Abstract 4182: The two novel BTK-inhibitors M2951 and M7583 show in vivo anti-tumor activity in pre-clinical models of B cell lymphoma

Abstract

Abstract Background. Diffuse large B cell lymphoma of the activated B cell like type (ABC DLBCL) is an aggressive lymphoma in which the inhibition of the Bruton’s tyrosine kinase (BTK) has shown biologic and clinical relevance. M7583 and M2951 are two novel highly selective irreversible BTK inhibitors (Fest C et al, 2016). M7583 has shown activity in a mouse model of lupus erythematosus (Bender et al, 2016). Here, we evaluated the anti-tumor activity of M2951 and M7583 in an in vivo ABC DLBCL model. Methods. Xenografts were established by s.c. injecting TMD8 lymphoma cells (100 µL of PBS, 107 cells/mouse) into the left flanks of female NOD-SCID mice (6 weeks of age and around 20g of body weight). Treatments (QD, po) were started with an average tumor volume of 100mm3 on groups of 10 mice each. Results. NOD-SCID mice engrafted with the ABC DLBCL TMD8 were treated with three different concentrations of M7583 (1 mg/Kg; 3 mg/Kg; 10mg/Kg) or M2951 (5 mg/Kg; 15 mg/Kg; 25mg/Kg) or vehicle, as control group. M2951 slowed tumor growth at all doses starting after 10 days of treatment. M7583 at 3 and 10 mg/Kg showed stronger anti-tumor activity than M2951, already evident after 5 days of treatment (P<0.05) and improving with time (after 10 days, P< 0.005). Moreover, while most groups had to be stopped after 2 weeks of treatment (D30 after engraftment) because of the reaching of the maximum tumor volume, allowed by the ethical veterinary committee, mice treated with M7583 at the two highest doses were able to continue treatment for additional six (3 mg/Kg) or ten days (10mg/Kg), when tumors became bigger than 2000 mm3, indicating a high activity of M7583. No body weight losses and sign of toxicity were detected. Conclusion. The two novel BTK inhibitors M2951 and M7583 showed promising in vivo anti-tumor activity in an ABC-DLBCL model. These data provide the rational for further investigating these compounds. Citation Format: Eugenio Gaudio, Chiara Tarantelli, Emanuele Zucca, Davide Rossi, Anastasios Stathis, Francesco Bertoni. The two novel BTK-inhibitors M2951 and M7583 show in vivo anti-tumor activity in pre-clinical models of B cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4182. doi:10.1158/1538-7445.AM2017-4182