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Sustained secretion of anti‐tumor necrosis factor α monoclonal antibody from ex vivo genetically engineered dermal tissue demonstrates therapeutic activity in mouse model of rheumatoid arthritis
Author(s) -
ZafirLavie Inbal,
Miari Reem,
Sherbo Shay,
Krispel Simi,
Tal Osnat,
Liran Atar,
Shatil Tamar,
Badinter Felix,
Goltsman Haim,
Shapir Nir,
Benhar Itai,
Neil Garry A.,
Panet Amos
Publication year - 2017
Publication title -
the journal of gene medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.689
H-Index - 91
eISSN - 1521-2254
pISSN - 1099-498X
DOI - 10.1002/jgm.2965
Subject(s) - adalimumab , ex vivo , medicine , monoclonal antibody , tumor necrosis factor alpha , in vivo , antibody , genetic enhancement , immunology , secretion , rheumatoid arthritis , cancer research , biology , gene , biochemistry , microbiology and biotechnology
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 naïve 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.