Portal de Periódicos da CAPES

Preclinical evaluation of a GFRA1 targeted antibody-drug conjugate in breast cancer

2018; Impact Journals LLC; Volume: 9; Issue: 33 Linguagem: Inglês

10.18632/oncotarget.25160

1949-2553

Emily E. Bosco, R. James Christie, Rosa A. Carrasco, Darrin Sabol, Jiping Zha, Karma Dacosta, Lee R. Brown, Maureen Kennedy, John Meekin, Sandrina Phipps, Joanne Ayriss, Qun Du, Binyam Bezabeh, Partha S. Chowdhury, Shannon Breen, Cui Chen, Molly Reed, MaryJane Hinrichs, Haihong Zhong, Zhan Xiao, Rakesh Dixit, Ronald Herbst, David A. Tice,

Advanced Breast Cancer Therapies

// 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.