B7-H3 protein expression turns up in more than 80% of non-small cell lung cancersmall cell lung cancer cases, and its overexpression tracks with poor survival outcomes across multiple solid tumor types, which explains why the target has become one of the more aggressively contested spaces in oncology drug development. Akeso’s clinical trial clearance for AK157D1, a B7-H3-targeting ADC now cleared by China’s NMPA Center for Drug Evaluation for Phase I in advanced solid tumors, signals that Akeso intends to compete in this space with a molecule built around a specific structural argument: that proprietary linker-payload design can sidestep the hematologic toxicity and interstitial lung disease that have constrained earlier-generation ADCs.
The structural details matter here. AK157D1 uses a site-specific conjugation strategy, attaching Dxd (the same topoisomerase I inhibitor payload class used across several leading ADC programs) to interchain cysteine residues via an MC-AAA linker. Site-specific conjugation produces a more homogeneous drug-to-antibody ratio than conventional approaches, which has historically translated into tighter therapeutic windows in preclinical models. B7-H3’s expression profile across NSCLC, SCLC, prostate, esophageal, colorectal, breast cancer, and glioblastoma gives a well-validated ADC a plausible path into multiple tumor indications from a single asset, which is the commercial logic behind targeting it at all.
What distinguishes Akeso’s positioning from most ADC developers is the combination angle. The company plans to evaluate AK157D1 alongside both ivonescimab (its approved PD-1/VEGF bispecific) and cadonilimab, treating those assets as the IO backbone into which ADC payloads slot. AK146D1, the TROP2/Nectin-4 ADC that preceded AK157D1 into the clinic, is already in Phase II combination studies with ivonescimab in breast cancer, providing a live template for this approach. The B7-H3 space remains actively competitive, with approved options limited and well-resourced programs in advanced development: ifinatamab deruxtecan from Daiichi Sankyo and Merck holds FDA Breakthrough Therapy Designation and Priority Review for extensive-stage SCLC, meaning AK157D1 enters a Phase I against a backdrop of well-resourced competitors already in advanced development.
The single number to track from this Phase I will be the maximum tolerated dose relative to the efficacious dose range, because Akeso’s entire differentiation claim rests on a wider therapeutic index than existing B7-H3 programs. If the safety data from the Phase I dose-escalation confirms that profile, the combination strategy with ivonescimab becomes executable at scale. If it does not, the structural argument collapses before the combination ever gets tested.
Jon Napitupulu is Director of Media Relations at The Clinical Trial Vanguard. Jon, a computer data scientist, focuses on the latest clinical trial industry news and trends.
