School of Life Sciences, Fudan University, Shanghai, China.
LongBio Pharma Co, Shanghai, China.
Proteins. 2023 Aug;91(8):1065-1076. doi: 10.1002/prot.26492. Epub 2023 Mar 25.
In recent years, the development of bispecific antibodies (bsAbs) has become a major trend in the biopharmaceutical industry. By simultaneously engaging two molecular targets, bsAbs have exhibited unique mechanisms of action that could lead to clinical benefits unattainable by conventional monoclonal antibodies. The type of structure used to construct a bsAb directly influences the distance, angle, degree of freedom, and affinity between the two antibody binding sites and the interaction between the two antigens or the cells where the antigens are located, which have been bound by the antibody. Consequently, the structure of the bsAb is one of the most vital factors affecting its function. Herein, we reported for the first time a novel basic module bsAb format, VFV (Variable domain-Fab-Variable domain). And then, the feasibility of the VFV format was demonstrated by constructing a series of engager-like basic module bsAbs. Next, a series of VFV bsAbs containing Fc (VFV-Ig), Fab (VFV-Fab), or Hinge (VFV-Hinge) were developed based on Hxb module, and all of them had adequate purity and activity. Finally, a T cell engager bsAb with the potential to overcome on-target off-tumor activity was constructed according to the structural characteristics of VFV, which validated that the VFV module can be used as a new brick for the construction of various bsAbs. In a word, the successful construction of this bsAb format for the first time not only enriches the arsenal of the bsAb format, but also provides inspiration for the construction of new bsAbs. Nevertheless, we are fully aware that as a proof-of-concept study, this paper has many shortcomings, and there is still a lot of work to be done to determine whether VFV can serve as a platform for drug development.
近年来，双特异性抗体（bsAb）的发展已成为生物制药行业的主要趋势。通过同时结合两个分子靶点，bsAb 表现出独特的作用机制，可能带来常规单克隆抗体无法实现的临床获益。构建 bsAb 所使用的结构类型直接影响两个抗体结合位点之间的距离、角度、自由度和亲和力，以及抗体结合的两个抗原或抗原所在细胞之间的相互作用。因此，bsAb 的结构是影响其功能的最重要因素之一。在此，我们首次报道了一种新型的基本模块 bsAb 结构形式，即 VFV（可变结构域-Fab-可变结构域）。然后，通过构建一系列类似衔接子的基本模块 bsAb 证明了 VFV 结构的可行性。接下来，基于 Hxb 模块构建了一系列含有 Fc（VFV-Ig）、Fab（VFV-Fab）或铰链（VFV-Hinge）的 VFV bsAb，它们均具有足够的纯度和活性。最后，根据 VFV 的结构特征构建了一种具有潜在克服靶外肿瘤活性的 T 细胞衔接子 bsAb，验证了 VFV 模块可作为构建各种 bsAb 的新模块。总之，首次成功构建这种 bsAb 结构不仅丰富了 bsAb 结构的种类，也为新型 bsAb 的构建提供了启示。然而，我们深知，作为概念验证研究，本文存在诸多不足，仍有大量工作需要完成，以确定 VFV 是否可以作为药物开发的平台。
