Anti-wt1/hla bi-specific antibody

Abstract

Disclosed herein is a bi-specific form of a T cell receptor mimic (TCRm) mAb with reactivity to human immune effector cell antigen and a WT1 peptide / HLA-A epitope. This antibody selectively bound to leukemias and solid tumor cells expressing WT1 and HLA-A as well as activated resting human T cells to release interferon-(IFN-gamma) and to kill the target cancer cells in vitro. Importantly, the antibody mediated autologous T cell proliferation and directed potent cytotoxicity against fresh ovarian cancer cells. Therapeutic activity in vivo of the antibody was demonstrated in NOD SCID SCID Yc*(NSG) mice with three different human cancers expressing WT1 / HLA-A2 including disseminated Ph+ acute lymphocytic leukemia (ALL), disseminated acute myeloid leukemia, and peritoneal mesothelioma. In both of the leukemia xenograft models, mice that received the antibody and T cells also showed longer survival and delayed limb paralysis. Also provided are methods for stimulating a primary T cell response comprising stimulating cytotoxic T cells against a first tumor antigen and a secondary T cell response comprising stimulating effector T cells and / or memory T cells against a first tumor antigen and / or against a second tumor antigen using the bi-specific antibodies described herein.

Description

[0001] Cross References to Related Applications [0002] The benefit of U.S. Provisional Application Serial No. 61 / 901,310, filed November 7, 2013, and U.S. Provisional Patent Application Serial No. 62 / 037,875, filed August 15, 2014 are hereby claimed pursuant to 35 U.S.C. § 119(e), The disclosures of these two priority documents are hereby incorporated by reference in their entirety. [0003] This application contains subject matter related to that of the following applications: U.S. Provisional Application Nos. 61 / 470,635, filed April 1, 2011, and U.S. Provisional Application Nos. 61 / 491,392, filed May 31, 2011, and U.S. Provisional Application Nos. 61 / 491,392, filed May 31, 2011, and U.S. Provisional Application Nos. U.S. Nonprovisional Application No. 14 / 008,447, filed March 27, titled "T-Cell Receptor Like Antibodies Specific for WT1 Peptides," and commonly assigned U.S. Provisional Application No. 61 / 798,563; the contents of each application are hereby incorporated by ref...

AI Technical Summary

Problems solved by technology

The low efficiency of T cell-based therapies has been attributed to low TCR affinity, limited in vivo potent cytotoxic response against high tumor burden, lack of persistence of effector cells, tolerance to self-tumor Ag and passage of Immunosuppression by T regulatory (T-reg) cells and cytokine production (Morris et al. Blood Reviews 2006;20:61-69; Konnig R. Curr OpinImmunol 2002:14(1)75-83)

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