Combination therapy for inducing immune response to disease
The present invention concerns combinations of two or more agents for inducing an immune response to cancer or infectious disease. Agents may include leukocyte redirecting complexes, antibody-drug conjugates, interferons (preferably interferon-α), and/or checkpoint inhibitor antibodies. The leukocyte redirecting complexes have at least one binding site for a leukocyte antigen and at least one binding site for an antigen on a diseased cell or pathogen. Preferably, the complex is a DNL™ complex. More preferably, the complex comprises a bispecific antibody (bsAb). Most preferably, the bsAb is an anti-CD3× anti-CD19 bispecific antibody, although antibodies against other leukocyte antigens and/or disease-associated antigens may be used. The complex is capable of targeting effector T cells, NK cells, monocytes or neutrophils to induce leukocyte-mediated cytotoxicity of cells associated with cancer or infectious disease. The cytotoxic immune response is enhanced by co-administration of interferon, checkpoint inhibitor antibody and/or ADC.
1. A method of treating a Trop-2+ cancer comprising:
a) administering to a human subject with a Trop-2+ cancer a trivalent T-cell redirecting complex comprising a bispecific antibody, wherein the bispecific antibody comprises (i) an anti-CD3 antibody moiety conjugated to an AD (anchoring domain) moiety from an AKAP protein, wherein the amino acid sequence of the AD moiety is SEQ ID NO:4 and (ii) an anti-Trop-2 antibody moiety conjugated to a DDD (dimerization and docking domain) moiety with an amino acid sequence of residues 1-44 of human protein kinase A (PKA) regulatory subunit RIIα, wherein two copies of the DDD moiety form a dimer that binds to one copy of the AD moiety to form a complex; and
b) administering to the subject a checkpoint inhibitor antibody selected from the group consisting of pembrolizumab (MK-3475), nivolumab (BMS-936558), and pidilizumab (CT-011).
2. The method according to claim 1 , wherein the complex comprises a first antibody moiety and a second antibody moiety.
3. The method according to claim 2 , wherein the first antibody moiety is an IgG antibody and the second antibody moiety is an antigen-binding antibody fragment.
4. The method of claim 2 , wherein the first and second antibody moieties are antigen-binding antibody fragments.
5. The method of claim 4 , wherein the antibody fragments are selected from the group consisting of a F(ab′) 2 , a Fab′, a F(ab) 2 , a Fab, a scFv, and a single domain antibody.
6. The method of claim 1 , further comprising administering to the individual interferon-α.
7. The method of claim 1 , further comprising inducing a T-cell mediated cytotoxic immune response against the cancer.
8. The method of claim 6 , wherein the combination of interferon and T-cell redirecting complex is more effective than interferon alone and T-cell redirecting complex alone.
9. The method of claim 6 , wherein the interferon is administered before, simultaneously with, or after the T-cell redirecting complex.
10. The method of claim 1 , wherein the checkpoint inhibitor antibody is administered before, simultaneously with, or after the T-cell redirecting complex.
11. The method of claim 1 , wherein the cancer is selected from the group consisting of colon cancer, rectal cancer, stomach cancer, lung cancer, breast cancer, ovarian cancer, prostate cancer, uterine cancer, urinary bladder cancer, pancreatic cancer, kidney cancer, and esophageal cancer.
12. The method of claim 1 , wherein the T-cell redirecting complex is administered intravenously or subcutaneously.
13. The method of claim 1 , wherein the checkpoint inhibitor antibody is pembrolizumab.