Tumor antigen CA125 suppresses antibody-dependent cellular cytotoxicity (ADCC) via direct antibody binding and suppressed Fc-γ receptor engagement

James Bradford Kline; Rina P. Kennedy; Earl Albone; Qimin Chao; Shawn Fernando; Jennifer M. McDonough; Katherine Rybinski; Wenquan Wang; Elizabeth B. Somers; Charles Schweizer; Luigi Grasso; Nicholas C. Nicolaides

doi:10.18632/oncotarget.19090

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Priority Research Papers:

Tumor antigen CA125 suppresses antibody-dependent cellular cytotoxicity (ADCC) via direct antibody binding and suppressed Fc-γ receptor engagement

James Bradford Kline _, Rina P. Kennedy, Earl Albone, Qimin Chao, Shawn Fernando, Jennifer M. McDonough, Katherine Rybinski, Wenquan Wang, Elizabeth B. Somers, Charles Schweizer, Luigi Grasso and Nicholas C. Nicolaides

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Oncotarget. 2017; 8:52045-52060. https://doi.org/10.18632/oncotarget.19090

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Abstract

James Bradford Kline1, Rina P. Kennedy1, Earl Albone1, Qimin Chao1, Shawn Fernando1, Jennifer M. McDonough1, Katherine Rybinski1, Wenquan Wang1, Elizabeth B. Somers1, Charles Schweizer1, Luigi Grasso1 and Nicholas C. Nicolaides1

1 Morphotek Inc., Exton, PA, USA

Correspondence to:

Nicholas C. Nicolaides, email:

Keywords: CA125, ADCC, farletuzumab, Fc-γ receptor, ovarian cancer

Received: May 15, 2017 Accepted: May 19, 2017 Published: July 07, 2017

Abstract

Cancers employ a number of mechanisms to evade host immune responses. Here we report the effects of tumor-shed antigen CA125/MUC16 on suppressing IgG1-mediated antibody-dependent cellular cytotoxicity (ADCC). This evidence stems from prespecified subgroup analysis of a Phase 3 clinical trial testing farletuzumab, a monoclonal antibody to folate receptor alpha, plus standard-of-care carboplatin-taxane chemotherapy in patients with recurrent platinum-sensitive ovarian cancer. Patients with low serum CA125 levels treated with farletuzumab demonstrated improvements in progression free survival (HR 0.49, p = 0.0028) and overall survival (HR 0.44, p = 0.0108) as compared to placebo. Farletuzumab’s pharmacologic activity is mediated in part through ADCC. Here we show that CA125 inhibits ADCC by directly binding to farletuzumab that in turn perturbs Fc-γ receptor engagement on effector cells.

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PII: 19090

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Priority Research Papers:

Tumor antigen CA125 suppresses antibody-dependent cellular cytotoxicity (ADCC) via direct antibody binding and suppressed Fc-γ receptor engagement

Abstract