Structure-Immunogenicity Relationships of Therapeutic Proteins
Rent the article at a discountRent now
* Final gross prices may vary according to local VAT.Get Access
As more recombinant human proteins become available on the market, the incidence of immunogenicity problems is rising. The antibodies formed against a therapeutic protein can result in serious clinical effects, such as loss of efficacy and neutralization of the endogenous protein with essential biological functions. Here we review the literature on the relations between the immunogenicity of the therapeutic proteins and their structural properties. The mechanisms by which protein therapeutics can induce antibodies as well as the models used to study immunogenicity are discussed. Examples of how the chemical structure (including amino acid sequence, glycosylation, and pegylation) can influence the incidence and level of antibody formation are given. Moreover, it is shown that physical degradation (especially aggregation) of the proteins as well as chemical decomposition (e.g., oxidation) may enhance the immune response. To what extent the presence of degradation products in protein formulations influences their immunogenicity still needs further investigation. Immunization of transgenic animals, tolerant for the human protein, with well-defined, artificially prepared degradation products of therapeutic proteins may shed more light on the structure-immunogenicity relationships of recombinant human proteins.
- G. Schernthaner. Immunogenicity and allergenic potential of animal and human insulins. Diabetes Care 16:155-165 (1993).
- G. Walsh. Pharmaceutical biotechnology products approved within the European Union. Eur. J. Pharm. Biopharm. 55:3-10 (2003).
- F. Adair and D. Ozanne. The immunogenicity of therapeutic proteins. BioPharm February:30-36 (2002).
- H. F. Bunn. Drug-induced autoimmune red-cell aplasia. N. Engl. J. Med. 346:522-523 (2002).
- N. Casadevall, J. Nataf, B. Viron, A. Kolta, J. J. Kiladjian, P. Martin-Dupont, P. Michaud, T. Papo, V. Ugo, I. Teyssandier, B. Varet, and P. Mayeux. Pure red-cell aplasia and antierythropoietin antibodies in patients treated with recombinant erythropoietin. N. Engl. J. Med. 346:469-475 (2002).
- S. K. Gershon, H. Luksenburg, T. R. Cote, and M. M. Braun. Pure red-cell aplasia and recombinant erythropoietin. N. Engl. J. Med. 346:1584-1586 (2002).
- M. F. Bachmann, U. H. Rohrer, T. M. Kundig, K. Burki, H. Hengartner, and R. M. Zinkernagel. The influence of antigen organization on B cell responsiveness. Science 262:1448-1451 (1993).
- N. R. Pritchard and K. G. Smith. B cell inhibitory receptors and autoimmunity. Immunology 108:263-273 (2003).
- B. Chackerian, P. Lenz, D. R. Lowy, and J. T. Schiller. Determinants of autoantibody induction by conjugated papillomavirus virus-like particles. J. Immunol. 169:6120-6126 (2002).
- F. Matesanz and A. Alcina. Induction of autoantibodies to different interleukin-2 allotypes. J. Autoimmun. 12:221-227 (1999).
- M. Van Ghelue, U. Moens, S. Bendiksen, and O. P. Rekvig. Autoimmunity to nucleosomes related to viral infection: a focus on hapten-carrier complex formation. J. Autoimmun. 20:171-182 (2003).
- J. L. Ottesen, P. Nilsson, J. Jami, D. Weilguny, M. Duhrkop, D. Bucchini, S. Havelund, and J. M. Fogh. The potential immunogenicity of human insulin and insulin analogues evaluated in a transgenic mouse model. Diabetologia 37:1178-1185 (1994).
- A. V. Palleroni, A. Aglione, M. Labow, M. J. Brunda, S. Pestka, F. Sinigaglia, G. Garotta, J. Alsenz, and A. Braun. Interferon immunogenicity: preclinical evaluation of interferon-alpha 2a. J. Interferon Cytokine Res. 17:S23-S27 (1997).
- T. A. Stewart, P. G. Hollingshead, S. L. Pitts, R. Chang, L. E. Martin, and H. Oakley. Transgenic mice as a model to test the immunogenicity of proteins altered by site-specific mutagenesis. Mol. Biol. Med. 6:275-281 (1989).
- C. M. Zwickl, K. S. Cocke, R. N. Tamura, L. M. Holzhausen, G. T. Brophy, P. H. Bick, and D. Wierda. Comparison of the immunogenicity of recombinant and pituitary human growth hormone in rhesus monkeys. Fundam. Appl. Toxicol. 16:275-287 (1991).
- A. Braun, L. Kwee, M. A. Labow, and J. Alsenz. Protein aggregates seem to play a key role among the parameters influencing the antigenicity of interferon alpha (IFN-alpha) in normal and transgenic mice. Pharm. Res. 14:1472-1478 (1997).
- M. Brickelmaier, P. S. Hochman, R. Baciu, B. Chao, J. H. Cuervo, and A. Whitty. ELISA methods for the analysis of antibody responses induced in multiple sclerosis patients treated with recombinant interferon-beta. J. Immunol. Methods 227:121-135 (1999).
- E. Hochuli. Interferon immunogenicity: technical evaluation of interferon-alpha 2a. J. Interferon Cytokine Res. 17:S15-S21 (1997).
