CFT7455, a Novel IKZF1/3 Degrader, Demonstrates Potent Anti-Tumor Activity in Models of Non-Hodgkin's Lymphoma As a Single Agent or in Combination with Clinically Approved Agents

Abstract

Immunomodulatory drugs, such as pomalidomide and lenalidomide are approved for the treatment of multiple subtypes of non-Hodgkin's lymphoma (NHL). These drugs induce an interaction between Ikaros family zinc finger proteins 1 and 3 (IKZF1/3) and cereblon (CRBN), an E3 ligase, resulting in IKZF1/3 degradation. IKZF1/3 are master transcription factors that play a key role in B and T-cell differentiation and maintain levels of interferon regulatory factor 4 (IRF4), a critical regulator in NHL. Clinically, immunomodulatory drugs have shown activity as single agents and when used in combination with several classes of targeted therapies, such as rituximab, in both first line and relapsed/refractory NHL subtypes. We previously described the preclinical characterization of CFT7455 as a novel IKZF1/3 degrader with 800-1600-fold increased potency over pomalidomide in CRBN binding and cellular IKZF1 degradation assays. We demonstrated that this increased activity translated into dramatically greater efficacy compared to pomalidomide in cellular and in vivo preclinical models of multiple myeloma and NHL. Here we show that the increased catalytic activity and improved potency of CFT7455 also translates into potent anti-tumor activity as single agent or in combination with clinically approved agents in central nervous system (CNS) and subcutaneous models of NHL. In both the Raji and OCI-Ly10 CNS xenograft models, CFT7455 (100 µg/kg/day) led to a significant increase in survival in comparison to pomalidomide (P=0.002, P=0.0002). The combination of immunomodulatory drugs with CD20, BTK, or HDAC targeting agents shows promising clinical activity in the treatment of NHL. Combination studies were conducted, dosing CFT7455 in combination with rituximab, ibrutinib, or the HDAC inhibitor romidepsin in several models of NHL. In the mantle cell lymphoma (MCL) model, Mino, the combination of CFT7455 with rituximab demonstrated synergistic activity and complete tumor regression. In the diffuse large B-cell lymphoma (DLBCL) model, TMD8, the combination of ibrutinib and CFT7455 was synergistic and resulted in a significant increase in survival probability. In the CNS NHL model, OCI-Ly10, the combination of CFT7455 with rituximab or ibrutinib also led to a significant increase in survival probability highlighting the therapeutic potential of this combination. Synergistic activity was also observed with the combination of CFT7455 and romidepsin in two models of anaplastic large cell lymphoma (ALCL). In conclusion, CFT7455 is a potent, selective catalytic degrader of IKZF1/3, with single agent and combination antitumor activity in DLBCL, ALCL, and MCL models, supporting clinical investigation of CFT7455 for NHL.