TW202246347A - 抗tim-3抗體及其用途 - Google Patents
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Abstract
本發明涉及特異性結合T細胞免疫球蛋白結構域和粘液素結構域3 (Tim-3)的抗體。抗Tim-3抗體可用於治療、預防或診斷免疫疾病、癌性疾病、感染性疾病或可通過Tim-3介導的功能調節的其他病理病症。
Description
本申請公開的是特異性結合T細胞免疫球蛋白結構域和粘蛋白結構域3 (Tim-3)的抗體。
本申請要求於2016年8月26日提交的國際申請No. PCT/CN2016/096924的優先權,其通過引用全部併入本申請。
T細胞免疫球蛋白結構域和粘蛋白結構域3 (Tim-3,HAVCR2或CD366)是33 KD I型跨膜糖蛋白,其是包含T細胞免疫球蛋白和粘蛋白結構域的家族的成員,在促進慢性病毒感染和腫瘤逃避免疫監視的T細胞耗竭中起重要作用(
Monney et al., 2002 Nature 415:536-541; Sanchez-Fueyo A, et al., 2003 Nat Immunol. 4:1093-101; Sabatos CA, et al., 2003 Nat Immunol. 4:1102-10; Anderson et al., 2006 Curr Opin Immunol. 18:665-669)。編碼Tim-3的基因和cDNA在小鼠和人中被克隆和表徵(
Monney et al., 2002 Nature 415:536-541; McIntire et al., 2001 Nat. Immunol. 2:1109-1116)。成熟的人Tim-3含有280個胺基酸殘基(
NCBI 登錄號 : NP_116171.3)。其胞外域(extracellular domain)由胺基酸殘基1-181組成,跨膜結構域和胞質C-末端尾部包含殘基182-280。沒有已知的抑制性信號傳導基序,諸如在胞質結構域中發現的基於免疫受體酪胺酸的抑制性基序(ITIM)和酪胺酸轉換基序(switch motif)(ITSM)。
Tim-3最初在Th1細胞中被鑒定出來。隨後的研究顯示除了T細胞之外,Tim-3還在其他類型的免疫細胞,諸如NK細胞、巨噬細胞、DC和肥大細胞中表現(
Hastings et al., 2009 Eur J Immunol 39:2492-2501; Anderson et al., 2007 Science 318: 1141-1143; Phong BL, et al., 2015 J Exp Med. pii: jem. 20150388)。Tim-3很少在其他人體組織中表現。在T細胞中,Tim-3表現通過TCR/CD3活化而被正調控(
Hastings et al., 2009 Eur J Immunol 39:2492-2501)。此外,普通的γ鏈細胞因子(例如IL-2、IL-7、IL-15和IL-21)也以PI-3激酶依賴性方式增加Tim-3表現(
Mujib S, et al., 2012 J Immunol. 188:3745-56)。腫瘤微環境(TME)中的T細胞通常與其他“檢查點”抑制性免疫受體諸如PD-1、Lag-3和Tigit共表現Tim-3 (
Fourcade J, et al., 2010 J Exp Med. 207:2175-86; Gros A, et al., 2014 J Clin Invest. 124:2246-59)。
迄今為止,已經報道了幾種Tim-3配位體(Tim-3L),其包括半乳糖凝集素-9和磷脂醯絲胺酸(PtdSer),被認為是兩種主要的Tim-3配位體(
Anderson AC, 2012 Curr Opin Immunol. 24:213-6)。Tim-3L與Tim-3受體的結合誘導抑制T細胞活化的細胞內信號傳導,從而導致細胞增生、IL-2和IFN-γ分泌減少(
Dekruyff et al., 2010 J. Immunol. 184:1918-1930; Zhu et al., 2005 Nat. Immunol. 6:1245-1252)。T細胞中Tim-3信號傳導的詳細機制仍然剩下大部分未知。一些研究顯示,Tim-3可被募集到免疫突觸並在與TCR相互作用時隔離Src激酶Lck,由此抑制其信號傳導,特別是NFAT信號傳導路徑(
Tomkowicz B, et al., 2015 PLoS One 10:e0140694; Clayton KL, et al., 2014 J. Immunol. 192:782-91)。
在癌症和病毒感染中,Tim-3信號傳導的活化促進免疫細胞功能障礙,導致癌症生長物(outgrowth)或擴大的病毒感染。在腫瘤浸潤性淋巴細胞(TIL)、巨噬細胞和腫瘤細胞中Tim-3表現的上調已經在許多類型的癌症諸如肺癌(
Zhuang X, et al., Am J Clin Pathol 2012 137: 978-985)、肝癌(
Li H, et al., Hepatology 2012 56:1342-1351)、胃癌(
Jiang et al., PLoS One 2013 8:e81799)、腎癌(
Komohara et al., Cancer Immunol Res. 2015 3:999-1000)、乳腺癌(
Heon EK, et al., 2015 Biochem Biophys Res Commun. 464:360-6)、結腸癌(
Xu et al., Oncotarget 2015)、黑素細胞癌(
Gros A, et al., 2014 J Clin Invest. 2014 124:2246-2259)和子宮頸癌(
Cao et al., PLoS One 2013 8:e53834)中報道。此等癌症中Tim-3表現的增加與患者生存預後不良的結果相關。Tim-3信號的上調不但在對癌症的免疫耐受中起重要作用,而且對慢性病毒感染也起作用。在HIV和HCV感染期間,T細胞上Tim-3的表現顯著高於健康人,並且與病毒載量和疾病進展呈正相關(
Jones RB, et al., 2008 J Exp Med. 205:2763-79; Sakhdari A, et al., 2012 PLoS One 7:e40146; Golden-Mason L, et al., 2009 J Virol. 83:9122-30; 2012 Moorman JP, et al., J Immunol. 189:755-66)。此外,阻斷Tim-3受體單獨或與PD-1/PD-L1阻斷聯合可在體外和體內拯救功能性“耗盡”的T細胞(
Dietze KK, et al., 2013 PLoS Pathog 9:e1003798; Golden-Mason L, et al., 2009 J Virol. 83:9122-30)。因此,通過治療劑調節Tim-3信號傳導可能使免疫細胞例如T細胞、NK細胞和巨噬細胞(Mφ)免於耐受,誘導有效的免疫響應以根除腫瘤或慢性病毒感染。
已經報道了一些抗體可在與其在細胞表面上的標靶結合時被內化(
Hurwitz E, et al., 1995, Proc Natl Acad Sci USA 92:3353-7; Poul MA, et al., 2000, J Mol Biol. 301:1149-61; Fischer E, et al., 2012, Clin Cancer Res. 18:6208-18)。抗體誘導的受體胞吞作用導致細胞表面受體的下調和受體依賴性信號傳導的抑制(
Liu L, et al., 2014, Clin Cancer Res. 20:6059-70)。由於抗體內化會降低受體的表面表現,通常需要對受體的抗體進行持久的內化。
因此,需要對Tim-3受體具有高親和力和特異性的抗Tim-3抗體,並且優選進一步具有Tim-3受體的持久內化。
本申請公開的是以高親和力和特異性結合Tim-3的抗體分子。具體而言,本申請公開的抗Tim-3抗體提供了Tim-3受體持續或持久的內化。還提供的是編碼抗體分子的核酸分子、表現載體、主體細胞和用於製備抗體分子的方法。也提供了包含抗體分子的醫藥組合物。本申請公開的抗Tim-3抗體分子可單獨使用或與其他藥劑或治療形式組合使用,以治療、預防和/或診斷與由Tim-3介導的細胞內信號傳導的免疫細胞抑制相關的疾病,例如,免疫病症、癌症、感染性疾病、克羅恩病、膿毒病、全身炎症反應綜合征(SIRS)和腎小球腎炎。因此,本申請公開了使用抗Tim-3抗體分子治療上述各種病症或疾病的組合物和方法,並且還提供了抗Tim-3抗體分子在製備用於治療上述各種病症或疾病的藥物中的用途。
在某些態樣,本申請提供了能夠結合人Tim-3的抗Tim-3抗體,其包括至少1個、2個、3個、4個、5個或6個互補決定區(CDR),其包含SEQ ID NO 3-8或26-27的胺基酸序列或其包含一個或多個保守取代的變異體。
在一些實施例中,抗Tim-3抗體包括至少1個、2個或3個來自重鏈可變區(VH)的CDR,所述重鏈可變區包含SEQ ID NO 3-5或26的胺基酸序列或其包含一個或多個保守取代的變異體。在一些實施例中,抗Tim-3抗體包括至少1個、2個或3個來自輕鏈可變區(VL)的CDR,所述輕鏈可變區包含SEQ ID NO 6-8或27的胺基酸序列或其包含一個或多個保守取代的變異體。
在一些實施例中,抗Tim-3抗體包括至少1個、2個、3個、4個、5個或6個來自重鏈和輕鏈可變區的CDR,所述重鏈和輕鏈可變區包含SEQ ID NO 3-8或26-27的胺基酸序列或其包含一個或多個保守取代的變異體。
在一些實施例中,抗Tim-3抗體包括6個來自重鏈和輕鏈可變區的CDR,所述重鏈和輕鏈可變區包含SEQ ID NO 3-8或26-27的胺基酸序列或其包含一個或多個保守取代的變異體。
在一些實施例中,抗Tim-3抗體包含:
(a) 重鏈可變區(VH),其包含1個、2個或3個選自SEQ ID NO 3、4、5或26的CDR胺基酸序列或其包含一個或多個保守取代的變異體;和/或
(b) 輕鏈可變區(VL),其包含1個、2個或3個選自SEQ ID NO 6、7、8或27的CDR胺基酸序列或其包含一個或多個保守取代的變異體。
在一些實施例中,抗Tim-3抗體包含:
(a) 重鏈可變區(VH),其包含SEQ ID NO 3的VH-CDR1胺基酸序列或其包含一個或多個保守取代的變異體,SEQ ID NO 4的VH-CDR2胺基酸序列或其包含一個或多個保守取代的變異體和SEQ ID NO 5的VH-CDR3胺基酸序列或其包含一個或多個保守取代的變異體;和輕鏈可變區(VL),其包含SEQ ID NO 6的VL-CDR1胺基酸序列或其包含一個或多個保守取代的變異體,SEQ ID NO 7的VL-CDR2胺基酸序列或其包含一個或多個保守取代的變異體和SEQ ID NO 8的VL-CDR3胺基酸序列或其包含一個或多個保守取代的變異體;
(b) 重鏈可變區(VH),其包含SEQ ID NO 3的VH-CDR1胺基酸序列或其包含一個或多個保守取代的變異體,SEQ ID NO 26的VH-CDR2胺基酸序列或其包含一個或多個保守取代的變異體和SEQ ID NO 5的VH-CDR3胺基酸序列或其包含一個或多個保守取代的變異體;和輕鏈可變區(VL),其包含SEQ ID NO 6的VL-CDR1胺基酸序列或其包含一個或多個保守取代的變異體,SEQ ID NO 7的VL-CDR2胺基酸序列或其包含一個或多個保守取代的變異體和SEQ ID NO 8的VL-CDR3胺基酸序列或其包含一個或多個保守取代的變異體;
(c) 重鏈可變區(VH),其包含SEQ ID NO 3的VH-CDR1胺基酸序列或其包含一個或多個保守取代的變異體,SEQ ID NO 4的VH-CDR2胺基酸序列或其包含一個或多個保守取代的變異體和SEQ ID NO 5的VH-CDR3胺基酸序列或其包含一個或多個保守取代的變異體;和輕鏈可變區(VL),其包含SEQ ID NO 6的VL-CDR1胺基酸序列或其包含一個或多個保守取代的變異體,SEQ ID NO 7的VL-CDR2胺基酸序列或其包含一個或多個保守取代的變異體和SEQ ID NO 27的VL-CDR3胺基酸序列或其包含一個或多個保守取代的變異體;或
(d) 重鏈可變區(VH),其包含SEQ ID NO 3的VH-CDR1胺基酸序列或其包含一個或多個保守取代的變異體,SEQ ID NO 26的VH-CDR2胺基酸序列或其包含一個或多個保守取代的變異體和SEQ ID NO 5的VH-CDR3胺基酸序列或其包含一個或多個保守取代的變異體;和輕鏈可變區(VL),其包含SEQ ID NO 6的VL-CDR1胺基酸序列或其包含一個或多個保守取代的變異體,SEQ ID NO 7的VL-CDR2胺基酸序列或其包含一個或多個保守取代的變異體和SEQ ID NO 27的VL-CDR3胺基酸序列或其包含一個或多個保守取代的變異體。
在一些實施例中,抗Tim-3抗體包含:
(a) 重鏈可變區(VH),其包含SEQ ID NO 3的VH-CDR1胺基酸序列,SEQ ID NO 4的VH-CDR2胺基酸序列和SEQ ID NO 5的VH-CDR3胺基酸序列;和輕鏈可變區(VL),其包含SEQ ID NO 6的VL-CDR1胺基酸序列,SEQ ID NO 7的VL-CDR2胺基酸序列和SEQ ID NO 8的VL-CDR3胺基酸序列;或
(b) 重鏈可變區(VH),其包含SEQ ID NO 3的VH-CDR1胺基酸序列,SEQ ID NO 26的VH-CDR2胺基酸序列和SEQ ID NO 5的VH-CDR3胺基酸序列;和輕鏈可變區(VL),其包含SEQ ID NO 6的VL-CDR1胺基酸序列,SEQ ID NO 7的VL-CDR2胺基酸序列和SEQ ID NO 27的VL-CDR3胺基酸序列。
在一些實施例中,抗Tim-3抗體是人源化抗體分子。
在一些實施例中,抗Tim-3抗體是人源化單克隆抗體(mAb)分子。
在一些實施例中,抗體包含與SEQ ID NO 9、17、28或40的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域。在一些實施例中,抗體包含與SEQ ID NO 9、17或28的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域。在一些實施例中,抗體包含與SEQ ID NO 11、19、30或36的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域。
在一些實施例中,抗Tim-3抗體包含:
(a) 與SEQ ID NO 9的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 11的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域;
(b) 與SEQ ID NO 9的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 19的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域;
(c) 與SEQ ID NO 9的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 30的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域;
(d) 與SEQ ID NO 9的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 36的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域;
(e) 與SEQ ID NO 17的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 11的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域;
(f) 與SEQ ID NO 17的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 19的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域;
(g) 與SEQ ID NO 17的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 30的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域;
(h) 與SEQ ID NO 17的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 36的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域;
(i) 與SEQ ID NO 28的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 11的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域;
(j) 與SEQ ID NO 28的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 19的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域;
(k) 與SEQ ID NO 28的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 30的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域;
(l) 與SEQ ID NO 28的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 36的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域;
(m) 與SEQ ID NO 40的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 11的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域;
(n) 與SEQ ID NO 40的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 19的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域;
(o) 與SEQ ID NO 40的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 30的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域;或
(p) 與SEQ ID NO 40的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 36的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域。
在一些實施例中,抗Tim-3抗體包含:
(a) 與SEQ ID NO 9的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 11的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域;
(b) 與SEQ ID NO 9的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 19的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域;
(c) 與SEQ ID NO 9的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 30的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域;
(d) 與SEQ ID NO 9的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 36的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域;
(e) 與SEQ ID NO 17的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 11的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域;
(f) 與SEQ ID NO 17的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 19的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域;
(g) 與SEQ ID NO 17的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 30的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域;
(h) 與SEQ ID NO 17的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 36的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域;
(i) 與SEQ ID NO 28的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 11的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域;
(j) 與SEQ ID NO 28的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 19的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域;
