A trypanosome-derived immunotherapeutics platform elicits potent high-affinity antibodies, negating the effects of the synthetic opioid fentanyl.
A trypanosome-derived immunotherapeutics platform elicits potent high-affinity antibodies, negating the effects of the synthetic opioid fentanyl.
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DOI：
10.1016/j.celrep.2023.112049
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发表时间：
2023-02-28
期刊：
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
--
作者：
免疫原性差的小分子对生产临床有效的疫苗和抗体构成挑战。为了解决这个问题，我们从非洲锥虫的免疫原性表面涂层中产生了一个免疫平台。通过排序酶将靶分子偶联到锥虫表面涂层的变异表面糖蛋白（VSG）上，利用排序酶标记（VAST）技术开发出变异表面糖蛋白免疫原阵列。在使用免疫原性差的分子芬太尼作为概念证明后，VAST在小鼠模型中引发抗原特异性记忆B细胞和抗体。我们还开发了一种基于单细胞RNA测序（RNA-seq）的计算方法，该方法与VAST协同识别记忆B细胞编码的抗体。所有通过计算选择的抗体都以皮摩尔亲和力结合芬太尼。此外，这些抗体在被动免疫后保护小鼠免受芬太尼的影响，表明这两种偶联技术能够引发针对挑战性免疫原的治疗性抗体。Triller等人利用布鲁氏锥虫表面涂层独特的免疫原性，生成了针对包括小分子在内的困难靶标的抗体激发平台。他们利用这个平台诱导合成阿片类药物芬太尼的高亲和力单克隆抗体，这种抗体可以用作过量预防药物。
Poorly immunogenic small molecules pose challenges for the production of clinically efficacious vaccines and antibodies. To address this, we generate an immunization platform derived from the immunogenic surface coat of the African trypanosome. Through sortase-based conjugation of the target molecules to the variant surface glycoprotein (VSG) of the trypanosome surface coat, we develop VSG-immunogen array by sortase tagging (VAST). VAST elicits antigen-specific memory B cells and antibodies in a murine model after deploying the poorly immunogenic molecule fentanyl as a proof of concept. We also develop a single-cell RNA sequencing (RNA-seq)-based computational method that synergizes with VAST to specifically identify memory B cell-encoded antibodies. All computationally selected antibodies bind to fentanyl with picomolar affinity. Moreover, these antibodies protect mice from fentanyl effects after passive immunization, demonstrating the ability of these two coupled technologies to elicit therapeutic antibodies to challenging immunogens. Triller et al. exploit the unique immunogenicity of Trypanosoma brucei surface coats to generate an antibody elicitation platform tailored to difficult targets including small molecules. They use this platform to elicit high-affinity monoclonal antibodies to the synthetic opioid fentanyl, which could be used as overdose-preventing prophylactics.
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DOI：
10.1111/j.1476-5381.1960.tb00277.x
发表时间：
1960-01-01
期刊：
BRITISH JOURNAL OF PHARMACOLOGY AND CHEMOTHERAPY
影响因子：
--
作者：
BILBEY, DLJ;SALEM, H;GROSSMAN, MH
通讯作者：
GROSSMAN, MH
影响因子：
48
作者：
Amezquita, Robert A.;Lun, Aaron T. L.;Hicks, Stephanie C.
通讯作者：
Hicks, Stephanie C.
DOI：
10.1093/bioinformatics/btw631
发表时间：
2017-02-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Canzar S;Neu KE;Tang Q;Wilson PC;Khan AA
通讯作者：
Khan AA
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH
影响因子：
1.5
作者：
Alsford, Sam;Horn, David
通讯作者：
Horn, David