Pharmacodynamics of CNTO 530 and Darbepoetin-α in Human TNF-α Transgenic Mice, a Murine Model of Anemia of Chronic Disease

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DOI: 10.4236/pp.2011.21003   PDF   HTML     3,933 Downloads   8,688 Views   Citations

Abstract

CNTO 530 and darbepoetin-a are long lived erythropoietin receptor agonists (ERAs). Clinically, anemia of chronic disease (ACD) is associated with increased expression of tumor necrosis factor-a (TNF-a) and mice transgenic for human TNF-a develop ACD. The purpose of this investigation was to compare the effects of these agents in a murine model of ACD. Human TNF-a expressing (Tg 197) mice were administered a single subcutaneous dose of CNTO 530 or darbepoetin-a and the pharmacodynamic response in bone marrow spleen and peripheral blood evaluated. RBC life span and reticulocyte age distribution were also evaluated. CNTO 530 induced a dose responsive increase in reticulocytes, RBCs and Hgb in both wild type and Tg197 mice. Although the reticulocyte response was similar to wild types, the RBC and Hgb response to CNTO 530 in Tg197 mice was blunted. There was no statistically significant difference in RBC life span with either compound. Darbepoetin-α caused a greater peak in % dead Pro/basophilic erythroblasts, greater peak EMH in the spleen and a greater increase in reticulocyte maturation time. In contrast, despite a similar peak increase, CNTO 530 caused a more sustained response of reticulocyte, EMH, RBC and Hgb, consistent with increased exposure. In conclusion, CNTO 530 and darbepoetin-a increased RBC and hemoglobin in a murine model of ACD. Compared to darbepoetin-a, CNTO 530 had a more sustained effect, consistent with increased exposure.

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R. Achuthanandam, D. Makropoulos, L. Johns, A. Volk, K. Brosnan, J. Lu, W. Krzyzanski and P. Bugelski, "Pharmacodynamics of CNTO 530 and Darbepoetin-α in Human TNF-α Transgenic Mice, a Murine Model of Anemia of Chronic Disease," Pharmacology & Pharmacy, Vol. 2 No. 1, 2011, pp. 17-30. doi: 10.4236/pp.2011.21003.

