A Novel T Cell-Engaging Bispecific Antibody for Treating Mesothelin-Positive Solid Tumors
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 a...
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MDPI AG
2020-03-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/10/3/399 |
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| author | Aerin Yoon Shinai Lee Sua Lee Sojung Lim Yong-Yea Park Eunjung Song Dong-Sik Kim Kisu Kim Yangmi Lim |
| author_facet | Aerin Yoon Shinai Lee Sua Lee Sojung Lim Yong-Yea Park Eunjung Song Dong-Sik Kim Kisu Kim Yangmi Lim |
| author_sort | Aerin Yoon |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-19T04:03:44Z |
| format | Article |
| id | doaj.art-908d6af7d96f4de19914b881dc4fb2c7 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-12-19T04:03:44Z |
| publishDate | 2020-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-908d6af7d96f4de19914b881dc4fb2c72022-12-21T20:36:35ZengMDPI AGBiomolecules2218-273X2020-03-0110339910.3390/biom10030399biom10030399A Novel T Cell-Engaging Bispecific Antibody for Treating Mesothelin-Positive Solid TumorsAerin Yoon0Shinai Lee1Sua Lee2Sojung Lim3Yong-Yea Park4Eunjung Song5Dong-Sik Kim6Kisu Kim7Yangmi Lim8Protein Engineering, Mogam Institute for Biomedical Research, Yongin, Gyeonggi-do 16924, KoreaProtein Engineering, Mogam Institute for Biomedical Research, Yongin, Gyeonggi-do 16924, KoreaProtein Engineering, Mogam Institute for Biomedical Research, Yongin, Gyeonggi-do 16924, KoreaProtein Engineering, Mogam Institute for Biomedical Research, Yongin, Gyeonggi-do 16924, KoreaProtein Engineering, Mogam Institute for Biomedical Research, Yongin, Gyeonggi-do 16924, KoreaProtein Engineering, Mogam Institute for Biomedical Research, Yongin, Gyeonggi-do 16924, KoreaProtein Engineering, Mogam Institute for Biomedical Research, Yongin, Gyeonggi-do 16924, KoreaProtein Engineering, Mogam Institute for Biomedical Research, Yongin, Gyeonggi-do 16924, KoreaProtein Engineering, Mogam Institute for Biomedical Research, Yongin, Gyeonggi-do 16924, KoreaAs 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.https://www.mdpi.com/2218-273X/10/3/399mesothelincd3bispecific antibodysolid tumorcancer immunotherapyt cell-engagingheterodimeric bivalentheterodimeric trivalenttumor regression |
| spellingShingle | Aerin Yoon Shinai Lee Sua Lee Sojung Lim Yong-Yea Park Eunjung Song Dong-Sik Kim Kisu Kim Yangmi Lim A Novel T Cell-Engaging Bispecific Antibody for Treating Mesothelin-Positive Solid Tumors Biomolecules mesothelin cd3 bispecific antibody solid tumor cancer immunotherapy t cell-engaging heterodimeric bivalent heterodimeric trivalent tumor regression |
| title | A Novel T Cell-Engaging Bispecific Antibody for Treating Mesothelin-Positive Solid Tumors |
| title_full | A Novel T Cell-Engaging Bispecific Antibody for Treating Mesothelin-Positive Solid Tumors |
| title_fullStr | A Novel T Cell-Engaging Bispecific Antibody for Treating Mesothelin-Positive Solid Tumors |
| title_full_unstemmed | A Novel T Cell-Engaging Bispecific Antibody for Treating Mesothelin-Positive Solid Tumors |
| title_short | A Novel T Cell-Engaging Bispecific Antibody for Treating Mesothelin-Positive Solid Tumors |
| title_sort | novel t cell engaging bispecific antibody for treating mesothelin positive solid tumors |
| topic | mesothelin cd3 bispecific antibody solid tumor cancer immunotherapy t cell-engaging heterodimeric bivalent heterodimeric trivalent tumor regression |
| url | https://www.mdpi.com/2218-273X/10/3/399 |
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