Enhanced Activity of GA101, a Novel Type II, Glycoengineered CD20 Antibody, In Combination with Bendamustine or Fludarabine, and with the Bcl-2 Family Inhibitors ABT-737 or ABT-263
Authors: Herting Frank , Bader Sabine , Umana Pablo , Klein Christian 
Published: October 2019

Abstract 3915

GA101 is type II, glycoengineered CD20 antibody currently in PhII/III clinical trials. GA101 mediates enhanced direct cell death with a concomitant reduction of CDC; and high ADCC induction due to increased affinity for FcgRIIIa. We have shown that GA101 compared to rituximab mediates superior efficacy in NHL xenograft models including the induction of complete tumor remission.

In clinical practice the combination of rituximab with chemotherapy e.g. CHOP, CVP, bendamustine, fludarabine or FC results in a substantial clinical benefit. To assess the potential of GA101 for combination with bendamustine or fludarabine, in vivo combination studies in s.c. Z138 (MCL) xenografts in Scid beige mice were devised. GA101 and rituximab at sub-optimal doses of 1 mg/kg (once weekly) were combined with 3 mg/kg bendamustine (days 19, 20, 21, 22); or with 40 mg/kg fludarabine (days 22, 23, 24) and compared to the corresponding monotherapy arms. GA101 in combination with bendamustine mediated statistically superior efficacy in terms of tumor growth inhibition (TGI) compared to the combination of rituximab and bendamustine: TGI values on day 33 were 29% for rituximab, 42% for rituximab + bendamustine, 47% for GA101 and 72% for GA101 + bendamustine. Treatment with bendamustine did not show significant antitumor activity. Statistical evaluation based on sAUC showed a more than additive and significant effect on tumor growth for the combination of GA101 with bendamustine compared to the corresponding monotherapy arms. GA101 in combination with fludarabine demonstrated statistically superior efficacy in terms of TGI and yielded a significant difference compared to the combination of rituximab and fludarabine or GA101 as monotherpy. TGI values on day 36 were 50% for fludarabine, 60% for rituximab, 85% for rituximab + fludarabine, 86% for GA101 and >100% for GA101 + fludarabine. Furthermore, the superiority of the GA101-fludarabine combination was demonstrated by the observation of 3 tumor-free animals at the end of the study.

ABT-263 (navitoclax) is a Bcl-2 family inhibitor that is currently in Phase I/II clinical trials for lymphoid malignancies. To provide evidence that GA101 can be combined with ABT-263 and the experimental Bcl-2 family inhibitor ABT-737, in vivo combination studies in s.c. SU-DHL4 (DLBCL) xenografts in Scid beige mice were devised. 10 mg/kg GA101 and rituximab (once weekly) were combined with 50 mg/kg ABT-737 (i.p., days 19, 22, 24, 26, 29, 31, 33). In a second study, 3 mg/kg GA101 or 10 mg/kg rituximab (once weekly) were combined with 100 mg/kg ABT-263 (orally, once daily). GA101 at a sub-optimal dose of 10 mg/kg demonstrated statistically superior efficacy in combination with ABT-737 in terms of tumor growth inhibition compared to GA101 alone or the combination of 10 mg/kg rituximab and ABT-737. Both combination treatments were statistically significant compared to the corresponding monotherapy arms. TGI values based on means on day 36 were 20% for ABT-737, 45% for rituximab, 92% for rituximab + ABT-737, 96% for GA101 and >100% for GA101 + ABT-737. The superiority of the combination of GA101 and ABT-737 was supported by complete tumor regression in all animals whereas none was observed with the combination of rituximab and ABT-737. GA101 at a sub-optimal dose of 3 mg/kg or rituximab at a dose of 10 mg/kg mediated statistically superior efficacy in terms of tumor growth inhibition in combination with ABT-263 compared to the respective monotherapy arms. TGI values based on means on day 43 were 15% for ABT-263, 89% for rituximab, >100% for rituximab + ABT-263, 80% for GA101 (at the sub-optimal dose) and >100% for GA101 (sub-optimal dose) + ABT-263.

Taken together i) GA101 as single agent was at least as efficacious as the combination of rituximab with bendamustine, fludarabine or ABT-737; ii) the combination of GA101 with bendamustine or fludarabine was superior to the respective monotherapy arms and resulted in an enhanced, at least additive effect of the combination; iii) the combination of GA101 with Bcl-2 family inhibitors ABT-737 and ABT-263 was superior to the respective monotherapy arms and resulted in an enhanced effect of the combination including the induction of tumor remission. These data strongly support the further clinical investigation of GA101 in combination with Fludarabine, Bendamustine or Bcl-2 family inhibitors.

Disclosures:

Herting: Roche: Employment. Bader:Roche: Employment. Umana:Roche: Employment, Equity Ownership. Klein:Roche: Employment, Equity Ownership.