Prescreening of Nicotine Hapten Linkers in Vitro To Select Hapten-Conjugate Vaccine Candidates for Pharmacokinetic Evaluation in Vivo.
Prescreening of Nicotine Hapten Linkers in Vitro To Select Hapten-Conjugate Vaccine Candidates for Pharmacokinetic Evaluation in Vivo.
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DOI：
10.1021/acscombsci.6b00179
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发表时间：
2017-05-08
影响因子：
--
通讯作者：
Chang Y
中科院分区：
文献类型：
--
作者：
Arutla V;Leal J;Liu X;Sokalingam S;Raleigh M;Adaralegbe A;Liu L;Pentel PR;Hecht SM;Chang Y
自从尼古丁疫苗被证明是烟草烟雾影响的一种可能的治疗干预措施以来，人们已经做出了广泛的努力来增强尼古丁特异性免疫。尼古丁半抗原的接头修饰一直是提高尼古丁免疫原性的研究重点，对这些修饰的评价通常依赖于体内动物模型，如小鼠、大鼠或非人类灵长类动物。在这里，我们提出了两种体外筛选策略来估计和预测我们新设计的尼古丁半抗原的免疫原性。一种是利用竞争酶联免疫吸附试验(ELISA)来分析尼古丁半抗原或半抗原蛋白结合物与尼古丁特异性抗体(多克隆和单克隆)的相互作用。另一种依赖于半抗原与载体蛋白结合部位附近氨基酸残基相互作用的计算机模拟，以推断接头-载体蛋白结合对抗烟碱抗体反应的影响。使用这两种体外方法，我们对具有不同连接子的半抗原进行了排序，以确定它们作为可行疫苗候选的潜力。基于酶联免疫吸附试验的半抗原排名与体内尼古丁药代动力学分析结果一致。在免疫小鼠中，半抗原对抗NIC单抗的平均结合亲和力(IC50)与平均脑尼古丁浓度之间存在相关性。半抗原和载体蛋白相互作用的计算模型有助于排除连接物-载体结合效应强和体内效率低的结合物。这些体外筛选策略的简单性应该有助于选择和开发更有效的尼古丁结合疫苗。此外，这些数据突显了之前被低估的连接子和半抗原蛋白结合物对结合疫苗免疫原性的贡献，因为它们包含在结合和激活B细胞的表位中。
Since the demonstration of nicotine vaccines as a possible therapeutic intervention for the effects of tobacco smoke, extensive effort has been made to enhance nicotine specific immunity. Linker modifications of nicotine haptens have been a focal point for improving the immunogenicity of nicotine, in which the evaluation of these modifications usually relies on in vivo animal models, such as mice, rats or nonhuman primates. Here, we present two in vitro screening strategies to estimate and predict the immunogenic potential of our newly designed nicotine haptens. One utilizes a competition enzyme-linked immunoabsorbent assay (ELISA) to profile the interactions of nicotine haptens or hapten-protein conjugates with nicotine specific antibodies, both polyclonal and monoclonal. Another relies on computational modeling of the interactions between haptens and amino acid residues near the conjugation site of the carrier protein to infer linker-carrier protein conjugation effect on antinicotine antibody response. Using these two in vitro methods, we ranked the haptens with different linkers for their potential as viable vaccine candidates. The ELISA-based hapten ranking was in an agreement with the results obtained by in vivo nicotine pharmacokinetic analysis. A correlation was found between the average binding affinity (IC50) of the haptens to an anti-Nic monoclonal antibody and the average brain nicotine concentration in the immunized mice. The computational modeling of hapten and carrier protein interactions helps exclude conjugates with strong linker-carrier conjugation effects and low in vivo efficacy. The simplicity of these in vitro screening strategies should facilitate the selection and development of more effective nicotine conjugate vaccines. In addition, these data highlight a previously under-appreciated contribution of linkers and hapten-protein conjugations to conjugate vaccine immunogenicity by virtue of their inclusion in the epitope that binds and activates B cells.
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影响因子：
32.4
作者：
Hou B;Saudan P;Ott G;Wheeler ML;Ji M;Kuzmich L;Lee LM;Coffman RL;Bachmann MF;DeFranco AL
通讯作者：
DeFranco AL
影响因子：
3.7
作者：
Pryde DC;Jones LH;Gervais DP;Stead DR;Blakemore DC;Selby MD;Brown AD;Coe JW;Badland M;Beal DM;Glen R;Wharton Y;Miller GJ;White P;Zhang N;Benoit M;Robertson K;Merson JR;Davis HL;McCluskie MJ
通讯作者：
McCluskie MJ
影响因子：
3.6
作者：
Isomura, S;Wirsching, P;Janda, KD
通讯作者：
Janda, KD
DOI：
10.1016/b978-0-12-420118-7.00014-7
发表时间：
2014-01-01
期刊：
EMERGING TARGETS & THERAPEUTICS IN THE TREATMENT OF PSYCHOSTIMULANT ABUSE
影响因子：
--
作者：
Pentel, Paul R.;LeSage, Mark G.
通讯作者：
LeSage, Mark G.
影响因子：
7.3
作者：
Lockner, Jonathan W.;Lively, Jenny M.;Janda, Kim D.
通讯作者：
Janda, Kim D.