title: Transport of anti-IL-6 antigen binding fragments into cartilage and the effects of injury.
abstract: 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.
authors: Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA 02139, United States.
authors: Sangwon
authors: S
authors: Byun
authors: Yunna L
authors: YL
authors: Sinskey
authors: Yihong C S
authors: YC
authors: Lu
authors: Tatiana
authors: T
authors: Ort
authors: Karl
authors: K
authors: Kavalkovich
authors: Pitchumani
authors: P
authors: Sivakumar
authors: Ernst B
authors: EB
authors: Hunziker
authors: Eliot H
authors: EH
authors: Frank
authors: Alan J
authors: AJ
authors: Grodzinsky
mesh_terms: D000328:Adult; D000818:Animals; D002358:Cartilage, Articular / Q000276:immunology / Q000293:injuries* / Q000378:metabolism*; D002417:Cattle; D005260:Female; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000276:immunology* / Q000378:metabolism* / Q000627:therapeutic use; D015850:Interleukin-6 / Q000276:immunology*; D021381:Protein Transport; D013314:Stress, Mechanical; D014409:Tumor Necrosis Factor-alpha / Q000627:therapeutic use
chemical_list: D007140:Immunoglobulin Fab Fragments; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha