Abstract 1043: Advances in cystine-dense peptide (CDP) screening and therapeutic applications

Cystine-dense peptides (CDPs) are a class of drug-like miniproteins that marry many of the advantages of biologics (high affinity and specificity) and small molecule therapeutics (high tissue permeability and low immunogenicity). The beneficial properties of CDPs, and miniproteins in general, have driven interest in therapeutic applications. However, CDP diversity is vast from every clade of life, and properly interrogating “CDP space” requires specialized screening and modeling tools. With this in mind, we have created an optimized mammalian surface display platform to screen for CDPs of clinical interest using libraries of structurally-diverse native scaffolds optimized for stability. These native CDPs can be structurally modeled, which we did in determining the structures of over 4200 native CDPs. This modeling permits further selection in silico as well as targeted mutagenesis for favorable target-binding capabilities. Hits from these screens are routinely matured to sub-nM affinity. These CDPs can play numerous roles in a drug design pipeline, from an independent drug candidate to a delivery agent for tissue-targeting to a module in a polyspecific biologic. Recent novel CDP candidates have shown promise in immune-oncology space as part of a bispecific T-cell engager targeting PD-L1, where a single 2-week treatment was capable of eliminating subcutaneous PC3 prostate cancer xenograft tumors in 27/30 mice. Besides bispecifics, future directions for the platform include exploring targeted protein degradation. Additionally, we are expanding upon our previous work on CDPs to explore CNS or tumor delivery of therapeutic cargo. The versatility of CDPs and novel screening tools to rapidly identify and mature candidates of interest can facilitate rapid advancement of CDP therapeutics to address difficult targets in oncology. Citation Format: Zachary R. Crook, Emily J. Girard, Gregory P. Sevilla, Mi-Youn Brusniak, Peter B. Rupert, Della J. Friend, Mesfin M. Gewe, Midori Clarke, Ida Lin, Raymond Ruff, Doan Phi, Ashok Bandaranayake, Colin E. Correnti, Andrew J. Mhyre, Natalie W. Nairn, Roland K. Strong, James M. Olson. Advances in cystine-dense peptide (CDP) screening and therapeutic applications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1043.