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

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.

Therapy for Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma in Children, Adolescents, and Young Adults

“…41 Obinutuzumab, a glycoengineered type II anti-CD20 monoclonal antibody specifically developed to overcome rituximab resistance, 42 has demonstrated enhanced antibody-dependent cellular cytotoxicity to rituximab. 43 We have an open trial at our center combining obinutuzumab and ICE (O-ICE) in CAYAs with R/R CD201 mature NHL (ClinicalTrials.gov identifier: NCT02393157). The 6 patients enrolled thus far, all with Burkitt lymphoma, tolerated O-ICE well with no grade $3 adverse events, and 5 of the 6 patients were able to successfully proceed to HSCT.…”

Serum immunoglobulin and the threshold of Fc receptor-mediated immune activation

“…Of significance, these afucosylated mAbs were also able to overcome the inhibitory effects of serum IgG [ 371 ]. Examples of such glyco-optimised mAbs for the treatment of malignancies include Obinutuzumab (anti-CD20) and TrasGEX (anti-HER2), which have both exhibited anti-tumour activity in mouse models [ 26 , 372 ]. Significantly, Obinutuzumab has also demonstrated considerable benefit to PFS compared to rituximab in the treatment of CLL [ 373 ] and follicular lymphoma [ 374 ], and has therefore been approved by the United States Food and Drug Administration (FDA) as frontline and secondline treatment respectively.…”