Preclinical Efficacy and Characterization of Candidate Vaccines for Treatment of Opioid Use Disorders Using Clinically Viable Carrier Proteins,Molecular Pharmaceutics

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Preclinical Efficacy and Characterization of Candidate Vaccines for Treatment of Opioid Use Disorders Using Clinically Viable Carrier Proteins
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2018-09-21 00:00:00 , DOI: 10.1021/acs.molpharmaceut.8b00592
Federico Baruffaldi ₁ , April Huseby Kelcher ₁ , Megan Laudenbach ₁ , Valeria Gradinati _{1,

2} , Ajinkya Limkar ₃ , Michaela Roslawski ₃ , Angela Birnbaum ₃ , Andrew Lees ₄ , Carla Hassler ₅ , Scott Runyon ₅ , Marco Pravetoni _{1,

6}

Affiliation

Vaccines may offer a new treatment strategy for opioid use disorders and opioid-related overdoses. To speed translation, this study evaluates opioid conjugate vaccines containing components suitable for pharmaceutical manufacturing and compares analytical assays for conjugate characterization. Three oxycodone-based haptens (OXY) containing either PEGylated or tetraglycine [(Gly)₄] linkers were conjugated to a keyhole limpet hemocyanin (KLH) carrier protein via carbodiimide (EDAC) or maleimide chemistry. The EDAC-conjugated OXY(Gly)₄-KLH was most effective in reducing oxycodone distribution to the brain in mice. Vaccine efficacy was T cell-dependent. The lead OXY hapten was conjugated to the KLH, tetanus toxoid, diphtheria cross-reactive material (CRM), as well as the E. coli-expressed CRM (EcoCRM) and nontoxic tetanus toxin heavy chain fragment C (rTTHc) carrier proteins. All vaccines induced early hapten-specific B cell expansion and showed equivalent efficacy against oxycodone in mice. However, some hapten-protein conjugates were easier to characterize for molecular weight and size. Finally, heroin vaccines formulated with either EcoCRM or KLH were equally effective in reducing heroin-induced antinociception and distribution to the brain of heroin and its metabolites in mice. This study identifies vaccine candidates and vaccine components for further development.

中文翻译：

临床上有效和表征使用临床上可行的载体蛋白治疗阿片类药物使用障碍的候选疫苗

疫苗可能为阿片类药物使用失调和与阿片类药物相关的药物过量提供新的治疗策略。为了加快翻译速度，本研究评估了含有适用于药物生产的成分的阿片类药物偶联疫苗，并比较了分析方法的偶联物表征。通过碳二亚胺（EDAC）或马来酰亚胺化学方法，将三个含有PEG化或四甘氨酸[（Gly）₄ ]接头的基于羟考酮的半抗原（OXY）偶联至匙孔血蓝蛋白（KLH）载体蛋白。结合EDAC的OXY（Gly）₄ -KLH在减少羟考酮在小鼠中向大脑的分布方面最有效。疫苗效力是T细胞依赖性的。OXY半抗原的铅与KLH，破伤风类毒素，白喉交叉反应物质（CRM）以及E。大肠杆菌表达的CRM（EcoCRM）和无毒的破伤风毒素重链片段C（rTTHc）载体蛋白。所有疫苗均能诱导半抗原特异性B细胞早期扩增，并在小鼠中显示出与羟考酮同等的功效。但是，某些半抗原-蛋白质结合物更易于表征分子量和大小。最后，用EcoCRM或KLH配制的海洛因疫苗在减少海洛因诱导的抗伤害感受以及海洛因及其代谢产物在小鼠脑中的分布方面同样有效。这项研究确定了候选疫苗和疫苗成分以供进一步开发。

更新日期：2018-09-21

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