Novel protein therapeutic joint retention strategy based on collagen-binding Avimers
| Autor: | Peng Li, Joanne T. Hulme, Helen J. McBride, Kim Merriam, Jiansong Xie, Alice Bakker, Hong Sun, Anielka Montalvan, Richard Smith, John E. Sims, Roy A. Black, Kevin Moore, Christopher A. Gabel, Natalia Grinberg, James B. Rottman, Angela Willee, Ryan Case, Amy N. Duguay, Warren N. D'Souza, Bo-Rin Park Yoon, Bin Fan, Benjamin M. Alba, Maria Rosalyn Dayao, Melissa Thomas, Khue Dang |
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| Rok vydání: | 2017 |
| Předmět: |
030203 arthritis & rheumatology
0301 basic medicine medicine.medical_specialty Chemistry Cartilage Type II collagen Osteoarthritis medicine.disease Avimer In vitro Surgery Cell biology Extracellular matrix 03 medical and health sciences 030104 developmental biology 0302 clinical medicine medicine.anatomical_structure In vivo medicine Orthopedics and Sports Medicine Receptor |
| Zdroj: | Journal of Orthopaedic Research. |
| ISSN: | 0736-0266 |
| Popis: | Designing drugs to treat diseases associated with articular joints, particularly those targeting chondrocytes, is challenging due to unique local environmental constraints including the avascular nature of cartilage, the absence of a closed joint compartment, and a highly cross-linked extracellular matrix. In an effort to address these challenges, we developed a novel strategy to prolong residence time of intra-articularly administered protein therapeutics. Avimer domains are naturally found in membrane polypeptides and mediate diverse protein-protein interactions. Screening of a phage Avimer domain library led to identification of several low affinity type II collagen-binding Avimers. Following several rounds of mutagenesis and reselection, these initial hits were transformed to high affinity, selective type II collagen-binding Avimers. One such Avimer (M26) persisted in rat knees for at least 1 month following intra-articular administration. Fusion of this Avimer to a candidate therapeutic payload, IL-1Ra, yielded a protein construct which simultaneously bound to type II collagen and to IL-1 receptor. In vitro, IL-1Ra_M26 bound selectively to cartilage explants and remained associated even after extensive washing. Binding appeared to occur preferentially to pericellular regions surrounding chondrocytes. An acute intra-articular IL-1-induced IL-6 challenge rat model was employed to assess in vivo pharmacodynamics. Whereas both IL-1Ra_M26 and native IL-1Ra inhibited IL-6 output when co-administered with the IL-1 challenge, only IL-1Ra_M26 inhibited when administered 1 week prior to IL-1 challenge. Collagen-binding Avimers thus represent a promising strategy for enhancing cartilage residence time of protein therapeutics. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1238-1247, 2018. |
| Databáze: | OpenAIRE |
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