Antitumor efficacy and reduced toxicity using an anti-CD137 Probody therapeutic
Menée in vitro et à l'aide de modèles murins, cette étude met en évidence l'intérêt thérapeutique d'un anticorps pro-médicament agoniste du récepteur CD137
CD137 (4-1BB) is a target for tumor immunotherapy, which has been pursued in clinical trials with agonist antibodies or the natural ligand (CD137L). Liver toxicity is a serious dose-limiting problem that may be circumvented by selective functional or physical targeting to the tumor microenvironment. A CD137 agonist antibody prodrug that is preferentially activated by tumor-associated proteases constitutes an appealing way to enhance safety while preserving efficacy.Costimulation via CD137 (4-1BB) enhances antitumor immunity mediated by cytotoxic T lymphocytes. Anti-CD137 agonist antibodies elicit mild liver inflammation in mice, and the maximum tolerated dose of Urelumab, an anti-human CD137 agonist monoclonal antibody, in the clinic was defined by liver inflammation–related side effects. A protease-activated prodrug form of the anti-mouse CD137 agonist antibody 1D8 (1D8 Probody therapeutic, Pb-Tx) was constructed and found to be selectively activated in the tumor microenvironment. This construct, which encompasses a protease-cleavable linker holding in place a peptide that masks the antigen binding site, exerted antitumor effects comparable to the unmodified antibody but did not result in liver inflammation. Moreover, it efficaciously synergized with both PD-1 blockade and adoptive T-cell therapy. Surprisingly, minimal active Pb-Tx reached tumor-draining lymph nodes, and regional lymphadenectomy did not abrogate antitumor efficacy. By contrast, S1P receptor–dependent recirculation of T cells was absolutely required for efficacy. The preferential cleavage of the anti-CD137 Pb-Tx by tumor proteases offers multiple therapeutic opportunities, including neoadjuvant therapy, as shown by experiments in which the Pb-Tx is given prior to surgery to avoid spontaneous metastases.All study data are included in the article and/or supporting information.