SEQ ID NO.129所示序列; (34)重鏈可變區序列為SEQ ID NO.111所示序列,輕鏈可變區的序列為SEQ ID NO.129所示序列; (35)重鏈可變區序列為SEQ ID NO.105所示序列,輕鏈可變區的序列為SEQ ID NO.130所示序列; (36)重鏈可變區序列為SEQ ID NO.105所示序列,輕鏈可變區的序列為SEQ ID NO.131所示序列; (37)重鏈可變區序列為SEQ ID NO.100所示序列,輕鏈可變區的序列為SEQ ID NO.132所示序列; (38)重鏈可變區序列為SEQ ID NO.114所示序列,輕鏈可變區的序列為SEQ ID NO.132所示序列; (39)重鏈可變區序列為SEQ ID NO.115所示序列,輕鏈可變區的序列為SEQ ID NO.133所示序列; (40)重鏈可變區序列為SEQ ID NO.117所示序列,輕鏈可變區的序列為SEQ ID NO.133所示序列; (41)重鏈可變區序列為SEQ ID NO.118所示序列,輕鏈可變區的序列為SEQ ID NO.133所示序列; (42)重鏈可變區序列為SEQ ID NO.119所示序列,輕鏈可變區的序列為SEQ ID NO.133所示序列; (43)重鏈可變區序列為SEQ ID NO.115所示序列,輕鏈可變區的序列為SEQ ID NO.134所示序列; (44)重鏈可變區序列為SEQ ID NO.117所示序列,輕鏈可變區的序列為SEQ ID NO.134所示序列; (45)重鏈可變區序列為SEQ ID NO.118所示序列,輕鏈可變區的序列為SEQ ID NO.134所示序列; (46)重鏈可變區序列為SEQ ID NO.119所示序列,輕鏈可變區的序列為SEQ ID NO.134所示序列; (47)重鏈可變區序列為SEQ ID NO.119所示序列,輕鏈可變區的序列為SEQ ID NO.135所示序列; (48)重鏈可變區序列為SEQ ID NO.120所示序列,輕鏈可變區的序列為SEQ ID NO.135所示序列; (49)重鏈可變區序列為SEQ ID NO.121所示序列,輕鏈可變區的序列為SEQ ID NO.135所示序列; (50)重鏈可變區序列為SEQ ID NO.90所示序列,輕鏈可變區的序列為SEQ ID NO.94所示序列; (51)重鏈可變區序列為SEQ ID NO.92所示序列,輕鏈可變區的序列為SEQ ID NO.94所示序列; (52)重鏈可變區序列為SEQ ID NO.90所示序列,輕鏈可變區的序列為SEQ ID NO.96所示序列; (53)重鏈可變區序列為SEQ ID NO.92所示序列,輕鏈可變區的序列為SEQ ID NO.96所示序列; (54)重鏈可變區序列為SEQ ID NO.90所示序列,輕鏈可變區的序列為SEQ ID NO.97所示序列;或 (55)重鏈可變區序列為SEQ ID NO.93所示序列,輕鏈可變區的序列為SEQ ID NO.97所示序列。
- 如請求項1-4任一項所述的抗GFRAL抗體或其抗原結合部分,其中重鏈CDR1的序列為SEQ ID NO.75所示序列,重鏈CDR2的序列為SEQ ID NO.76所示序列,重鏈CDR3的序列為SEQ ID NO.99所示序列,輕鏈CDR1的序列為SEQ ID NO.128所示序列,輕鏈CDR2的序列為SEQ ID NO.80所示序列,輕鏈CDR3的序列為SEQ ID NO.123所示序列;優選地,重鏈可變區序列為SEQ ID NO.105所示序列,輕鏈可變區的序列為SEQ ID NO.127所示序列;進一步優選地,所述抗GFRAL抗體或其抗原結合部分包含人IgG1、IgG2或IgG4重鏈恒定區和人κ輕鏈恒定區或λ輕鏈恒定區;最優選地,所述抗GFRAL抗體或其抗原結合部分包含人IgG4重鏈恒定區和人κ輕鏈恒定區。
- 抗GFRAL抗體或其抗原結合部分,所述抗GFRAL抗體或其抗原結合部分包括重鏈可變區和輕鏈可變區,其中 重鏈可變區具有SEQ ID NO.4、12、20、27、34、42、48、52、55、63、71、78、85、90、92、93、98、100、101、102、103、104、105、106、107、108、109、110、111、112、113、114、115、117、118、119、120、121所示氨基酸序列或與SEQ ID NO.4、12、20、27、34、42、48、52、55、63、71、78、85、90、92、93、98、100、101、102、103、104、105、106、107、108、109、110、111、112、113、114、115、117、118、119、120、121所示氨基酸序列具有至少80%、至少90%、至少95%或至少99%同一性的氨基酸序列;和/或 輕鏈可變區具有SEQ ID NO.8、16、23、30、38、44、51、59、67、74、81、89、94、96、97、122、124、125、127、129、130、131、132、133、134或135所示氨基酸序列或與SEQ ID NO.8、16、23、30、38、44、51、59、67、74、81、89、94、96、97、122、124、125、127、129、130、131、132、133、134或135所示氨基酸序列具有至少80%、至少90%、至少95%或至少99%同一性的氨基酸序列。
