Deciphering BGB-A445: A Non-Blocking OX40 Agonist with Exceptional Anti-Tumor Potential in Preclinical Studies

The text discusses a study on BGB-A445, a humanized antibody targeting the OX40 receptor, which is part of the TNFRSF and is involved in immune cell activation. Unlike current clinical agonistic anti-OX40 antibodies, BGB-A445 is a non-blocking agonist, meaning it does not hinder the interaction between OX40 and its ligand, OX40L. This interaction is crucial for enhancing anti-tumor immunity. The study utilized cell-based flow cytometry to assess BGB-A445's effect on OX40-OX40L binding and found it did not interfere even at high concentrations. The molecular binding mechanism was elucidated through the co-crystal structure of the OX40/BGB-A445 Fab complex, showing that BGB-A445 binds to a region distinct from the OX40L binding site.

In a mixed lymphocyte reaction assay, BGB-A445 was found to co-stimulate CD4+ T-cells to secrete IL-2 in a dose-dependent manner when used in conjunction with an anti-PD-1 antibody, unlike another anti-OX40 antibody, MOXR0916. The anti-tumor efficacy of BGB-A445 was evaluated in mouse models of colon cancer and demonstrated significant effectiveness both as a standalone treatment and in combination with anti-PD-1. Notably, BGB-A445 also showed promise in a pancreatic cancer model that is resistant to anti-PD-1 treatment.

The study concludes that BGB-A445 is a promising candidate for further clinical investigation due to its unique non-blocking mechanism and its demonstrated ability to stimulate the immune system and combat tumors, either alone or in combination with anti-PD-1 therapy.