TUMOR NECROSIS FACTOR-LIKE LIGAND 1A SPECIFIC ANTIBODIES AND COMPOSITIONS AND USES THEREOF

摘要

The present invention provides antibodies, or antigen-binding fragment thereof, which specifically bind to TL1A. The invention further provides a method of obtaining such antibodies and nucleic acids encoding the same. The invention further relates to compositions and therapeutic methods for use of these antibodies for the treatment and/or prevention of TL1A mediated diseases, disorders or conditions.

主权项

1. An isolated antibody or antigen-binding fragment thereof that specifically binds tumor necrosis factor-like ligand 1A (TL1A) and comprises:
a. a heavy chain variable region (VH) comprising a VH complementarity determining region one (CDR-H1) comprising the amino acid sequence of SEQ ID NO:374, a VH complementarity determining region two (CDR-H2) comprising the amino acid sequence of SEQ ID NO: 377, and a VH complementarity determining region three (CDR-H3) comprising the amino acid sequence of SEQ ID NO: 380; b. a heavy chain variable region (VH) comprising a CDR-H1 comprising the amino acid sequence of SEQ ID NO:375, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 378, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 381; c. a heavy chain variable region (VH) comprising a CDR-H1 comprising the amino acid sequence of SEQ ID NO:376, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 379, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 382; d. a heavy chain variable region (VH) comprising:
i. a CDR-H1 comprising the amino acid sequence of SEQ ID NO:202;ii. a CDR-H2 comprising the amino acid sequence selected from SEQ ID NO: 203, 210, 217, 224, 231, 238, 245, or 252;iii. a CDR-H2 comprising the amino acid sequence selected from SEQ ID NO:204, 211, 218, 225, 232, 239, 246, or 253; anda VL comprising a CDR-L1 comprising the amino acid sequence of SEQ ID NO:110, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:111, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:112; e. a VH comprising the CDR-H1 amino acid sequence of SEQ ID NO:113, the CDR-H2 amino acid sequence of SEQ NO:114, the CDR-H3 amino acid sequence of SEQ ID NO:115, and a VL comprising the CDR-L1 amino acid sequence of SEQ ID NO:110, the CDR-L2 amino acid sequence of SEQ ID NO:111, and the CDR-L3 amino acid sequence of SEQ ID NO:112; f. a VH comprising the CDR-H1, CDR-H2, and CDR-H3 of the VH amino acid sequence of SEQ ID NO:104, and a VL comprising the CDR-L1, CDR-L2, and CDR-L3 of the VL amino acid sequence of SEQ ID NO:102; g. a VH comprising the amino acid sequence of SEQ ID NO:104 and a VL comprising the amino acid sequence of SEQ ID NO:102; h. a heavy chain comprising the amino acid sequence of SEQ ID NO:108 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO:106; i. a VH comprising the CDR-H1, CDR-H2, and CDR-H3 encoded by the nucleic acid sequence of SEQ ID NO:105, and a VL comprising the CDR-L1, CDR-L2, and CDR-L3 encoded by the nucleic acid sequence of SEQ ID NO:103; j. a VH encoded by the nucleic acid sequence of SEQ ID NO:105, and a VL encoded by the nucleic acid sequence of SEQ ID NO:103; k. a heavy chain encoded by the nucleic acid sequence of SEQ ID NO:109, and a light chain encoded by the nucleic acid sequence of SEQ ID NO:107; l. a VH comprising the CDR-H1 amino