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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.

Original publication




Journal article


Proceedings of the National Academy of Sciences of the United States of America

Publication Date





Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Universidad de Navarra, 31008 Pamplona, Spain.


Liver, Lymph Nodes, Cell Line, Tumor, Animals, Humans, Mice, Lung Neoplasms, Inflammation, Peptide Hydrolases, Antineoplastic Agents, Antibodies, Monoclonal, Immunotherapy, Neoadjuvant Therapy, Tumor Necrosis Factor Receptor Superfamily, Member 9