4 . 2019

The problems connected with unwanted immunogenicity of biotechnological medicines (therapeutic proteins). Part 2. Clinical aspects

Abstract

Biotechnological medicines, the so-called therapeutic proteins in some patients can cause the development of an immune response, which may not be clinically manifested or provoke immune-mediated adverse reactions. Manifestations of the unwanted immunogenicity of therapeutic proteins depends on the properties of the medicine, characteristics of the patient and the underlying disease, as well as on the dosage, dosing schedule, the route of administration of the drug, concomitant therapy, etc. The review provides information on the clinical manifestations of the immune response to therapeutic protein, its consequences on pharmacokinetics, safety and efficacy of the medicine. The information on the principles of immunogenicity study and risk assessment of unwanted immune response at the stage of development, preclinical and clinical studies and after medicine marketing authorization is given.

Keywords:immunogenicity; therapeutic proteins; biotechnological medicines; anti-drug antibodies; risk of development of the immuno-mediated adverse effect; clinical consequences of the immune response; efficacy and safety

Received 24.05.2019 Accepted 16.06.2019

For citation: Avdeeva Zh.I., Soldatov A.A., Mosyagin V.D., Medunitsyn N.V. The problems connected with unwanted immunogenicity of biotechnological medicines (therapeutic proteins). Part 2. Clinical aspects. Immunologiya. 2019; 40 (4): doi: 10.24411/0206-4952-2019-14004.

Acknowledgements. The work performed within the state task of Scientific Centre for Expert Evaluation of Medicinal Products No. 056-00154-19-00 to conduct applied scientific research (the number of state accounting research – AAAA-A18-118021590046-9).

Conflict of interest. The authors declare no conflict of interests.

References

1. Sigidin Ya.A., Lukina G.V. Biological therapy inrheumatology. Moscow: Prakticheskaya Meditsina, 2009. (in Russian)

2. Nasonov E.L., Denisov L.N., Stanislav M.L., Ilina A.E. Prospects of pharmacotherapy of rheumatoid arthritis: monoclonal antibodies. Prakticheskaya revmatologiya. 2012; 52 (3): 75-82. (in Russian)

3. Moiseenko V.M. Features of monoclonal antibodies inthetreatment of malignant tumors. Prakticheskaya onkologiya. 2002; 3 (4): 253-61. (in Russian)

4. Nuriev R.I., Karaulov A.V., Kisielewski M.V. Novel treatment strategies for patients with cancer: immunotherapeutic approach. Immunologiya. 2017; 38 (1): 39-48. (in Russian)

5. Merelli B., Massi D., Cattaneo L., Mandala M. Targeting the PD1/PD-L1 axis in melanoma: biological rationale, clinical challenges and opportunities. Crit. Rev. Oncol. Hematol. 2014; 89 (1): 140-65.

6. Quesada S., Peggs K. Exploiting CTLA-4, PD-1 and PD-L1 to reactivate the host immune response against cancer. Br. J. Cancer. 2013; 108: 1560-5.

7. Maio M., Grob J.J., Aamdal S., Bondarenko I., et al. Five-year survival rates for treatment-naive patients with advanced melanoma who received ipilimumab plus dacarbazine in a phase III trial. J. Clin. Oncol. 2015; 33 (10): 1191-6.

8. Garnock-Jones K.P. Secukinumab: a review in moderate to severe plaque psoriasis. Am. J. Clin. Dermatol. 2015; 16 (4): 323-30.

9. Carrascosa J.M. Immunogenicity in biologic therapy: implications for dermatology. Actas Dermosifiliogr. 2013; 104.(6): 471-9.

10. Wolbink G.J., Vis M., Lems W., Voskuyl A.E., et al. Development of antiinfliximab antibodies and relationship to clinical response in patients with rheumatoid arthritis. Arthritis Rheum. 2006; 54: 711-5.

11. Wyneski M.J., Green A., Kay M., Wyllie R., et al.Safety and efficacy of adalimumab in pediatric patients with Crohn disease. J. Pediatr. Gastrointerol. Nutr. 2008; 47: 19-25.

12. de Vries M.K., Wolbink G.J., Stapel S.O., de Vrieze H., et al. Decreased clinical response to infliximab in ankylosing spondylitis is correlated with anti-infliximab formation. Ann. Rheum. Dis. 2007; 66: 1252-4.

13. DiMichele D. Inhibitor development in hemophilia B: an orphan disease in need of attention. Br. J. Haematol. 2007; 138 (3): 303-15.

14. West R.L., Zelinkova Z., Wolbink G.J., Kuipers E.J., et al. Immunogenicity negatively influences the outcome of adalimumab treatment in Crohn’s disease. Aliment. Pharmacol. Ther. 2008; 28: 1122-6.

15. Bartelds G.M., Krieckaert C.L., Nurmohamed M.T., van Schouwenburg P.A., et al. Development of antidrug antibodies against adalimumab and association with disease activity and treatment failure during long-term follow-up. JAMA. 2011; 305: 1460-8.

16. Avdeeva Zh.I., Alpatova N.A., Soldatov A.A., Bondarev V.P., et al. The safety of medicinal products monoclonal antibodies, associated with the manifestation of their immunogenicity. Immunologiya. 2015; 36 (4): 247-56. (in Russian)

17. Hwang W.Y., Foote J. Immunogenicity of engineered antibodies. Methods. 2005; 36: 3-10.

18. Hermeling S., Crommelin D.J.A., Schellekens H., Jiskoot W. Structure-immunogenicity relationships of therapeutic proteins. Pharm. Res. 2004; 21: 897-903.

19. Rosenberg A.S. Effects of protein aggregates: an immunologic perspective. AAPS J. 2006; 8 (3): E501-8.

20. Koren E., Zuckerman L.A., Mire-Sluis A.R. Immune responses to therapeutic proteins in humans-clinical significance, assessment and prediction. Curr. Pharm. Biotechnol. 2002; 3: 349-60.

21. Buttel I.C., Chamberlain P., Chowers Y., Ehmann F., et al. Taking immunogenicity assessment of therapeutic proteins to the next level. Biologicals. 2011; 39: 100-9.

22. Soldatov A.A., Avdeeva Zh.I., Medunicyn N.V., Kryuchkov N.A. Mechanisms of development of an undesirable immune response when using biotechnological drugs. Immunologiya. 2017; 38 (5): 271-83. (in Russian)

23. Avdeeva Zh. I., Soldatov A.A., Bondarev V.P., Merkulov V.A., et al. The problems connected with undesirable immunogenicity of biotechnological medicines (therapeutic proteins) message 1. Methodological approaches to the assessment of immunogenicity. Immunologiya. 2019; 40 (3): 51-64. (in Russian)

24. Suntharalingam G., Perry M.R., Ward S., Brett S.J., et al. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N. Engl. J. Med. 2006; 355: 1018-28.

25. Kang S.P. Salf M.W. Infusion-related and hypersensitivity reactions of monoclonal antibodies used to treat colorectal cancer - identification, prevention and management. J. Support. Oncol. 2007; 5: 451-7.

26. García-Nares H., Leyva-Carmona M.I., Pérez-Xochipa N., Chiquete E. Hypersensitivity reaction to a biosimilar insulin glargine. J. Diabetes. 2014; 7: 155-7.

27. Guideline for the examination of drugs. Vol. I. Moscow: Grif i K, 2013. (in Russian)

28. Guideline on immunogenicity assessment of biotechnology-derived therapeutic proteins (EMEA/CHMP/BMWP/14327/2006). London: European Medicines Agency, January 2007.

29. Guideline on the quality, safety, and efficacy of biotherapeutic protein products prepared by recombinant DNA technology. Replacement of Annex 3 of WHO Technical Report Series, No. 814. World Health Organization, October 2013.

30. Hwang W.Y., Foote J. Immunogenicity of engineered antibodies. Methods. 2005; 36: 3-10.

31. Guideline for conducting clinical trials of drugs. Part I. Moscow: Grif i K, 2012. (in Russian)

32. Guidelines for good clinical practice (GCP) for trials on pharmaceutical product. Annex 3 in WHO Expert Committee on Selection and Use of Essential Medicines. Sixth Report. Geneva: World Health Organization, 1995 (WHO Technical Report Series, No. 850).

33. ICH E6 guideline. Guideline for good clinical practice. Geneva: International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 1996.

34. Guideline for the examination of drugs. Vol. III. Moscow: POLIGRAF-PLYUS, 2014. (in Russian)

35. Guideline on immunogenicity assessment of monoclonal antibodies intended for in vivo clinical use (EMA/CHMP/BMWP/86289/2010). London: European Medicines Agency, 2012.

36. Rules of research of biological medicines of the Eurasian economic Union. Decision of the Council of the Eurasian economic Commission No. 89 dated 03.11.2016. Moscow, 2016. (in Russian)

37. ICH S6(R1) Guideline. Preclinical safety evaluation of biotechnology-derived pharmaceuticals. Geneva : International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2011.

38. Bugelski P.J., Treacy G. Predictive power of preclinical studies in animals for the immunogenicity of recombinant therapeutic proteins in humans. Curr. Opin. Mol. Ther. 2004; 6 (1): 10-6.

39. Swanson S.J., Bussiere J. Immunogenicity assessment in non-clinical studies. Curr. Opin. Microbiol. 2012; 15: 337-47.