acid sequence of SEQ ID NO:230, the CDR-H2 amino acid sequence of SEQ NO:231, the CDR-H3 amino acid sequence of SEQ ID NO:232, and a VL comprising the CDR-L1 amino acid sequence of SEQ ID NO:110, the CDR-L2 amino acid sequence of SEQ ID NO:111, and the CDR-L3 amino acid sequence of SEQ ID NO:112; m. a VH comprising the CDR-H1, CDR-H2, and CDR-H3 of the VH amino acid sequence of SEQ ID NO:226, and a VL comprising the CDR-L1, CDR-L2, and CDR-L3 of the VL amino acid sequence of SEQ ID NO:102; n. a VH comprising the amino acid sequence of SEQ ID NO:226 and a VL comprising the amino acid sequence of SEQ ID NO:102; o. a heavy chain comprising the amino acid sequence of SEQ ID NO:228 and a light chain comprising the amino acid sequence of SEQ ID NO:106; p. a VH comprising the CDR-H1, CDR-H2, and CDR-H3 encoded by the nucleic acid sequence of SEQ ID NO:227, and a VL comprising the CDR-L1, CDR-L2, and CDR-L3 encoded by the nucleic acid sequence of SEQ ID NO:103; q. a VH encoded by the nucleic acid sequence of SEQ ID NO:227, and a VL encoded by the nucleic acid sequence of SEQ ID NO:103; r. a heavy chain encoded by the nucleic acid sequence of SEQ ID NO:229, and a light chain encoded by the nucleic acid sequence of SEQ ID NO:107; s. a VH comprising the CDR-H1 amino acid sequence of SEQ ID NO:202, the CDR-H2 amino acid sequence of SEQ NO:203, the CDR-H3 amino acid sequence of SEQ ID NO:204, and a VL comprising the CDR-L1 amino acid sequence of SEQ ID NO:110, the CDR-L2 amino acid sequence of SEQ ID NO:111, and the CDR-L3 amino acid sequence of SEQ ID NO:112; t. a VH comprising the CDR-H1, CDR-H2, and CDR-H3 of the VH amino acid sequence of SEQ ID NO:198, and a VL comprising the CDR-L1, CDR-L2, and CDR-L3 of the VL amino acid sequence of SEQ ID NO:102; u. a VH comprising the amino acid sequence of SEQ ID NO:198 and a VL comprising the amino acid sequence of SEQ ID NO:102; v. a heavy chain comprising the amino acid sequence of SEQ ID NO:200 and a light chain comprising the amino acid sequence of SEQ ID NO:106; w. a VH comprising the CDR-H1, CDR-H2, and CDR-H3 encoded by the nucleic acid sequence of SEQ ID NO:199, and a VL comprising the CDR-L1, CDR-L2, and CDR-L3 encoded by the nucleic acid sequence of SEQ ID NO:103; x. a VH encoded by the nucleic acid sequence of SEQ ID NO:199, and a VL encoded by the nucleic acid sequence of SEQ ID NO:103; y. a heavy chain encoded by the nucleic acid sequence of SEQ ID NO:201, and a light chain encoded by the nucleic acid sequence of SEQ ID NO:107; z. a VH comprising the CDR-H1 amino acid sequence of SEQ ID NO:209, the CDR-H2 amino acid sequence of SEQ NO:210, the CDR-H3 amino acid sequence of SEQ ID NO:211, and a VL comprising the CDR-L1 amino acid sequence of SEQ ID NO:110, the CDR-L2 amino acid sequence of SEQ ID NO:111, and the CDR-L3 amino acid sequence of SEQ ID NO:112; aa. a VH comprising the CDR-H1, CDR-H2, and CDR-H3 of the VH amino acid sequence of SEQ ID NO:205, and a VL comprising the CDR-L1, CDR-L2, and CDR-L3 of the VL amino acid sequence of SEQ ID NO:102; bb. a VH comprising the amino acid sequence of SEQ ID NO:205 and a VL comprising the amino acid sequence of SEQ ID NO:102; cc. a heavy chain comprising the amino acid sequence of SEQ ID NO:207 and a light chain comprising the amino acid sequence of SEQ ID NO:106; dd. a VH comprising