JP2023072038A - プログラム死リガンド1(pd-l1)に対するヒトモノクローナル抗体 - Google Patents
プログラム死リガンド1(pd-l1)に対するヒトモノクローナル抗体 Download PDFInfo
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Abstract
Description
本出願は、その全体が参照により本明細書に組み入れられる2005年7月1日に出願された米国特許仮出願第60/696,426号の恩典を主張する。
プログラム死1(PD-1)は、CD28、CTLA-4、ICOS、PD-1、およびBTLAを含む、受容体のCD28ファミリーのメンバーである。ファミリーの最初のメンバーであるCD28およびICOSは、モノクローナル抗体の添加後に増加するT細胞増殖に対する機能的作用によって発見された(Hutloff et al. (1999)Nature 397:263-266; Hansen et al. (1980) Immunogenics 10:247-260)。PD-1に対する2種類の細胞表面糖タンパク質リガンド、すなわちPD-L1およびPD-L2が同定されており、かつ、PD-1に結合すると、T細胞活性化およびサイトカイン分泌を下方調節することが示された(Freeman et al. (2000) J Exp Med 192:1027-34; Latchman et al. (2001) Nat Immunol 2:261-8; Carter et al. (2002) Eur J Immunol 32:634-43; Ohigashi et al. (2005) Clin Cancer Res 11:2947-53)。PD-L1(B7-H1)およびPD-L2(B7-DC)の両方とも、PD-1に結合するが、他のCD28ファミリーメンバーに結合しない、B7ホモログである(Blank et al. (2004))。細胞表面上でのPD-L1の発現が、IFN-γ刺激によって上方調節されることも示された。
本発明は、PD-L1に結合し、かつ多数の望ましい特性を示す、単離されたモノクローナル抗体、特にヒトモノクローナル抗体を提供する。これらの特性には、ヒトPD-L1に結合する高親和性が含まれる。さらになお、本発明の抗体は、混合リンパ球反応においてT細胞増殖、IFN-γ分泌、およびIL-2分泌を増大させることも示された。
(a)1×10-7Mもしくはそれ以下のKDでヒトPD-L1に結合する;
(b)混合リンパ球反応(MLR)アッセイ法においてT細胞増殖を増加させる;
(c)MLRアッセイ法においてインターフェロン-γ産生を増加させる;
(d)MLRアッセイ法においてIL-2分泌を増加させる;
(e)抗体応答を刺激する;または、
(f)T細胞エフェクター細胞および/もしくは樹状細胞に対する調節性T細胞の作用を逆転させる。
(a)SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:4、SEQ ID NO:5、SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:9、およびSEQ ID NO:10からなる群より選択されるアミノ酸配列を含むヒト重鎖可変領域、ならびに
(b)SEQ ID NO:11、SEQ ID NO:12、SEQ ID NO:13、SEQ ID NO:14、SEQ ID NO:15、SEQ ID NO:16、SEQ ID NO:17、SEQ ID NO:18、SEQ ID NO:19、およびSEQ ID NO:20からなる群より選択されるアミノ酸配列を含むヒト軽鎖可変領域。
(a)SEQ ID NO:1のアミノ酸配列を含む重鎖可変領域;および
(b)SEQ ID NO:11のアミノ酸配列を含む軽鎖可変領域を含むか、
または、参照抗体は、
(a)SEQ ID NO:2のアミノ酸配列を含む重鎖可変領域;および
(b)SEQ ID NO:12のアミノ酸配列を含む軽鎖可変領域を含むか、
または、参照抗体は、
(a)SEQ ID NO:3のアミノ酸配列を含む重鎖可変領域;および
(b)SEQ ID NO:13のアミノ酸配列を含む軽鎖可変領域を含むか、
または、参照抗体は、
(a)SEQ ID NO:4のアミノ酸配列を含む重鎖可変領域;および
(b)SEQ ID NO:14のアミノ酸配列を含む軽鎖可変領域を含むか、
または、参照抗体は、
(a)SEQ ID NO:5のアミノ酸配列を含む重鎖可変領域;および
(b)SEQ ID NO:15のアミノ酸配列を含む軽鎖可変領域を含むか、
または、参照抗体は、
(a)SEQ ID NO:6のアミノ酸配列を含む重鎖可変領域;および
(b)SEQ ID NO:16のアミノ酸配列を含む軽鎖可変領域を含むか、
または、参照抗体は、
(a)SEQ ID NO:7のアミノ酸配列を含む重鎖可変領域;および
(b)SEQ ID NO:17のアミノ酸配列を含む軽鎖可変領域を含むか、
または、参照抗体は、
(a)SEQ ID NO:8のアミノ酸配列を含む重鎖可変領域;および
(b)SEQ ID NO:18のアミノ酸配列を含む軽鎖可変領域を含むか、
または、参照抗体は、
(a)SEQ ID NO:9のアミノ酸配列を含む重鎖可変領域;および
(b)SEQ ID NO:19のアミノ酸配列を含む軽鎖可変領域を含むか、
または、参照抗体は、
(a)SEQ ID NO:10のアミノ酸配列を含む重鎖可変領域;および
(b)SEQ ID NO:20のアミノ酸配列を含む軽鎖可変領域を含む。
(a)ヒトVH1-18遺伝子の重鎖可変領域;および
(b)ヒトVKL6遺伝子の軽鎖可変領域。
(a)ヒトVH1-69遺伝子の重鎖可変領域;および
(b)ヒトVKL6遺伝子の軽鎖可変領域。
(a)ヒトVH1-3遺伝子の重鎖可変領域;および
(b)ヒトVKL15遺伝子の軽鎖可変領域。
(a)ヒトVH1-69遺伝子の重鎖可変領域;および
(b)ヒトVKA27遺伝子の軽鎖可変領域。
(a)ヒトVH3-9遺伝子の重鎖可変領域;および
(b)ヒトVKL15遺伝子の軽鎖可変領域。
(a)ヒトVH3-9遺伝子の重鎖可変領域;および
(b)ヒトVKL18遺伝子の軽鎖可変領域。
(a)重鎖可変領域のCDR3配列が、SEQ ID NO:41、SEQ ID NO:42、SEQ ID NO:43、SEQ ID NO:44、SEQ ID NO:45、SEQ ID NO:46、SEQ ID NO:47、SEQ ID NO:48、SEQ ID NO:49、およびSEQ ID NO:50、ならびにそれらの保存的改変体からなる群より選択されるアミノ酸配列を含み;
(b)軽鎖可変領域のCDR3配列が、SEQ ID NO:71、SEQ ID NO:72、SEQ ID NO:73、SEQ ID NO:74、SEQ ID NO:75、SEQ ID NO:76、SEQ ID NO:77、SEQ ID NO:78、SEQ ID NO:79、およびSEQ ID NO:80、ならびにそれらの保存的改変体からなる群より選択されるアミノ酸配列を含み;かつ、
(c)抗体が、ヒトPD-L1に特異的に結合する、
単離されたモノクローナル抗体またはその抗原結合部分を提供する。
(a)重鎖可変領域が、SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:4、SEQ ID NO:5、SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:9、およびSEQ ID NO:10からなる群より選択されるアミノ酸配列に少なくとも80%相同であるアミノ酸配列を含み;
(b)軽鎖可変領域が、SEQ ID NO:11、SEQ ID NO:12、SEQ ID NO:13、SEQ ID NO:14、SEQ ID NO:15、SEQ ID NO:16、SEQ ID NO:17、SEQ ID NO:18、SEQ ID NO:19、およびSEQ ID NO:20からなる群より選択されるアミノ酸配列に少なくとも80%相同であるアミノ酸配列を含み;かつ、
(c)抗体が、1×10-7Mまたはそれ以下のKDでヒトPD-L1に結合する、
単離されたモノクローナル抗体またはその抗原結合部分を提供する。
(a)抗体が、混合リンパ球反応(MLR)アッセイ法においてT細胞増殖を増加させる;または、
(b)抗体が、MLRアッセイ法においてインターフェロン-γ産生を増加させる;
(c)抗体が、MLRアッセイ法においてIL-2分泌を増加させる。
(a)SEQ ID NO:21、SEQ ID NO:22、SEQ ID NO:23、SEQ ID NO:24、SEQ ID NO:25、SEQ ID NO:26、SEQ ID NO:27、SEQ ID NO:28、SEQ ID NO:29、およびSEQ ID NO:30からなる群より選択されるアミノ酸配列を含む、重鎖可変領域のCDR1;
(b)SEQ ID NO:31、SEQ ID NO:32、SEQ ID NO:33、SEQ ID NO:34、SEQ ID NO:35、SEQ ID NO:36、SEQ ID NO:37、SEQ ID NO:38、SEQ ID NO:39、およびSEQ ID NO:40からなる群より選択されるアミノ酸配列を含む、重鎖可変領域のCDR2;
(c)SEQ ID NO:41、SEQ ID NO:42、SEQ ID NO:43、SEQ ID NO:44、SEQ ID NO:45、SEQ ID NO:46、SEQ ID NO:47、SEQ ID NO:48、SEQ ID NO:49、およびSEQ ID NO:50からなる群より選択されるアミノ酸配列を含む、重鎖可変領域のCDR3;
(d)SEQ ID NO:51、SEQ ID NO:52、SEQ ID NO:53、SEQ ID NO:54、SEQ ID NO:55、SEQ ID NO:56、SEQ ID NO:57、SEQ ID NO:58、SEQ ID NO:59、およびSEQ ID NO:60からなる群より選択されるアミノ酸配列を含む、軽鎖可変領域のCDR1;
(e)SEQ ID NO:61、SEQ ID NO:62、SEQ ID NO:63、SEQ ID NO:64、SEQ ID NO:65、SEQ ID NO:66、SEQ ID NO:67、SEQ ID NO:68、SEQ ID NO:69、およびSEQ ID NO:70からなる群より選択されるアミノ酸配列を含む、軽鎖可変領域のCDR2;ならびに、
(f)SEQ ID NO:71、SEQ ID NO:72、SEQ ID NO:73、SEQ ID NO:74、SEQ ID NO:75、SEQ ID NO:76、SEQ ID NO:77、SEQ ID NO:78、SEQ ID NO:79、およびSEQ ID NO:80からなる群より選択されるアミノ酸配列を含む、軽鎖可変領域のCDR3。
(a)SEQ ID NO:21を含む重鎖可変領域CDR1;
(b)SEQ ID NO:31を含む重鎖可変領域CDR2;
(c)SEQ ID NO:41を含む重鎖可変領域CDR3;
(d)SEQ ID NO:51を含む軽鎖可変領域CDR1;
(e)SEQ ID NO:61を含む軽鎖可変領域CDR2;および
(f)SEQ ID NO:71を含む軽鎖可変領域CDR3。
(a)SEQ ID NO:22を含む重鎖可変領域CDR1;
(b)SEQ ID NO:32を含む重鎖可変領域CDR2;
(c)SEQ ID NO:42を含む重鎖可変領域CDR3;
(d)SEQ ID NO:52を含む軽鎖可変領域CDR1;
(e)SEQ ID NO:62を含む軽鎖可変領域CDR2;および
(f)SEQ ID NO:72を含む軽鎖可変領域CDR3。
(a)SEQ ID NO:23を含む重鎖可変領域CDR1;
(b)SEQ ID NO:33を含む重鎖可変領域CDR2;
(c)SEQ ID NO:43を含む重鎖可変領域CDR3;
(d)SEQ ID NO:53を含む軽鎖可変領域CDR1;
(e)SEQ ID NO:63を含む軽鎖可変領域CDR2;および
(f)SEQ ID NO:73を含む軽鎖可変領域CDR3。
(a)SEQ ID NO:24を含む重鎖可変領域CDR1;
(b)SEQ ID NO:34を含む重鎖可変領域CDR2;
(c)SEQ ID NO:44を含む重鎖可変領域CDR3;
(d)SEQ ID NO:54を含む軽鎖可変領域CDR1;
(e)SEQ ID NO:64を含む軽鎖可変領域CDR2;および
(f)SEQ ID NO:74を含む軽鎖可変領域CDR3。
(a)SEQ ID NO:25を含む重鎖可変領域CDR1;
(b)SEQ ID NO:35を含む重鎖可変領域CDR2;
(c)SEQ ID NO:45を含む重鎖可変領域CDR3;
(d)SEQ ID NO:55を含む軽鎖可変領域CDR1;
(e)SEQ ID NO:65を含む軽鎖可変領域CDR2;および
(f)SEQ ID NO:75を含む軽鎖可変領域CDR3。
(a)SEQ ID NO:26を含む重鎖可変領域CDR1;
(b)SEQ ID NO:36を含む重鎖可変領域CDR2;
(c)SEQ ID NO:46を含む重鎖可変領域CDR3;
(d)SEQ ID NO:56を含む軽鎖可変領域CDR1;
(e)SEQ ID NO:66を含む軽鎖可変領域CDR2;および
(f)SEQ ID NO:76を含む軽鎖可変領域CDR3。
(a)SEQ ID NO:27を含む重鎖可変領域CDR1;
(b)SEQ ID NO:37を含む重鎖可変領域CDR2;
(c)SEQ ID NO:47を含む重鎖可変領域CDR3;
(d)SEQ ID NO:57を含む軽鎖可変領域CDR1;
(e)SEQ ID NO:67を含む軽鎖可変領域CDR2;および
(f)SEQ ID NO:77を含む軽鎖可変領域CDR3。
(a)SEQ ID NO:28を含む重鎖可変領域CDR1;
(b)SEQ ID NO:38を含む重鎖可変領域CDR2;
(c)SEQ ID NO:48を含む重鎖可変領域CDR3;
(d)SEQ ID NO:58を含む軽鎖可変領域CDR1;
(e)SEQ ID NO:68を含む軽鎖可変領域CDR2;および
(f)SEQ ID NO:78を含む軽鎖可変領域CDR3。
(a)SEQ ID NO:29を含む重鎖可変領域CDR1;
(b)SEQ ID NO:39を含む重鎖可変領域CDR2;
(c)SEQ ID NO:49を含む重鎖可変領域CDR3;
(d)SEQ ID NO:59を含む軽鎖可変領域CDR1;
(e)SEQ ID NO:69を含む軽鎖可変領域CDR2;および
(f)SEQ ID NO:79を含む軽鎖可変領域CDR3。
(a)SEQ ID NO:30を含む重鎖可変領域CDR1;
(b)SEQ ID NO:40を含む重鎖可変領域CDR2;
(c)SEQ ID NO:50を含む重鎖可変領域CDR3;
(d)SEQ ID NO:60を含む軽鎖可変領域CDR1;
(e)SEQ ID NO:70を含む軽鎖可変領域CDR2;および
(f)SEQ ID NO:80を含む軽鎖可変領域CDR3。
(a)SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:4、SEQ ID NO:5、SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:9、およびSEQ ID NO:10からなる群より選択されるアミノ酸配列を含む重鎖可変領域;ならびに、
(b)SEQ ID NO:11、SEQ ID NO:12、SEQ ID NO:13、SEQ ID NO:14、SEQ ID NO:15、SEQ ID NO:16、SEQ ID NO:17、SEQ ID NO:18、SEQ ID NO:19、およびSEQ ID NO:20からなる群より選択されるアミノ酸配列を含む軽鎖可変領域。
(a)SEQ ID NO:1のアミノ酸配列を含む重鎖可変領域;および
(b)SEQ ID NO:11のアミノ酸配列を含む軽鎖可変領域。
(a)SEQ ID NO:2のアミノ酸配列を含む重鎖可変領域;および
(b)SEQ ID NO:12のアミノ酸配列を含む軽鎖可変領域。
(a)SEQ ID NO:3のアミノ酸配列を含む重鎖可変領域;および
(b)SEQ ID NO:13のアミノ酸配列を含む軽鎖可変領域。
(a)SEQ ID NO:4のアミノ酸配列を含む重鎖可変領域;および
(b)SEQ ID NO:14のアミノ酸配列を含む軽鎖可変領域。
(a)SEQ ID NO:5のアミノ酸配列を含む重鎖可変領域;および
(b)SEQ ID NO:15のアミノ酸配列を含む軽鎖可変領域。
(a)SEQ ID NO:6のアミノ酸配列を含む重鎖可変領域;および
(b)SEQ ID NO:16のアミノ酸配列を含む軽鎖可変領域。
(a)SEQ ID NO:7のアミノ酸配列を含む重鎖可変領域;および
(b)SEQ ID NO:17のアミノ酸配列を含む軽鎖可変領域。
(a)SEQ ID NO:8のアミノ酸配列を含む重鎖可変領域;および
(b)SEQ ID NO:18のアミノ酸配列を含む軽鎖可変領域。
(a)SEQ ID NO:9のアミノ酸配列を含む重鎖可変領域;および
(b)SEQ ID NO:19のアミノ酸配列を含む軽鎖可変領域。
(a)SEQ ID NO:10のアミノ酸配列を含む重鎖可変領域;および
(b)SEQ ID NO:20のアミノ酸配列を含む軽鎖可変領域。
(a)(i)SEQ ID NO:21、SEQ ID NO:22、SEQ ID NO:23、SEQ ID NO:24、SEQ ID NO:25、SEQ ID NO:26、SEQ ID NO:27、SEQ ID NO:28、SEQ ID NO:29、およびSEQ ID NO:30からなる群より選択されるCDR1配列、SEQ ID NO:31、SEQ ID NO:32、SEQ ID NO:33、SEQ ID NO:34、SEQ ID NO:35、SEQ ID NO:36、SEQ ID NO:37、SEQ ID NO:38、SEQ ID NO:39、およびSEQ ID NO:40からなる群より選択されるCDR2配列、ならびにSEQ ID NO:41、SEQ ID NO:42、SEQ ID NO:43、SEQ ID NO:44、SEQ ID NO:45、SEQ ID NO:46、SEQ ID NO:47、SEQ ID NO:48、SEQ ID NO:49、およびSEQ ID NO:50からなる群より選択されるCDR3配列を含む重鎖可変領域抗体配列、または(ii)SEQ ID NO:51、SEQ ID NO:52、SEQ ID NO:53、SEQ ID NO:54、SEQ ID NO:55、SEQ ID NO:56、SEQ ID NO:57、SEQ ID NO:58、SEQ ID NO:59、およびSEQ ID NO:60からなる群より選択されるCDR1配列、SEQ ID NO:61、SEQ ID NO:62、SEQ ID NO:63、SEQ ID NO:64、SEQ ID NO:65、SEQ ID NO:66、SEQ ID NO:67、SEQ ID NO:68、SEQ ID NO:69、およびSEQ ID NO:70からなる群より選択されるCDR2配列、ならびにSEQ ID NO:71、SEQ ID NO:72、SEQ ID NO:73、SEQ ID NO:74、SEQ ID NO:75、SEQ ID NO:76、SEQ ID NO:77、SEQ ID NO:78、SEQ ID NO:79、およびSEQ ID NO:80からなる群より選択されるCDR3配列を含む軽鎖可変領域抗体配列を提供する段階;
(b)重鎖可変領域抗体配列および軽鎖可変領域抗体配列より選択される少なくとも1つの可変領域抗体配列内の少なくとも1つのアミノ酸残基を改変して、少なくとも1つの改変抗体配列を作製する段階;ならびに
(c)改変抗体配列をタンパク質として発現させる段階。
1つの局面において、本開示は、PD-L1に特異的に結合する、単離されたモノクローナル抗体、特にヒトモノクローナル抗体に関する。特定の態様において、本発明の抗体は、PD-L1に結合する高親和性、混合リンパ球反応において、T細胞増殖、IFN-γおよび/もしくはIL-2分泌を増加させる能力、PD-1受容体へのPD-L1の結合を阻害する能力、抗体応答を刺激する能力、ならびに/または調節性T細胞の抑制機能を逆転させる能力など1種または複数種の望ましい機能特性を示す。さらに、またはあるいは、本発明の抗体は、特定の重鎖生殖系列配列および軽鎖生殖系列配列に由来し、かつ/または、特定のアミノ酸配列を含むCDR領域のような特定の構造的特徴を含む。
本発明の抗体は、抗体の特定の機能的特徴または特性を特徴とする。例えば、これらの抗体は、ヒトPD-L1に特異的に結合する。好ましくは、本発明の抗体は、高親和性で、例えば1×10-7Mもしくはそれ以下のKDでPD-L1に結合する。本発明の抗PD-L1抗体は、好ましくは、以下の特徴のうち1種または複数種を提示する:
(a)1×10-7Mもしくはそれ以下のKDでヒトPD-L1に結合する;
(b)混合リンパ球反応(MLR)アッセイ法においてT細胞増殖を増加させる;
(c)MLRアッセイ法においてインターフェロン-γ産生を増加させる;
(d)MLRアッセイ法においてIL-2分泌を増加させる;
(e)抗体応答を刺激する;ならびに/または、
(f)T細胞エフェクター細胞および/もしくは樹状細胞に対する調節性T細胞の作用を逆転させる。
本発明の好ましい抗体は、実施例1および実施例2で説明されるように単離され、かつ構造的に特徴付けられる、ヒトモノクローナル抗体3G10、12A4、10A5、5F8、10H10、1B12、7H1、11E6、12B7、および13G4である。3G10、12A4、10A5、5F8、10H10、1B12、7H1、11E6、12B7、および13G4のVHアミノ酸配列は、それぞれ、SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:4、SEQ ID NO:5、SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:9、およびSEQ ID NO:10において示される。3G10、12A4、10A5、5F8、10H10、1B12、7H1、11E6、12B7、および13G4のVLアミノ酸配列は、それぞれ、SEQ ID NO:11、SEQ ID NO:12、SEQ ID NO:13、SEQ ID NO:14、SEQ ID NO:15、SEQ ID NO:16、SEQ ID NO:17、SEQ ID NO:18、SEQ ID NO:19、およびSEQ ID NO:20において示される。
