Introduction

Despite rapid advances in immunotherapeutic options for precursor B-acute lymphoblastic leukemia (BCP-ALL), outcomes remain poor especially for adult ALL and relapsed pediatric ALL. With conventional chemotherapy remission percentages in adult ALL range from 75 to 90%, but relapse rates are high and long-term leukemia-free survival ranges between 35-70% depending on age and risk group. The introduction of CD19-targeting immunotherapy has significantly improved patient outcomes in (relapsed) BCP-ALL. However, tumor escape via downregulation of CD19 occurs in a significant number of patients. An ongoing medical need remains for the identification of alternative immunotherapeutic targets for treatment of ALL.

Methods

CD9 is expressed in 60-80% of BCP-ALL, is correlated with adverse prognosis and has been proposed as therapeutic target for BCP-ALL. AT1412 is a fully human CD9-targeting antibody, that was identified from a patient cured of metastatic melanoma after adoptive T-cell therapy, using our B-cell immortalization technology (AIMSelect) [Kwakkenbos et al. Nat. Med. 2010]. The antibody was selected based on differential binding to melanoma cells as compared to healthy melanocytes and was shown to be successful in killing melanoma cells in vitro and in vivo.

Results

Binding of AT1412 to BCP-ALL cell lines SUP-B15, MHH-CALL-2 and CCRF-SB varied as expected based on CD9 levels that we detected using a commercial CD9 antibody. AT1412-induced antibody dependent cellular cytotoxicity (ADCC) and antibody dependent cellular phagocytosis (ADCP) correlated with the level of AT1412 binding. No binding was seen to the T-ALL cell line Jurkat. These findings were confirmed in primary ALL samples, obtained prospectively at diagnosis from a cohort of patients with T- or B-ALL (n=38). AT1412 showed binding to the majority of B-ALL samples but not to T-ALL samples. AT1412 induced ADCC of nearly all B-ALL samples it bound to (10/11) and of none of the non-binding B-ALL or T-ALL samples. Cytotoxicity significantly correlated with the level of AT1412 binding. These findings were corroborated by the observation that AT1412 induced specific B-ALL cell death when a bone marrow sample from a newly diagnosed BCP-ALL patient was incubated with AT1412. Remarkably, AT1412 induced cell death in the absence of added effector cells or other (chemo)therapeutic agents, while the sample contained over 80% blasts and as little as 3% lymphocytes. We are currently investigating the in vivo efficacy of the antibody in a humanized immune system mouse model with human BCP-ALL.

Conclusion

Taken together, the majority of BCP-ALL express CD9 and this is associated with poor prognosis. Our data demonstrate that CD9 can be successfully targeted by the human CD9 antibody AT1412, suggesting that AT1412 has the potential to be developed as a therapeutic antibody for B-ALL. AT1412 is currently being advanced through preclinical development.

Citation Format: Greta de Jong, Sophie E. Levie, Remko Schotte, Wouter Pos, Daniel Go, Etsuko Yasuda, Madalina Cercel, Susan E. van Hal, Esmay Frankin, Aniko Szabo, Martijn Kedde, Els Verdegaal, Julien Villaudy, Sjoerd van der Burg, Pauline M. van Helden, Hans van Eenennaam, Hergen Spits, Anita van Rijneveld, Mette D. Hazenberg. AT1412, a patient-derived antibody in development for the treatment of CD9-positive precursor B-acute lymphoblastic leukemia [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 531.