the CDR-H1, CDR-H2, and CDR-H3 encoded by the nucleic acid sequence of SEQ ID NO:206, and a VL comprising the CDR-L1, CDR-L2, and CDR-L3 encoded by the nucleic acid sequence of SEQ ID NO:103; ee. a VH encoded by the nucleic acid sequence of SEQ ID NO:206, and a VL encoded by the nucleic acid sequence of SEQ ID NO:103; ff. a heavy chain encoded by the nucleic acid sequence of SEQ ID NO:208, and a light chain encoded by the nucleic acid sequence of SEQ ID NO:107; gg. a VH comprising the CDR-H1 amino acid sequence of SEQ ID NO:216, the CDR-H2 amino acid sequence of SEQ NO:217, the CDR-H3 amino acid sequence of SEQ ID NO:218, and a VL comprising the CDR-L1 amino acid sequence of SEQ ID NO:110, the CDR-L2 amino acid sequence of SEQ ID NO:111, and the CDR-L3 amino acid sequence of SEQ ID NO:112; hh. a VH comprising the CDR-H1, CDR-H2, and CDR-H3 of the VH amino acid sequence of SEQ ID NO:212, and a VL comprising the CDR-L1, CDR-L2, and CDR-L3 of the VL amino acid sequence of SEQ ID NO:102; ii. a VH comprising the amino acid sequence of SEQ ID NO:212 and a VL comprising the amino acid sequence of SEQ ID NO:102; jj. a heavy chain comprising the amino acid sequence of SEQ ID NO:214 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO:106; kk. a VH comprising the CDR-H1, CDR-H2, and CDR-H3 encoded by the nucleic acid sequence of SEQ ID NO:213, and a VL comprising the CDR-L1, CDR-L2, and CDR-L3 encoded by the nucleic acid sequence of SEQ ID NO:103; ll. a VH encoded by the nucleic acid sequence of SEQ ID NO:213, and a VL encoded by the nucleic acid sequence of SEQ ID NO:103; mm. a heavy chain encoded by the nucleic acid sequence of SEQ ID NO:215, and a light chain encoded by the nucleic acid sequence of SEQ ID NO:107; nn. a VH comprising the CDR-H1 amino acid sequence of SEQ ID NO:223, the CDR-H2 amino acid sequence of SEQ NO:224, the CDR-H3 amino acid sequence of SEQ ID NO:225, and a VL comprising the CDR-L1 amino acid sequence of SEQ ID NO:110, the CDR-L2 amino acid sequence of SEQ ID NO:111, and the CDR-L3 amino acid sequence of SEQ ID NO:112; oo. a VH comprising the CDR-H1, CDR-H2, and CDR-H3 of the VH amino acid sequence of SEQ ID NO:219, and a VL comprising the CDR-L1, CDR-L2, and CDR-L3 of the VL amino acid sequence of SEQ ID NO:102; pp. a VH comprising the amino acid sequence of SEQ ID NO:219 and a VL comprising the amino acid sequence of SEQ ID NO:102; qq. a heavy chain comprising the amino acid sequence of SEQ ID NO:221 and a light chain comprising the amino acid sequence of SEQ ID NO:106; rr. a VH comprising the CDR-H1, CDR-H2, and CDR-H3 encoded by the nucleic acid sequence of SEQ ID NO:220, and a VL comprising the CDR-L1, CDR-L2, and CDR-L3 encoded by the nucleic acid sequence of SEQ ID NO:103; ss. a VH encoded by the nucleic acid sequence of SEQ ID NO:220, and a VL encoded by the nucleic acid sequence of SEQ ID NO:103; tt. a heavy chain encoded by the nucleic acid sequence of SEQ ID NO:222, and a light chain encoded by the nucleic acid sequence of SEQ ID NO:107; uu. a VH comprising the CDR-H1 amino acid sequence of SEQ ID NO:237, the CDR-H2 amino acid sequence of SEQ NO:238, the CDR-H3 amino acid sequence of SEQ ID NO:239, and a VL comprising the CDR-L1 amino acid sequence of SEQ ID NO:110, the CDR-L2 amino acid sequence of SEQ ID NO:111, and the CDR-L3 