(k) 與SEQ ID NO 28的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 30的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域;或
(l) 與SEQ ID NO 28的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 36的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域。
在一些實施例中,抗Tim-3抗體包含:
(a) 包含SEQ ID NO 9的胺基酸序列的重鏈可變結構域,和包含SEQ ID NO 11的胺基酸序列的輕鏈可變結構域;
(b) 包含SEQ ID NO 17的胺基酸序列的重鏈可變結構域,和包含SEQ ID NO 19的胺基酸序列的輕鏈可變結構域;
(c) 包含SEQ ID NO 28的胺基酸序列的重鏈可變結構域,和包含SEQ ID NO 30的胺基酸序列的輕鏈可變結構域;
(d) 包含SEQ ID NO 28的胺基酸序列的重鏈可變結構域,和包含SEQ ID NO 36的胺基酸序列的輕鏈可變結構域;
(e) 包含SEQ ID NO 40的胺基酸序列的重鏈可變結構域,和包含SEQ ID NO 36的胺基酸序列的輕鏈可變結構域。
在一些實施例中,抗Tim-3抗體包含:
(a) 包含SEQ ID NO 9的胺基酸序列的重鏈可變結構域,和包含SEQ ID NO 11的胺基酸序列的輕鏈可變結構域;
(b) 包含SEQ ID NO 17的胺基酸序列的重鏈可變結構域,和包含SEQ ID NO 19的胺基酸序列的輕鏈可變結構域;
(c) 包含SEQ ID NO 28的胺基酸序列的重鏈可變結構域,和包含SEQ ID NO 30的胺基酸序列的輕鏈可變結構域;或
(d) 包含SEQ ID NO 28的胺基酸序列的重鏈可變結構域,和包含SEQ ID NO 36的胺基酸序列的輕鏈可變結構域。
在一些實施例中,抗Tim-3抗體包含所述抗體包含與SEQ ID NO 13、22或32的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈。在一些實施例中,抗Tim-3抗體包含與SEQ ID NO 15、24、34或38的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈。
在一些實施例中,抗Tim-3抗體包含:
(a) 與SEQ ID NO 13的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈,和與SEQ ID NO 15的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈;
(b) 與SEQ ID NO 13的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈,和與SEQ ID NO 24的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈;
(c) 與SEQ ID NO 13的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈,和與SEQ ID NO 34的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈;
(d) 與SEQ ID NO 13的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈,和與SEQ ID NO 38的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈;
(e) 與SEQ ID NO 22的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈,和與SEQ ID NO 15的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈;
(f) 與SEQ ID NO 22的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈,和與SEQ ID NO 24的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈;
(g) 與SEQ ID NO 22的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈,和與SEQ ID NO 34的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈;
(h) 與SEQ ID NO 22的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈,和與SEQ ID NO 38的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈;
(i) 與SEQ ID NO 32的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈,和與SEQ ID NO 15的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈;
(j) 與SEQ ID NO 32的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈,和與SEQ ID NO 24的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈;
(k) 與SEQ ID NO 32的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈,和與SEQ ID NO 34的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈;或
(l) 與SEQ ID NO 32的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈,和與SEQ ID NO 38的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈。
在一些實施例中,抗Tim-3抗體包含:
(a) 包含SEQ ID NO 13的胺基酸序列的重鏈,和包含SEQ ID NO 15的胺基酸序列的輕鏈;
(b) 包含SEQ ID NO 22的胺基酸序列的重鏈,和包含SEQ ID NO 24的胺基酸序列的輕鏈;
(c) 包含SEQ ID NO 32的胺基酸序列的重鏈,和包含SEQ ID NO 34的胺基酸序列的輕鏈;或
(d) 包含SEQ ID NO 32的胺基酸序列的重鏈,和包含SEQ ID NO 38的胺基酸序列的輕鏈。
在一些實施例中,抗Tim-3抗體包含以下的一種或多種:
(a) 在SEQ ID NO 24的1位具有天門冬胺酸到麩胺酸突變的輕鏈;
(b) 在SEQ ID NO 24的4位具有白胺酸到甲硫胺酸突變的輕鏈;
(c) 在SEQ ID NO 24的62位具有纈胺酸到異白胺酸突變的輕鏈;
(d) 在SEQ ID NO 24的74位具有天門冬胺酸到麩胺酸突變的輕鏈;
(e) 在SEQ ID NO 24的96位具有甲硫胺酸到白胺酸突變的輕鏈;
(f) 在SEQ ID NO 22的59位具有苯丙胺酸到酪胺酸突變的重鏈;
(g) 在SEQ ID NO 22的60位具有脯胺酸到纈胺酸突變的重鏈;
(h) 在SEQ ID NO 22的77位具有絲胺酸到蘇胺酸突變的重鏈;或
(i) 在SEQ ID NO 22的78位具有半胱胺酸到白胺酸突變的重鏈。
在一些實施例中,抗Tim-3抗體是Fab、F(ab’)2、Fv或單鏈Fv (ScFv)。
在一些實施例中,抗Tim-3抗體包含亞類IgG1、IgG2、IgG3或IgG4或其變異體的重鏈恒定區,和κ或λ型的輕鏈恒定區或其變異體。
在一些實施例中,抗Tim-3抗體包含變異體人IgG1重鏈恒定區,其包含SEQ ID NO 21的胺基酸序列,和人κ輕鏈恒定區。
在一些實施例中,抗Tim-3抗體是分離的或重組體。
在某些態樣,本申請提供了組合物,例如,醫藥組合物,其包含本申請所述的抗體分子的至少一種,和醫藥上可接受之賦形劑。在一些實施例中,醫藥組合物包括抗Tim-3抗體和一種或多種其他藥劑的組合,例如,治療劑或其他抗體分子。在一些實施例中,抗Tim-3抗體與標記或治療劑綴合。
在某些態樣,本申請還提供了刺激個體的免疫響應的方法。所述方法包括向個體單獨施用或與一種或多種藥劑或操作組合施用本申請所述的抗體(例如,治療有效量的抗Tim-3抗體分子)。
在某些態樣,本申請還提供了治療(例如,一種或多種降低、抑制或延遲進展)個體的癌症或腫瘤的方法。所述方法包括,向個體單獨施用或與一種或多種藥劑或操作組合施用本申請所述的抗體(例如,治療有效量的抗Tim-3抗體分子)。在一些實施例中,抗Tim-3抗體與化學療法、靶向療法、溶瘤藥物、細胞毒劑、基於免疫的療法、細胞因子、外科手術、放射操作、協同刺激分子的活化劑、抑制性分子的抑制劑、疫苗或細胞免疫療法組合施用。在一些實施例中,抗Tim-3抗體與選自PD-1、PD-L1、PD-L2、CTLA-4、LAG-3、CEACAM-1、CEACAM-5、VISTA、BTLA、TIGIT、LAIR1、CD160、2B4或TGFR的免疫檢查點分子的抑制劑組合施用。在一些實施例中,抗Tim-3抗體與抗PD-1 mAb 317-4B6 (也稱為Hu317-4B6, 317-4B6/IgG4mt10,在美國專利No. 8,735,553中描述)組合施用。
在某些實施例中,癌症包括,但不限於,肺癌、肝癌、胃癌、宮頸癌、黑素瘤、腎癌、乳腺癌、結直腸癌、白血病、淋巴瘤、卵巢癌、頭頸癌或癌症的轉移病灶。
在另外的態樣,本申請提供了治療感染性疾病的方法,其包括向個體單獨施用或與一種或多種藥劑或操作組合施用治療有效量的本申請所述的抗Tim-3抗體。在一些實施例中,感染性疾病是選自HIV感染和HCV感染的慢性病毒感染性疾病。
在一些態樣,本申請還提供了抗Tim-3抗體分子在製備用於治療本申請所述的各種病症或疾病的藥物中的用途。
本申請所述的抗Tim-3抗體分子顯示一套特別的效應物功能和物理化學特性,其可抑制免疫細胞中Tim-3介導的細胞信號傳導,重新活化免疫細胞並增強免疫力。並且,具有修飾重鏈恒定區的全長人IgG1形式的mAb在效應物功能方面具有一套獨特的特徵。抗Tim-3 mAb也被人源化,與人抗體分子具有高度相似性。此外,抗Tim-3抗體可與抗PD-1抗體協同作用,在體外活化T細胞,減少腫瘤生長。因此,本申請公開的抗Tim-3抗體在治療癌症、病毒感染和理論上與免疫耐受或“耗盡”相關的其他人類疾病中可具有治療效用。
定義
示例性保守胺基酸取代取代
原始胺基酸殘基 | 1 個字母和 3 個字母的代碼 | 保守取代 |
丙胺酸 | A 或 Ala | Gly; Ser |
精胺酸 | R 或 Arg | Lys; His |
天門冬醯胺酸 | N 或 Asn | Gln; His |
天門冬胺酸 | D 或 Asp | Gln; Asn |
半胱胺酸 | C 或 Cys | Ser; Ala |
麩醯胺酸 | Q 或 Gln | Asn |
麩胺酸 | E 或 Glu | Asp; Gln |
甘胺酸 | G 或 Gly | Ala |
組胺酸 | H 或 His | Asn; Gln |
異白胺酸 | I 或 Ile | Leu; Val |
白胺酸 | L 或 Leu | Ile; val |
離胺酸 | K 或 Lys | Arg; His |
甲硫胺酸 | M 或 Met | Leu; Ile; Tyr |
苯丙胺酸 | F 或 Phe | Tyr; Met; Leu |
脯胺酸 | P 或 Pro | Ala |
絲胺酸 | S 或 Ser | Thr |
蘇胺酸 | T 或 Thr | Ser |
色胺酸 | W 或 Trp | Tyr; Phe |
酪胺酸 | Y 或 Tyr | Trp; Phe |
纈胺酸 | V 或 Val | Ile; Leu |
除非在本文件中另有具體定義,否則本申請所使用的所有技術和科學術語具有與本發明所屬領域普通技術人員通常理解的含義。
除非上下文另有明確規定,否則如本申請包括所附申請專利範圍所使用的單詞的單數形式,諸如“
一”、“
一個”和“
該”,包括它們相應的複數引用。
除非上下文另有明確規定,否則術語“
或”用來指術語“和/或”,並可與術語“和/或”互換使用。
除非上下文另有需要,否則在整個說明書以及隨後的申請專利範圍中,單詞“包含(
comprise)”和變異體諸如“包含(comprises)”和“包含(comprising)”將被理解為意味著包含所述的胺基酸序列、DNA序列、步驟或其組,但是不排除任何其他胺基酸序列、DNA序列、步驟。當在本申請中使用時,術語“包含(comprising)”可使用術語“含有”、“包括”或有時使用“具有”代替。
術語“
Tim-3”包括各種哺乳動物同種型,例如,人Tim-3、人Tim-3的物種同系物和包含Tim-3中至少一個抗原決定基的類似物。並且,Tim-3,例如人Tim-3的胺基酸序列和編碼該序列的核苷酸序列是本領域中已知的。
本申請中的術語“施用(
administration)”、“給藥(administering)”、“處理(treating)”和“治療(treatment)”,當用於動物、人、實驗個體、細胞、組織、器官或生物體液時,指外源藥劑、治療劑、診斷劑或組合物與動物、人、個體、細胞、組織、器官或生物體液接觸。細胞的處理包括使試劑與細胞接觸,以及使試劑與體液接觸,其中體液與細胞接觸。術語“施用(
administration)”和“治療(
treatment)”也指通過試劑、診斷、結合化合物或另一種細胞進行例如細胞的體外和活體外治療。本申請中的術語“個體”包括任何有機體,優選動物,更優選哺乳動物(例如,大鼠、小鼠、犬、貓、兔),並且最優選人。
抗體或抗體分子
本申請公開的是以高親和力和特異性結合Tim-3的抗體分子。
在一些實施例中,抗Tim-3抗體包括至少1個、2個、3個、4個、5個或6個互補決定區(CDR),其包含SEQ ID NO 3-8或26-27的胺基酸序列或其包含一個或多個保守取代的變異體。
在一些實施例中,抗Tim-3抗體包括至少1個、2個或3個來自重鏈可變區(VH)的CDR,所述重鏈可變區包含SEQ ID NO 3-5或26的胺基酸序列或其包含一個或多個保守取代的變異體。在一些實施例中,抗Tim-3抗體包括至少1個、2個或3個來自輕鏈可變區(VL)的CDR,所述輕鏈可變區包含SEQ ID NO 6-8或27的胺基酸序列或其包含一個或多個保守取代的變異體。
在一些實施例中,抗Tim-3抗體包括至少1個、2個、3個、4個、5個或6個來自重鏈和輕鏈可變區的CDR,所述重鏈和輕鏈可變區包含SEQ ID NO 3-8或26-27的胺基酸序列或其包含一個或多個保守取代的變異體。
在一些實施例中,抗Tim-3抗體包括6個來自重鏈和輕鏈可變區的CDR,所述重鏈和輕鏈可變區包含SEQ ID NO 3-8或26-27的胺基酸序列或其包含一個或多個保守取代的變異體。
在一些實施例中,抗Tim-3抗體包含:
(a) 重鏈可變區(VH),其包含1個、2個或3個選自SEQ ID NO 3、4、5或26的CDR胺基酸序列或其包含一個或多個保守取代的變異體;和/或
(b) 輕鏈可變區(VL),其包含1個、2個或3個選自SEQ ID NO 6、7、8或27的CDR胺基酸序列或其包含一個或多個保守取代的變異體。
在一些實施例中,抗Tim-3抗體包含:
(a) 重鏈可變區(VH),其包含SEQ ID NO 3的VH-CDR1胺基酸序列或其包含一個或多個保守取代的變異體,SEQ ID NO 4的VH-CDR2胺基酸序列或其包含一個或多個保守取代的變異體和SEQ ID NO 5的VH-CDR3胺基酸序列或其包含一個或多個保守取代的變異體;和輕鏈可變區(VL),其包含SEQ ID NO 6的VL-CDR1胺基酸序列或其包含一個或多個保守取代的變異體,SEQ ID NO 7的VL-CDR2胺基酸序列或其包含一個或多個保守取代的變異體和SEQ ID NO 8的VL-CDR3胺基酸序列或其包含一個或多個保守取代的變異體;
(b) 重鏈可變區(VH),其包含SEQ ID NO 3的VH-CDR1胺基酸序列或其包含一個或多個保守取代的變異體,SEQ ID NO 26的VH-CDR2胺基酸序列或其包含一個或多個保守取代的變異體和SEQ ID NO 5的VH-CDR3胺基酸序列或其包含一個或多個保守取代的變異體;和輕鏈可變區(VL),其包含SEQ ID NO 6的VL-CDR1胺基酸序列或其包含一個或多個保守取代的變異體,SEQ ID NO 7的VL-CDR2胺基酸序列或其包含一個或多個保守取代的變異體和SEQ ID NO 8的VL-CDR3胺基酸序列或其包含一個或多個保守取代的變異體;
(c) 重鏈可變區(VH),其包含SEQ ID NO 3的VH-CDR1胺基酸序列或其包含一個或多個保守取代的變異體,SEQ ID NO 4的VH-CDR2胺基酸序列或其包含一個或多個保守取代的變異體和SEQ ID NO 5的VH-CDR3胺基酸序列或其包含一個或多個保守取代的變異體;和輕鏈可變區(VL),其包含SEQ ID NO 6的VL-CDR1胺基酸序列或其包含一個或多個保守取代的變異體,SEQ ID NO 7的VL-CDR2胺基酸序列或其包含一個或多個保守取代的變異體和SEQ ID NO 27的VL-CDR3胺基酸序列或其包含一個或多個保守取代的變異體;或
(d) 重鏈可變區(VH),其包含SEQ ID NO 3的VH-CDR1胺基酸序列或其包含一個或多個保守取代的變異體,SEQ ID NO 26的VH-CDR2胺基酸序列或其包含一個或多個保守取代的變異體和SEQ ID NO 5的VH-CDR3胺基酸序列或其包含一個或多個保守取代的變異體;和輕鏈可變區(VL),其包含SEQ ID NO 6的VL-CDR1胺基酸序列或其包含一個或多個保守取代的變異體,SEQ ID NO 7的VL-CDR2胺基酸序列或其包含一個或多個保守取代的變異體和SEQ ID NO 27的VL-CDR3胺基酸序列或其包含一個或多個保守取代的變異體。
在一些實施例中,抗Tim-3抗體包含:
(a) 重鏈可變區(VH),其包含SEQ ID NO 3的VH-CDR1胺基酸序列,SEQ ID NO 4的VH-CDR2胺基酸序列和SEQ ID NO 5的VH-CDR3胺基酸序列;和輕鏈可變區(VL),其包含SEQ ID NO 6的VL-CDR1胺基酸序列,SEQ ID NO 7的VL-CDR2胺基酸序列和SEQ ID NO 8的VL-CDR3胺基酸序列;或
(b) 重鏈可變區(VH),其包含SEQ ID NO 3的VH-CDR1胺基酸序列,SEQ ID NO 26的VH-CDR2胺基酸序列和SEQ ID NO 5的VH-CDR3胺基酸序列;和輕鏈可變區(VL),其包含SEQ ID NO 6的VL-CDR1胺基酸序列,SEQ ID NO 7的VL-CDR2胺基酸序列和SEQ ID NO 27的VL-CDR3胺基酸序列。
在一些實施例中,抗Tim-3抗體是人源化抗體分子。
在一些實施例中,抗Tim-3抗體是人源化單克隆抗體(mAb)。
在一些實施例中,抗體包含與SEQ ID NO 9、17、28或40的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域。在一些實施例中,抗體包含與SEQ ID NO 9、17或28的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域。在一些實施例中,抗Tim-3抗體包含與SEQ ID NO 11、19、30或36的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域。
在一些實施例中,抗Tim-3抗體包含:
(a) 與SEQ ID NO 9的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 11的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域;
(b) 與SEQ ID NO 9的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 19的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域;
(c) 與SEQ ID NO 9的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 30的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域;
(d) 與SEQ ID NO 9的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 36的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域;
(e) 與SEQ ID NO 17的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 11的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域;
(f) 與SEQ ID NO 17的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 19的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域;
(g) 與SEQ ID NO 17的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 30的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域;
(h) 與SEQ ID NO 17的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 36的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域;
