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The pharmacological basis of anti-IgE therapy

Nature Biotechnology volume 18, pages 157–162 (2000)Cite this article

Abstract

The treatment of asthma and allergic rhinitis using unique, humanized anti-IgE monoclonal antibodies with very particular binding specificities is now supported by the results of multiple phase II and III human clinical studies. The therapeutic efficacy of this approach is attributable to several pharmacological mechanisms. In addition to the expected effects of these monoclonal antibodies in neutralizing free IgE and inhibiting IgE production by B cells, several indirect biochemical and cellular effects have been uncovered during the course of the clinical trials. These include the accumulation of potentially beneficial IgE–anti-IgE immune complexes and the downregulation of the high-affinity IgE Fc receptors (FcɛRI) on basophils and mast cells. This article analyzes the structural basis of the specificity of the anti-IgE antibodies and pertinent results from in vitro experiments, animal model studies, and human clinical trials in an attempt to provide a cogent pharmacological interpretation of the therapeutic effects of anti-IgE therapy in both the near- and long term. The development of anti-IgE therapy over the past 10 years provides an interesting example of the emergence of a conceptually new, biotechnology-produced pharmaceutical.

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Figure 1
Figure 2: The relationship between binding sites for anti-IgE and FcɛRI or FcɛRII.
Figure 3: Probable largest stable structures of complexes formed by IgE and anti-IgE antibodies.
Figure 4: Kinetics of IgE and IgE–anti-IgE immune complexes.
Figure 5: The effect of continual anti-IgE treatment on accumulation of IgE–anti-IgE immune complexes and the downregulation of FcɛRI.

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References

  1. Janeway, C.A., Travers, P. & Walport, M. Immunobiology: the immune system in health and disease , Edn. 4 (Elsevier Science Ltd., London; 1999).

    Google Scholar 

  2. Carter, S.E. & Patts-Mills, T.A. Searching for the cause of the increase in asthma. Curr. Opin. Pediatr. 10, 594–599 (1998).

    Article  Google Scholar 

  3. Lundback, B. Epidemiology of rhinitis and asthma. Clin. Exp. Allergy 28 (suppl. 2), 3–10 ( 1998).

    PubMed  Google Scholar 

  4. Juniper, E.F. Quality of life in adults and children with asthma and rhinitis. Allergy 52, 971–977 ( 1997).

    Article  CAS  Google Scholar 

  5. Smith, D.H. et al. A national estimate of the economic costs of asthma. Am. J. Respir. Crit. Care Med. 156, 787–793 (1997).

    Article  CAS  Google Scholar 

  6. O'Hehir, R.E., Gamen, R.D., Greenstein, J.L. & Lamb, J.R. The specificity and regulation of T-cell responsiveness to allergens. Annu. Rev. Immunol. 9, 67–95 (1991).

    Article  CAS  Google Scholar 

  7. Durham, S.R. et al. Long-term clinical efficacy of grass pollen immunotherapy. N. Engl. J. Med. 341, 468–475 (1999).

    Article  CAS  Google Scholar 

  8. Davis, F.M. et al. Can anti-IgE be used to treat allergy? Springer Semin. Immunopathol. 15, 51–73 ( 1993).

    Article  CAS  Google Scholar 

  9. Heusser, C. & Jardieu, P. Therapeutic potential of anti-IgE antibodies. Curr. Opin. Immunol. 9, 805– 813 (1997).

    Article  CAS  Google Scholar 

  10. Corne, J. et al. The effect of intravenous administration of a chimeric anti-IgE antibody on serum IgE levels in atopic subjects: efficacy, safety, and pharmacokinetics . J. Clin. Invest. 99, 879– 887 (1997).

    Article  CAS  Google Scholar 

  11. Racine-Poon, A. et al. Clinical efficacy of CGP 51901, an anti-IgE chimeric monoclonal antibody, in patients with allergic rhinitis: is it related to the extent of IgE suppression and pharmacokinetics? Clin. Pharmcol. Ther. 62, 675–690 ( 1997).

