Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Cell Rep. 2022 Feb 15;38(7):110367. doi: 10.1016/j.celrep.2022.110367.
L9 is a potent human monoclonal antibody (mAb) that preferentially binds two adjacent NVDP minor repeats and cross-reacts with NANP major repeats of the Plasmodium falciparum circumsporozoite protein (PfCSP) on malaria-infective sporozoites. Understanding this mAb's ontogeny and mechanisms of binding PfCSP will facilitate vaccine development. Here, we isolate mAbs clonally related to L9 and show that this B cell lineage has baseline NVDP affinity and evolves to acquire NANP reactivity. Pairing the L9 kappa light chain (L9κ) with clonally related heavy chains results in chimeric mAbs that cross-link two NVDPs, cross-react with NANP, and more potently neutralize sporozoites in vivo compared with their original light chain. Structural analyses reveal that the chimeric mAbs bound minor repeats in a type-1 β-turn seen in other repeat-specific antibodies. These data highlight the importance of L9κ in binding NVDP on PfCSP to neutralize sporozoites and suggest that PfCSP-based immunogens might be improved by presenting ≥2 NVDPs.
L9 是一种有效的人源单克隆抗体（mAb），它优先结合两个相邻的 NVDP 小重复序列，并与疟原虫裂殖子表面蛋白（PfCSP）上的 NANP 大重复序列发生交叉反应。了解这种 mAb 的发生发展和结合 PfCSP 的机制将有助于疫苗的开发。在这里，我们分离出与 L9 克隆相关的 mAb，并表明该 B 细胞系具有基线 NVDP 亲和力，并进化获得 NANP 反应性。将 L9κ 轻链与克隆相关的重链配对，会产生嵌合 mAb，这些 mAb 可以交联两个 NVDP，与 NANP 发生交叉反应，并比其原始轻链更有效地中和体内的孢子。结构分析表明，嵌合 mAb 结合 PfCSP 上的小重复序列，形成了在其他重复特异性抗体中可见的 1 型 β 转角。这些数据突出了 L9κ 在结合 PfCSP 上的 NVDP 以中和孢子方面的重要性，并表明 PfCSP 为基础的免疫原可能通过呈现≥2 个 NVDP 而得到改善。
Nat Med. 2024-1
J Genet Eng Biotechnol. 2023-11-30
Infect Drug Resist. 2023-4-12
Nature. 2022-11
Zotero 插件