(i) 與SEQ ID NO 28的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 11的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域;
(j) 與SEQ ID NO 28的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 19的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域;
(k) 與SEQ ID NO 28的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 30的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域;
(m) 與SEQ ID NO 28的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 36的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域;與SEQ ID NO 40的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 11的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域;
(n) 與SEQ ID NO 40的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 19的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域;
(o) 與SEQ ID NO 40的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 30的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域;或
(q) 與SEQ ID NO 40的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 36的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域。
在一些實施例中,抗Tim-3抗體包含:
(a) 與SEQ ID NO 9的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 11的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域;
(b) 與SEQ ID NO 9的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 19的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域;
(c) 與SEQ ID NO 9的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 30的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域;
(d) 與SEQ ID NO 9的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 36的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域;
(e) 與SEQ ID NO 17的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 11的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域;
(f) 與SEQ ID NO 17的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 19的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域;
(g) 與SEQ ID NO 17的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 30的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域;
(h) 與SEQ ID NO 17的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 36的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域;
(i) 與SEQ ID NO 28的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 11的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域;
(j) 與SEQ ID NO 28的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 19的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域;
(k) 與SEQ ID NO 28的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 30的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域;或
(l) 與SEQ ID NO 28的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 36的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域。
在一些實施例中,抗Tim-3抗體包含:
(a) 包含SEQ ID NO 9的胺基酸序列的重鏈可變結構域,和包含SEQ ID NO 11的胺基酸序列的輕鏈可變結構域;
(b) 包含SEQ ID NO 17的胺基酸序列的重鏈可變結構域,和包含SEQ ID NO 19的胺基酸序列的輕鏈可變結構域;
(c) 包含SEQ ID NO 28的胺基酸序列的重鏈可變結構域,和包含SEQ ID NO 30的胺基酸序列的輕鏈可變結構域;
(d) 包含SEQ ID NO 28的胺基酸序列的重鏈可變結構域,和包含SEQ ID NO 36的胺基酸序列的輕鏈可變結構域;或
(e) 包含SEQ ID NO 40的胺基酸序列的重鏈可變結構域,和包含SEQ ID NO 36的胺基酸序列的輕鏈可變結構域。
在一些實施例中,抗Tim-3抗體包含:
(a) 包含SEQ ID NO 9的胺基酸序列的重鏈可變結構域,和包含SEQ ID NO 11的胺基酸序列的輕鏈可變結構域;
(b) 包含SEQ ID NO 17的胺基酸序列的重鏈可變結構域,和包含SEQ ID NO 19的胺基酸序列的輕鏈可變結構域;
(c) 包含SEQ ID NO 28的胺基酸序列的重鏈可變結構域,和包含SEQ ID NO 30的胺基酸序列的輕鏈可變結構域;或
(d) 包含SEQ ID NO 28的胺基酸序列的重鏈可變結構域,和包含SEQ ID NO 36的胺基酸序列的輕鏈可變結構域。
在一些實施例中,抗Tim-3抗體包含所述抗體包含與SEQ ID NO 13、22或32的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈。在一些實施例中,抗Tim-3抗體包含與SEQ ID NO 15、24、34或38的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈。
在一些實施例中,抗Tim-3抗體包含:
(a) 與SEQ ID NO 13的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈,和與SEQ ID NO 15的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈;
(b) 與SEQ ID NO 13的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈,和與SEQ ID NO 24的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈;
(c) 與SEQ ID NO 13的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈,和與SEQ ID NO 34的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈;
(d) 與SEQ ID NO 13的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈,和與SEQ ID NO 38的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈;
(e) 與SEQ ID NO 22的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈,和與SEQ ID NO 15的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈;
(f) 與SEQ ID NO 22的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈,和與SEQ ID NO 24的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈;
(g) 與SEQ ID NO 22的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈,和與SEQ ID NO 34的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈;
(h) 與SEQ ID NO 22的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈,和與SEQ ID NO 38的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈;
(i) 與SEQ ID NO 32的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈,和與SEQ ID NO 15的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈;
(j) 與SEQ ID NO 32的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈,和與SEQ ID NO 24的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈;
(k) 與SEQ ID NO 32的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈,和與SEQ ID NO 34的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈;或
(l) 與SEQ ID NO 32的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈,和與SEQ ID NO 38的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈。
在一些實施例中,抗Tim-3抗體包含:
(a) 包含SEQ ID NO 13的胺基酸序列的重鏈,和包含SEQ ID NO 15的胺基酸序列的輕鏈;
(b) 包含SEQ ID NO 22的胺基酸序列的重鏈,和包含SEQ ID NO 24的胺基酸序列的輕鏈;
(c) 包含SEQ ID NO 32的胺基酸序列的重鏈,和包含SEQ ID NO 34的胺基酸序列的輕鏈;或
(d) 包含SEQ ID NO 32的胺基酸序列的重鏈,和包含SEQ ID NO 38的胺基酸序列的輕鏈。
在一些實施例中,抗Tim-3抗體包含以下的一種或多種:
(a) 在SEQ ID NO 24的1位具有天門冬胺酸到麩胺酸突變的輕鏈;
(b) 在SEQ ID NO 24的4位具有白胺酸到甲硫胺酸突變的輕鏈;
(c) 在SEQ ID NO 24的62位具有纈胺酸到異白胺酸突變的輕鏈;
(d) 在SEQ ID NO 24的74位具有天門冬胺酸到麩胺酸突變的輕鏈;
(e) 在SEQ ID NO 24的96位具有甲硫胺酸到白胺酸突變的輕鏈;
(f) 在SEQ ID NO 22的59位具有苯丙胺酸到酪胺酸突變的重鏈;
(g) 在SEQ ID NO 22的60位具有脯胺酸到纈胺酸突變的重鏈;
(h) 在SEQ ID NO 22的77位具有絲胺酸到蘇胺酸突變的重鏈;或
(i) 在SEQ ID NO 22的78位具有半胱胺酸到白胺酸突變的重鏈。
在一些實施例中,抗Tim-3抗體是Fab、F(ab’)2、Fv或單鏈Fv (ScFv)。
在一些實施例中,抗Tim-3抗體包含亞類IgG1、IgG2、IgG3或IgG4的重鏈恒定區或其變異體,和κ或λ型的輕鏈恒定區或其變異體。
在一些實施例中,抗Tim-3抗體包含亞類IgG1、IgG2、IgG3或IgG4的變異體重鏈恒定區,其中變異體重鏈恒定區提供了減少或消除的效應物功能,諸如抗體依賴性細胞介導的細胞毒性(ADCC)或補體依賴性細胞毒性(CDC)。
在一些實施例中,抗Tim-3抗體包含人IgG1的重鏈恒定區或其變異體。在更優選的實施例中,抗Tim-3抗體包含人IgG1的變異體重鏈恒定區,其包含一種或多種選自下組的突變:E
233P、L
234A、L
235A、L
236Δ和P
329A。在一些實施例中,抗Tim-3抗體包含變異體人IgG1重鏈恒定區,其包含SEQ ID NO 21的胺基酸序列,和人κ輕鏈恒定區。
在一些實施例中,抗Tim-3抗體是分離的或重組體。
在一些實施例中,抗Tim-3抗體包含至少一個抗原結合位點,或至少一個可變區。在一些實施例中,抗Tim-3抗體包含來自本申請所述的抗體的抗原結合片段。
本申請中的術語“
抗體”以最廣泛的意義使用,並且具體地涵蓋抗體(包括全長單克隆抗體)和抗體片段,只要它們識別抗原,例如Tim-3、PD-1。抗體通常是單特異性的,但是也可描述為自特異性的(idiospecific)、異特異性的(heterospecific)或多特異性的(polyspecific)。抗體分子通過特異性結合位點結合抗原上的特異性抗原決定簇或抗原決定基。
本申請中的術語“
單克隆抗體”或“
mAb”或“
Mab”指基本上同源的抗體的群體,即除了可能少量存在的自然發生的突變之外,包含在胺基酸序列相同的群體中的抗體分子。與之相比,習知(多克隆)抗體製劑通常包括大量在它們的可變結構域,特別是它們的通常對不同抗原決定基具有特異性的互補決定區(CDR)中具有不同胺基酸序列的不同抗體。修飾語“單克隆”表示抗體獲自基本上同源的抗體群體的特點,並且不被解釋為需要通過任何特定方法產生抗體。單克隆抗體(mAb)可通過本領域技術人員已知的方法獲得。參見,例如
Kohler G et al., Nature 1975 256:495-497; 美國專利申請 No. 4,376,110; Ausubel FM et al.,CURRENT PROTOCOLS IN MOLECULAR BIOLOGY 1992
; Harlow E et al.,ANTIBODIES: A LABORATORY MANUAL, Cold spring Harbor Laboratory
1988; 和 Colligan JE et al.,CURRENT PROTOCOLS IN IMMUNOLOGY
1993。本申請公開的mAb可以是包括IgG、IgM、IgD、IgE、IgA的任何免疫球蛋白種類及其任何亞類。產生mAb的雜交瘤可在體外或在體內培養。高mAb效價可在體內生產中獲得,其中將來自單個雜交瘤的細胞腹膜內注射至小鼠,諸如原始-始發態(pristine-primed) Balb/c小鼠,產生含有高濃度所需mAb的腹水。同種型IgM或IgG的mAb可使用本領域技術人員已知的柱層析法從這樣的腹水或從培養上清液中純化。
通常,基本抗體結構單元包含四聚體。每個四聚體包含兩個相同多肽鏈對,每對具有一條“
輕鏈”(大約25 kDa)和一條“
重鏈”(大約50-70 kDa)。每條鏈的胺基末端部分包含主要負責抗原識別的具有大約100至110個或更多個胺基酸的可變區。重鏈的碳末端部分可定義為主要負責效應物功能的恒定區。通常,人輕鏈被分為κ和λ輕鏈。此外,人重鏈通常被分為α、δ、ε、γ或μ,並且分別將抗體的同種型定義為IgA、IgD、IgE、IgG和IgM。在輕鏈和重鏈中,可變區和恒定區通過大約12個或更多個胺基酸的“J”區連接,其中重鏈還包括大約10個或更多個胺基酸的“D”區。
每個輕鏈/重鏈(VL/VH)對的可變區形成抗體結合位點。因此,通常,完整的抗體具有兩個結合位點。除了在雙功能或雙特異性抗體中以外,兩個結合位點通常相同。
通常,重鏈和輕鏈兩者的可變結構域包含三個高變區,也稱為“
互補決定區 (CDR)”,其位於相對保守的框架區(FR)之間。CDR通常通過框架區對齊,從而能夠結合特定抗原決定基。通常,從N末端到C末端,重鏈和輕鏈可變結構域兩者均包含FR-1 (或FR1)、CDR-1 (或CDR1)、FR-2 (FR2)、CDR-2 (CDR2)、FR-3 (或FR3)、CDR-3 (CDR3)和FR-4 (或FR4)。通常,根據Sequences of Proteins of Immunological Interest,
Kabat, et al., National Institutes of Health, Bethesda, Md. ; 5<m> ed.; NIH Publ. No. 91-3242 (1991); Kabat (1978) Adv. Prot. Chem. 32: 1-75; Kabat, et al., (1977) J. Biol. Chem. 252:6609-6616; Chothia, et al, (1987) J Mol. Biol. 196:901-917 or Chothia, et al, (1989) Nature 342:878-883的定義,將胺基酸分配至每個結構域。
術語“
高變區”指負責抗原結合的抗體的胺基酸殘基。高變區包含來自“CDR” (即, 輕鏈可變結構域的VL-CDR1、VL-CDR2和VL-CDR3和重鏈可變結構域的VH-CDR1、VH-CDR2和VH-CDR3)的胺基酸殘基。參見,
Kabat et al. (1991) Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (通過序列定義抗體的CDR區); 也可參見
Chothia and Lesk (1987) J. Mol. Biol. 196: 901-917(通過結構定義抗體的CDR區)。術語“框架”或“FR”殘基指除了高變區殘基之外在本申請中被定義為CDR殘基的彼等可變結構域殘基。
除非另有說明,否則“
抗體片段”或“
抗原結合片段”指抗體的抗原結合片段,即保留與全長抗體結合的抗原特異性結合的能力的抗體片段,例如,保留一個或多個CDR區的片段。抗原結合片段的實例包括,但不限於,Fab、Fab'、F(ab')2和Fv片段;雙抗體;線性抗體;單鏈抗體分子,例如,單鏈Fv (ScFv);納米抗體和由抗體片段形成的多特異性抗體。
特異性結合特定靶蛋白的抗體被描述為特異性結合特定靶蛋白。這意味著與其他蛋白相比,抗體顯示出優先結合該標靶,但是這種特異性不需要絕對結合特異性。例如,在不產生不良結果諸如假陽性的情況下,如果其結合是樣品中靶蛋白存在的決定性因素,則抗體被認為對於其預期標靶是“特異性的”。用於本發明的抗體或其結合片段,將以比非靶蛋白的親和力大至少兩倍,優選至少10倍,更優選至少20倍,並且最優選至少100倍的親和力結合靶蛋白。據說,本申請中的抗體特異性結合包含給定的胺基酸序列,例如成熟人Tim-3分子的胺基酸序列的多肽,如果其結合包含此序列的多肽但是不結合缺乏此序列的蛋白質。
本申請中的術語“
人抗體”指僅包含人免疫球蛋白序列的抗體。人抗體如果在小鼠中、在小鼠細胞中或在源自小鼠細胞的雜交瘤中產生,則可含有鼠型碳水化合物鏈。類似地,“
小鼠抗體”或“大鼠抗體”分別指僅包含小鼠或大鼠免疫球蛋白序列的抗體。
術語“
人源化抗體”指含有來自非人(例如鼠類)抗體以及人抗體的序列的抗體形式。這種抗體含有極少源自非人免疫球蛋白的序列。通常,人源化抗體將包含至少一個,通常兩個可變結構域的基本上全部,其中全部或基本上全部的高變區環(hypervariable loop)與非人免疫球蛋白的高變區環對應,並且全部或基本上全部的FR區是人免疫球蛋白序列的FR區。人源化抗體還將可選地包含至少一部分免疫球蛋白恒定區(Fc),典型的是人免疫球蛋白的恒定區。必要時,將前綴“
hum”、“
hu”、“
Hu”或“
h”添加至抗體克隆名稱以區分人源化抗體與親本齧齒動物抗體。雖然為了增加親和性、增加人源化抗體的穩定性或由於其他原因可包括某些胺基酸取代,但是齧齒動物抗體的人源化形式通常將包含親本齧齒動物抗體的相同CDR序列。
本申請中的術語“
癌症”或“
腫瘤”指或描述哺乳動物的生理狀況,其典型特徵在於未受調節的細胞生長。癌症的實例包括但不限於,肺癌(其包括小細胞肺癌或非小細胞肺癌)、腎上腺癌、肝癌、胃癌、宮頸癌、黑素瘤、腎癌、乳腺癌、結直腸癌、白血病、膀胱癌、骨癌、腦癌、子宮內膜癌、頭頸癌、淋巴瘤、卵巢癌、皮膚癌、甲狀腺癌或癌症的轉移病灶。
除非另有說明,否則術語“
CDR”指免疫球蛋白可變區中的互補決定區,其使用Kabat編號系統定義。
醫藥組合物和套組
在一些態樣,本申請提供了組合物,例如,醫藥上可接受之組合物,其包含本申請所述的抗Tim-3抗體,與至少一種醫藥上可接受之賦形劑一起配製。本申請使用的術語“醫藥上可接受之賦形劑”包括生理學上相容的任何和所有溶劑、分散介質、等滲劑和吸收延遲劑等。賦形劑可適合於靜脈內、肌內、皮下、腸胃外、直腸、脊髓或表皮施用(例如通過注射或輸注)。
