内化
癌胚抗原
抗体-药物偶联物
体内
细胞内
癌症研究
抗原
抗体
免疫疗法
医学
癌胚抗原
药理学
药物输送
化学
单克隆抗体
癌症
免疫学
免疫系统
生物
内科学
受体
细胞生物学
生物技术
有机化学
肿瘤相关抗原
作者
Ian Nessler,Baron Rubahamya,Anna Kopp,Scott Hofsess,Thomas M. Cardillo,Nalini Sathyanarayan,Jennifer Donnell,Serengulam V. Govindan,Greg M. Thurber
出处
期刊:Molecular Cancer Therapeutics
[American Association for Cancer Research]
日期:2023-11-01
卷期号:23 (3): 343-353
被引量:1
标识
DOI:10.1158/1535-7163.mct-23-0437
摘要
Solid tumor antibody-drug conjugates (ADC) have experienced more clinical success in the last 5 years than the previous 18-year span since the first ADC approval in 2000. While recent advances in protein engineering, linker design, and payload variations have played a role in this success, high expression and readily internalized targets have also been crucial to solid tumor therapy. However, these factors are also paradoxically connected to poor tissue penetration and lower efficacy. Previous work shows that potent ADCs can benefit from slower internalization under subsaturating doses to improve tissue penetration and increase tumor response. In contrast, faster internalization is predicted to increase efficacy under higher, tumor saturating doses. In this work, the intracellular delivery of SN-38 conjugated to an anti-carcinoembryonic antigen (anti-CEA) antibody (Ab) is increased by coadministering a noncompeting (cross-linking) anti-CEA Ab to improve efficacy in a colorectal carcinoma animal model. The SN-38 payload enables broad tumor saturation with clinically-tolerable doses, and under these saturating conditions, using a second CEA receptor cross-linking Ab yields faster internalization, which increases tumor killing efficacy. Our spheroid results show indirect bystander killing can also occur, but the more efficient direct cell killing from targeted intracellular payload release drives a greater tumor response. These results provide a strategy to increase therapeutic effectiveness with improved intracellular delivery under tumor saturating doses with the potential to expand the ADC target repertoire.
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