A Novel T Cell-Engaging Bispecific Antibody for Treating Mesothelin-Positive Solid Tumors

• Published in: Biomolecules (Basel, Switzerland) Vol. 10; no. 3; p. 399
• Main Authors: Yoon, Aerin, Lee, Shinai, Lee, Sua, Lim, Sojung, Park, Yong-Yea, Song, Eunjung, Kim, Dong-Sik, Kim, Kisu, Lim, Yangmi
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 04.03.2020; MDPI
• Subjects: Animals; Antibodies; Antibodies, Bispecific - immunology; Antibodies, Bispecific - pharmacology; Antineoplastic Agents, Immunological - immunology; Antineoplastic Agents, Immunological - pharmacology; bispecific antibody; cancer immunotherapy; cd3; GPI-Linked Proteins - immunology; Health aspects; heterodimeric bivalent; heterodimeric trivalent; Humans; Immunoglobulin G - immunology; Immunoglobulin G - pharmacology; Jurkat Cells; mesothelin; Mice; Mice, Inbred NOD; Mice, SCID; Neoplasm Proteins - immunology; Neoplasms - drug therapy; Neoplasms - immunology; Neoplasms - pathology; solid tumor; t cell-engaging; T cells; T-Lymphocytes - immunology; T-Lymphocytes - pathology; tumor regression; Xenograft Model Antitumor Assays; Japan; CD3; cancer immunotherapy; heterodimeric trivalent; bispecific antibody; solid tumor; T cell-engaging; tumor regression; heterodimeric bivalent; mesothelin
• ISSN: 2218-273X; 2218-273X
• 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.