本申請中的組合物可以是各種形式。此等包括,例如,液體、半固體和固體劑型,諸如液體溶液(例如,可注射和輸注溶液)、分散體或混懸液、脂質體和栓劑。適合的形式取決於預期的施用模式和治療應用。典型適合的組合物是可注射或輸注溶液的形式。一個適合的施用模式是腸胃外(例如,靜脈內、皮下、腹膜內、肌內)。在一些實施例中,抗體通過靜脈輸注或注射施用。在某些實施例中,抗體通過肌內或皮下注射施用。
本申請使用的術語“
治療有效量”指當向個體施用用於治療疾病,或者至少一種疾病或病症的臨床症狀時,足以進行對疾病、病症或症狀的這種治療的抗體的量。“治療有效量”可隨著抗體,疾病、病症和/或疾病或病症的症狀,疾病、病症和/或疾病或病症的症狀的嚴重性,待治療的個體的年齡,和/或待治療的個體的體重而變化。任何給定情況中適當的量對本領域技術人員可以是顯而易見的或可通過習知實驗確定。在聯合治療的情況下,“治療有效量”指有效治療疾病、病症或狀況的組合對象的總量。
“
個體”是哺乳動物,例如靈長類動物,優選高等靈長類,例如人(例如,本申請所述的具有病症或處於具有病症的風險的患者)。
實例 實例 1 :抗 Tim-3 單克隆抗體的產生
基於傳統雜交瘤技術(de StGroth and Sheidegger, 1980, J Immunol Methods 35:1; Mechetner, 2007, Methods Mol Biol 378:1)產生許多鼠抗Tim-3單克隆抗體(mAb)。選擇酶聯免疫吸附測定(ELISA)和熒光活化細胞分選(FACS)測定中具有高結合活性的mAb進一步表徵。
免疫和結合測定的
Tim-3
重組蛋白
基於GenBank序列(登錄號:AF450242.1)合成編碼全長人Tim-3 (SEQ ID NO. 1)的cDNA。將由Tim-3 (SEQ ID NO. 2)的胺基酸(AA) 1-202組成的胞外域(ECD)的編碼區PCR擴增,並克隆至基於pcDNA3.1的表現載體(Invitrogen, Carlsbad, CA, USA),其C末端融合至小鼠IgG2a (GenBank登錄號: CAC20702)的Fc區或融合至人IgG1重鏈(UniProtKB/Swiss-Prot登錄號: P01857)的Fc區,分別產生兩種重組融合蛋白表現質粒Tim-3-mIgG2a和Tim-3-huIgG1。Tim-3融合蛋白的示意圖示於
圖 1。為了重組融合蛋白產生,Tim-3-mIgG2a和Tim-3-huIgG1質粒被瞬間轉染至基於HEK293的哺乳動物細胞表現系統(內部開發)並在裝備有旋轉振盪器的CO
2恒溫箱中培養5-7天。收集含有重組蛋白的上清液並通過離心澄清。使用Protein G Sepharose Fast Flow柱(Cat. No.: 17061805, GE Life Sciences)純化Tim-3-mIgG2a和Tim-3-huIgG1。Tim-3-mIgG2a和Tim-3-huIgG1蛋白質用磷酸鹽緩衝鹽水(PBS)透析並以小等分試樣儲存在-80
oC冰箱中。
穩定的表現細胞株
為了建立表現全長人Tim-3 (huTim-3)或猴Tim-3 (mkTim-3, 該基因可從ZYAGE獲得, Cat. No.: KD-702)的穩定細胞株,將
Tim-3基因克隆至逆轉錄病毒載體pFB-Neo (Cat. No.: 217561, Agilent, USA)。根據先前的方案(
Zhang T, et al., 2005, Blood 106:1544-51)產生雙嗜逆轉錄病毒載體(Dual-trophic retroviral vector)。將含有
huTim-3和
mkTim-3的載體分別轉導至HuT78和NK92MI細胞(ATCC, Manassas, VA, USA),以產生細胞株HuT78/huTim-3和NK92MI/mkTim-3。通過在含有10% FBS和G418的完全RPMI1640培養基中培養和FACS結合測定來選擇高表現細胞株。
免疫、雜交瘤融合和克隆
使用100 µl含有10 µg Tim-3-mIgG2a 和水溶性助劑(Cat. No.: KX0210041, KangBiQuan, Beijing, China)的抗原溶液腹膜內(i.p.)免疫8-12周齡Balb/c小鼠(HFK BIOSCIENCE CO., LTD, Beijing, China)。三周後重複該操作。第二次免疫後兩周,通過ELISA和FACS評價小鼠血清的Tim-3結合。血清篩選後10天,使用50 µg Tim-3-mIgG2a腹膜內增強具有最高抗Tim-3抗體血清效價的小鼠。增強後3天,分離脾臟淋巴細胞,並使用標準技術(
Colligan JE, et al., CURRENT PROTOCOLS IN IMMUNOLOGY, 1993)將其融合至鼠骨髓瘤細胞株SP2/0細胞(ATCC)。
通過
ELISA
和
FACS
評估抗體的
Tim-3
結合親和力
首先通過如Methods in Molecular Biology (2007) 378:33-52所述的ELISA篩選雜交瘤克隆的上清液並進行一些修改。簡言之,將Tim-3-huIgG1蛋白包被在96孔平板中。使用HRP連接的抗小鼠IgG抗體(Cat. No.: 7076S, Cell Signaling Technology, USA)和底物(Cat. No.: 00-4201-56, eBioscience, USA)進行顯影(development),並且在450 nm波長的吸收信號使用酶標儀(SpectraMax Paradigm, Molecular Devices, USA)量測。ELISA陽性克隆使用上述HuT78/huTim-3或NK92mi/mkTim-3細胞通過FACS進一步驗證。Tim-3表現細胞(10
5個細胞/孔)與ELISA陽性雜交瘤上清液一起溫育,接著與Alexa Fluro-647標記的山羊抗小鼠IgG抗體(Cat. No.: A0473, Beyotime Biotechnology, China)結合。使用流式細胞儀(Guava easyCyte 8HT, Merck-Millipore, USA)定量細胞熒光。
來自在ELISA和FACS篩選兩者中顯示陽性信號的雜交瘤的條件培養基經過功能測定,在基於人免疫細胞的測定(見下節)中識別具有良好功能活性的抗體。具有所需功能活性的抗體被進一步亞克隆和表徵。
雜交瘤的亞克隆和雜交瘤對無血清或低血清培養基的適應
主要通過ELISA、FACS和功能測定(在實例7和8中描述)篩選後,陽性雜交瘤克隆通過有限稀釋進行亞克隆。通過功能測定驗證的頂部抗體亞克隆適應於在具有3% FBS的CDM4MAb培養基(Cat. No.: SH30801.02, Hyclone, USA)中生長。
單克隆抗體的表現和純化
將雜交瘤細胞在CDM4MAb培養基(Cat. No.: SH30801.02, Hyclone)中培養,並且在37
oC在CO
2恒溫箱中溫育5至7天。通過離心收集條件培養基,並且在純化前經過0.22 μm膜過濾。按照製造商的指南,將含有鼠抗體的上清液施加並結合到蛋白A柱(Cat. No.: 17127901, GE Life Sciences)上。將蛋白A-親和純化抗體用PBS透析或使用HiLoad 16/60 Superdex200柱(Cat. No.: 17531801, GE Life Sciences)進一步純化以除去聚集體。蛋白質濃度通過量測在280nm的吸光度確定。將最終抗體製劑以等分試樣儲存在-80
oC冰箱中。
實例 2. Tim-3 抗體的克隆和序列分析
收穫鼠雜交瘤細胞以基於製造商的方案使用Ultrapure RNA套組(Cat. No.: 74104, QIAGEN, Germany)製備總RNA。第一股cDNA使用來自Invitrogen (Cat. No.: 18080-051)的cDNA合成套組合成,鼠mAb的
Vh和
Vk基因的PCR擴增使用PCR套組(Cat. No.: CW0686, CWBio, Beijing, China)進行。基於先前報道的序列(Brocks et al., 2001 Mol Med 7:461)合成用於重鏈可變區(
Vh)和κ輕鏈可變區(
Vk)的抗體cDNA克隆的寡聚引子。然後將PCR產物亞克隆至pEASY-Blunt克隆載體(Cat. No.: CB101-02, TransGen, China)並測序。從DNA測序結果中推斷
Vh和
Vk區的胺基酸序列。
鼠mAb通過比較序列同源性分析,並基於序列相似性分組(
圖 2)。互補決定區(CDR)基於Kabat (
Wu and Kabat, 1970, J. Exp. Med. 132:211-250)和IMGT (
Lefranc, 1999, Nucleic Acids Research 27:209-212)系統通過序列標注並通過基於互聯網的序列分析(http://www.imgt.org/IMGT_vquest/share/textes/index.html)來定義。代表性頂部克隆mu425 (Vh和Vk)的胺基酸序列列於下
表 1(SEQ ID NO. 9和11)。mu425的CDR序列列於下
表 2(SEQ ID NO 3-8)。
表
1. mu425 VH
和
VK
區的胺基酸序列
序列 | SEQ ID NO | |
mu425 VH | EVKLVESGGGLVKPGGSLKLSCAASGFTFSRYAMSWVRQIPEKRLEWVAAISSGGSLYFPDSVKGRFTISRDNARNICYLQMNSLRSDDTAMYYCARGREADGGYFDYWGQGTTLTVSS | 9 |
mu425 VK | DIVLTQSPASLAVSLGQRATISCRASESVEYYGTSLMQWYQQKPGQPPKLLIYAASNVESGVPARFSGSGSGTDFSLNIHPVEEDDIAMYFCQQSMKVPLTFGAGTKLELK | 11 |
表
2. mu425 VH
和
VK
區的
CDR
序列
(
胺基酸
)
實例
3.
通過
SPR
進行純化鼠抗
Tim-3
抗體的親和力測定
CDR1 | SEQ ID NO | CDR2 | SEQ ID NO | CDR3 | SEQ ID NO | |
mu425, VH | RYA MS | 3 | AISSGGSLYFPDSVKG | 4 | GREADGGYFDY | 5 |
mu425, VK | RASESVEYYGTSLMQ | 6 | AASNVES | 7 | QQSMKVPLT | 8 |
在ELISA和FACS中具有高結合活性,以及在基於細胞的測定(實例7和8所述)中具有強大功能活性的Tim-3抗體通過SPR測定使用BIAcore
TMT-200 (GE Life Sciences)來表徵它們的結合動力學。簡言之,將抗人IgG抗體固定在活化的CM5生物傳感器芯片(Cat. No.: BR100530, GE Life Sciences)上。使人帶Fc標簽的Tim-3 IgV結構域流過芯片表面並且被抗人IgG抗體捕獲。然後使連續稀釋的純化的鼠抗體流過芯片表面,並且分析表面等離子體共振信號的變化以通過使用一對一Langmuir結合模型(BIA Evaluation Software, GE Life Sciences)計算結合速率(
k on)和解離速率(
k off)。以
k off/
k on的比率計算平衡解離常數(
K D)。包括mu425、mu44、mu225和mu411的頂部mAb的結合親和力概況示於
表 3。
表
3.
通過
SPR
比較雜交瘤抗體結合親和力
實例
4.
鼠抗人
Tim-3 mAb mu425
的人源化
抗體 | k on (M -1s -1) | k off (s -1) | K D(nM) |
mu425 | 1.59 x 10 6 | 9.33 x 10 -5 | 0.058 |
mu44 | 1.24 x 10 6 | 1.86 x 10 -4 | 0.150 |
mu255 | 5.52 x 10 5 | 7.84 x 10 -4 | 1.42 |
mu411 | 1.44 x 10 6 | 3.36 x 10 -4 | 0.234 |
mAb
人源化和工程改造
為了mu425的人源化,通過爆破IMGT (http://www.imgt.org/IMGT_vquest/share/textes/ index.html)和NCBI (http://www.ncbi.nlm.nih.gov/igblast/)網站的人免疫球蛋白基因資料庫搜索與mu425可變區的cDNA序列具有高度同源性的人種系IgG基因的序列。選擇存在于高頻率的人抗體庫(human antibody repertoires)(Glanville, 2009, PNAS 106:20216-20221)並且與mu425高度同源的人IGVH和IGVK基因作為人源化的模板。在人源化之前,將mu425重鏈和輕鏈可變區分別融合至稱為人IgG1mf (SEQ ID NO. 21)的經修飾人IgG1恒定區和人κ恒定區。IgG1mf (SEQ ID NO: 21)是IgG1突變異體,其與野生型人IgG1比較含有突變E
233P、L
234A、L
235A、L
236Δ和P
329A (基於EU系統的胺基酸編碼)的組合。
人源化通過CDR移植(Methods in Molecular Biology, Vol 248: Antibody Engineering, Methods and Protocols, Humana Press)進行,並且人源化抗體(hu425s)以人IgG1形式工程改造。在人源化的初始循環中,從鼠到人框架區的胺基酸殘基的突變通過模擬3D結構來指導,並且用於保持CDR的典範結構(canonical structure)的結構重要性的鼠框架殘基被保留在人源化抗體425, hu425-1-1 (在SEQ ID NO. 22和24中設定重鏈和輕鏈的胺基酸序列)的第一版本中。具體地,將mu425 V
k的CDR移植到保留(在SEQ ID NO. 19中設定輕鏈可變結構域的胺基酸序列) 4個鼠框架殘基(D1、L4、V62和D74)的人種系可變基因IGVK3-15的框架中。將mu425 Vh的CDR移植到保留(在SEQ ID NO. 17中設定重鏈可變結構域的胺基酸序列) 1個鼠框架(C
78)殘基的人種系可變基因IGVH3-7的框架中。
使用內部開發的表現載體以人全長抗體形式構建Hu425-1-1,所述表現載體分別含有稱為IgG1mf (SEQ ID NO.21)的人IgG1變異體的恒定區和κ鏈,具有容易適應的亞克隆位點。hu425-1-1抗體的表現和製備通過將上述兩個構建體共轉染到293G細胞中並通過使用蛋白A柱(Cat. No.: 17543802, GE Life Sciences)的純化來實現。將純化的抗體在PBS中濃縮至0.5-5 mg/mL,並且以等分試樣儲存在-80
oC冰箱中。
基於hu425-1-1模板,吾等製備了許多將V
k框架區中保留的鼠殘基轉化成相應的人種系殘基的單突變,其中包括V
k的D1E,L4M,V62I和D74E。所得hu425-1-2a (D1E)、hu425-1-2b (L4M)、hu425-1-2c (V62I)和hu425-1-2d (D74E)均具有與hu425-1-1相似的結合和功能活性。為了進一步改善重鏈的人源化水準,吾等還將保留的殘基C78和來自鼠序列的H-CDR2 (Kabat的定義)的C末端部分改為相應的人種系殘基。3種人源化抗體的規格是hu425-2A-1 (
Vh的F59Y)、hu425-2B-1 (
Vh的P60V)和hu425-2C-1 (
Vh的C78L)。所有人源化突變使用在特定位置含有突變的引子和定點突變套組(Cat. No. FM111-02, TransGen, Beijing, China)製備。所需突變通過序列分析驗證。此等hu425變異體抗體在前述結合和功能測定中測試。與hu425-1-1相比,hu425-2B-1具有顯著降低的結合親和力和功能性(未顯示資料),而hu425人源化變異體的其餘版本具有與hu425-1-1相似的結合和功能活性。
Hu425抗體通過在CDR和框架區中引入突變來進一步工程改造,以改善人類治療用途的分子生化和生物物理性質。考慮因素包括胺基酸組成、熱穩定性(Tm)、表面疏水性和等電點(pIs),同時保持功能活性。
總之,兩種精心設計的人源化單克隆抗體的版本,hu425-2-2(在SEQ ID NO. 28和30中設定重鏈和輕鏈可變區的胺基酸序列)和hu425-2-3b (在SEQ ID NO. 28和36中設定重鏈和輕鏈可變區的胺基酸序列)源於上述突變過程,並且被詳細表徵。hu425-2-2和hu425-2-3b兩者均包含H-CDR2 (SEQ ID NO: 26)和L-CDR3 (SEQ ID NO: 27)的突變。重鏈/輕鏈可變區的胺基酸序列和hu425-2-2和hu425-2-3b的6個CDR列於下
表 4和
表 5。結果顯示hu425-2-3b和hu425-2-2兩者在結合親和力和功能活性,諸如抑制Tim-3介導的下游信號傳導方面非常相似。
表
4. hu425-2-2
和
hu425-2-3b
的
VH
和
VK
區的胺基酸序列
序列 | SEQ ID NO | |
hu425-2-2 VH | EVQLVESGGGLVQPGGSLRLSCAASGFTFSRYAMSWVRQAPGKGLEWVAAISSGGSLYYPDSVKGRFTISRDNAKNTLYLQMNSLRAEDTAVYYCARGREADGGYFDYWGQGTLVTVSS | 28 |
hu425-2-2 VK | EIVMTQSPATLSVSPGERATLSCRASESVEYYGTSLMQWYQQKPGQAPRLLIYAASNVESGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQSLKVPLTFGGGTKVEIK | 30 |
hu425-2-3b VH | EVQLVESGGGLVQPGGSLRLSCAASGFTFSRYAMSWVRQAPGKGLEWVAAISSGGSLYYPDSVKGRFTISRDNAKNTLYLQMNSLRAEDTAVYYCARGREADGGYFDYWGQGTLVTVSS | 28 |
hu425-2-3b VK | EIVLTQSPATLSVSPGERATLSCRASESVEYYGTSLMQWYQQKPGQAPRLLIYAASNVESGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQSLKVPLTFGGGTKVEIK | 36 |
表
5.
hu425-2-2
和
hu425-2-3b
的
VH
和
VK
區的
CDR
序列
(
胺基酸
)
CDR1 | SEQ ID NO | CDR2 | SEQ ID NO | CDR3 | SEQ ID NO | |
hu425-2-2 VH | RYAMS | 3 | AISSGGSLYYPDSVKG | 26 | GREADGGYFDY | 5 |
hu425-2-2 VK | RASESVEYYGTSLMQ | 6 | AASNVES | 7 | QQSLKVPLT | 27 |
hu425-2-3b VH | RYAMS | 3 | AISSGGSLYYPDSVKG | 26 | GREADGGYFDY | 5 |
hu425-2-3b VK | RASESVEYYGTSLMQ | 6 | AASNVES | 7 | QQSLKVPLT | 27 |
對於親和力測定,來自hu425 mAb系列的Fab使用Pierce Fab製備套組(Cat. No. 44985, ThermoFisher Scientific)製備,並且用於基於表面等離子共振(SPR)技術的親和力-測定。抗Tim-3 Fab抗體的SPR測定結合概況的結果匯總於
表 6。hu425-2-2和hu425-2-3b的Fab具有非常相似的結合概況,平均解離常數分別為0.419 nM和0.361 nM,其與hu425-1-1的平均解離常數接近。
表 6. 通過 SPR 比較 hu425 Fab 結合親和力
*ch425由融合至人IgG1mf/小鼠κ恒定區的mu425可變結構域組成(在SEQ ID NO. 13和15中設定重鏈和輕鏈的胺基酸序列)
** NA: 不可用。
抗 Tim-3 Fabs | 測試 1 | 測試 2 | 平均數 | ||||
k on (M -1s -1) | k off (s -1) | K D(nM) | k on (M -1s -1) | k off (s -1) | K D(nM) | K D(nM) | |
ch425* | 1.67 x 10 6 | 2.04 x 10 -4 | 0.122 | NA** | |||
hu425-1-1 | 6.79 x 10 5 | 1.08 x 10 -4 | 0.159 | 1.26 x 10 6 | 4.35 x 10 -4 | 0.346 | 0.253 |
hu425-2-2 | 1.71 x 10 6 | 7.40 x 10 -4 | 0.434 | 1.97 x 10 6 | 7.95 x 10 -4 | 0.404 | 0.419 |
hu425-2-3b | 1.60 x 10 6 | 5.70 x 10 -4 | 0.356 | 1.75 x 10 6 | 6.40 x 10 -4 | 0.366 | 0.361 |
還證實了上面顯示的所有人源化抗體在來自健康供體的原代人免疫細胞上的功能活性。
實例 5. 通過 SPR 進行抗 Tim-3 抗體的親和力比較
Hu425-2-3b和兩種已知的Tim-3抗體,Ab1 (包含SEQ ID NO: 40的重鏈可變區和SEQ ID NO: 41的輕鏈可變區)和Ab2 (包含SEQ ID NO: 42的重鏈可變區和SEQ ID NO: 43的輕鏈可變區),以帶有S228P突變的人IgG4形式產生,並且通過使用BIAcore
TMT-200 (GE Life Sciences)的SPR測定表徵它們的結合動力學。
簡言之,將抗人Fab抗體固定在活化的CM5生物傳感器芯片(Cat.: BR100530, GE Life Sciences)上。使抗Tim-3流過芯片表面並且被抗人Fab抗體捕獲。然後使連續稀釋(0.12 nM至30 nM)的Tim-3-his流過芯片表面,並且分析表面等離子共振信號的變化以通過使用一對一Langmuir結合模型(BIA Evaluation Software, GE Life Sciences)計算結合速率(
k on)和解離速率(
k off)。以
k off/
k on的比率計算平衡解離常數(
K D)。Hu425-2-3b、Ab1和Ab2展現出相當的結合親和力。抗體hu425-2-3b以與納摩爾KD劑量相關方式特異性結合Tim-3。
表
7.
