A Non-immunogenic Bivalent d-Protein Potently Inhibits Retinal Vascularization and Tumor Growth
| Autor: | Kyle E Landgraf, Maruti Uppalapati, Qiyang Jiang, Annalise Petriello, Stephen B. H. Kent, Gang Chen, Paul S Marinec, Daniel Xie, Dana Ault-Riche, Sachdev S. Sidhu, Kurt Deshayes, Yanlong Zhao |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Models Molecular Vascular Endothelial Growth Factor A Phage display Protein Conformation Drug Evaluation Preclinical Antineoplastic Agents Eye 01 natural sciences Biochemistry Affinity maturation 03 medical and health sciences chemistry.chemical_compound Mice In vivo Peptide Library Neoplasms Animals Humans Amino Acid Sequence Receptor Binding Sites biology 010405 organic chemistry Antagonist Retinal Vessels Retinal General Medicine 0104 chemical sciences Cell biology Bevacizumab Vascular endothelial growth factor A 030104 developmental biology Receptors Vascular Endothelial Growth Factor chemistry biology.protein Molecular Medicine Female Rabbits Antibody Protein Multimerization Peptides Protein Binding |
| Zdroj: | ACS chemical biology. 16(3) |
| ISSN: | 1554-8937 |
| Popis: | We report a general approach to engineering multivalent d-proteins with antibody-like activities in vivo. Mirror-image phage display and structure-guided design were utilized to create a d-protein that uses receptor mimicry to antagonize vascular endothelial growth factor A (VEGF-A). Selections against the d-protein form of VEGF-A using phage-displayed libraries of two different domain scaffolds yielded two proteins that bound distinct receptor interaction sites on VEGF-A. X-ray crystal structures of the d-protein/VEGF-A complexes were used to guide affinity maturation and to construct a heterodimeric d-protein VEGF-A antagonist with picomolar activity. The d-protein VEGF-A antagonist prevented vascular leakage in a rabbit eye model of wet age-related macular degeneration and slowed tumor growth in the MC38 syngeneic mouse tumor model with efficacies comparable to those of approved antibody drugs, and in contrast with antibodies, the d-protein was non-immunogenic during treatment and following subcutaneous immunizations. |
| Databáze: | OpenAIRE |
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