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常规与化学程序化不对称双特异性抗体靶向叶酸受体 1。

Conventional and Chemically Programmed Asymmetric Bispecific Antibodies Targeting Folate Receptor 1.

机构信息

Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL, United States.

Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, United States.

出版信息

Front Immunol. 2019 Aug 21;10:1994. doi: 10.3389/fimmu.2019.01994. eCollection 2019.

DOI:10.3389/fimmu.2019.01994
PMID:31497024
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6712926/
Abstract

T-cell engaging bispecific antibodies (biAbs) can mediate potent and specific tumor cell eradication in liquid cancers. Substantial effort has been invested in expanding this concept to solid cancers. To explore their utility in the treatment of ovarian cancer, we built a set of asymmetric biAbs in IgG1-like format that bind CD3 on T cells with a conventional scFv arm and folate receptor 1 (FOLR1) on ovarian cancer cells with a conventional or a chemically programmed Fab arm. For avidity engineering, we also built an asymmetric biAb format with a tandem Fab arm. We show that both conventional and chemically programmed CD3 × FOLR1 biAbs exert specific and cytotoxicity toward FOLR1-expressing ovarian cancer cells by recruiting and activating T cells. While the conventional T-cell engaging biAb was curative in an aggressive mouse model of human ovarian cancer, the potency of the chemically programmed biAb was significantly boosted by avidity engineering. Both conventional and chemically programmed CD3 × FOLR1 biAbs warrant further investigation for ovarian cancer immunotherapy.

摘要

T 细胞衔接双特异性抗体（双抗）可介导液体肿瘤中强大且特异性的肿瘤细胞清除。人们投入了大量精力将这一概念扩展到实体瘤。为了探索其在卵巢癌治疗中的应用，我们构建了一组 IgG1 样格式的不对称双抗，其中常规 scFv 臂结合 T 细胞上的 CD3，常规或化学程序化 Fab 臂结合卵巢癌细胞上的叶酸受体 1（FOLR1）。为了进行亲和力工程，我们还构建了具有串联 Fab 臂的不对称双抗格式。我们表明，通过招募和激活 T 细胞，常规和化学程序化的 CD3×FOLR1 双抗均对表达 FOLR1 的卵巢癌细胞表现出特异性和细胞毒性。虽然常规的 T 细胞衔接双抗在侵袭性人源卵巢癌小鼠模型中具有治愈作用，但通过亲和力工程，化学程序化双抗的效力显著提高。常规和化学程序化的 CD3×FOLR1 双抗均值得进一步研究，以用于卵巢癌免疫治疗。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/624a/6712926/f9d4c786a9f7/fimmu-10-01994-g0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/624a/6712926/126eaefacce9/fimmu-10-01994-g0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/624a/6712926/4ad770d23eaa/fimmu-10-01994-g0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/624a/6712926/a11c281dcedf/fimmu-10-01994-g0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/624a/6712926/0b6cc3af1dc8/fimmu-10-01994-g0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/624a/6712926/9bcb4f06a9da/fimmu-10-01994-g0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/624a/6712926/0f3962797ebd/fimmu-10-01994-g0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/624a/6712926/f9d4c786a9f7/fimmu-10-01994-g0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/624a/6712926/126eaefacce9/fimmu-10-01994-g0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/624a/6712926/4ad770d23eaa/fimmu-10-01994-g0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/624a/6712926/a11c281dcedf/fimmu-10-01994-g0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/624a/6712926/0b6cc3af1dc8/fimmu-10-01994-g0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/624a/6712926/9bcb4f06a9da/fimmu-10-01994-g0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/624a/6712926/0f3962797ebd/fimmu-10-01994-g0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/624a/6712926/f9d4c786a9f7/fimmu-10-01994-g0007.jpg

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