通過
SPR
比較抗
Tim-3
的結合親和力
實例
6. mu425/hu425 CDR
對
Tim-3
結合的貢獻
抗 Tim-3 | Ka (1/Ms) | Kd (1/s) | KD (M) |
Hu425-2-3b | 5.28E+05 | 7.78E-04 | 1.47E-09 |
Ab1 | 4.44E+05 | 1.20E-04 | 2.71E-10 |
Ab2 | 6.27E+05 | 0.0122 | 1.94E-08 |
在人源化過程中,產生來自hu425-1-1的具有胺基酸突變的幾個變異體。如
圖 3所示,兩種這樣的突變變異體幾乎完全消除了與Tim-3的結合,但是在重鏈的CDR3中各自僅具有中性(化學相似的)胺基酸取代,D102E (mAb稱為hu425-2E-1)和G103A (稱為hu425-2F-1)。彼等發現支持了mu425人源化抗體中重鏈的CDR3對Tim-3結合功能具有顯著貢獻的觀點。
另一態樣,mu425/hu425輕鏈的CDR1和CDR2與小鼠種系基因IGKV3-1相同。還發現幾個鼠抗體在它們的輕鏈可變區中含有相同的鼠種系CDR1和CDR2序列,例如Ab2000 (美國專利No. 7,989,597)和mAb 1G5 (美國專利No.7,563,874)。吾等研究了此等抗體是否還可結合Tim-3。為此,Ab2000和1G5以人IgG1mf形式產生,並且通過ELISA對Tim-3-mIg結合進行評價。如
圖 4所示,與hu425-2-3b相比,Ab2000或1G5均不能產生任何Tim-3結合信號。因此,鼠種系基因IGKV3-1的CDR1和CDR2對Tim-3結合不充分。
為了進一步評價CDR對Tim-3結合的貢獻,通過抗體hu425-2-3b和抗體Ab1彼此交換重鏈和輕鏈產生兩種雜交抗體。hu425-2-3b和Ab1兩者是源於小鼠的抗Tim-3,並且它們與小鼠種系IGKV3-1中的彼等共用相同的L-CDR1和L-CDR2。共表現hu425-2-3b的重鏈和Ab1的輕鏈以產生雜交抗體425 HC/Ab1 LC,而雜交抗體Ab1 HC/425 LC通過共表現Ab1的重鏈和hu425-2-3b的輕鏈來製備。雜交抗體的結合活性通過生物膜干涉(BioLayer Interferometry) (ForteBio Octet)來分析。雜交抗體通過蛋白A吸頭捕獲,然後浸入Tim-3-his溶液用於BLI結合信號分析。觀察到Ab1 HC/425 LC保留Tim-3結合能力,而捕獲的425 HC/Ab1 LC未能產生顯著的結合信號。這表明hu425-2-3b的LC-CDR3是其與Tim3結合所需的,而其L-CDR1和L-CDR2對結合Tim3是不充分的,或可能不是結合Tim3所需的。
實例 7. 通過抗 Tim-3 抗體阻斷 Tim-3 介導的吞噬作用
已經顯示出Tim-3經其IgV結構域結合磷酯醯絲胺酸(PtdSer),並介導凋亡細胞的吞噬作用
(DeKruyff et al., J. Immunol, 2010, 184:1918-1930; Nakayama et al., Blood, 2009, 113: 3821-3830)。PtdSer是磷脂,其被限制在正常哺乳動物細胞中質膜的內葉,但是暴露在凋亡細胞的外表面上。PtdSer通過阻礙免疫響應參與腫瘤微環境的免疫抑制(
Fadok et al., J Clin Invest, 1998, 101:890-898; Frey et al., Semin Immunopathol., 2011, 33:497-516)。抗Tim-3抗體的體內施用導致凋亡細胞的清除減少,增加局部炎症並破壞免疫耐受,這表明PtdSer-Tim-3軸參與體內免疫抑制(
Chabtini et al., J. Immunol 190:88-96, 2013; Nakayama et al., Blood 113: 3821-30, 2009)。
為了確定抗Tim-3抗體是否能阻斷Tim-3介導的吞噬作用,基於細胞的測定使用傳感器和功能性讀數細胞株THP-1/Tim-3,即使用全長
Tim-3基因穩定轉染的THP-1 (ATCC, 人單核細胞細胞株)來建立。在該測定中,通過使用2%乙醇過夜處理而誘導HuT78 (ATCC)經受有限的凋亡,接著根據製造商的說明使用CFSE染料(Invitrogen, 1 μM)標記。然後,THP-1/Tim-3細胞與CFSE標記的凋亡HuT78細胞在抗Tim-3人源化抗體的存在下共同培養6小時。Tim-3介導的吞噬作用被確定為CFSE
+THP-1/Tim-3與總THP-1/Tim-3細胞(門控CD3-群體)的百分比。如
圖 5所示,hu425-2-3b劑量依賴性地抑制THP-1/Tim-3細胞對凋亡HuT78細胞的吞噬作用。
實例 8. 通過與 T 細胞接合物表現腫瘤細胞共培養的原代人 PBMC 中的抗 Tim-3 抗體活化 IFN-γ 分泌
據報道,Tim-3和PD-1兩者都是在活化的T細胞中表現的抑制性受體,其可能起到誘導T細胞耗竭的作用(
Anderson AC. et al., 2016, Immunity 44:989-1004)。來自癌症患者的Tim-3
+CD4和CD8 T細胞實際上比Tim-3
-T細胞分泌更少的Th1細胞因子IFN-γ(
Arai Y. et al., 2012, Yonago Acta medica 55:1-9; Xu B, et al., 2015, Oncotarget 6:20592-603)。
吾等已經在人PBMC中使用抗CD3 mAb OKT3活化的T細胞探索了Tim-3和抗Tim-3抗體的功能。外周血單核細胞(PBMC)使用Histopaque-1077 (Cat. No.: 10771, Sigma)用密度梯度離心方案從健康供體中分離。測定前的三天,PBMC使用40 ng/mL抗CD3 mAb OKT3 (Cat. No.: 16-0037, eBioscience, USA)刺激以擴增用作效應物細胞的CD3
+T細胞。基於美國專利No. 8,735,553所述的方法,稱為A549/OS8的靶細胞是使用T細胞接合物(engager)(OS8)穩定轉染的肺癌細胞株A549 (ATCC)。OS8在N末端結構域含有抗人CD3 mAb OKT3的scFv,其直接與TCR/CD3複合物作用並活化T細胞。效應物細胞PBMC與絲裂黴素C短暫處理的A549/OS8靶細胞共同培養以模擬在TCR/CD3複合物接合時活化的T細胞對腫瘤細胞的響應。測定在96孔平底板中存在或缺乏抗Tim-3抗體下進行。在共同培養15-18小時後,培養上清液通過使用Ready-Set-Go! ELISA套組(Cat. No.: 88-7316, eBiosciences)的ELISA來測定IFN-γ水準。如
圖 6所示,當A549/OS8靶細胞與效應物細胞共同培養時,抗Tim-3抗體(ch425和hu425-1-1)誘導效應物細胞中增加的IFN-γ分泌。
實例 9. 通過抗 Tim-3 抗體活化 CMV 特異性人 T 細胞
Tim-3抗體的功能活性使用天然來源的識別人CMV PP65肽(NLVPMVATV, 495-503, HLA-A2.1-限制性的) (
Boeckh M, Boeckh M and Geballe AP, 2011, J Clin Invest. 121:1673-80)的T細胞進一步評估。簡言之,來自健康供體的PBMC首先通過使用抗HLA-A2 mAb的FACS篩選。然後在含有10% FBS的完全RPMI中,使用PP65肽(>98%純度,由GL Biochem,Shanghai合成)模擬HLA-A2
+PBMC一周。
靶細胞株A549/A2.1通過HLA-A2.1的穩定轉染來建立。在絲裂黴素-c (100 μg/ml)處理和pp65肽(5 μg/ml)脈衝30分鐘後,在存在或缺乏抗Tim-3抗體或對照下,A549/A2.1細胞(10
4)與96孔板中的相等數量的pp65敏化PBMC共同培養過夜。培養上清液中的IFN-γ通過ELISA確定。所有條件一式三份進行。如
圖 7所示,hu425-2-3b促進pp65特異性T細胞將IFN-γ分泌到細胞培養上清液中。
實例 10. 抗 Tim-3 抗體增強 NK 細胞介導的細胞毒性
已知Tim-3以相對高的水準在自然殺傷(NK)細胞上組成性表現(
Ndhlovu LC, et al., 2012,
Blood 119:3734-43; da Silva IP, et al., 2014, Cancer Immunol Res. 2:410-22
)。在黑素瘤中,發現在NK細胞上的較高Tim-3表現與晚期腫瘤階段和預後差相關。此外,NK細胞功能似乎受Tim-3活性影響(
da Silva IP, et al., 2014, Cancer Immunol Res. 2:410-22)。
為了證實人源化抗Tim-3抗體是否能夠促進NK介導的細胞毒性,原代NK細胞根據製造商的說明使用來自Miltenyi Biotec (德國)的NK細胞分離套組從健康供體的PBMC中分離。在使用人IL-2 (1000 U/ml)刺激一天后,NK細胞與K562細胞在37
oC在抗Tim-3抗體、佈雷菲德菌素A (brefeldin A)和抗CD107a-APC (eBioscience)的存在下共同培養5小時。CD3
-CD56
+NK細胞上的CD107a表現通過流式細胞儀定量。結果顯示抗Tim-3抗體hu425-2-3b增加了通過平均熒光強度(MFI)和細胞數的百分比量測的CD107a表現(
圖 8)。
實例 11. 抗 Tim-3 抗體降低 Tim-3 受體的表面表現
為了解決包括hu425-2-3b的Tim-3內化的可能性,首先在完全RPMI1640培養基中,將來自健康供體的NK細胞與hu425-2-3b (10 μg/mL)在37°C或4°C溫育1小時。Tim-3受體的表面表現通過使用非競爭性Tim-3 Ab mu420 (內部產生的)染色,接著使用山羊抗小鼠IgG-APC (Biolegend)染色來確定。如
圖 9所示,與陰性對照經人IgG處理的細胞相比,hu425-2-3b在37°C引起Tim-3表面表現的顯著降低。降低可能是由於抗Tim-3抗體誘導的受體內化,因為它在短時間內表現出明顯的溫度依賴。結果明顯表現出hu4-25-2-3b誘導的Tim-3受體的下調,可能歸因於Tim-3的內化。通過誘導Tim-3內化,預期hu425-2-3b將降低Tim-3與其多種配位體(諸如半乳凝集素-9和PtdSer)的相互作用。
實例 12. 抗 Tim-3 抗體展現增加的內化率
為了進一步研究抗體的內化,在不同時間點(1、3、5和18小時)使用Tim-3表現NK細胞株(NK92MI/huTim-3)確定抗Tim-3抗體誘導的內化。簡言之,將抗Tim-3抗體(10μg/ml),其包括hu425-2-3b、Ab1和Ab2,在37°C或4°C與NK92MI/huTim-3 (5x10
4)一起溫育18小時。Tim-3受體的表面表現通過使用山羊抗人IgG-FITC染色來確定。內化的%被計算為在37°的Tim-3表面表現與在4°C的表現水準相比的降低(%)。如
圖 10所示,在更短溫育(1-5小時)過程中,hu425-2-3b誘導與Ab1和Ab2相當的Tim-3內化水準。在溫育18小時後,確實表現出比Ab1和Ab2兩者都顯著持久的內化,這表明hu425-2-3b對Tim-3內化的持久活性。
實例 13. 人源化抗 Tim-3 mAb 單獨和與 PD-1 mAb 組合刺激免疫細胞
已經報道了免疫抑制性受體PD-1和Tim-3在患有晚期腫瘤和慢性病毒傳染的患者中的“功能失調”腫瘤抗原特異性CD8
+T細胞中上調(
Fourcade J, et al., 2010, J Exp Med. 207:2175-86; Thommen DS, et al., 2015, Cancer Immunol Res. 3:1344-55; Jin HT, et al., 2010, Proc Natl Acad Sci USA. 107:14733-8)。同時阻斷PD-1和Tim-3受體兩者可擴大疫苗誘導的NY-ESO-1特異性CD8
+T細胞(
Fourcade J., et al., 2014, Cancer Res. 74:1045-55)。建立習知T細胞響應測定,混合淋巴細胞反應(MLR)以通過抗Tim-3和抗PD-1抗體表徵潛在的共刺激效應。簡言之,“刺激物(stimulator) PBMC”使用絲裂黴素c (100 μg/ml, Sigma)預處理,並且與不同供體的“響應物(responder) PBMC”以1:1的比例在具有10% AB血清(Sigma)和抗Tim-3和/或抗PD-1 mAb 317-4B6 (也稱為hu317-4B6、317-4B6/IgG4mt10, 述於美國專利申請No. 8,735,553)的完全RPMI1640培養基中共同培養。反應在96孔平底板中進行4天,每個條件一式三份資料點設置。細胞培養上清液中的IFN-γ分泌作為讀數進行分析。
結果顯示hu425-2-3b劑量依賴性地顯著增強MLR中的IFN-γ產生。hu425-2-3b與317-4B6 (50 ng/ml)的組合導致IFN-γ產生的增加高於單獨的hu425-2-3b或抗PD-1抗體,這表明抗Tim-3 mAb與抗PD-1 mAb的共同刺激作用(
圖 11)。
絲裂黴素C預處理的“刺激物PBMC”與“響應物PBMC”在96孔平底板中在抗Tim-3 mAb、hu425-2-3b或hu425-2-3b加抗PD-1 Ab hu317-4b6 (50 ng/ml)的存在下共同培養4天。上清液中的IFN-γ通過ELISA確定。所有條件一式三份進行,結果以平均值+SD顯示。
實例 14. Hu425-2-3b 沒有 ADCC 和 CDC 效應物功能
hu425-2-3b誘導ADCC和CDC的能力使用下述體外測定來確定。IgG1mf (SEQ ID NO: 21)是含有突變E
233P、L
234A、L
235A、L
236Δ和P
329A (基於EU系統的胺基酸編號)的組合的IgG1突變異體。設計此等突變以消除Fc與所有FcγR以及C1q的結合。
ADCC (
抗體依賴性細胞介導的細胞毒性
)
設置經典的ADCC測定以確定hu425-2-3b是否能誘導ADCC。測定效應物細胞株NK92MI/CD16V細胞通過共轉導含有
CD16
V158 (V158等位基因)和
FcRγcDNA的表現質粒從NK92MI細胞(ATCC)產生。Tim-3表現T細胞株HuT78/Tim-3用作靶細胞。效應物細胞(4x10
4)在hu425-2-3b或對照抗體、陽性對照抗MHC-I A,B,C (Biolegend)或陰性對照人IgG的存在下與相等數量的靶細胞共培養5小時。細胞毒性通過乳酸脫氫酶(LDH)釋放測定使用CytoTox 96非放射性細胞毒性測定套組(Promega, Madison, WI)來確定。特異性裂解通過以下等式確定。
結果證實hu425-2-3b與陰性對照具有相同ADCC基礎水準,而抗MHC-I A,B,C以劑量依賴性方式誘導ADCC (
圖 12A)。
CDC (
補體依賴性細胞毒性
)
使用預活化的人PBMC和來自健康供體的新鮮自體血清確定hu425-2-3b是否會引發CDC。通過Celltiter glo測定套組(Promega, Beijing, China)確定CDC的細胞裂解。簡言之,將來自健康供體的PBMC用PHA (10μg/ml, Sigma)預活化3天,然後在37℃在RPMI1640加自體血清(15%)和hu425-2-3b或對照抗體(0.04-30 μg/mL)中溫浴過夜。由CDC引起的細胞死亡是通過反應結束後的細胞裂解後從活細胞釋放的ATP的減少來測定的。抗MHC-I A,B,C用作陽性對照。使用96孔熒光計(PHERA Star FS, BMG LABTECH)進行熒光讀數,並且如下從相對熒光單位(RFU)讀數計算CDC活性:%CDC活性 = [(RFU測試-RFU背景) / (總細胞裂解的RFU - RFU背景)]×100。實驗結果表明,使用從兩個不同供體分離的PBMC,hu425-2-3b不具有可偵測的CDC。與之相比,陽性對照抗體抗MHC-I誘導顯著的CDC活性(
圖 12B)。
結果顯示,hu425-2-3b消除ADCC和CDC效應物功能,同時保持最佳物理化學性質。
實例 15. 抗 Tim-3 抗體與抗 PD-1 抗體組合抑制小鼠異種移植癌症模型中的腫瘤生長
通過異種移植癌症模型與抗PD-1抗體組合評價Tim-3抗體的潛在抗癌活性,其中免疫受損小鼠移植有人癌細胞和同種異體PBMC。簡言之,NOD/SCID小鼠在腫瘤接種前用環磷醯胺(150 mg/kg)預處理2天。從健康志願者的外周血中分離人PBMC,與基質膠中的A431表皮樣癌細胞(Cat. No. CRL-1555, ATCC)混合,並將其皮下注射到動物中。從第0天開始,將動物隨機分成4組,每組5-10只小鼠。小鼠每週一次(QW)經腹膜內(i.p.)注射媒劑(PBS)、5 mg/kg抗Tim-3 mAb嵌合體425 (ch425)、抗PD-1抗體317-4B6 (1 mg/kg)或組合療法(5 mg/kg ch425 + 1 mg/k 317-4B6)治療4周。每週兩次記錄小鼠的腫瘤大小,在研究期間每天監測小鼠的臨床毒性指征。使用公式:[D × (d
2)]/2計算腫瘤體積,其中D表示腫瘤的長直徑,d表示短直徑。所有動物研究均按照Beigene動物護理和使用程式進行。
如
圖 13所示,以5 mg/kg的劑量單獨用ch425治療對腫瘤生長幾乎沒有影響或沒有影響。317-4B6在1 mg/kg的劑量顯示腫瘤生長延遲趨勢,而無統計學顯著性(
P>0.05)。然而,ch425和317-4B6的組合治療顯示顯著的協同效應,相對於媒劑治療組抑制腫瘤生長超過60%。
結果表明,ch425與317-4B6的組合療法可激活人免疫細胞以抑制小鼠體內癌症模型中的腫瘤生長,這與實例11中所述的體外資料一致。
無
[ 圖 1]顯示Tim-3-mIgG2a (頂部)和Tim-3-huIgG1(底部)的示意圖,其中L是連接子,N是N末端,C是C末端。
[ 圖 2A-2B]顯示抗Tim-3抗體的系統發生樹(phylogenetic tree)。
圖 2A顯示抗Tim-3抗體重鏈可變(Vh)區的系統發生樹;
圖 2B顯示抗Tim-3抗體輕鏈可變(Vl)區的系統發生樹。使用DNASTAR`s Megalign軟體比對總共23個Tim-3 Vh和20個Vκ序列。在系統發生樹中展現出序列同源性。
[ 圖 3]顯示在ELISA中hu425-2E-1和hu425-2F-1的Tim-3結合親和力與hu425-1-1的Tim-3結合親和力的比較。
[ 圖 4]顯示在ELISA中mAbs 1G5和Ab2000與hu425-2-3b一起的Tim-3結合親和力。
[ 圖 5]顯示通過抗Tim-3抗體hu425-2-3b抑制Tim-3介導的吞噬作用。
[ 圖 6]顯示在原代人PBMC中通過包括ch425和hu425-1-1的抗Tim-3抗體活化IFN-γ分泌。
[ 圖 7]顯示通過抗Tim-3抗體hu425-2-3b活化CMV特異性人T細胞。
[ 圖 8A-8B]顯示抗Tim-3抗體hu425-2-3b促進NK細胞介導的細胞毒性。
[ 圖 9]顯示抗Tim-3抗體hu425-2-3b降低Tim-3受體的表面表現。
[ 圖 10]顯示抗Tim-3抗體(hu425-2-3b、Ab1和Ab2)的Tim-3受體的內化。
[ 圖 11]顯示抗Tim-3抗體hu425-2-3b單獨或與抗PD-1抗體hu317-4B6組合增強MLR中的IFN-γ分泌。
[ 圖 12A-12B]顯示抗Tim-3抗體hu425-2-3b未誘導ADCC (抗體依賴性細胞介導的細胞毒性)和CDC (補體依賴性細胞毒性)。
[ 圖 13]顯示抗Tim-3抗體ch425、抗PD-1抗體hu317-4B6及其組合在人A431同種異體的異種移植物模型(allogeneic xenograft model)中的抗腫瘤作用。
<![CDATA[<110> 英屬開曼群島商百濟神州有限公司(BeiGene, Ltd)]]> <![CDATA[<120> 抗Tim-3抗體及其用途]]> <![CDATA[<150> PCT/CN2016/096924]]> <![CDATA[<151> 2016-08-26]]> <![CDATA[<160> 43 ]]> <![CDATA[<170> PatentIn第3.5版]]> <![CDATA[<210> 1]]> <![CDATA[<211> 301]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人]]> <![CDATA[<400> 1]]> Met Phe Ser His Leu Pro Phe Asp Cys Val Leu Leu Leu Leu Leu Leu 1 5 10 15 Leu Leu Thr Arg Ser Ser Glu Val Glu Tyr Arg Ala Glu Val Gly Gln 20 25 30 Asn Ala Tyr Leu Pro Cys Phe Tyr Thr Pro Ala Ala Pro Gly Asn Leu 35 40 45 Val Pro Val Cys Trp Gly Lys Gly Ala Cys Pro Val Phe Glu Cys Gly 50 55 60 Asn Val Val Leu Arg Thr Asp Glu Arg Asp Val Asn Tyr Trp Thr Ser 65 70 75 80 Arg Tyr Trp Leu Asn Gly Asp Phe Arg Lys Gly Asp Val Ser Leu Thr 85 90 95 Ile Glu Asn Val Thr Leu Ala Asp Ser Gly Ile Tyr Cys Cys Arg Ile 100 105 110 Gln Ile Pro Gly Ile Met Asn Asp Glu Lys Phe Asn Leu Lys Leu Val 115 120 125 Ile Lys Pro Ala Lys Val Thr Pro Ala Pro Thr Leu Gln Arg Asp Phe 130 135 140 Thr Ala Ala Phe Pro Arg Met Leu Thr Thr Arg Gly His Gly Pro Ala 145 150 155 160 Glu Thr Gln Thr Leu Gly Ser Leu Pro Asp Ile Asn Leu Thr Gln Ile 165 170 175 Ser Thr Leu Ala Asn Glu Leu Arg Asp Ser Arg Leu Ala Asn Asp Leu 180 185 190 Arg Asp Ser Gly Ala Thr Ile Arg Ile Gly Ile Tyr Ile Gly Ala Gly 195 200 205 Ile Cys Ala Gly Leu Ala Leu Ala Leu Ile Phe Gly Ala Leu Ile Phe 210 215 220 Lys Trp Tyr Ser His Ser Lys Glu Lys Ile Gln Asn Leu Ser Leu Ile 225 230 235 240 Ser Leu Ala Asn Leu Pro Pro Ser Gly Leu Ala Asn Ala Val Ala Glu 245 250 255 Gly Ile Arg Ser Glu Glu Asn Ile Tyr Thr Ile Glu Glu Asn Val Tyr 260 265 270 Glu Val Glu Glu Pro Asn Glu Tyr Tyr Cys Tyr Val Ser Ser Arg Gln 275 280 285 Gln Pro Ser Gln Pro Leu Gly Cys Arg Phe Ala Met Pro 290 295 300 <![CDATA[<210> 2]]> <![CDATA[<211> 202]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人]]> <![CDATA[<400> 2]]> Met Phe Ser His Leu Pro Phe Asp Cys Val Leu Leu Leu Leu Leu Leu 1 5 10 15 Leu Leu Thr Arg Ser Ser Glu Val Glu Tyr Arg Ala Glu Val Gly Gln 20 25 30 Asn Ala Tyr Leu Pro Cys Phe Tyr Thr Pro Ala Ala Pro Gly Asn Leu 35 40 45 Val Pro Val Cys Trp Gly Lys Gly Ala Cys Pro Val Phe Glu Cys Gly 50 55 60 Asn Val Val Leu Arg Thr Asp Glu Arg Asp Val Asn Tyr Trp Thr Ser 65 70 75 80 Arg Tyr Trp Leu Asn Gly Asp Phe Arg Lys Gly Asp Val Ser Leu Thr 85 90 95 Ile Glu Asn Val Thr Leu Ala Asp Ser Gly Ile Tyr Cys Cys Arg Ile 100 105 110 Gln Ile Pro Gly Ile Met Asn Asp Glu Lys Phe Asn Leu Lys Leu Val 115 120 125 Ile Lys Pro Ala Lys Val Thr Pro Ala Pro Thr Leu Gln Arg Asp Phe 130 135 140 Thr Ala Ala Phe Pro Arg Met Leu Thr Thr Arg Gly His Gly Pro Ala 145 150 155 160 Glu Thr Gln Thr Leu Gly Ser Leu Pro Asp Ile Asn Leu Thr Gln Ile 165 170 175 Ser Thr Leu Ala Asn Glu Leu Arg Asp Ser Arg Leu Ala Asn Asp Leu 180 185 190 Arg Asp Ser Gly Ala Thr Ile Arg Ile Gly 195 200 <![CDATA[<210> 3]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 小鼠]]> <![CDATA[<400> 3]]> Arg Tyr Ala Met Ser 1 5 <![CDATA[<210> 4]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 小鼠]]> <![CDATA[<400> 4]]> Ala Ile Ser Ser Gly Gly Ser Leu Tyr Phe Pro Asp Ser Val Lys Gly 1 5 10 15 <![CDATA[<210> 5]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 小鼠]]> <![CDATA[<400> 5]]> Gly Arg Glu Ala Asp Gly Gly Tyr Phe Asp Tyr 1 5 10 <![CDATA[<210> 6]]> <![CDATA[<211> 15]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 小鼠]]> <![CDATA[<400> 6]]> Arg Ala Ser Glu Ser Val Glu Tyr Tyr Gly Thr Ser Leu Met Gln 1 5 10 15 <![CDATA[<210> 7]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 小鼠]]> <![CDATA[<400> 7]]> Ala Ala Ser Asn Val Glu Ser 1 5 <![CDATA[<210> 8]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 小鼠]]> <![CDATA[<400> 8]]> Gln Gln Ser Met Lys Val Pro Leu Thr 1 5 <![CDATA[<210> 9]]> <![CDATA[<211> 119]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 小鼠]]> <![CDATA[<400> 9]]> 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 Arg Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ile Pro Glu Lys Arg Leu Glu Trp Val 35 40 45 Ala Ala Ile Ser Ser Gly Gly Ser Leu Tyr Phe Pro Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Arg Asn Ile Cys Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ser Asp Asp Thr Ala Met Tyr Tyr Cys Ala 85 90 95 Arg Gly Arg Glu Ala Asp Gly Gly Tyr Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Thr Leu Thr Val Ser Ser 115 <![CDATA[<210> 10]]> <![CDATA[<211> 