A Nature publication has given South San Francisco-based Apeximmune Therapeutics substantial external validation, with two independent research teams converging on the same immune checkpoint target — phospholipase A2 group IID (PLA2G2D) — as a mechanism underlying resistance to anti-PD-1 therapy. The convergence, achieved through entirely different methodologies, strengthens the scientific rationale for Apeximmune's lead antibody AI-306.
Apeximmune's team, led by founder and CEO Li-Fen Lee, PhD, identified PLA2G2D by applying a proprietary bioinformatics algorithm to more than 9,000 primary tumor samples from The Cancer Genome Atlas, where PLA2G2D ranked above known checkpoints PD-1 and CTLA-4 among 70 candidate novel immune checkpoints. Researchers at Erasmus University Medical Center (Erasmus MC) in Rotterdam arrived at the same target independently using spatial proteogenomics on melanoma patient samples, identifying PLA2G2D as a top hit in dendritic cell and macrophage populations interacting with CD8+ T cells in patients with worse clinical outcomes.
The mechanistic finding that distinguishes this work from prior attempts to drug the secreted phospholipase A2 (sPLA2) family is the discovery that PLA2G2D's immunosuppressive activity is independent of its enzymatic function. Earlier small-molecule programs targeting the broader sPLA2 family — including late-stage programs from major pharmaceutical companies that were terminated — had assumed enzymatic activity was central to the molecule's biology. Apeximmune demonstrated that an enzyme-dead form of PLA2G2D retains potent immunosuppressive activity, which the company said reframes how the target should be approached therapeutically.
Preclinical data reported in the Nature paper indicate that PD-1 and PLA2G2D are nonredundant and reciprocally regulated. Blockade of PLA2G2D restored anti-tumor immunity in models resistant to anti-PD-1 therapy and also potentiated anti-PD-1 activity in tumor types that are otherwise unresponsive to checkpoint inhibition — suggesting two distinct clinical settings where the target could be relevant.