Immunoconjugates with an Intracellularly-Cleavable Linkage

Patent metadata

Field	Value
Publication number	US-2016287722-A1
Application number	US-201615174304-A
Country	US
Kind code	A1
Filing date	Jun 6, 2016
Priority date	Dec 13, 2002
Publication date	Oct 6, 2016
Grant date	—

Abstract

The invention relates to therapeutic conjugates with improved ability to target various cancer cells containing a targeting moiety and a therapeutic moiety. The targeting and therapeutic moieties are linked via an acid cleavable linkage that increases therapeutic efficacy of the immunoconjugate.

First claim

What is claimed is:

1 . An immunoconjugate comprising:
a) an antibody or an antigen-binding fragment thereof; and b) six or more molecules of a camptothecin moiety covalently attached to the antibody or antibody fragment.

2 . The immunoconjugate of claim 1 , wherein the camptothecin moiety is attached to the antibody or antibody fragment by a linker moiety.

3 . The immunoconjugate of claim 2 , wherein the linker moiety comprises a maleimide moiety that binds to a reduced sulfhydryl on the antibody or antibody fragment.

4 . The immunoconjugate of claim 2 , wherein the linker is an intracellularly cleavable linker.

5 . The immunoconjugate of claim 4 , wherein the linker comprises a peptide moiety that is cleavable by a lysosomal enzyme.

6 . The immunoconjugate of claim 1 , wherein 7 to 12 camptothecin moieties are attached to the antibody or antibody fragment.

7 . The method of claim 1 , wherein the camptothecin is selected from the group consisting of irinotecan, topotecan, 10-hydroxy-camptothecin and SN-38.

8 . The immunoconjugate of claim 1 , wherein the antibody is a chimeric, humanized or human antibody.

9 . The immunoconjugate of claim 1 , wherein the antibody is selected from the group consisting of hLL1, hLL2, hL243, hA20, hRS7, hPAM4, KC4, hMN-14, hMN-15, hMu-9, hIMMU31, CC49, J591 and G250.

10 . The immunoconjugate of claim 1 , wherein the antibody or antigen-binding antibody fragment binds to an antigen selected from the group consisting of alpha-fetoprotein, carbonic anhydrase IX, CD19, CD20, CD21, CD22, CD23, CD30, CD33, CD37, CD45, CD74, CD80, carcinoembryonic antigen (CEA, CEACAM5), CEACAM6, CSAp (colon-specific antigen-p), EGF receptor, EGP-1 (TROP2), EGP-2, Ep-CAM, folate receptor, HER-2/neu, HCG, HLA-DR, Ia, IL-2, IL-6, KS-1, MAGE, MUC1, MUC2, MUC3, MUC4, MUC5ac, 5100, P1GF, PSA (prostate specific antigen), PSMA (prostate-specific membrane antigen), tenascin, Thomas-Friedreich antigens, tumor necrosis antigens, tumor angiogenesis antigens, T101, TAC, TAG-72 and VEGF.

11 . The immunoconjugate of claim 1 , wherein the antibody fragment is selected from the group consisting of a Fab, Fab′, F(ab) 2 , F(ab′) 2 and scFv antibody fragment.

12 . The immunoconjugate according to claim 1 , wherein said antibody or antibody fragment comprises light chain variable region complementarity determining region (CDR) sequences CDR1 (KASQDVSIAVA, SEQ ID NO:7), CDR2 (SASYRYT, SEQ ID NO:8) and CDR3 (QQHYITPLT, SEQ ID NO:9) and heavy chain variable region CDR sequences CDR1 (NYGMN, SEQ ID NO:10), CDR2 (WI[[T]]NTYTGEPTYTDDFKG, SEQ ID NO:11) and CDR3 (GGFGSSYWYFDV, SEQ ID NO:12).

13 . The immunoconjugate according to claim 1 , wherein said antibody or antibody fragment comprises heavy chain variable region CDR sequences CDR1 (NYGVN, SEQ ID NO:16), CDR2 (WINPNTGEPTFDDDFKG, SEQ ID NO:17) and CDR3 (SRGKNEAWFAY, SEQ ID NO: 18) and light chain variable region CDR sequences CDR1 (RSSQSLVHRNGNTYLH, SEQ ID NO:13), CDR2 (TVSNRFS, SEQ ID NO:14) and CDR3 (SQSSHVPPT, SEQ ID NO:15).

