气候变化领域集成服务门户(CCPortal): Generating tumor-selective conditionally active biologic anti-CTLA4 antibodies via protein-associated chemical switches

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DOI	10.1073/pnas.2020606118
	Generating tumor-selective conditionally active biologic anti-CTLA4 antibodies via protein-associated chemical switches
	Chang H.W.; Frey G.; Liu H.; Xing C.; Steinman L.; Boyle W.J.; Short J.M.
发表日期	2021
ISSN	00278424
卷号	118 期号:9
英文摘要	Anticytotoxic T lymphocyte-associated protein 4 (CTLA4) antibodies have shown potent antitumor activity, but systemic immune activation leads to severe immune-related adverse events, limiting clinical usage. We developed novel, conditionally active biologic (CAB) anti-CTLA4 antibodies that are active only in the acidic tumor microenvironment. In healthy tissue, this binding is reversibly inhibited by a novel mechanism using physiological chemicals as protein-associated chemical switches (PaCS). No enzymes or potentially immunogenic covalent modifications to the antibody are required for activation in the tumor. The novel antiCTLA4 antibodies show similar efficacy in animal models compared to an analog of a marketed anti-CTLA4 biologic, but have markedly reduced toxicity in nonhuman primates (in combination with an anti-PD1 checkpoint inhibitor), indicating a widened therapeutic index (TI). The PaCS encompass mechanisms that are applicable to a wide array of antibody formats (e.g., ADC, bispecifics) and antigens. Examples shown here include antibodies to EpCAM, Her2, Nectin4, CD73, and CD3. Existing antibodies can be engineered readily to be made sensitive to PaCS, and the inhibitory activity can be optimized for each antigen's varying expression level and tissue distribution. PaCS can modulate diverse physiological molecular interactions and are applicable to various pathologic conditions, enabling differential CAB antibody activities in normal versus disease microenvironments. © This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).
英文关键词	Conditionally active biologics; CTLA4; Immunooncology; Monoclonal antibodies; Protein-associated chemical switches
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/180483
作者单位	BioAtla, Inc., San Diego, CA 92121, United States; Stanford University School of Medicine, Stanford University, Stanford, CA 94305, United States
推荐引用方式 GB/T 7714	Chang H.W.,Frey G.,Liu H.,et al. Generating tumor-selective conditionally active biologic anti-CTLA4 antibodies via protein-associated chemical switches[J],2021,118(9).
APA	Chang H.W..,Frey G..,Liu H..,Xing C..,Steinman L..,...&Short J.M..(2021).Generating tumor-selective conditionally active biologic anti-CTLA4 antibodies via protein-associated chemical switches.Proceedings of the National Academy of Sciences of the United States of America,118(9).
MLA	Chang H.W.,et al."Generating tumor-selective conditionally active biologic anti-CTLA4 antibodies via protein-associated chemical switches".Proceedings of the National Academy of Sciences of the United States of America 118.9(2021).