Protein Engineering, Mogam Institute for Biomedical Research, Yongin, Gyeonggi-do 16924, Korea.
Biomolecules. 2020 Mar 4;10(3):399. doi: 10.3390/biom10030399.
As mesothelin is overexpressed in various types of cancer, it is an attractive target for therapeutic antibodies. T-cell bispecific antibodies bind to target cells and engage T cells via binding to CD3, resulting in target cell killing by T-cell activation. However, the affinity of the CD3-binding arm may influence CD3-mediated plasma clearance or antibody trapping in T-cell-containing tissues. This may then affect the biodistribution of bispecific antibodies. In this study, we used scFab and knob-into-hole technologies to construct novel IgG-based 1 + 1 MG1122-A and 2 + 1 MG1122-B bispecific antibodies against mesothelin and CD3ε. MG1122-B was designed to be bivalent to mesothelin and monovalent to CD3ε, using a 2 + 1 head-to-tail format. Activities of the two antibodies were evaluated in mesothelin-positive tumor cells in vitro and xenograft models in vivo. Although both antibodies exhibited target cell killing efficacy and produced regression of xenograft tumors with CD8+ T-cell infiltration, the antitumor efficacy of MG1122-B was significantly higher. MG1122-B may improve tumor targeting because of its bivalency for tumor antigen. It may also reduce systemic toxicity by limiting the activation of circulating T cells. Thus, MG1122-B may be useful for treating mesothelin-positive solid tumors.
由于间皮素在多种类型的癌症中过表达，因此它是治疗性抗体的一个有吸引力的靶标。T 细胞双特异性抗体通过与 CD3 结合来结合靶细胞，并使 T 细胞与之结合，从而通过 T 细胞激活导致靶细胞杀伤。然而，CD3 结合臂的亲和力可能会影响 CD3 介导的血浆清除或抗体在含有 T 细胞的组织中的捕获。这可能会影响双特异性抗体的生物分布。在这项研究中，我们使用 scFab 和 knob-into-hole 技术构建了针对间皮素和 CD3ε 的新型 IgG 基 1 + 1 MG1122-A 和 2 + 1 MG1122-B 双特异性抗体。MG1122-B 被设计为对间皮素具有二价性，对 CD3ε 具有单价性，采用 2 + 1 头对头尾格式。在体外间皮素阳性肿瘤细胞和体内异种移植模型中评估了两种抗体的活性。尽管两种抗体均表现出靶细胞杀伤效力，并导致伴有 CD8+T 细胞浸润的异种移植肿瘤消退，但 MG1122-B 的抗肿瘤功效明显更高。MG1122-B 可能通过其对肿瘤抗原的二价性来改善肿瘤靶向性。它还可以通过限制循环 T 细胞的激活来降低系统毒性。因此，MG1122-B 可能对治疗间皮素阳性实体瘤有用。
