Preclinical evaluation of a GFRA1 targeted antibody-drug conjugate in breast cancer
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Emily E. Bosco1, R. James Christie2, Rosa Carrasco1, Darrin Sabol1, Jiping Zha3,8, Karma DaCosta3, Lee Brown4, Maureen Kennedy1, John Meekin1, Sandrina Phipps2, Joanne Ayriss2,6, Qun Du2, Binyam Bezabeh2,7, Partha Chowdhury2,9, Shannon Breen1, Cui Chen1, Molly Reed5, MaryJane Hinrichs5, Haihong Zhong1, Zhan Xiao1, Rakesh Dixit5, Ronald Herbst1 and David A. Tice1
1Oncology Research, MedImmune, LLC, Gaithersburg, Maryland, United States of America
2Antibody Discovery and Protein Engineering, MedImmune, LLC, Gaithersburg, Maryland, United States of America
3Pathology, MedImmune, LLC, Gaithersburg, Maryland, United States of America
4Pathology, MedImmune, Ltd, Cambridge, United Kingdom
5Biologics Safety Assessment, MedImmune, LLC, Gaithersburg, Maryland, United States of America
6Department of Global Biotherapeutics, Pfizer, Cambridge, Massachusetts, United States of America
7Research, Salubris Biotherapeutics, Gaithersburg, Maryland, United States of America
8Translational Sciences, NGM Biopharmaceuticals, South San Francisco, California, United States of America
9Biologics Discovery, Sanofi Genzyme, Cambridge, MA, United States of America
*These authors contributed equally to this work
Emily E. Bosco, email: [email protected]
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
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.
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