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Patent
Sloan Kettering Cancer Center and Eureka Therapeutics | Date: 2016-11-30

The present invention provides antigen binding proteins that specifically bind to Wilms tumor protein (WT1), including humanized, chimeric and fully human antibodies against WT1, antibody fragments, chimeric antigen receptors (CARs), fusion proteins, and conjugates thereof. The antigen binding proteins and antibodies bind to HLA-A0201-restricted WT1 peptide. Such antibodies, fragments, fusion proteins and conjugates thereof are useful for the treatment of WT1 associated cancers, including for example, breast cancer, ovarian cancer, prostate cancer, chronic myelocytic leukemia, multiple myeloma, acute lymphoblastic leukemia (ALL), acute myeloid/myelogenous leukemia (AML) and myelodysplastic syndrome (MDS). In more particular embodiments, the anti-WT1/A antibodies may comprise one or more framework region amino acid substitutions designed to improve protein stability, antibody binding and/or expression levels.


Liu H.,University of California at San Francisco | Liu H.,Eureka Therapeutics | Radisky D.C.,Mayo Clinic Cancer Center | Yang D.,University of California at San Francisco | And 4 more authors.
Nature Cell Biology | Year: 2012

Overexpression of MYC transforms cells in culture, elicits malignant tumours in experimental animals and is found in many human tumours. We now report the paradoxical finding that this powerful oncogene can also act as a suppressor of cell motility, invasiveness and metastasis. Overexpression of MYC stimulated proliferation of breast cancer cells both in culture and in vivo as expected, but inhibited motility and invasiveness in culture, and lung and liver metastases in xenografted tumours. We show further that MYC represses transcription of both subunits of α vβ 3 integrin, and that exogenous expression of β 3 integrin in human breast cancer cells that do not express this integrin rescues invasiveness and migration when MYC is downregulated. These data uncover an unexpected function of MYC, provide an explanation for the hitherto puzzling literature on the relationship between MYC and metastasis, and reveal a variable that could influence the development of therapies that target MYC. © 2012 Macmillan Publishers Limited. All rights reserved.


Rebagay G.,Sloan Kettering Cancer Center | Rebagay G.,Georgia Regents University | Yan S.,Eureka Therapeutics | Liu C.,Eureka Therapeutics | Cheung N.-K.,Sloan Kettering Cancer Center
Frontiers in Oncology | Year: 2012

Targeted therapies require cellular protein expression that meets specific requirements that will maximize effectiveness, minimize off-target toxicities, and provide an opportunity for a therapeutic effect. The receptor tyrosine kinase-like orphan receptors (ROR) are possible targets for therapy that may meet such requirements. RORs are transmembrane proteins that are part of the receptor tyrosine kinase (RTK) family. The RORs have been shown to play a role in tumor-like behavior, such as cell migration and cell invasiveness and are normally not expressed in normal adult tissue. As part of the large effort in target discovery, ROR proteins have recently been found to be expressed in human cancers. Their unique expression profiles may provide a novel class of therapeutic targets for small molecules against the kinase or for antibody-based therapies against these receptors. Being restricted on tumor cells and not on most normal tissues, RORs are excellent targets for the treatment of minimal residual disease, the final hurdle in the curative approach to many cancers, including solid tumors such as neuroblastoma. In this review, we summarize the biology of RORs as they relate to human cancer, and highlight the therapeutic approaches directed toward them. © 2012 Rebagay, Yan, Liu and Cheung.


Patent
Eureka Therapeutics and Sloan Kettering Cancer Center | Date: 2012-04-02

The present invention provides antigen binding proteins that specifically bind to Wilms tumor protein (WT1), including humanized, chimeric and fully human antibodies against WT1, antibody fragments, chimeric antigen receptors (CARs), fusion proteins, and conjugates thereof. The antigen binding proteins and antibodies bind to HLA-A0201-restricted WT1 peptide. Such antibodies, fragments, fusion proteins and conjugates thereof are useful for the treatment of WT1 associated cancers, including for example, breast cancer, ovarian cancer, prostate cancer, chronic myelocytic leukemia, multiple myeloma, acute lymphoblastic leukemia (ALL), acute myeloid/myelogenous leukemia (AML) and myelodysplastic syndrome (MDS). In more particular embodiments, the anti-WT1/A antibodies may comprise one or more framework region amino acid substitutions designed to improve protein stability, antibody binding and/or expression levels.


Patent
Sloan Kettering Cancer Center and Eureka Therapeutics | Date: 2014-11-07

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-) 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.


Patent
Sloan Kettering Cancer Center and Eureka Therapeutics | Date: 2015-05-28

The present invention provides antigen binding proteins that specifically bind to Wilms tumor protein (WT1), including humanized, chimeric and fully human antibodies against WT1, antibody fragments, chimeric antigen receptors (CARs), fusion proteins, and conjugates thereof. The antigen binding proteins and antibodies bind to HLA-A0201-restricted WT1 peptide. Such antibodies, fragments, fusion proteins and conjugates thereof are useful for the treatment of WT1 associated cancers, including for example, breast cancer, ovarian cancer, prostate cancer, chronic myelocytic leukemia, multiple myeloma, acute lymphoblastic leukemia (ALL), acute myeloid/myelogenous leukemia (AML) and myelodysplastic syndrome (MDS). In more particular embodiments, the anti-WT1/A antibodies may comprise one or more framework region amino acid substitutions designed to improve protein stability, antibody binding and/or expression levels.


Patent
Sloan Kettering Cancer Center and Eureka Therapeutics | Date: 2014-11-07

The present disclosure relates to an anti-WT-1/HLA/A2 antibody with enhanced antibody dependent cell-mediated cytotoxicity (ADCC) function due to altered Fc glycosylation. The antibody, which has reduced fucose and/or galactose, was compared to its normally glycosylated counterpart in binding assays, in vitro ADCC assays, and mesothelioma and leukemia therapeutic models and pharmacokinetic studies in mice. The antibody with normal glycosylation mediated ADCC against hematopoietic and solid tumor cells at concentrations below 1 g/ml, but the reduced fucosylated antibody was about 5-10 fold more potent in vitro against multiple cancer cell lines, was more potent in vivo against JMN mesothelioma, and effective against SET2 AML and fresh ALL xenografts. ESKM had a shortened half-life (4.9 vs 6.5 days), but an identical biodistribution pattern in C57BL6/J mice. At therapeutic doses of ESKM, there was no difference in half-life or biodistribution in HLA-A2.1+ transgenic mice compared to the parent strain. Importantly, therapeutic doses of ESKM in these mice caused no depletion of total WBCs or hematopoietic stem cells, or pathologic tissue damage.


Trademark
Eureka Therapeutics | Date: 2016-01-20

Pharmaceutical preparations of chimeric immune cell antigen receptors for therapeutic use for the treatment of cancers, for the treatment of proliferative cell diseases, and in transplantation.


Patent
Eureka Therapeutics | Date: 2011-11-29

The present disclosure provides compositions and methods comprising cells producing glycoproteins with variant glycosylation patterns. The methods and compositions may be used in producing antibodies and proteins of therapeutic value.


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