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Clinical Pharmacokinetics

, Volume 32, Issue 4, pp 313–323 | Cite as

Oral Delivery of Antibodies

Future Pharmacokinetic Trends
  • Raymond M. Reilly
  • Rommel Domingo
  • Jasbir Sandhu
Review Article Drug Delivery Systems

Summary

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.

Keywords

Adis International Limited Chymotrypsin Bovine Milk Oral Delivery Oral Dosage Form 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Reilly RM, Sandhu J, Alvarez-Diez TM, et al. Problems of delivery of monoclonal antibodies: pharmaceutical and pharmacokinetic solutions. Clin Pharmacokinet 1995; 28: 126–42PubMedCrossRefGoogle Scholar
  2. 2.
    Haber E. In vivo diagnostic and therapeutic uses of monoclonal antibodies in cardiology. Annu Rev Med 1986; 37: 249–61PubMedCrossRefGoogle Scholar
  3. 3.
    Steplewski Z. Advances and outlooks for immunotherapy of cancer. Hybridoma 1993; 12: 493–500PubMedCrossRefGoogle Scholar
  4. 4.
    Guarino A, Canani RB, Russo S, et al. Oral immunoglobulins for treatment of acute rotaviral gastroenteritis. Pediatrics 1994; 93(1): 12–6PubMedGoogle Scholar
  5. 5.
    Morelli D, Menard S, Colnaghi MI, et al. Oral administration of anti-doxorubicin monoclonal antibody prevents chemotherapy-induced gastrointestinal toxicity in mice. Cancer Res 1996; 56: 2082–5PubMedGoogle Scholar
  6. 6.
    Van deGraaff KM. Anatomy and physiology of the gastrointestinal tract. Pediatr Infect Dis J 1986; 5: S11–6CrossRefGoogle Scholar
  7. 7.
    Britton JR, Koldovsky O. The development of luminal protein digestion: implications for biologically-active dietary polypeptides. J Pediatr Gastroenterol Nutr 1989; 9: 114–61CrossRefGoogle Scholar
  8. 8.
    Hatta H, Tsuda K, Akachi S, et al. Oral passive immunization effect of anti-human rotavirus IgY and its behaviour against proteolytic enzymes. Biosci Biotechnol Biochem 1993; 57(7): 1077–81PubMedCrossRefGoogle Scholar
  9. 9.
    Neu J. Functional development of the fetal gastrointestinal tract. Semin Perinatol 1989; 13: 224–35PubMedGoogle Scholar
  10. 10.
    Madsen JL. Gastrointestinal transit measurements: a scintigraphic method. Dan Med Bull 1994; 41: 398–411PubMedGoogle Scholar
  11. 11.
    Ritschel WA. Targeting in the gastrointestinal tract: new approaches. Methods Find Exp Clin Pharmacol 1991; 13: 313–36PubMedGoogle Scholar
  12. 12.
    Fallingborg J, Christensen LA, Ingeman-Nielsen M, et al. Measurement of gastrointestinal pH and regional transit times in normal children. J Pediatr Gastroenterol Nutr 1990; 11: 211–4PubMedCrossRefGoogle Scholar
  13. 13.
    Alpers DH, Johnson LR, editors. Digestion and absorption of carbohydrates and proteins. In: Physiology of the gastrointestinal tract. New York: Raven Press, 1987: 1469–87Google Scholar
  14. 14.
    Gardner MG. Intestinal assimilation of intact peptides and proteins from the diet: a neglected field? Biol Rev 1984; 59: 289–331PubMedCrossRefGoogle Scholar
  15. 15.
    Gardner MLG. Passage of intact peptides across the intestine. Adv Biosci 1987; 65: 99–106Google Scholar
  16. 16.
    Saffran M. Oral administration of peptides. Endocrinol Exp 1982; 16: 327–33PubMedGoogle Scholar
  17. 17.
    Warshaw AL, Walker WA, Isselbacher KJ. Protein uptake by the intestine: evidence for absorption of intact macromolecules. Gastroenterology 1974; 66: 987–92PubMedGoogle Scholar
  18. 18.
    Walker WA, Isselbacher KJ. Uptake and transport of macromolecules by the intestine: possible role in clinical disorders. Gastroenterology 1967; 67: 531–50Google Scholar
  19. 19.