357]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 小鼠]]> <![CDATA[<400> 10]]> gaagtgaagc tggtggagtc tgggggaggc ttagtgaagc ctggagggtc cctgaaactc 60 tcctgtgcag cctctggatt cactttcagt aggtatgcca tgtcttgggt tcgccagatt 120 ccagagaaga ggctggagtg ggtcgcagcc attagtagtg gtggtagttt atactttcca 180 gacagtgtga agggccgatt caccatctcc agagataatg ccaggaacat ctgctacctg 240 caaatgaaca gtctgaggtc tgacgacacg gccatgtatt actgtgcaag aggccgggag 300 gccgacggag gctactttga ctactggggc caaggcacca ctctcacagt ctcctca 357 <![CDATA[<210> 11]]> <![CDATA[<211> 111]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 小鼠]]> <![CDATA[<400> 11]]> 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 Glu Tyr Tyr 20 25 30 Gly Thr Ser Leu Met Gln Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro 35 40 45 Lys Leu Leu Ile Tyr Ala Ala Ser Asn Val Glu 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 Val Glu Glu Asp Asp Ile Ala Met Tyr Phe Cys Gln Gln Ser Met 85 90 95 Lys Val Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys 100 105 110 <![CDATA[<210> 12]]> <![CDATA[<211> 333]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 小鼠]]> <![CDATA[<400> 12]]> gacattgtgc tcacccaatc tccagcttct ttggctgtgt ctctagggca gagagccacc 60 atctcctgca gagccagtga aagtgttgaa tattatggca caagtttaat gcagtggtac 120 caacagaaac caggacaacc acccaaactc ctcatctatg ctgcatccaa cgtagaatct 180 ggggtccctg ccaggtttag tggcagtggg tctgggacag acttcagcct caacatccat 240 cctgtggagg aggatgatat tgcaatgtat ttctgtcagc aaagtatgaa ggttcctctc 300 acgttcggtg ctgggaccaa gctggagctg aaa 333 <![CDATA[<210> 13]]> <![CDATA[<211> 448]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> ch425重鏈pro]]> <![CDATA[<400> 13]]> 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 Arg Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ile Pro Glu Lys Arg Leu Glu Trp Val 35 40 45 Ala Ala Ile Ser Ser Gly Gly Ser Leu Tyr Phe Pro Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Arg Asn Ile Cys Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ser Asp Asp Thr Ala Met Tyr Tyr Cys Ala 85 90 95 Arg Gly Arg Glu Ala Asp Gly Gly Tyr Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro Ala Ala Gly Pro Ser 225 230 235 240 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 245 250 255 Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 260 265 270 Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 275 280 285 Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 290 295 300 Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 305 310 315 320 Lys Cys Lys Val Ser Asn Lys Ala Leu Ala Ala Pro Ile Glu Lys Thr 325 330 335 Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 340 345 350 Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys 355 360 365 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 370 375 380 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 385 390 395 400 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 405 410 415 Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 420 425 430 Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <![CDATA[<210> 14]]> <![CDATA[<211> 1347]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> ch425重鏈DNA]]> <![CDATA[<400> 14]]> gaagtgaagc tggtggagtc tgggggaggc ttagtgaagc ctggagggtc cctgaaactc 60 tcctgtgcag cctctggatt cactttcagt aggtatgcca tgtcttgggt tcgccagatt 120 ccagagaaga ggctggagtg ggtcgcagcc attagtagtg gtggtagttt atactttcca 180 gacagtgtga agggccgatt caccatctcc agagataatg ccaggaacat ctgctacctg 240 caaatgaaca gtctgaggtc tgacgacacg gccatgtatt actgtgcaag aggccgggag 300 gccgacggag gctactttga ctactggggc caaggcacca ctctcacagt ctcctcagcc 360 tccaccaagg gcccatcggt cttccccctg gcaccctcct ccaagagtac ttctgggggc 420 acagcggccc tgggctgcct ggtcaaggac tacttccccg aaccggtgac ggtgtcgtgg 480 aactcaggcg ccctgaccag cggcgtgcac accttcccgg ctgtcctaca gtcctcagga 540 ctctactccc tcagcagcgt ggtgaccgtg ccctccagca gcttgggcac ccagacctac 600 atctgcaacg tgaatcacaa gcccagcaac accaaggtgg acaagaaagt tgagcccaaa 660 tcttgtgaca aaactcacac atgcccaccg tgcccagcac ctcctgctgc cggaccgtca 720 gtcttcctct tccccccaaa acccaaggac accctcatga tctcccggac ccctgaggtc 780 acatgcgtgg tggtggacgt gagccacgaa gaccctgagg tcaagttcaa ctggtacgtg 840 gacggcgtgg aggtgcataa tgccaagaca aagccgcggg aggagcagta caacagcacg 900 taccgtgtgg tcagcgtcct caccgtcctg caccaggact ggctgaatgg caaggagtac 960 aagtgcaagg tctccaacaa agccctcgcc gcccccatcg agaaaaccat ctccaaagcc 1020 aaagggcagc cccgagaacc acaggtgtac accctgcccc catcccggga tgagctgacc 1080 aagaaccagg tcagcctgac ctgcctggtc aaaggcttct atcccagcga catcgccgtg 1140 gagtgggaga gcaatgggca gccggagaac aactacaaga ccacgcctcc cgtgctggac 1200 tccgacggct ccttcttcct ctacagcaag ctcaccgtgg acaagagcag gtggcagcag 1260 gggaacgtct tctcatgctc cgtgatgcat gaggctctgc acaaccacta cacgcagaag 1320 agcctctccc tgtctccggg taaatga 1347 <![CDATA[<210> 15]]> <![CDATA[<211> 218]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> ch425輕鏈pro]]> <![CDATA[<400> 15]]> 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 Glu Tyr Tyr 20 25 30 Gly Thr Ser Leu Met Gln Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro 35 40 45 Lys Leu Leu Ile Tyr Ala Ala Ser Asn Val Glu 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 Val Glu Glu Asp Asp Ile Ala Met Tyr Phe Cys Gln Gln Ser Met 85 90 95 Lys Val Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg 100 105 110 Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln 115 120 125 Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr 130 135 140 Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln 145 150 155 160 Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr 165 170 175 Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg 180 185 190 His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro 195 200 205 Ile Val Lys Ser Phe Asn Arg Asn Glu Cys 210 215 <![CDATA[<210> 16]]> <![CDATA[<211> 657]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> ch425輕鏈DNA]]> <![CDATA[<400> 16]]> gacattgtgc tcacccaatc tccagcttct ttggctgtgt ctctagggca gagagccacc 60 atctcctgca gagccagtga aagtgttgaa tattatggca caagtttaat gcagtggtac 120 caacagaaac caggacaacc acccaaactc ctcatctatg ctgcatccaa cgtagaatct 180 ggggtccctg ccaggtttag tggcagtggg tctgggacag acttcagcct caacatccat 240 cctgtggagg aggatgatat tgcaatgtat ttctgtcagc aaagtatgaa ggttcctctc 300 acgttcggtg ctgggaccaa gctggagctg aaacgggctg atgctgcacc aactgtatcc 360 atcttcccac catccagtga gcagttaaca tctggaggtg cctcagtcgt gtgcttcttg 420 aacaacttct accccaaaga catcaatgtc aagtggaaga ttgatggcag tgaacgacaa 480 aatggcgtcc tgaacagttg gactgatcag gacagcaaag acagcaccta cagcatgagc 540 agcaccctca cgttgaccaa ggacgagtat gaacgacata acagctatac ctgtgaggcc 600 actcacaaga catcaacttc acccattgtc aagagcttca acaggaatga gtgttag 657 <![CDATA[<210> 17]]> <![CDATA[<211> 119]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> hu425-1-1 VH pro]]> <![CDATA[<400> 17]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Arg Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Ala Ile Ser Ser Gly Gly Ser Leu Tyr Phe Pro Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Cys Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Gly Arg Glu Ala Asp Gly Gly Tyr Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <![CDATA[<210> 18]]> <![CDATA[<211> 357]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> hu425-1-1 VH DNA]]> <![CDATA[<400> 18]]> gaagtgcagc tggtcgaatc aggggggggg ctggtgcagc ctggaggcag cctgagactg 60 tcctgcgccg cttctggctt cacctttagc agatacgcca tgtcctgggt gcggcaggct 120 cctggcaagg gactggagtg ggtggccgct atcagctccg gcggctccct gtacttcccc 180 gattccgtga agggccggtt caccatcagc agggacaacg ccaagaacag ctgctatctg 240 cagatgaact ctctgagggc cgaggataca gccgtgtact attgcgctcg gggcagagaa 300 gcagatggcg gctacttcga ctattggggc cagggcaccc tggtgacagt gtctagc 357 <![CDATA[<210> 19]]> <![CDATA[<211> 111]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> hu425-1-1 VK pro]]> <![CDATA[<400> 19]]> Asp Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Glu Ser Val Glu Tyr Tyr 20 25 30 Gly Thr Ser Leu Met Gln Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro 35 40 45 Arg Leu Leu Ile Tyr Ala Ala Ser Asn Val Glu Ser Gly Val Pro Ala 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 Ser Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Met 85 90 95 Lys Val Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110 <![CDATA[<210> 20]]> <![CDATA[<211> 333]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> hu425-1-1 VK DNA]]> <![CDATA[<400> 20]]> gacatcgtcc tgactcagtc ccctgccact ctgtcagtga gcccaggaga gcgagctacc 60 ctgtcctgca gagcatccga gtctgtcgaa tactatggca cctctctgat gcagtggtac 120 cagcagaagc cagggcaggc tcccaggctg ctgatctatg ccgcttctaa cgtggagagt 180 ggcgtcccag cacgcttcag tggctcaggg agcggaacag actttaccct gacaattagc 240 tccctgcaga gtgaagattt cgccgtgtac tattgccagc agagcatgaa ggtccccctg 300 acatttggcg ggggaactaa ggtggagatc aaa 333 <![CDATA[<210> 21]]> <![CDATA[<211> 329]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> IgG1mf pro]]> <![CDATA[<400> 21]]> Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110 Pro Ala Pro Pro Ala Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 115 120 125 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 130 135 140 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 145 150 155 160 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 165 170 175 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 180 185 190 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 195 200 205 Ala Leu Ala Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 210 215 220 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu 225 230 235 240 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 245 250 255 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 260 265 270 Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 275 280 285 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 290 295 300 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 305 310 315 320 Lys Ser Leu Ser Leu Ser Pro Gly Lys 325 <![CDATA[<21]]>0> 22]]> <br/><![CDATA[<211> 448]]> <br/><![CDATA[<212]]><![CDATA[> PRT]]> <br/><![CDATA[<213> 人工序列]]> <br/> <br/><![CDATA[<220>]]> <br/><![CDATA[<223> hu425-1-1重鏈pro]]> <br/> <br/><![CDATA[<400> 22]]> <br/> <br/><![CDATA[Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Arg Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Ala Ile Ser Ser Gly Gly Ser Leu Tyr Phe Pro Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Cys Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Gly Arg Glu Ala Asp Gly Gly Tyr Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro Ala Ala Gly Pro Ser 225 230 235 240 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 245 250 255 Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 260 265 270 Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 275 280 285 Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 290 295 300 Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 305 310 315 320 Lys Cys Lys Val Ser Asn Lys Ala Leu Ala Ala Pro Ile Glu Lys Thr 325 330 335 Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 340 345 350 Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys 355 360 365 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 370 375 380 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 385 390 395 400 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 405 410 415 Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 420 425 430 Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <![CDATA[<210> 23]]> <![CDATA[<211> 1347]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> hu425-1-1重鏈DNA]]> <![CDATA[<400> 23]]> gaagtgcagc tggtcgaatc aggggggggg ctggtgcagc ctggaggcag cctgagactg 60 tcctgcgccg cttctggctt cacctttagc agatacgcca tgtcctgggt gcggcaggct 120 cctggcaagg gactggagtg ggtggccgct atcagctccg gcggctccct gtacttcccc 180 gattccgtga agggccggtt caccatcagc agggacaacg ccaagaacag ctgctatctg 240 cagatgaact ctctgagggc cgaggataca gccgtgtact attgcgctcg gggcagagaa 300 gcagatggcg gctacttcga ctattggggc cagggcaccc tggtgacagt gtctagcgct 360 agcaccaaag gccccagcgt gtttcctctg gctccatcct ctaaatccac ctctggcggc 420 acagccgctc tgggctgtct ggtgaaggat tacttcccag agcccgtgac agtgtcttgg 480 aacagcggcg ccctgacctc cggcgtgcac acatttcctg ctgtgctgca gagctccggc 540 ctgtacagcc tgtctagcgt ggtgaccgtg ccatcctcta gcctgggcac ccagacatat 600 atctgcaacg tgaatcacaa gcccagcaat acaaaggtgg ataagaaggt ggagccaaag 660 tcctgtgaca agacccacac atgcccccct tgtcctgctc caccagctgc aggaccaagc 720 gtgttcctgt ttccacccaa gcccaaggat accctgatga tctctcggac cccagaggtg 780 acatgcgtgg tggtggatgt gagccacgag gaccccgagg tgaagttcaa ctggtatgtg 840 gacggcgtgg aggtgcacaa tgctaagacc aagcccaggg aggagcagta caactccacc 900 tatagagtgg tgtctgtgct gacagtgctg caccaggatt ggctgaacgg caaggagtat 960 aagtgcaagg tgtccaataa ggccctggcc gctcctatcg agaagaccat ctctaaggcc 1020 aagggccagc ccagagagcc tcaggtgtac acactgcctc catcccggga tgagctgacc 1080 aagaaccagg tgtctctgac atgtctggtc aagggcttct atccctctga catcgccgtg 1140 gagtgggaga gcaatggcca gcctgagaac aattacaaga ccacaccccc tgtgctggat 1200 tccgacggct ctttctttct gtatagcaag