Characterization of LY4257496, a novel GRPR antagonist radiolabeled with lutetium-177

Background: Gastrin-releasing peptide receptor (GRPR) is a G protein-coupled receptor overexpressed in HR+ breast cancer and other solid tumors while having low expression in normal tissues. Although first generation GRPR antagonists have demonstrated utility in diagnostics, their therapeutic potential is limited by poor in vivo stability. Here, we present the preclinical profile of LY4257496, a novel GRPR antagonist labeled with lutetium-177, which shows favorable biodistribution, resistance to systemic cleavage, and promising tumor-to-healthy tissue uptake ratio. Methods: The binding affinity of LY4257496 was evaluated by a competitive binding assay in CHO cells engineered to express human, mouse, and rat specific GRPR isoforms. Biodistribution of LY4257496 (10MBq, 100MBq/nmol) was evaluated in T47D-tumor bearing and non-tumor bearing female mice. Efficacy of LY4257496 was evaluated as mono- and combination therapy in T47D xenografts and clinically relevant HR+ breast cancer PDX models. Results: A competitive binding assay revealed that LY4257496 specifically bound to GRPR in human, mouse, and rat at comparable nanomolar potency of 8.5, 7.2, and 10.6 nM respectively. In biodistribution analyses, LY4257496 exhibited favorable pharmacokinetics with rapid tumor targeting and prolonged retention (% ID/g 22.6 at 1h, 11.6 at 24h), fast clearance from normal organs (all tissues below 3.5 % ID/g at 24h), and > 50% renal excretion. LY4257496 was well tolerated at 10, 20 and 30MBq (Q14DX2), and efficacy was dose dependent in T47D xenografts (26, 72, and 72 % TGI, respectively). Efficacy was additive when 20MBq (Q14DX2) LY4257496 dose was given in combination with standard-of-care (SoC) therapies including imlunestrant, fulvestrant, and abemaciclib resulting in 40, 32, and 38% tumor regression, respectively at end of treatment (day 28). No tumor regression was observed with SoC therapies alone. LY4257496 also potently inhibited tumor growth in 3 HR+ breast cancer PDX models; 92% TGI (HER2+, PIK3CA:H1047R, and ESR1:Y537S), 58% TGI (HER2-), and 56% TGI (HER2+). These findings demonstrate that LY4257496 is a promising targeted radioligand therapy for tumors with GRPR expression. OMNIRAY, a phase 1 study evaluating LY4257496 in patients with GRPR+ advanced or metastatic disease is ongoing (NCT07114601).