    Hemmings WA, Williams EW. Transport of large breakdown products of dietary protein through the gut wall. Gut 1978; 19: 715–23PubMedCrossRefGoogle Scholar
  20. 20.
    Iyengar L, Selvaraj RJ. Intestinal absorption of immunoglobulins by newborn infants. Arch Dis Child 1972; 47: 411–7PubMedCrossRefGoogle Scholar
  21. 21.
    Petschow BW, Talbott RD. Reduction in virus-neutralizing activity of a bovine colostrum immunoglobulin concentrate by gastric acid and digestive enzymes. J Pediatr Gastroenterol Nutr 1994; 19(2): 228–35PubMedCrossRefGoogle Scholar
  22. 22.
    de Rham O, Isliker H. Proteolysis of bovine immunoglobulins. Int Arch Allergy Appl Immunol 1977; 55(1-6): 61–9PubMedCrossRefGoogle Scholar
  23. 23.
    Hilpert H, Brussow H, Mietens C, et al. Use of bovine milk concentrate containing antibody to rotavirus to treat rotavirus gastroenteritis in infants. J Infect Dis 1987; 156(1): 158–66PubMedCrossRefGoogle Scholar
  24. 24.
    Hatta H, Tsuda K, Sigemitu A, et al. Productivity and some properties of egg yolk antibody (IgY) against human rotavirus compared with rabbit IgG. Biosci Biotechnol Biochem 1993; 57(3): 450–4PubMedCrossRefGoogle Scholar
  25. 25.
    Shimizu M, Fitzsimmons RC, Nakai S. Anti-Zs. coli immunoglobulin Y isolated from egg yolk of immunized chickens as a potential food ingredient. J Food Sci 1988; 53(5): 1360–6CrossRefGoogle Scholar
  26. 26.
    Blum PM, Phelps DM, Ank BJ, et al. Survival of oral human immune serum immunoglobulin in the gastrointestinal tract of low birth weight infants. Pediatric Res 1981; 15(9): 1256–60CrossRefGoogle Scholar
  27. 27.
    Shimizu M, Nagashima H, Sano K, et al. Molecular stability of chicken and rabbit immunoglobulin G. Biosci Biotechnol Biochem 1992; 56(2): 270–4PubMedCrossRefGoogle Scholar
  28. 28.
    Eibl MM, Wolf HM, Furnkranz H, et al. Prevention of necrotizing enterocolitis in low-birth weight infants by IgA-IgG feeding. N Engl J Med 1988; 319(1): 1–7PubMedCrossRefGoogle Scholar
  29. 29.
    Zinkernagel RM. The digestion of colostral bovine immunoglobulins in infants. Experientia 1972; 28: 741CrossRefGoogle Scholar
  30. 30.
    Losonsky G, Johnson JP, Winkelstein JA, et al. Oral administration of human serum immunoglobulin in immunodeficient patients with viral gastroenteritis: a pharmacokinetic and functional analysis. J Clin Invest 1985; 76(6): 2362–7PubMedCrossRefGoogle Scholar
  31. 31.
    Roos N, Mahe S, Benamouzig R, et al. 15N-labeled immunoglobulins from bovine colostrum are partially resistant to digestion in human intestine. J Nutr 1995; 125(5): 1238–44PubMedGoogle Scholar
  32. 32.
    Martin MG, Wu SV, Ohning G, et al. Parenterally or enterally administered anti-somatostatin antibody induces increased gastrin in suckling rats. Am J Physiol 1994; 266 (3 Pt 1): G417–24PubMedGoogle Scholar
  33. 33.
    Shimizu M, Miwa Y, Hashimoto K, et al. Encapsulation of chicken egg yolk immunoglobulin G (IgY) by liposomes. Biosci Biotechnol Biochem 1993; 57(9): 1445–9PubMedCrossRefGoogle Scholar
  34. 34.
    Shimizu M, Nakane Y. Encapsulation of biologically active proteins in a multiple emulsion. Biosci Biotechnol Biochem 1995; 59(3): 492–6PubMedCrossRefGoogle Scholar
  35. 35.
    Cornes J. Number, size, and distribution of Peyer’s Patches in the human small intestine: II. The effect of aging on Peyer’s Patches. Gut 1965; 6: 230CrossRefGoogle Scholar
  36. 36.
    Heizer WD, Laster L. Peptide hydrolase activities of the mucosa of human small intestine. J Clin Invest 1969; 48: 210–28PubMedCrossRefGoogle Scholar
  37. 37.
    Sandhu JS. Protein engineering of antibodies. Crit Rev Biotechnol 1992; 12: 437–62PubMedCrossRefGoogle Scholar
