Abstract LB211: Discovery of RenNano®-derived human heavy-chain-only antibodies that cross the blood-brain barrier

转铁蛋白受体 抗体 跨细胞 人源化抗体 单克隆抗体 血脑屏障 抗原 转铁蛋白 受体 免疫球蛋白轻链 免疫学 生物 生物化学 中枢神经系统 内吞作用 内分泌学
作者
Yiqing Hu,Lijun Zhang,Wenying Wang,Huizhen Zhao,Jiawei Yao,Chunhui Lv,Yunsheng Yao,Hui Li,Qingcong Lin,Taolin Liu,Yuelei Shen
出处
期刊:Cancer Research [American Association for Cancer Research]
卷期号:83 (8_Supplement): LB211-LB211
标识
DOI:10.1158/1538-7445.am2023-lb211
摘要

Abstract Therapeutic antibodies have been successfully used to treat several diseases, such as cancers and autoimmune diseases. However, the utility of conventional antibodies for neurological conditions is limited by the blood-brain barrier (BBB). Several strategies to address this issue have been reported, including receptor-mediated transcytosis (RMT) of antibodies using transferrin receptors. We hypothesize that this strategy could be further improved by the use of single-domain antibodies (sdAbs), such as the variable domain of heavy-chain-only antibodies (HCAbs), or variable new antigen receptors (VNARs), which are significantly smaller, and therefore could be used to more efficiently transport drugs of interest across the BBB. To this end, we developed anti-transferrin receptor 1 (TFR1) HCAbs utilizing our fully human heavy-chain-only antibody mice (RenNano®). We immunized RenNano® mice with recombinant TFR1 proteins, isolated the B cells from spleen and lymph nodes, and performed single B cell antibody screening using the Beacon® Optofluidic system. Most of the antibodies tested were cross-reactive to human and monkey TFR1. Furthermore, even though the antigen specificity relies on the VHH domain instead of a conventional antibody variable domain, the affinity of these HCAbs can reach 10−8-10−9 (KD). Of the 7 HCAbs tested, 6 were internalized into the human brain microvascular endothelial cell line, hCMEC/D3. To assess brain penetration of these antibodies in vivo, mice expressing human TFR1 (hTFR1 mice) received a tail vein injection with either isotype control, positive control pabinafusp alfa (a BBB penetrating anti-TFR1 monoclonal antibody enzyme conjugate) analog or RenNano®-derived HCAbs. After 0.5, 6, 24, and 72 h of exposure, mice brains were dissected for the quantification of HCAbs and for immunohistochemical analyses. The levels of anti-TFR1 HCAbs in the parenchyma was significantly higher than isotype controls and pabinafusp alfa analog. In brain sections, HCAbs were clearly observed in the parenchyma, and were colocalized with TFR1-expressing cells. These results demonstrate that HCAbs developed from RenNano® mice are able to penetrate the BBB. Taken together, these data highlight the tremendous potential for HCAbs and its variable domain sdAbs for transporting cargo across the BBB. Due to their smaller size and simpler structure, sdAbs could ultimately provide therapeutic benefit for neurodegenerative diseases, and offer promising potential for tumor penetration. Citation Format: Yiqing Hu, Lijun Zhang, Wenying Wang, Huizhen Zhao, Jiawei Yao, Chunhui Lv, Yunsheng Yao, Li Hui, Qingcong Lin, Taolin Liu, Yuelei Shen. Discovery of RenNano®-derived human heavy-chain-only antibodies that cross the blood-brain barrier [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB211.

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