Human Health Therapeutics Research Centre, Life Sciences Division, National Research Council Canada, 100 Sussex Drive, Ottawa, Ontario K1A 0R6, Canada.
Department of Biochemistry, Microbiology & Immunology, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada.
Protein Eng Des Sel. 2021 Feb 15;34. doi: 10.1093/protein/gzab012.
Interest in single-domain antibodies (sdAbs) stems from their unique structural/pronounced, hence therapeutically desirable, features. From the outset-as therapeutic modalities-human antibody heavy chain variable domains (VHs) attracted a particular attention compared with 'naturally-occurring' camelid and shark heavy-chain-only antibody variable domains (VHHs and VNARs, respectively) due to their perceived lack of immunogenicity. However, they have not quite lived up to their initial promise as the VH hits, primarily mined from synthetic VH phage display libraries, have too often been plagued with aggregation tendencies, low solubility and low affinity. Largely unexplored, synthetic camelized human VH display libraries appeared to have remediated the aggregation problem, but the low affinity of the VH hits still persisted, requiring undertaking additional, laborious affinity maturation steps to render VHs therapeutically feasible. A wholesome resolution has recently emerged with the development of non-canonical transgenic rodent antibody discovery platforms that appear to facilely and profusely generate high affinity, high solubility and aggregation-resistant human VHs.
人们对单域抗体（sdAb）的兴趣源于其独特的结构/显著的特点，因此具有治疗上的优势。从一开始，作为治疗方式，与“天然”的骆驼科和鲨鱼重链仅有抗体可变区（VHH 和 VNAR）相比，人类抗体重链可变区（VH）由于其被认为缺乏免疫原性而引起了特别关注。然而，它们并没有完全实现最初的承诺，因为主要从合成 VH 噬菌体展示文库中挖掘的 VH 命中往往存在聚集倾向、低溶解度和低亲和力的问题。尚未得到充分探索的合成骆驼化人类 VH 展示文库似乎已经解决了聚集问题，但 VH 命中的低亲和力仍然存在，需要进行额外的、费力的亲和力成熟步骤，才能使 VH 具有治疗可行性。最近，随着非典型转基因啮齿动物抗体发现平台的发展，出现了一个整体解决方案，该平台似乎能够轻松、丰富地产生高亲和力、高溶解度和抗聚集的人类 VH。
