Abstract 582P
Background
Despite recent advances in treatment of precursor B-acute lymphoblastic leukemia (B-ALL) there is still a need for novel targeted therapies. The tetraspanin CD9 is expressed in 60-80% of B-ALL and correlates with adverse prognosis. Recently, the mouse CD9 antibody ALB6 was shown to induce leukemia rejection in NOD/SCID mice. However, clinical development of ALB6 and other CD9-targeting antibodies was hampered by their CD9 mediated induction of platelet aggregation.
Methods
AT1412 is a fully human antibody isolated from B cells of a patient that was cured from stage IV metastatic melanoma.
Results
AT1412 targets CD9, without inducing platelet aggregation in vitro or thrombosis in cynomolgus monkeys after intravenous administration at therapeutic dose levels. By crystallography AT1412 was shown to bind a unique epitope distinct from those recognized by mouse CD9 antibodies. AT1412 binds a majority of patient B-ALL samples, but not T-ALL and induces ADCC of CD9 positive B-ALL primary cells and the level of cytotoxicity significantly correlated with that of AT1412 binding. In immunodeficient mice harboring a human immune system AT1412 demonstrated a strong, dose-dependent tumor rejection of B ALL, most pronounced in the extramedullary sites. In addition, AT1412 showed accumulation of T cells and CD14+ myeloid cells at the tumor sites. To support clinical development, pre-clinical safety of AT1412 was evaluated in cynomolgus monkeys. AT1412 demonstrated a half-life of 8.5 days, supporting 2-3 weekly administration. Besides transient thrombocytopenia no other pathological deviations were observed. The thrombocytopenia is reversible and its recovery accelerated in those animals developing anti-AT1412 antibodies. No effect on coagulation parameters, bruising or bleeding were observed macro- or microscopically.
Conclusions
Taken together, we demonstrate that CD9 on B-ALL cells can be successfully targeted by AT1412. AT1412 targets a unique epitope and does not induce thrombosis. Pre-clinical safety assessment is supporting that AT1412 can be safely administered. A First in Human clinical study is scheduled to start early 2021 and will evaluate AT1412 in B-ALL as well as CD9+ solid tumors.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
AIMM Therapeutics.
Disclosure
J. Villaudy: Shareholder/Stockholder/Stock options, Full/Part-time employment: AIMM Therapeutics. R. Schotte: Shareholder/Stockholder/Stock options, Full/Part-time employment: AIMM Therapeutics. G. de Jong: Full/Part-time employment: AIMM Therapeutics. V. Neviani: Full/Part-time employment: Utrecht University. W. Pos: Full/Part-time employment: AIMM Therapeutics. S. Levie: Shareholder/Stockholder/Stock options, Full/Part-time employment: AIMM Therapeutics. E. Yasuda: Shareholder/Stockholder/Stock options, Full/Part-time employment: AIMM Therapeutics. M. Cercel: Shareholder/Stockholder/Stock options, Full/Part-time employment: AIMM Therapeutics. A. Szabó: Full/Part-time employment: Erasmus University Medical Center. C. Fatmawati: Shareholder/Stockholder/Stock options, Full/Part-time employment: AIMM Therapeutics. M. Kedde: Shareholder/Stockholder/Stock options, Full/Part-time employment: AIMM Therapeutics. S. Horbach: Honoraria (self): Sjeng Horbach Consultancy. E.M.E. Verdegaal: Full/Part-time employment: Leiden University. P. van Helden: Shareholder/Stockholder/Stock options, Full/Part-time employment: AIMM Therapeutics. S.H. van der Burg: Full/Part-time employment: Leiden University. A. Rijneveld: Full/Part-time employment: Erasmus University. P. Gros: Full/Part-time employment: Utrecht University. H. Spits: Shareholder/Stockholder/Stock options, Full/Part-time employment: AIMM Therapeutics. M. Hazenberg: Spouse/Financial dependant: AIMM Therapeutics. H. van Eenennaam: Shareholder/Stockholder/Stock options, Full/Part-time employment: AIMM Therapeutics.