Abstract 2909: CD123-CODV-TCE bispecific T-cell engager for acute myeloid leukemia (AML): Activity on primary AML and safety in non-human primates
Authors: Bonnevaux Helene , Courta Jacqueline , Passe-Coutrin Wilfried , Bauchet Anne-Laure , Roobrouck Annelies , Amara Celine , Beys Eric , Balzano Marielle , Moulard Maxime , Meloni Marco , Dullaers Melissa , Chiron Marielle , Virone-Oddos Angela 
Published: June 2022

Acute myeloid leukemia (AML) is characterized by accumulation of abnormal blast cells in the bone marrow and blood. Although treatments like chemotherapy, allogeneic stem cell transplantation and new biotherapies improve the survival of patients, relapse is common and may be due to residual leukemic stem cells (LSCs). Since LSCs express high levels of CD123 (interleukin-3 receptor), CD123 represents an attractive target for relapsed/refractory (R/R) AML patients. Here, the expression of CD123 on leukemic cells and LSCs from fresh AML patient samples was confirmed, with a similar receptor density ranging from 350 to 12,500 and from 1,200 to 29,000 sites per cell, respectively. Also, the cytotoxic activity of the bispecific T-cell engager (TCE) CD123-CODV-TCE (that binds to CD3 on T cells and CD123 on blast cells) against primary blast cells isolated from the blood of 30 AML patients was evaluated. CD123-CODV-TCE induced high killing of AML blast cells with both high and low CD123 antigen density (from 298 to 18,719 sites per cell). The Effector: Target (E:T) ratio was highly variable among all patients, ranging from less than 1 to more than 100 blast cells for one T cell, and did not impact the activity of CD123-CODV-TCE. Since cytokine release syndrome is associated with TCE therapies, the release of proinflammatory cytokines was monitored in parallel to cytotoxicity. CD123-CODV-TCE induced the release of all tested cytokines (IL-6, IFNγ, TNFα and IL-8) without clear correlation with blast killing efficacy level. Since a similar CD123 expression pattern in human and cynomolgus monkey tissues was found, and CD123-CODV-TCE binds to human and cynomolgus CD3ε and CD123, non-human primates were used for the evaluation of pharmacodynamic effects and safety. A repeat-dose monkey study was performed using a progressive, weekly (X4) intra-monkey dose escalation scheme. The depletion of CD123 positive cells in blood was evidenced from the lowest dose tested (0.1 μg/kg) to the highest (5 µg/kg) with no adverse effects observed at 0.1 µg/kg. The main adverse effect consisted of a marked increase of the level of cytokines at 5 hours following compound administration at 1 μg/kg and above. Importantly, following the dose-escalation scheme 0.1/1/3/3 µg/kg, only limited cytokine release after the 4th administration was observed, suggesting that mitigation of cytokine release can be obtained by progressive intra-monkey dose escalation. Taken together, these results indicate that CD123-CODV-TCE leads to potent and specific leukemic cancer cell killing independently of CD123 receptor density and E:T ratio, and that studies monitoring cytokine release in monkeys can be useful for future clinical development of TCEs in the setting of R/R AML.

Citation Format: Helene Bonnevaux, Jacqueline Courta, Wilfried Passe-Coutrin, Anne-Laure Bauchet, Annelies Roobrouck, Celine Amara, Eric Beys, Marielle Balzano, Maxime Moulard, Marco Meloni, Melissa Dullaers, Marielle Chiron, Angela Virone-Oddos. CD123-CODV-TCE bispecific T-cell engager for acute myeloid leukemia (AML): Activity on primary AML and safety in non-human primates [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2909.