Oral delivery of antibodies. Future pharmacokinetic trends.
Antibodies have been investigated as specific targeting agents for cancer diagnosis and therapy, to inactivate toxic substances including drugs and also as passive immunotherapy for neoplastic or infectious diseases. In most cases the antibodies were administered systemically by the intravenous route. More recently, however, there has been increasing interest in the oral administration of antibodies for localised treatment of infections or other conditions in the gastrointestinal tract. The normal physiological handling of ingested proteins is degradation by proteases in the stomach and intestine into small peptides or amino acids which are subsequently absorbed. Proteolytic enzymes involved in the degradation of orally administered immunoglobulins include pepsin, trypsin, chymotrypsin, carboxypeptidase and elastase. These enzymes initially degrade the antibodies to F(ab')2. Fab and Fc fragments. The F(ab')2 and Fab fragments, however, retain some of their neutralising activity locally in the gastrointestinal tract. Various approaches are possible to increase the stability of orally administered antibodies against proteolysis, including formulation in liposomes, coating with polymers and genetic engineering of resistant forms. The clinical application of orally administered antibodies includes the treatment and prevention of gastrointestinal infections caused by enteric pathogens such as rotavirus, Escherichia coli or Vibrio cholerae in susceptible individuals including those with immunodeficiency diseases and patients with bone marrow transplants. There is also a suggestion that such agents may be useful in preventing chemotherapy-induced gastrointestinal mucositis. Future opportunities for research include the design of oral dosage forms of antibodies which resist proteolysis and can deliver a greater fraction of immunoreactive antibody locally in the gastrointestinal tract for the treatment of infections or perhaps even to allow the absorption of antibodies for the treatment or prevention of systemic conditions.
Reilly
R M
RM
Division of Nuclear Medicine, Toronto Hospital, Ontario, Canada.
Domingo
R
R
Sandhu
J
J
D000284:Administration, Oral; D000906:Antibodies / Q000008:administration & dosage* / Q000378:metabolism; D004064:Digestive System / Q000187:drug effects / Q000378:metabolism; D005767:Gastrointestinal Diseases / Q000628:therapy; D005818:Genetic Engineering; D006801:Humans; D007116:Immunization, Passive; D007136:Immunoglobulins / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D066298:In Vitro Techniques; D007239:Infections / Q000628:therapy; D007413:Intestinal Mucosa / Q000473:pathology / Q000502:physiology; D010447:Peptide Hydrolases / Q000737:chemistry / Q000378:metabolism; D010455:Peptides / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*
D000906:Antibodies; D007136:Immunoglobulins; D010455:Peptides; D010447:Peptide Hydrolases