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Glycoengineering eCD4-Ig

糖工程 eCD4-Ig

基本信息

批准号：
10589151
负责人：
MICHAEL DAVID ALPERT
金额：
$ 100万
依托单位：
EMMUNE, INC
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-09 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10589151
关键词：
Antibodies Area Asialoglycoprotein Receptor Binding Carbohydrates Cell Line Chinese Hamster Ovary Cell Circulation Cyclic GMP DNA cassette Data Dose Drug Kinetics Engineering Enzymes FCGR3B gene Fucose Galactose Glucosamine Glycoengineering Goals HIV HIV Infections HIV Receptors Half-Life Human Infection Injectable Link Longevity Macaca mulatta Mannose Mediating Muscle National Institute of Allergy and Infectious Disease Pharmaceutical Preparations Plasma Polysaccharides Primates Property Proteins Recombinant Proteins SIV Sialic Acids Testing Therapeutic Therapeutic antibodies Time Transgenic Mice Treatment Efficacy Viral Load result Work adeno-associated viral vector antibody mimetics antibody-dependent cell cytotoxicity carbohydrate structure dimer glycosylation head-to-head comparison improved inhibiting antibody knock-down manufacture mouse model neonatal Fc receptor neutralizing antibody overexpression peptidomimetics prevent receptor receptor binding sialylation small hairpin RNA stable cell line sugar therapeutic protein viral resistance

项目摘要

ABSTRACT We are developing eCD4-Ig, an antibody-like molecule constructed from CD4, a coreceptor-mimetic peptide, and an antibody Fc, as a long-acting injectable therapeutic for HIV. Our progress to-date includes having extended the plasma half-life of eCD4-Ig to the point that it now rivals or surpasses that of the leading broadly neutralizing antibodies (bNAbs) being developed as long-acting injectables. In a head-to-head comparison of pharmacokinetics (PK) in the human FcRn-transgenic mouse model, eCD4-Ig had significantly better PK than a VRC01 protein that had a half-life of 71 days in humans (Gaudinski et al., PLoS Med, 2018). With support from NIAID, we have developed a CHO cell line for manufacturing eCD4-Ig under cGMP conditions. However, in-depth analysis of the composition of the N-linked glycans (NLGs) at N297 of the Fc of the protein made by the cell line has highlighted a problem shared by the entire field: The large majority of the NLGs are forms detrimental to PK. This problem is particularly pronounced among the afucosylated forms that are active for antibody- dependent cell-mediated cytotoxicity (ADCC). Indeed, only a few percent of the NLGs are afucosylated forms that allow both ADCC and a long half-life. Therefore, we propose glycoengineering our cell line for manufacturing eCD4-Ig. To do so, we will develop a glycoengineering gene cassette, introduce it into the cell line, and derive a glycoengineered clone for manufacturing eCD4-Ig under cGMP conditions. Although our primary goal is to manufacture eCD4-Ig protein consisting almost entirely of a single long-lived glycoform that is active for ADCC, the same glycoengineering gene cassette can be used to manufacture other antibody therapeutics, including bNAbs, to similarly extend effector function and plasma half-life. This work will reduce the therapeutic concentration and increase the interval at which long-acting protein therapeutics for treating and preventing HIV infection can be dosed.

摘要