    Article  CAS  Google Scholar 

  12. Kolbinger, F., Saldanha, J., Hardman, N. & Bendig, M.M. Humanization of a mouse anti-human IgE antibody: a potential therapeutic for IgE-mediated allergies. Protein Eng. 6, 971–980 (1993).

    Article  CAS  Google Scholar 

  13. Presta, L.G. et al. Humanization of an antibody directed against IgE. J. Immunol. 151, 2623–2632 ( 1993).

    CAS  PubMed  Google Scholar 

  14. Fahy, J.V. et al. The effect of an anti-IgE monoclonal antibody on the early- and late-phase responses to allergen inhalation in asthmatic patients. Am. J. Respir. Crit. Care Med. 155, 1824– 1834 (1997).

    Google Scholar 

  15. Boulet, L.P. et al. Inhibitory effects of an anti-IgE antibody E25 on allergen-induced early asthmatic response. Am. J. Respir. Crit. Care Med. 155, 1835–1840 (1997).

    Article  CAS  Google Scholar 

  16. Milgrom, E. et al. Treatment of allergic asthma with monoclonal anti-IgE antibody. N. Engl. J. Med. 341, 1966–1973 (1999).

    Article  CAS  Google Scholar 

  17. Adelroth, E. et al. RhuMAb-E25 treatment controls the symptoms of birch pollen induced scasonal allergic rhinitis adn reduces the treatment for rescue medication . Oral presentation at the 20th Nordic Congress of Allergology, Oslo, Norway, May 14, 1999.

  18. Demoly, P & Bousquet, J. Anti-IgE therapy for asthma. Am. J. Respir. Crit. Care Med. 155, 1825– 1827 (1997).

    Article  CAS  Google Scholar 

  19. Barnes, P.J. Anti-IgE antibody therapy for asthma. N. Engl. J. Med. 341, 2006–2008 (1999).

    Article  CAS  Google Scholar 

  20. Chang, T.W. Treating hypersensitivities with anti-IgE monoclonal antibodies that bind to IgE-expressing B cells but not to basophils. US Patent 5,543,144 (1996).

  21. Chang, T.W. et al. Monoclonal antibodies specific for human IgE-producing B cells: a potential therapeutic for IgE-mediated allergic diseases. Bio/Technology 8, 122–126 ( 1990).

    CAS  PubMed  Google Scholar 

  22. Bialy, H. Can antibodies to IgE act as anti-allergics? Bio/Technology 8, 96 (1990).

    Google Scholar 

  23. Hook, W.A., Zinsser, F.U., Berenstein, E.H. & Siraganian, R.P. Monoclonal antibodies defining epitopes on human IgE. Mol. Immunol. 28, 631–639 ( 1991).

    Article  CAS  Google Scholar 

  24. MacGlashan, D.W. Releasability of human basophils: cellular sensitivity and maximal histamine release are independent variables. J. Allergy Clin. Immunol. 91, 605–615 (1993).

    Article  Google Scholar 

  25. Helm, B. et al. Blocking of passive sensitization of human mast cells and basophil granulocytes with IgE antibodies by a recombinant human ɛ-chain fragment of 76 amino acids. Proc. Natl. Acad. Sci. USA 86, 9465 –9469 (1989).

    Article  CAS  Google Scholar 

  26. Nissim, A., Jouvin, M.H. & Eshhar, Z. Mapping of the high affinity Fc epsilon receptor binding site to the third constant domain of IgE. EMBO J. 10 , 101–107 (1991).

    Article  CAS  Google Scholar 

  27. Presta, L. et al. The binding site on human immunoglobulin E for its high affinity receptor . J. Biol. Chem. 269, 26368– 26373 (1994).

    CAS  PubMed  Google Scholar 

  28. Henry, A.J. et al. Participation of the N-terminal region of Cɛ3 in the binding of human IgE to its high-affinity receptor FcɛRI. Biochemistry 36, 15568–15578 ( 1997).

