通过跨谱系免疫受体库挖掘对抗 TREM2 的临床先导抗体进行快速亲和力优化。
Rapid affinity optimization of an anti-TREM2 clinical lead antibody by cross-lineage immune repertoire mining.
机构信息
Department of Antibody Engineering, Genentech, South San Francisco, CA, 94080, USA.
Department of Structural Biology, Genentech, South San Francisco, CA, USA.
出版信息
Nat Commun. 2024 Sep 27;15(1):8382. doi: 10.1038/s41467-024-52442-y.
We describe a process for rapid antibody affinity optimization by repertoire mining to identify clones across B cell clonal lineages based on convergent immune responses where antigen-specific clones with the same heavy (V) and light chain germline segment pairs, or parallel lineages, bind a single epitope on the antigen. We use this convergence framework to mine unique and distinct V lineages from rat anti-triggering receptor on myeloid cells 2 (TREM2) antibody repertoire datasets with high diversity in the third complementarity-determining loop region (CDR H3) to further affinity-optimize a high-affinity agonistic anti-TREM2 antibody while retaining critical functional properties. Structural analyses confirm a nearly identical binding mode of anti-TREM2 variants with subtle but significant structural differences in the binding interface. Parallel lineage repertoire mining is uniquely tailored to rationally explore the large CDR H3 sequence space in antibody repertoires and can be easily and generally applied to antibodies discovered in vivo.
我们描述了一种通过库挖掘快速优化抗体亲和力的方法,该方法基于抗原特异性克隆具有相同重链(V)和轻链胚系片段对或平行谱系的收敛免疫反应,从而鉴定基于抗原上单个表位的 B 细胞克隆谱系。我们使用这个收敛框架从具有高度多样性的第三互补决定区(CDR H3)的大鼠抗髓样细胞触发受体 2(TREM2)抗体库数据集,挖掘独特且不同的 V 谱系,以进一步优化高亲和力激动剂抗 TREM2 抗体,同时保留关键的功能特性。结构分析证实,抗 TREM2 变体的结合模式几乎相同,只是在结合界面上有细微但显著的结构差异。平行谱系库挖掘是专门为合理探索抗体库中庞大的 CDR H3 序列空间而设计的,并且可以很容易地和广泛地应用于体内发现的抗体。