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1] G. S. Alarcon, “Epidemiology of Rheumatoid Arthritis,” Rheumatologic Disease Clinics of North America, Vol. 21, No. 3, 1995, pp. 589-604.
[2] K. C. Das and M. A. Sattar, “Serum and Red Cell Ferritin Content in the Evaluation of Iron Status in Rheumatoid Arthritis,” Scandinavian Journal of Rheumatology, Vol. 18, 1989, pp. 399-405. doi:10.3109/03009748909102102
[3] P. P. Sfikakis and G. Kollias, “Tumor Necrosis Factor Biology in Experimental and Clinical Arthritis,” Current Opinion in Rheumatology, Vol. 2003, No. 15, 2005, pp. 380-386.
[4] M. Jongen-Lavrencic, H. R. Peeters, A. Wognum, G. Vreugdenhil, F. C. Breedveld and A. J. Swaak, “Elevated Levels of Inflammatory Cytokines in Bone Marrow of Patients with Rheumatoid Arthritis and Anemia of Chronic Disease,” Journal of Rheumatology, Vol. 24, No. 8, 1997, pp. 1504-1509.
[5] R. T. Means, Jr., “Recent Developments in the Anemia of Chronic Disease,” Current Hematology Reports, Vol. 2, No. 2, 2003, pp. 116-121.
[6] L. L. Moldawer, M. A. Marano, H. Wei, et al., “Cachectin/Tumor Necrosis Factor-Alpha Alters Red Blood Cell Kinetics and Induces Anemia in vivo,” FASEB Journal, Vol. 3, No. 5, 1989, pp.1637-1643.
[7] P. J. Bugelski, T. Nesspor, A. Volk, et al., “Pharmacodynamics of Recombinant Human Erythropoietin in Murine Bone Marrow,” Pharmaceutics Research, Vol. 25, No. 2, 2008, pp. 369-378. doi:10.1007/s11095-007-9372-7
[8] P. Sathyanarayana, E. Houde, D. Marshall, et al., “CNTO 530 Functions as a Potent EPO Mimetic via Unique Sustained Effects on Bone Marrow Proerythroblast Pools,” Blood, Vol. 113, No. 20, 2009, pp. 4955-4962.doi:10.1182/blood-2008-08-172320
[9] D. L. Johnson, F. X. Farrell, F. P. Barbone, et al., “Identification of a 13 Amino Acid Peptide Mimetic of Erythropoietin and Description of Amino Acids Critical for the Mimetic Activity of EMP1,” Biochemistry, Vol. 37, No. 11, 1998, pp. 3699-3710. doi:10.1021/bi971956y
[10] O. Livnah, D. L. Johnson, E. A. Stura, et al., “An Antagonist Peptide-EPO Receptor Complex Suggests that Receptor Dimerization is not Sufficient for Activation,” Nature Structural Biology, Vol. 5, No. 11, 1998, pp. 993-1004. doi:10.1038/2965
[11] J. Keffer, L. Probert, H. Cazlaris, et al., “Transgenic Mice Expressing Human Tumour Necrosis Factor: A Predictive Genetic Model of Arthritis,” EMBO Journal, Vol. 10, No. 13, 1991, pp. 4025-4031.
[12] P. J. Bugelski, R. J. Capocasale, D. Makropoulos, et al., “CNTO 530: Molecular Pharmacology in Human UT-7EPO Cells and Pharmacokinetics and Pharmacodynamics in Mice,” Journal of Biotechnology, Vol. 134, No. 1-2, 2008, pp. 171-180. doi:10.1016/j.jbiotec.2007.12.005.
[13] R. Achuthanandam, J. Quinn, R. J. Capocasale, P. J. Bugelski, L. Hrebien and M. Kam, “Sequential Univariate Gating Approach to Study the Effects of Erythropoietin in Murine Bone Marrow,” Cytometry A, Vol. 73, No. 8, 2008, pp. 702-714. doi:10.1002/cyto.a.20584
[14] G. Hoffmann-Fezer, C. Trastl, W. Beisker, et al. “Preclinical Evaluation of Biotin Labeling for Red Cell Survival Testing,” Annals of Hematology, Vol. 74, No. 5, 1997, pp. 231-238. doi:10.1007/s002770050290
[15] T. Suzuki and G. L. Dale, “Biotinylated Erythrocytes: In Vivo Survival and In Vitro Recovery,” Blood, Vol. 70, No. 3, 1987, pp. 791-795.
[16] A. C. Dornhorst, “The Interpretation of Red Cell Survival Curves,” Blood, Vol. 6, No. 12, 1951, pp. 1284-1292.
[17] H. Breny, “Non-Stationary Models,” in: J. M. Paulus, Ed., Platelet Kinetics: Radioisotopic, Cytological, Mathematical and Clinical Aspects, North-Holland, Amsterdam, The Netherlands, 1971.
[18] D. M. Mock, G. L. Lankford, J. A. Widness, L. F. Burmeister, D. Kahn and R. G. Strauss, “Measurement of Red Cell Survival Using Biotin-Labeled Red Cells: Validation Against 51Cr-Labeled Red Cells,” Transfusion, Vol. 39, No. 2, 1999, pp. 156-162. doi:10.1046/j.1537-2995.1999.39299154729.x
[19] M. Kotilainen, “Linear and Exponential Components of Platelet Turnover: A Computer Analysis,” in: J. M. Paulus, Ed., Platelet Kinetics: Radioisotopic, Cytological, Mathematical and Clinical Aspects, North-Holland, Amsterdam, The Netherlands, 1971.
