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• W2802956075 abstract "// Emily E. Bosco 1 , R. James Christie 2 , Rosa Carrasco 1 , Darrin Sabol 1 , Jiping Zha 3, 8 , Karma DaCosta 3 , Lee Brown 4 , Maureen Kennedy 1 , John Meekin 1 , Sandrina Phipps 2 , Joanne Ayriss 2, 6 , Qun Du 2 , Binyam Bezabeh 2, 7 , Partha Chowdhury 2, 9 , Shannon Breen 1 , Cui Chen 1 , Molly Reed 5 , MaryJane Hinrichs 5 , Haihong Zhong 1 , Zhan Xiao 1 , Rakesh Dixit 5 , Ronald Herbst 1 and David A. Tice 1 1 Oncology Research, MedImmune, LLC, Gaithersburg, Maryland, United States of America 2 Antibody Discovery and Protein Engineering, MedImmune, LLC, Gaithersburg, Maryland, United States of America 3 Pathology, MedImmune, LLC, Gaithersburg, Maryland, United States of America 4 Pathology, MedImmune, Ltd, Cambridge, United Kingdom 5 Biologics Safety Assessment, MedImmune, LLC, Gaithersburg, Maryland, United States of America 6 Department of Global Biotherapeutics, Pfizer, Cambridge, Massachusetts, United States of America 7 Research, Salubris Biotherapeutics, Gaithersburg, Maryland, United States of America 8 Translational Sciences, NGM Biopharmaceuticals, South San Francisco, California, United States of America 9 Biologics Discovery, Sanofi Genzyme, Cambridge, MA, United States of America * These authors contributed equally to this work Correspondence to: Emily E. Bosco, email: boscoe@medimmune.com Keywords: GFRA1; antibody-drug conjugate (ADC); pyrrolobenzodiazepine (PBD); anti-tumor activity; breast cancer Received: January 12, 2018      Accepted: April 05, 2018      Published: May 01, 2018 ABSTRACT Despite recent advances in treatment, breast cancer remains the second-most common cause of cancer death among American women. A greater understanding of the molecular characteristics of breast tumors could ultimately lead to improved tumor-targeted treatment options, particularly for subsets of breast cancer patients with unmet needs. Using an unbiased genomics approach to uncover membrane-localized tumor-associated antigens (TAAs), we have identified glial cell line derived neurotrophic factor (GDNF) family receptor α 1 (GFRA1) as a breast cancer TAA. Immunohistochemistry (IHC) revealed that GFRA1 displays a limited normal tissue expression profile coupled with overexpression in specific breast cancer subsets. The cell surface localization as determined by fluorescence-activated cell sorting (FACS) and the rapid internalization kinetics of GFRA1 makes it an ideal target for therapeutic exploitation as an antibody-drug conjugate (ADC). Here, we describe the development of a pyrrolobenzodiazepine (PBD)-armed, GFRA1-targeted ADC that demonstrates cytotoxicity in GFRA1-positive cell lines and patient-derived xenograft (PDX) models. The safety profile of the rat cross-reactive GFRA1-PBD was assessed in a rat toxicology study to find transient cellularity reductions in the bone marrow and peripheral blood, consistent with known off-target effects of PBD ADC’s. These studies reveal no evidence of on-target toxicity and support further evaluation of GFRA1-PBD in GFRA1-positive tumors." @default.
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• W2802956075 date "2018-05-01" @default.
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• W2802956075 title "Preclinical evaluation of a GFRA1 targeted antibody-drug conjugate in breast cancer" @default.
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• W2802956075 doi "https://doi.org/10.18632/oncotarget.25160" @default.
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