Fc?RIIB engagement drives agonistic activity of Fc-engineered ?OX40 antibody to stimulate human tumor-infiltrating T cells.

ABSTRACT: BACKGROUND:OX40 (CD134) is a costimulatory molecule of the tumor necrosis factor receptor superfamily that is currently being investigated as a target for cancer immunotherapy. However, despite promising results in murine tumor models, the clinical efficacy of agonistic ?OX40 antibodies in the treatment of patients with cancer has fallen short of the high expectation in earlier-stage trials. METHODS:Using lymphocytes from resected tumor, tumor-free (TF) tissue and peripheral blood mononuclear cells (PBMC) of 96 patients with hepatocellular and colorectal cancers, we determined OX40 expression and the in vitro T-cell agonistic activity of OX40-targeting compounds. RNA-Seq was used to evaluate OX40-mediated transcriptional changes in CD4+ and CD8+ human tumor-infiltrating lymphocytes (TILs). RESULTS:Here, we show that OX40 was overexpressed on tumor-infiltrating CD4+ T cells compared with blood and TF tissue-derived T cells. In contrast to a clinical candidate ?OX40 antibody, treatment with an Fc-engineered ?OX40 antibody (?OX40_v12) with selectively enhanced Fc?RIIB affinity, stimulated in vitro CD4+ and CD8+ TIL expansion, as well as cytokine and chemokine secretions. The activity of ?OX40_v12 was dependent on Fc?RIIB engagement and intrinsic CD3/CD28 signals. The transcriptional landscape of CD4+ and CD8+ TILs shifted toward a prosurvival, inflammatory and chemotactic profile on treatment with ?OX40_v12. CONCLUSIONS:OX40 is overexpressed on CD4+ TILs and thus represents a promising target for immunotherapy. Targeting OX40 with currently used agonistic antibodies may be inefficient due to lack of OX40 multimerization. Thus, Fc engineering is a powerful tool in enhancing the agonistic activity of ?OX40 antibody and may shape the future design of antibody-mediated ?OX40 immunotherapy.

SUBMITTER: Campos Carrascosa L 

PROVIDER: S-EPMC7478034 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature