Combination therapy for inducing immune response to disease
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 bispecific antibody that comprises
a) a first antibody moiety that binds to human CD3, conjugated to an AD (anchoring domain) moiety from an AKAP protein; and
b) a second antibody moiety that binds to human Trop-2, conjugated to a DDD (dimerization and docking domain) moiety, wherein the amino acid sequence of said DDD moiety is residues 1-44 of human protein kinase A (PKA) RIIα;
wherein two copies of the DDD moiety form a dimer that binds to one copy of the AD moiety to form the bispecific antibody.
2. 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.
3. The composition of claim 1 , wherein the second antibody moiety comprises a humanized RS7 (anti-Trop-2) antibody or antigen-binding fragment thereof.
4. The composition of claim 1 , wherein the first antibody comprises an Okt3 (anti-CD3) antibody or antigen-binding fragment thereof.
5. A bispecific antibody comprising
a) a first antibody moiety that binds to human CD3, conjugated to an AD (anchoring domain) moiety from an AKAP protein; and
b) a second antibody moiety that binds to human Trop-2, conjugated to a DDD (dimerization and docking domain) moiety, wherein the amino acid sequence of said DDD moiety is residues 1-44 of human protein kinase A (PKA) RIIα;
wherein two copies of the DDD moiety form a dimer that binds to one copy of the AD moiety to form the bispecific antibody.
6. The bispecific antibody of claim 5 , wherein the second antibody moiety comprises a humanized RS7 (anti-Trop-2) antibody or antigen-binding fragment thereof.
7. The bispecific antibody of claim 5 , wherein the first antibody moiety comprises an Okt3 (anti-CD3) antibody or antigen-binding fragment thereof.
8. The bispecific antibody of claim 5 , wherein the bispecific antibody comprises at least one antibody fragment selected from the group consisting of an scFv, a Fab and a dAb.