    Article  CAS  Google Scholar 

  29. Wright, J.D. & Lim, C. Prediction of an anti-IgE binding site on IgE. Protein Eng. 11, 421– 427 (1998).

    Article  CAS  Google Scholar 

  30. Zheng, Y., Shopes, B., Holowka, D. & Baird, B. Conformations of IgE bound to its receptor FcɛRI and in solution. Biochemistry 30, 9125–9132 ( 1991).

    Article  CAS  Google Scholar 

  31. Keown, M.B., Ghirlando, R., Mackay, G.A., Sutton, B.J. & Gould, H.J. Basis of the 1:1 stoichiometry of the high affinity receptor FcɛRI–IgE complex. Eur. Biophys. J. 25, 471–476 (1997).

    Article  CAS  Google Scholar 

  32. Sechi, S., Roller, P.P., Willette-Brown, J. & Kinet, J.P. A conformational rearrangement upon binding of IgE to its high affinity receptor . J. Biol. Chem. 271, 19256– 19263 (1996).

    Article  CAS  Google Scholar 

  33. Keown, M.B., Henry, A.J., Ghirlando, R., Sutton, B.J. & Gould, H.J. Thermodynamics of the interaction of human immunoglobulin E with its high-affinity receptor FcɛRI. Biochemistry 23, 8863–8869 (1998).

    Article  Google Scholar 

  34. Dierks, S.E. et al. The oligomeric nature of the murine FcɛRII/CD23. Implications for function. J. Immunol. 150, 2372– 2382 (1993).

    CAS  PubMed  Google Scholar 

  35. Sutton, B.J. & Gould, H.J. The human IgE network. Nature 366, 421–428 ( 1993).

    Article  CAS  Google Scholar 

  36. Stämpfli, M.R., Miescher, S., Aebischer, I., Zurcher, A.W. & Stadler, B.M. Inhibition of human IgE synthesis by anti-IgE antibodies requires divalent recognition. Eur. J. Immunol. 24, 2161–2167 ( 1994).

    Article  Google Scholar 

  37. Peng, C. et al. A new isoform of human membrane-bound IgE. J. Immunol. 148, 129–136 (1992).

    CAS  PubMed  Google Scholar 

  38. Reth, M. B-cell antigen receptors. Curr. Opin. Immunol. 6, 3–8 (1994).

    Article  CAS  Google Scholar 

  39. Miller, L., Blank, U., Metzger, H. & Kinet, J.P. Expression of high-affinity binding of human immunoglobulin E by transfected cells. Science 244, 334–337 ( 1989).

    Article  CAS  Google Scholar 

  40. Zetterstrom, O. & Johansson, S.G. IgE concentrations measured by PRIST in serum of healthy adults and in patients with respiratory allergy. A diagnostic approach. Allergy 36, 537–547 (1981).

    Article  CAS  Google Scholar 

  41. Warner, G.L. & Scott, D.W. A polyclonal model for B cell tolerance. Fc-dependent and Fc-independent induction of nonresponsiveness by pretreatment of normal splenic B cells with anti-Ig. J. Immunol. 146, 2185–2191 (1991).

    CAS  PubMed  Google Scholar 

  42. Eray, M. et al. Cross-linking of surface IgG induces apoptosis in a bcl-2 expressing human follicular lymphoma line of mature B cell phenotype. Int. Immunol. 6, 1817–1827 ( 1994).

    Article  CAS  Google Scholar 

  43. Heusser, C.H. et al. Demonstration of the therapeutic potential of non–anaphylactogenic anti-IgE antibodies in murine models of skin reaction, lung function and inflammation . Int. Arch. Allergy Immunol. 113, 231– 235 (1997).

    Article  CAS  Google Scholar 

  44. Haba, S. & Nisonoff, A. Effects of syngeneic anti-IgE antibodies on the development of IgE memory and on the secondary IgE response. J. Immunol. 152, 51–57 ( 1994).

    CAS  PubMed  Google Scholar 

  45. Manoney, D.G. et al. IDEC-C2B8: results of a phase I multiple-dose trial in patients with relapsed non-Hodgkin's lymphoma. J. Clin. Oncol. 15 , 3266–3274 (1997).

