Dock-and-Lock (DNL) Vaccines for Cancer Therapy

Abstract

The present invention concerns methods and compositions for forming anti-cancer vaccine DNL complexes using dock-and-lock technology. In preferred embodiments, the anti-cancer vaccine DNL 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 DNL complex. The anti-cancer vaccine DNL 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.

What is claimed is: 
     
         1 . A method of treating cancer comprising:
 a) obtaining a DNL complex comprising; i) a chimeric, humanized or human anti-CD74 antibody moiety that binds to human CD74, wherein the antibody moiety is attached to an AD (anchor domain) moiety, wherein the AD moiety has an amino acid sequence selected from the group consisting of SEQ ID NO:13; SEQ ID NO:12; SEQ ID NO:19; SEQ ID NO:20; SEQ ID NO:21; SEQ ID NO:22; SEQ ID NO:23; SEQ ID NO:24; SEQ ID NO:25; SEQ ID NO:26; SEQ ID NO:27 and SEQ ID NO:28; and ii) a mouse xenoantigen moiety selected from the group consisting of carbonic anhydrase IX, alpha-fetoprotein (AFP), α-actinin-4, CD1, CD3, CD4, CD5, CD8, CD11A, CD14, CD15, CD16, CD18, CD19, CD20, CD21, CD22, CD23, CD25, CD29, CD30, CD33, CD37, CD38, CD40, CD40L, CD45, CD46, CD52, CD54, CD55, CD59, CD64, CD74, CD79a, CD80, CD83, CD95, CD126, CD138, CD147, CD154, PSMA, fibronectin, folate receptor, IL-6R, IL-13R, IL-17R, IL-18R, IL-6, IL-8, IL-12, IL-15, IL-17, IL-18, IFN-γ, IFN-α, IFN-β, macrophage migration inhibitory factor (MIF), mCRP, MIP-1B, MUC1, MUC2, MUC4, placental growth factor, p53, prostatic acid phosphatase, RANTES, tenascin, and TNF-α, wherein the xenoantigen moiety is attached to a DDD (dimerization and docking domain) moiety, wherein the amino acid sequence of the 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 the AD moiety to form the DNL complex; and   b) administering the complex to a human subject with cancer to induce an immune response against the cancer.   
     
     
         2 . The method of  claim 1 , wherein the antibody moiety comprises two heavy chains and each heavy chain is attached at its C-terminal end to an AD moiety and the complex comprises one antibody moiety and four xenoantigen moieties. 
     
     
         3 . The method of  claim 1 , wherein the xenoantigen is CD20. 
     
     
         4 . The method of  claim 1 , wherein the amino acid sequence of the DDD moiety is selected from the group consisting of SEQ ID NO:11 and SEQ ID NO:10. 
     
     
         5 . The method of  claim 1 , wherein the amino acid sequence of the DDD moiety is SEQ ID NO:11. 
     
     
         6 . The method of  claim 1 , wherein the amino acid sequence of the AD moiety is SEQ ID NO:13. 
     
     
         7 . The method of  claim 1 , wherein the antibody moiety is a humanized or chimeric LL1 anti-CD74 antibody or antigen-binding fragment thereof comprising the light chain variable complementarity-determining region (CDR) sequences CDR1 (RSSQSLVHRNGNTYLH; SEQ ID NO:1), CDR2 (TVSNRFS; SEQ ID NO:2), and CDR3 (SQSSHVPPT; SEQ ID NO:3) and the heavy chain variable region CDR sequences CDR1 (NYGVN; SEQ ID NO:4), CDR2 (WINPNTGEPTFDDDFKG; SEQ ID NO:5), and CDR3 (SRGKNEAWFAY; SEQ ID NO:6). 
     
     
         8 . The method of  claim 3 , wherein the amino acid sequence of the CD20 xenoantigen moiety is SEQ ID NO:7. 
     
     
         9 . The method of  claim 1 , wherein the DNL complex is capable of inducing an immune response against CD138 neg CD20 +  MM stem cells.