(a)SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:4、SEQ ID NO:5、SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:9、およびSEQ ID NO:10からなる群より選択されるアミノ酸配列を含む重鎖可変領域;ならびに、
(b)SEQ ID NO:11、SEQ ID NO:12、SEQ ID NO:13、SEQ ID NO:14、SEQ ID NO:15、SEQ ID NO:16、SEQ ID NO:17、SEQ ID NO:18、SEQ ID NO:19、およびSEQ ID NO:20からなる群より選択されるアミノ酸配列を含む軽鎖可変領域。
(a)SEQ ID NO:1のアミノ酸配列を含む重鎖可変領域;および(b)SEQ ID NO:11のアミノ酸配列を含む軽鎖可変領域;または
(a)SEQ ID NO:2のアミノ酸配列を含む重鎖可変領域;および(b)SEQ ID NO:12のアミノ酸配列を含む軽鎖可変領域;または
(a)SEQ ID NO:3のアミノ酸配列を含む重鎖可変領域;および(b)SEQ ID NO:13のアミノ酸配列を含む軽鎖可変領域;または
(a)SEQ ID NO:4のアミノ酸配列を含む重鎖可変領域;および(b)SEQ ID NO:14のアミノ酸配列を含む軽鎖可変領域;または
(a)SEQ ID NO:5のアミノ酸配列を含む重鎖可変領域;および(b)SEQ ID NO:15のアミノ酸配列を含む軽鎖可変領域;または
(a)SEQ ID NO:6のアミノ酸配列を含む重鎖可変領域;および(b)SEQ ID NO:16のアミノ酸配列を含む軽鎖可変領域;または
(a)SEQ ID NO:7のアミノ酸配列を含む重鎖可変領域;および(b)SEQ ID NO:17のアミノ酸配列を含む軽鎖可変領域;または
(a)SEQ ID NO:8のアミノ酸配列を含む重鎖可変領域;および(b)SEQ ID NO:18のアミノ酸配列を含む軽鎖可変領域;または
(a)SEQ ID NO:9のアミノ酸配列を含む重鎖可変領域;および(b)SEQ ID NO:19のアミノ酸配列を含む軽鎖可変領域;または
(a)SEQ ID NO:10のアミノ酸配列を含む重鎖可変領域;および(b)SEQ ID NO:20のアミノ酸配列を含む軽鎖可変領域。
(a)SEQ ID NO:21、SEQ ID NO:22、SEQ ID NO:23、SEQ ID NO:24、SEQ ID NO:25、SEQ ID NO:26、SEQ ID NO:27、SEQ ID NO:28、SEQ ID NO:29、およびSEQ ID NO:30からなる群より選択されるアミノ酸配列を含む、重鎖可変領域のCDR1;
(b)SEQ ID NO:31、SEQ ID NO:32、SEQ ID NO:33、SEQ ID NO:34、SEQ ID NO:35、SEQ ID NO:36、SEQ ID NO:37、SEQ ID NO:38、SEQ ID NO:39、およびSEQ ID NO:40からなる群より選択されるアミノ酸配列を含む、重鎖可変領域のCDR2;
(c)SEQ ID NO:41、SEQ ID NO:42、SEQ ID NO:43、SEQ ID NO:44、SEQ ID NO:45、SEQ ID NO:46、SEQ ID NO:47、SEQ ID NO:48、SEQ ID NO:49、およびSEQ ID NO:50からなる群より選択されるアミノ酸配列を含む、重鎖可変領域のCDR3;
(d)SEQ ID NO:51、SEQ ID NO:52、SEQ ID NO:53、SEQ ID NO:54、SEQ ID NO:55、SEQ ID NO:56、SEQ ID NO:57、SEQ ID NO:58、SEQ ID NO:59、およびSEQ ID NO:60からなる群より選択されるアミノ酸配列を含む、軽鎖可変領域のCDR1;
(e)SEQ ID NO:61、SEQ ID NO:62、SEQ ID NO:63、SEQ ID NO:64、SEQ ID NO:65、SEQ ID NO:66、SEQ ID NO:67、SEQ ID NO:68、SEQ ID NO:69、およびSEQ ID NO:70からなる群より選択されるアミノ酸配列を含む、軽鎖可変領域のCDR2;ならびに、
(f)SEQ ID NO:71、SEQ ID NO:72、SEQ ID NO:73、SEQ ID NO:74、SEQ ID NO:75、SEQ ID NO:76、SEQ ID NO:77、SEQ ID NO:78、SEQ ID NO:79、およびSEQ ID NO:80からなる群より選択されるアミノ酸配列を含む、軽鎖可変領域のCDR3。
(a)SEQ ID NO:21を含む重鎖可変領域CDR1;
(b)SEQ ID NO:31を含む重鎖可変領域CDR2;
(c)SEQ ID NO:41を含む重鎖可変領域CDR3;
(d)SEQ ID NO:51を含む軽鎖可変領域CDR1;
(e)SEQ ID NO:61を含む軽鎖可変領域CDR2;および
(f)SEQ ID NO:71を含む軽鎖可変領域CDR3。
(a)SEQ ID NO:22を含む重鎖可変領域CDR1;
(b)SEQ ID NO:32を含む重鎖可変領域CDR2;
(c)SEQ ID NO:42を含む重鎖可変領域CDR3;
(d)SEQ ID NO:52を含む軽鎖可変領域CDR1;
(e)SEQ ID NO:62を含む軽鎖可変領域CDR2;および
(f)SEQ ID NO:72を含む軽鎖可変領域CDR3。
(a)SEQ ID NO:23を含む重鎖可変領域CDR1;
(b)SEQ ID NO:33を含む重鎖可変領域CDR2;
(c)SEQ ID NO:43を含む重鎖可変領域CDR3;
(d)SEQ ID NO:53を含む軽鎖可変領域CDR1;
(e)SEQ ID NO:63を含む軽鎖可変領域CDR2;および
(f)SEQ ID NO:73を含む軽鎖可変領域CDR3。
(a)SEQ ID NO:24を含む重鎖可変領域CDR1;
(b)SEQ ID NO:34を含む重鎖可変領域CDR2;
(c)SEQ ID NO:44を含む重鎖可変領域CDR3;
(d)SEQ ID NO:54を含む軽鎖可変領域CDR1;
(e)SEQ ID NO:64を含む軽鎖可変領域CDR2;および
(f)SEQ ID NO:74を含む軽鎖可変領域CDR3。
(a)SEQ ID NO:25を含む重鎖可変領域CDR1;
(b)SEQ ID NO:35を含む重鎖可変領域CDR2;
(c)SEQ ID NO:45を含む重鎖可変領域CDR3;
(d)SEQ ID NO:55を含む軽鎖可変領域CDR1;
(e)SEQ ID NO:65を含む軽鎖可変領域CDR2;および
(f)SEQ ID NO:75を含む軽鎖可変領域CDR3。
(a)SEQ ID NO:26を含む重鎖可変領域CDR1;
(b)SEQ ID NO:36を含む重鎖可変領域CDR2;
(c)SEQ ID NO:46を含む重鎖可変領域CDR3;
(d)SEQ ID NO:56を含む軽鎖可変領域CDR1;
(e)SEQ ID NO:66を含む軽鎖可変領域CDR2;および
(f)SEQ ID NO:76を含む軽鎖可変領域CDR3。
(a)SEQ ID NO:27を含む重鎖可変領域CDR1;
(b)SEQ ID NO:37を含む重鎖可変領域CDR2;
(c)SEQ ID NO:47を含む重鎖可変領域CDR3;
(d)SEQ ID NO:57を含む軽鎖可変領域CDR1;
(e)SEQ ID NO:67を含む軽鎖可変領域CDR2;および
(f)SEQ ID NO:77を含む軽鎖可変領域CDR3。
(a)SEQ ID NO:28を含む重鎖可変領域CDR1;
(b)SEQ ID NO:38を含む重鎖可変領域CDR2;
(c)SEQ ID NO:48を含む重鎖可変領域CDR3;
(d)SEQ ID NO:58を含む軽鎖可変領域CDR1;
(e)SEQ ID NO:68を含む軽鎖可変領域CDR2;および
(f)SEQ ID NO:78を含む軽鎖可変領域CDR3。
(a)SEQ ID NO:29を含む重鎖可変領域CDR1;
(b)SEQ ID NO:39を含む重鎖可変領域CDR2;
(c)SEQ ID NO:49を含む重鎖可変領域CDR3;
(d)SEQ ID NO:59を含む軽鎖可変領域CDR1;
(e)SEQ ID NO:69を含む軽鎖可変領域CDR2;および
(f)SEQ ID NO:79を含む軽鎖可変領域CDR3。
(a)SEQ ID NO:30を含む重鎖可変領域CDR1;
(b)SEQ ID NO:40を含む重鎖可変領域CDR2;
(c)SEQ ID NO:50を含む重鎖可変領域CDR3;
(d)SEQ ID NO:60を含む軽鎖可変領域CDR1;
(e)SEQ ID NO:70を含む軽鎖可変領域CDR2;および
(f)SEQ ID NO:80を含む軽鎖可変領域CDR3。
特定の態様において、本発明の抗体は、特定の生殖系列重鎖免疫グロブリン遺伝子に由来する重鎖可変領域および/または特定の生殖系列軽鎖免疫グロブリン遺伝子に由来する軽鎖可変領域を含む。
(a)(SEQ ID NO:101、SEQ ID NO:102、SEQ ID NO:103、およびSEQ ID NO:104において示されるアミノ酸配列をそれぞれコードする)ヒトVH1-18遺伝子、ヒトVH1-69遺伝子、ヒトVH1-3遺伝子、またはヒトVH3-9遺伝子の産物であるか、またはそれらに由来する重鎖可変領域を含み、
(b)(SEQ ID NO:105、SEQ ID NO:106、SEQ ID NO:107、およびSEQ ID NO:108において示されるアミノ酸配列をそれぞれコードする)ヒトVKL6遺伝子、ヒトVKL15遺伝子、ヒトVKA27遺伝子、またはヒトVKL18遺伝子の産物であるか、またはそれらに由来する軽鎖可変領域を含み、かつ、
(c)PD-L1、好ましくは、ヒトPD-L1に特異的に結合する。
さらに別の態様において、本発明の抗体は、本発明の抗PD-L1抗体の望ましい機能特性を保持している、本明細書において説明する好ましい抗体のアミノ酸配列に相同であるアミノ酸配列を含む重鎖可変領域および軽鎖可変領域を含む。
(a)重鎖可変領域は、SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:4、SEQ ID NO:5、SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:9、およびSEQ ID NO:10からなる群より選択されるアミノ酸配列に少なくとも80%相同であるアミノ酸配列を含み;
(b)軽鎖可変領域は、SEQ ID NO:11、SEQ ID NO:12、SEQ ID NO:13、SEQ ID NO:14、SEQ ID NO:15、SEQ ID NO:16、SEQ ID NO:17、SEQ ID NO:18、SEQ ID NO:19、およびSEQ ID NO:20からなる群より選択されるアミノ酸配列に少なくとも80%相同であるアミノ酸配列を含み;
(c)抗体は、1×10-7Mまたはそれ以下のKDでヒトPD-L1に結合し;
(d)抗体は、混合リンパ球反応(MLR)アッセイ法においてT細胞増殖を増加させ;
(e)抗体は、MLRアッセイ法においてインターフェロン-γ産生を増加させ;
(f)抗体は、MLRアッセイ法においてIL-2分泌を増加させ;
(g)抗体は、抗体応答を刺激し;かつ、
(h)T細胞エフェクター細胞および/または樹状細胞に対する調節性T細胞の作用を逆転させる。
特定の態様において、本発明の抗体は、CDR1配列、CDR2配列、およびCDR3配列を含む重鎖可変領域、ならびにCDR1配列、CDR2配列、およびCDR3配列を含む軽鎖可変領域を含み、これらのCDR配列のうち1つまたは複数は、本明細書において説明する好ましい抗体(例えば、3G10、12A4、10A5、5F8、10H10、1B12、7H1、11E6、12B7、もしくは13G4)をベースとする指定されたアミノ酸配列またはそれらの保存的改変体を含み、かつこれらの抗体は、本発明の抗PD-L1抗体の望ましい機能的特性を保持する。したがって、本発明は、単離されたモノクローナル抗体またはその抗原結合部分であって、CDR1配列、CDR2配列、およびCDR3配列を含む重鎖可変領域ならびにCDR1配列、CDR2配列、およびCDR3配列を含む軽鎖可変領域を含み、
(a)重鎖可変領域のCDR3配列が、SEQ ID NO:41、SEQ ID NO:42、SEQ ID NO:43、SEQ ID NO:44、SEQ ID NO:45、SEQ ID NO:46、SEQ ID NO:47、SEQ ID NO:48、SEQ ID NO:49、およびSEQ ID NO:50のアミノ酸配列ならびにそれらの保存的改変体からなる群より選択されるアミノ酸配列を含み;
(b)軽鎖可変領域のCDR3配列が、SEQ ID NO:71、SEQ ID NO:72、SEQ ID NO:73、SEQ ID NO:74、SEQ ID NO:75、SEQ ID NO:76、SEQ ID NO:77、SEQ ID NO:78、SEQ ID NO:79、およびSEQ ID NO:80のアミノ酸配列ならびにそれらの保存的改変体からなる群より選択されるアミノ酸配列を含み;
(c)抗体が、1×10-7Mまたはそれ以下のKDでヒトPD-L1に結合し;
(d)抗体が、混合リンパ球反応(MLR)アッセイ法においてT細胞増殖を増加させ;
(e)抗体が、MLRアッセイ法においてインターフェロン-γ産生を増加させ;
(f)抗体が、MLRアッセイ法においてIL-2分泌を増加させ;
(g)抗体が、抗体応答を刺激し;かつ、
(h)T細胞エフェクター細胞および/または樹状細胞に対する調節性T細胞の作用を逆転させる、
単離されたモノクローナル抗体またはその抗原結合部分を提供する。
別の態様において、本発明は、本発明のPD-L1モノクローナル抗体のいずれかと同じヒトPD-L1上のエピトープに結合する抗体(すなわち、PD-L1への結合に関して、本発明のモノクローナル抗体のいずれかと交差競合する能力を有する抗体)を提供する。好ましい態様において、交差競合研究のための参照抗体は、モノクローナル抗体3G10(SEQ ID NO:1およびSEQ ID NO:11においてそれぞれ示すVH配列およびVL配列を有する)、またはモノクローナル抗体12A4(SEQ ID NO:2およびSEQ ID NO:12においてそれぞれ示すVH配列およびVL配列を有する)、またはモノクローナル抗体10A5(SEQ ID NO:3およびSEQ ID NO:13においてそれぞれ示すVH配列およびVL配列を有する)、またはモノクローナル抗体10A5(SEQ ID NO:3およびSEQ ID NO:13においてそれぞれ示すVH配列およびVL配列を有する)、またはモノクローナル抗体5F8(SEQ ID NO:4およびSEQ ID NO:14においてそれぞれ示すVH配列およびVL配列を有する)、またはモノクローナル抗体10H10(SEQ ID NO:5およびSEQ ID NO:15においてそれぞれ示すVH配列およびVL配列を有する)、またはモノクローナル抗体1B12(SEQ ID NO:6およびSEQ ID NO:16においてそれぞれ示すVH配列およびVL配列を有する)、またはモノクローナル抗体7H1(SEQ ID NO:7およびSEQ ID NO:17においてそれぞれ示すVH配列およびVL配列を有する)、またはモノクローナル抗体11E6(SEQ ID NO:8およびSEQ ID NO:18においてそれぞれ示すVH配列およびVL配列を有する)、またはモノクローナル抗体12B7(SEQ ID NO:9およびSEQ ID NO:19においてそれぞれ示すVH配列およびVL配列を有する)、またはモノクローナル抗体13G4(SEQ ID NO:10およびSEQ ID NO:20においてそれぞれ示すVH配列およびVL配列を有する)でよい。このような交差競合する抗体は、標準的なPD-L1結合アッセイ法において、3G10、12A4、10A5、5F8、10H10、1B12、7H1、11E6、12B7、または13G4と交差競合する能力に基づいて同定することができる。例えば、BIAcore解析、ELISAアッセイ法、またはフローサイトメトリーを使用して、本発明の抗体との交差競合を実証することができる。ある試験抗体が、例えば、3G10、12A4、10A5、5F8、10H10、1B12、7H1、11E6、12B7、または13G4のヒトPD-L1への結合を阻害できる場合、その試験抗体は、ヒトPD-L1への結合に際して3G10、12A4、10A5、5F8、10H10、1B12、7H1、11E6、12B7、または13G4と競合することができ、したがって、3G10、12A4、10A5、5F8、10H10、1B12、7H1、11E6、12B7、または13G4と同じヒトPD-L1上のエピトープに結合することが実証される。好ましい態様において、3G10、12A4、10A5、5F8、10H10、1B12、7H1、11E6、12B7、または13G4と同じヒトPD-L1上のエピトープに結合する抗体は、ヒトモノクローナル抗体である。このようなヒトモノクローナル抗体は、実施例において説明するようにして調製および単離することができる。
本発明の抗体はさらに、本明細書において開示される1つまたは複数のVH配列および/またはVL配列を有する抗体を、改変抗体を操作するための出発材料として用いて調製することもでき、この改変抗体は、出発抗体から変化した特性を有し得る。抗体は、一方または両方の可変領域(すなわち、VHおよび/またはVL)内、例えば、1つもしくは複数のCDR領域内および/または1つもしくは複数のフレームワーク領域内の1つまたは複数の残基を改変することによって操作することができる。さらに、またはあるいは、抗体は、例えば、抗体のエフェクター機能を変更するために、定常領域内の残基を改変することによって操作することもできる。
(a)SEQ ID NO:21、SEQ ID NO:22、SEQ ID NO:23、SEQ ID NO:24、SEQ ID NO:25、SEQ ID NO:26、SEQ ID NO:27、SEQ ID NO:28、SEQ ID NO:29、およびSEQ ID NO:30からなる群より選択されるアミノ酸配列、またはSEQ ID NO:21、SEQ ID NO:22、SEQ ID NO:23、SEQ ID NO:24、SEQ ID NO:25、SEQ ID NO:26、SEQ ID NO:27、SEQ ID NO:28、SEQ ID NO:29、およびSEQ ID NO:30と比べて1つ、2つ、3つ、4つ、もしくは5つのアミノ酸置換、欠失、もしくは付加を有するアミノ酸配列を含む、VHCDR1領域;
(b)SEQ ID NO:31、SEQ ID NO:32、SEQ ID NO:33、SEQ ID NO:34、SEQ ID NO:35、SEQ ID NO:36、SEQ ID NO:37、SEQ ID NO:38、SEQ ID NO:39、およびSEQ ID NO:40からなる群より選択されるアミノ酸配列、またはSEQ ID NO:31、SEQ ID NO:32、SEQ ID NO:33、SEQ ID NO:34、SEQ ID NO:35、SEQ ID NO:36、SEQ ID NO:37、SEQ ID NO:38、SEQ ID NO:39、およびSEQ ID NO:40と比べて1つ、2つ、3つ、4つ、もしくは5つのアミノ酸置換、欠失、もしくは付加を有するアミノ酸配列を含む、VHCDR2領域;
(c)SEQ ID NO:41、SEQ ID NO:42、SEQ ID NO:43、SEQ ID NO:44、SEQ ID NO:45、SEQ ID NO:46、SEQ ID NO:47、SEQ ID NO:48、SEQ ID NO:49、およびSEQ ID NO:50からなる群より選択されるアミノ酸配列、またはSEQ ID NO:41、SEQ ID NO:42、SEQ ID NO:43、SEQ ID NO:44、SEQ ID NO:45、SEQ ID NO:46、SEQ ID NO:47、SEQ ID NO:48、SEQ ID NO:49、およびSEQ ID NO:50と比べて1つ、2つ、3つ、4つ、もしくは5つのアミノ酸置換、欠失、もしくは付加を有するアミノ酸配列を含む、VHCDR3領域;
(d)SEQ ID NO:51、SEQ ID NO:52、SEQ ID NO:53、SEQ ID NO:54、SEQ ID NO:55、SEQ ID NO:56、SEQ ID NO:57、SEQ ID NO:58、SEQ ID NO:59、およびSEQ ID NO:60からなる群より選択されるアミノ酸配列、またはSEQ ID NO:51、SEQ ID NO:52、SEQ ID NO:53、SEQ ID NO:54、SEQ ID NO:55、SEQ ID NO:56、SEQ ID NO:57、SEQ ID NO:58、SEQ ID NO:59、およびSEQ ID NO:60と比べて1つ、2つ、3つ、4つ、もしくは5つのアミノ酸置換、欠失、もしくは付加を有するアミノ酸配列を含む、VKCDR1領域;
(e)SEQ ID NO:61、SEQ ID NO:62、SEQ ID NO:63、SEQ ID NO:64、SEQ ID NO:65、SEQ ID NO:66、SEQ ID NO:67、SEQ ID NO:68、SEQ ID NO:69、およびSEQ ID NO:70からなる群より選択されるアミノ酸配列、またはSEQ ID NO:61、SEQ ID NO:62、SEQ ID NO:63、SEQ ID NO:64、SEQ ID NO:65、SEQ ID NO:66、SEQ ID NO:67、SEQ ID NO:68、SEQ ID NO:69、およびSEQ ID NO:70と比べて1つ、2つ、3つ、4つ、もしくは5つのアミノ酸置換、欠失、もしくは付加を有するアミノ酸配列を含む、VKCDR2領域;ならびに
(f)SEQ ID NO:71、SEQ ID NO:72、SEQ ID NO:73、SEQ ID NO:74、SEQ ID NO:75、SEQ ID NO:76、SEQ ID NO:77、SEQ ID NO:78、SEQ ID NO:79、およびSEQ ID NO:80からなる群より選択されるアミノ酸配列、またはSEQ ID NO:71、SEQ ID NO:72、SEQ ID NO:73、SEQ ID NO:74、SEQ ID NO:75、SEQ ID NO:76、SEQ ID NO:77、SEQ ID NO:78、SEQ ID NO:79、およびSEQ ID NO:80と比べて1つ、2つ、3つ、4つ、または5つのアミノ酸置換、欠失、または付加を有するアミノ酸配列を含む、VKCDR3領域。
