A bivalent, bispecific Dab-Fc antibody molecule for dual targeting of HER2 and HER3
Dual targeting of surface receptors with bispecific antibodies is attracting increasing interest in cancer therapy. Here, we present a novel bivalent and bispecific antagonistic molecule (Dab-Fc) targeting human epidermal growth factors 2 and 3 (HER2 and HER3) derived from the Db-Ig platform, which...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2021-01-01
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| Series: | mAbs |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/19420862.2021.1902034 |
| _version_ | 1828427487571345408 |
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| author | Alexander Rau Katharina Kocher Mirjam Rommel Lennart Kühl Maximilian Albrecht Hannes Gotthard Nadine Aschmoneit Bettina Noll Monilola A. Olayioye Roland E. Kontermann Oliver Seifert |
| author_facet | Alexander Rau Katharina Kocher Mirjam Rommel Lennart Kühl Maximilian Albrecht Hannes Gotthard Nadine Aschmoneit Bettina Noll Monilola A. Olayioye Roland E. Kontermann Oliver Seifert |
| author_sort | Alexander Rau |
| collection | DOAJ |
| description | Dual targeting of surface receptors with bispecific antibodies is attracting increasing interest in cancer therapy. Here, we present a novel bivalent and bispecific antagonistic molecule (Dab-Fc) targeting human epidermal growth factors 2 and 3 (HER2 and HER3) derived from the Db-Ig platform, which was developed for the generation of multivalent and multispecific antibody molecules. Dab-Fc comprises the variable domains of the anti-HER2 antibody trastuzumab and the anti-HER3 antibody 3–43 assembled into a diabody-like structure stabilized by CH1 and CL domains and further fused to a human γ1 Fc region. The resulting Dab-Fc 2 × 3 molecule retained unhindered binding to both antigens and was able to bind both antigens sequentially. In cellular experiments, the Dab-Fc 2 × 3 molecule strongly bound to different tumor cell lines expressing HER2 and HER3 and was efficiently internalized. This was associated with potent inhibition of the proliferation and migration of these tumor cell lines. Furthermore, IgG-like pharmacokinetics and anti-tumoral activity were demonstrated in a xenograft tumor model of the gastric cancer cell-line NCI-N87. These results illustrate the suitability of our versatile Db-Ig platform technology for the generation of bivalent bispecific molecules, which has been successfully used here for the dual targeting of HER2 and HER3. |
| first_indexed | 2024-12-10T17:02:34Z |
| format | Article |
| id | doaj.art-8f87b491057b4795a191a891a563a0e7 |
| institution | Directory Open Access Journal |
| issn | 1942-0862 1942-0870 |
| language | English |
| last_indexed | 2024-12-10T17:02:34Z |
| publishDate | 2021-01-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | mAbs |
| spelling | doaj.art-8f87b491057b4795a191a891a563a0e72022-12-22T01:40:32ZengTaylor & Francis GroupmAbs1942-08621942-08702021-01-0113110.1080/19420862.2021.1902034A bivalent, bispecific Dab-Fc antibody molecule for dual targeting of HER2 and HER3Alexander Rau0Katharina Kocher1Mirjam Rommel2Lennart Kühl3Maximilian Albrecht4Hannes Gotthard5Nadine Aschmoneit6Bettina Noll7Monilola A. Olayioye8Roland E. Kontermann9Oliver Seifert10Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, GermanyInstitute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, GermanyInstitute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, GermanyInstitute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, GermanyInstitute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, GermanyInstitute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, GermanyInstitute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, GermanyInstitute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, GermanyInstitute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, GermanyInstitute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, GermanyInstitute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, GermanyDual targeting of surface receptors with bispecific antibodies is attracting increasing interest in cancer therapy. Here, we present a novel bivalent and bispecific antagonistic molecule (Dab-Fc) targeting human epidermal growth factors 2 and 3 (HER2 and HER3) derived from the Db-Ig platform, which was developed for the generation of multivalent and multispecific antibody molecules. Dab-Fc comprises the variable domains of the anti-HER2 antibody trastuzumab and the anti-HER3 antibody 3–43 assembled into a diabody-like structure stabilized by CH1 and CL domains and further fused to a human γ1 Fc region. The resulting Dab-Fc 2 × 3 molecule retained unhindered binding to both antigens and was able to bind both antigens sequentially. In cellular experiments, the Dab-Fc 2 × 3 molecule strongly bound to different tumor cell lines expressing HER2 and HER3 and was efficiently internalized. This was associated with potent inhibition of the proliferation and migration of these tumor cell lines. Furthermore, IgG-like pharmacokinetics and anti-tumoral activity were demonstrated in a xenograft tumor model of the gastric cancer cell-line NCI-N87. These results illustrate the suitability of our versatile Db-Ig platform technology for the generation of bivalent bispecific molecules, which has been successfully used here for the dual targeting of HER2 and HER3.https://www.tandfonline.com/doi/10.1080/19420862.2021.1902034Bispecific antibodydiabody-igDb-Igdual targetingHER2HER3 |
| spellingShingle | Alexander Rau Katharina Kocher Mirjam Rommel Lennart Kühl Maximilian Albrecht Hannes Gotthard Nadine Aschmoneit Bettina Noll Monilola A. Olayioye Roland E. Kontermann Oliver Seifert A bivalent, bispecific Dab-Fc antibody molecule for dual targeting of HER2 and HER3 mAbs Bispecific antibody diabody-ig Db-Ig dual targeting HER2 HER3 |
| title | A bivalent, bispecific Dab-Fc antibody molecule for dual targeting of HER2 and HER3 |
| title_full | A bivalent, bispecific Dab-Fc antibody molecule for dual targeting of HER2 and HER3 |
| title_fullStr | A bivalent, bispecific Dab-Fc antibody molecule for dual targeting of HER2 and HER3 |
| title_full_unstemmed | A bivalent, bispecific Dab-Fc antibody molecule for dual targeting of HER2 and HER3 |
| title_short | A bivalent, bispecific Dab-Fc antibody molecule for dual targeting of HER2 and HER3 |
| title_sort | bivalent bispecific dab fc antibody molecule for dual targeting of her2 and her3 |
| topic | Bispecific antibody diabody-ig Db-Ig dual targeting HER2 HER3 |
| url | https://www.tandfonline.com/doi/10.1080/19420862.2021.1902034 |
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