amino acid sequence of SEQ ID NO:112; vv. a VH comprising the CDR-H1, CDR-H2, and CDR-H3 of the VH amino acid sequence of SEQ ID NO:233, and a VL comprising the CDR-L1, CDR-L2, and CDR-L3 of the VL amino acid sequence of SEQ ID NO:102; ww. a VH comprising the amino acid sequence of SEQ ID NO:233 and a VL comprising the amino acid sequence of SEQ ID NO:102; xx. a heavy chain comprising the amino acid sequence of SEQ ID NO:235 and a light chain comprising the amino acid sequence of SEQ ID NO:106; yy. a VH comprising the CDR-H1, CDR-H2, and CDR-H3 encoded by the nucleic acid sequence of SEQ ID NO:234, and a VL comprising the CDR-L1, CDR-L2, and CDR-L3 encoded by the nucleic acid sequence of SEQ ID NO:103; zz. a VH encoded by the nucleic acid sequence of SEQ ID NO:234, and a VL encoded by the nucleic acid sequence of SEQ ID NO:103; aaa. a heavy chain encoded by the nucleic acid sequence of SEQ ID NO:236, and a light chain encoded by the nucleic acid sequence of SEQ ID NO:107; bbb. a VH comprising the CDR-H1 amino acid sequence of SEQ ID NO:244, the CDR-H2 amino acid sequence of SEQ NO:245, the CDR-H3 amino acid sequence of SEQ ID NO:246, and a VL comprising the CDR-L1 amino acid sequence of SEQ ID NO:110, the CDR-L2 amino acid sequence of SEQ ID NO:111, and the CDR-L3 amino acid sequence of SEQ ID NO:112; ccc. a VH comprising the CDR-H1, CDR-H2, and CDR-H3 of the VH amino acid sequence of SEQ ID NO:240, and a VL comprising the CDR-L1, CDR-L2, and CDR-L3 of the VL amino acid sequence of SEQ ID NO:102; ddd. a VH comprising the amino acid sequence of SEQ ID NO:240 and a VL comprising the amino acid sequence of SEQ ID NO:102; eee. a heavy chain comprising the amino acid sequence of SEQ ID NO:242 and a light chain comprising the amino acid sequence of SEQ ID NO:106; fff. a VH comprising the CDR-H1, CDR-H2, and CDR-H3 encoded by the nucleic acid sequence of SEQ ID NO:241, and a VL comprising the CDR-L1, CDR-L2, and CDR-L3 encoded by the nucleic acid sequence of SEQ ID NO:103; ggg. a VH encoded by the nucleic acid sequence of SEQ ID NO:241, and a VL encoded by the nucleic acid sequence of SEQ ID NO:103; hhh. a heavy chain encoded by the nucleic acid sequence of SEQ ID NO:243, and a light chain encoded by the nucleic acid sequence of SEQ ID NO:107; iii. a VH comprising the CDR-H1 amino acid sequence of SEQ ID NO:251, the CDR-H2 amino acid sequence of SEQ NO:252, the CDR-H3 amino acid sequence of SEQ ID NO:253, and a VL comprising the CDR-L1 amino acid sequence of SEQ ID NO:110, the CDR-L2 amino acid sequence of SEQ ID NO:111, and the CDR-L3 amino acid sequence of SEQ ID NO:112; jjj. a VH comprising the CDR-H1, CDR-H2, and CDR-H3 of the VH amino acid sequence of SEQ ID NO:247, and a VL comprising the CDR-L1, CDR-L2, and CDR-L3 of the VL amino acid sequence of SEQ ID NO:102; kkk. a VH comprising the amino acid sequence of SEQ ID NO:247 and a VL comprising the amino acid sequence of SEQ ID NO:102; lll. a heavy chain comprising the amino acid sequence of SEQ ID NO:249 and a light chain comprising the amino acid sequence of SEQ ID NO:106; mmm. a VH comprising the CDR-H1, CDR-H2, and CDR-H3 encoded by the nucleic acid sequence of SEQ ID NO:248, and a VL comprising the CDR-L1, CDR-L2, and CDR-L3 encoded by the nucleic acid sequence of SEQ ID NO:103; nnn. a VH encoded by the nucleic