前述したように、本明細書において開示するVH配列およびVK配列を有する抗PD-L1抗体を使用して、VH配列および/もしくはVK配列、またはそれに結合している定常領域を改変することにより、新しい抗PD-L1抗体を作製することができる。したがって、本発明の別の局面において、本発明の抗PD-L1抗体、例えば、3G10、12A4、10A5、5F8、10H10、1B12、7H1、11E6、12B7、または13G4の構造的特徴を使用して、ヒトPD-L1への結合のような本発明の抗体の少なくとも1種の機能特性を保持している、構造的に関連した抗PD-L1抗体を作製する。例えば、3G10、12A4、10A5、5F8、10H10、1B12、7H1、11E6、12B7、もしくは13G4、またはそれらの変異体の1つまたは複数のCDR領域を、前述したように、公知のフレームワーク領域および/または他のCDRと組換えによって組み合わせて、組換えによって操作されたさらなる本発明の抗PD-L1抗体を作製することができる。他のタイプの改変には、以前のセクションにおいて説明したものが含まれる。操作方法のための出発材料は、本明細書において提供される1つもしくは複数のVH配列および/もしくはVK配列、またはそれらの1つもしくは複数のCDR領域である。操作された抗体を作製するためには、本明細書において提供される1つもしくは複数のVH配列および/もしくはVK配列、またはそれらの1つもしくは複数のCDR領域を有する抗体を実際に調製する(すなわち、タンパク質として発現させる)ことは必要ではない。より正確に言えば、配列中に含まれる情報は、元の配列に由来する「第2世代」配列を作製するための出発材料として使用され、次いで、その「第2世代」配列が、タンパク質として調製および発現される。
(a)(i)SEQ ID NO:21、SEQ ID NO:22、SEQ ID NO:23、SEQ ID NO:24、SEQ ID NO:25、SEQ ID NO:26、SEQ ID NO:27、SEQ ID NO:28、SEQ ID NO:29、およびSEQ ID NO:30からなる群より選択されるCDR1配列、SEQ ID NO:31、SEQ ID NO:32、SEQ ID NO:33、SEQ ID NO:34、SEQ ID NO:35、SEQ ID NO:36、SEQ ID NO:37、SEQ ID NO:38、SEQ ID NO:39、およびSEQ ID NO:40からなる群より選択されるCDR2配列、ならびに/もしくはSEQ ID NO:41、SEQ ID NO:42、SEQ ID NO:43、SEQ ID NO:44、SEQ ID NO:45、SEQ ID NO:46、SEQ ID NO:47、SEQ ID NO:48、SEQ ID NO:49、およびSEQ ID NO:50からなる群より選択されるCDR3配列を含む重鎖可変領域抗体配列;ならびに/または(ii)SEQ ID NO:51、SEQ ID NO:52、SEQ ID NO:53、SEQ ID NO:54、SEQ ID NO:55、SEQ ID NO:56、SEQ ID NO:57、SEQ ID NO:58、SEQ ID NO:59、およびSEQ ID NO:60からなる群より選択されるCDR1配列、SEQ ID NO:61、SEQ ID NO:62、SEQ ID NO:63、SEQ ID NO:64、SEQ ID NO:65、SEQ ID NO:66、SEQ ID NO:67、SEQ ID NO:68、SEQ ID NO:69、およびSEQ ID NO:70からなる群より選択されるCDR2配列、ならびに/もしくはSEQ ID NO:71、SEQ ID NO:72、SEQ ID NO:73、SEQ ID NO:74、SEQ ID NO:75、SEQ ID NO:76、SEQ ID NO:77、SEQ ID NO:78、SEQ ID NO:79、およびSEQ ID NO:80からなる群より選択されるCDR3配列を含む軽鎖可変領域抗体配列を提供する段階;
(b)重鎖可変領域抗体配列および/または軽鎖可変領域抗体配列内の少なくとも1つのアミノ酸残基を変更して、少なくとも1つの改変抗体配列を作製する段階;ならびに
(c)改変抗体配列をタンパク質として発現させる段階。
(i)1×10-7Mもしくはそれ以下のKDでヒトPD-L1に結合する;
(ii)混合リンパ球反応(MLR)アッセイ法においてT細胞増殖を増加させる;
(iii)MLRアッセイ法においてインターフェロン-γ産生を増加させる;
(iv)MLRアッセイ法においてIL-2分泌を増加させる;
(v)抗体応答を刺激する;ならびに/または、
(vi)T細胞エフェクター細胞および/もしくは樹状細胞に対する調節性T細胞の作用を逆転させる。
本開示の別の局面は、本発明の抗体をコードする核酸分子に関する。核酸は、全細胞中、細胞溶解物中、または部分的に精製された形態もしくは実質的に純粋な形態で存在してよい。核酸は、アルカリ/SDS処理、CsClバンディング、カラムクロマトグラフィー、アガロースゲル電気泳動、および当技術分野において周知の他の技術を含む標準的な技術によって、他の細胞構成要素または他の混在物、例えば他の細胞の核酸もしくはタンパク質から離れるように精製された場合、「単離」されているか、または「実質的に純粋にされて」いる。F. Ausubel, et al.編、(1987) Current Protocols in Molecular Biology, Greene Publishing and Wiley Interscience, New Yorkを参照されたい。本発明の核酸は、例えば、DNAまたはRNAでよく、かつイントロン配列を含んでも含まなくてもよい。好ましい態様において、核酸はcDNA分子である。
本発明のモノクローナル抗体(mAb)は、従来のモノクローナル抗体方法論、例えばKohlerおよびMilstein (1975) Nature 256:495の標準的な体細胞ハイブリダイゼーション技術を含む、様々な技術によって作製することができる。体細胞ハイブリダイゼーション手順が好ましいが、原則としては、モノクローナル抗体を作製するための他の技術、例えばBリンパ球のウイルス性形質転換または癌性形質転換を使用することができる。
本発明のヒト抗体を産生させるためにヒトIgマウスが使用される場合、このようなマウスは、Lonberg, N. et al. (1994) Nature 368(6474):856-859、Fishwild, D. et al. (1996) Nature Biotechnology 14:845-851、ならびにPCT公報WO 98/24884およびWO 01/14424に記載されているように、PD-L1抗原および/もしくは組換えPD-L1、またはPD-L1融合タンパク質の精製調製物または濃縮調製物で免疫化することができる。好ましくは、マウスは、初回注入時に6~16週齢である。例えば、PD-L1抗原の精製調製物または組換え調製物(5μg~50μg)を使用して、腹腔内によりヒトIgマウスを免疫化することができる。
本発明のヒトモノクローナル抗体を産生するハイブリドーマを作製するために、免疫化マウス由来の脾細胞および/またはリンパ節細胞を単離し、かつ、マウス骨髄腫細胞株のような適切な不死化細胞株に融合させることができる。結果として生じるハイブリドーマを、抗原特異的な抗体の産生についてスクリーニングすることができる。例えば、免疫化マウス由来の脾臓リンパ球の単細胞懸濁液を、50%PEGを用いて、6分の1の数のP3X63-Ag8.653非分泌性マウス骨髄腫細胞(ATCC、CRL 1580)に融合させてよい。約2×105個の細胞を平底マイクロタイタープレート中に播種し、続いて、20%胎児クローン血清、18%「653」馴化培地、5%オリゲン(origen)(IGEN)、4mM L-グルタミン、1mMピルビン酸ナトリウム、5mM HEPES、0.055mM 2-メルカプトエタノール、50ユニット/mlペニシリン、50mg/mlストレプトマイシン、50mg/mlゲンタマイシン、および1×HAT(Sigma; HATは融合後24時間目に添加する)を含む選択培地中で2週間インキュベーションする。約2週間後、細胞は、HATをHTに交換した培地中で培養してよい。次いで、個々のウェルを、ELISAにより、ヒトモノクローナルIgM抗体およびIgG抗体についてスクリーニングすることができる。大規模なハイブリドーマ増殖が一度起こったら、通常10~14日後に培地を観察してよい。抗体を分泌するハイブリドーマを再度播種し、再びスクリーニングしてよく、かつ、ヒトIgGについて依然として陽性である場合は、モノクローナル抗体を限界希釈によって少なくとも2回サブクローニングすることができる。次いで、安定なサブクローンをインビトロで培養して、特徴付けのために組織培養培地中で少量の抗体を生成させることができる。
本発明の抗体はまた、例えば、当技術分野において周知の組換えDNA技術および遺伝子トランスフェクション方法の組合せ(例えば、Morrison, S.(1985) Science 229:1202)を用いて、宿主細胞トランスフェクトーマにおいて産生させることもできる。
本発明の抗体は、例えば、標準的なELISAによって、PD-L1に対する結合について試験することができる。手短に言えば、マイクロタイタープレートを0.25μg/mlのPBS中精製PD-L1でコーティングし、次いでPBS中5%ウシ血清アルブミンでブロッキングする。抗体の希釈物(例えば、PD-L1で免疫化したマウスに由来する血漿の希釈物)を各ウェルに添加し、かつ37℃で1時間~2時間インキュベートする。これらのプレートをPBS/Tweenで洗浄し、次いで、アルカリ性ホスファターゼに結合させた二次反応物(例えば、ヒト抗体に対しては、ヤギ抗ヒトIgG Fc特異的ポリクローナル反応物)と共に、37℃で1時間インキュベートする。洗浄後、これらのプレートをpNPP基質(1mg/ml)を用いて発色させ、かつ405~650のODで解析する。好ましくは、最も高い力価を示すマウスが、融合に使用される。
本発明の抗体は、抗PD-L1抗体の様々な物理的特性によってさらに特徴付けすることができる。様々なアッセイ法が、これらの物理的特性に基づいて様々なクラスの抗体を検出および/または区別するのに使用され得る。
別の局面において、本発明は、サイトトキシン、薬物(例えば免疫抑制薬)、または放射性毒素などの治療的部分に結合された、抗PD-L1抗体またはその断片を特徴とする。このような複合体は、本明細書において「免疫複合体」と呼ばれる。1種または複数種のサイトトキシンを含む免疫複合体は、「免疫毒素」と呼ばれる。サイトトキシンまたは細胞傷害性物質には、細胞に有害である(例えば死滅させる)任意の作用物質が含まれる。例には、タキソール、サイトカラシンB、グラミシジンD、臭化エチジウム、エメチン、マイトマイシン、エトポシド、テノポシド、ビンクリスチン、ビンブラスチン、コルヒチン、ドキソルビシン、ダウノルビシン、ジヒドロキシアントラシンジオン、ミトキサントロン、ミトラマイシン、アクチノマイシンD、1-デヒドロテストステロン、糖質コルチコイド、プロカイン、テトラカイン、リドカイン、プロプラノロール、およびピューロマイシン、ならびにそれらの類似体またはホモログが含まれる。治療物質には、例えば、代謝拮抗剤(例えば、メトトレキサート、6-メルカプトプリン、6-チオグアニン、シタラビン、5-フルオロウラシルデカルバジン(decarbazine))、アルキル化剤(例えば、メクロレタミン、チオエパクロラムブシル(thioepa chlorambucil)、メルファラン、カルムスチン(BSNU)およびロムスチン(CCNU)、シクロトスファミド(cyclothosphamide)、ブスルファン、ジブロモマンニトール、ストレプトゾトシン、マイトマイシンC、およびcis-ジクロロジアミン白金(II)(DDP)シスプラチン)、アントラサイクリン(例えばダウノルビシン(以前はダウノマイシン)およびドキソルビシン)、抗生物質(例えば、ダクチノマイシン(以前はアクチノマイシン)、ブレオマイシン、ミトラマイシン、およびアントラマイシン(AMC))、ならびに抗有糸分裂物質(例えば、ビンクリスチンおよびビンブラスチン)も含まれる。
別の局面において、本発明は、本発明の抗PD-L1抗体またはその断片を含む二重特異性分子を特徴とする。本発明の抗体またはその抗原結合部分を誘導体化するか、または別の機能的分子、例えば、別のペプチドもしくはタンパク質(例えば別の抗体もしくは受容体に対するリガンド)に連結させて、少なくとも2種の異なる結合部位または標的分子に結合する二重特異性分子を作製することができる。本発明の抗体を実際に誘導体化するか、または他の複数の機能的分子に連結させて、2種より多い異なる結合部位および/または標的分子に結合する多重特異性分子を作製することができる。このような多重特異性分子もまた、本明細書において使用される「二重特異性分子」という用語に包含されると意図される。本発明の二重特異性分子を作製するために、本発明の抗体を、二重特異性分子が結果として生じるように、別の抗体、抗体断片、ペプチド、または結合ミメティックなど1種または複数種の他の結合分子に(例えば、化学結合、遺伝的融合、非共有結合、または別の方法によって)機能的に連結させることができる。
別の局面において、本発明は、薬学的に許容される担体と共に調剤された、本発明のモノクローナル抗体またはその抗原結合部分の1つまたは組合せを含む組成物、例えば薬学的組成物を提供する。このような組成物には、1つまたは組合せの(例えば2つもしくはそれ以上の異なる)本発明の抗体、または免疫複合体もしくは二重特異性分子が含まれ得る。例えば、本発明の薬学的組成物は、標的抗原上の異なるエピトープに結合するか、または相補的活性を有する抗体(または免疫複合体もしくは二重特異性物質)の組合せを含み得る。
本発明の抗体、抗体組成物、および方法は、例えば、PD-L1の検出またはPD-L1の遮断による免疫応答の増強を含む、インビトロおよびインビボでの多数の有用性を有する。好ましい態様において、本発明の抗体は、ヒト抗体である。例えば、これらの分子は、培養状態の細胞に、インビボもしくはエクスビボで、またはヒト対象に、例えばインビボで投与して、様々な状況における免疫を増強することができる。したがって、1つの局面において、本発明は、対象における免疫応答を変更する方法であって、対象における免疫応答が変更されるように、本発明の抗体またはその抗原結合部分を対象に投与する段階を含む方法を提供する。好ましくは、応答は、増強されるか、刺激されるか、または上方調節される。
抗体によってPD-L1を遮断することにより、癌細胞に対する患者の免疫応答を増強することができる。PD-L1は、正常なヒト細胞においては発現されないが、様々なヒト癌において豊富である(Dong et al. (2002) Nat Med 8:787-9)。PD-1とPD-L1の相互作用は、腫瘍浸潤リンパ球の減少、T細胞受容体を介した増殖の減少、および癌細胞による免疫回避をもたらす(Dong et al. (2003) J Mol Med 81:281-7; Blank et al. (2004)Cancer Immunol. Immunother. [電子出版]; Konishi et al. (2004) Clin. Cancer Res. 10:5094-100)。免疫抑制は、PD-1に対するPD-1の局所的相互作用を阻害することによって逆転させることができ、かつ、PD-L1に対するPD-L2の相互作用も同様に妨害される場合、効果は相加的である(Iwai et al. (2002) PNAS 99:12293-7; Brown et al. (2003) J. Immunol. 170:1257-66)。抗PD-L1抗体は、癌性腫瘍の増殖を阻害するために、単独で使用され得る。あるいは、抗PD-L1抗体は、後述するように、他の免疫原性物質、標準的な癌治療薬、または他の抗体と組み合わせて使用され得る。
本発明の他の方法は、特定の毒素または病原体に曝露された患者を治療するのに使用される。したがって、本発明の別の局面は、対象において感染症を治療する方法であって、対象の感染症が治療されるように、抗PD-L1抗体またはその抗原結合部分を対象に投与する段階を含む方法を提供する。好ましくは、抗体は、(本明細書において説明するヒト抗PD-L1抗体のいずれかのような)ヒト抗ヒトPD-L1抗体である。さらに、またはあるいは、抗体は、キメラ抗体またはヒト化抗体でよい。
抗PD-L1抗体は、自己免疫反応を喚起および増幅し得る。実際、腫瘍細胞およびペプチドワクチンを用いた抗腫瘍応答の誘導により、多くの抗腫瘍応答が、抗自己反応性(前記のvan Elsasらの抗CTLA-4+GM-CSF改変B16黒色腫で観察された色素脱失;Trp-2をワクチン接種されたマウスにおける色素脱失(Overwijk, W. et al. (1999) Proc. Natl. Acad. Sci. U.S.A. 96:2982-2987);TRAMP腫瘍細胞ワクチン(Hurwitz, A. (2000) 前記)、黒色腫ペプチド抗原ワクチン接種によって誘発される自己免疫性前立腺炎、およびヒト臨床試験において観察された白斑(Rosenberg, SAおよびWhite, DE (1996) J. Immunother Emphasis Tumor Immunol 19(1):81-4))を伴うことが明らかになっている。
抗PD-L1抗体は、抗PD-L1抗体と関心対象の抗原(例えばワクチン)の同時投与によって抗原特異的免疫応答を刺激するのに使用され得る。したがって、別の局面において、本発明は、対象における抗原に対する免疫応答を増強する方法であって、対象における抗原に対する免疫応答が増強されるように、(i)抗原、および(ii)抗PD-L1抗体またはその抗原結合部分を対象に投与する段階を含む方法を提供する。好ましくは、抗体は、(本明細書において説明するヒト抗PD-L1抗体のいずれかのような)ヒト抗ヒトPD-L1抗体である。さらに、またはあるいは、抗体は、キメラ抗体またはヒト化抗体でよい。抗原は、例えば、腫瘍抗原、ウイルス抗原、細菌抗原、または病原体由来の抗原でよい。このような抗原の非限定的な例には、上記の腫瘍抗原(もしくは腫瘍ワクチン)、または前述のウイルス、細菌、もしくは他の病原体に由来する抗原など上記のセクションで考察したものが含まれる。
実施例1:PD-L1に対するヒトモノクローナル抗体の作製
抗原
免疫化プロトコールは、(i)PD-L1の細胞外部分を含む組換え融合タンパク質、および(ii)膜結合型の完全長PD-L1の両方を抗原として使用した。いずれの抗原も、CHO細胞株において組換えトランスフェクション法によって作製した。
PD-L1に対する完全なヒトモノクローナル抗体を、ヒト抗体遺伝子を発現する染色体導入されたトランスジェニックマウスのKM系統を用いて調製した。このマウス系統において、内因性のマウスκ軽鎖遺伝子は、Chen et al. (1993) EMBO J. 12:811-820で説明されているように、ホモ接合性に破壊されており、かつ内因性のマウス重鎖遺伝子は、PCT公報WO 01/09187の実施例1で説明されているように、ホモ接合性に破壊されている。さらに、このマウス系統は、Fishwild et al. (1996) Nature Biotechnology 14:845-851に記載されているヒトκ軽鎖導入遺伝子のKCo5、およびPCT公報WO 02/43478に記載されているSC20導入染色体を有する。
PD-L1に対する完全なヒトモノクローナル抗体を作製するために、KM Mouse(登録商標)系統のマウスの同齢集団を、抗原としての精製組換えPD-L1-IgおよびPD-L1をトランスフェクトされたCHO細胞で免疫化した。HuMabマウスに対する一般的な免疫化スキームは、Lonberg, N. et al (1994) Nature 368(6474):856-859; Fishwild, D. et al. (1996) Nature Biotechnology 14:845-851、およびPCT公報WO 98/24884に記載されている。マウスは、抗原の初回注入時に6~16週齢であった。PD-L1-Ig抗原の精製組換え調製物(5μg~50μg)および5~10×106個の細胞を用いて、腹腔内(IP)経由、皮下(Sc)経由、または足蹠注射によって、HuMabマウスを免疫化した。
PD-L1に結合した抗体を産生するHuMabマウスを選択するために、免疫化したマウスに由来する血清を、Fishwild, D. et al. (1996)によって説明されているように、ELISAによって試験した。手短に言えば、マイクロタイタープレートを、PBS中に1μg/ml~2μg/mlで溶かしたトランスフェクトCHO細胞由来の精製組換えPD-L1融合タンパク質(100μl/ウェル)でコーティングし、4℃で一晩インキュベートし、次いで、200μl/ウェルのPBS/Tween(0.05%)中5%ウシ胎児血清でブロッキングした。PD-L1免疫化マウス由来の血清の希釈物を各ウェルに添加し、かつ周囲温度で1時間~2時間インキュベートした。これらのプレートをPBS/Tweenで洗浄し、次いで、西洋ワサビペルオキシダーゼ(HRP)と結合させたヤギ抗ヒトIgGポリクローナル抗体と共に、室温で1時間インキュベートした。洗浄後、これらのプレートをABTS基質(Sigma、A-1888、0.22mg/ml)を用いて発色させ、かつ分光光度計により、OD415~495で解析した。最も高力価の抗PD-L1抗体を示したマウスを融合に使用した。後述するように融合を実施し、かつ、ハイブリドーマ上清の抗PD-L1活性をELISAによって試験した。
KMマウスから単離したマウス脾細胞を、標準的なプロトコールに基づいて、PEGを用いてマウス骨髄腫細胞株に融合させた。次いで、結果として生じるハイブリドーマを、抗原特異的抗体の産生についてスクリーニングした。免疫化マウス由来の脾細胞の単細胞懸濁液を、50%PEG(Sigma)を用いて、4分の1の数のSP2/0非分泌性マウス骨髄腫細胞(ATCC、CRL 1581)に融合させた。細胞を約1×105個/ウェルで平底マイクロタイタープレート中に播種し、続いて、10%胎児クローン血清、10% P388D1(ATCC、CRL TIB-63)馴化培地、DMEM(Mediatech、CRL 10013、高グルコース、L-グルタミン、およびピルビン酸ナトリウムを含む)および5mM HEPES中3%~5%オリゲン(origen)(IGEN)、0.055mM 2-メルカプトエタノール、50mg/mlゲンタマイシン、および1×HAT(Sigma、CRL P-7185)を含む選択培地中で約2週間インキュベーションした。1~2週間後、細胞を、HATをHTに交換した培地中で培養した。次いで、個々のウェルを、(前述の)ELISAにより、ヒト抗PD-L1モノクローナルIgG抗体についてスクリーニングした。大規模なハイブリドーマ増殖が一度起こったら、通常10日~14日後に培地を観察した。抗体を分泌するハイブリドーマを再度播種し、再びスクリーニングし、かつ、ヒトIgGについて依然として陽性である場合は、抗PD-L1モノクローナル抗体を限界希釈によって少なくとも2回サブクローニングした。次いで、安定なサブクローンをインビトロで培養して、さらに特徴付けするために組織培養培地中で少量の抗体を生成させた。
