Development stage: Phase I
The project APN401 targets the E3 ubiquitin ligase Cbl-b, a central checkpoint for limiting immune responses. Inhibition of Cbl-b is therefore a new strategy for checkpoint blockade, designed to activate the immune system against cancer. T cells that are deficient in Cbl-b are more strongly activated, produce enhanced levels of cytokines and proliferate longer. Hence, Cbl-b knockout mice spontaneously reject various tumors. Apeiron works with PBMCs (peripheral blood mononuclear cells) from patients and silences Cbl-b ex vivo by siRNA (electroporation).
A phase I clinical trial studying safety, tolerability and optimal dose of APN401 is ongoing at the Wake Forest Baptist Medical Center, in North Carolina, USA.
Literature about Cbl-b (APN401)
Bachmaier, K. et al. Negative regulation of lymphocyte activation and autoimmunity by the molecular adaptor Cbl-b. Nature 403, 211-216 (2000).
Jeon, M.S. et al. Essential role of the E3 ubiquitin ligase Cbl-b in T cell anergy induction. Immunity 21, 167-177 (2004).
Krawczyk, C.M. et al. Differential control of CD28-regulated in vivo immunity by the E3 ligase Cbl-b. J Immunol 174, 1472-1478 (2005).