Development stage: end Phase I

The project APN401 targets the E3 ubiquitin ligase Cbl-b, an intracellular master checkpoint for limiting immune responses. Inhibition of Cbl-b is 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) and re-infuses the thereby activated cells. The whole process can be done within a few hours, „on the bed side“.

A phase I clinical trial studying safety, tolerability and optimal dose of APN401 in advanced cancer patients has recently successfully be completed at the Wake Forest Baptist Medical Center, in North Carolina, USA. A Phase Ib trial with multiple applications is ongoing, a Phase II controlled study in pancreatic cabcer in advanced preparation.


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).

Lutz-Nicoladoni C et al. Reinforcement of cancer immunotherapy by adoptive transfer of cblb-deficient CD8+ T cells combined with a DC vaccine. Immunol Cell Biol. 2012 Jan;90(1):130-4.