Obinutuzumab (GA101) vs. rituximab significantly enhances cell death, antibody-dependent cytotoxicity and improves overall survival against CD20+ primary mediastinal B-cell lymphoma (PMBL) in a xenograft NOD-scid IL2Rgnull (NSG) mouse model: a potential targeted agent in the treatment of PMBL
Yaya Chu, Aradhana Awasthi, Sanghoon Lee, Dina Edani, Changhong Yin, Jessica Hochberg, Tishi Shah, Tae‐Hoon Chung, Janet Ayello, Carmella van de Ven, Christian Klein, Dean A. Lee, Mitchell S. Cairo
Abstract
// Yaya Chu 1 , * , Aradhana Awasthi 1 , * , Sanghoon Lee 1 , 2 , Dina Edani 1 , Changhong Yin 1 , Jessica Hochberg 1 , Tishi Shah 1 , Tae-Hoon Chung 6 , Janet Ayello 1 , Carmella van de Ven 1 , Christian Klein 7 , Dean Lee 8 and Mitchell S. Cairo 1 , 2 , 3 , 4 , 5 1 Department of Pediatrics, New York Medical College, Valhalla, NY, USA 2 Department of Cell Biology & Anatomy, New York Medical College, Valhalla, NY, USA 3 Department of Microbiology & Immunology, New York Medical College, Valhalla, NY, USA 4 Department of Medicine, New York Medical College, Valhalla, NY, USA 5 Department of Pathology, New York Medical College, Valhalla, NY, USA 6 Cancer Science Institute of Singapore, National University of Singapore, Singapore 7 Roche Pharmaceutical Research & Early Development, Roche Innovation Center, Zurich, Switzerland 8 Department of Pediatrics, Nationwide Children’s Hospital, Columbus, Ohio, USA * Co-first authors Correspondence to: Mitchell S. Cairo, email: [email protected] Keywords: Obinutuzumab; rituximab; survival; primary mediastinal large B-cell lymphoma; antibody-dependent cellular cytotoxicity Received: March 06, 2020     Accepted: July 14, 2020     Published: August 11, 2020 ABSTRACT Primary mediastinal large B-cell lymphoma (PMBL), a distinct mature B-cell lymphoma, expresses CD20 and has recently been successfully treated with the combination of a type I anti-CD20 monoclonal antibody, rituximab, with multiple combination chemotherapy regimens. Obinutuzumab is a glycoengineered type II anti-CD20 monoclonal antibody (mAb), recognizing a unique CD20 extracellular membrane epitope with enhanced antibody dependent cellular cytotoxicity (ADCC) vs rituximab. We hypothesize that obinutuzumab vs rituximab will significantly enhance in-vitro and in-vivo cytotoxicity against PMBL. PMBL cells were treated with equal dose of obinutuzumab and rituximab for 24 hours (1–100 μg/ml). ADCC were performed with ex-vivo expanded natural killer cells at 10:1 E: T ratio. Mice were xenografted with intravenous injections of luciferase expressing Karpas1106P cells and treated every 7 days for 8 weeks. Tumor burden was monitored by IVIS spectrum system. Compared with rituximab, obinutuzumab significantly inhibited PMBL cell proliferation ( p = 0.01), promoted apoptosis ( p = 0.05) and enhanced ADCC ( p = 0.0002) against PMBL. Similarly, in PMBL xenografted NOD scid gamma mice, obinutuzumab significantly enhanced survival than rituximab when treated with equal doses ( p = 0.05). Taken together our results suggest that obinutuzumab significantly enhanced natural killer cytotoxicity, reduced PMBL proliferation and prolonged the overall survival in humanized PMBL xenografted NOD scid gamma mice.