Transport of anti-IL-6 antigen binding fragments into cartilage and the effects of injury
The efficacy of biological therapeutics against cartilage degradation in osteoarthritis is restricted by the limited transport of macromolecules through the dense, avascular extracellular matrix. The availability of biologics to cell surface and matrix targets is limited by steric hindrance of the m...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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Elsevier
2015
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| Online Access: | http://hdl.handle.net/1721.1/99412 https://orcid.org/0000-0002-4942-3456 |
| _version_ | 1826199829422800896 |
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| author | Byun, Sangwon Sinskey, Yunna L. Lu, Yihong C. S. Ort, Tatiana Kavalkovich, Karl Sivakumar, Pitchumani Hunziker, Ernst B. Grodzinsky, Alan J. Frank, Eliot |
| author2 | Massachusetts Institute of Technology. Center for Biomedical Engineering |
| author_facet | Massachusetts Institute of Technology. Center for Biomedical Engineering Byun, Sangwon Sinskey, Yunna L. Lu, Yihong C. S. Ort, Tatiana Kavalkovich, Karl Sivakumar, Pitchumani Hunziker, Ernst B. Grodzinsky, Alan J. Frank, Eliot |
| author_sort | Byun, Sangwon |
| collection | MIT |
| description | The efficacy of biological therapeutics against cartilage degradation in osteoarthritis is restricted by the limited transport of macromolecules through the dense, avascular extracellular matrix. The availability of biologics to cell surface and matrix targets is limited by steric hindrance of the matrix, and the microstructure of matrix itself can be dramatically altered by joint injury and the subsequent inflammatory response. We studied the transport into cartilage of a 48 kDa anti-IL-6 antigen binding fragment (Fab) using an in vitro model of joint injury to quantify the transport of Fab fragments into normal and mechanically injured cartilage. The anti-IL-6 Fab was able to diffuse throughout the depth of the tissue, suggesting that Fab fragments can have the desired property of achieving local delivery to targets within cartilage, unlike full-sized antibodies which are too large to penetrate beyond the cartilage surface. Uptake of the anti-IL-6 Fab was significantly increased following mechanical injury, and an additional increase in uptake was observed in response to combined treatment with TNFα and mechanical injury, a model used to mimic the inflammatory response following joint injury. These results suggest that joint trauma leading to cartilage degradation can further alter the transport of such therapeutics and similar-sized macromolecules. |
| first_indexed | 2024-09-23T11:26:25Z |
| format | Article |
| id | mit-1721.1/99412 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T11:26:25Z |
| publishDate | 2015 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | mit-1721.1/994122022-10-01T03:38:48Z Transport of anti-IL-6 antigen binding fragments into cartilage and the effects of injury Byun, Sangwon Sinskey, Yunna L. Lu, Yihong C. S. Ort, Tatiana Kavalkovich, Karl Sivakumar, Pitchumani Hunziker, Ernst B. Grodzinsky, Alan J. Frank, Eliot Massachusetts Institute of Technology. Center for Biomedical Engineering Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Biology Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science Massachusetts Institute of Technology. Department of Mechanical Engineering Byun, Sangwon Sinskey, Yunna L. Lu, Yihong C. S. Frank, Eliot Grodzinsky, Alan J. The efficacy of biological therapeutics against cartilage degradation in osteoarthritis is restricted by the limited transport of macromolecules through the dense, avascular extracellular matrix. The availability of biologics to cell surface and matrix targets is limited by steric hindrance of the matrix, and the microstructure of matrix itself can be dramatically altered by joint injury and the subsequent inflammatory response. We studied the transport into cartilage of a 48 kDa anti-IL-6 antigen binding fragment (Fab) using an in vitro model of joint injury to quantify the transport of Fab fragments into normal and mechanically injured cartilage. The anti-IL-6 Fab was able to diffuse throughout the depth of the tissue, suggesting that Fab fragments can have the desired property of achieving local delivery to targets within cartilage, unlike full-sized antibodies which are too large to penetrate beyond the cartilage surface. Uptake of the anti-IL-6 Fab was significantly increased following mechanical injury, and an additional increase in uptake was observed in response to combined treatment with TNFα and mechanical injury, a model used to mimic the inflammatory response following joint injury. These results suggest that joint trauma leading to cartilage degradation can further alter the transport of such therapeutics and similar-sized macromolecules. National Institute of Arthritis and Musculoskeletal and Skin Diseases (U.S.) (Grant AR45779) National Institute of Arthritis and Musculoskeletal and Skin Diseases (U.S.) (Grant AR60331) Janssen Pharmaceutical Ltd. (Research and Development Grant) 2015-10-22T14:23:09Z 2015-10-22T14:23:09Z 2013-01 202-12 Article http://purl.org/eprint/type/JournalArticle 00039861 1096-0384 http://hdl.handle.net/1721.1/99412 Byun, Sangwon, Yunna L. Sinskey, Yihong C.S. Lu, Tatiana Ort, Karl Kavalkovich, Pitchumani Sivakumar, Ernst B. Hunziker, Eliot H. Frank, and Alan J. Grodzinsky. “Transport of Anti-IL-6 Antigen Binding Fragments into Cartilage and the Effects of Injury.” Archives of Biochemistry and Biophysics 532, no. 1 (April 2013): 15–22. https://orcid.org/0000-0002-4942-3456 en_US http://dx.doi.org/10.1016/j.abb.2012.12.020 Archives of Biochemistry and Biophysics Creative Commons Attribution http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier Elsevier |
| spellingShingle | Byun, Sangwon Sinskey, Yunna L. Lu, Yihong C. S. Ort, Tatiana Kavalkovich, Karl Sivakumar, Pitchumani Hunziker, Ernst B. Grodzinsky, Alan J. Frank, Eliot Transport of anti-IL-6 antigen binding fragments into cartilage and the effects of injury |
| title | Transport of anti-IL-6 antigen binding fragments into cartilage and the effects of injury |
| title_full | Transport of anti-IL-6 antigen binding fragments into cartilage and the effects of injury |
| title_fullStr | Transport of anti-IL-6 antigen binding fragments into cartilage and the effects of injury |
| title_full_unstemmed | Transport of anti-IL-6 antigen binding fragments into cartilage and the effects of injury |
| title_short | Transport of anti-IL-6 antigen binding fragments into cartilage and the effects of injury |
| title_sort | transport of anti il 6 antigen binding fragments into cartilage and the effects of injury |
| url | http://hdl.handle.net/1721.1/99412 https://orcid.org/0000-0002-4942-3456 |
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