Research article
Selective targeted delivery of the TNF-alpha receptor p75 and uteroglobin to the vasculature of inflamed tissues: a preliminary report
-
* Corresponding author: Luciano Zardi zardi43@yahoo.it
1 Laboratory of Therapeutic Recombinant Proteins, Centro Biotecnologie Avanzate, Largo Rosanna Benzi, 1016132 Genoa, Italy
2 Laboratory of Oncology, G. Gaslini Institue, 16147 Genoa, Italy
3 Laboratory of Cell Biology and Immunology, National Institute for Research on Cancer, Largo Rosanna Benzi, 1016132 Genoa, Italy
BMC Biotechnology 2011, 11:104 doi:10.1186/1472-6750-11-104
Published: 10 November 2011Abstract
Background
Ligand-targeted approaches have proven successful in improving the therapeutic index of a number of drugs. We hypothesized that the specific targeting of TNF-alpha antagonists to inflamed tissues could increase drug efficacy and reduce side effects.
Results
Using uteroglobin (UG), a potent anti-inflammatory protein, as a scaffold, we prepared a bispecific tetravalent molecule consisting of the extracellular ligand-binding portion of the human TNF-alpha receptor P75 (TNFRII) and the scFv L19. L19 binds to the ED-B containing fibronectin isoform (B-FN), which is expressed only during angiogenesis processes and during tissue remodeling. B-FN has also been demonstrated in the pannus in rheumatoid arthritis. L19-UG-TNFRII is a stable, soluble homodimeric protein that maintains the activities of both moieties: the immuno-reactivity of L19 and the capability of TNFRII to inhibit TNF-alpha. In vivo bio-distribution studies demonstrated that the molecule selectively accumulated on B-FN containing tissues, showing a very fast clearance from the blood but a very long residence time on B-FN containing tissues. Despite the very fast clearance from the blood, this fusion protein was able to significantly improve the severe symptomatology of arthritis in collagen antibody-induced arthritis (CAIA) mouse model.
Conclusions
The recombinant protein described here, able to selectively deliver the TNF-alpha antagonist TNFRII to inflamed tissues, could yield important contributions for the therapy of degenerative inflammatory diseases.