Nasdaq-listed Adlai Nortye Biopharma Co., Ltd. (Nasdaq: ANL) has initiated a first-in-human clinical trial of AN8025, a tri-specific antibody fusion protein designed to simultaneously engage PD-L1, a CD86 variant, and a LAG-3 variant, in patients with unresectable advanced or metastatic solid tumors. The trial's expansion cohort is restricted to patients who have already progressed on anti-PD-1/PD-L1 therapy, positioning AN8025 explicitly as a candidate for checkpoint-refractory disease — a population with limited effective options and where single-agent PD-1 inhibition has already failed.
The Phase I study (NCT07639047) will enroll approximately 91 adults across two parts. Part A conducts multiple ascending dose escalation in unselected advanced solid tumors; Part B opens up to two 20-patient expansion cohorts in tumor types to be identified following dose escalation. Enrollment in Part B requires documented PD-L1 expression on at least 1% of tumor cells by validated immunohistochemistry, and patients must have demonstrated radiographically confirmed progression on prior anti-PD-1 or PD-L1 monoclonal antibody therapy. The study is open at sites in Australia and China, with a primary completion date of July 2027. Primary endpoints focus on dose-limiting toxicities, maximum tolerated dose, and the recommended dose for expansion; secondary endpoints include pharmacokinetic characterization and preliminary antitumor activity.
Biological rationale: Three targets, one molecule
AN8025 is engineered on the backbone of an approved anti-PD-L1 antibody, to which functionally optimized extracellular domain variants of CD86 and LAG-3 are fused. The design departs from conventional checkpoint blockade in a mechanistically meaningful way. The anti-PD-L1 component maintains checkpoint inhibition, but the two fusion domains serve distinct immunostimulatory functions: the CD86 variant is intended to amplify tumor-specific T cell responses, while the LAG-3 variant is designed to promote antigen-presenting cell differentiation and maturation. Preclinical data presented at the American Association for Cancer Research Annual Meeting 2025 described this coordinated T cell and APC modulation as the molecule's central mechanistic rationale.
The LAG-3 application here is unconventional. In most clinical programs, LAG-3 is targeted as an inhibitory receptor on T cells — the approach taken by Bristol Myers Squibb's relatlimab (Opdualag), which blocks LAG-3 to relieve T cell suppression. AN8025 instead uses the LAG-3 extracellular domain as a fusion partner to stimulate APCs, exploiting LAG-3's known interaction with MHC class II molecules on antigen-presenting cells rather than its inhibitory signaling on T cells. Whether this mechanistic distinction translates into differentiated clinical activity in checkpoint-refractory patients remains to be demonstrated.