Antitumor efficacy and reduced toxicity using an anti-CD137 Probody therapeutic
Iñaki Etxeberría, Elixabet Bolaños, Álvaro Teijeira, Saray Garasa, Alba Yanguas, Arantza Azpilikueta, W. Michael Kavanaugh, Olga Vasiljeva, Marcia Belvin, Bruce Howng, Bryan Irving, Kimberly Tipton, James W. West, Mei Li, Alan J. Korman, Emanuela Sega, Irene Olivera, Assunta Cirella, María C. Ochoa, María E Rodríguez, Ana Melero, Miguel F. Sanmamed, John Engelhardt, Ignacio Melero
Abstract
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.