Expanding the repertoire of Antibody Drug Conjugate (ADC) targets with improved tumor selectivity and range of potent payloads through in-silico analysis

生物信息学 有效载荷(计算) 计算生物学 药品 癌症研究 生物 计算机科学 基因 药理学 遗传学 计算机网络 网络数据包
作者
Umesh Kathad,Neha Biyani,Raniero L. Peru y Colón De Portugal,Jianli Zhou,Harry Kochat,Kishor Bhatia
出处
期刊:PLOS ONE [Public Library of Science]
卷期号:19 (8): e0308604-e0308604
标识
DOI:10.1371/journal.pone.0308604
摘要

Antibody-Drug Conjugates (ADCs) have emerged as a promising class of targeted cancer therapeutics. Further refinements are essential to unlock their full potential, which is currently limited by a lack of validated targets and payloads. Essential aspects of developing effective ADCs involve the identification of surface antigens, ideally distinguishing target tumor cells from healthy types, uniformly expressed, accompanied by a high potency payload capable of selective targeting. In this study, we integrated transcriptomics, proteomics, immunohistochemistry and cell surface membrane datasets from Human Protein Atlas, Xenabrowser and Gene Expression Omnibus utilizing Lantern Pharma’s proprietary AI platform Response Algorithm for Drug positioning and Rescue (RADR ® ). We used this in combination with evidence based filtering to identify ADC targets with improved tumor selectivity. Our analysis identified a set of 82 targets and a total of 290 target indication combinations for effective tumor targeting. We evaluated the impact of tumor mutations on target expression levels by querying 416 genes in the TCGA mutation database against 22 tumor subtypes. Additionally, we assembled a catalog of compounds to identify potential payloads using the NCI-Developmental Therapeutics Program. Our payload mining strategy classified 729 compounds into three subclasses based on GI 50 values spanning from pM to 10 nM range, in combination with sensitivity patterns across 9 different cancer indications. Our results identified a diverse range of both targets and payloads, that can serve to facilitate multiple choices for precise ADC targeting. We propose an initial approach to identify suitable target-indication-payload combinations, serving as a valuable starting point for development of future ADC candidates.
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