Novel peptide binder for EphA2-targeted radiopharmaceutical therapy for multiple solid tumors.

• DOI: 10.1200/jco.2023.41.16_suppl.e15113
• Publication Date: 2023-06-04T15:35:13Z
• Authors: Renee Clift; Samantha Richardson; Takeru Ehara; Hayato Yanagida; Ivy Hung; Zaid Amso; Katrina Salvador; Matt Guest; Guangzhou Han; Abhijit Bhat; Derek Cole; Eric Bischoff; Gary Li
• Keywords: EPH receptor A2

e15113 Background: Ephrin type-A receptor 2 (EphA2) is a glycoprotein of the ephrin subfamily. EphA2 primarily involved in tissue patterning during embryonic development, and its expression levels are low or absent normal adult tissues. However, overexpression has been observed multiple malignant tumors such as bladder, cervical, ovarian, colorectal, lung esophageal cancers. In addition to being tumor biomarker, plays an active role survival, metastasis neo-angiogenesis, which can lead poor prognosis for cancer patients. The broad solid relatively tissues make attractive targeted radiopharmaceutical therapy (RPT). Methods: RAYZ-6114 comprised macrocyclic peptide binder EphA2, linker, DOTA chelator be complexed with different radiometals. RAYZ-6283 shares same but differs linker. binding affinity, selectivity cross-species reactivity other proteins were determined by surface plasma resonance (SPR). Target-mediated internalization was measured using flow cytometry. vivo biodistribution anti-tumor efficacy studies performed tumor-bearing athymic nude mice. A coagulopathy study Sprague Dawley rats. For type identification, immunohistochemistry (IHC) on microarrays (TMA) representing diverse types. Results: IHC analyses TMAs confirmed multitude tumors, highest positivity rates pancreatic, esophageal, non-small cell showed high affinity human K D 0.03 nM. High-affinity conserved across mouse, cynomolgus monkey, EphA2. No type-B detected, nor EphA2-knockout cells. rapidly efficiently internalized EphA2-positive H1299 cells upon target engagement, ~75% 1 hour. PC3 xenograft mice, 177 Lu-RAYZ-6283 sustained uptake (~25% ID/g) up 48 hours tumor/kidney ratios 2.7, 3.3, 5.9 at 24h, 48h, day 7, respectively. Low seen Both Lu- 225 Ac- labelled significantly inhibited growth. Particularly, durable regression survival benefit achieved single dose Ac-RAYZ-6114 (3 uCi), out-performing Lu-RAYZ-6114 dosed 3 mCi. All treatments well tolerated. Conclusions: first-in-class, highly potent selective binders. Preclinical pharmacodynamic, pharmacokinetic, data demonstrated their potential treatment patients tumors.