Orally administered L. lactis secreting an anti-TNF Nanobody demonstrate efficacy in chronic colitis

• Published in: Mucosal immunology Vol. 3; no. 1; pp. 49 - 56
• Main Authors: Vandenbroucke, K, de Haard, H, Beirnaert, E, Dreier, T, Lauwereys, M, Huyck, L, Van Huysse, J, Demetter, P, Steidler, L, Remaut, E, Cuvelier, C, Rottiers, P
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 2010; Elsevier Limited
• Subjects: Administration, Oral; Allergology; Animals; Antibodies; Antibodies, Bispecific - administration & dosage; Antibodies, Bispecific - genetics; Biomedical and Life Sciences; Biomedicine; Cell Line; Chronic Disease; Colitis - chemically induced; Colitis - drug therapy; Colitis - immunology; Colitis - physiopathology; Dextran Sulfate - administration & dosage; Female; Gastroenterology; Genetic Engineering; Immunology; Lactococcus lactis - genetics; Lactococcus lactis - immunology; Mice; Mice, Inbred BALB C; Mice, Knockout; Nanoparticles - administration & dosage; Tumor Necrosis Factor-alpha - immunology
• ISSN: 1933-0219; 1935-3456
• DOI: 10.1038/mi.2009.116

Inflammatory bowel disease (IBD) is a chronic inflammatory gastrointestinal disorder. Systemic treatment of IBD patients with anti-tumor necrosis factor (TNF)-α antibodies has proven to be a highly promising approach, but several drawbacks remain, including side effects related to systemic administration and high cost of treatment. Lactococcus lactis was engineered to secrete monovalent and bivalent murine (m)TNF-neutralizing Nanobodies as therapeutic proteins. These therapeutic proteins are derived from fragments of heavy-chain camelid antibodies and are more stable than conventional antibodies. L. lactis -secreted anti-mTNF Nanobodies neutralized mTNF in vitro . Daily oral administration of Nanobody-secreting L. lactis resulted in local delivery of anti-mTNF Nanobodies at the colon and significantly reduced inflammation in mice with dextran sulfate sodium (DSS)-induced chronic colitis. In addition, this approach was also successful in improving established enterocolitis in interleukin 10 (IL10) –/– mice. Finally, L. lactis -secreted anti-mTNF Nanobodies did not interfere with systemic Salmonella infection in colitic IL10 –/– mice. In conclusion, this report details a new therapeutic approach for treatment of chronic colitis, involving in situ secretion of anti-mTNF Nanobodies by orally administered L. lactis bacteria. Therapeutic application of these engineered bacteria could eventually lead to more effective and safer management of IBD in humans.