Disease therapy by inducing immune response to Trop-2 expressing cells
The present invention concerns compositions and methods of use of bispecific antibodies comprising at least one binding site for Trop-2 (EGP-1) and at least one binding site for CD3. The bispecific antibodies are of use for inducing an immune response against a Trop-2 expressing tumor, such as carcinoma of the esophagus, pancreas, lung, stomach, colon, rectum, urinary bladder, breast, ovary, uterus, kidney or prostate. The methods may comprising administering the bispecific antibody alone, or with one or more therapeutic agents such as antibody-drug conjugates, interferons (preferably interferon-α), and/or checkpoint inhibitor antibodies. The bispecific antibody is capable of targeting effector T cells, NK cells, monocytes or neutrophils to induce leukocyte-mediated cytotoxicity of Trop-2 + cancer cells. The cytotoxic immune response is enhanced by co-administration of interferon, checkpoint inhibitor antibody and/or ADC.
1. A method of inducing an immune response to a Trop-2 expressing cancer comprising:
a) administering to a subject with a Trop-2 expressing cancer a bispecific antibody that comprises (i) at least one anti-Trop-2 antibody or antigen-binding fragment thereof and one anti-CD3 antibody or antigen-binding fragment thereof, wherein the at least one anti-Trop-2 antibody or fragment thereof binds to the same epitope as an anti-Trop-2 antibody comprising the light chain CDR sequences CDR1 (KASQDVSIAVA, SEQ ID NO:115); CDR2 (SASYRYT, SEQ ID NO:116); and CDR3 (QQHYITPLT, SEQ ID NO:117) and the heavy chain CDR sequences CDR1 (NYGMN, SEQ ID NO:118); CDR2 (WINTYTGEPTYTDDFKG, SEQ ID NO:119) and CDR3 (GGFGSSYWYFDV, SEQ ID NO:120); and
b) administering to the subject at least one therapeutic agent selected from the group consisting of (i) interferon α; and (ii) a checkpoint inhibitor antibody.
2. The method of claim 1 , wherein the checkpoint inhibitor antibody is selected from the group consisting of lambrolizumab (MK-3475), nivolumab (BMS-936558), pidilizumab (CT-011), AMP-224, MDX-1105, MEDI4736, MPDL3280A, BMS-936559, ipilimumab, lirilumab, IPH2101 and tremelimumab.
3. The method of claim 1 , wherein the checkpoint inhibitor antibody binds to an antigen selected from the group consisting of CTLA4, PD1, PD-L1, LAG3, B7-H3, B7-H4, KIR and TIM3.
4. The method of claim 1 , wherein the bispecific antibody and the therapeutic agent are administered simultaneously.
5. The method of claim 1 , wherein the interferon-α is administered as free interferon, PEGylated interferon, an interferon fusion protein or interferon conjugated to an antibody.
6. The method of claim 1 , wherein the bispecific antibody comprises at least one antibody fragment selected from the group consisting of a scFv, a Fab and a dAb.
7. The method of claim 1 , wherein the Trop-2 expressing cancer is a carcinoma of the esophagus, pancreas, lung, stomach, colon, rectum, urinary bladder, breast, ovary, uterus, kidney or prostate.
8. The method of claim 1 , further comprising administering to the subject an anti-cancer agent selected from the group consisting of a second antibody or antigen-binding fragment thereof, a drug, a toxin, an enzyme, an anti-angiogenic agent, a pro-apoptotic agent, an antibiotic, a hormone, an immunomodulator, a cytokine, a boron compound and a radioisotope.
9. The method of claim 1 , wherein the bispecific antibody comprises a humanized RS7 (anti-Trop-2) antibody or antigen-binding fragment thereof.
10. The method of claim 1 , wherein the bispecific antibody comprises an Okt3 (anti-CD3) antibody or antigen-binding fragment thereof.
11. The method of claim 1 , wherein the bispecific antibody comprises the amino acid sequence of SEQ ID NO:107.
12. The method of claim 1 , wherein the bispecific antibody induces an immune response to a Trop-2 expressing cancer without increasing cytokine production to levels capable of inducing cytokine release syndrome (CRS).
13. The method of claim 1 , wherein the bispecific antibody induces trogocytosis of cell surface antigens between Trop-2 expressing cancer cells and T cells.
14. The method of claim 1 , wherein the bispecific antibody and the therapeutic agent are administered sequentially.