The advent of ibrutinib has represented a new era in the treatment of B-cell malignancies, with remarkable clinical efficacy shown in previously difficult to treat lymphomas. Now, second generation Bruton's tyrosine kinase (BTK) inhibitors are in development with more refined pharmacologic profiles that maintain the potent anti-tumor effects of ibrutinib, but that improve upon overall tolerability and circumvent ibrutinib's inhibitory effect on antibody-dependent cell-mediated cytotoxicity (ADCC).
M7583 is a potent, orally administered, highly selective, adenosine triphosphate (ATP)-competitive, second generation, irreversible inhibitor of BTK. Kinase specificity has been determined in vitro using the Merck Millipore Kinase Profiler panel. Only 3 kinases (Blk, BMX, and Txk) had IC50s within a 10-fold range of BTK (BTK IC50 = 18.5 nM; Blk IC50 = 77 nM; BMX IC50= 5 nM; Txk IC50 = 62 nM). Target inhibition was confirmed with a concentration dependent decrease in BTK auto-phosphorylation detected by western blot in the Ramos cell line (human Burkitt's B-cell lymphoma). To examine the impact of kinase selectivity on the overall efficacy of M7583, its preclinical activity was compared with that of ibrutinib in a series of in vitro studies. M7583 inhibited the growth of diffuse large B-cell lymphoma (DLBCL) cell lines and primary chronic lymphocytic leukemia (CLL) blasts. In vivo , treatment with M7583 inhibited tumor growth in mantle cell lymphoma cell line-derived xenografts and patient-derived xenograft (PDX) models of DLBCL with the activated B-cell like diffuse large B-cell lymphoma (ABC-DLBCL) subtype being the most sensitive to M7583; consistent with the findings for other BTK inhibitors. To examine the potential for inhibition of ADCC by therapeutic antibodies, M7583 and ibrutinib were combined with rituximab or an ADCC incompetent version of rituximab in ADCC cell lysis experiments. At clinically relevant concentrations, ibrutinib inhibited the ADCC mechanism of rituximab, whereas M7583 did not. Collectively, these findings show the potency and selectivity of M7583 for BTK, as well as its efficacy in models of B-cell malignancies. The safety and efficacy of M7583 is currently being investigated in Phase I/II trials in patients with B-cell malignancies.
Goodstal: EMD Serono: Employment. Ma: EMD Serono: Employment. Lin: EMD Serono: Employment. Crandall: EMD Serono: Employment. Crowley: EMD Serono: Employment. Bender: EMD Serono: Employment. Iadevaia: EMD Serono: Employment. Clark: EMD Serono: Employment.
Asterisk with author names denotes non-ASH members.
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