生物信息学
免疫原性
体外
化学
计算生物学
对接(动物)
体内
生物化学
癌症研究
生物物理学
抗体
生物
免疫学
医学
基因
生物技术
护理部
作者
Zachary R. Crook,Emily J. Girard,Gregory P. Sevilla,Mi‐Youn Brusniak,Peter B. Rupert,Della Friend,Mesfin Gewe,Midori Clarke,Ida Lin,Raymond Ruff,Fiona Pakiam,Tinh-Doan Phi,Ashok D. Bandaranayake,Colin Correnti,Andrew J. Mhyre,Natalie W. Nairn,Roland K. Strong,James M. Olson
标识
DOI:10.1126/scitranslmed.abn0402
摘要
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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