Lipid nanoparticle delivery of unmodified mRNAs encoding multiple monoclonal antibodies targeting poxviruses in rabbits.
Lipid nanoparticle delivery of unmodified mRNAs encoding multiple monoclonal antibodies targeting poxviruses in rabbits.
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DOI：
10.1016/j.omtn.2022.05.025
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发表时间：
2022-06-14
期刊：
影响因子：
--
通讯作者：
Hooper JW
中科院分区：
文献类型：
--
作者：
Mucker EM;Thiele-Suess C;Baumhof P;Hooper JW
痘病毒是一个庞大而复杂的病毒家族，其成员包括猴痘病毒和天花病毒。猴痘病毒（或相关痘病毒）爆发或天花病毒滥用的可能性证明有必要制定对策。此外，痘病毒可以是开发涉及抗体疗法的技术的有用替代物。在我们的实验中，我们探索了利用编码三种先前描述的单克隆抗体c8A、c6C和c7D11的未经修饰的mRNA作为相对较大（>3 kg）的实验室动物（兔）中的天花对策的可行性。我们证实了mRNA构建体的体外翻译、分泌和生物活性，并从提供临床益处的鼠牛痘病毒模型中鉴定了靶单克隆抗体水平。单独地，我们能够在肌内喷射注射脂质纳米颗粒（LNP）配制的mRNA的1天内检测到兔血清中的c7D11、c8A和c6C。注射编码三种不同抗体的三种LNP配制的mRNA构建体的组合产生与单独施用的每种单独构建体接近相等的血清水平。这些数据是第一批证明在大型非啮齿动物物种中使用mRNA构建体发射多种抗体的可行性的数据之一。根据经验推导的目标血清水平和观察到的衰减率，达到的抗体水平不太可能提供保护。Hooper及其同事证明了通过肌肉注射mRNA同时向相对较大的动物（兔）递送三种单克隆抗体（mAb）的可行性。将未修饰的mRNA进行LNP配制并通过无针喷射注射递送。所有三种抗痘病毒mAb均在mRNA注射后1天内在血清中检测到，并且具有生物活性。
Poxviruses are a large and complex family of viruses with members such as monkeypox virus and variola virus. The possibility of an outbreak of monkeypox virus (or a related poxvirus) or the misuse of variola virus justifies the development of countermeasures. Furthermore, poxviruses can be a useful surrogate for developing technology involving antibody therapies. In our experiments, we explored the feasibility of utilizing unmodified mRNA that encodes three previously described monoclonal antibodies, c8A, c6C, and c7D11, as countermeasures to smallpox in a relatively large (>3 kg) laboratory animal (rabbits). We confirmed in vitro translation, secretion, and biological activity of mRNA constructs and identified target monoclonal antibody levels from a murine vaccinia virus model that provided a clinical benefit. Individually, we were able to detect c7D11, c8A, and c6C in the serum of rabbits within 1 day of an intramuscular jet injection of lipid nanoparticle (LNP)-formulated mRNA. Injection of a combination of three LNP-formulated mRNA constructs encoding the three different antibodies produced near equivalent serum levels compared with each individual construct administered alone. These data are among the first demonstrating the feasibility of launching multiple antibodies using mRNA constructs in a large, nonrodent species. Based on empirically derived target serum level and the observed decay rate, the antibody levels attained were unlikely to provide protection. Hooper and colleagues demonstrate the feasibility of simultaneously delivering three monoclonal antibodies (mAbs) via intramuscular administration of mRNA to relatively large animals (rabbits). The unmodified mRNAs were LNP formulated and delivered via needle-free jet injection. All three anti-poxvirus mAbs were detected in sera within 1 day of mRNA injection and were biologically active.
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影响因子：
32.4
作者：
Alameh MG;Tombácz I;Bettini E;Lederer K;Sittplangkoon C;Wilmore JR;Gaudette BT;Soliman OY;Pine M;Hicks P;Manzoni TB;Knox JJ;Johnson JL;Laczkó D;Muramatsu H;Davis B;Meng W;Rosenfeld AM;Strohmeier S;Lin PJC;Mui BL;Tam YK;Karikó K;Jacquet A;Krammer F;Bates P;Cancro MP;Weissman D;Luning Prak ET;Allman D;Locci M;Pardi N
通讯作者：
Pardi N
影响因子：
3.7
作者：
Golden, Joseph W.;Josleyn, Matthew;Hooper, Jay W.
通讯作者：
Hooper, Jay W.
影响因子：
3.6
作者：
Kwilas S;Kishimori JM;Josleyn M;Jerke K;Ballantyne J;Royals M;Hooper JW
通讯作者：
Hooper JW
影响因子：
16.6
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
通讯作者：
Weissman D
DOI：
10.1016/j.jconrel.2015.08.007
发表时间：
2015-11-10
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
--
作者：
Pardi N;Tuyishime S;Muramatsu H;Kariko K;Mui BL;Tam YK;Madden TD;Hope MJ;Weissman D
通讯作者：
Weissman D