AKY-2519, a novel B7-H3-targeted radioconjugate, and its biodistribution profile in patients with mCRPC.

3097 Background: AKY-2519 is a 6.1 kDa B7-H3 (CD276) targeting miniprotein with an N-terminal short polyethylene glycol linker and dodecane tetraacetic acid chelator designed to deliver actinium (Ac)-225 for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) and other solid tumors. Miniproteins are a novel radioconjugate therapy (RCT) format affording high affinity, selectivity, deep tumor penetration and internalization prolonging tumor retention and rapid plasma clearance limiting exposure to normal tissues. B7-H3 is highly expressed in multiple solid tumor cancers and absent in normal tissues such as salivary glands. These properties render B7-H3 a promising target specifically for Ac-225 delivering RCT in mCRPC. We evaluated biodistribution and tumor uptake of AKY-2519 relative to PSMA-11 and assessed estimated radiation doses to tumors and normal tissues in 16 mCRPC patients. Methods: Sixteen mCRPC patients were imaged with [ 68 Ga]Ga-AKY-2519 and [ 68 Ga]Ga-PSMA-11 PET/CTs to assess biodistribution and tumor uptake by SUV. Patients then received low dose [ 177 Lu]Lu-AKY-2519 (~0.37-0.56 GBq) followed by SPECT/CT at 3, 24, and 144 hours post-injection for normal tissue and tumor dosimetry analyses. SPECT images were reconstructed with MIM SPECTRA Recon Software and mean human absorbed dose coefficients (Gy/GBq) were generated with MIM SurePlan MRT. To assess tumor doses, representative lesions including nodal, skeletal and primary disease sites were analyzed across multiple patients. Results: No AEs were reported throughout the imaging assessment. PET and SPECT/CTs showed robust tumor uptake with prolonged retention. High lesion concordance was observed between AKY-2519 and PSMA-11 supporting B7-H3 as a novel target in mCRPC and further suggesting co-expression of B7-H3 and PSMA. No accumulation of AKY-2519 was noted in normal tissues with initial activity in the liver rapidly clearing out. Of the normal tissues of interest including kidneys, salivary glands, liver and bone marrow, the mean absorbed doses were below established clinical thresholds when scaled up to a full therapeutic treatment course. The predicted absorbed tumor doses were within expected therapeutic ranges and exceeded normal tissue exposures indicative of a potentially favorable risk-benefit profile for [ 225 Ac]Ac-AKY-2519. Conclusions: These are the first clinical data showing concordance between PSMA and B7-H3 on PET-CT imaging in a substantial cohort of patients supporting B7-H3 as a novel target in mCRPC. The normal tissue to tumor dose ratios observed with AKY-2519 suggest a wide therapeutic window as an Ac-225 delivering therapeutic. The low predicted dose to salivary glands supports its use as an actinium delivering RCT for mCRPC, with dosing under IND expected to start in 2H-2026.