  38. 38.
    Hozumi N, Sandhu JS. Recombinant antibody technology: its advent and advances. Cancer Invest 1993; 11: 714–23PubMedCrossRefGoogle Scholar
  39. 39.
    McCafferty J, Griffiths AD, Winter G, et al. Phage antibodies: filamentous phage displaying antibody variable domains. Nature 1990; 348: 552–4PubMedCrossRefGoogle Scholar
  40. 40.
    Sandhu JS. A simple and rapid method of humanisation of antibodies. Gene 1994; 150: 409–10PubMedCrossRefGoogle Scholar
  41. 41.
    Hammarstrom L, Gardulf A, Hammarstrom V, et al. Systemic and topical immunoglobulin treatment in immunocom-promised patients. Immunol Rev 1994; 139: 43–70PubMedCrossRefGoogle Scholar
  42. 42.
    Hilpert H, Gerber H, Amster H, et al. Bovine milk immunoglobulins (Ig), their possible utilization in industrially prepared infants’ milk formula. In: Hambraeus L, Hanson LA, McFarl-ane H, editors. Proceedings of a symposium of the Swedish Medical Research Council. Stockholm: Almqvist and Wiksell International, 1977: 182–96Google Scholar
  43. 43.
    Mietens A, Keinhorst H, Hilpert H, et al. Treatment of infantile E. coli gastroenteritis with specific bovine anti-E. coli milk immunoglobulins. Eur J Pediatr 1979; 132: 239PubMedCrossRefGoogle Scholar
  44. 44.
    Nord J, Ma P, DiJohn D, et al. Treatment with bovine hyperimmune colostrum of cryptosporidial diarrhea in AIDS patients. AIDS 1990; 4: 581–4PubMedCrossRefGoogle Scholar
  45. 45.
    Ungar BLP, Ward DJ, Fayer R, et al. Cessation of cryptosporidium-associated diarrhea in an acquired immunodeficiency syndrome patient after treatment with hyperimmune bovine colostrum. Gastroenterology 1990; 98: 486–9PubMedGoogle Scholar
  46. 46.
    Copelan EA, Avalos BR, Kapoor N, et al. Alternate applications of immunoglobulin following bone marrow transplantation. Semin Hematol 1992; 29 (3 Suppl. 2): 96–9PubMedGoogle Scholar
  47. 47.
    Copelan EA, Bechtel TP, Klein JP, et al. Controlled trial of orally administered immunoglobulin following bone marrow transplantation. Bone Marrow Transplant 1994; 13(1): 87–91PubMedGoogle Scholar
  48. 48.
    Hollwarth ME, Schuber P, Pfleger A, et al. Necrotising enterocolitis: results of surgery. Pediatr Surg Int 1992; 7: 421–7Google Scholar
  49. 49.
    Kanto WP, Wilson R, Ricketts RR. Management and outcome of NEC. Clin Pediatr 1985; 24: 79–82CrossRefGoogle Scholar
  50. 50.
    Lucas A, Cole TJ. Breast milk and neonatal necrotising enterocolitis. Lancet 1990; 336: 1519–23PubMedCrossRefGoogle Scholar
  51. 51.
    Wolf HM, Eibl MM. The anti-inflammatory effect of an oral immunoglobulin (IgA-IgG) preparation and its possible relevance for the prevention of necrotizing enterocolitis. Acta Pediatr 1994; 396 Suppl.: 37–40CrossRefGoogle Scholar
  52. 52.
    Chabner B A, Myers CE. Antitumour antibiotics. In: De Vita VT, Hellman S, Rosenberg SA, editors. Cancer principles and practice of oncology. Philadelphia: Lippincott, 1993: 374–84Google Scholar
  53. 53.
    Bernhisel-Broadbent J, Yolken RH, Sampson HA. Allergenicity of orally administered immunoglobulin preparation in food-allergic children. Pediatrics 1991; 87: 208–14PubMedGoogle Scholar

Copyright information

© Adis International Limited 1997

Authors and Affiliations

  • Raymond M. Reilly
    • 1
    • 3
  • Rommel Domingo
    • 1
  • Jasbir Sandhu
    • 2
  1. 1.Division of Nuclear MedicineThe Toronto HospitalTorontoCanada
  2. 2.Samuel Lunenfeld Research Institute, Mount Sinai HospitalTorontoCanada
  3. 3.Faculty of PharmacyUniversity of TorontoTorontoCanada

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