Scientific Abstract

Proposal No. IBD-0123
Principal Investigator:  Pieter Rottiers, Ph.D. (replacement PI); Claude Cuvelier, M.D., Ph.D. (original PI)
Current Applicant Organization:  Flanders Interuniversity Institute for Biotechnology vzw (Ghent, Belgium)
Original Applicant Organization:  Ghent University (Belgium)
Project Title:  Treatment of experimental colitis by camelid antibody fragments:  local delivery by genetically engineered lactococci administration and evaluation of their therapeutic potential
Period of Award:  July 1, 2004 - June 30, 2006

Tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) are both key cytokines involved in the inflammatory reaction observed in Crohn’s disease (CD).  The treatment of CD with antibodies against TNF-α has been shown to be very promising and has become an approved therapy in the U.S.A. and Europe.  Treatment with anti-IFN-γ monoclonal antibodies is currently being evaluated in a clinical trial.  Although antibody therapy has emerged as a valuable tool in the treatment of CD, its adverse systemic side effects and the high cost hamper its success.

The proposed project aims at obtaining proof of principle for the therapeutic efficacy of camelid antibodies against TNF-α and IFN-γ in IBD, delivered directly to the inflamed gut by Lactococcus lactis.  Antibodies derived from camelids are devoid of the light chains of conventional antibodies; accordingly, their antigen binding sites are limited to single domains, referred to as VHH’s.  Such domains are the smallest antigen-binding fragments of naturally occurring single-domain antibodies that have evolved to be fully functional in the absence of a light chain.  These small-sized molecules are well expressed, are non-immunogenic, show good specificity towards their corresponding antigen, and can be obtained with high affinity.  VHH’s are much more stable than conventional antibodies and can withstand conditions of extreme pH, making them suitable for oral delivery.  Genetically modified food-grade Lactococcus lactis, on the other hand, provides a possible means for targeting therapeutic biological molecules to the intestinal mucosa.  In vivo production of VHH’s locally in the intestine circumvents the potential problem of degradation of orally administered antibodies in the stomach, and reduces the risk of adverse effects.  

We previously constructed recombinant Lactococcus lactis strains for the production and intestinal delivery of cytokines and other immunomodulatory proteins.  By applying camelid antibody fragments, administered by the Lactococcus lactis-mediated delivery system, we hope to develop a new, cost-effective approach of local immune therapy to treat intestinal inflammation.