Guiding bispecific monovalent antibody formation through proteolysis of IgG1 single-chain
| Autor: | Saravanan Rajan, Binyam Bezabeh, Li Zhuang, Changshou Gao, Carl Hay, Erin Sult, Peter Cariuk, Michael A. Bowen, Ryan Fleming, Andrew Buchanan, Nazzareno Dimasi, Herren Wu, Kris Sachsenmeier, Jincheng Wu |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Proteolysis Immunology Sequence (biology) Single chain Protein Engineering Immunoglobulin light chain Receptor IGF Type 1 03 medical and health sciences Growth factor receptor Antibodies Bispecific medicine Animals Humans Immunology and Allergy Epidermal growth factor receptor biology medicine.diagnostic_test Chemistry Molecular biology ErbB Receptors 030104 developmental biology Immunoglobulin G biology.protein Biophysics Antibody Antibody formation Single-Chain Antibodies Reports |
| Zdroj: | mAbs. 9:438-454 |
| ISSN: | 1942-0870 1942-0862 |
| Popis: | We developed an IgG1 domain-tethering approach to guide the correct assembly of 2 light and 2 heavy chains, derived from 2 different antibodies, to form bispecific monovalent antibodies in IgG1 format. We show here that assembling 2 different light and heavy chains by sequentially connecting them with protease-cleavable polypeptide linkers results in the generation of monovalent bispecific antibodies that have IgG1 sequence, structure and functional properties. This approach was used to generate a bispecific monovalent antibody targeting the epidermal growth factor receptor and the type I insulin-like growth factor receptor that: 1) can be produced and purified using standard IgG1 techniques; 2) exhibits stability and structural features comparable to IgG1; 3) binds both targets simultaneously; and 4) has potent anti-tumor activity. Our strategy provides new engineering opportunities for bispecific antibody applications, and, most importantly, overcomes some of the limitations (e.g., half-antibody and homodimer formation, light chains mispairing, multi-step purification), inherent with some of the previously described IgG1-based bispecific monovalent antibodies. |
| Databáze: | OpenAIRE |
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