A bivalent, bispecific Dab-Fc antibody molecule for dual targeting of HER2 and HER3
Autor: | Oliver Seifert, Monilola A. Olayioye, Alexander Rau, Lennart Kühl, Maximilian Albrecht, Mirjam Rommel, Katharina Kocher, Nadine Aschmoneit, Bettina Noll, Roland E. Kontermann, Hannes Gotthard |
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Jazyk: | angličtina |
Rok vydání: | 2021 |
Předmět: |
Bispecific antibody
Dual targeting Receptor ErbB-3 Receptor ErbB-2 Immunology Cancer therapy Mice SCID Bivalent (genetics) 03 medical and health sciences 0302 clinical medicine Antineoplastic Agents Immunological HER3 Cell Movement Stomach Neoplasms Report HER2 Antibodies Bispecific Immunology and Allergy Animals Humans Neoplasm Invasiveness Molecular Targeted Therapy Receptor skin and connective tissue diseases 030304 developmental biology Cell Proliferation 0303 health sciences diabody-ig Chemistry dual targeting Antibody-Dependent Cell Cytotoxicity Xenograft Model Antitumor Assays Immunoglobulin Fc Fragments Antibody molecule 030220 oncology & carcinogenesis Cancer research MCF-7 Cells Db-Ig Signal Transduction |
Zdroj: | mAbs article-version (VoR) Version of Record |
ISSN: | 1942-0870 1942-0862 |
Popis: | 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. |
Databáze: | OpenAIRE |
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