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ABT-263 is an orally bioavailable small molecule inhibitor of Bcl-2 family proteins with a Ki of ≤ 1 nM against Bcl-2, Bcl-XL, and Bcl-w. Non-Hodgkin’s B-cell lymphomas represent clinically relevant disease targets for this molecule due, in part, to strong expression of Bcl-2 often associated with various types of NHL (frequently involving a t(14;18) translocation including the Bcl-2 locus). ABT-263 exhibits sub-micromolar in vitro activity against a variety of NHL cell lines. DoHH-2 and WSU-DLCL2 are two B-cell NHL lines harboring the t(14;18) translocation that exhibit differential in vitro sensitivity to ABT-263. Granta-519 is a mantle cell lymphoma line with the characteristic t(11;14)(q13:q32) translocation resulting in overexpression of cyclin D1. ABT-263 has an EC50 of approximately 150 nM in the Granta-519 cell line. Here we present efficacy data evaluating the activity of ABT-263 in several NHL xenograft models. ABT-263 has significant in vivo anti-tumor efficacy in established flank tumor models both as monotherapy and in combination with cytotoxic agents. The efficacy of ABT-263 at 100 mg/kg/day, p.o., q.d. ×21 was evaluated as monotherapy and in combination with etoposide, vincristine, modified CHOP, R-CHOP, bortezomib, rapamycin, and rituximab. Results show that ABT-263 significantly inhibits tumor growth as a monotherapy (~50–60% tumor growth inhibition) and enhances the efficacy of these cytotoxic agents in combination therapy. Statistically significant enhancement of tumor growth inhibition was observed for each combination relative to monotherapy treatment. Efficacy was maintained even when therapy was initiated on larger (~500 mm3) tumors. Combinations of ABT-263 + rapamycin and ABT-263 + rituximab result in complete regression of a significant percentage of established B cell lymphoma tumors for a sustained period of time in vivo. The combination of ABT-263 + R-CHOP resulted in complete regression of 100% of the tumors in the mantle cell lymphoma model. The strong in vitro potency and tumor regressions seen in vivo suggest that ABT-263 has great potential for the oral treatment of NHL B-cell lymphomas.

ABT-263 is an orally bioavailable small molecule inhibitor of Bcl-2 family proteins with a Ki of ≤ 1 nM against Bcl-2, Bcl-XL, and Bcl-w. Potent cytotoxic effects have been demonstrated against small cell lung carcinomas and lymphomas (EC50 of less than 500 nM in vitro against numerous cell lines). Tumor growth stasis and regression in xenograft models confirmed this activity. However, a unique thrombocytopenia has been observed in mice, rats, and dogs. Using a mouse model to characterize the extent and duration of decreased circulating platelets, outbred CF-1 or inbred scid-bg mice were treated with increasing doses of ABT-263. Blood samples were collected at various times post dosing and platelet numbers were determined using automated hematology analysis. The results showed a rapid, dose-dependent reduction in circulating platelet counts with a platelet nadir (>80% reduction relative to baseline) occurring approximately 6 hours after a single 100 mg/kg oral dose of ABT-263. Platelet counts returned to normal levels by 72 hrs post-dose. Analysis of bleeding times using a tail-nick method demonstrated a correlation between reduced platelet count and increased bleeding time. At doses of 50 mg/kg and higher, bleed times were increased by more than 5-fold relative to vehicle controls. In multi-dose studies, platelet levels did not continue to decline relative to the first dose of ABT-263. Mice treated with ABT-263 at 100 mg/kg/day for as long as 21 days exhibited no overt signs of toxicity (bleeding, significant weight loss, etc). Because the spleen is a potential site for clearing of damaged or aggregated platelets, a study using splenectomized mice was also conducted. The kinetics of platelet reduction and recovery were similar in splenectomized vs. intact mice with no additional adverse events noted. Evaluations of plasma drug levels associated with preclinical anti-tumor efficacy vs. thrombocytopenic effects indicate that a reasonable therapeutic window exists for ABT-263.