acid sequence of SEQ ID NO:248, and a VL encoded by the nucleic acid sequence of SEQ ID NO:103; ooo. a heavy chain encoded by the nucleic acid sequence of SEQ ID NO:250, and a light chain encoded by the nucleic acid sequence of SEQ ID NO:107; ppp. a VH encoded by the nucleic acid sequence of the insert of the vector deposited as 1D1 1.31 VH having ATCC accession number PTA-120639 and a VL encoded by the nucleic acid sequence of the insert of the vector deposited as 1D1 1.31 VL having ATCC accession number PTA-120640; qqq. a VH comprising:
i. a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 389;ii. a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 390;iii. a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 391;iv. an A or T at position H85, as determined by Kabat numbering of the VH;v. a M or L at position 108, as determined by Kabat numbering of the VH; anda VL comprising a CDR-L1 having the amino acid sequence of SEQ ID NO:76, a CDR-L2 having the amino acid sequence of SEQ ID NO:77, and a CDR-L3 having the amino acid sequence of SEQ ID NO:78; and a F or Y at position L83, as determined by Kabat numbering of the VL; rrr. a VH comprising SEQ ID NO:66, 68 or 70, and a VL comprising SEQ ID NO:1 or 64; sss. a VH comprising
i. the CDR-H1 amino acid sequence of SEQ ID NO:79, the CDR-H2 amino acid sequence of SEQ NO:80, and the CDR-H3 amino acid sequence of SEQ ID NO:81;ii. the CDR-H1 amino acid sequence of SEQ ID NO:82, the CDR-H2 amino acid sequence of SEQ NO:83, and the CDR-H3 amino acid sequence of SEQ ID NO:84; oriii. the CDR-H1 amino acid sequence of SEQ ID NO:85, the CDR-H2 amino acid sequence of SEQ NO:86, and the CDR-H3 amino acid sequence of SEQ ID NO:87; and
a VL comprising the CDR-L1 amino acid sequence of SEQ ID NO:76, the CDR-L2 amino acid sequence of SEQ ID NO:77, and the CDR-L3 amino acid sequence of SEQ ID NO:78; ttt. a VH comprising the CDR-H1, CDR-H2, and CDR-H3 of the VH amino acid sequence of SEQ ID NO:66, and a VL comprising the CDR-L1, CDR-L2, and CDR-L3 of the VL amino acid sequence of SEQ ID NO:64; uuu. a VH comprising the CDR-H1, CDR-H2, and CDR-H3 of the VH amino acid sequence of SEQ ID NO:68, and a VL comprising the CDR-L1, CDR-L2, and CDR-L3 of the VL amino acid sequence of SEQ ID NO:64; vvv. a VH comprising the CDR-H1, CDR-H2, and CDR-H3 of the VH amino acid sequence of SEQ ID NO:70, and a VL comprising the CDR-L1, CDR-L2, and CDR-L3 of the VL amino acid sequence of SEQ ID NO:64; www. a VH comprising the amino acid sequence of SEQ ID NO:66 and a VL comprising the amino acid sequence of SEQ ID NO:64; xxx. a VH comprising the amino acid sequence of SEQ ID NO:68 and a VL comprising the amino acid sequence of SEQ ID NO:64; yyy. a VH comprising the amino acid sequence of SEQ ID NO:70 and a VL comprising the amino acid sequence of SEQ ID NO:64; zzz. a heavy chain comprising the amino acid sequence of SEQ ID NO:74 and a light chain comprising the amino acid sequence of SEQ ID NO:72; aaaa. a VH comprising the CDR-H1, CDR-H2, and CDR-H3 encoded by the nucleic acid sequence of SEQ ID NO:67, and a VL comprising the CDR-L1, CDR-L2, and CDR-L3 encoded by the nucleic acid sequence of SEQ ID NO:65; bbbb. a VH comprising the CDR-H1, CDR-H2, and CDR-H3 encoded by the nucleic acid sequence of SEQ ID NO:69, and a VL comprising the CDR-L1, CDR-L2, and