鲨源单域抗体的研究进展

Progress in shark single-domain antibody

摘要:

单克隆抗体是重要的生物大分子，在免疫检测、体外诊断以及药物开发等领域获得广泛的应用。但是单克隆抗体的分子量大、结构复杂等固有属性正日益成为制约其进一步发展的关键因素。因此，当前迫切需要开发单克隆抗体的替代品。鲨源单域抗体即鲨源新抗原受体可变区 (Variable domain of immunoglobulin new antigen receptor，VNAR)，是基于鲨总目鱼类天然存在的新抗原受体 (Immunoglobulin new antigen receptor，IgNAR) 并通过基因工程技术获得的抗原结合域，其分子量仅为12 kDa，是目前已知脊椎动物中尺寸最小的抗原结合域。鲨源单域抗体具有分子量小、亲和力高、稳定性强、溶解度好、组织穿透性强以及可识别隐藏抗原表位等优点，在免疫试剂以及药物开发等领域受到广泛的关注。文中综述了鲨源单域抗体的结构及功能特性、制备及人源化改造技术、亲和力成熟策略以及应用领域，并系统性分析了鲨源单域抗体的优缺点，最后对其发展前景进行了展望。

Abstract:

Monoclonal antibody (mAb) is an important biological macromolecule and widely used in immune detection, in vitro diagnostics, and drug discovery. However, the inherent properties of mAb restrict its further development, such as high molecular weight and complex structure. Therefore, there is an urgent need to develop alternatives for mAb. Various types of miniaturized antibodies have been developed, among which the variable domain of immunoglobulin new antigen receptor (VNAR) is very attractive. The shark single-domain antibody, also known as shark VNAR, is an antigen-binding domain obtained by genetic engineering technology based on the immunoglobulin new antigen receptor (IgNAR) that naturally exists in selachimorpha. It has a molecular weight of 12 kDa, which is the smallest antigen-binding domain found in the known vertebrates at present. Compared with mAb, the shark VNAR exhibits various superiorities, such as low molecular weight, high affinity, tolerance to the harsh environment, good water solubility, strong tissue penetration, and recognition of the hidden epitopes. It has attracted wide attention in the fields of immunochemical reagents and drug discovery. In this review, various aspects of shark VNAR are elaborated, including the structural and functional characteristics, generating and humanization techniques, affinity maturation strategies, application fields, advantages and disadvantages, and prospects.