DISCOVERY OF A NOVEL, POTENTIAL FIRST‐IN‐CLASS MALT1 PROTEASE INHIBITOR FOR THE TREATMENT OF B CELL LYMPHOMAS (2019)

Introduction: Constitutive activation of the classical nuclear factor kappa-light-chain-enhancer of activated B‑cells (NF‑κB) pathway is a clear driver of B‑cell lymphomas, especially the aggressive activated B‑cell (ABC) subtype of diffuse large B‑cell lymphoma (DLBCL). Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is a key mediator of the classical NF-κB signaling pathway downstream of B-cell and T-cell receptor. MALT1 possesses 2 functions: a scaffolding function to recruit NF-κB signaling proteins and a protease function to cleave and inactivate inhibitors of the NF-κB signaling pathway. Methods: Using a high-throughput screen followed by iterative structure-activity relationship (SAR) analyses, a lead MALT1 inhibitor was identified. The lead compound was evaluated using biochemical, in vitro cellular, in vivo tumor efficacy and safety models. Results: The lead compound is a potent, selective, allosteric inhibitor of MALT1 protease activity as measured by biochemical assays, downstream cellular cytokine readouts (IL 6/10) or direct MALT1 substrate cleavage (RelB, BCL10). The compound inhibits proliferation of activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL) cell lines bearing CD79b or CARD11 mutations as well as models mimicking resistance to covalent Bruton's Tyrosine Kinase (BTK) inhibitors. Furthermore, combination effects were observed in CD79b-mutant cellular ABC-DLBCL models when the lead MALT1 inhibitor was combined with a BTK inhibitor. The lead MALT1 inhibitor leads to potent in vivo pharmacodynamic shutdown in CD79b- as well as CARD11-mutant ABC-DLBCL models as measured by serum IL10 or uncleaved BCL10 levels in tumors. The lead MALT1 inhibitor exhibits potent tumor growth inhibition in two human DLBCL xenograft models, OCI-Ly3 and OCI-Ly10. To address the role of MALT1 inhibition in T cells, primary human T cells derived from normal healthy volunteers were treated with the lead MALT1 inhibitor in vitro. Dose dependent inhibition of the generation of Tregs (CD4+CD25+FoxP3+) following CD3/28 stimulation was observed upon treatment with the lead MALT1 inhibitor suggesting a potential immune modulatory role of MALT1 inhibition. Conclusions: Phase 1 clinical trials assessing the safety and efficacy of the lead MALT1 inhibitor are planned to initiate in 2019. This MALT1 inhibitor is a combination partner for BTK inhibitors and a promising treatment option for BTKi-resistant tumors with demonstrated preclinical activity in CARD11 mutant tumors. In addition to ABC-DLBCL, a MALT1 inhibitor is a promising treatment option for patients with CLL, MCL, WM and FL whose tumors have been shown to be sensitive to inhibition of BTK. MALT lymphomas, characterized by MALT1 and BCL10 translocations, represent another attractive target for MALT1 inhibition. Keywords: BTK inhibitors; diffuse large B-cell lymphoma (DLBCL); MALT1. Disclosures: Philippar, U: Employment Leadership Position: Janssen R&D. Lu, T: Employment Leadership Position: Janssen R&D. Vloemans, N: Employment Leadership Position: Janssen R&D. Bekkers, M: Employment Leadership Position: Janssen R&D. van Nuffel, L: Employment Leadership Position: Janssen R&D. Gaudiano, M: Employment Leadership Position: Janssen R&D. Wnuk-Lipinska, K: Employment Leadership Position: Janssen R&D. Van Der Leede, B: Employment Leadership Position: Janssen R&D. Amssoms, K: Employment Leadership Position: Janssen R&D. Kimpe, K: Employment Leadership Position: Janssen R&D. Medaer, B: Employment Leadership Position: Janssen R&D. Greway, T: Employment Leadership Position: Janssen R&D. Abraham, Y: Employment Leadership Position: Janssen R&D. Cummings, M: Employment Leadership Position: Janssen R&D. Trella, E: Employment Leadership Position: Janssen R&D. Vanhoof, G: Employment Leadership Position: Janssen R&D. Sun, W: Employment Leadership Position: Janssen R&D. Thuring, J: Employment Leadership Position: Janssen R&D. Connolly, P: Employment Leadership Position: Janssen R&D. Linders, J: Employment Leadership Position: Janssen R&D. Gerecitano, J: Employment Leadership Position: Janssen R&D. Goldberg, J: Employment Leadership Position: Janssen R&D. Edwards, J: Employment Leadership Position: Janssen R&D. Elsayed, Y: Employment Leadership Position: Janssen R&D. Smit, J: Employment Leadership Position: Janssen R&D. Bussolari, J: Employment Leadership Position: Janssen R&D. Attar, R: Employment Leadership Position: Janssen R&D.