40. Hanke T. Lssons from TGN1412. Lancet. 2006; 368: 1569-70.

41. St Clair E.W. The calm after the cytokine storm: lessons from the TGN1412 trail. J. Clin. Invest. 2008; 118: 1344-7.

42. Guideline for the examination of drugs. Vol. IV. Moscow: POLIGRAF-PLYUS. 2014. (in Russian)

43. The European Medicines Agency. Similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues (EMEA/CHMP/BMWP/49348/2005).

44. The European Medicines Agency. Guideline on similar biological medicinal products containing monoclonal antibodies - non-clinical and clinical issues - (EMA/CHMP/BMWP/403543/2010). 2012.

45. Guidance for Industry. Scientific considerations in demonstrating biosimilarity to a reference product. U.S. Department of Health and Human Services Food and Drug Administration. Biosimilarity, February 2012.

46. Guidelines on evaluation of similar biotherapeutic products (SBPs). Annex 2. WHO Technical Report Series No. 977, 2013.

47. Guideline on immunogenicity assessment of therapeutic proteins (EMEA/CHMP/BMWP/14327/2006 Rev 1) Committee for Medicinal Products for Human Use (CHMP), 18 May 2017.

48. Guideline on bioanalytical method validation (EMEA/CHMP/EWP/192217/2009 Rev. 1 Corr.).

49. ICH Harmonized Tripartite Guideline: validation of analytical procedures: text and methodology Q2(R1). 2005.

50. Soldatov A.A., Avdeeva J.I., Kryuchkov N.A., Skosyreva E.S. Safety concerns of biosimilar hormone products. Curr. Med. Res. Opin. 2019; 35 (6): 1003-9.

51. Calvez T., Chambost H., Claeyssens-Donadel S., d’Oiron R., Goulet V., et al. Recombinant factor VIII products and inhibitor development in previously untreated boys with severe hemophilia A. Blood. 2014; 27; 124 (23): 3398-408.

52. DiMichele D. Inhibitor development in hemophilia B: an orphan disease in need of attention. Br. J. Haematol. 2007; 138 (3): 303-15.

53. Agostini D., Rosset C., Botton M.R., Kappel D.B., et al. Immune system polymorphisms and factor VIII inhibitor formation in Brazilian haemophilia A severe patients. Haemophilia. 2012; 18 (suppl. 6): 416-28.

54. Boven K., Knight J., Bader F., Rosser J., et al. Epoetin-associated pure red cell aplasia in patients with chronic kidney disease: solving the mystery. Nephrol. Dial. Transplant. 2005; 20 (suppl. 3): 33-40.

55. Seidl A., Hainzl O., Richter M., Fischer R., et al. Tungsten-induced denaturation and aggregation of epoetin alfa during primary packaging as a cause of immunogenicity. Pharm. Res. 2012; 29 (6): 1454-67.

56. Kenter M.J., Cohen A.F. Establishing risk of human experimentation with drugs: lessons from TGN1412. Lancet. 2006; 368: 1387-91.

57. Dayan C.M., Wraith D.C. Preparing for first-in-man studies: the challenges for translational immunology post - TGN1412. Clin. Exp. Immunol. 2008; 151: 231-4.

58. Bugelski P.J., Achuthanandam R., Capocasale R.J., Treacy G., et al. Monoclonal antibody-induced cytokine-release syndrome. Expert Rev. Clin. Immunol. 2009; 5 (5): 499-521.

59. Kang P., Saif M. Infusion-related and hypersensitivity reactions of monoclonal antibodies used to treat colorectal cancer - identification, prevention, and management. J. Support. Oncol. 2007; 5: 451-57.

60. Rup B., Pallardy M., Sikkema D., Albert T., et al. Standardizing terms, definitions and concepts for describing and interpreting unwanted immunogenicity of biopharmaceuticals: recommendations of the Innovative Medicines Initiative ABIRISK consortium. Clin. Exp. Immunol. 2015; 181: 385-400.

61. Shankar G., Arkin S., Cocea L., Devanarayan V., et al. Assessment and reporting of the clinical immunogenicity of therapeutic proteins and peptides-harmonized terminology and tactical recommendations. AAPS J. 2014; 16: 658-73/

62. ICH Q5E Guideline. Comparability of biotechnological/biological products subject to changes in their manufacturing process. Geneva: International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2004.

63. Guideline on comparability of biotechnology-derived medicinal products after a change in the manufacturing process - non-clinical and clinical issues. (EMEA/CHMP/BMWP/101695/2006). London: European Medicines Agency. 2007.

64. Macdonald J.C., Hartman H., Jacobs I.A. Regulatory considerations in oncologic biosimilar drug development. mAbs. 2015; 7 (4): 653-61.