    Article  Google Scholar 

  46. Peeters, S.H. & Carter, B.G. Regulation of the IgE antibody response in mice. II. radioresistance of established IgE antibody production . Immunology 43, 25–32 (1981).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Vitetta, E.S. et al. Memory B and T cells. Ann. Rev. Immunol. 9 , 193–217 (1991).

    Article  CAS  Google Scholar 

  48. Haba, S. & Nisonoff, A. Effects of syngeneic anti-IgE antibodies on the development of IgE memory and on the secondary IgE response. J. Immunol. 152, 51–57 ( 1994).

    CAS  PubMed  Google Scholar 

  49. Ogawa, M. et al. Biologic properties of E myeloma proteins. Am. J. Med. 51, 193–199 (1971).

    Article  CAS  Google Scholar 

  50. Liu, J., Lester, P., Builder, S. & Shire, S.J. Characterization of complex formation by humanized anti-IgE monoclonal antibody and monoclonal human IgE. Biochemistry 34, 10474– 10482 (1995).

    Article  CAS  Google Scholar 

  51. Peng, Z.K., Naclerio, R.M., Norman, P.S. & Adkinson, N.F. Quantitative IgE- and IgG-subclass responses during and after long-term ragweed immunotherapy. J. Allergy Clin. Immunol. 89, 519–529 (1992).

    Article  CAS  Google Scholar 

  52. Chen, H.D. Chen, C.L. & Huang, S.W. Characterization of latex allergens and correlation of serum IgE/IgG antibody ratio with clinical symptoms. Allergy Asthma Proc. 17, 143–148 ( 1996).

    Article  CAS  Google Scholar 

  53. Celis, E. & Chang, T.W. Antibodies to hepatitis B surface antigen potentiate the response of human T lymphocyte clones to the same antigen . Science 224, 297–299 (1984).

    Article  CAS  Google Scholar 

  54. Liu, C., Gosselin, E.J. & Guyre, P.M. FcɛRII on human B cells can mediate enhanced antigen presentation. Cell Immunol. 167, 188–194 (1996).

    Article  CAS  Google Scholar 

  55. Muddle, G.C., Bheekha, R. & Bruijnzeel-Koomen, C.A. Consequences of IgE/CD23-mediated antigen presentation in allergy. Immunol. Today 16, 380– 383 (1995).

    Article  Google Scholar 

  56. Maurer, D. et al. The high affinity IgE receptor (FcɛRI) mediates IgE–dependent allergen presentation. J. Immunol. 154, 6285–6290 (1995).

    CAS  PubMed  Google Scholar 

  57. Malveaux, F.J., Conroy, M.C., Adkinson, N.F. & Lichtenstein, L.M. IgE receptors on human basophils. Relationship to serum IgE concentration . J. Clin. Invest. 62, 176– 181 (1978).

    Article  CAS  Google Scholar 

  58. MacGlashan, D.W. et al. Down-regulation of FcɛRI expression on human basophils during in vivo treatment of atopic patients with anti-IgE antibody. J. Immunol. 158, 1438–1445 (1997).

    CAS  PubMed  Google Scholar 

  59. MacGlashan, D.W et al. In vitro regulation of FcɛRIα expression on human basophils by IgE antibody. Blood 91, 1633–1643 (1998).

    CAS  PubMed  Google Scholar 

  60. Lantz, C.S. et al. IgE regulates mouse basophil FcɛRI expression in vivo. J. Immunol. 158, 2517–2521 (1997).

    CAS  PubMed  Google Scholar 

  61. LoBuglio, A.F. et al. Mouse/human chimeric monoclonal antibody in man: kinetics and immune response. Proc. Natl. Acad. Sci. USA 86, 4220–4224 (1989).

    Article  CAS  Google Scholar 

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  1. Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan

    Tse Wen Chang

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Chang, T. The pharmacological basis of anti-IgE therapy. Nat Biotechnol 18, 157–162 (2000). https://doi.org/10.1038/72601

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