CIRCULATING ANTIBODIES TO ERYTHROPOIETIN ARE ASSOCIATED WITH LOWER EFFICACY OF RECOMBINANT EPOETIN TREATMENT IN PATIENTS UNDERGOING HAEMODIALYSIS

Biological preparations (BP) obtained by gene engineering possess a special characteristic called immunogenicity, i.e. propensity of biological drugs to induce an undesired immune response associated with arising anti-drug antibodies. These antibodies can change BP pharmacokinetics and pharmacodynamics, and therapeutical efficacy. A significant proportion of hemodialysis patients with end-stage renal disease treated by recombinant erythropoietin (rEPO) have clinical features of resistance to such therapy. The aim of the study was to investigate whether anti-rEPO antibodies are associated with hemoglobin concentrations (Hb) and red blood cells counts (RBC) in hemodialysis patients, receiving long-term rEPO therapy. This research was performed at the Research Institute of Nephrology at the First St. Petersburg I.Pavlov State Medical University. Thirty-seven hemodialysis patients (pts) with end-stage renal disease and anemia treated with different rEPO formulations were included into the study. The patients were further divided into two groups: those with diminished and normal clinical response to rEPO therapy (DCR, n = 21 vs NCR group, n = 16, respectively). To determine threshold levels of antibodies to rEPO-beta (Roche, Switzerland) we tested blood serum samples of 35 healthy blood donors who never received rEPO in the past. Concentration of antibodies was measured by means of dot-blot method. The threshold antibody concentrations were defined by measurement of anti-rEPO concentrations in 2-fold stepwise dilutions (1:10 to 1:200) of blood sera from 35 healthy donors .The threshold value for rEPO-binding antibodies was 20.27 µg/ml (95 CI%±0.43). Antibodies to rEPO were found in 54 % of serum samples in the patients. Anti-rEPO antibodies concentrations correlated with mean values of hemoglobin and erythrocyte counts over a period of 12-months for the entire group of hemodialysis patients (r = -0.368, p = 0.025 and r = -0.336, p = 0.042 respectively). Concentration of anti-rEPO antibodies, and the mean weekly rEPO dose were significantly higher in DCR group, compared to NCR group (p = 0.0019). In conclusion, higher levels of anti-rEPO binding antibodies seem to be associated with decreased therapeutic response to the clinically applied rEPO formulations.

1. Добронравов В.А., Смирнов А.В., Безруких А.М., Быстрова Н.Н., Дроздова Ю.В., Орлова С.А. Анемия и преддиализные стадии хронической болезни почек: клиническое значение, распространенность и факторы риска // Нефрология, 2006. Т. 10, № 3. С. 7-13. [Dobronravov V.A., Smirnov A.V., Bezrukikh A.M., Bystrova N.N., Drozdova Yu.V., Orlova S.A. Anemia and pre-dialysis stages of chronic kidney disease: clinical significance, incidence and risk factors. Nefrologiya = Nephrology, 2006, Vol. 10, no. 3, pp. 7-13. (In Russ.)]

2. Лапин С.В., Тотолян А.А. Иммунологическая диагностика поражений почек при васкулитах // Нефрология, 2003. Т. 7, № 1. С. 109-119. [Lapin S.V., Totolian A.A. Immunological diagnosis of lesions to the kidneys with vasculites. Nefrologiya = Nephrology, 2003, Vol. 7, no. 1, pp. 109-119. (In Russ.)]

3. Назаров В.Д., Лапин С.В.,Мазинг А.В., Евдошенко Е.П., Тотолян А.А. Проблема иммуногенности генно-инженерных лекарственных препаратов интерферона-бета // Биохимия, 2016. Т. 81, вып. 11. С. 1658-1664. [Nazarov V.D., Lapin S.V., Mazing A.V., Evdoshenko E.P., Totolian A.A. Immunogenicity of human recombinant interferon-beta. Biohimiya = Biochemistry, 2016, Vol. 81, Iss. 11, pp. 1658-1664. (In Russ.)]

4. Alqahwaji D.B., Shubair M.E., Sirdah M. Detection of anti-erythropoietin antibodies among hemodialyzed patients treated with recombinant human-erythropoietin. Sky Journal of Medicines and Medical Sciences, 2014, Vol. 2, no. 4, pp. 016-020.

5. Alves M.D., Simone S. Resistance of dialyzed patients to erythropoietin. Rev. Bras. Hematol. Hemoter., 2015, Vol. 37, no. 3, pp. 190-197.

6. Castelli G., Famularo A., Semino C., Machi A.M., Ceci A., Cannella G., Melioli G. Detection of anti-erythropoietin antibodies in haemodialysis patients treated with recombinant human-erythropoietin. Pharmacological Research, 2000, Vol. 41, no. 3, pp. 313-318.

7. Colombel J.F., Feagan B.G., Sandborn W.J., van Assche G., Robinson A.M. Therapeutic Drug monitoring of biologics for inflammatory bowel disease. Inflamm. Bowel Dis., 2012, Vol. 18, no. 2, pp. 349-358.

8. El-Din M., Attia F., Labib S., Omar W. Detection of circulating antierythropoietin antibodies in patients with end stage renal disease on regular hemodialysis. Int. J. Lab. Hematol., 2010, Vol. 32, no. 3, pp. 336-343.

9. Howman R., Kulkarni H. Antibody-mediated acquired pure red cell aplasia (PRCA) aſter treatment with darbepoetin. Nephrol. Dial. Transplant., Vol. 22, no. 5, pp. 1462-1464.

10. Praditpornsilpa K., Tiranathanagul K., Kupatawintu P., Jootar S., Intragumtornchai T., Tungsanga K., Teerapornlertratt T., Lumlertkul D., Townamchai N., Susantitaphong P., Katavetin P., Kanjanabuch T., Avihingsanon Y., Eiam-Ong S. Biosimilar recombinant human erythropoietin induces the production of neutralizing antibodies. Kidney Int., 2011, Vol. 80, no. 1, pp. 88-92.

11. Rader R. Redefining biopharmaceutical. Nat. Biotechnol., 2008, Vol. 26. no. 7, pp. 743-751.

12. Öztürk S., Gümüş A., Memili V., Düz M.E., Cebeci E., Koldaş M., Kazancioğlu R. Antierythropoietin antibodies in hemodialysis patients treated with recombinant erythropoietin. The Turkish Nephrology, Dialysis and Transplantation Journal, 2014, Vol. 23, no. 2, pp. 125-130.

13. van Beers M.M.C., Bardor M. Minimizing immunogenicity of biopharmaceuticals by controlling critical quality attributes of proteins. Biotechnol. J., 2012, Vol. 7, pp. 1473-1484.

14. Wadhwa M., Knezevic I., Kang H.N., Thorpe R. Immunogenicity assessment of biotherapeutic products: An overview of assays and their utility. Biologicals, 2015, Vol. 43, no. 5, pp. 298-306.

15. Zoccali C., Abramowicz D., Cannata-Andia J.B., Cochat P., Covic A., Eckardt K.U., Fouque D., Heimburger O., McLeod A., Lindley E., Locatelli F., Spasovski G., Tattersall J., van Biesen W., Wanner C., Vanholder R. European Best Practice Guidelines; European Renal Best Practice. European best practice quo vadis? From European best practice guidelines (EBPG) to European renal best practice (ERBP). Nephrol. Dial. Transplant., 2008, Vol. 23, no. 7, pp. 2162-2166.