- 抗GFRAL抗體或其抗原結合部分,所述抗GFRAL抗體或其抗原結合部分包括重鏈可變區,其中所述重鏈可變區包括重鏈CDR1(HCDR1)、重鏈CDR2(HCDR2)和重鏈CDR3(HCDR3),其中: (1)重鏈CDR1的序列為SEQ ID NO.75所示序列或與SEQ ID NO.75所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.76或SEQ ID NO.116所示序列或與SEQ ID NO.76或SEQ ID NO.116所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.77或SEQ ID NO.99所示序列或與SEQ ID NO.77或SEQ ID NO.99所示序列具有至少80%、85%、90%或95%同一性;或 (2)重鏈CDR1的序列為SEQ ID NO.68所示序列或與SEQ ID NO.68所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.69或SEQ ID NO.91所示序列或與SEQ ID NO.69或SEQ ID NO.91所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.70所示序列或與SEQ ID NO.70所示序列具有至少80%、85%、90%或95%同一性;或 (3)重鏈CDR1的序列為SEQ ID NO.1所示序列或與SEQ ID NO.1所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.2所示序列或與SEQ ID NO.2所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.3所示序列或與SEQ ID NO.3所示序列具有至少80%、85%、90%或95%同一性;或 (4) 重鏈CDR1的序列為SEQ ID NO.9所示序列或與SEQ ID NO.9所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.10所示序列或與SEQ ID NO.10所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.11所示序列或與SEQ ID NO.11所示序列具有至少80%、85%、90%或95%同一性;或 (5)重鏈CDR1的序列為SEQ ID NO.17所示序列或與SEQ ID NO.17所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.18所示序列或與SEQ ID NO.18所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.19所示序列或與SEQ ID NO.19所示序列具有至少80%、85%、90%或95%同一性;或 (6)重鏈CDR1的序列為SEQ ID NO.24所示序列或與SEQ ID NO.24所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.25所示序列或與SEQ ID NO.25所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.26所示序列或與SEQ ID NO.26所示序列具有至少80%、85%、90%或95%同一性;或 (7)重鏈CDR1的序列為SEQ ID NO.31所示序列或與SEQ ID NO.31所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.32所示序列或與SEQ ID NO.32所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.33所示序列或與SEQ ID NO.33所示序列具有至少80%、85%、90%或95%同一性;或 (8)重鏈CDR1的序列為SEQ ID NO.39所示序列或與SEQ ID NO.39所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.40所示序列或與SEQ ID NO.40所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.41所示序列或與SEQ ID NO.41所示序列具有至少80%、85%、90%或95%同一性;或 (9)重鏈CDR1的序列為SEQ ID NO.45所示序列或與SEQ ID NO.45所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.46所示序列或與SEQ ID NO.46所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.47所示序列或與SEQ ID NO.47所示序列具有至少80%、85%、90%或95%同一性;或 (10)重鏈CDR1的序列為SEQ ID NO.31所示序列或與SEQ ID NO.31所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.53所示序列或與SEQ ID NO.53所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.54所示序列或與SEQ ID NO.54所示序列具有至少80%、85%、90%或95%同一性;或 (11)重鏈CDR1的序列為SEQ ID NO.60所示序列或與SEQ ID NO.60所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.61所示序列或與SEQ ID NO.61所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.62所示序列或與SEQ ID NO.62所示序列具有至少80%、85%、90%或95%同一性;或 (12) 重鏈CDR1的序列為SEQ ID NO.82所示序列或與SEQ ID NO.82所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR2的序列為SEQ ID NO.83所示序列或與SEQ ID NO.83所示序列具有至少80%、85%、90%或95%同一性,重鏈CDR3的序列為SEQ ID NO.84所示序列或與SEQ ID NO.84所示序列具有至少80%、85%、90%或95%同一性; 其中重鏈CDR1-3的氨基酸序列根據IMGT定義。