3G10、12A4、10A5、5F8、10H10、1B12、7H1、11E6、12B7、および13G4モノクローナル抗体の重鎖可変領域および軽鎖可変領域をコードしているcDNA配列を、標準的なPCR技術を用いて、それぞれ、3G10、12A4、10A5、5F8、10H10、1B12、7H1、11E6、12B7、および13G4ハイブリドーマから獲得し、かつ、標準的なDNA配列決定技術を用いて配列決定した。
抗PD-L1ヒトモノクローナル抗体の結合特異性および結合動態の特徴付け
本実施例において、抗PD-L1抗体の結合親和性および結合動態をBiacore解析によって検査した。結合特異性および交差競合は、フローサイトメトリーによって検査した。
抗PD-L1抗体を、Biacore解析(Biacore AB、Uppsala、Sweden)により、親和性および結合動態に関して特徴付けした。精製した組換えヒトPD-L1融合タンパク質を、標準的なアミンカップリング化学反応およびBiacoreによって提供されるキットを用いて、562RUの密度まで、第1級アミンを介してCM5チップ(カルボキシメチルデキストランでコーティングされたチップ)に共有結合的に連結させた。結合は、(Biacore ABによって提供される)HBS EP緩衝液に溶かした濃度133nMの抗体を流速50μl/分で流すことによって測定した。抗原-抗体の結合動態を1分間追跡し、かつ、解離動態を1分間追跡した。結合曲線および解離曲線を、BIA評価ソフトウェア(Biacore AB)を用いて、1:1ラングミュア結合モデルにフィッティングさせた。結合定数の概算において結合活性の影響を最小化するために、結合段階および解離段階に対応するデータの最初の部分のみをフィッティングに使用した。決定されたKD、kon、およびkoffの値を表2に示す。
細胞表面で組換えヒトPD-L1を発現するチャイニーズハムスター卵巣(CHO)細胞株を開発し、かつ、フローサイトメトリーによってPD-L1ヒトモノクローナル抗体の特異性を決定するのに使用した。CHO細胞を、膜貫通型PD-L1をコードする完全長cDNAを含む発現プラスミドでトランスフェクトした。トランスフェクトした細胞を抗PD-L1ヒトモノクローナル抗体と共にインキュベートすることにより、3G10、10A5、および12A4抗PD-L1ヒトモノクローナル抗体の結合を評価した。これらの細胞を洗浄し、かつ、FITC標識抗ヒトIgG Abを用いて結合を検出した。FACScanフローサイトメトリー(Becton Dickinson、San Jose、CA)を用いて、フローサイトメトリー解析を実施した。結合を親CHO細胞株と比較した。これらの結果は、図32A(HuMAb 3G10)、図32B(HuMAb 10A5)、および図32C(HuMAb 12A4)に示す。また、様々な濃度の抗PD-L1抗体を用いて結合を試験した。これらの結果を図33に示す。抗PD-L1ヒトモノクローナル抗体3G10、10A5、および12A4は、PD-L1をトランスフェクトされたCHO細胞に、濃度依存的な様式で結合した。これらのデータにより、抗PD-L1ヒトモノクローナル抗体が、細胞表面PD-L1に特異的に結合することが実証される。
抗PD-L1モノクローナル抗体の特異性を、免疫グロブリンFc領域に対するヒトPD-L1融合物への結合に関して標準的なELISAアッセイ法を用いて決定した。
抗PD-L1抗体を、表面でPD-L1を発現する活性化されたヒトT細胞またはカニクイザルT細胞への結合に関して、フローサイトメトリーによって試験した。
抗PD-L1抗体を、細胞表面でPD-L1を発現する活性化されたヒトT細胞への結合に関して、フローサイトメトリーによって試験した。
細胞表面でヒトPD-L1を発現するES-2ヒト卵巣癌細胞株を使用して、PD-L1ヒトモノクローナル抗体の特異性をフローサイトメトリーによって決定した。ES-2細胞を500IU/mLの組換えhIFN-γで一晩処理して、PD-L1発現を基礎レベルより高くまで増大させた。誘導した細胞を抗PD-L1ヒトモノクローナル抗体の段階希釈物と共にインキュベートすることにより、12A4、1B12、3G10、10A5、12B7、13G4、11E6、および5F8抗PD-L1ヒトモノクローナル抗体の結合を評価した。これらの細胞を洗浄し、かつ、PE標識抗ヒトIgGAbを用いて結合を検出した。FACScaliburフローサイトメトリー(Becton Dickinson、San Jose、CA)を用いて、フローサイトメトリー解析を実施した。結合を、アイソタイプ対照抗体と比較した。これらの結果を図38に示す。抗PD-L1ヒトモノクローナル抗体12A4、1B12、3G10、10A5、12B7、13G4、11E6、および5F8は、濃度依存的な様式で、hIFN-γで誘導されたES-2細胞に結合した。これらのデータにより、抗PD-L1ヒトモノクローナル抗体が、細胞表面PD-L1に特異的に結合することが実証される。
混合リンパ球反応を用いて、リンパ球エフェクター細胞へのPD-L1/PD-1経路妨害の効果を実証した。T細胞を、アッセイ法において、抗PD-L1ヒトモノクローナル抗体の存在下または不在下での増殖、IFN-γ分泌、およびIL-2分泌に関して試験した。
調節性T細胞(CD4+、CD25+)は、免疫応答を抑制するリンパ球である。抗PD-L1ヒトモノクローナル抗体の存在下または不在下での同種異系の樹状細胞およびT細胞のMLRにおける、増殖およびIFN-γ分泌に対する調節性T細胞の添加の影響を試験した。
CMV抗原応答性のヒトPBMC(Astarte Biologics、Redmond、WA)を、0.5ug/ml CMV溶解物(Astarte Biologics)+/-力価検定した抗PD-L1抗体の存在下、TC処理した平底96ウェルプレート中に2e5個の細胞/ウェルで培養した。加熱不活性化したFBS(最終濃度10%)を添加したAIM-V培地(Invitrogen)を、総体積200ul/ウェルで使用した。これらの細胞を37℃、5%CO2で4日間培養し、このときに、分泌されたインターフェロン-γをELISA(OptEIA hIFN-γELISAキット、BD Biosciences)によって測定するために、培養上清を採取した。これらの結果を図44に示す。抗PD-L1ヒトモノクローナル抗体は、CMVに特異的なT細胞によるIFN-γ分泌を用量依存的な様式で促進する。アイソタイプ対照と比べて最も強い応答は、抗体13G4、1B12、および12A4によって生じた。これらの結果は、抗PD-L1 HuMAbが、抗原に対して予め刺激されたPBMC細胞からの記憶T細胞応答におけるIFN-γ放出を刺激し得ることを示す。
抗PD-L1ヒトモノクローナル抗体を、細胞数測定法を用いることによって、トランスフェクトされたCHO細胞上で発現されるPD-1へのリガンドPD-L1の結合を妨害する能力に関して試験した。
抗PD-L1ヒトモノクローナル抗体を、フローサイトメトリーアッセイ法を用いて、hIFN-γで誘導されたES-2ヒト卵巣癌細胞上で発現されるPD-L1への可溶性2量体型のPD-1受容体(PD-1-hFc)の結合を妨害する能力に関して試験した。妨害は、アイソタイプ対照抗体と比較した。
癌性腫瘍を移植されたマウスを、抗PD-L1抗体を用いてインビボで治療して、腫瘍増殖に対する抗体のインビボでの効果を検査する。腫瘍研究のために、6~8週齢の間のメスのAJマウス(Harlan Laboratories)を体重に基づいて無作為に6群に分ける。0日目に、DMEM培地200μlに溶解させたSA1/N線維肉腫細胞2×106個をこれらのマウスの右側腹部に皮下移植する。これらのマウスを、PBSビヒクルまたは10mg/kgの抗PD-L1抗体で処置する。1日目、4日目、8日目、および11日目に、腹腔内注射によって、抗体を含むPBSまたはビヒクル約200μlをこれらの動物に投与する。各群は10匹の動物を含み、これらの群は、(i)ビヒクル群、(ii)対照マウスIgG、および(iii)抗PD-L1抗体からなる。マウスの腫瘍増殖を1週2回、約6週間モニターする。電気式カリパスを用いて、腫瘍の3寸法を測定し(高さ×幅×長さ)、腫瘍体積を算出する。腫瘍が腫瘍の終点(1500mm3)に到達したか、または15%を超える体重減少を示す場合、マウスを安楽死させる。
MC38結腸直腸癌細胞(Dr. N. Restifo、国立癌研究所(National Cancer Institute)、Bethesda、MD;またはJeffrey Schlom、国立衛生研究所(National Institutes of Health)、Bethesda、MDから入手可能)をC57BL/6マウスに移植し(2×106細胞/マウス)、かつ、腫瘍サイズが100mm3~200mm3に達した際に治療用に選択した。0日目(すなわち、処置の最初の日)に、マウス各10匹の4群それぞれに、以下のうち1種を腹腔内(IP)注射した:(1)10mg/kgのマウスIgGおよび10mg/kgのラットIgG(対照)、(2)10mg/kgの抗CTLA-4モノクローナル抗体9D9(マウス抗マウスCTLA-4、J.Allison、Memorial Sloan-Kettering Cancer Center、New York、NYから入手)および10mg/kgのラットIgG、(3)抗PD-L1モノクローナル抗体MIH5(ラット抗マウスPD-L1、eBioscience)および10mg/kgのマウスIgG、または(4)10mg/kgの抗CTLA-4抗体9D9および10mg/kgの抗PD-L1抗体MIH5。次いで、3日目および6日目にもさらに、抗体注射を実施した。電気式カリパスを用いて、腫瘍の3寸法を測定し(高さ×幅×長さ)、腫瘍体積を算出した。腫瘍が指定の腫瘍の終点に達したら、マウスを安楽死させた。結果を図47に示す。
HuMab抗PD-L1の組織結合プロファイルを評価するために、未改変の12A4、13G4、3G10、および12B7を、脾臓、扁桃腺、大脳、小脳、心臓、肝臓、肺、腎臓、膵臓、脳下垂体、皮膚、表皮、および小腸を含む正常な(非腫瘍性)ヒト組織、ならびに肺癌組織のパネル(1サンプル/各組織)において検査した。ES-2細胞を陽性対照として使用した。Hu-IgG1およびHu-IgG4をアイソタイプ対照抗体として使用した。
SEQUENCE LISTING
<110> E. R. SQUIBB & SONS L.L.C.
<120> HUMAN MONOCLONAL ANTIBODIES TO
PROGRAMMED DEATH LIGAND 1 (PD-L1)
<150> US 60/696,426
<151> 2005-07-01
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Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Ile Phe Gly Lys Ala His Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Thr Thr Ala 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 Lys Tyr Asp Tyr Val Ser Gly Ser Pro Phe Gly Met Asp Val
100 105 110
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 8
<211> 121
<212> PRT
<213> Homo sapiens
<400> 8
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 Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Ile Phe Gly Ser Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Asp Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Ala Ala 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 Asp Ser Ser Gly Trp Ser Arg Tyr Tyr Met Asp Val Trp Gly
100 105 110
Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 9
<211> 123
<212> PRT
<213> Homo sapiens
<400> 9
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Glu Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Asn Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Leu Phe Gly Ile Ala His Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Asn Thr Ala Tyr
65 70 75 80
Met Asp Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Lys Tyr Ser Tyr Val Ser Gly Ser Pro Phe Gly Met Asp Val
100 105 110
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 10
<211> 121
<212> PRT
<213> Homo sapiens
<400> 10
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ile Thr Phe Asp Asp Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Trp Asn Arg Gly Arg Ile Glu Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Lys Gly Arg Phe Arg Tyr Phe Asp Trp Phe Leu Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 11
<211> 107
<212> PRT
<213> Homo sapiens
<400> 11
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
Leu Val Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Arg
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 12
<211> 106
<212> PRT
<213> Homo sapiens
<400> 12
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Thr
85 90 95
Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 13
<211> 107
<212> PRT
<213> Homo sapiens
<400> 13
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 Gly Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Glu Lys Ala Pro Lys Ser Leu Ile
35 40 45
Tyr Ala Ala Ser Ser 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 Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 14
<211> 108
<212> PRT
<213> Homo sapiens
<400> 14
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro
85 90 95
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 15
<211> 107
<212> PRT
<213> Homo sapiens
<400> 15
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 Gly Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Glu Lys Ala Pro Lys Ser Leu Ile
35 40 45
Tyr Ala Ala Ser Ser 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 Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 16
<211> 106
<212> PRT
<213> Homo sapiens
<400> 16
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Thr
85 90 95
Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 17
<211> 106
<212> PRT
<213> Homo sapiens
<400> 17
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Thr
85 90 95
Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 18
<211> 106
<212> PRT
<213> Homo sapiens
<400> 18
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 19
<211> 106
<212> PRT
<213> Homo sapiens
<400> 19
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Thr
85 90 95
Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
100 105
<210> 20
<211> 107
<212> PRT
<213> Homo sapiens
<400> 20
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 Gln Gly Ile Ser Ser Ala
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Ser Leu Glu 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 Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Phe
85 90 95
Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys
100 105
<210> 21
<211> 5
<212> PRT
<213> Homo sapiens
<400> 21
Asp Tyr Gly Phe Ser
1 5
<210> 22
<211> 5
<212> PRT
<213> Homo sapiens
<400> 22
Thr Tyr Ala Ile Ser
1 5
<210> 23
<211> 5
<212> PRT
<213> Homo sapiens
<400> 23
Ser Tyr Asp Val His
1 5
<210> 24
<211> 5
<212> PRT
<213> Homo sapiens
<400> 24
Thr Tyr Ala Ile Asn
1 5
<210> 25
<211> 5
<212> PRT
<213> Homo sapiens
<400> 25
Asp Tyr Val Val His
1 5
<210> 26
<211> 5
<212> PRT
<213> Homo sapiens
<400> 26
Ser Tyr Ala Ile Ser
1 5
<210> 27
<211> 5
<212> PRT
<213> Homo sapiens
<400> 27
Ser Tyr Ala Ile Ser
1 5
<210> 28
<211> 5
<212> PRT
<213> Homo sapiens
<400> 28
Ser Tyr Ala Ile Asn
1 5
<210> 29
<211> 5
<212> PRT
<213> Homo sapiens
<400> 29
Ser Tyr Ala Ile Ser
1 5
<210> 30
<211> 5
<212> PRT
<213> Homo sapiens
<400> 30
Asp Tyr Gly Met His
1 5
<210> 31
<211> 17
<212> PRT
<213> Homo sapiens
<400> 31
Trp Ile Thr Ala Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Leu Gln
1 5 10 15
Gly
<210> 32
<211> 17
<212> PRT
<213> Homo sapiens
<400> 32
Gly Ile Ile Pro Ile Phe Gly Lys Ala His Tyr Ala Gln Lys Phe Gln
