To enhance the effectiveness and safety of stimulatory receptor agonist antibodies, Palmeri et al. developed a collagen-targeting 4-1BB agonist Ab (4-1BB-LAIR) and delivered it directly into B16 melanoma tumors along with systemic delivery of a tumor antigen-targeted antibody (TA99). Modest antitumor activity of 4-1BB-LAIR was significantly enhanced by depletion of CD4+ cells, but development of protective memory required depletion of Tregs (FoxP3-DTR or anti-CTLA-4 Ab) and maintenance of effector CD4+ T cells. Activity required a single round of priming in tumor-draining lymph nodes, and 4-1BB-LAIR/TA99 enhanced effector differentiation in the tumor.
Contributed by Ed Fritsch
ABSTRACT: Although co-stimulation of T cells with agonist antibodies targeting 4-1BB (CD137) improves antitumor immune responses in preclinical studies, clinical development has been hampered by on-target, off-tumor toxicity. Here, we report the development of a tumor-anchored α4-1BB agonist (α4-1BB-LAIR), which consists of an α4-1BB antibody fused to the collagen binding protein LAIR. While combination treatment with an antitumor antibody (TA99) displayed only modest efficacy, simultaneous depletion of CD4 + T cells boosted cure rates to over 90% of mice. We elucidated two mechanisms of action for this synergy: αCD4 eliminated tumor draining lymph node Tregs, enhancing priming and activation of CD8 + T cells, and TA99 + α4-1BB-LAIR supported the cytotoxic program of these newly primed CD8 + T cells within the tumor microenvironment. Replacement of αCD4 with αCTLA-4, a clinically approved antibody that enhances T cell priming, produced equivalent cure rates while additionally generating robust immunological memory against secondary tumor rechallenge.
Author Info: (1) Koch Institute for Integrative Cancer Research; Cambridge, MA
(2) Department of Chemical Engineering of Massachusetts Institute of Technology (MIT); Cambridge, MA
(3) Departmen
Author Info: (1) Koch Institute for Integrative Cancer Research; Cambridge, MA
(2) Department of Chemical Engineering of Massachusetts Institute of Technology (MIT); Cambridge, MA
(3) Department of Biological Engineering of Massachusetts Institute of Technology (MIT); Cambridge, MA(
(4) Ragon Institute of MIT, MGH, and Harvard; Cambridge, MA
