Abstract 2970: Overcoming mechanisms of escape from treatments for multiple myeloma with ISB 2001, a potential first-in-class trispecific BCMA and CD38 targeted T cell engager

Immune therapies targeting a single tumor associated antigen (TAA) have demonstrated their efficacy against multiple myeloma (MM) in recent years. However, durable responses are still limited, which may be due to downregulation of the targeted TAA or expansion of clones with low target expression . To improve binding to tumor cells and enhance tumor cell killing, we propose to simultaneously target BCMA and CD38 using ISB 2001, a potential first-in-class TREAT™ trispecific CD3 T-cell engager based on Ichnos’ proprietary BEAT platform. To understand whether dual targeting could improve binding to tumors and enhance killing, we compared ISB 2001 to control molecules lacking one of the two TAA binders. Potency of ISB 2001 was greater than control molecules lacking either BCMA or CD38 used alone or in combination in a re-directed lysis assay on multiple myeloma cells These results were consistent with the binding to tumor cell lines, in which ISB 2001 showed higher maximal binding than control molecules lacking either CD38 or BCMA binding domains. We also compared the tumor killing potency of ISB 2001 to teclistamab, a BCMAxCD3 bispecific antibody recently approved to treat relapsed/refractory (RR) MM patients who have received prior lines of treatment. To mimic the heterogeneity of tumor cells, the killing of MM cell lines expressing varying levels of BCMA and CD38 was evaluated. ISB 2001 exhibited potent killing of the cell lines with EC50 ranging from 0.2 to 1.5 pM, which was statistically superior to that of teclistamab. These results were consistent with elevated binding of ISB 2001 to MM cells compared to teclistamab. In the presence of soluble BCMA or APRIL, ISB 2001 was 100-fold more potent than teclistamab. When evaluated in a therapeutic PBMC-humanized mouse model subcutaneously engrafted with BCMAlow/CD38low KMS-12-BM cells, ISB 2001 resulted in complete tumor regression and showed statistically higher potency than teclistamab at 0.1 mg/kg dose. In addition, ISB 2001 showed more potent anti-tumor activity than teclistamab in bone marrow aspirates of MM patients, indicating that ISB 2001 to leverage its cytotoxic properties with available immune cells. Taken together, we show that there is a clear advantage of avid binding achieved by the dual targeting using a TREAT-based ISB 2001, which results in potent and efficacious killing of tumor cells in vitro and in vivo. These data support clinical development of ISB 2001 as a promising treatment of RRMM through co-targeting of BCMA and CD38. Significant benefit is anticipated for RRMM patients who may experience tumor escape through target downregulation mechanisms. The evaluation of ISB2001 in a phase 1 clinical trial is planned for the first half of 2023. Citation Format: Maria Pihlgren, Laura Carretero, Jeremy Berret, Olivia Hall, Carole Estoppey, Adam Drake, Daniela Pais, Julie Macoin, Myriam Chimen, Perrine Suere, Emily Nallet, Blandine Pouleau, Elodie Stainnack, Jeremy Loyau, Thierry Monney, Aurore Delachat, Cyrille Dreyfus, Stan Blein, Zeynep Kaya, Thomas Matthes, Rebecca Croasdale-wood, James Edwards, Claire Edwards, Lamine Mbow, Michael Dyson, Cyril Konto, Ankita Srivastava, Eugene Zhukovshy, Mario Perro. Overcoming mechanisms of escape from treatments for multiple myeloma with ISB 2001, a potential first-in-class trispecific BCMA and CD38 targeted T cell engager [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2970.