Attenuating nicotine's effects with high affinity human anti-nicotine monoclonal antibodies.
Attenuating nicotine's effects with high affinity human anti-nicotine monoclonal antibodies.
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DOI：
10.1371/journal.pone.0254247
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发表时间：
2021
期刊：
影响因子：
3.7
通讯作者：
Kalnik MW
中科院分区：
文献类型：
--
作者：
Raleigh MD;Beltraminelli N;Fallot S;LeSage MG;Saykao A;Pentel PR;Fuller S;Thisted T;Biesova Z;Horrigan S;Sampey D;Zhou B;Kalnik MW
使用尼古丁特异性单抗(MAbs)隔离和减少尼古丁在大脑中的分布，已被认为是治疗尼古丁成瘾(烟草使用障碍的基础)的一种方法。从接种疫苗的吸烟者B细胞中分离到一系列高亲和力的抗尼古丁单抗(Nic·mAbs)。克隆了32个尼古丁结合抗体的编码基因，表达并通过表面等离子共振检测其与S-(-)-尼古丁的亲和力。亲和力最高的Nic·mAbs的结合亲和常数(Kd)在5~67 nM之间。选择亲和力最高的4株Nic·mAb进行抗原特异性、蛋白质性质(包括聚集性和稳定性)的二次筛选和体内功能研究，以评估它们减少尼古丁在大鼠脑内分布的能力。对单剂量尼古丁药代动力学实验中最强的2株Nic·mAb进行了体内剂量-反应实验。根据这些研究的结果，最有效的铅ATI-1013被选为铅候选者。在模拟重度吸烟的重复尼古丁剂量实验中，40和80 mg/kg ATI-1013预处理分别将大脑尼古丁水平降低56%和95%。ATI-1013治疗的大鼠的尼古丁自身给药也显著减少。在尼古丁存在的情况下，试验性大鼠30天重复剂量毒理学研究(4x200 mg/kg ATI-1013)表明没有与药物相关的安全问题。这些数据为ATI-1013可能成为治疗尼古丁成瘾的潜在疗法提供了证据。
Use of nicotine-specific monoclonal antibodies (mAbs) to sequester and reduce nicotine distribution to brain has been proposed as a therapeutic approach to treat nicotine addiction (the basis of tobacco use disorder). A series of monoclonal antibodies with high affinity for nicotine (nic•mAbs) was isolated from B-cells of vaccinated smokers. Genes encoding 32 unique nicotine binding antibodies were cloned, and the mAbs expressed and tested by surface plasmon resonance to determine their affinity for S-(–)-nicotine. The highest affinity nic•mAbs had binding affinity constants (KD) between 5 and 67 nM. The 4 highest affinity nic•mAbs were selected to undergo additional secondary screening for antigen-specificity, protein properties (including aggregation and stability), and functional in vivo studies to evaluate their capacity for reducing nicotine distribution to brain in rats. The 2 most potent nic•mAbs in single-dose nicotine pharmacokinetic experiments were further tested in a dose-response in vivo study. The most potent lead, ATI-1013, was selected as the lead candidate based on the results of these studies. Pretreatment with 40 and 80 mg/kg ATI-1013 reduced brain nicotine levels by 56 and 95%, respectively, in a repeated nicotine dosing experiment simulating very heavy smoking. Nicotine self-administration was also significantly reduced in rats treated with ATI-1013. A pilot rat 30-day repeat-dose toxicology study (4x200mg/kg ATI-1013) in the presence of nicotine indicated no drug-related safety concerns. These data provide evidence that ATI-1013 could be a potential therapy for the treatment of nicotine addiction.
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影响因子：
24.7
作者：
Jabbour, Elias;Richard-Carpentier, Guillaume;Kantarjian, Hagop
通讯作者：
Kantarjian, Hagop
影响因子：
3.6
作者：
Isomura, S;Wirsching, P;Janda, KD
通讯作者：
Janda, KD
影响因子：
1.4
作者：
Cahill, Kate;Stead, Lindsay F.;Polonio, Igor Bastos
通讯作者：
Polonio, Igor Bastos
影响因子：
3.4
作者：
Hieda, Y;Keyler, DE;Pentel, PR
通讯作者：
Pentel, PR
影响因子：
3.5
作者：
Carrera, MRA;Ashley, JA;Janda, KD
通讯作者：
Janda, KD