a EpimAb Biotherapeutics , Shanghai , China.
MAbs. 2017 Oct;9(7):1118-1128. doi: 10.1080/19420862.2017.1345401. Epub 2017 Jul 10.
In recent years, the development of bispecific antibody (bsAb) has become a major trend in the biopharmaceutical industry. By simultaneously engaging 2 molcular targets, bsAbs show unique mechanisms of action that could lead to clinical benefits unattainable by conventional monoclonal antibodies. Various bsAb generation formats have been described, and several are being investigated in clinical development. However, some bsAb constructs have proven to be problematic due to their unfavorable physicochemical and pharmacokinetic properties, as well as poor manufacturing efficiencies. We describe here a new bispecific design, Fabs-in-tandem immunoglobulin (FIT-Ig), in which 2 antigen-binding fragments are fused directly in a crisscross orientation without any mutations or use of peptide linkers. This unique design provides a symmetric IgG-like bispecific molecule with correct association of 2 sets of VH/VL pairs. We show that FIT-Ig molecules exhibit favorable drug-like properties, in vitro and in vivo functions, as well as manufacturing efficiency for commercial 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 2 个分子靶点，bsAbs 表现出独特的作用机制，这可能带来传统单克隆抗体无法实现的临床获益。已经描述了各种 bsAb 生成形式，其中一些正在临床开发中进行研究。然而，由于某些 bsAb 结构证明存在不利的物理化学和药代动力学特性以及较差的制造效率，因此有些结构被证明存在问题。我们在这里描述了一种新的双特异性设计，Fabs-in-tandem 免疫球蛋白（FIT-Ig），其中 2 个抗原结合片段以交错的方向直接融合，而不进行任何突变或使用肽接头。这种独特的设计提供了一种对称的 IgG 样双特异性分子，其中正确地结合了 2 组 VH/VL 对。我们表明，FIT-Ig 分子表现出有利的药物样特性、体外和体内功能以及商业开发的制造效率。
