Orally administered L. lactis secreting an anti-TNF Nanobody demonstrate efficacy in chronic colitis.
Inflammatory bowel disease (IBD) is a chronic inflammatory gastrointestinal disorder. Systemic treatment of IBD patients with anti-tumor necrosis factor (TNF)-alpha 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.
Vandenbroucke
K
K
Department for Molecular Biomedical Research, VIB, Zwijnaarde, Belgium.
de Haard
H
H
Beirnaert
E
E
Dreier
T
T
Lauwereys
M
M
Huyck
L
L
Van Huysse
J
J
Demetter
P
P
Steidler
L
L
Remaut
E
E
Cuvelier
C
C
Rottiers
P
P
D000284:Administration, Oral; D000818:Animals; D018033:Antibodies, Bispecific / Q000008:administration & dosage / Q000235:genetics; D002460:Cell Line; D002908:Chronic Disease; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology* / Q000503:physiopathology; D016264:Dextran Sulfate / Q000008:administration & dosage; D005260:Female; D005818:Genetic Engineering; D013294:Lactococcus lactis / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D053758:Nanoparticles / Q000008:administration & dosage; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*
D018033:Antibodies, Bispecific; D014409:Tumor Necrosis Factor-alpha; D016264:Dextran Sulfate