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A specific and antibody-based technology, applied in the field of antibodies against cytosolic proteins, can solve problems such as low TCR affinity, lack of persistence of effector cells, and low efficiency
Active Publication Date: 2017-02-15
MEMORIAL SLOAN KETTERING CANCER CENT +1
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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, t...
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[0172] Materials and methods
[0173] Cell samples, cell lines and antibodies. Peripheral blood mononuclear cells (PBMC) from HLA-typed healthy donors and patients were obtained by Ficoll density centrifugation. The sources used to obtain human leukemia and solid tumor cell lines have been described previously (Dao et al., supra). The cell lines used in this study include: AML lines HL60, SET-2, Ph+ALL line BV173, mesothelioma cell lines JMN and MSTO. All cells have been HLA-typed. at 37C / 5% CO 2 The cell lines were cultured in RPMI 1640 supplemented with 5% FCS, penicillin, streptomycin, 2mmol / L glutamine and 2-mercaptoethanol. Tumor cells for animal studies were transduced with GFP / luciferase as previously described (Dao et al., supra). ESK1 and its control human IgG1 were produced by Eureka Therapeutics Inc (Emeryville, CA), and APC conjugation was performed according to the manufacturer's instructions (Dao et al., supra). Monoclonal antibody (mAb) against human HLA-A...
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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.
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[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...
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