CDR-L3 encoded by the nucleic acid sequence of SEQ ID NO:65; cccc. a VH comprising the CDR-H1, CDR-H2, and CDR-H3 encoded by the nucleic acid sequence of SEQ ID NO:71, and a VL comprising the CDR-L1, CDR-L2, and CDR-L3 encoded by the nucleic acid sequence of SEQ ID NO:65; dddd. a VH encoded by the nucleic acid sequence of SEQ ID NO:67, and a VL encoded by the nucleic acid sequence of SEQ ID NO:65; eeee. a VH encoded by the nucleic acid sequence of SEQ ID NO:69, and a VL encoded by the nucleic acid sequence of SEQ ID NO:65; ffif. a VH encoded by the nucleic acid sequence of SEQ ID NO:71, and a VL encoded by the nucleic acid sequence of SEQ ID NO:65; gggg. a heavy chain encoded by the nucleic acid sequence of SEQ ID NO:75, and a light chain encoded by the nucleic acid sequence of SEQ ID NO:73; hhhh. a VH comprising the CDR-H1 amino acid sequence of SEQ ID NO:16, the CDR-H2 amino acid sequence of SEQ NO:17, the CDR-H3 amino acid sequence of SEQ ID NO:18, and a VL comprising the CDR-L1 amino acid sequence of SEQ ID NO:13, the CDR-L2 amino acid sequence of SEQ ID NO:14, and the CDR-L3 amino acid sequence of SEQ ID NO:15; iiii. a VH comprising the CDR-H1 amino acid sequence of SEQ ID NO:19, the CDR-H2 amino acid sequence of SEQ NO:20, the CDR-H3 amino acid sequence of SEQ ID NO:21, and a VL comprising the CDR-L1 amino acid sequence of SEQ ID NO:13, the CDR-L2 amino acid sequence of SEQ ID NO:14, and the CDR-L3 amino acid sequence of SEQ ID NO:15; jjjj. a VH comprising the CDR-H1, CDR-H2, and CDR-H3 of the VH amino acid sequence of SEQ ID NO:3, and a VL comprising the CDR-L1, CDR-L2, and CDR-L3 of the VL amino acid sequence of SEQ ID NO:1; kkkk. a VH comprising the CDR-H1, CDR-H2, and CDR-H3 of the VH amino acid sequence of SEQ ID NO:5, and a VL comprising the CDR-L1, CDR-L2, and CDR-L3 of the VL amino acid sequence of SEQ ID NO:1; llll. a VH comprising the amino acid sequence of SEQ ID NO:3 and a VL comprising the amino acid sequence of SEQ ID NO:1; mmmm. a VH comprising the amino acid sequence of SEQ ID NO:5 and a VL comprising the amino acid sequence of SEQ ID NO:1; nnnn. a heavy chain comprising the amino acid sequence of SEQ ID NO:9 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO:7; oooo. a heavy chain comprising the amino acid sequence of SEQ ID NO:11 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO:7; pppp. a VH comprising the CDR-H1, CDR-H2, and CDR-H3 encoded by the nucleic acid sequence of SEQ ID NO:4, and a VL comprising the CDR-L1, CDR-L2, and CDR-L3 encoded by the nucleic acid sequence of SEQ ID NO:2; qqqq. a VH comprising the CDR-H1, CDR-H2, and CDR-H3 encoded by the nucleic acid sequence of SEQ ID NO:6, and a VL comprising the CDR-L1, CDR-L2, and CDR-L3 encoded by the nucleic acid sequence of SEQ ID NO:2; rrrr. a VH encoded by the nucleic acid sequence of SEQ ID NO:4, and a VL encoded by the nucleic acid sequence of SEQ ID NO:2; ssss. a VH encoded by the nucleic acid sequence of SEQ ID NO:6, and a VL encoded by the nucleic acid sequence of SEQ ID NO:2; tttt. a heavy chain encoded by the nucleic acid sequence of SEQ ID NO:10, and a light chain encoded by the nucleic acid sequence of SEQ ID NO:8; or uuuu. a heavy chain encoded by the nucleic acid sequence of SEQ ID NO:12, and a light chain encoded by the nucleic acid sequence of SEQ ID NO:8.