Journal
SCIENCE TRANSLATIONAL MEDICINE
Volume 14, Issue 645, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.abn0402
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Funding
- NIH [P30CA015704, R01CA223674, U01CA232490, R01CA114567, S10OD020069, S10OD028685]
- Project Violet
- Unravel Pediatric Cancer
- Washington Research Foundation
- Blaze Bioscience
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In this study, CDP scaffolds were structurally predicted using I-TASSER and Rosetta protein modeling software, and computationally screened for CDP binders to targets of interest. The resulting high-affinity CDP molecule showed potent T cell killing ability and outperformed a comparator antibody-based molecule in both in vitro and in vivo experiments. This research provides a new approach and tools for the development of CDP therapeutics.
Cystine-dense peptides (CDPs) are a miniprotein class that can drug difficult targets with high affinity and low immunogenicity. Tools for their design, however, are not as developed as those for small-molecule and antibody drugs. CDPs have diverse taxonomic origins, but structural characterization is lacking. Here, we adapted Iterative Threading ASSEmbly Refinement (I-TASSER) and Rosetta protein modeling software for structural prediction of 4298 CDP scaffolds and performed in silico prescreening for CDP binders to targets of interest. Mammalian display screening of a library of docking-enriched, methionine and tyrosine scanned (DEMYS) CDPs against PD-L1 yielded binders from four distinct CDP scaffolds. One was affinity- matured, and cocrystallography yielded a high-affinity (K-D = 202 pM) PD-L1-binding CDP that competes with PD-1 for PD-L1 binding. Its subsequent incorporation into a CD3-binding bispecific T cell engager produced a molecule with pM-range in vitro T cell killing potency and which substantially extends survival in two different xenograft tumor-bearing mouse models. Both in vitro and in vivo, the CDP-incorporating bispecific molecule outperformed a comparator antibody-based molecule. This CDP modeling and DEMYS technique can accelerate CDP therapeutic development.
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