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 inducing a T-cell mediated immune response against a human cancer cell that expresses MUC5ac, or CEACAM5, comprising administering to a subject with a human cancer that expresses MUC5ac or CEACAM5 a leukocyte redirecting bispecific antibody comprising a first antibody or antigen-binding fragment thereof that binds to human CD3 and a second antibody or antigen-binding fragment thereof that binds to a human target antigen selected from the group consisting of MUC5ac, and CEACAM5;
wherein administration of the bispecific antibody induces a leukocyte-mediated immune response against the cancer and wherein the bispecific antibody comprises: (i) a first antibody moiety conjugated to an AD (anchoring domain) moiety from an AKAP protein; and (ii) a second antibody moiety 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, and 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 method of claim 1 , further comprising administering interferon-a to the subject.
3. The method of claim 1 , wherein the second antibody is selected from the group consisting of hPAM4 (anti-MUC5ac) and hMN-14 (anti-CEACAM5).
4. The method of claim 2 , wherein the interferon is administered as free interferon, PEGylated interferon, an interferon fusion protein or interferon conjugated to an antibody.
5. The method of claim 1 , wherein the cancer is selected from the group consisting of oral cavity cancer, gastrointestinal tract cancer, colon cancer, stomach cancer, lung cancer, breast cancer, ovarian cancer, prostate cancer, uterine cancer, urinary bladder cancer, pancreatic cancer, and kidney cancer.
6. The method of claim 1 , further comprising administering a therapeutic agent to the subject.
7. The method of claim 6 , wherein the therapeutic agent is selected from the group consisting of a drug, a toxin, an enzyme, a cytotoxic agent, an anti-angiogenic agent, a pro-apoptotic agent, a hormone, an immunomodulator, a cytokine, a chemokine, a boron compound and a radioisotope.
8. The method of claim 7 , wherein the drug is selected from the group consisting of 5-fluorouracil, afatinib, aplidin, azaribine, anastrozole, anthracyclines, axitinib, bendamustine, bleomycin, bortezomib bosutinib, bryostatin-1, busulfan, calicheamycin, camptothecin, carboplatin, 10-hydroxycamptothecin, carmustine, celecoxib, chlorambucil, cisplatinum, Cox-2 inhibitors, irinotecan (CPT-11), SN-38, cladribine, camptothecans, crizotinib, cyclophosphamide, cytarabine, dacarbazine, dasatinib, dinaciclib, docetaxel, dactinomycin, daunorubicin, doxorubicin, 2-pyrrolinodoxorubicine (2P-DOX), cyano-morpholino doxorubicin, doxorubicin glucuronide, epirubicin glucuronide, erlotinib, estramustine, epidophyllotoxin, erlotinib, entinostat, etoposide (VP16), etoposide glucuronide, etoposide phosphate, exemestane, fingolimod, floxuridine (FUdR), 3′,5′-O-dioleoyl-FudR (FUdR-dO), fludarabine, flutamide, flavopiridol, fostamatinib, ganetespib, gefitinib, gemcitabine, hydroxyurea, ibrutinib, idarubicin, idelalisib, ifosfamide, imatinib, L-asparaginase, lapatinib, lenolidamide, leucovorin, lomustine, mechlorethamine, melphalan, mercaptopurine, 6-mercaptopurine, methotrexate, mitoxantrone, mithramycin, mitomycin, mitotane, navelbine, neratinib, nilotinib, nitrosurea, olaparib, plicomycin, procarbazine, paclitaxel, pentostatin, Pro-2-P-Dox, raloxifene, semustine, sorafenib, streptozocin, sunitinib, tamoxifen, temazolomide, transplatinum, thalidomide, thioguanine, thiotepa, teniposide, topotecan, uracil mustard, vatalanib, vinorelbine, vinblastine, vincristine, and vinca alkaloids.
9. The method of claim 7 , wherein the chemokine is selected from the group consisting of RANTES, MCAF, MIP1-alpha, MIP1-Beta and IP-10.
10. The method of claim 7 , wherein the immunomodulator is selected from the group consisting of a cytokine, a stem cell growth factor, a lymphotoxin, a hematopoietic factor, a colony stimulating factor (CSF), an interferon (IFN), erythropoietin and thrombopoietin.
11. The method of claim 7 , wherein the cytokine is selected from the group consisting of human growth hormone, N-methionyl human growth hormone, bovine growth hormone, parathyroid hormone, thyroxin, insulin, proinsulin, relaxin, prorelaxin, follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), luteinizing hormone (LH), hepatic growth factor, prostaglandin, fibroblast growth factor, prolactin, placental lactogen, OB protein, tumor necrosis factor-α, tumor necrosis factor-β, mullerian-inhibiting substance, mouse gonadotropin-associated peptide, inhibin, activin, vascular endothelial growth factor, integrin, thrombopoietin (TPO), a nerve growth factor (NGF), NGF-β, platelet-growth factor, a transforming growth factors (TGF), TGF-α, TGF-β, insulin-like growth factor-I, insulin-like growth factor-II, erythropoietin (EPO), an osteoinductive factor, an interferon, interferon-α, interferon-β, interferon-λ, a colony stimulating factors (CSF), macrophage-CSF (M-CSF), granulocyte-macrophage-CSF (GM-CSF), granulocyte-CSF (G-CSF), interleukin-1 (IL-1), IL-1α, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-21, LIF, kit-ligand, FLT-3, angiostatin, thrombospondin, endostatin, tumor necrosis factor and LT (lymphotoxin).
12. A method of inducing an immune response to cancer comprising administering to a human subject with a cancer that expresses MUC5ac a leukocyte redirecting bispecific antibody comprising a first antibody or antigen-binding fragment thereof that binds to human CD3 and a second antibody or antigen-binding fragment thereof that binds to human MUC5ac, wherein administration of the bispecific antibody induces a leukocyte-mediated immune response against the MUC5ac-expressing cancer and wherein the bispecific antibody comprises: (i) a first antibody moiety conjugated to an AD (anchoring domain) moiety from an AKAP protein; and (ii) a second antibody moiety 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, and wherein two copies of the DDD moiety form a dimer that binds to one copy of the AD moiety to form the complex.
13. A method of inducing an immune response to cancer comprising administering to a human subject with a cancer that expresses CEACAM5 a leukocyte redirecting bispecific antibody comprising a first antibody or antigen-binding fragment thereof that binds to human CD3 and a second antibody or antigen-binding fragment thereof that binds to human CEACAM5, wherein administration of the bispecific antibody induces a leukocyte-mediated immune response against the CEACAM5-expressing cancer and wherein the bispecific antibody comprises: (i) a first antibody moiety conjugated to an AD (anchoring domain) moiety from an AKAP protein; and (ii) a second antibody moiety 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, and wherein two copies of the DDD moiety form a dimer that binds to one copy of the AD moiety to form the complex.