Sustained secretion of anti-tumor necrosis factor α monoclonal antibody fromex vivogenetically engineered dermal tissue demonstrates therapeutic activity in mouse model of rheumatoid arthritis
| Autor: | Nir Shapir, Garry A. Neil, Osnat Tal, Itai Benhar, Simi Krispel, Tamar Shatil, Felix Badinter, Reem Miari, Atar Liran, Haim Goltsman, Inbal Zafir-Lavie, Amos Panet, Shay Sherbo |
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| Rok vydání: | 2017 |
| Předmět: |
Male
musculoskeletal diseases 0301 basic medicine medicine.drug_class Genetic enhancement Mice SCID Pharmacology Monoclonal antibody Viral vector Arthritis Rheumatoid Mice 03 medical and health sciences Drug Discovery Genetics Adalimumab Animals Humans Medicine Molecular Biology Genetics (clinical) biology Tumor Necrosis Factor-alpha business.industry Antibodies Monoclonal Genetic Therapy medicine.disease Disease Models Animal Methotrexate Treatment Outcome 030104 developmental biology Rheumatoid arthritis biology.protein Cytokines Molecular Medicine Female Tumor necrosis factor alpha Antibody Genetic Engineering business Ex vivo medicine.drug |
| Zdroj: | The Journal of Gene Medicine. 19:e2965 |
| ISSN: | 1099-498X |
| Popis: | Background Rheumatoid arthritis (RA) is a symmetric inflammatory polyarthritis associated with high concentrations of pro-inflammatory, cytokines including tumor necrosis factor (TNF)-α. Adalimumab is a monoclonal antibody (mAb) that binds TNF-α, and is widely used to treat RA. Despite its proven clinical efficacy, adalimumab and other therapeutic mAbs have disadvantages, including the requirement for repeated bolus injections and the appearance of treatment limiting anti-drug antibodies. To address these issues, we have developed an innovative ex vivo gene therapy approach, termed transduced autologous restorative gene therapy (TARGT), to produce and secrete adalimumab for the treatment of RA. Methods Helper-dependent (HD) adenovirus vector containing adalimumab light and heavy chain coding sequences was used to transduce microdermal tissues and cells of human and mouse origin ex vivo, rendering sustained secretion of active adalimumab. The genetically engineered tissues were subsequently implanted in a mouse model of RA. Results Transduced human microdermal tissues implanted in SCID mice demonstrated 49 days of secretion of active adalimumab in the blood, at levels of tens of microgram per milliliter. In addition, transduced autologous dermal cells were implanted in the RA mouse model and demonstrated statistically significant amelioration in RA symptoms compared to naive cell implantation and were similar to recombinant adalimumab bolus injections. Conclusions The results of the present study report microdermal tissues engineered to secrete active adalimumab as a proof of concept for sustained secretion of antibody from the novel ex vivo gene therapy TARGT platform. This technology may now be applied to a range of antibodies for the therapy of other diseases. |
| Databáze: | OpenAIRE |
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