- 抗GFRAL抗體或其抗原結合部分,所述抗GFRAL抗體或其抗原結合部分包括輕鏈可變區,其中所述輕鏈可變區包括輕鏈CDR1(HCDR1)、輕鏈CDR2(HCDR2)和輕鏈CDR3(HCDR3),其中: (1)輕鏈CDR1的序列為SEQ ID NO.79或SEQ ID NO.126或SEQ ID NO.128所示序列或與SEQ ID NO.79或SEQ ID NO.126或SEQ ID NO.128所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.80所示序列或與SEQ ID NO.80所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.50或SEQ ID NO.123所示序列或與SEQ ID NO.50或SEQ ID NO.123所示序列具有至少80%、85%、90%或95%同一性;或 (2)輕鏈CDR1的序列為SEQ ID NO.72或SEQ ID NO.95所示序列或與SEQ ID NO.72或SEQ ID NO.95所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.65所示序列或與SEQ ID NO.65所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.73所示序列或與SEQ ID NO.73所示序列具有至少80%、85%、90%或95%同一性;或 (3)輕鏈CDR1的序列為SEQ ID NO.5所示序列或與SEQ ID NO.5所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.6所示序列或與SEQ ID NO.6所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.7所示序列或與SEQ ID NO.7所示序列具有至少80%、85%、90%或95%同一性;或 (4)輕鏈CDR1的序列為SEQ ID NO.13所示序列或與SEQ ID NO.13所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.14所示序列或與SEQ ID NO.14所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.15所示序列或與SEQ ID NO.15所示序列具有至少80%、85%、90%或95%同一性;或 (5)輕鏈CDR1的序列為SEQ ID NO.21所示序列或與SEQ ID NO.21所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.6所示序列或與SEQ ID NO.6所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.22所示序列或與SEQ ID NO.22所示序列具有至少80%、85%、90%或95%同一性;或 (6)輕鏈CDR1的序列為SEQ ID NO.28所示序列或與SEQ ID NO.28所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.6所示序列或與SEQ ID NO.6所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.29所示序列或與SEQ ID NO.29所示序列具有至少80%、85%、90%或95%同一性;或 (7)輕鏈CDR1的序列為SEQ ID NO.35所示序列或與SEQ ID NO.35所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.36所示序列或與SEQ ID NO.36所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.37所示序列或與SEQ ID NO.37所示序列具有至少80%、85%、90%或95%同一性;或 (8)輕鏈CDR1的序列為SEQ ID NO.43所示序列或與SEQ ID NO.43所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.6所示序列或與SEQ ID NO.6所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.22所示序列或與SEQ ID NO.22所示序列具有至少80%、85%、90%或95%同一性;或 (9)輕鏈CDR1的序列為SEQ ID NO.49所示序列或與SEQ ID NO.49所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.6所示序列或與SEQ ID