Abstract

GA101 is a third generation, glycoengineered type II IgG1 anti-CD20 monoclonal antibody (Mab) with enhanced ADCC and superior caspase-independent apoptosis induction in comparison to other anti-CD20 antibodies, including rituximab which is a type I antibody. We compared the antitumor efficacy of GA101 and rituximab in established RL human lymphoma xenografts in SCID beige mice. One million exponentially growing RL cells were injected SC, yielding fast growing xenografts. GA101 was given twice weekly at 3 dosages (10, 30 and 100 mg/kg), whereas Rituximab was given at fixed dose of 30 mg/kg twice weekly. Both Mabs were administered as intravenous injections, for a total of 5 injections. GA101 was dose-related active against RL xenografts in terms of tumor growth inhibition (TGI). TGI was calculated using NCI formula and showed values of 25, 75 and 85% for the 10, 30 and 100 mg/kg dosages of GA101 respectively while the 30 mg/kg dose of rituximab induced a TGI of 43% only. Both higher doses of 30 and 100 mg/kg significantly inhibited the growth of RL tumors and resulted in some complete tumor remissions (10–30 %). The antitumor activity of Rituximab against RL xenografts was inferior to equivalent dosing of GA101. Toxicity of GA101 with these regimens was excellent with no toxic deaths and no significant modification of body weight. In a separate series of experiments rituximab 30 mg/kg and GA101 30 mg/kg administered once weekly i.v. for 4 weeks were combined or not to cyclophosphamide 50 mg/kg administered once weekly intraperitoneally for 4 weeks. This study confirmed the previous observation that the new anti CD20 GA101 was more active than rituximab administered at similar doses on established RL tumors. TGI values were 79, 35% and 93% for GA101, rituximab and cyclophosphamide administered as single agents when compared to untreated controls. When groups receiving combined therapy were compared to the groups receiving the corresponding single agent Mab, cyclophosphamide increased antitumor efficacy with TGI values of 83 and 94% for rituximab and GA101, respectively. Thus using a suboptimal dose of the classical antilymphoma alkylating agent cyclophosphamide, the combination of either antibody with cyclophosphamide was more active than either agent alone, and the most active combination was GA101 with cyclophosphamide. These results show that GA101 is more active than rituximab on RL xenografts at similar doses, both administered as a single agent or in combination with cyclophosphamide. In the SCID mice model it is not expected that a major contribution to antitumor efficacy comes from the interaction of glycoengineered Mab with murine FcgRIV receptors. Complementary experiments with cobra venom factor, which is used for in vivo complement inhibition, suggest that rituximab antitumor effect was strongly dependent on complement dependent cytotoxicity while GA101 remained active when complement was depleted.

Disclosures: Herting:Roche: Employment. Klein:Roche: Employment. Umana:Glycart: Employment, Patents & Royalties. Dumontet:Roche: Research Funding.

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