- P. Fireman, S. E. Fineberg, and J. A. Galloway. Development of IgE antibodies to human (recombinant DNA), porcine, and bovine insulins in diabetic subjects. Diabetes Care 5:119-125 (1982).
- S. E. Fineberg, J. A. Galloway, and N. S. Fineberg. J. Goldman. Effects of species of origin purification levels and formulation on insulin immunogenicity. Diabetes 32:592-599 (1983).
- X. Du and J. G. Tang. Effects of deleting A19 tyrosine from insulin. Biochem. Mol. Biol. Int. 44:507-513 (1998).
- H. Lis and N. Sharon. Protein glycosylation. Structural and functional aspects. Eur. J. Biochem. 218:1-27 (1993).
- C. F. Goochee and T. Monica. Environmental effects on protein glycosylation. Biotechnology (N Y) 8:421-427 (1990).
- J. G. Gribben, S. Devereux, N. S. Thomas, M. Keim, H. M. Jones, A. H. Goldstone, and D. C. Linch. Development of antibodies to unprotected glycosylation sites on recombinant human GM-CSF. Lancet 335:434-437 (1990).
- G. R. Adolf, I. Kalsner, H. Ahorn, I. Maurer-Fogy, and K. Cantell. Natural human interferon-alpha 2 is O-glycosylated. Biochem. J. 276:511-518 (1991).
- P. Kontsek, H. Liptakova, and E. Kontsekova. Immunogenicity of interferon-alpha 2 in therapy: structural and physiological aspects. Acta Virol. 43:63-70 (1999).
- C. B. Colby, M. Inoue, M. Thompson, and Y. H. Tan. Immunologic differentiation between E. coli and CHO cell-derived recombinant and natural human beta-interferons. J. Immunol. 133:3091-3095 (1984).
- D. Bhadra, S. Bhadra, P. Jain, and N. K. Jain. Pegnology: a review of PEG-ylated systems. Pharmazie 57:5-29 (2002).
- F. F. Davis. The origin of pegnology. Adv. Drug Deliv. Rev. 54:457-458 (2002).
- F. M. Veronese. Peptide and protein PEGylation: a review of problems and solutions. Biomaterials 22:405-417 (2001).
- K. Rajender Reddy, M. W. Modi, and S. Pedder. Use of peginterferon alfa-2a (40 KD) (Pegasys) for the treatment of hepatitis C. Adv. Drug Deliv. Rev. 54:571-586 (2002).
- C. M. Perry and B. Jarvis. Peginterferon-alpha-2a (40 kD): a review of its use in the management of chronic hepatitis C. Drugs 61:2263-2288 (2001).
- K. D. Hinds and S. W. Kim. Effects of PEG conjugation on insulin properties. Adv. Drug Deliv. Rev. 54:505-530 (2002).
- D. C. Robbins, S. M. Cooper, S. E. Fineberg, and P. M. Mead. Antibodies to covalent aggregates of insulin in blood of insulin-using diabetic patients. Diabetes 36:838-841 (1987).
- J. C. Ryff. Clinical investigation of the immunogenicity of interferon-alpha 2a. J. Interferon Cytokine Res. 17:S29-S33 (1997).
- W. V. Moore and P. Leppert. Role of aggregated human growth hormone (hGH) in development of antibodies to hGH. J. Clin. Endocrinol. Metab. 51:691-697 (1980).
- M. Xie and R. L. Schowen. Secondary structure and protein deamidation. J. Pharm. Sci. 88:8-13 (1999).
- M. C. Lai and E. M. Topp. Solid-state chemical stability of proteins and peptides. J. Pharm. Sci. 88:489-500 (1999).
- J. L. Cleland, M. F. Powell, and S. J. Shire. The development of stable protein formulations: a close look at protein aggregation, deamidation, and oxidation. Crit. Rev. Ther. Drug Carrier Syst. 10:307-377 (1993).
- H. T. Wright. Sequence and structure determinants of the nonenzymatic deamidation of asparagine and glutamine residues in proteins. Protein Eng. 4:283-294 (1991).
- W. Chen, N. J. Ede, D. C. Jackson, J. McCluskey, and A. W. Purcell. CTL recognition of an altered peptide associated with asparagine bond rearrangement. Implications for immunity and vaccine design. J. Immunol. 157:1000-1005 (1996).
- H. Schellekens. Bioequivalence and the immunogenicity of biopharmaceuticals. Nat. Rev. Drug Discov. 1:457-462 (2002).
- R. E. Chance, E. P. Kroeff, J. A. Hoffmann, and B. H. Frank. Chemical, physical, and biologic properties of biosynthetic human insulin. Diabetes Care 4:147-154 (1981).
- Structure-Immunogenicity Relationships of Therapeutic Proteins
Volume 21, Issue 6 , pp 897-903
- Cover Date
- Print ISSN
- Online ISSN
- Kluwer Academic Publishers-Plenum Publishers
- Additional Links
- animal models
- protein structure
- therapeutic proteins
- Industry Sectors
- Author Affiliations
- 1. Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht, The Netherlands
- 2. Central Laboratory Animal Institute, Utrecht University, Utrecht, The Netherlands