Abstract P39: CFT7455, a novel IKZF1/3 degrader enhances the anti-myeloma activity of monoclonal and bispecific antibodies by augmenting immune responses
Authors: Totman Jennifer A , Bret-Mounet Vanessa , Perino Samantha , Henderson James A , Pollock Roy M , Fisher Stewart L , Thomenius Michael J 
Published: March 2024

Immunomodulatory drugs (IIDs), such as pomalidomide (Pom), degrade the multiple myeloma (MM) survival transcription factors IKZF1 and IKZF3 and are widely used in the treatment of MM. We previously described CFT7455, a novel IKZF1/3 degrader, that is under investigation in a Phase 1/2 clinical trial (NCT04756726). CFT7455 demonstrates greatly increased target degradation potency compared to approved IIDs, leading to improved responses in preclinical models of sensitive and IID-resistant MM. In addition to direct anti-MM activity, IKZF1/3 degraders also induce immune responses through activation of T and NK cells. Antibody-based therapies, such as monoclonal antibodies (mAbs) and bispecific T-cell engagers (BiTEs), have dramatically changed the MM therapeutic landscape. These therapies lead to enhanced interactions between MM cells and immune effector cells. IKZF1/3 degraders may be particularly beneficial when used in combination with antibody therapies because they have the potential to amplify anti-MM immune responses. In this study, we investigated the effects of CFT7455 on immune cell activation and determined if clinically relevant concentrations of CFT7455 were able to enhance the anti-MM activity of daratumumab (anti-CD38 mAb) and teclistamab (BCMA BiTE) in in vitro models of antibody dependent cellular cytotoxicity (ADCC) and T-cell dependent cellular cytotoxicity (TDCC) respectively. Enhanced T-cell activation was evaluated by measuring T-cell proliferation and release of pro-inflammatory cytokines. Growth of T-cell populations was evaluated at 3 and 6-days post treatment. T-cell supernatants were evaluated for secretion of inflammatory cytokines using the Meso Scale Discovery (MSD) platform. IKZF1/3 levels were determined by western blot to evaluate target engagement in T-cells. ADCC and TDCC assays were performed with mAbs and BiTEs, respectively. CFT7455 induced potent and selective degradation of IKZF1/3 in T-cells. This reduction of IZKF1/3 levels directly correlated with increased T-cell proliferation at concentrations &gt;1000-fold lower than Pom. T-cell proliferation was increased by 5-fold following 6 days of treatment with CFT7455 compared to DMSO. These results were reproducible across two donors. Analysis of supernatants from CFT7455 treated T-cells demonstrated a dose-dependent increase in cytokines such as IL-2, INFγ, and TNFα. Release of cytotoxic effector proteins, Granzyme B and Perforin, occurred in a dose-dependent manner. The activity of daratumumab and teclistamab was enhanced in the presence of CFT7455 treated PBMCs relative to untreated PBMCs in ADCC and TDCC assays. Activation of T-cells, proinflammatory cytokine secretion, and improved ADCC/TDCC activity were observed at clinically relevant concentrations of CFT7455. The enhanced activity of CFT7455-treated effector cells led to improved anti-MM responses to daratumumab and teclistamab in ADCC and TDCC assays, respectively. The ability of CFT7455 to increase T-cell activation provides a strong rationale for combination with mAbs and BiTEs for the treatment of MM.

Citation Format: Jennifer A Totman, Vanessa Bret-Mounet, Samantha Perino, James A Henderson, Roy M Pollock, Stewart L Fisher, Michael J Thomenius. CFT7455, a novel IKZF1/3 degrader enhances the anti-myeloma activity of monoclonal and bispecific antibodies by augmenting immune responses [abstract]. In: Proceedings of the Blood Cancer Discovery Symposium; 2024 Mar 4-6; Boston, MA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(2_Suppl):Abstract nr P39.