Humanized antibodies against TL1A

1. A method of treating or diagnosing a disease selected from the group consisting of an inflammatory disease, an immune disease, and a malignant disease, wherein the disease is associated with TL1A, and wherein the method comprises administering to a subject in need thereof a composition comprising:

(A) an isolated antigen-binding polypeptide that binds specifically to TL1A comprising:

(1) a humanized heavy chain variable region comprising

(a) CDR-H1 comprises the amino acid sequence LYGMN (SEQ ID NO:11) or NYGMN (SEQ ID NO:12);

(b) CDR-H2 comprises the amino acid sequence (WINTYTGEPTYADDFKG) (SEQ ID NO:13); and

(c) CDR-H3 comprises the amino acid sequence DTAMDYAMAY (SEQ ID NO:14) or DYGKYGDYYAMDY (SEQ ID NO:15); and

(2) a humanized light chain variable region comprising

(d) CDR-L1 comprises the amino acid sequence KSSQNIVHSDGNTYLE (SEQ ID NO:16) or RSSQSIVHSNGNTYLD (SEQ ID NO:17);

(e) CDR-L2 comprises the amino acid sequence KVSNRFS (SEQ ID NO:18); and

(f) CDR-L3 comprises the amino acid sequence FQGSHVPLT (SEQ ID NO:19); and

(B) at least one pharmaceutically acceptable carrier.

2. A method of treating or diagnosing a disease selected from the group consisting of an inflammatory disease, an immune disease, and a malignant disease, wherein the disease is associated with TL1A, and wherein the method comprises administering to a subject in need thereof a composition comprising:

(A) an isolated antigen-binding polypeptide that binds specifically to TL1A comprising:

(a) the humanized heavy chain variable region comprises:

(1) a CDR-H1 comprising the amino acid sequence TSNMGVV (SEQ ID NO:7);

(2) a CDR-H2 comprising the amino acid sequence

(SEQ ID NO: 8)

HILWDDREYSNPALKS;

and

(3) a CDR-H3 comprising the amino acid sequence

(SEQ ID NO: 9)

MSRNYYGSSYVMDY;

and

(b) the humanized light chain variable region comprises:

(1) a CDR-L1 comprising the amino acid sequence SASSSVNYMH (SEQ ID NO:35);

(2) a CDR-L2 comprising the amino acid sequence STSNLAS (SEQ ID NO:36) and;

(3) a CDR-L3 comprising the amino acid sequence HQWNNYGT (SEQ ID NO:37); and

(B) at least one pharmaceutically acceptable carrier.

3. The method of claim 2 , wherein the humanized heavy chain variable region comprises the amino acid sequence:

(SEQ ID NO: 10)

QVTLKESGPALVKPTQTLTLTCTFSGFSLSTSNMGVVWIRQPPGKALEW

LAHILWDDREYSNPALKSRLTISKDTSKNQVVLTMTNMDPVDTATYYCA

RMSRNYYGSSYVMDYWGQGTLVTVSS.

4. The method of claim 1 , wherein the humanized heavy chain variable region comprises an amino acid sequence selected from the group consisting of:

(a)

(SEQ ID NO: 21)

QVQLVQSGSELKKPGASVKVSCKASGYTFTLYGMNWVRQAPGQGLEWMG

WINTYTGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCAR

DTAMDYAMAYWGQGTLVTVSS;

(b)

(SEQ ID NO: 22)

QVQLVQSGSELKKPGASVKVSCKASGYTFTLYGMNWVKQAPGKGLKWMG

WINTYTGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYFCAR

DTAMDYAMAYWGQGTLVTVSS;

(c)

(SEQ ID NO: 23)

QVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMG

WINTYTGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCAR

DYGKYGDYYAMDYWGQGTLVTVSS;

and

(d)

(SEQ ID NO: 24)

QVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMNWVRQAPGKGLKWMG

WINTYTGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYFCAR

DYGKYGDYYAMDYWGQGTLVTVSS.

5. The method of claim 2 , wherein the humanized light chain variable region comprises the amino acid sequence:

(SEQ ID NO: 38)

DIQLTQSPSFLSASVGDRVTITCSASSSVNYMHWYQQKPGKAPKLLIYS

TSNLASGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCHQWNNYGTFGQ

GTKVEIKR.

6. The method of claim 1 , wherein the humanized light chain variable region comprises an amino acid sequence selected from the group consisting of:

(a)

(SEQ ID NO: 27)

DVVMTQSPLSLPVTLGQPASISCKSSQNIVHSDGNTYLEWFQQRPGQSP

RRLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSH

VPLTFGGGTKVEIKR;

(b)

(SEQ ID NO: 28)

DVVMTQSPLSLPVTLGQPASISCKSSQNIVHSDGNTYLEWFQQRPGQSP

RRLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSH

VPLTFGQGTKVEIKR;

(c)

(SEQ ID NO: 26)

DVVMTQTPLSLPVTPGEPASISCKSSQNIVHSDGNTYLEWYLQKPGQSP

QLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSH

VPLTFGGGTKVEIKR;

(d)

(SEQ ID NO: 66)

DVVMTQTPLSLPVSLGDQASISCKSSQNIVHSDGNTYLEWYLQKPGQSP

KVLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSH

VPLTFGGGTKVEIKR;

(e)

(SEQ ID NO: 41)

DVVMTQSPLSLPVTLGQPASISCRSSQSIVHSNGNTYLDWFQQRPGQSP

RRLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSH

VPLTFGGGTKVEIKR;

(f)

(SEQ ID NO: 42)

DVVMTQSPLSLPVTLGQPASISCRSSQSIVHSNGNTYLDWFQQRPGQSP

RRLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSH

VPLTFGQGTKVEIKR;

(g)

(SEQ ID NO: 43)

DVVMTQTPLSLPVTPGEPASISCRSSQSIVHSNGNTYLDWYLQKPGQSP

QLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSH

VPLTFGGGTKVEIKR;

and

(h)

(SEQ ID NO: 44)

DVVMTQTPLSLPVSLGDQASISCRSSQSIVHSNGNTYLDWYLQKPGQSP

KVLIYKVSNRFSGVPDRFSGSGSGTDFTLKINRVEAEDLGVYFCFQGSH

VPLTFGGGTKLEIKR.