ctgaccgtgg acaagtcccg gtggcagcag 1260 ggcaacgtgt tcagctgttc cgtgatgcac gaagctctgc ataatcacta tactcagaaa 1320 tccctgtcac tgtcacctgg taaatga 1347 <![CDATA[<210> 24]]> <![CDATA[<211> 218]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> hu425-1-1輕鏈pro]]> <![CDATA[<400> 24]]> Asp Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Glu Ser Val Glu Tyr Tyr 20 25 30 Gly Thr Ser Leu Met Gln Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro 35 40 45 Arg Leu Leu Ile Tyr Ala Ala Ser Asn Val Glu Ser Gly Val Pro Ala 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 Ser Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Met 85 90 95 Lys Val Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 100 105 110 Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln 115 120 125 Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr 130 135 140 Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser 145 150 155 160 Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr 165 170 175 Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys 180 185 190 His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro 195 200 205 Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <![CDATA[<210> 25]]> <![CDATA[<211> 657]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> hu425-1-1輕鏈DNA]]> <![CDATA[<400> 25]]> gacatcgtcc tgactcagtc ccctgccact ctgtcagtga gcccaggaga gcgagctacc 60 ctgtcctgca gagcatccga gtctgtcgaa tactatggca cctctctgat gcagtggtac 120 cagcagaagc cagggcaggc tcccaggctg ctgatctatg ccgcttctaa cgtggagagt 180 ggcgtcccag cacgcttcag tggctcaggg agcggaacag actttaccct gacaattagc 240 tccctgcaga gtgaagattt cgccgtgtac tattgccagc agagcatgaa ggtccccctg 300 acatttggcg ggggaactaa ggtggagatc aaacgaacag tggcagcccc ttccgtcttc 360 atttttcccc cttctgacga acagctgaaa tcaggaactg ctagcgtggt ctgtctgctg 420 aacaatttct accccagaga ggccaaggtg cagtggaaag tcgataacgc tctgcagtcc 480 ggcaattctc aggagagtgt gaccgaacag gactcaaagg atagcacata ttccctgtct 540 agtactctga ccctgagcaa agcagactac gagaagcaca aagtgtatgc ctgtgaagtc 600 acacaccagg ggctgagttc accagtcacc aagagtttca acagagggga atgctaa 657 <![CDATA[<210> 26]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> hu425-2-2 HCDR2]]> <![CDATA[<400> 26]]> Ala Ile Ser Ser Gly Gly Ser Leu Tyr Tyr Pro Asp Ser Val Lys Gly 1 5 10 15 <![CDATA[<210> 27]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> hu425-2-2 LCDR3]]> <![CDATA[<400> 27]]> Gln Gln Ser Leu Lys Val Pro Leu Thr 1 5 <![CDATA[<210> 28]]> <![CDATA[<211> 119]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> hu425-2-2 VH pro]]> <![CDATA[<400> 28]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Arg Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Ala Ile Ser Ser Gly Gly Ser Leu Tyr 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 Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Gly Arg Glu Ala Asp Gly Gly Tyr Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <![CDATA[<210> 29]]> <![CDATA[<211> 357]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> hu425-2-2 VH DNA]]> <![CDATA[<400> 29]]> gaagtgcagc tggtcgaatc aggggggggg ctggtgcagc ctggaggcag cctgagactg 60 tcctgcgccg cttctggctt cacctttagc agatacgcca tgtcctgggt gcggcaggct 120 cctggcaagg gactggagtg ggtggccgct atcagctccg gcggctccct gtactatccc 180 gattccgtga agggccggtt caccatcagc agggacaacg ccaagaacac actgtatctg 240 cagatgaact ctctgagggc cgaggataca gccgtgtact attgcgctcg gggcagagaa 300 gcagatggcg gctacttcga ctattggggc cagggcaccc tggtgacagt gtctagc 357 <![CDATA[<210> 30]]> <![CDATA[<211> 11]]>1 <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> hu425-2-2 VK pro]]> <![CDATA[<400> 30]]> Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Glu Ser Val Glu Tyr Tyr 20 25 30 Gly Thr Ser Leu Met Gln Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro 35 40 45 Arg Leu Leu Ile Tyr Ala Ala Ser Asn Val Glu Ser Gly Ile Pro Ala 50 55 60 Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser 65 70 75 80 Ser Leu Gln Ser Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Leu 85 90 95 Lys Val Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110 <![CDATA[<210> 31]]> <![CDATA[<211> 333]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> hu425-2-2 VK DNA]]> <![CDATA[<400> 31]]> gagatcgtca tgactcagtc ccctgccact ctgtcagtga gcccaggaga gcgagctacc 60 ctgtcctgca gagcatccga gtctgtcgaa tactatggca cctctctgat gcagtggtac 120 cagcagaagc cagggcaggc tcccaggctg ctgatctatg ccgcttctaa cgtggagagt 180 ggcatcccag cacgcttcag tggctcaggg agcggaacag agtttaccct gacaattagc 240 tccctgcaga gtgaagattt cgccgtgtac tattgccagc agagcctgaa ggtccccctg 300 acatttggcg ggggaactaa ggtggagatc aaa 333 <![CDATA[<210> 32]]> <![CDATA[<211> 448]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> hu425-2-2重鏈pro]]> <![CDATA[<400> 32]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Arg Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Ala Ile Ser Ser Gly Gly Ser Leu Tyr 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 Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Gly Arg Glu Ala Asp Gly Gly Tyr Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro Ala Ala Gly Pro Ser 225 230 235 240 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 245 250 255 Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 260 265 270 Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 275 280 285 Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 290 295 300 Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 305 310 315 320 Lys Cys Lys Val Ser Asn Lys Ala Leu Ala Ala Pro Ile Glu Lys Thr 325 330 335 Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 340 345 350 Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys 355 360 365 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 370 375 380 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 385 390 395 400 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 405 410 415 Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 420 425 430 Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <![CDATA[<210> 33]]> <![CDATA[<211> 1347]]> <![CDATA[<212> DNA]]> <![CDATA[<213> ]]>人工序列 <![CDATA[<220>]]> <![CDATA[<223> hu425-2-2重鏈DNA]]> <![CDATA[<400> 33]]> gaagtgcagc tggtcgaatc aggggggggg ctggtgcagc ctggaggcag cctgagactg 60 tcctgcgccg cttctggctt cacctttagc agatacgcca tgtcctgggt gcggcaggct 120 cctggcaagg gactggagtg ggtggccgct atcagctccg gcggctccct gtactatccc 180 gattccgtga agggccggtt caccatcagc agggacaacg ccaagaacac actgtatctg 240 cagatgaact ctctgagggc cgaggataca gccgtgtact attgcgctcg gggcagagaa 300 gcagatggcg gctacttcga ctattggggc cagggcaccc tggtgacagt gtctagcgct 360 agcaccaaag gccccagcgt gtttcctctg gctccatcct ctaaatccac ctctggcggc 420 acagccgctc tgggctgtct ggtgaaggat tacttcccag agcccgtgac agtgtcttgg 480 aacagcggcg ccctgacctc cggcgtgcac acatttcctg ctgtgctgca gagctccggc 540 ctgtacagcc tgtctagcgt ggtgaccgtg ccatcctcta gcctgggcac ccagacatat 600 atctgcaacg tgaatcacaa gcccagcaat acaaaggtgg ataagaaggt ggagccaaag 660 tcctgtgaca agacccacac atgcccccct tgtcctgctc caccagctgc aggaccaagc 720 gtgttcctgt ttccacccaa gcccaaggat accctgatga tctctcggac cccagaggtg 780 acatgcgtgg tggtggatgt gagccacgag gaccccgagg tgaagttcaa ctggtatgtg 840 gacggcgtgg aggtgcacaa tgctaagacc aagcccaggg aggagcagta caactccacc 900 tatagagtgg tgtctgtgct gacagtgctg caccaggatt ggctgaacgg caaggagtat 960 aagtgcaagg tgtccaataa ggccctggcc gctcctatcg agaagaccat ctctaaggcc 1020 aagggccagc ccagagagcc tcaggtgtac acactgcctc catcccggga tgagctgacc 1080 aagaaccagg tgtctctgac atgtctggtc aagggcttct atccctctga catcgccgtg 1140 gagtgggaga gcaatggcca gcctgagaac aattacaaga ccacaccccc tgtgctggat 1200 tccgacggct ctttctttct gtatagcaag ctgaccgtgg acaagtcccg gtggcagcag 1260 ggcaacgtgt tcagctgttc cgtgatgcac gaagctctgc ataatcacta tactcagaaa 1320 tccctgtcac tgtcacctgg taaatga 1347 <![CDATA[<210> 34]]> <![CDATA[<211> 218]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> hu425-2-2輕鏈pro]]> <![CDATA[<400> 34]]> Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Glu Ser Val Glu Tyr Tyr 20 25 30 Gly Thr Ser Leu Met Gln Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro 35 40 45 Arg Leu Leu Ile Tyr Ala Ala Ser Asn Val Glu Ser Gly Ile Pro Ala 50 55 60 Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser 65 70 75 80 Ser Leu Gln Ser Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Leu 85 90 95 Lys Val Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 100 105 110 Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln 115 120 125 Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr 130 135 140 Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser 145 150 155 160 Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr 165 170 175 Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys 180 185 190 His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro 195 200 205 Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <![CDATA[<210> 35]]> <![CDATA[<211> 657]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> hu425-2-2輕鏈DNA]]> <![CDATA[<400> 35]]> gagatcgtca tgactcagtc ccctgccact ctgtcagtga gcccaggaga gcgagctacc 60 ctgtcctgca gagcatccga gtctgtcgaa tactatggca cctctctgat gcagtggtac 120 cagcagaagc cagggcaggc tcccaggctg ctgatctatg ccgcttctaa cgtggagagt 180 ggcatcccag cacgcttcag tggctcaggg agcggaacag agtttaccct gacaattagc 240 tccctgcaga gtgaagattt cgccgtgtac tattgccagc agagcctgaa ggtccccctg 300 acatttggcg ggggaactaa ggtggagatc aaacgaacag tggcagcccc ttccgtcttc 360 atttttcccc cttctgacga acagctgaaa tcaggaactg ctagcgtggt ctgtctgctg 420 aacaatttct accccagaga ggccaaggtg cagtggaaag tcgataacgc tctgcagtcc 480 ggcaattctc aggagagtgt gaccgaacag gactcaaagg atagcacata ttccctgtct 540 agtactctga ccctgagcaa agcagactac gagaagcaca aagtgtatgc ctgtgaagtc 600 acacaccagg ggctgagttc accagtcacc aagagtttca acagagggga atgctaa 657 <![CDATA[<210> 36]]> <![CDATA[<211> 111]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> hu425-2-3b VK pro]]> <![CDATA[<400> 36]]> Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Glu Ser Val Glu Tyr Tyr 20 25 30 Gly Thr Ser Leu Met Gln Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro 35 40 45 Arg Leu Leu Ile Tyr Ala Ala Ser Asn Val Glu Ser Gly Ile Pro Ala 50 55 60 Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser 65 70 75 80 Ser Leu Gln Ser Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Leu 85 90 95 Lys Val Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110 <![CDATA[<210> 37]]> <![CDATA[<211> 333]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> hu425-2-3b VK DNA]]> <![CDATA[<400> 37]]> gagatcgtcc tgactcagtc ccctgccact ctgtcagtga gcccaggaga gcgagctacc 60 ctgtcctgca gagcatccga gtctgtcgaa tactatggca cctctctgat gcagtggtac 120 cagcagaagc cagggcaggc tcccaggctg ctgatctatg ccgcttctaa cgtggagagt 180 ggcatcccag cacgcttcag tggctcaggg agcggaacag agtttaccct gacaattagc 240 tccctgcaga gtgaagattt cgccgtgtac tattgccagc agagcctgaa ggtccccctg 300 acatttggcg ggggaactaa ggtggagatc aaa 333 <![CDATA[<210> 38]]> <![CDATA[<211> 218]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> hu425-2-3b輕鏈pro]]> <![CDATA[<400> 38]]> Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Glu Ser Val Glu Tyr Tyr 20 25 30 Gly Thr Ser Leu Met Gln Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro 35 40 45 Arg Leu Leu Ile Tyr Ala Ala Ser Asn Val Glu Ser Gly Ile Pro Ala 50 55 60 Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser 65 70 75 80 Ser Leu Gln Ser Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Leu 85 90 95 Lys Val Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 100 105 110 Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln 115 120 125 Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr 130 135 140 Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser 145 150 155 160 Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr 165 170 175 Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys 180 185 190 His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro 195 200 205 Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <![CDATA[<210> 39]]> <![CDATA[<211> 657]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> hu425-2-3b輕鏈DNA]]> <![CDATA[<400> 39]]> gagatcgtcc tgactcagtc ccctgccact ctgtcagtga gcccaggaga gcgagctacc 60 ctgtcctgca gagcatccga gtctgtcgaa tactatggca cctctctgat gcagtggtac 120 cagcagaagc cagggcaggc tcccaggctg ctgatctatg ccgcttctaa cgtggagagt 180 ggcatcccag cacgcttcag tggctcaggg agcggaacag agtttaccct gacaattagc 240 tccctgcaga gtgaagattt cgccgtgtac tattgccagc agagcctgaa ggtccccctg 300 acatttggcg ggggaactaa ggtggagatc aaacgaacag tggcagcccc ttccgtcttc 360 atttttcccc cttctgacga acagctgaaa tcaggaactg ctagcgtggt ctgtctgctg 420 aacaatttct accccagaga ggccaaggtg cagtggaaag tcgataacgc tctgcagtcc 480 ggcaattctc aggagagtgt gaccgaacag gactcaaagg atagcacata ttccctgtct 540 agtactctga ccctgagcaa agcagactac gagaagcaca aagtgtatgc ctgtgaagtc 600 acacaccagg ggctgagttc accagtcacc aagagtttca acagagggga atgctaa 657 <![CDATA[<210> 40]]> <![CDATA[<211> 118]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列]]> <![CDATA[<400> 40]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asn Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Asp Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Val Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Val Gly Gly Ala Phe Pro Met Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Thr Val Thr Val Ser Ser 115 <![CDATA[<210> 41]]> <![CDATA[<211> 111]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列]]> <![CDATA[<400> 41]]> Ala Ile Gln Leu 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 Tyr Tyr 20 25 30 Gly Thr Ser Leu Met Gln Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro 35 40 45 Lys Leu Leu Ile Tyr Ala Ala Ser Asn Val 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 Phe Cys Gln Gln Ser Arg 85 90 95 Lys Asp Pro Ser Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110 <![CDATA[<210> 42]]> <![CDATA[<211> 114]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列]]> <![CDATA[<400> 42]]> Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ala Ser Gly Phe Thr Phe Ser Ser 20 25 30 Tyr Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Asp Trp 35 40 45 Val Ser Thr Ile Ser Gly Gly Gly Thr Tyr Thr Tyr Tyr Gln Asp Ser 50 55 60 Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu 65 70 75 80 Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Ser Met Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser 100 105 110 Ser Ala <![CDATA[<210> 43]]> <![CDATA[<211> 108]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列]]> <![CDATA[<400> 43]]> 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 Ser Ile Arg Arg Tyr 20 25 30 Leu Asn Trp Tyr His Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Thr Leu Gln Ser 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 Val Tyr Tyr Cys Gln Gln Ser His Ser Ala Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 100 105
