AKY-2519: Phase 1b Trial Targets B7-H3 in Metastatic Prostate Cancer

AKY-2519, a miniprotein radioconjugate targeting B7-H3, has entered a Phase 1b clinical trial in patients with metastatic castration-resistant prostate cancer (mCRPC). The open-label study enrolls both PLUVICTO-naïve and PLUVICTO-experienced patients at multiple U.S. radioligand therapy centers, evaluating three dose levels in each cohort before expanding at selected doses. Preliminary safety and efficacy data from this mCRPC-focused trial are anticipated in 2027.

This trial forms part of a dual Phase 1b strategy, with a second basket trial planned for the second half of 2026 in lung, colorectal, and other B7-H3-expressing solid tumors. The approach allows assessment across diverse patient groups while generating targeted data for decisions on next steps. FDA cleared the investigational new drug application for AKY-2519 in March 2026, accelerating its path to clinic after initial imaging and dosimetry studies.

Prior to dosing, AKY-2519 underwent clinical imaging with 64Cu-AKY-2519 and 68Ga-AKY-2519 to confirm biodistribution, tumor uptake, and predicted absorbed doses from its therapeutic actinium-225 payload. The miniprotein design promotes high tumor penetration, rapid internalization, retention in cancer cells, and quick clearance from normal tissues, paired with alpha-emitting Ac-225 for potent cell-killing while minimizing off-target effects.

B7-H3, also called CD276, emerges as a compelling target in mCRPC due to its overexpression in metastatic lesions compared to primary tumors or benign tissue, often independent of PSMA levels. Studies show elevated B7-H3 mRNA in mCRPC (median TPM 87-115 vs. 60 in normal prostate), associating with aggressive disease and poor outcomes. This positions AKY-2519 to serve PSMA-low or resistant patients, where current radioligands like lutetium-177 vipivotide tetraxetan (Pluvicto) fall short.

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