Strategies for improved cancer vaccines
The present invention concerns methods and compositions for forming anti-cancer vaccine complexes. In preferred embodiments, the anti-cancer vaccine complex comprises an antibody moiety that binds to dendritic cells, such as an anti-CD74 antibody or antigen-binding fragment thereof, attached to an AD (anchoring domain) moiety and a xenoantigen, such as CD20, attached to a DDD (dimerization and docking domain) moiety, wherein two copies of the DDD moiety form a dimer that binds to the AD moiety, resulting in the formation of the vaccine complex. The anti-cancer vaccine complex is capable of inducing an immune response against xenoantigen expressing cancer cells, such as CD138 neg CD20 + MM stem cells, and inducing apoptosis of and inhibiting the growth of or eliminating the cancer cells.
1. A method of treating a B-cell cancer comprising:
a) obtaining a complex consisting essentially of;
iii) an antibody moiety that binds to a CD74 dendritic cell antigen, wherein the antibody moiety is attached to a DDD (dimerization and docking domain) moiety, wherein the amino acid sequence of the DDD moiety is selected from the group consisting of SEQ ID NO: 1 and SEQ ID NO: 2; and
iv) a tumor antigen moiety that is a CD20 xenoantigen, wherein the antigen moiety is attached to an AD (anchor domain) moiety, wherein the amino acid sequence of the AD moiety is selected from the group consisting of SEQ ID NO:3; SEQ ID NO:4; SEQ ID NO:7; SEQ ID NO:8; SEQ ID NO:9; SEQ ID NO:10; SEQ ID NO:11; SEQ ID NO:12; SEQ ID NO:13; SEQ ID NO:14; SEQ ID NO:15 and SEQ ID NO:16; wherein two copies of the DDD moiety form a dimer that binds to the AD moiety to form the complex; and
b) administering the complex to a human subject with a B-cell cancer.
2. The method of claim 1 , wherein the cancer is selected from the group consisting of B-cell lymphoma, B-cell leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, follicular lymphoma, mantle cell lymphoma, small lymphocytic lymphoma, diffuse B-cell lymphoma, marginal zone lymphoma, multiple myeloma, Burkitt lymphoma, Hodgkin's lymphoma and non-Hodgkin's lymphoma.
3. The method of claim 2 , wherein the cancer is multiple myeloma.
4. The method of claim 1 , further comprising administering one or more therapeutic agents to the subject, wherein the one or more therapeutic agents are selected from the group consisting of an immunomodulator, an anti-angiogenic agent, a cytokine, a chemokine, a growth factor, a hormone, a drug, a prodrug, an enzyme, a pro-apoptotic agent, a photoactive therapeutic agent, a cytotoxic agent, a chemotherapeutic agent; and a toxin.
5. The method of claim 4 , wherein the one or more therapeutic agents are administered to the subject prior to or simultaneously with the complex.
6. The method of claim 4 , wherein the drug is selected from the group consisting of nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas, gemcitabine, triazenes, folic acid analogs, anthracyclines, taxanes, COX-2 inhibitors, pyrimidine analogs, purine analogs, antibiotics, enzyme inhibitors, epipodophyllotoxins, platinum coordination complexes, vinca alkaloids, substituted ureas, methyl hydrazine derivatives, adrenocortical suppressants, hormone antagonists, endostatin, taxols, camptothecins, SN-38, doxorubicins and their analogs, antimetabolites, alkylating agents, antimitotics, anti-angiogenic agents, tyrosine kinase inhibitors, mTOR inhibitors, heat shock protein (HSP90) inhibitors, proteosome inhibitors, HDAC inhibitors, pro-apoptotic agents, methotrexate and CPT-11.
7. The method of claim 4 , wherein the toxin selected from the group consisting of ricin, abrin, alpha toxin, saporin, ribonuclease (RNase), DNase I, Staphylococcal enterotoxin-A, pokeweed antiviral protein, gelonin, diphtheria toxin, Pseudomonas exotoxin, and Pseudomonas endotoxin.
8. The method of claim 4 , 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 interleukin (IL), an interferon (IFN), erythropoietin, thrombopoietin, tumor necrosis factor (TNF), granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), and the stem cell growth factor designated “S1 factor”.
9. The method of claim 8 , wherein the cytokine is selected from the group consisting of tumor necrosis factor-α, tumor necrosis factor-β, mullerian-inhibiting substance, thrombopoietin (TPO), platelet-growth factor, TGF-α, TGF-β, insulin-like growth factor-I, insulin-like growth factor-II, erythropoietin (EPO), osteoinductive factors, interferon-α, interferon-β, interferon-γ, macrophage-CSF (M-CSF), 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, IL-25, LIF, angiostatin, thrombospondin, endostatin, and lymphotoxin (LT).
10. The method of claim 3 , further comprising inducing an immune response against CD138 neg CD20 + multiple myeloma (MM) stem cells.
11. The method of claim 3 , further comprising inducing apoptosis of CD138 neg CD20 + MM stem cells.
12. The method of claim 3 , wherein said administration is effective to inhibit or eliminate MM stem cells.
13. The method of claim 6 , wherein the drug is a COX-2 inhibitor.
14. A method of inducing an immune response against CD138 neg CD20 + MM stem cells comprising:
a) obtaining a complex consisting essentially of
i) an antibody moiety that binds to a dendritic cell antigen selected from the group consisting of CD209 (DC-SIGN), CD74 and CD205, wherein the antibody moiety is attached to a DDD (dimerization and docking domain) moiety, wherein the amino acid sequence of the DDD moiety is selected from the group consisting of SEQ ID NO: 1 and SEQ ID NO: 2; and
ii) a CD20 xenoantigen moiety attached to an AD (anchor domain) moiety, wherein the amino acid sequence of the DDD moiety is selected from the group consisting of SEQ ID NO:3; SEQ ID NO:4; SEQ ID NO:7; SEQ ID NO:8; SEQ ID NO:9; SEQ ID NO:10; SEQ ID NO:11; SEQ ID NO:12; SEQ ID NO:13; SEQ ID NO:14; SEQ ID NO:15 and SEQ ID NO:16; wherein two copies of the DDD moiety form a dimer that binds to the AD moiety to form the complex; and
b) administering the complex to a human subject with multiple myeloma.
15. The method of claim 14 , further comprising inducing apoptosis of CD138 neg CD20 + MM stem cells.
16. The method of claim 14 , wherein said administration is effective to inhibit or eliminate MM stem cells.