Immunostimulatory agonist antibodies to CD137 have antitumor activity in preclinical models, but concomitant serious liver inflammation has precluded clinical dosing to therapeutic levels. Etxeberria et al. report on Pb-Tx-1D8, (anti-CD137 Probody Therapeutic), a prodrug antibody that recognizes CD137 only after proteolytic cleavage (by proteases present in TMEs) of a peptide coupled to the antigen binding site. Pb-Tx-1D8 had antitumor activity comparable to conventional anti-CD137, but liver adverse effects (as measured by ALT, CD8+ T liver infiltration, and extravascular T cell clusters) were reduced. Synergy was observed with anti-PD-1.
Contributed by Margot O’Toole
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.
Author Info: (1) Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Universidad de Navarra, 31008 Pamplona, Spain. Centro de Investigacin Biomdica en Red de Cn
Author Info: (1) Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Universidad de Navarra, 31008 Pamplona, Spain. Centro de Investigacin Biomdica en Red de Cncer, 28029 Madrid, Spain. Navarra Institute for Health Research, 31008 Pamplona, Spain. Department of Immunology, Clinica Universidad de Navarra, 31008 Pamplona, Spain. (2) Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Universidad de Navarra, 31008 Pamplona, Spain. Centro de Investigacin Biomdica en Red de Cncer, 28029 Madrid, Spain. Navarra Institute for Health Research, 31008 Pamplona, Spain. (3) Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Universidad de Navarra, 31008 Pamplona, Spain. Centro de Investigacin Biomdica en Red de Cncer, 28029 Madrid, Spain. Navarra Institute for Health Research, 31008 Pamplona, Spain. (4) Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Universidad de Navarra, 31008 Pamplona, Spain. Centro de Investigacin Biomdica en Red de Cncer, 28029 Madrid, Spain. Navarra Institute for Health Research, 31008 Pamplona, Spain. (5) Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Universidad de Navarra, 31008 Pamplona, Spain. Centro de Investigacin Biomdica en Red de Cncer, 28029 Madrid, Spain. Navarra Institute for Health Research, 31008 Pamplona, Spain. (6) Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Universidad de Navarra, 31008 Pamplona, Spain. Centro de Investigacin Biomdica en Red de Cncer, 28029 Madrid, Spain. Navarra Institute for Health Research, 31008 Pamplona, Spain. (7) CytomX Therapeutics, Inc., South San Francisco, CA 94080. (8) CytomX Therapeutics, Inc., South San Francisco, CA 94080. (9) CytomX Therapeutics, Inc., South San Francisco, CA 94080. (10) CytomX Therapeutics, Inc., South San Francisco, CA 94080. (11) CytomX Therapeutics, Inc., South San Francisco, CA 94080. (12) CytomX Therapeutics, Inc., South San Francisco, CA 94080. (13) CytomX Therapeutics, Inc., South San Francisco, CA 94080. (14) CytomX Therapeutics, Inc., South San Francisco, CA 94080. (15) Vir Biotechnology, San Francisco, CA 94158. Immuno-Oncology Discovery, Bristol-Myers Squibb, Redwood City, CA 94063. (16) Immuno-Oncology Discovery, Bristol-Myers Squibb, Redwood City, CA 94063. (17) Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Universidad de Navarra, 31008 Pamplona, Spain. Centro de Investigacin Biomdica en Red de Cncer, 28029 Madrid, Spain. Navarra Institute for Health Research, 31008 Pamplona, Spain. (18) Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Universidad de Navarra, 31008 Pamplona, Spain. Centro de Investigacin Biomdica en Red de Cncer, 28029 Madrid, Spain. Navarra Institute for Health Research, 31008 Pamplona, Spain. (19) Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Universidad de Navarra, 31008 Pamplona, Spain. Centro de Investigacin Biomdica en Red de Cncer, 28029 Madrid, Spain. Navarra Institute for Health Research, 31008 Pamplona, Spain. (20) Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Universidad de Navarra, 31008 Pamplona, Spain. Department of Oncology, Clinica Universidad de Navarra, 31008 Pamplona, Spain. (21) Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Universidad de Navarra, 31008 Pamplona, Spain. Department of Oncology, Clinica Universidad de Navarra, 31008 Pamplona, Spain. (22) Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Universidad de Navarra, 31008 Pamplona, Spain. Department of Oncology, Clinica Universidad de Navarra, 31008 Pamplona, Spain. (23) Immuno-Oncology Discovery, Bristol-Myers Squibb, Redwood City, CA 94063. (24) Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Universidad de Navarra, 31008 Pamplona, Spain; imelero@unav.es. Centro de Investigacin Biomdica en Red de Cncer, 28029 Madrid, Spain. Navarra Institute for Health Research, 31008 Pamplona, Spain. Department of Immunology, Clinica Universidad de Navarra, 31008 Pamplona, Spain.