NO.6所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.50所示序列或與SEQ ID NO.50所示序列具有至少80%、85%、90%或95%同一性;或 (10)輕鏈CDR1的序列為SEQ ID NO.56所示序列或與SEQ ID NO.56所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.57所示序列或與SEQ ID NO.57所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.58所示序列或與SEQ ID NO.58所示序列具有至少80%、85%、90%或95%同一性;或 (11)輕鏈CDR1的序列為SEQ ID NO.64所示序列或與SEQ ID NO.64所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.65所示序列或與SEQ ID NO.65所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.66所示序列或與SEQ ID NO.66所示序列具有至少80%、85%、90%或95%同一性;或 (12)輕鏈CDR1的序列為SEQ ID NO.86所示序列或與SEQ ID NO.86示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR2的序列為SEQ ID NO.87所示序列或與SEQ ID NO.87所示序列具有至少80%、85%、90%或95%同一性,輕鏈CDR3的序列為SEQ ID NO.88所示序列或與SEQ ID NO.88所示序列具有至少80%、85%、90%或95%同一性; 其中輕鏈CDR1-3的氨基酸序列根據IMGT定義。
- 如請求項1-8任一項的抗體或其抗原結合部分,其中: 所述抗GFRAL抗體為全抗體、單鏈抗體(scFv)、雙特異性抗體或多特異性抗體;和/或 所述抗GFRAL抗體的抗原結合部分為Fab、Fab’、Fv或F(ab’)2;和/或 所述抗GFRAL抗體為鼠源抗體、嵌合抗體、人源化抗體或全人源抗體;和/或 所述抗GFRAL抗體為單克隆抗體;和/或 所述抗GFRAL抗體為IgG1、IgG2或IgG4同種型的;和/或 所述抗GFRAL抗體包含κ亞型或者λ亞型的輕鏈恒定區;和/或 所述抗GFRAL抗體包含人IgG1重鏈恒定區和人κ輕鏈恒定區;和/或 所述抗GFRAL抗體包含人IgG4重鏈恒定區和人κ輕鏈恒定區。
- 如請求項1-9任一項的抗體或其抗原結合部分,其用於醫療療法。
- 分離的核酸分子,其編碼請求項1-10任一項所述的抗GFRAL抗體或其抗原結合部分。
- 載體,其含有請求項11所述的核酸分子。
- 宿主細胞,其含有請求項11所述的核酸分子或請求項12所述的載體。
- 抗體藥物偶聯物,其包含與治療劑偶聯的請求項1-10任一項所述的抗GFRAL抗體或其抗原結合部分。
- 如請求項14所述的抗體藥物偶聯物,其中所述治療劑為抗腫瘤藥物,例如,細胞毒性藥物、免疫增強劑或放射性同位素。
- 藥物組合物,其包含請求項1-10任一項所述的抗GFRAL抗體或其抗原結合部分或請求項14或15所述的抗體藥物偶聯物,以及藥學可接受的載體。
- 如請求項16所述的藥物組合物,其用於治療或預防GFRAL介導的或GFRAL-RET-GDF15信號通路介導的疾病或異常,例如,所述疾病或異常為惡病質綜合征(例如腫瘤導致的惡病質綜合征)、腫瘤(包括癌症)、心血管疾病、腎臟疾病、局部缺血性疾病、代謝紊亂、神經退行性疾病、厭食或厭食導致的體重減輕。
- 請求項1-10任一項所述的抗體或其抗原結合部分、請求項11所述的核酸分子、請求項12所述的載體、請求項13所述的宿主細胞或請求項14或15所述的抗體藥物偶聯物在製備用於治療或預防GFRAL介導的或GFRAL-RET-GDF15信號通路介導的疾病或異常的藥物中的用途,例如,所述疾病或異常為惡病質綜合征(例如腫瘤導致的惡病質綜合征)、腫瘤(包括癌症)、心血管疾病、腎臟疾病、局部缺血性疾病、代謝紊亂、神經退行性疾病、厭食或厭食導致的體重減輕。
- 如請求項17所述的藥物組合物或如請求項18所述的用途,其中所述腫瘤(包括癌症)為血液瘤或實體瘤。
- 如請求項19所述的藥物組合物或用途,其中所述血液瘤為淋巴瘤或白血病,例如骨髓瘤、B-細胞淋巴瘤、套細胞淋巴瘤、非霍奇金B-細胞淋巴瘤、非霍奇金淋巴瘤T-細胞淋巴瘤、皮膚淋巴瘤、間變性大細胞淋巴瘤、多發性骨髓瘤、惰性非霍奇金淋巴瘤、漿細胞瘤、慢性淋巴細胞白血病、小淋巴細胞淋巴瘤、濾泡性淋巴瘤;任選地,所述血液瘤為復發或難治性的。
- 如請求項19所述的藥物組合物或用途,其中所述實體瘤選自:呼吸系統腫瘤、消化道腫瘤、泌尿系統腫瘤、男性器官腫瘤、女性器官腫瘤、皮膚癌、內皮細胞腫瘤、腦部腫瘤、神經系統腫瘤、內分泌器官腫瘤。
- 如請求項19所述的藥物組合物或用途,其中所述實體瘤選自:膀胱癌、腦癌、乳腺癌、宮頸癌、胸部腫瘤、子宮內膜癌、食管鱗癌、胃癌、頭部腫瘤、胰腺癌、膽管癌、結直腸癌、眼癌、頭頸鱗癌、尿路上皮癌、腎癌、肝癌、淋巴結癌、肺癌、口腔癌、頸部腫瘤、卵巢癌、前列腺癌、睾丸癌、喉癌和子宮癌、黑色素瘤、唾液腺癌、纖維肉瘤、軟組織肉瘤和骨肉瘤;任選地,所述實體瘤為復發或難治性的。
- 綴合物,其包含請求項1-10任一項所述的抗GFRAL抗體或其抗原結合部分以及可檢測標記物。
- 包含請求項1-10任一項所述的抗GFRAL抗體或其抗原結合部分的融合蛋白。
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