Preclinical Evaluation of a Novel MALT1 Inhibitor CTX-177 for Relapse/Refractory Lymphomas

Abstract

Among various subtypes of malignant lymphomas, activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL), mantle cell lymphoma (MCL), and adult T-cell leukemia/lymphoma (ATL) are clinically intractable as patients with these lymphomas carry a dismal prognosis, with long-term survival rates of 10-30%. Therefore, a novel therapeutic strategy is required to better manage patients with these malignancies. Recently, we and other investigators performed comprehensive genetic studies and revealed frequent genetic alterations in B and T cell antigen receptor signaling and NF-κB pathway, such as CD79A/B and CARD11 mutations in ABC-DLBCL and PLCG1, PRKCB, and CARD11 mutations in ATL, suggesting the biological relevance of this pathway. To exploit a new treatment strategy in these malignant lymphomas, we focused on the protease mucosa-associated lymphoid tissue lymphoma translocation 1 (MALT1) which is a key regulator of the antigen receptor signaling and NF-κB pathway and forms a complex with CARD11 and BCL10, and developed a novel compound CTX-177 to inhibit MALT1 with high potency and specificity. CTX-177 was efficacious against ABC-DLBCL and MCL models in vitro and in vivo. Moreover, CTX-177 exhibited combination synergistic effect with BTK inhibitor. In addition, the MALT1 inhibitor showed an anti-tumor effect against CARD11 mutated ABC-DLBCL model, which is resistant to BTK inhibitor. To further explore efficacy of CTX-177 against malignant lymphomas, we generated animal models such as genetically engineered mice and patient-derived xenograft models recapitulating molecular features of these diseases, and examined the response to the MALT1 inhibitor. In these experiments, target engagement of CTX-177 was confirmed by detecting digested substrates of MALT1, and mode of action was evaluated by downregulation of oncogenic transcriptional factor IRF4 which is critical for lymphoma survival. Importantly, the relationship of susceptibility to MALT1 inhibition and gene mutations was analyzed to identity a patient selection biomarker for CTX-177. In summary, the novel, selective, small-molecule MALT1 inhibitor CTX-177 demonstrated preclinical efficacy along with target engagement in several lymphoma models with activated antigen receptor signaling and NF-κB pathway. Our results underscore the preclinical therapeutic potential of CTX-177 as a single-agent or in combination with other inhibitors like BTK inhibitor for the treatment of malignant lymphomas. Disclosures Morishita: Chordia Therapeutics Inc.: Current Employment, Current equity holder in private company. Mizutani:Chordia Therapeutics Inc.: Current Employment, Current equity holder in private company. Tozaki:Chordia Therapeutics Inc.: Current Employment, Current equity holder in private company. Arikawa:Chordia Therapeutics Inc.: Current Employment, Current equity holder in private company. Kataoka:CHUGAI PHARMACEUTICAL CO., LTD.: Research Funding; Takeda Pharmaceutical Company: Research Funding; Otsuka Pharmaceutical: Research Funding; Asahi Genomics: Current equity holder in private company. Yoda:Chordia Therapeutics Inc.: Research Funding. Izutsu:Symbio: Research Funding; Solasia: Research Funding; Celgene: Research Funding; Chugai: Research Funding; Novartis: Research Funding; Ono Pharmaceutical: Research Funding; Bayer pharmaceuticals: Research Funding; Daiichi Sankyo: Research Funding; AstraZeneca: Research Funding; Eisai: Research Funding; Incyte: Research Funding; Abbvie pharmaceuticals: Research Funding; HUYA Japan: Research Funding; Sanofi: Research Funding; Janssen: Research Funding; Yakult: Research Funding. Minami:Bristol-Myers Squibb Company: Honoraria; Novartis Pharma KK: Honoraria; Pfizer Japan Inc.: Honoraria; Takeda: Honoraria. Shimoda:Otsuka Pharmaceutical: Research Funding; Pfizer Inc.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; CHUGAI PHARMACEUTICAL CO., LTD.: Research Funding; Merck & Co.: Research Funding; Astellas Pharma: Research Funding; AbbVie Inc.: Research Funding; PharmaEssentia Japan: Research Funding; Perseus Proteomics: Research Funding; Celgene: Honoraria; Shire plc: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda Pharmaceutical Company: Honoraria; Novartis: Honoraria, Research Funding; Asahi Kasei Medical: Research Funding; Japanese Society of Hematology: Research Funding; The Shinnihon Foundation of Advanced Medical Treatment Research: Research Funding. Miyake:Chordia Therapeutics Inc.: Current Employment, Current equity holder in private company. Ogawa:KAN Research Institute, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Chordia Therapeutics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Asahi Genomics Co., Ltd.: Current equity holder in private company; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding.