Two Independent Teams Converge on PLA2G2D as a Novel Immune Checkpoint to Overcome Anti-PD-1 Resistance
核心洞察
A Nature publication validates PLA2G2D (搜索) as a mechanistically distinct immune checkpoint, identified independently by Apeximmune and Erasmus MC through computational and spatial proteogenomic approaches.
Apeximmune demonstrated that an enzyme-dead form of PLA2G2D (搜索) retains potent immunosuppressive activity, revealing a non-enzymatic mechanism the field had previously overlooked.
Preclinical data show PLA2G2D (搜索) blockade restores anti-tumor immunity in anti-PD-1 (搜索)-resistant models and potentiates anti-PD-1 activity in otherwise unresponsive tumors.
Apeximmune Therapeutics (搜索), an IND-stage immuno-oncology company based in South San Francisco, announced the publication of research in Nature validating phospholipase A2 group IID (PLA2G2D (搜索)) as a novel and mechanistically distinct immune checkpoint capable of addressing resistance to anti-PD-1 (搜索) therapy. The publication, titled "PLA2G2D in tumour-draining lymph nodes regulates anti-tumour immunity," represents the convergence of two independent research programs—one led by Apeximmune and the other by researchers at Erasmus University Medical Center (Erasmus MC) in Rotterdam—that arrived at the same target using fundamentally different scientific approaches.
Anti-PD-1 (搜索) therapies have transformed the treatment of certain cancers, but the majority of patients across indications either fail to respond or eventually relapse. Response rates fall to single digits in gastrointestinal cancers and other tumor types, and overcoming this resistance remains one of the most significant unmet needs in oncology.
Two Paths, One Target
Apeximmune and Erasmus MC reached PLA2G2D (搜索) by markedly different routes. Apeximmune's team, led by founder and CEO Li-Fen Lee, PhD, applied a proprietary bioinformatics algorithm to more than 9,000 primary tumor samples from The Cancer (搜索) Genome Atlas (TCGA), surfacing 70 candidate novel immune checkpoints. PLA2G2D emerged as the top-ranked hit, ranking well ahead of known checkpoints PD-1 (搜索) and CTLA-4 (搜索) in the same analysis.
Erasmus MC, working in parallel and unaware of Apeximmune's program, applied a spatial proteogenomic approach to melanoma (搜索) patient samples from individuals who had divergent clinical outcomes. Their analysis independently identified PLA2G2D (搜索) as a top hit in the dendritic cell and macrophage populations interacting with CD8+ T cells in patients with worse outcomes.
"The independent identification of the same target by the Erasmus team, using entirely different methods and starting from patient samples rather than computational discovery, is the strongest possible validation of the underlying biology," said Li-Fen Lee, PhD, founder and CEO of Apeximmune.
A Mechanism the Field Had Overlooked
Beyond identifying the target, the Apeximmune team uncovered a mechanism that had eluded prior investigators. PLA2G2D (搜索) has long been characterized for its phospholipase activity, and previous efforts to drug the broader sPLA2 family—including terminated late-stage small-molecule programs for inflammation from major pharmaceutical companies—had assumed its enzymatic function was central to its biology. Apeximmune demonstrated that an enzyme-dead form of PLA2G2D retains potent immunosuppressive activity, establishing that the molecule's role in tumor immune evasion is independent of its enzymatic activity.
Floris Dammeijer, MD, PhD, of Erasmus MC, described the origin of the work: "When we began this work, we were asking a straightforward question: how do cancer (搜索) cells block effective anti-tumor immune responses where they are first generated, in the lymph node? The answer, unexpectedly, kept pointing to PLA2G2D (搜索)."
Preclinical Data Suggest a Dual Therapeutic Opportunity
Data reported in the Nature publication indicate that PD-1 (搜索) and PLA2G2D (搜索) are nonredundant and reciprocally regulated. Blockade of PLA2G2D not only restores anti-tumor immunity in preclinical models resistant to anti-PD-1 therapy but also potentiates the activity of anti-PD-1 in tumor types that are otherwise unresponsive to checkpoint inhibition.
Together, the Nature findings point to two potential paths for patient benefit: a new therapeutic option for patients who have failed anti-PD-1 (搜索) therapy, and a way to extend the reach of anti-PD-1 into tumors currently considered "cold." Ralph Stadhouders, PhD, of Erasmus MC, noted: "Discovering that a team at Apeximmune had independently reached the same target, from an entirely different starting point, was extraordinary. The collaboration that followed has produced a body of evidence neither group could have generated alone."
AI-306 Advances Toward the Clinic
AI-306, Apeximmune's lead product candidate, is a first-in-class monoclonal antibody that blocks both the enzymatic and non-enzymatic activity of PLA2G2D (搜索). Backed by key patents covering target antagonism, antibody constructs, and combination therapies, AI-306 is currently in IND-enabling development with cell line development underway. GLP toxicology studies are scheduled to initiate in late 2026, and an IND filing is targeted for the second quarter of 2027. Apeximmune has developed proprietary PLA2G2D knockout and humanized mouse models that support the program.
Dan Ross, managing partner at BioPharma Capital and advisor to Apeximmune, said: "This publication marks an inflection point for Apeximmune and the AI-306 program. We are actively engaging with partners who share our commitment to bringing this therapy to patients as quickly as possible."
The Nature publication is dated September 9, 2026, with DOI 10.1038/s41586-026-10954-1.