[20] P. Wiczling and W. Krzyzanski, “Flow Cytometric Assessment of Homeostatic Aging of Reticulocytes in Rats,” Experimental Hematology, Vol. 36, No. 2, 2008, pp. 119-127. doi:10.1016/j.exphem.2007.09.002
[21] R. J. Capocasale, D. A. Makropoulos, R. Achuthanandam, et al., “Myelodysplasia and Anemia of Chronic Disease in Human Tumor Necrosis Factor-Alpha Transgenic Mice,” Cytometry A, Vol. 73, No. 2, 2008, pp. 148-159. doi:10.1002/cyto.a.20512
[22] C. S. Johnson, C. A. Cook and P. Furmanski, “In vivo Suppression of Erythropoiesis by Tumor Necrosis Factor-Alpha (TNF-alpha): Reversal with Exogenous Erythropoietin (EPO),” Experimental Hematology, Vol. 18, No. 2, 1990, pp. 109-113.
[23] R. A. Johnson, T. A. Waddelow, J. Caro, A. Oliff and G. D. Roodman, “Chronic Exposure to Tumor Necrosis Factor in vivo Preferentially Inhibits Erythropoiesis in Nude Mice,” Blood, Vol. 74, No. 1, 1989, pp. 130-138.
[24] H. Glosli, O. P. Veiby, H. Fjerdingstad, et al., “Effects of hTNFalpha Expression in T Cells on Haematopoiesis in Transgenic Mice,” European Journal of Haematology, Vol. 63, No. 1, 1999, pp. 50-60. doi:10.1111/j.1600-0609.1999.tb01850.x
[25] H. A. Papadaki, H. D. Kritikos, V. Valatas, D. T. Boumpas and G. D. Eliopoulos, “Anemia of Chronic Disease in Rheumatoid Arthritis is Associated with Increased Apoptosis of Bone Marrow Erythroid Cells: Improvement Following Anti-Tumor Necrosis Factor-Alpha Antibody Therapy,” Blood, Vol. 100, No. 2, 2002, pp. 474-482. doi:10.1182/blood-2002-01-0136
[26] G. Vreugdenhil, A. W. Wognum, H. G. van Eijk and A. J. Swaak, “Anaemia in Rheumatoid Arthritis: The Role of Iron, Vitamin B12, and Folic Acid Deficiency, and Erythropoietin Responsiveness,” Annals of Rheumatic Disease, Vol. 49, No. 2, 1990, pp. 93-98. doi:10.1136/ard.49.2.93
[27] M. Lewis, L. A. Tartaglia, A. Lee, et al., “Cloning and Expression of cDNAs for Two Distinct Murine Tumor Necrosis Factor Receptors Demonstrate One Receptor is Species Specific,” Proceeding of the National Academy of Science (USA), Vol. 88, No. 7, 1991, pp. 2830-2834. doi:10.1073/pnas.88.7.2830
[28] M. A. Coccia, K. Cooke, G. Stoney, et al., “Novel Erythropoiesis Stimulating Protein (Darbepoetin Alfa) Alleviates Anemia Associated with Chronic Inflammatory Disease in a Rodent Model,” Experimental Hematology, Vol. 29, No. 10, 2001, pp. 1201-1209. doi:10.1016/S0301-472X(01)00723-8
[29] U. Testa, “Apoptotic Mechanisms in the Control of Erythropoiesis,” Leukemia, Vol. 18, No. 7, 2004, 1176-1199. doi:10.1038/sj.leu.2403383
[30] M. J. Weiss and C. O. dos Santos, “Chaperoning Erythropoiesis,” Blood, Vol. 113, No. 10, 2009, pp. 2136-2144. doi:10.1182/blood-2008-09-115238
[31] K. H. Chang, M. Tam and M. M. Stevenson, “Inappropriately Low Reticulocytosis in Severe Malarial Anemia Correlates with Suppression in the Development of late Erythroid Precursors,” Blood, Vol. 103, No. 10, 2004, pp. 3727-3735. doi:10.1182/blood-2003-08-2887
[32] Y. Robinson, A. Matenov, S. K. Tschoke, et al., “Impaired Erythropoiesis after Haemorrhagic Shock in Mice is Associated with Erythroid Progenitor Apoptosis in vivo,” Acta Anaesthesiologica Scandinavia, Vol. 52, No. 5, 2008, pp. 605-613. doi:10.1111/j.1399-6576.2008.01656.x
[33] M. Kato, Y. Kato and Y. Sugiyama, “Mechanism of the Upregulation of Erythropoietin-Induced Uptake Clearance by the Spleen,” American Journal of Physiology, Vol. 276, No. 5, 1999, pp. E887-E895.
[34] W. Nijhof, H. Goris, B, Dontje, J. Dresz and M. Loeffler, “Optimal Erythroid Cell Production during Erythropoietin Treatment of Mice Occurs by Exploiting the Splenic Microenvironment,” Experimental Hematology, Vol. 21, No. 4, 1993, pp. 496-501.
[35] D. Kapa, L. Biljanovic-Paunovic, P. Milenkovic and V. Pavlovic-Kentera, “Effect of Suppression and Stimulation of Erythropoiesis on CFU-E in Mouse Spleen,” Acta Haematologica, Vol. 72, No. 5, 1984, pp. 295-302. doi:10.1159/000206405

  
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