1. A Novel T Cell-Engaging Bispecific Antibody for Treating Mesothelin-Positive Solid Tumors
- Author
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Aerin Yoon, Shinai Lee, Sua Lee, Sojung Lim, Yong-Yea Park, Eunjung Song, Dong-Sik Kim, Kisu Kim, and Yangmi Lim
- Subjects
mesothelin ,cd3 ,bispecific antibody ,solid tumor ,cancer immunotherapy ,t cell-engaging ,heterodimeric bivalent ,heterodimeric trivalent ,tumor regression ,Microbiology ,QR1-502 - Abstract
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.
- Published
- 2020
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