Many Routes to an Antibody Heavy-Chain CDR3: Necessary, Yet Insufficient, for Specific Binding.
Many Routes to an Antibody Heavy-Chain CDR3: Necessary, Yet Insufficient, for Specific Binding.
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DOI：
10.3389/fimmu.2018.00395
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发表时间：
2018
影响因子：
7.3
通讯作者：
Bradbury ARM
中科院分区：
文献类型：
--
作者：
D'Angelo S;Ferrara F;Naranjo L;Erasmus MF;Hraber P;Bradbury ARM
由于其巨大的多样性潜力，免疫球蛋白重链互补决定区3(HCDR3)被认为是抗体分子中赋予结合活性和特异性的最重要的成分。出于这个原因，HCDR3已经被用作唯一的识别符来研究体内的适应性免疫反应，并在使用显示系统的体外选择输出中进行表征。在这里，我们展示了许多不同的HCDR3可以在体外选择后在靶向特异性抗体群体中被识别。对于每一种已鉴定的HCDR3，都可以在其他地方找到一些不同的抗体。在这些选定的人群中，所有具有相同HCDR3的抗体都能识别目标，尽管亲和力不同。相反，在未经选择的群体中，具有相同HCDR3序列的大多数抗体不结合靶标。在一个深入研究的HCDR3中，所有靶向特异性抗体来自相同的VDJ重排，而具有相同HCDR3的非结合抗体来自许多不同的V和D基因重排。对之前发表的活体数据集的仔细检查发现，不同个体之间和不同个体内部共享的HCDR3也可以起源于不同V和D基因的重排，多达26种不同的重排产生相同的HCDR3序列。在这些观察的基础上，我们得出结论，相同的HCDR3可以通过许多不同的重排产生，但特定的靶结合是独特重排和VL配对的结果：对于特定的抗体结合，HCDR3是必要的，尽管不够。
Because of its great potential for diversity, the immunoglobulin heavy-chain complementarity-determining region 3 (HCDR3) is taken as an antibody molecule’s most important component in conferring binding activity and specificity. For this reason, HCDR3s have been used as unique identifiers to investigate adaptive immune responses in vivo and to characterize in vitro selection outputs where display systems were employed. Here, we show that many different HCDR3s can be identified within a target-specific antibody population after in vitro selection. For each identified HCDR3, a number of different antibodies bearing differences elsewhere can be found. In such selected populations, all antibodies with the same HCDR3 recognize the target, albeit at different affinities. In contrast, within unselected populations, the majority of antibodies with the same HCDR3 sequence do not bind the target. In one HCDR3 examined in depth, all target-specific antibodies were derived from the same VDJ rearrangement, while non-binding antibodies with the same HCDR3 were derived from many different V and D gene rearrangements. Careful examination of previously published in vivo datasets reveals that HCDR3s shared between, and within, different individuals can also originate from rearrangements of different V and D genes, with up to 26 different rearrangements yielding the same identical HCDR3 sequence. On the basis of these observations, we conclude that the same HCDR3 can be generated by many different rearrangements, but that specific target binding is an outcome of unique rearrangements and VL pairing: the HCDR3 is necessary, albeit insufficient, for specific antibody binding.
影响因子：
2.2
作者：
Ferrara, Fortunato;Naranjo, Leslie A.;D'Angelo, Sara;Kiss, Csaba;Bradbury, Andrew R. M.
通讯作者：
Bradbury, Andrew R. M.