14 . The immunoconjugate according to claim 1 , wherein said antibody comprises the light chain variable region CDR sequences CDR1 (RASSSVSYIH, SEQ ID NO:30), CDR2 (ATSNLAS, SEQ ID NO:31) and CDR3 (QQWTSNPPT, SEQ ID NO:32) and heavy chain variable region CDR sequences CDR1 (SYNMH, SEQ ID NO:33), CDR2 (AIYPGNGDTSYNQKFKG, SEQ ID NO:34) and CDR3 (STYYGGDWYFDV, SEQ ID NO:35).

15 . The immunoconjugate according to claim 1 , wherein said antibody comprises the light chain variable region CDR sequences CDR1 (SASSSVSSSYLY, SEQ ID NO:19), CDR2 (STSNLAS, SEQ ID NO:20) and CDR3 (HQWNRYPYT, SEQ ID NO:21) and heavy chain variable region CDR sequences CDR1 (SYVLH, SEQ ID NO:22), CDR2 (YINPYNDGTQYNEKFKG, SEQ ID NO:23) and CDR3 (GFGGSYGFAY, SEQ ID NO:24).

16 . The immunoconjugate according to claim 1 , wherein said antibody comprises the heavy chain variable region CDR sequences CDR1 (EYVIT, SEQ ID NO:28), CDR2 (EIYPGSGSTSYNEKFK, SEQ ID NO:29) and CDR3 (EDL) and light chain variable region CDR sequences CDR1 (RSSQSIVHSNGNTYLE, SEQ ID NO:25), CDR2 (KVSNRFS, SEQ ID NO:26) and CDR3 (FQGSRVPYT, SEQ ID NO:27).

17 . The immunoconjugate according to claim 1 , wherein said antibody comprises the heavy chain variable region CDR sequences CDR1 (SYVIH, SEQ ID NO:1), CDR2 (YIHPYNGGTKYNEKYKG, SEQ ID NO:2) and CDR3 (SGGGDPFAY, SEQ ID NO:3) and light chain variable CDR region sequences CDR1 (KASQDINKYIG, SEQ ID NO:4), CDR2 (YTSALLP, SEQ ID NO:5) and CDR3 (LQYDDLWT, SEQ ID NO:6).

18 . The immunoconjugate according to claim 1 , wherein said antibody comprises the heavy chain variable region CDR sequences CDR1 (TYWMS, SEQ ID NO:36), CDR2 (EIHPDSSTINYAPSLKD, SEQ ID NO:37) and CDR3 (LYFGFPWFAY, SEQ ID NO:38) and light chain variable region CDR sequences CDR1 (KASQDVGTSVA, SEQ ID NO:39), CDR2 (WTSTRHT, SEQ ID NO:40) and CDR3 (QQYSLYRS, SEQ ID NO:41).

19 . The immunoconjugate of claim 1 , wherein the antibody or antibody fragment comprises light chain variable region CDR sequences CDR1 (RSSQSLVHRNGNTYLH, SEQ ID NO:13), CDR2 (TVSNRFS, SEQ ID NO:14), and CDR3 (SQSSHVPPT, SEQ ID NO:15) and heavy chain variable region CDR sequences CDR1 (NYGVN, SEQ ID NO:16), CDR2 (WINPNTGEPTFDDDFKG, SEQ ID NO:17), and CDR3 (SRGKNEAWFAY, SEQ ID NO:18).

20 . The immunoconjugate of claim 1 , wherein the antibody or antibody fragment binds to Trop-2.

21 . The immunoconjugate of claim 1 , wherein the antibody is a humanized antibody.

22 . A method of delivering a camptothecin to a target cell, comprising administering to an individual comprising the target cell an immunoconjugate according to any of claims 1 to 21 .

Assignees

• Immunomedics Inc

Inventors

• Govindan Serengulam V

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P7/06

  Antianaemics · CPC title

• A61P33/02

  Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis · CPC title

• A61P35/00

  Antineoplastic agents · CPC title