Administration of nucleoside-modified mRNA encoding broadly neutralizing antibody protects humanized mice from HIV-1 challenge.
Administration of nucleoside-modified mRNA encoding broadly neutralizing antibody protects humanized mice from HIV-1 challenge.
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DOI：
10.1038/ncomms14630
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发表时间：
2017-03-02
影响因子：
16.6
通讯作者：
Weissman D
中科院分区：
文献类型：
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作者：
Pardi N;Secreto AJ;Shan X;Debonera F;Glover J;Yi Y;Muramatsu H;Ni H;Mui BL;Tam YK;Shaheen F;Collman RG;Karikó K;Danet-Desnoyers GA;Madden TD;Hope MJ;Weissman D
单克隆抗体是增长最快的一类药物产品，然而，其潜力受到开发和制造成本高的限制。在这里，我们提出了一个安全和具有成本效益的平台，用于使用核苷修饰的mRNA在体内表达治疗性抗体。为了证明可行性和保护功效，产生编码广泛中和抗HIV-1抗体VRC 01的轻链和重链的核苷修饰的mRNA，并将其封装到脂质纳米颗粒中。向小鼠全身给予1.4 mg kg−1的mRNA导致注射后24 h血浆中的170 μg ml−1 VRC 01抗体浓度。每周向免疫缺陷小鼠注射1 mg kg−1的mRNA，可使VRC 01谷水平保持在40 μg ml−1以上。最重要的是，来自单次注射VRC 01 mRNA的翻译抗体保护人源化小鼠免受静脉内HIV-1攻击，表明核苷修饰的mRNA代表了针对HIV-1的被动免疫疗法的可行递送平台，并扩展到各种疾病。单克隆抗体是可以作为蛋白质或编码的DNA或mRNA递送的高效治疗剂。在这里，作者开发了脂质纳米颗粒配制的核苷修饰的mRNA编码HIV-1中和抗体，并在治疗小鼠中观察到持续和保护性的抗体水平。
Monoclonal antibodies are one of the fastest growing classes of pharmaceutical products, however, their potential is limited by the high cost of development and manufacturing. Here we present a safe and cost-effective platform for in vivo expression of therapeutic antibodies using nucleoside-modified mRNA. To demonstrate feasibility and protective efficacy, nucleoside-modified mRNAs encoding the light and heavy chains of the broadly neutralizing anti-HIV-1 antibody VRC01 are generated and encapsulated into lipid nanoparticles. Systemic administration of 1.4 mg kg−1 of mRNA into mice results in ∼170 μg ml−1 VRC01 antibody concentrations in the plasma 24 h post injection. Weekly injections of 1 mg kg−1 of mRNA into immunodeficient mice maintain trough VRC01 levels above 40 μg ml−1. Most importantly, the translated antibody from a single injection of VRC01 mRNA protects humanized mice from intravenous HIV-1 challenge, demonstrating that nucleoside-modified mRNA represents a viable delivery platform for passive immunotherapy against HIV-1 with expansion to a variety of diseases. Monoclonal antibodies are highly effective therapeutics that can be delivered as proteins or encoded DNA or mRNA. Here the authors develop lipid nanoparticle-formulated nucleoside-modified mRNA encoding an HIV-1 neutralizing antibody and see sustained and protective antibody levels in treated mice.