1 5 10 15
Gly
<210> 33
<211> 17
<212> PRT
<213> Homo sapiens
<400> 33
Trp Leu His Ala Asp Thr Gly Ile Thr Lys Phe Ser Gln Lys Phe Gln
1 5 10 15
Gly
<210> 34
<211> 17
<212> PRT
<213> Homo sapiens
<400> 34
Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn His Ala Gln Lys Phe Gln
1 5 10 15
Gly
<210> 35
<211> 17
<212> PRT
<213> Homo sapiens
<400> 35
Gly Ile Ser Gly Asn Ser Gly Asn Ile Gly Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 36
<211> 17
<212> PRT
<213> Homo sapiens
<400> 36
Gly Ile Ile Pro Ile Phe Gly Arg Ala His Tyr Ala Gln Lys Phe Gln
1 5 10 15
Gly
<210> 37
<211> 17
<212> PRT
<213> Homo sapiens
<400> 37
Gly Ile Ile Pro Ile Phe Gly Lys Ala His Tyr Ala Gln Lys Phe Gln
1 5 10 15
Gly
<210> 38
<211> 17
<212> PRT
<213> Homo sapiens
<400> 38
Gly Ile Ile Pro Ile Phe Gly Ser Ala Asn Tyr Ala Gln Lys Phe Gln
1 5 10 15
Asp
<210> 39
<211> 17
<212> PRT
<213> Homo sapiens
<400> 39
Gly Ile Ile Pro Leu Phe Gly Ile Ala His Tyr Ala Gln Lys Phe Gln
1 5 10 15
Gly
<210> 40
<211> 17
<212> PRT
<213> Homo sapiens
<400> 40
Gly Ile Ser Trp Asn Arg Gly Arg Ile Glu Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 41
<211> 8
<212> PRT
<213> Homo sapiens
<400> 41
Asp Tyr Phe Tyr Gly Met Asp Val
1 5
<210> 42
<211> 14
<212> PRT
<213> Homo sapiens
<400> 42
Lys Phe His Phe Val Ser Gly Ser Pro Phe Gly Met Asp Val
1 5 10
<210> 43
<211> 9
<212> PRT
<213> Homo sapiens
<400> 43
Glu Arg Ile Gln Leu Trp Phe Asp Tyr
1 5
<210> 44
<211> 11
<212> PRT
<213> Homo sapiens
<400> 44
Asp Gln Gly Ile Ala Ala Ala Leu Phe Asp Tyr
1 5 10
<210> 45
<211> 4
<212> PRT
<213> Homo sapiens
<400> 45
Pro Phe Asp Tyr
1
<210> 46
<211> 14
<212> PRT
<213> Homo sapiens
<400> 46
Lys Phe His Phe Val Ser Gly Ser Pro Phe Gly Met Asp Val
1 5 10
<210> 47
<211> 14
<212> PRT
<213> Homo sapiens
<400> 47
Lys Tyr Asp Tyr Val Ser Gly Ser Pro Phe Gly Met Asp Val
1 5 10
<210> 48
<211> 12
<212> PRT
<213> Homo sapiens
<400> 48
Asp Ser Ser Gly Trp Ser Arg Tyr Tyr Met Asp Val
1 5 10
<210> 49
<211> 14
<212> PRT
<213> Homo sapiens
<400> 49
Lys Tyr Ser Tyr Val Ser Gly Ser Pro Phe Gly Met Asp Val
1 5 10
<210> 50
<211> 12
<212> PRT
<213> Homo sapiens
<400> 50
Gly Arg Phe Arg Tyr Phe Asp Trp Phe Leu Asp Tyr
1 5 10
<210> 51
<211> 11
<212> PRT
<213> Homo sapiens
<400> 51
Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu Val
1 5 10
<210> 52
<211> 11
<212> PRT
<213> Homo sapiens
<400> 52
Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu Ala
1 5 10
<210> 53
<211> 11
<212> PRT
<213> Homo sapiens
<400> 53
Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala
1 5 10
<210> 54
<211> 12
<212> PRT
<213> Homo sapiens
<400> 54
Arg Ala Ser Gln Ser Val Ser Ser Ser Tyr Leu Ala
1 5 10
<210> 55
<211> 11
<212> PRT
<213> Homo sapiens
<400> 55
Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala
1 5 10
<210> 56
<211> 11
<212> PRT
<213> Homo sapiens
<400> 56
Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu Ala
1 5 10
<210> 57
<211> 11
<212> PRT
<213> Homo sapiens
<400> 57
Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu Ala
1 5 10
<210> 58
<211> 12
<212> PRT
<213> Homo sapiens
<400> 58
Arg Ala Ser Gln Ser Val Ser Ser Ser Tyr Leu Ala
1 5 10
<210> 59
<211> 11
<212> PRT
<213> Homo sapiens
<400> 59
Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu Ala
1 5 10
<210> 60
<211> 11
<212> PRT
<213> Homo sapiens
<400> 60
Arg Ala Ser Gln Gly Ile Ser Ser Ala Leu Ala
1 5 10
<210> 61
<211> 7
<212> PRT
<213> Homo sapiens
<400> 61
Asp Ala Ser Asn Arg Ala Thr
1 5
<210> 62
<211> 7
<212> PRT
<213> Homo sapiens
<400> 62
Asp Ala Ser Asn Arg Ala Thr
1 5
<210> 63
<211> 7
<212> PRT
<213> Homo sapiens
<400> 63
Ala Ala Ser Ser Leu Gln Ser
1 5
<210> 64
<211> 7
<212> PRT
<213> Homo sapiens
<400> 64
Gly Ala Ser Ser Arg Ala Thr
1 5
<210> 65
<211> 7
<212> PRT
<213> Homo sapiens
<400> 65
Ala Ala Ser Ser Leu Gln Ser
1 5
<210> 66
<211> 7
<212> PRT
<213> Homo sapiens
<400> 66
Asp Ala Ser Asn Arg Ala Thr
1 5
<210> 67
<211> 7
<212> PRT
<213> Homo sapiens
<400> 67
Asp Ala Ser Asn Arg Ala Thr
1 5
<210> 68
<211> 7
<212> PRT
<213> Homo sapiens
<400> 68
Gly Ala Ser Ser Arg Ala Thr
1 5
<210> 69
<211> 7
<212> PRT
<213> Homo sapiens
<400> 69
Asp Ala Ser Asn Arg Ala Thr
1 5
<210> 70
<211> 7
<212> PRT
<213> Homo sapiens
<400> 70
Asp Ala Ser Ser Leu Glu Ser
1 5
<210> 71
<211> 9
<212> PRT
<213> Homo sapiens
<400> 71
Gln Gln Arg Ser Asn Trp Pro Arg Thr
1 5
<210> 72
<211> 8
<212> PRT
<213> Homo sapiens
<400> 72
Gln Gln Arg Ser Asn Trp Pro Thr
1 5
<210> 73
<211> 9
<212> PRT
<213> Homo sapiens
<400> 73
Gln Gln Tyr Asn Ser Tyr Pro Tyr Thr
1 5
<210> 74
<211> 9
<212> PRT
<213> Homo sapiens
<400> 74
Gln Gln Tyr Gly Ser Ser Pro Trp Thr
1 5
<210> 75
<211> 9
<212> PRT
<213> Homo sapiens
<400> 75
Gln Gln Tyr Asn Ser Tyr Pro Tyr Thr
1 5
<210> 76
<211> 8
<212> PRT
<213> Homo sapiens
<400> 76
Gln Gln Arg Ser Asn Trp Pro Thr
1 5
<210> 77
<211> 8
<212> PRT
<213> Homo sapiens
<400> 77
Gln Gln Arg Ser Asn Trp Pro Thr
1 5
<210> 78
<211> 7
<212> PRT
<213> Homo sapiens
<400> 78
Gln Gln Tyr Gly Ser Ser Pro
1 5
<210> 79
<211> 8
<212> PRT
<213> Homo sapiens
<400> 79
Gln Gln Arg Ser Asn Trp Pro Thr
1 5
<210> 80
<211> 9
<212> PRT
<213> Homo sapiens
<400> 80
Gln Gln Phe Asn Ser Tyr Pro Phe Thr
1 5
<210> 81
<211> 351
<212> DNA
<213> Homo sapiens
<220>
<221> CDS
<222> (1)..(351)
<400> 81
cag gtt cag ctg gtg cag tct gga gct gag gtg aag aag cct ggg gcc 48
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
tca gtg aag gtc tcc tgc aag gct tct ggt tac acc ttt acc gac tat 96
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
ggt ttc agc tgg gtg cga cag gcc cct gga caa ggg ctt gag tgg atg 144
Gly Phe Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
gga tgg atc acc gct tac aat ggt aac aca aac tat gca cag aag ctc 192
Gly Trp Ile Thr Ala Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Leu
50 55 60
cag ggc aga gtc acc atg acc aca gac aca tcc acg agc aca gtc tac 240
Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
atg gag ctg agg agc ctg aga tct gac gac acg gcc gtg tat tac tgt 288
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
gcg aga gac tac ttc tac ggt atg gac gtc tgg ggc caa ggg acc acg 336
Ala Arg Asp Tyr Phe Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr
100 105 110
gtc acc gtc tcc tca 351
Val Thr Val Ser Ser
115
<210> 82
<211> 369
<212> DNA
<213> Homo sapiens
<220>
<221> CDS
<222> (1)..(369)
<400> 82
cag gtc cag ctg gtg cag tct ggg gct gag gtg aag aag cct ggg tcc 48
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
tcg gtg aag gtc tcc tgc aag act tct gga gac acc ttc agc acc tat 96
Ser Val Lys Val Ser Cys Lys Thr Ser Gly Asp Thr Phe Ser Thr Tyr
20 25 30
gct atc agc tgg gtg cga cag gcc cct gga caa ggg ctt gag tgg atg 144
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
gga ggg atc atc cct ata ttt ggt aaa gca cac tac gca cag aag ttc 192
Gly Gly Ile Ile Pro Ile Phe Gly Lys Ala His Tyr Ala Gln Lys Phe
50 55 60
cag ggc aga gtc acg att acc gcg gac gaa tcc acg agc aca gcc tac 240
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
atg gag ctg agc agc ctg aga tct gag gac acg gcc gtg tat ttt tgt 288
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys
85 90 95
gcg aga aag ttt cac ttt gtt tcg ggg agc ccc ttc ggt atg gac gtc 336
Ala Arg Lys Phe His Phe Val Ser Gly Ser Pro Phe Gly Met Asp Val
100 105 110
tgg ggc caa ggg acc acg gtc acc gtc tcc tca 369
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 83
<211> 354
<212> DNA
<213> Homo sapiens
<220>
<221> CDS
<222> (1)..(354)
<400> 83
cag gtc caa ctt gtg cag tct ggg gct gag gtg aag aag cct ggg gcc 48
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
tca gtg aag gtt tcc tgc aag gct tct gga tac acc ttc act agc tat 96
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
gat gta cat tgg gtg cgc cag gcc ccc gga caa agg ctt gag tgg atg 144
Asp Val His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
gga tgg ctc cac gct gac act ggt atc aca aaa ttt tca cag aag ttc 192
Gly Trp Leu His Ala Asp Thr Gly Ile Thr Lys Phe Ser Gln Lys Phe
50 55 60
cag ggc aga gtc acc att acc agg gac aca tcc gcg agc aca gcc tac 240
Gln Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
atg gag ctg agc agc ctg aga tct gaa gac acg gct gtg tat tac tgt 288
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
gcg agg gag agg ata cag cta tgg ttt gac tac tgg ggc cag gga acc 336
Ala Arg Glu Arg Ile Gln Leu Trp Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
ctg gtc acc gtc tcc tca 354
Leu Val Thr Val Ser Ser
115
<210> 84
<211> 360
<212> DNA
<213> Homo sapiens
<220>
<221> CDS
<222> (1)..(360)
<400> 84
cag gtc cag ctg gtg cag tct ggg gct gag gtg aag aag cct ggg tcc 48
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
tcg gtg aag gtc tcc tgc aag gtt tct gga ggc atc ttc agc acc tat 96
Ser Val Lys Val Ser Cys Lys Val Ser Gly Gly Ile Phe Ser Thr Tyr
20 25 30
gct atc aac tgg gtg cga cag gcc cct gga caa ggg ctt gag tgg atg 144
Ala Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
gga ggg atc atc cct atc ttt ggt aca gca aac cac gca cag aag ttc 192
Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn His Ala Gln Lys Phe
50 55 60
cag ggc aga gtc acg att acc gcg gac gaa tcc acg agc aca gcc tac 240
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
atg gag ctg agc agc ctg aga tct gag gac acg gcc gtg tat tac tgt 288
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
gcg aga gat cag ggt ata gca gca gcc ctt ttt gac tac tgg ggc cag 336
Ala Arg Asp Gln Gly Ile Ala Ala Ala Leu Phe Asp Tyr Trp Gly Gln
100 105 110
gga acc ctg gtc acc gtc tcc tca 360
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 85
<211> 339
<212> DNA
<213> Homo sapiens
<220>
<221> CDS
<222> (1)..(339)
<400> 85
gaa gtg cag ctg gtg gag tct ggg gga ggc ttg gta cag cct ggc agg 48
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
tcc ctg aga ctc tcc tgt gca gtc tct gga ttc acc ttt gat gat tat 96
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
gtc gtg cac tgg gtc cgg caa gct cca ggg aag ggc ctg gag tgg gtc 144
Val Val His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
