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
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Yaya Chu1,*, Aradhana Awasthi1,*, Sanghoon Lee1,2, Dina Edani1, Changhong Yin1, Jessica Hochberg1, Tishi Shah1, Tae-Hoon Chung6, Janet Ayello1, Carmella van de Ven1, Christian Klein7, Dean Lee8 and Mitchell S. Cairo1,2,3,4,5
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
|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
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.
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