Claims (33)
- 一種能夠結合人Tim-3的抗體,其包含: (a) 重鏈可變區(VH),其包含一個、兩個或三個選自SEQ ID NO 3、4、5或26的CDR胺基酸序列或其包含一個或多個保守取代的變異體;和/或 (b) 輕鏈可變區(VL),其包含一個、兩個或三個選自SEQ ID NO 6、7、8或27的CDR胺基酸序列或其包含一個或多個保守取代的變異體。
- 如請求項1的抗體,其中所述抗體包含: (a) 重鏈可變區(VH),其包含SEQ ID NO 3的VH-CDR1胺基酸序列或其包含一個或多個保守取代的變異體,SEQ ID NO 4的VH-CDR2胺基酸序列或其包含一個或多個保守取代的變異體和SEQ ID NO 5的VH-CDR3胺基酸序列或其包含一個或多個保守取代的變異體;和輕鏈可變區(VL),其包含SEQ ID NO 6的VL-CDR1胺基酸序列或其包含一個或多個保守取代的變異體,SEQ ID NO 7的VL-CDR2胺基酸序列或其包含一個或多個保守取代的變異體和SEQ ID NO 8的VL-CDR3胺基酸序列或其包含一個或多個保守取代的變異體; (b) 重鏈可變區(VH),其包含SEQ ID NO 3的VH-CDR1胺基酸序列或其包含一個或多個保守取代的變異體,SEQ ID NO 26的VH-CDR2胺基酸序列或其包含一個或多個保守取代的變異體和SEQ ID NO 5的VH-CDR3胺基酸序列或其包含一個或多個保守取代的變異體;和輕鏈可變區(VL),其包含SEQ ID NO 6的VL-CDR1胺基酸序列或其包含一個或多個保守取代的變異體,SEQ ID NO 7的VL-CDR2胺基酸序列或其包含一個或多個保守取代的變異體和SEQ ID NO 8的VL-CDR3胺基酸序列或其包含一個或多個保守取代的變異體; (c) 重鏈可變區(VH),其包含SEQ ID NO 3的VH-CDR1胺基酸序列或其包含一個或多個保守取代的變異體,SEQ ID NO 4的VH-CDR2胺基酸序列或其包含一個或多個保守取代的變異體和SEQ ID NO 5的VH-CDR3胺基酸序列或其包含一個或多個保守取代的變異體;和輕鏈可變區(VL),其包含SEQ ID NO 6的VL-CDR1胺基酸序列或其包含一個或多個保守取代的變異體,SEQ ID NO 7的VL-CDR2胺基酸序列或其包含一個或多個保守取代的變異體和SEQ ID NO 27的VL-CDR3胺基酸序列或其包含一個或多個保守取代的變異體;或 (d) 重鏈可變區(VH),其包含SEQ ID NO 3的VH-CDR1胺基酸序列或其包含一個或多個保守取代的變異體,SEQ ID NO 26的VH-CDR2胺基酸序列或其包含一個或多個保守取代的變異體和SEQ ID NO 5的VH-CDR3胺基酸序列或其包含一個或多個保守取代的變異體;和輕鏈可變區(VL),其包含SEQ ID NO 6的VL-CDR1胺基酸序列或其包含一個或多個保守取代的變異體,SEQ ID NO 7的VL-CDR2胺基酸序列或其包含一個或多個保守取代的變異體和SEQ ID NO 27的VL-CDR3胺基酸序列或其包含一個或多個保守取代的變異體。
- 如請求項1的抗體,其中所述抗體包含: (a) 重鏈可變區(VH),其包含SEQ ID NO 3的VH-CDR1胺基酸序列,SEQ ID NO 4的VH-CDR2胺基酸序列和SEQ ID NO 5的VH-CDR3胺基酸序列;和輕鏈可變區(VL),其包含SEQ ID NO 6的VL-CDR1胺基酸序列,SEQ ID NO 7的VL-CDR2胺基酸序列和SEQ ID NO 8的VL-CDR3胺基酸序列;或 (b) 重鏈可變區(VH),其包含SEQ ID NO 3的VH-CDR1胺基酸序列,SEQ ID NO 26的VH-CDR2胺基酸序列和SEQ ID NO 5的VH-CDR3胺基酸序列;和輕鏈可變區(VL),其包含SEQ ID NO 6的VL-CDR1胺基酸序列,SEQ ID NO 7的VL-CDR2胺基酸序列和SEQ ID NO 27的VL-CDR3胺基酸序列。
- 如請求項1的抗體,其中所述抗體是人源化抗體分子。
- 如請求項1的抗體,其中所述抗體包含與SEQ ID NO 9、17、28或40的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域。
- 如請求項1的抗體,其中所述抗體包含與SEQ ID NO 9、17或28的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域。
- 如請求項1的抗體,其中所述抗體包含與SEQ ID NO 11、19、30或36的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域。
- 如請求項1的抗體,其中所述抗體包含: (a) 與SEQ ID NO 9的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 11的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域; (b) 與SEQ ID NO 9的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 19的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域; (c) 與SEQ ID NO 9的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 30的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域; (d) 與SEQ ID NO 9的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 36的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域; (e) 與SEQ ID NO 17的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 11的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域; (f) 與SEQ ID NO 17的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 19的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域; (g) 與SEQ ID NO 17的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 30的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域; (h) 與SEQ ID NO 17的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 36的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域; (i) 與SEQ ID NO 28的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 11的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域; (j) 與SEQ ID NO 28的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 19的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域; (k) 與SEQ ID NO 28的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 30的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域; (l) 與SEQ ID NO 28的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 36的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域; (m) 與SEQ ID NO 40的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 11的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域; (n) 與SEQ ID NO 40的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 19的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域; (o) 與SEQ ID NO 40的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 30的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域;或 (p) 與SEQ ID NO 40的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 36的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域。
- 如請求項1的抗體,其中所述抗體包含: (a) 與SEQ ID NO 9的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 11的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域; (b) 與SEQ ID NO 9的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 19的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域; (c) 與SEQ ID NO 9的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 30的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域; (d) 與SEQ ID NO 9的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 36的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域; (e) 與SEQ ID NO 17的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 11的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域; (f) 與SEQ ID NO 17的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 19的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域; (g) 與SEQ ID NO 17的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 30的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域; (h) 與SEQ ID NO 17的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 36的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域; (i) 與SEQ ID NO 28的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 11的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域; (j) 與SEQ ID NO 28的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 19的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域; (k) 與SEQ ID NO 28的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 30的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域;或 (l) 與SEQ ID NO 28的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈可變結構域,和與SEQ ID NO 36的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈可變結構域。
- 如請求項1的抗體,其中所述抗體包含: (a) 包含SEQ ID NO 9的胺基酸序列的重鏈可變結構域,和包含SEQ ID NO 11的胺基酸序列的輕鏈可變結構域; (b) 包含SEQ ID NO 17的胺基酸序列的重鏈可變結構域,和包含SEQ ID NO 19的胺基酸序列的輕鏈可變結構域; (c) 包含SEQ ID NO 28的胺基酸序列的重鏈可變結構域,和包含SEQ ID NO 30的胺基酸序列的輕鏈可變結構域; (d) 包含SEQ ID NO 28的胺基酸序列的重鏈可變結構域,和包含SEQ ID NO 36的胺基酸序列的輕鏈可變結構域; (e) 包含SEQ ID NO 40的胺基酸序列的重鏈可變結構域,和包含SEQ ID NO 36的胺基酸序列的輕鏈可變結構域。
- 如請求項1的抗體,其中所述抗體包含: (a) 包含SEQ ID NO 9的胺基酸序列的重鏈可變結構域,和包含SEQ ID NO 11的胺基酸序列的輕鏈可變結構域; (b) 包含SEQ ID NO 17的胺基酸序列的重鏈可變結構域,和包含SEQ ID NO 19的胺基酸序列的輕鏈可變結構域; (c) 包含SEQ ID NO 28的胺基酸序列的重鏈可變結構域,和包含SEQ ID NO 30的胺基酸序列的輕鏈可變結構域;或 (d) 包含SEQ ID NO 28的胺基酸序列的重鏈可變結構域,和包含SEQ ID NO 36的胺基酸序列的輕鏈可變結構域。
- 如請求項1的抗體,其中所述抗體包含與SEQ ID NO 13、22或32的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈。
- 如請求項1的抗體,其中所述抗體包含與SEQ ID NO 15、24、34或38的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈。
- 如請求項1的抗體,其中所述抗體包含: (a) 與SEQ ID NO 13的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈,和與SEQ ID NO 15的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈; (b) 與SEQ ID NO 13的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈,和與SEQ ID NO 24的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈; (c) 與SEQ ID NO 13的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈,和與SEQ ID NO 34的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈; (d) 與SEQ ID NO 13的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈,和與SEQ ID NO 38的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈; (e) 與SEQ ID NO 22的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈,和與SEQ ID NO 15的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈; (f) 與SEQ ID NO 22的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈,和與SEQ ID NO 24的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈; (g) 與SEQ ID NO 22的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈,和與SEQ ID NO 34的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈; (h) 與SEQ ID NO 22的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈,和與SEQ ID NO 38的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈; (i) 與SEQ ID NO 32的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈,和與SEQ ID NO 15的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈; (j) 與SEQ ID NO 32的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈,和與SEQ ID NO 24的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈; (k) 與SEQ ID NO 32的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈,和與SEQ ID NO 34的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈;或 (l) 與SEQ ID NO 32的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的重鏈,和與SEQ ID NO 38的胺基酸序列具有至少95%、96%、97%、98%、99%或100%序列同一性的輕鏈。
- 如請求項1的抗體,其中所述抗體包含: (a) 包含SEQ ID NO 13的胺基酸序列的重鏈,和包含SEQ ID NO 15的胺基酸序列的輕鏈; (b) 包含SEQ ID NO 22的胺基酸序列的重鏈,和包含SEQ ID NO 24的胺基酸序列的輕鏈; (c) 包含SEQ ID NO 32的胺基酸序列的重鏈,和包含SEQ ID NO 34的胺基酸序列的輕鏈;或 (d) 包含SEQ ID NO 32的胺基酸序列的重鏈,和包含SEQ ID NO 38的胺基酸序列的輕鏈。
- 如請求項1-15中任一項的抗體,其中所述抗體包含以下的一種或多種: (a) 在SEQ ID NO 24的1位具有天門冬胺酸到麩胺酸突變的輕鏈; (b) 在SEQ ID NO 24的4位具有白胺酸到甲硫胺酸突變的輕鏈; (c) 在SEQ ID NO 24的62位具有纈胺酸到異白胺酸突變的輕鏈; (d) 在SEQ ID NO 24的74位具有天門冬胺酸到麩胺酸突變的輕鏈; (e) 在SEQ ID NO 24的96位具有甲硫胺酸到白胺酸突變的輕鏈; (f) 在SEQ ID NO 22的59位具有苯丙胺酸到酪胺酸突變的重鏈; (g) 在SEQ ID NO 22的60位具有脯胺酸到纈胺酸突變的重鏈; (h) 在SEQ ID NO 22的77位具有絲胺酸到蘇胺酸突變的重鏈;或 (i) 在SEQ ID NO 22的78位具有半胱胺酸到白胺酸突變的重鏈。
- 如請求項1的抗體,其中所述抗體是Fab、F(ab’)2、Fv或單鏈Fv (ScFv)。
- 如請求項1的抗體,其中所述抗體包含亞類IgG1、IgG2、IgG3或IgG4或其變異體的重鏈恒定區,和κ或λ型的輕鏈恒定區或其變異體。
- 如請求項18的抗體,其中所述抗體包含亞類IgG1、IgG2、IgG3或IgG4的變異體重鏈恒定區,其中所述變異體重鏈恒定區提供減少或消除的效應物功能。
- 如請求項19的抗體,其中所述效應物功能是抗體依賴性細胞介導的細胞毒性(ADCC)或補體依賴性細胞毒性(CDC)。
- 如請求項18的抗體,其中所述抗體包含人IgG1的重鏈恒定區或其變異體。
- 如請求項21的抗體,其中所述變異體人IgG1的重鏈恒定區包含一種或多種選自下組的突變:E 233P、L 234A、L 235A、L 236Δ和P 329A。
- 如請求項22的抗體,其中所述變異體人IgG1重鏈恒定區包含SEQ ID NO 21的胺基酸序列,和人κ輕鏈恒定區。
- 一種醫藥組合物,其包含請求項1-23中任一項的抗體,和醫藥上可接受之賦形劑。
- 一種刺激個體的免疫響應的方法,其包括以有效刺激免疫響應的量向有此需要的個體施用請求項1的抗體。
- 一種治療癌症或腫瘤的方法,其包括以有效治療癌症或腫瘤的量向有此需要的個體施用請求項1的抗體。
- 如請求項26的方法,其中所述癌症選自肺癌、肝癌、胃癌、宮頸癌、黑素瘤、腎癌、乳腺癌、結直腸癌、白血病、淋巴瘤、卵巢癌、頭頸癌或癌症的轉移病灶。
- 如請求項26的方法,其中所述抗體與第二治療劑或操作組合施用,其中所述第二治療劑或操作選自化學療法、靶向療法、溶瘤藥物、細胞毒劑、基於免疫的療法、細胞因子、外科手術、放射操作、協同刺激分子的活化劑、抑制性分子的抑制劑、疫苗或細胞免疫療法。
- 如請求項26的方法,其中所述抗體與選自PD-1、PD-L1、PD-L2、CTLA-4、LAG-3、CEACAM-1、CEACAM-5、VISTA、BTLA、TIGIT、LAIR1、CD160、2B4或TGFR的免疫檢查點分子的抑制劑組合施用。
- 如請求項26的方法,其中所述抗體與抗PD-1 mAb 317-4B6或317-4B6/IgG4mt10組合施用。
- 一種治療感染性疾病的方法,其包括以有效治療感染性疾病的量向有此需要的個體施用請求項1的抗體。
- 如請求項31的方法,其中所述感染性疾病是選自HIV感染和HCV感染的慢性病毒感染。
- 如請求項1-23中任一項的抗Tim-3抗體分子在製備用於治療癌症、腫瘤或感染性疾病的藥物中的用途。
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CN (3) | CN109790218B (zh) |
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US11203637B2 (en) | 2021-12-21 |
AU2017317227A1 (en) | 2019-04-11 |
EP3970749A1 (en) | 2022-03-23 |
CN116655790A (zh) | 2023-08-29 |
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CA3034962A1 (en) | 2018-03-01 |
KR102460525B1 (ko) | 2022-11-01 |
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EP3504243A1 (en) | 2019-07-03 |
US20190276533A1 (en) | 2019-09-12 |
EA201990594A1 (ru) | 2019-08-30 |
CN116478290A (zh) | 2023-07-25 |
ZA201901113B (en) | 2020-10-28 |
TW201819414A (zh) | 2018-06-01 |
CN109790218A (zh) | 2019-05-21 |
US20240076375A1 (en) | 2024-03-07 |
TWI769174B (zh) | 2022-07-01 |
CN109790218B (zh) | 2023-03-03 |
SG11201901548SA (en) | 2019-03-28 |
KR20190042037A (ko) | 2019-04-23 |
EP3504243A4 (en) | 2020-03-11 |
BR112019003976A2 (pt) | 2019-05-28 |
JP7158552B2 (ja) | 2022-10-21 |
JP2022027659A (ja) | 2022-02-10 |
MX2019002242A (es) | 2019-08-16 |
SG10201912199XA (en) | 2020-02-27 |
NZ751246A (en) | 2023-04-28 |
JP6968872B2 (ja) | 2021-11-17 |
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