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 composition comprising:
a) a bispecific antibody that comprises (i) at least one anti-Trop-2 antibody or antigen-binding fragment thereof and (ii) one anti-CD3 antibody or antigen-binding fragment thereof; and
b) at least one therapeutic agent selected from the group consisting of (iii) interferon-α; and (iv) a checkpoint inhibitor antibody that binds to an antigen selected from the group consisting of PD1, PD-L1, LAG3, B7-H3, B7-H4, KIR and TIM3.
2. The composition of claim 1 , wherein the checkpoint inhibitor antibody is selected from the group consisting of pembrolizumab (MK-3475), nivolumab (BMS-936558), pidilizumab (CT-011), AMP-224, MDX-1105, durvalumab (MEDI4736), atezolizumab (MPDL3280A), BMS-936559, lirilumab, IPH2101, avelumab.
3. The composition of claim 1 , wherein the interferon-α is selected from the group consisting of free interferon, PEGylated interferon, an interferon fusion protein or interferon conjugated to an antibody.
4. The composition 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.
5. The composition of claim 1 , wherein the bispecific antibody comprises a humanized RS7 antibody or antigen-binding fragment thereof 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).
6. The composition of claim 1 , wherein the anti-Trop-2 antibody or antigen-binding fragment thereof binds to the same epitope of Trop-2 as an RS7 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).
7. The composition of claim 1 , wherein the bispecific antibody comprises an Okt3 antibody or antigen-binding fragment thereof.
8. The composition of claim 1 , wherein the bispecific antibody comprises the amino acid sequence of SEQ ID NO:107.