Contribution of Antibody-Mediated Effector Functions to the Mechanism of Efficacy of Vaccines for Opioid Use Disorders.
Contribution of Antibody-Mediated Effector Functions to the Mechanism of Efficacy of Vaccines for Opioid Use Disorders.
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DOI：
10.4049/jimmunol.2100204
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发表时间：
2021-08-01
期刊：
影响因子：
--
通讯作者：
Pravetoni M
中科院分区：
文献类型：
--
作者：
Huseby Kelcher AM;Baehr CA;Hamid FA;Hart GT;Pravetoni M
疫苗和单克隆抗体（mAb）为治疗物质使用障碍（SUD）和预防药物过量提供了有前途的策略。尽管针对SUD的疫苗和mAb在动物模型中证明了有效性、选择性和安全性，但尚不清楚这些免疫治疗剂的作用机制是否仅依赖于抗体：药物复合物的形成，或者还涉及抗体介导的效应子功能。因此，本研究检测了针对滥用药物的主动和被动免疫的有效性是否需要吞噬作用、抗药抗体的完整Fc部分、Fcγ受体（FcγR）或新生儿Fc受体（FcRn）。在巨噬细胞或粒细胞耗竭后，铅疫苗对羟考酮的有效性并未降低。与完整mAb相比，抗羟考酮F（ab '）2片段导致F（ab'）2的血清水平较低，并且F（ab '）2在减少羟考酮向脑的分布方面不如母体mAb有效。在FcγIII或FcγI-IV消融（−/−）小鼠中，疫苗和mAb对羟考酮的有效性得以保留，表明FcγR不是抗体有效性所必需的。最后，与野生型对照小鼠相比，FcRn−/−小鼠中针对羟考酮的主动和被动免疫均产生降低的效力。这些数据确定了FcRn在介导疫苗和mAb对SUD的疗效中的作用，但不是吞噬作用或Fc依赖性效应子功能。本研究支持疫苗和mAb的合理设计，工程化以获得最大中和活性和最佳FcRn结合。
Vaccines and monoclonal antibodies (mAb) offer promising strategies to treat substance use disorders (SUD) and prevent overdose. Despite vaccines and mAb against SUD demonstrating proof of efficacy, selectivity, and safety in animal models, it is unknown whether the mechanism of action of these immunotherapeutics relies exclusively on formation of antibody:drug complexes, or also involves antibody-mediated effector functions. Hence, this study tested whether the efficacy of active and passive immunization against drugs of abuse requires phagocytosis, intact Fc portion of the anti-drug antibody, Fcγ receptors (FcγR), or the neonatal Fc receptor (FcRn). The efficacy of a lead vaccine against oxycodone was not diminished in mice after depletion of macrophages or granulocytes. Anti-oxycodone F(ab’)2 fragments resulted in lower serum level of F(ab’)2 compared to intact mAb, and F(ab’)2 were not as effective as the parent mAb in reducing distribution of oxycodone to the brain. Efficacy of vaccine and mAb against oxycodone was preserved in either FcγIII or FcγI-IV ablated (−/−) mice, suggesting FcγR are not required for antibody efficacy. Finally, both active and passive immunization against oxycodone in FcRn−/− mice yielded reduced efficacy compared to wild-type control mice. These data identified a role for FcRn, but not for phagocytosis or Fc-dependent effector functions, in mediating efficacy of vaccines and mAb against SUD. This study supports rational design of vaccines and mAb engineered for maximal neutralization activity and optimal FcRn binding.
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影响因子：
7.3
作者：
Pravetoni, Marco;Le Naour, Morgan;Tucker, Ashli M.;Harmon, Theresa M.;Hawley, Tara M.;Portoghese, Philip S.;Pentel, Paul R.
通讯作者：
Pentel, Paul R.
影响因子：
4.6
作者：
Laudenbach M;Baruffaldi F;Robinson C;Carter P;Seelig D;Baehr C;Pravetoni M
通讯作者：
Pravetoni M
影响因子：
5.8
作者：
Pravetoni, M.;Keyler, D. E.;Pentel, P. R.
通讯作者：
Pentel, P. R.
时间轴：疫苗。
影响因子：
64.5
作者：
Rappuoli R
通讯作者：
Rappuoli R
影响因子：
29.7
作者：
Bournazos S;Wang TT;Dahan R;Maamary J;Ravetch JV
通讯作者：
Ravetch JV