7. The method of claim 1 , wherein the humanized heavy chain variable region comprises:

(a) a humanized heavy chain variable region comprising an amino acid sequence selected from the group consisting of:

(ii) SEQ ID NO:21;

(iii) SEQ ID NO:22;

(iv) SEQ ID NO:23; and

(v) SEQ ID NO:24; and

(b) a humanized light chain variable region comprising an amino acid sequence selected from the group consisting of:

(ii) SEQ ID NO:27;

(iii) SEQ ID NO:28;

(iv) SEQ ID NO:26;

(v) SEQ ID NO:66;

(vi) SEQ ID NO:41;

(vii) SEQ ID NO:42;

(viii) SEQ ID NO:43; and

(ix) SEQ ID NO:44.

8. The method of claim 2 , wherein the polypeptide comprises:

(a) a humanized variable light chain region comprising the amino acid sequence:

(SEQ ID NO: 38)

DIQLTQSPSFLSASVGDRVTITCSASSSVNYMHWYQQKPGKAPKLLIYS

TSNLASGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCHQWNNYGTFGQ

GTKVEIKR;

and

(b) a humanized variable heavy chain region comprising the sequence:

(SEQ ID NO: 10)

QVTLKESGPALVKPTQTLTLTCTFSGFSLSTSNMGVVWIRQPPGKALEW

LAHILWDDREYSNPALKSRLTISKDTSKNQVVLTMTNMDPVDTATYYCA

RMSRNYYGSSYVMDYWGQGTLVTVSS.

9. The method of claim 1 , wherein the polypeptide is selected from the group consisting of an antibody molecule, a Fab fragment, a Fab′ fragment, a F(ab′) 2 fragment, and an scFv molecule.

10. The method of claim 9 , wherein the polypeptide is an antibody molecule.

11. The method of claim 10 , wherein the antibody is a chimeric antibody comprising a humanized heavy chain constant region and a humanized light chain constant region.

12. The method of claim 10 , wherein the antibody is an IgG molecule.

13. The method of claim 9 , wherein the polypeptide is an scFv molecule.

14. The method of claim 13 , wherein the scFv molecule has a formula selected from the group consisting of NH 2 -L-VH-X-VK-COOH and NH 2 -L-VK-X-VH-COOH, wherein:

(a) L is a leader sequence;

(b) VH is the humanized antibody heavy chain variable region;

(c) X is a linking polypeptide; and

(d) VK is the humanized antibody light chain variable region.

15. The method of claim 9 , wherein the polypeptide is a Fab HSA fusion molecule.

16. The method of claim 15 , wherein the Fab HSA fusion molecule has a formula selected from the group consisting of NH 2 -VH-CH1-HSA-COOH and NH 2 -HSA-CH1-VH-COOH combined with NH 2 -VK-CK-COOH,

wherein VH-CH1-HSA or HSA-CH1-VH is the humanized antibody heavy chain variable region (VH) and human constant heavy chain domain 1 (CH1) produced as a fusion protein with human serum albumin (HSA) which folds with its cognate humanized antibody light chain variable region (VK) and human constant kappa domain (CK) to form the Fab-HSA or HSA-Fab fusion protein.

17. The method of claim 1 , wherein the polypeptide is conjugated to a therapeutic or diagnostic agent.

18. The method of claim 17 , wherein:

(a) the therapeutic agent is selected from the group consisting of a cytotoxic agent, a radioactive label, an immunomodulator, a hormone, an enzyme, an oligonucleotide, a photoactive therapeutic agent or a combination thereof; or

(b) the diagnostic agent is selected from the group consisting of a radioactive label, a photoactive diagnostic agent, an ultrasound-enhancing agent or a non-radioactive label.

19. The method of claim 1 , wherein the polypeptide binds to TL1A with an affinity constant of at least about 10 6 M −1 .

20. The method of claim 1 , wherein the composition further comprises an additional therapeutic or diagnostic agent.

21. The method of claim 1 , wherein the disease to be treated is an inflammatory disease.

22. The method of claim 1 , wherein the disease to be treated is an immune disease.

23. The method of claim 1 , wherein the disease to be treated is a malignant disease.

24. The method of claim 1 , wherein the inflammatory or immune disease is selected from the group consisting of lupus, inflammatory bowel disease (IBD), chronic obstructive pulmonary disease (COPD), arthritis, rheumatoid arthritis, multiple sclerosis, transplant rejection, central nervous system injury, Th1-mediated intestinal disease, Crohn's disease, psoriasis and atherosclerosis.

25. The method of claim 1 , wherein the malignant disease is selected from the group consisting of: leukemia, lymphoma, chronic lymphocytic leukemia (CLL), lung carcinoma, and colon carcinoma.