Immunoconjugates with an intracellularly-cleavable linkage
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.
1. An immunoconjugate comprising:
a) an anti-EGP-1 antibody or an antigen-binding fragment thereof; and
b) six or more molecules of SN-38 covalently attached to the antibody or antibody fragment, wherein the attachment between SN-38 and antibody or antibody fragment involves a covalent bond with the C-20 hydroxyl group of the SN-38.
2. The immunoconjugate of claim 1 , wherein the antibody is a chimeric, humanized or human antibody.
3. The immunoconjugate of claim 1 , further comprising a linker between the antibody or antibody fragment and the SN-38.
4. The immunoconjugate of claim 3 , wherein the linker is an intracellularly cleavable linker.
5. The immunoconjugate of claim 1 , wherein the antibody is hRS7.
6. 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.
7. 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 (WINTYTGEPTYTDDFKG, SEQ ID NO:11) and CDR3 (GGFGSSYWYFDV, SEQ ID NO:12).
8. An immunoconjugate comprising:
a) an anti-EGP-1 antibody or antigen-binding fragment thereof; and
b) at least one molecule of SN-38 covalently attached to the antibody or antibody fragment, wherein the attachment between SN-38 and antibody or antibody fragment involves a covalent bond with the C-20 hydroxyl group of the SN-38.
9. The immunoconjugate of claim 8 wherein the antibody is RS7.
10. The immunoconjugate of claim 8 , wherein the antibody or antibody fragment comprises light chain variable 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 (WINTYTGEPTYTDDFKG, SEQ ID NO:11) and CDR3 (GGFGSSYWYFDV, SEQ ID NO:12).
11. The immunoconjugate of claim 8 , wherein the antibody is a humanized antibody.