tca ggt att agt ggg aat agt ggt aac ata ggc tat gcg gac tct gtg 192
Ser Gly Ile Ser Gly Asn Ser Gly Asn Ile Gly Tyr Ala Asp Ser Val
50 55 60
aag ggc cga ttc acc atc tcc aga gac aac gcc aag aac tcc ctg tat 240
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
ctg caa atg aac agt ctg aga gct gag gac acg gcc ttg tat tac tgt 288
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
gcg gtc ccc ttt gac tac tgg ggc cag gga acc ctg gtc acc gtc tcc 336
Ala Val Pro Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
100 105 110
tca 339
Ser
<210> 86
<211> 369
<212> DNA
<213> Homo sapiens
<220>
<221> CDS
<222> (1)..(369)
<400> 86
cag gtc cag ctg gtg cag tct ggg gct gag gtg aag aag cct ggg tcc 48
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
tcg gtg aag gtc tcc tgc aag act tct gga gac acc ttc agc agc tat 96
Ser Val Lys Val Ser Cys Lys Thr Ser Gly Asp Thr Phe Ser Ser Tyr
20 25 30
gct atc agc tgg gtg cga cag gcc cct gga caa ggg ctt gag tgg atg 144
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
gga ggg atc atc cct atc ttt ggt aga gca cac tac gca cag aag ttc 192
Gly Gly Ile Ile Pro Ile Phe Gly Arg Ala His Tyr Ala Gln Lys Phe
50 55 60
cag ggc aga gtc acg att acc gcg gac gaa tcc acg agc aca gcc tac 240
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
atg gag ctg agc agc ctg aga tct gag gac acg gcc gtg tat ttt tgt 288
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys
85 90 95
gcg aga aag ttt cac ttt gtt tcg ggg agc ccc ttc ggt atg gac gtc 336
Ala Arg Lys Phe His Phe Val Ser Gly Ser Pro Phe Gly Met Asp Val
100 105 110
tgg ggc caa ggg acc acg gtc acc gtc tcc tca 369
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 87
<211> 369
<212> DNA
<213> Homo sapiens
<220>
<221> CDS
<222> (1)..(369)
<400> 87
cag gtc cag ctg gtg cag tct ggg gct gag gtg aag aag cct ggg tcc 48
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
tcg gtg aag gtc tcc tgc aag act tct gga ggc acc ttc agc agc tat 96
Ser Val Lys Val Ser Cys Lys Thr Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
gct atc agc tgg gtg cga cag gcc cct gga caa ggg ctt gag tgg atg 144
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
gga ggg atc atc cct atc ttt ggt aaa gca cac tac gca cag aag ttc 192
Gly Gly Ile Ile Pro Ile Phe Gly Lys Ala His Tyr Ala Gln Lys Phe
50 55 60
cag ggc aga gtc acg att acc gcg gac gaa tcc acg acc aca gcc tac 240
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Thr Thr Ala Tyr
65 70 75 80
atg gag ctg agc agc ctg aga tct gag gac acg gcc gtg tat tac tgt 288
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
gcg aga aag tat gac tat gtt tcg ggg agc ccc ttc ggt atg gac gtc 336
Ala Arg Lys Tyr Asp Tyr Val Ser Gly Ser Pro Phe Gly Met Asp Val
100 105 110
tgg ggc caa ggg acc acg gtc acc gtc tcc tca 369
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 88
<211> 363
<212> DNA
<213> Homo sapiens
<220>
<221> CDS
<222> (1)..(363)
<400> 88
cag gtc cag ctg gtg cag tct ggg gct gag gtg aag aag cct ggg tcc 48
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
tcg gtg aag gtc tcc tgc aag gct tct gga ggc acc ttc agc agc tat 96
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
gct atc aac tgg gtg cga cag gcc cct gga caa ggg ctt gag tgg atg 144
Ala Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
gga ggg atc atc cct atc ttt ggt tca gca aac tac gca cag aag ttc 192
Gly Gly Ile Ile Pro Ile Phe Gly Ser Ala Asn Tyr Ala Gln Lys Phe
50 55 60
cag gac aga gtc acg att acc gcg gac gaa tcc acg agc gca gcc tac 240
Gln Asp Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Ala Ala Tyr
65 70 75 80
atg gag ctg agc agc ctg aga tct gag gac acg gcc gta tat tac tgt 288
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
gcg aga gac agc agt ggc tgg tct cgg tac tat atg gac gtc tgg ggc 336
Ala Arg Asp Ser Ser Gly Trp Ser Arg Tyr Tyr Met Asp Val Trp Gly
100 105 110
caa ggg acc acg gtc acc gtc tcc tca 363
Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 89
<211> 369
<212> DNA
<213> Homo sapiens
<220>
<221> CDS
<222> (1)..(369)
<400> 89
cag gtc cag ctg gtg cag tct ggg gct gag gtg aag gag cct ggg tcc 48
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Glu Pro Gly Ser
1 5 10 15
tcg gtg aag gtc tcc tgc aag gct tct gga ggc acc ttc aac agc tat 96
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Asn Ser Tyr
20 25 30
gct atc agc tgg gtg cga cag gcc cct gga caa ggg ctt gag tgg atg 144
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
gga ggg atc atc cct ctt ttc ggt ata gca cac tac gca cag aag ttc 192
Gly Gly Ile Ile Pro Leu Phe Gly Ile Ala His Tyr Ala Gln Lys Phe
50 55 60
cag ggc aga gtc acg att acc gcg gac gaa tcc acg aac aca gcc tat 240
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Asn Thr Ala Tyr
65 70 75 80
atg gac ctg agc agc ctg aga tct gag gac acg gcc gta tat tat tgt 288
Met Asp Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
gcg aga aag tat tcc tat gtt tcg ggg agc ccc ttc ggt atg gac gtc 336
Ala Arg Lys Tyr Ser Tyr Val Ser Gly Ser Pro Phe Gly Met Asp Val
100 105 110
tgg ggc caa ggg acc acg gtc acc gtc tcc tca 369
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 90
<211> 363
<212> DNA
<213> Homo sapiens
<220>
<221> CDS
<222> (1)..(363)
<400> 90
gaa gtg cag ttg gtg gag tct ggg gga ggc ttg gta cag cct ggc agg 48
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
tcc ctg aga ctc tcc tgt gca gcc tct gga atc acc ttt gat gat tat 96
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ile Thr Phe Asp Asp Tyr
20 25 30
ggc atg cac tgg gtc cgg caa gct cca ggg aag ggc ctg gag tgg gtc 144
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
tca ggt att agc tgg aat aga ggt aga ata gag tat gcg gac tct gtg 192
Ser Gly Ile Ser Trp Asn Arg Gly Arg Ile Glu Tyr Ala Asp Ser Val
50 55 60
aag ggc cga ttc acc atc tcc aga gac aac gcc aag aac tcc ctg tat 240
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
ctg caa atg aac agt ctg aga gct gag gac acg gcc ttg tat tac tgt 288
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
gca aaa ggg cgg ttc cga tat ttt gac tgg ttt ctt gac tac tgg ggc 336
Ala Lys Gly Arg Phe Arg Tyr Phe Asp Trp Phe Leu Asp Tyr Trp Gly
100 105 110
cag gga acc ctg gtc acc gtc tcc tca 363
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 91
<211> 321
<212> DNA
<213> Homo sapiens
<220>
<221> CDS
<222> (1)..(321)
<400> 91
gaa att gtg ttg aca cag tct cca gcc acc ctg tct ttg tct cca ggg 48
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
gaa aga gcc acc ctc tcc tgc agg gcc agt cag agt gtt agc agc tac 96
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
tta gtc tgg tac caa cag aaa cct ggc cag gct ccc agg ctc ctc atc 144
Leu Val Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
tat gat gca tcc aac agg gcc act ggc atc cca gcc agg ttc agt ggc 192
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
agt ggg tct ggg aca gac ttc act ctc acc atc agc agc cta gag cct 240
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
gaa gat ttt gca gtt tat tac tgt cag cag cgt agc aac tgg cct cgg 288
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Arg
85 90 95
acg ttc ggc caa ggg acc aag gtg gaa atc aaa 321
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 92
<211> 318
<212> DNA
<213> Homo sapiens
<220>
<221> CDS
<222> (1)..(318)
<400> 92
gaa att gtg ttg aca cag tct cca gcc acc ctg tct ttg tct cca ggg 48
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
gaa aga gcc acc ctc tcc tgc agg gcc agt cag agt gtt agc agc tac 96
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
tta gcc tgg tac caa cag aaa cct ggc cag gct ccc agg ctc ctc atc 144
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
tat gat gca tcc aac agg gcc act ggc atc cca gcc agg ttc agt ggc 192
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
agt ggg tct ggg aca gac ttc act ctc acc atc agc agc cta gag cct 240
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
gaa gat ttt gca gtt tat tac tgt cag cag cgt agc aac tgg ccg acg 288
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Thr
85 90 95
ttc ggc caa ggg acc aag gtg gaa atc aaa 318
Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 93
<211> 321
<212> DNA
<213> Homo sapiens
<220>
<221> CDS
<222> (1)..(321)
<400> 93
gac atc cag atg acc cag tct cca tcc tca ctg tct gca tct gta gga 48
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
gac aga gtc acc atc act tgt cgg gcg agt cag ggt att agc agc tgg 96
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp
20 25 30
tta gcc tgg tat cag cag aaa cca gag aaa gcc cct aag tcc ctg atc 144
Leu Ala Trp Tyr Gln Gln Lys Pro Glu Lys Ala Pro Lys Ser Leu Ile
35 40 45
tat gct gca tcc agt ttg caa agt ggg gtc cca tca agg ttc agc ggc 192
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
agt gga tct ggg aca gat ttc act ctc acc atc agc agc ctg cag cct 240
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
gaa gat ttt gca act tat tac tgc caa cag tat aat agt tac ccg tac 288
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Tyr
85 90 95
act ttt ggc cag ggg acc aag ctg gag atc aaa 321
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 94
<211> 324
<212> DNA
<213> Homo sapiens
<220>
<221> CDS
<222> (1)..(324)
<400> 94
gaa att gtg ttg acg cag tct cca ggc acc ctg tct ttg tct cca ggg 48
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
gaa aga gcc acc ctc tcc tgc agg gcc agt cag agt gtt agc agc agc 96
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
tac tta gcc tgg tac cag cag aaa cct ggc cag gct ccc agg ctc ctc 144
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
atc tat ggt gca tcc agc agg gcc act ggc atc cca gac agg ttc agt 192
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
ggc agt ggg tct ggg aca gac ttc act ctc acc atc agc aga ctg gag 240
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
cct gaa gat ttt gca gtg tat tac tgt cag cag tat ggt agc tca ccg 288
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro
85 90 95
tgg acg ttc ggc caa ggg acc aag gtg gaa atc aaa 324
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 95
<211> 321
<212> DNA
<213> Homo sapiens
<220>
