Pre-Clinical Evaluation of a New-Generation Orally Bioavailable Dual Bcl-2/Bcl-Xl Inhibitor LP-118 in Mantle Cell Lymphoma

Introduction

Mantle cell lymphoma (MCL) is an aggressive form of non-Hopkins lymphoma with poor prognosis. The current frontline therapy of MCL is immunochemotherapy. For relapsed and refractory MCL, BTK inhibitor (BTKi) has become the standard of care, however, relapse is common after treatment with BTKi. Therefore, novel treatments with different mechanisms of action are needed for MCL patients. LP-118 is a new generation dual Bcl-2/Bcl-xL inhibitor with potent activity against wildtype and mutant Bcl-2 and moderate activity against Bcl-xL, and it is currently in Phase 1 clinical trials for multiple types of hematological cancers and solid tumors. In this study, we evaluated the preclinical activity of LP-118 in two MCL cell lines, REC-1 and Granta519, in vitro and in vivo. We also screened multiple combinations of LP-118 plus chemotherapeutic or targeted agents, in order to explore the optimal drug combinations for MCL treatment.

Methods

In vitro cell viability assay was performed with CellTiterGlo method in MCL cell lines REC-1 and Granta519 to examine cellular activity of LP-118. To determine the synergy of the combinations of LP-118 with standard of care agents, matrix combinations were performed with different concentrations of LP-118 and different drugs including vincristine, bendamustine, cytarabine, docetaxel, doxorubicin, cisplatin, and bortezomib. The data were analyzed using SynergyFinder (2.0), an online program for synergy scores. For in vivo experiments, Granta519 and REC-1-derived xenograft models were established and treated with different regimens: for Granta519 model, mice were treated with vehicle, BR (bendamustine, 25mg/kg, iv, day 1 and rituximab, 10mg/kg, iv, day 1), LP-118 (75mg/kg, po, qd, 28 days) in combination with BR. For REC-1 models, mice were treated with vehicle, LP-118 (50mg/kg, po, qd, 28 days) plus a BTK inhibitor LP-168 (25mg/kg, po, bid, 28 days), or ABT-199 (50mg/kg, po, qd, 28 days) plus ibrutinib (25mg/kg, po, qd,13 days, then bid, 28 days), and tumor growth/remission were examined to determine the in vivo anticancer activity.

Results

LP-118 is highly active in cell viability assays with Granta519 and REC-1 cells, with IC ₅₀ of 0.6 nM and 1.96 nM, respectively. And compared to venetoclax, LP-118 is 8 to18 times more potent in REC-1 and Granta519 cells. In the matrix combination studies with REC-1 cells, combinations of LP-118 with SOC agents showed synergistic anticancer effects with all the tested drugs, including vincristine, bendamustine, cytarabine, docetaxel, doxorubicin, cisplatin, and bortezomib. Moreover, the combination of LP-118 with BR induced complete tumor regression of Grana519 xenografts in all mice (7/7) at day 45 with no significant body weight changes, whereas no complete tumor regression was observed in the BR group, indicating that combination of LP-118 with BR was more effective than the treatment with BR alone. Similarly, the combination of LP-118 with LP-168 (BTKi) also resulted in complete tumor regression in REC-1 xenograft models at day 40, while the combination of ABT-199 plus ibrutinib showed no significant tumor growth inhibition, suggesting that combination of LP-118 and LP-168, a new generation BTKi currently also in clinical trial, might be more effective against MCL than the combination of ABT-199 plus ibrutinib in clinic.

Conclusion

LP-118 showed encouraging anti-MCL activity as single agent and in combination with standard of care agents in vitro and in vivo, warranting further evaluation of these combinations in clinical trials.