Targeting Anti–TGF-β Therapy to Fibrotic Kidneys with a Dual Specificity Antibody Approach
| Autor: | Anthony M. Giamis, Andrew Goodearl, Christine Grinnell, Kelly J. Doyle, Katherine Salte, Victor Sun, Todd B. Cole, Murali Gopalakrishnan, L. Olson, Susan E. Lacy, Meha Chhaya, Yanping Luo, Steve McGaraughty, Arthur L. Nikkel, Rachel Davis-Taber, Chang Z. Zhu, Gregory M. Preston |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Pathology medicine.medical_specialty Kidney biology medicine.drug_class business.industry General Medicine Monoclonal antibody Fibronectin 03 medical and health sciences 030104 developmental biology 0302 clinical medicine medicine.anatomical_structure Downregulation and upregulation Nephrology 030220 oncology & carcinogenesis biology.protein Systemic administration Cancer research medicine Renal fibrosis Immunohistochemistry business TIMP1 |
| Zdroj: | Journal of the American Society of Nephrology. 28:3616-3626 |
| ISSN: | 1533-3450 1046-6673 |
| DOI: | 10.1681/asn.2017010013 |
| Popis: | Targeted delivery of a therapeutic agent to a site of pathology to ameliorate disease while limiting exposure at undesired tissues is an aspirational treatment scenario. Targeting diseased kidneys for pharmacologic treatment has had limited success. We designed an approach to target an extracellular matrix protein, the fibronectin extra domain A isoform (FnEDA), which is relatively restricted in distribution to sites of tissue injury. In a mouse unilateral ureteral obstruction (UUO) model of renal fibrosis, injury induced significant upregulation of FnEDA in the obstructed kidney. Using dual variable domain Ig (DVD-Ig) technology, we constructed a molecule with a moiety to target FnEDA and a second moiety to neutralize TGF-β After systemic injection of the bispecific TGF-β + FnEDA DVD-Ig or an FnEDA mAb, chemiluminescent detection and imaging with whole-body single-photon emission computed tomography (SPECT) revealed significantly higher levels of each molecule in the obstructed kidney than in the nonobstructed kidney, the ipsilateral kidney of sham animals, and other tissues. In comparison, a systemically administered TGF-β mAb accumulated at lower concentrations in the obstructed kidney and exhibited a more diffuse whole-body distribution. Systemic administration of the bispecific DVD-Ig or the TGF-β mAb (1-10 mg/kg) but not the FnEDA mAb attenuated the injury-induced collagen deposition detected by immunohistochemistry and elevation in Col1a1, FnEDA, and TIMP1 mRNA expression in the obstructed kidney. Overall, systemic delivery of a bispecific molecule targeting an extracellular matrix protein and delivering a TGF-β mAb resulted in a relatively focal uptake in the fibrotic kidney and reduced renal fibrosis. |
| Databáze: | OpenAIRE |
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