<221> CDS
<222> (1)..(321)
<400> 95
gac atc cag atg acc cag tct cca tcc tca ctg tct gca tct gta gga 48
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
gac aga gtc acc atc act tgt cgg gcg agt cag ggt att agc agc tgg 96
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp
20 25 30
tta gcc tgg tat cag cag aaa cca gag aaa gcc cct aag tcc ctg atc 144
Leu Ala Trp Tyr Gln Gln Lys Pro Glu Lys Ala Pro Lys Ser Leu Ile
35 40 45
tat gct gca tcc agt ttg caa agt ggg gtc cca tca agg ttc agc ggc 192
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
agt gga tct ggg aca gat ttc act ctc acc atc agc agc ctg cag cct 240
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
gaa gat ttt gca act tat tac tgc caa cag tat aat agt tac ccg tac 288
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Tyr
85 90 95
act ttt ggc cag ggg acc aag ctg gag atc aaa 321
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 96
<211> 318
<212> DNA
<213> Homo sapiens
<220>
<221> CDS
<222> (1)..(318)
<400> 96
gaa att gtg ttg aca cag tct cca gcc acc ctg tct ttg tct cca ggg 48
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
gaa aga gcc acc ctc tcc tgc agg gcc agt cag agt gtt agc agc tac 96
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
tta gcc tgg tac caa cag aaa cct ggc cag gct ccc agg ctc ctc atc 144
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
tat gat gca tcc aac agg gcc act ggc atc cca gcc agg ttc agt ggc 192
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
agt ggg tct ggg aca gac ttc act ctc acc atc agc agc cta gag cct 240
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
gaa gat ttt gca gtt tat tac tgt cag cag cgt agc aac tgg ccg acg 288
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Thr
85 90 95
ttc ggc caa ggg acc aag gtg gaa atc aaa 318
Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 97
<211> 318
<212> DNA
<213> Homo sapiens
<220>
<221> CDS
<222> (1)..(318)
<400> 97
gaa att gtg ttg aca cag tct cca gcc acc ctg tct ttg tct cca ggg 48
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
gaa aga gcc acc ctc tcc tgc agg gcc agt cag agt gtt agc agc tac 96
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
tta gcc tgg tac caa cag aaa cct ggc cag gct ccc agg ctc ctc atc 144
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
tat gat gca tcc aac agg gcc act ggc atc cca gcc agg ttc agt ggc 192
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
agt ggg tct ggg aca gac ttc act ctc acc atc agc agc cta gag cct 240
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
gaa gat ttt gca gtt tat tac tgt cag cag cgt agc aac tgg ccg acg 288
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Thr
85 90 95
ttc ggc caa ggg acc aag gtg gaa atc aaa 318
Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 98
<211> 318
<212> DNA
<213> Homo sapiens
<220>
<221> CDS
<222> (1)..(318)
<400> 98
gaa att gtg ttg acg cag tct cca ggc acc ctg tct ttg tct cca ggg 48
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
gaa aga gcc acc ctc tcc tgc agg gcc agt cag agt gtt agc agc agc 96
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
tac tta gcc tgg tac cag cag aaa cct ggc cag gct ccc agg ctc ctc 144
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
atc tat ggt gca tcc agc agg gcc act ggc atc cca gac agg ttc agt 192
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
ggc agt ggg tct ggg aca gac ttc act ctc acc atc agc aga ctg gag 240
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
cct gaa gat ttt gca gtg tat tac tgt cag cag tat ggt agc tca cct 288
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro
85 90 95
ttc ggc gga ggg acc aag gtg gag atc aaa 318
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 99
<211> 318
<212> DNA
<213> Homo sapiens
<220>
<221> CDS
<222> (1)..(318)
<400> 99
gaa att gtg ttg aca cag tct cca gcc acc ctg tct ttg tct cca ggg 48
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
gaa aga gcc acc ctc tcc tgc agg gcc agt cag agt gtt agc agc tac 96
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
tta gcc tgg tac caa cag aaa cct ggc cag gct ccc agg ctc ctc atc 144
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
tat gat gca tcc aac agg gcc act ggc atc cca gcc agg ttc agt ggc 192
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
agt ggg tct ggg aca gac ttc act ctc acc atc agc agc cta gag cct 240
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
gaa gat ttt gca gtt tat tac tgt cag cag cgt agc aac tgg ccc acc 288
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Thr
85 90 95
ttc ggc caa ggg aca cga ctg gag att aaa 318
Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
100 105
<210> 100
<211> 321
<212> DNA
<213> Homo sapiens
<220>
<221> CDS
<222> (1)..(321)
<400> 100
gcc atc cag ttg acc cag tct cca tcc tcc ctg tct gca tct gta gga 48
Ala Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
gac aga gtc acc atc act tgc cgg gca agt cag ggc att agc agt gct 96
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Ala
20 25 30
tta gcc tgg tat cag cag aaa cca ggg aaa gct cct aag ctc ctg atc 144
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
tat gat gcc tcc agt ttg gaa agt ggg gtc cca tca agg ttc agc ggc 192
Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
agt gga tct ggg aca gat ttc act ctc acc atc agc agc ctg cag cct 240
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
gaa gat ttt gca act tat tac tgt caa cag ttt aat agt tac cca ttc 288
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Phe
85 90 95
act ttc ggc cct ggg acc aaa gtg gat atc aaa 321
Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys
100 105
<210> 101
<211> 98
<212> PRT
<213> Homo sapiens
<400> 101
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Ser Ala Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Leu
50 55 60
Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg
<210> 102
<211> 98
<212> PRT
<213> Homo sapiens
<400> 102
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 Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala 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
<210> 103
<211> 98
<212> PRT
<213> Homo sapiens
<400> 103
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Ala Gly Asn Gly Asn Thr Lys Tyr Ser Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala 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
<210> 104
<211> 97
<212> PRT
<213> Homo sapiens
<400> 104
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala
<210> 105
<211> 95
<212> PRT
<213> Homo sapiens
<400> 105
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro
85 90 95
<210> 106
<211> 95
<212> PRT
<213> Homo sapiens
<400> 106
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 Gly Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Glu Lys Ala Pro Lys Ser Leu Ile
35 40 45
Tyr Ala Ala Ser Ser 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 Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro
85 90 95
<210> 107
<211> 96
<212> PRT
<213> Homo sapiens
<400> 107
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro
85 90 95
<210> 108
<211> 95
<212> PRT
<213> Homo sapiens
<400> 108
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 Gln Gly Ile Ser Ser Ala
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Ser Leu Glu 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 Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro
85 90 95
<210> 109
<211> 107
<212> PRT
<213> Homo sapiens
<400> 109
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 110
<211> 16
<212> PRT
<213> Homo sapiens
<400> 110
Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
1 5 10 15
<210> 111
<211> 14
<212> PRT
<213> Homo sapiens
<400> 111
Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
1 5 10
<210> 112
<211> 16
<212> PRT
<213> Homo sapiens
<400> 112
Tyr Tyr Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
1 5 10 15
<210> 113
<211> 13
<212> PRT
<213> Homo sapiens
<400> 113
Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
1 5 10
<210> 114
<211> 12
<212> PRT
<213> Homo sapiens
<400> 114
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
1 5 10
<210> 115
<211> 11
<212> PRT
<213> Homo sapiens
<400> 115
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
1 5 10
<210> 116
<211> 12
<212> PRT
<213> Homo sapiens
<400> 116
Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
1 5 10
<210> 117
<211> 10
<212> PRT
<213> Homo sapiens
<400> 117
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
1 5 10
<210> 118
<211> 11
<212> PRT
<213> Homo sapiens
<400> 118
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
1 5 10
<210> 119
<211> 11
<212> PRT
<213> Homo sapiens
<400> 119
Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
1 5 10
<210> 120
<211> 12
<212> PRT
<213> Homo sapiens
<400> 120
Phe Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys
1 5 10
Claims (67)
- ヒトPD-L1に特異的に結合し、かつ以下の特性のうち少なくとも1種を示す、単離されたヒトモノクローナル抗体、またはその抗原結合部分:
(a)1×10-7Mもしくはそれ以下のKDでヒトPD-L1に結合する;
(b)混合リンパ球反応(MLR)アッセイ法においてT細胞増殖を増加させる;
(c)MLRアッセイ法においてインターフェロン-γ産生を増加させる;または
(d)MLRアッセイ法においてインターロイキン-2(IL-2)分泌を増加させる。 - アイソタイプIgG1、IgG2、またはIgG4の完全長抗体である、請求項1記載の抗体。
- 抗体断片または単鎖抗体である、請求項1記載の抗体。
- 5×10-9Mもしくはそれ以下のKDでヒトPD-L1に結合する、請求項1記載の抗体。
- 2×10-9Mもしくはそれ以下のKDでヒトPD-L1に結合する、請求項1記載の抗体。
- PD-L1への結合に関して、以下を含む参照抗体と交差競合する、単離されたヒトモノクローナル抗体、またはその抗原結合部分:
(a)SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:4、SEQ ID NO:5、SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:9、およびSEQ ID NO:10からなる群より選択されるアミノ酸配列を含むヒト重鎖可変領域、ならびに
(b)SEQ ID NO:11、SEQ ID NO:12、SEQ ID NO:13、SEQ ID NO:14、SEQ ID NO:15、SEQ ID NO:16、SEQ ID NO:17、SEQ ID NO:18、SEQ ID NO:19、およびSEQ ID NO:20からなる群より選択されるアミノ酸配列を含むヒト軽鎖可変領域。 - ヒト重鎖可変領域が、SEQ ID NO:1のアミノ酸配列を含み、かつヒト軽鎖可変領域が、SEQ ID NO:11のアミノ酸配列を含む、請求項6記載の抗体。
- ヒト重鎖可変領域が、SEQ ID NO:2のアミノ酸配列を含み、かつヒト軽鎖可変領域が、SEQ ID NO:12のアミノ酸配列を含む、請求項6記載の抗体。
- ヒト重鎖可変領域が、SEQ ID NO:3のアミノ酸配列を含み、かつヒト軽鎖可変領域が、SEQ ID NO:13のアミノ酸配列を含む、請求項6記載の抗体。
- ヒトVH1-18遺伝子の産物であるか、またはヒトVH1-18遺伝子に由来する重鎖可変領域を含む、PD-L1に特異的に結合する単離されたモノクローナル抗体、またはその抗原結合部分。
- ヒトVH1-69遺伝子の産物であるか、またはヒトVH1-69遺伝子に由来する重鎖可変領域を含む、PD-L1に特異的に結合する単離されたモノクローナル抗体、またはその抗原結合部分。
- ヒトVH1-3遺伝子の産物であるか、またはヒトVH1-3遺伝子に由来する重鎖可変領域を含む、PD-L1に特異的に結合する単離されたモノクローナル抗体、またはその抗原結合部分。
- ヒトVKL6遺伝子の産物であるか、またはヒトVKL6遺伝子に由来する軽鎖可変領域を含む、PD-L1に特異的に結合する単離されたモノクローナル抗体、またはその抗原結合部分。
- ヒトVKL15遺伝子の産物であるか、またはヒトVKL15遺伝子に由来する軽鎖可変領域を含む、PD-L1に特異的に結合する単離されたモノクローナル抗体、またはその抗原結合部分。
- 以下を含む、PD-L1に特異的に結合する単離されたモノクローナル抗体、またはその抗原結合部分:
(a)ヒトVH1-18遺伝子の重鎖可変領域;および
(b)ヒトVkL6遺伝子の軽鎖可変領域。 - 以下を含む、PD-L1に特異的に結合する単離されたモノクローナル抗体、またはその抗原結合部分:
(a)ヒトVH1-69遺伝子の重鎖可変領域;および
(b)ヒトVkL6遺伝子の軽鎖可変領域。 - 以下を含む、PD-L1に特異的に結合する単離されたモノクローナル抗体、またはその抗原結合部分:
(a)ヒトVH1-3遺伝子の重鎖可変領域;および
(b)ヒトVkL15遺伝子の軽鎖可変領域。 - CDR1配列、CDR2配列、およびCDR3配列を含む重鎖可変領域;ならびにCDR1配列、CDR2配列、およびCDR3配列を含む軽鎖可変領域を含み、
(a)重鎖可変領域のCDR3配列が、SEQ ID NO:41、SEQ ID NO:42、SEQ ID NO:43、SEQ ID NO:44、SEQ ID NO:45、SEQ ID NO:46、SEQ ID NO:47、SEQ ID NO:48、SEQ ID NO:49、およびSEQ ID NO:50、ならびにそれらの保存的改変体からなる群より選択されるアミノ酸配列を含み、
(b)軽鎖可変領域のCDR3配列が、SEQ ID NO:71、SEQ ID NO:72、SEQ ID NO:73、SEQ ID NO:74、SEQ ID NO:75、SEQ ID NO:76、SEQ ID NO:77、SEQ ID NO:78、SEQ ID NO:79、およびSEQ ID NO:80、ならびにそれらの保存的改変体からなる群より選択されるアミノ酸配列を含み;かつ、
(c)抗体が、ヒトPD-L1に特異的に結合する、
単離されたモノクローナル抗体またはその抗原結合部分。 - 重鎖可変領域のCDR2配列が、SEQ ID NO:31、SEQ ID NO:32、SEQ ID NO:33、SEQ ID NO:34、SEQ ID NO:35、SEQ ID NO:36、SEQ ID NO:37、SEQ ID NO:38、SEQ ID NO:39、およびSEQ ID NO:40のアミノ酸配列ならびにそれらの保存的改変体からなる群より選択されるアミノ酸配列を含み、かつ、軽鎖可変領域のCDR2配列が、SEQ ID NO:61、SEQ ID NO:62、SEQ ID NO:63、SEQ ID NO:64、SEQ ID NO:65、SEQ ID NO:66、SEQ ID NO:67、SEQ ID NO:68、SEQ ID NO:69、およびSEQ ID NO:70のアミノ酸配列ならびにそれらの保存的改変体からなる群より選択されるアミノ酸配列を含む、請求項18記載の抗体。
- 重鎖可変領域のCDR1配列が、SEQ ID NO:21、SEQ ID NO:22、SEQ ID NO:23、SEQ ID NO:24、SEQ ID NO:25、SEQ ID NO:26、SEQ ID NO:27、SEQ ID NO:28、SEQ ID NO:29、およびSEQ ID NO:30のアミノ酸配列ならびにそれらの保存的改変体からなる群より選択されるアミノ酸配列を含み、かつ、軽鎖可変領域のCDR1配列が、SEQ ID NO:51、SEQ ID NO:52、SEQ ID NO:53、SEQ ID NO:54、SEQ ID NO:55、SEQ ID NO:56、SEQ ID NO:57、SEQ ID NO:58、SEQ ID NO:59、およびSEQ ID NO:60のアミノ酸配列ならびにそれらの保存的改変体からなる群より選択されるアミノ酸配列を含む、請求項19記載の抗体。
- 重鎖可変領域および軽鎖可変領域を含み、
(a)重鎖可変領域が、SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:4、SEQ ID NO:5、SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:9、およびSEQ ID NO:10からなる群より選択されるアミノ酸配列に少なくとも80%相同であるアミノ酸配列を含み、
(b)軽鎖可変領域が、SEQ ID NO:11、SEQ ID NO:12、SEQ ID NO:13、SEQ ID NO:14、SEQ ID NO:15、SEQ ID NO:16、SEQ ID NO:17、SEQ ID NO:18、SEQ ID NO:19、およびSEQ ID NO:20からなる群より選択されるアミノ酸配列に少なくとも80%相同であるアミノ酸配列を含み;かつ、
抗体が、1×10-7Mまたはそれ以下のKDでヒトPD-L1に結合する、
単離されたモノクローナル抗体またはその抗原結合部分。 - 以下より選択される1種または複数種の特性をさらに含む、請求項21記載の抗体:
(a)抗体が、混合リンパ球反応(MLR)アッセイ法においてT細胞増殖を増加させる;
(b)抗体が、MLRアッセイ法においてインターフェロン-γ産生を増加させる;および
(c)抗体が、MLRアッセイ法においてIL-2分泌を増加させる。 - 以下を含む、PD-L1に特異的に結合する単離されたモノクローナル抗体、またはその抗原結合部分:
(a)SEQ ID NO:21、SEQ ID NO:22、SEQ ID NO:23、SEQ ID NO:24、SEQ ID NO:25、SEQ ID NO:26、SEQ ID NO:27、SEQ ID NO:28、SEQ ID NO:29、およびSEQ ID NO:30からなる群より選択されるアミノ酸配列を含む、重鎖可変領域のCDR1;
(b)SEQ ID NO:31、SEQ ID NO:32、SEQ ID NO:33、SEQ ID NO:34、SEQ ID NO:35、SEQ ID NO:36、SEQ ID NO:37、SEQ ID NO:38、SEQ ID NO:39、およびSEQ ID NO:40からなる群より選択されるアミノ酸配列を含む、重鎖可変領域のCDR2;
(c)SEQ ID NO:41、SEQ ID NO:42、SEQ ID NO:43、SEQ ID NO:44、SEQ ID NO:45、SEQ ID NO:46、SEQ ID NO:47、SEQ ID NO:48、SEQ ID NO:49、およびSEQ ID NO:50からなる群より選択されるアミノ酸配列を含む、重鎖可変領域のCDR3;
(d)SEQ ID NO:51、SEQ ID NO:52、SEQ ID NO:53、SEQ ID NO:54、SEQ ID NO:55、SEQ ID NO:56、SEQ ID NO:57、SEQ ID NO:58、SEQ ID NO:59、およびSEQ ID NO:60からなる群より選択されるアミノ酸配列を含む、軽鎖可変領域のCDR1;
(e)SEQ ID NO:61、SEQ ID NO:62、SEQ ID NO:63、SEQ ID NO:64、SEQ ID NO:65、SEQ ID NO:66、SEQ ID NO:67、SEQ ID NO:68、SEQ ID NO:69、およびSEQ ID NO:70からなる群より選択されるアミノ酸配列を含む、軽鎖可変領域のCDR2;ならびに、
(f)SEQ ID NO:71、SEQ ID NO:72、SEQ ID NO:73、SEQ ID NO:74、SEQ ID NO:75、SEQ ID NO:76、SEQ ID NO:77、SEQ ID NO:78、SEQ ID NO:79、およびSEQ ID NO:80からなる群より選択されるアミノ酸配列を含む、軽鎖可変領域のCDR3。 - 以下を含む、請求項23記載の抗体:
(a)SEQ ID NO:21を含む重鎖可変領域CDR1;
(b)SEQ ID NO:31を含む重鎖可変領域CDR2;
(c)SEQ ID NO:41を含む重鎖可変領域CDR3;
(d)SEQ ID NO:51を含む軽鎖可変領域CDR1;
(e)SEQ ID NO:61を含む軽鎖可変領域CDR2;および
(f)SEQ ID NO:71を含む軽鎖可変領域CDR3。 - 以下を含む、請求項23記載の抗体:
(a)SEQ ID NO:22を含む重鎖可変領域CDR1;
(b)SEQ ID NO:32を含む重鎖可変領域CDR2;
(c)SEQ ID NO:42を含む重鎖可変領域CDR3;
(d)SEQ ID NO:52を含む軽鎖可変領域CDR1;
(e)SEQ ID NO:62を含む軽鎖可変領域CDR2;および
(f)SEQ ID NO:72を含む軽鎖可変領域CDR3。 - 以下を含む、請求項23記載の抗体:
(a)SEQ ID NO:23を含む重鎖可変領域CDR1;
(b)SEQ ID NO:33を含む重鎖可変領域CDR2;
(c)SEQ ID NO:43を含む重鎖可変領域CDR3;
(d)SEQ ID NO:53を含む軽鎖可変領域CDR1;
(e)SEQ ID NO:63を含む軽鎖可変領域CDR2;および
(f)SEQ ID NO:73を含む軽鎖可変領域CDR3。 - 以下を含む、PD-L1に特異的に結合する単離されたモノクローナル抗体、またはその抗原結合部分
(a)SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:4、SEQ ID NO:5、SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:9、およびSEQ ID NO:10からなる群より選択されるアミノ酸配列を含む重鎖可変領域;ならびに、
(b)SEQ ID NO:11、SEQ ID NO:12、SEQ ID NO:13、SEQ ID NO:14、SEQ ID NO:15、SEQ ID NO:16、SEQ ID NO:17、SEQ ID NO:18、SEQ ID NO:19、およびSEQ ID NO:20からなる群より選択されるアミノ酸配列を含む軽鎖可変領域。 - 以下を含む、請求項27記載の抗体:
(a)SEQ ID NO:1のアミノ酸配列を含む重鎖可変領域;および
(b)SEQ ID NO:11のアミノ酸配列を含む軽鎖可変領域。 - 以下を含む、請求項27記載の抗体:
(a)SEQ ID NO:2のアミノ酸配列を含む重鎖可変領域;および
(b)SEQ ID NO:12のアミノ酸配列を含む軽鎖可変領域。 - 以下を含む、請求項27記載の抗体:
(a)SEQ ID NO:3のアミノ酸配列を含む重鎖可変領域;および
(b)SEQ ID NO:13のアミノ酸配列を含む軽鎖可変領域。 - 請求項1~30のいずれか一項記載の抗体またはその抗原結合部分および薬学的に許容される担体を含む、組成物。
- 治療物質に連結された請求項1~30のいずれか一項記載の抗体またはその抗原結合部分を含む、免疫複合体。
- 請求項32記載の免疫複合体および薬学的に許容される担体を含む、組成物。
- 治療物質がサイトトキシンである、請求項32記載の免疫複合体。
- 請求項34記載の免疫複合体および薬学的に許容される担体を含む、組成物。
- 治療物質が放射性同位体である、請求項32記載の免疫複合体。
- 請求項34記載の免疫複合体および薬学的に許容される担体を含む、組成物。
- 抗体またはその抗原結合部分とは異なる結合特異性を有する第2の機能的部分に連結された、請求項1~30のいずれか一項記載の抗体またはその抗原結合部分を含む二重特異性分子。
- 請求項38記載の二重特異性分子および薬学的に許容される担体を含む、組成物。
- 請求項1~30のいずれか一項記載の抗体またはその抗原結合部分をコードする、単離された核酸分子。
- 請求項40の核酸分子を含む発現ベクター。
- 請求項41の発現ベクターを含む宿主細胞。
- 請求項1~30のいずれか一項記載の抗体を発現する、ヒト免疫グロブリンの重鎖導入遺伝子および軽鎖導入遺伝子を含むトランスジェニックマウス。
- 抗体を産生する、請求項43記載のマウスから調製されたハイブリドーマ。
- 対象における免疫応答を調整する方法であって、対象における免疫応答が調整されるように、請求項1~30のいずれか一項記載の抗体またはその抗原結合部分を対象に投与する段階を含む方法。
- 対象において腫瘍細胞の増殖を阻害する方法であって、治療的有効量の抗PD-L1抗体またはその抗原結合部分を対象に投与する段階を含む方法。
- 抗体がキメラ抗体である、請求項46記載の方法。
- 抗体がヒト化抗体である、請求項46記載の方法。
- 抗体が完全なヒト抗体である、請求項46記載の方法。
- 腫瘍細胞が、黒色腫、腎臓癌、前立腺癌、乳癌、結腸癌、および肺癌からなる群より選択される癌のものである、請求項46記載の方法。
- 腫瘍細胞が、骨癌、膵臓癌、皮膚癌、頭部または頸部の癌、皮膚または眼内の悪性黒色腫、子宮癌、卵巣癌、直腸癌、肛門領域の癌、胃癌、精巣癌、子宮癌、ファロピウス管癌、子宮内膜癌、子宮頸癌、腟癌、外陰癌、ホジキン病、非ホジキンリンパ腫、食道癌、小腸癌、内分泌系の癌、甲状腺癌、副甲状腺癌、副腎癌、軟部組織肉腫、尿道癌、陰茎癌、急性骨髄性白血病、慢性骨髄性白血病、急性リンパ芽球性白血病、慢性リンパ球性白血病を含む慢性または急性の白血病、幼児期の固形腫瘍、リンパ球性リンパ腫、膀胱癌、腎臓または尿管の癌、腎う癌、中枢神経系(CNS)の新生物、原発性CNSリンパ腫、腫瘍血管新生、脊椎腫瘍、脳幹神経膠腫、脳下垂体腺腫、カポジ肉腫、類表皮癌、扁平上皮癌、T細胞リンパ腫、アスベストによって誘発されるものを含む環境的に誘発される癌、および前記癌の組合せからなるリストより選択される癌のものである、請求項46記載の方法。
- 対象において腫瘍細胞の増殖を阻害する方法であって、腫瘍細胞の増殖を阻害するのに有効な量の、請求項1~30のいずれか一項記載の抗体またはその抗原結合部分を対象に投与する段階を含む方法。
- 対象において感染症を治療する方法であって、対象の感染症が治療されるように、請求項1~30のいずれか一項記載の抗体またはその抗原結合部分を対象に投与する段階を含む方法。
- 感染症が、以下からなるリストより選択される、請求項53記載の方法:HIV、インフルエンザ(Influenza)、ヘルペス(Herpes)、ジアルジア(Giardia)、マラリア(Malaria)、リーシュマニア(Leishmania);肝炎ウイルス(A、B、およびC)、ヘルペスウイルス(例えば、VZV、HSV-1、HAV-6、HSV-II、およびCMV、エプスタイン・バー(Epstein-Barr)ウイルス、アデノウイルス、インフルエンザウイルス、フラビウイルス、エコーウイルス、ライノウイルス、コクサッキーウイルス、コルノウイルス(cornovirus)、呼吸器合胞体ウイルス、ムンプスウイルス、ロタウイルス、麻疹ウイルス、風疹ウイルス、パルボウイルス、ワクシニアウイルス、HTLVウイルス、デング熱ウイルス、パピローマウイルス、軟属腫ウイルス、ポリオウイルス、狂犬病ウイルス、JCウイルス、およびアルボウイルス脳炎ウイルスによる病原性感染症;クラミジア(chlamydia)、リケッチア細菌、ミコバクテリア(mycobacteria)、ブドウ球菌(staphylococci)、連鎖球菌(streptococci)、肺炎連鎖球菌(pneumonococci)、髄膜炎菌(meningococci)およびコノコッカス(conococci)、クレブシエラ(klebsiella)、プロテウス(proteus)、セラチア(serratia)、シュードモナス(pseudomonas)、レジオネラ(legionella)、ジフテリア(diphtheria)、サルモネラ(salmonella)、桿菌(bacilli)、コレラ菌、破傷風菌、ボツリヌス菌、炭疽菌、ペスト菌、レプトスピラ菌、およびライム病菌による病原性感染症;真菌のカンジダ属(Candida)(アルビカンス(albicans)、クルセイ(krusei)、グラブラタ(glabrata)、トロピカリス(tropicalis)など)、クリプトコックス・ネオフォルマンス(Cryptococcus neoformans)、アスペルギルス(Aspergillus)属(フミガーツス(fumigatus)、ニガー(niger)など)、ケカビ目(Mucorales)の属(ケカビ属(mucor)、アブシディア属(absidia)、クモノスカビ属(rhizophus))、スポロスリックス・シェンキー(Sporothrix schenkii)、ブラストミセス・デルマチチジス(Blastomyces dermatitidis)、ブラジル・パラコクシジオイデス(Paracoccidioides brasiliensis)、コクシジオイデス・イミチス(Coccidioides immitis)およびヒストプラスマ・カプスラーツム(Histoplasma capsulatum)による病原性感染症;ならびに、寄生虫の赤痢アメーバ(Entamoeba histolytica)、大腸バランチジウム(Balantidium coli)、ネグレリア・フォーレリ(Naegleria fowleri)、アカントアメーバ(Acanthamoeba)種、ランブル鞭毛虫(Giardia lambia)、クリプトスポリジウム(Cryptosporidium)種、ニューモシスティス・カリニ(Pneumocystis carinii)、三日熱マラリア原虫(Plasmodium vivax)、ネズミバベシア(Babesia microti)、トリパノソーマ・ブルセイ(Trypanosoma brucei)、クルーズ・トリパノソーマ(Trypanosoma cruzi)、ドノバンリーシュマニア(Leishmania donovani)、トキソプラズマ・ゴンジ(Toxoplasma gondii)、ブラジル鉤虫(Nippostrongylus brasiliensis)による病原性感染症。
- 対象における抗原に対する免疫応答を増強する方法であって、対象における抗原に対する免疫応答が増強されるように、(i)抗原、および(ii)請求項1~30のいずれか一項記載の抗体またはその抗原結合部分を対象に投与する段階を含む方法。
- 抗原が、腫瘍抗原、ウイルス抗原、細菌抗原、または病原体由来の抗原である、請求項55記載の方法。
- 対象において炎症性疾患を治療または予防する方法であって、対象の炎症性疾患が治療されるように、請求項1~30のいずれか一項記載の抗体またはその抗原結合部分を対象に投与する段階を含む方法。
- 炎症性疾患が扁平苔癬(LP)である、請求項57記載の方法。
- 以下の段階を含む、抗PD-L1抗体を調製するための方法:
(a)(i)SEQ ID NO:21、SEQ ID NO:22、SEQ ID NO:23、SEQ ID NO:24、SEQ ID NO:25、SEQ ID NO:26、SEQ ID NO:27、SEQ ID NO:28、SEQ ID NO:29、およびSEQ ID NO:30からなる群より選択されるCDR1配列、SEQ ID NO:31、SEQ ID NO:32、SEQ ID NO:33、SEQ ID NO:34、SEQ ID NO:35、SEQ ID NO:36、SEQ ID NO:37、SEQ ID NO:38、SEQ ID NO:39、およびSEQ ID NO:40からなる群より選択されるCDR2配列、ならびにSEQ ID NO:41、SEQ ID NO:42、SEQ ID NO:43、SEQ ID NO:44、SEQ ID NO:45、SEQ ID NO:46、SEQ ID NO:47、SEQ ID NO:48、SEQ ID NO:49、およびSEQ ID NO:50からなる群より選択されるCDR3配列を含む重鎖可変領域抗体配列、または(ii)SEQ ID NO:51、SEQ ID NO:52、SEQ ID NO:53、SEQ ID NO:54、SEQ ID NO:55、SEQ ID NO:56、SEQ ID NO:57、SEQ ID NO:58、SEQ ID NO:59、およびSEQ ID NO:60からなる群より選択されるCDR1配列、SEQ ID NO:61、SEQ ID NO:62、SEQ ID NO:63、SEQ ID NO:64、SEQ ID NO:65、SEQ ID NO:66、SEQ ID NO:67、SEQ ID NO:68、SEQ ID NO:69、およびSEQ ID NO:70からなる群より選択されるCDR2配列、ならびにSEQ ID NO:71、SEQ ID NO:72、SEQ ID NO:73、SEQ ID NO:74、SEQ ID NO:75、SEQ ID NO:76、SEQ ID NO:77、SEQ ID NO:78、SEQ ID NO:79、およびSEQ ID NO:80からなる群より選択されるCDR3配列を含む軽鎖可変領域抗体配列を提供する段階;
(b)重鎖可変領域抗体配列および軽鎖可変領域抗体配列より選択される少なくとも1つの可変領域抗体配列内の少なくとも1つのアミノ酸残基を変更して、少なくとも1つの改変抗体配列を作製する段階;ならびに
(c)改変抗体配列をタンパク質として発現させる段階。 - 腫瘍細胞の増殖を阻害する方法において使用するための、抗PD-L1抗体またはその抗原結合部分。
- 腫瘍細胞の増殖を阻害するための医用薬剤を調製するための、抗PD-L1抗体またはその抗原結合部分の使用。
- 腫瘍細胞の増殖を阻害する方法において使用するための、請求項1~30のいずれか一項記載の抗体またはその抗原結合部分。
- 腫瘍細胞の増殖を阻害するための医用薬剤を調製するための、請求項1~30のいずれか一項記載の抗体またはその抗原結合部分の使用。
- 感染症を治療する方法において使用するための、請求項1~30のいずれか一項記載の抗体またはその抗原結合部分。
- 感染症を治療するための医用薬剤を調製するための、請求項1~30のいずれか一項記載の抗体またはその抗原結合部分の使用。
- 炎症性疾患を治療する方法において使用するための、請求項1~30のいずれか一項記載の抗体またはその抗原結合部分。
- 炎症性疾患を治療するための医用薬剤を調製するための、請求項1~30のいずれか一項記載の抗体またはその抗原結合部分の使用。
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