Advertisement

Preclinical Safety Considerations for the Development of Antibody-Based Therapeutics

  • Lolke de Haan
Chapter

Abstract

It is now clear that the preclinical safety assessment of biologics is a holistic approach that first and foremost takes into account species relevance and requires an in-depth scientific understanding of the in vitro and in vivo properties of the antibody. An in-depth understanding of these properties may allow for the prediction of safe starting doses for clinical first in human trials and for continued patient safety during subsequent clinical development phases. In this chapter, considerations for preclinical safety testing of monoclonal antibodies as well as the relevant regulatory guidelines are described.

Keywords

Reproductive Toxicity Clinical Candidate Preclinical Species Preclinical Safety Human Equivalent Dose 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. Agoram BM (2009) Use of pharmacokinetic/pharmacodynamic modelling for starting dose selection in first-in-human trials of high-risk biologics. Br J Clin Pharmacol 67:153–160PubMedCrossRefGoogle Scholar
  2. Anderson D, Chambers K, Hanna N, Leonard J, Reff M, Newman R, Baldoni J, Dunleavy D, Reddy M, Sweet R, Truneh A (1997) A primatized MAb to human CD4 causes receptor modulation, without marked reduction in CD4 + T cells in chimpanzees: in vitro and in vivo characterization of a MAb (IDEC-CE9.1) to human CD4. Clin Immunol Immunopathol 84:73–84PubMedCrossRefGoogle Scholar
  3. Brennan FR, Morton LD, Spindeldreher S, Kiessling A, Allenspach R, Hey A, Muller PY, Frings W, Sims J (2010) Safety and immunotoxicity assessment of immunomodulatory monoclonal antibodies. MAbs 2:233–255PubMedCrossRefGoogle Scholar
  4. Bugelski PJ, Herzyk DJ, Rehm S, Harmsen AG, Gore EV, Williams DM, Maleeff BE, Badger AM, Truneh A, O’Brien SR, Macia RA, Wier PJ, Morgan DG, Hart TK (2000) Preclinical development of keliximab, a primatized anti-CD4 monoclonal antibody, in human CD4 transgenic mice: characterization of the model and safety studies. Hum Exp Toxicol 19:230–243PubMedCrossRefGoogle Scholar
  5. Burleson GR, Burleson FG (2008) Testing human biologicals in animal host resistance models. J Immunotoxicol 5:23–31PubMedCrossRefGoogle Scholar
  6. Buse E (2005) Development of the immune system in the cynomolgus monkey: the appropriate model in human targeted toxicology? J Immunotoxicol 2:211–216PubMedCrossRefGoogle Scholar
  7. Bussiere JL (2008) Species selection considerations for preclinical toxicology studies for biotherapeutics. Expert Opin Drug Metab Toxicol 4:871–877PubMedCrossRefGoogle Scholar
  8. Bussiere JL, Martin P, Horner M, Couch J, Flaherty M, Andrews L, Beyer J, Horvath C (2009) Alternative strategies for toxicity testing of species–specific biopharmaceuticals. Int J Toxicol 28:230–253PubMedCrossRefGoogle Scholar
  9. Chapman K, Pullen N, Graham M, Ragan I (2007) Preclinical safety testing of monoclonal antibodies: the significance of species relevance. Nat Rev Drug Discov 6:120–126PubMedCrossRefGoogle Scholar
  10. Chellman GJ, Bussiere JL, Makori N, Martin PL, Ooshima Y, Weinbauer GF (2009) Developmental and reproductive toxicology studies in nonhuman primates. Birth Defects Res 86:446–462CrossRefGoogle Scholar
  11. Chirmule N, Truneh A, Haecker SE, Tazelaar J, Gao G, Raper SE, Hughes JV, Wilson JM (1999) Repeated administration of adenoviral vectors in lungs of human CD4 transgenic mice treated with a nondepleting CD4 antibody. J Immunol 163:448–455PubMedGoogle Scholar
  12. Chucri TM, Monteiro JM, Lima AR, Salvadori ML, Kfoury JR Jr, Miglino MA (2010) A review of immune transfer by the placenta. J Reprod Immunol 87:14–20PubMedCrossRefGoogle Scholar
  13. Clarke J, Leach W, Pippig S, Joshi A, Wu B, House R, Beyer J (2004) Evaluation of a surrogate antibody for preclinical safety testing of an anti-CD11a monoclonal antibody. Reg Toxicol Pharmacol 40:219–226CrossRefGoogle Scholar
  14. Clarke J, Hurst C, Martin P, Vahle J, Ponce R, Mounho B, Heidel S, Andrews L, Reynolds T, Cavagnaro J (2008) Duration of chronic toxicity studies for biotechnology-derived pharmaceuticals: is 6 months still appropriate? Reg Toxicol Pharmacol 50:2–22CrossRefGoogle Scholar
  15. Coe CL, Kemnitz JW, Schneider ML (1993) Vulnerability of placental antibody transfer and fetal complement synthesis to disturbance of the pregnant monkey. J Med Primatol 22:294–300PubMedGoogle Scholar
  16. De Groot AS, Scott DW (2007) Immunogenicity of protein therapeutics. Trends Immunol 28:482–490PubMedCrossRefGoogle Scholar
  17. Douni E, Akassoglou K, Alexopoulou L, Georgopoulos S, Haralambous S, Hill S, Kassiotis G, Kontoyiannis D, Pasparakis M, Plows D, Probert L, Kollias G (1995) Transgenic and knockout analyses of the role of TNF in immune regulation and disease pathogenesis. J Inflamm 47:27–38PubMedGoogle Scholar
  18. Draize JH (1959) Appraisal of the safety of chemicals in foods, drugs and cosmetics. The Association of Food and Drug Officials of the United States, Austin, pp 46–49Google Scholar
  19. Eastwood D, Findlay L, Poole S, Bird C, Wadhwa M, Moore M, Burns C, Thorpe R, Stebbings R (2010) Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4+ effector memory T-cells. Br J Pharmacol 161:512–526PubMedCrossRefGoogle Scholar
  20. Finch DK, Midha A, Buchanan CL, Cochrane D, Craggs RI, Cruwys S, Grahames C, Kolbeck R, Lowe DC, Maltby J, Pattison DV, Vousden KA, Ward A, Sleeman MA, Mallinder PR (2011) Identification of a potent anti-IL-15 antibody with opposing mechanisms of action in vitro and in vivo. Br J Pharmacol 162:480–490PubMedCrossRefGoogle Scholar
  21. Frei Y, Lambris JD, Stockinger B (1987) Generation of a monoclonal antibody to mouse C5 application in an ELISA assay for detection of anti-C5 antibodies. Mol Cell Probes 1:141–149PubMedCrossRefGoogle Scholar
  22. Fujimoto K, Terao K, Cho F, Honjo S (1983) The placental transfer of IgG in the cynomolgus monkey. Jpn J Med Sci Biol 36:171–176PubMedGoogle Scholar
  23. Gitlin D, Morphis LG (1969) Systems of materno-foetal transport of gamma G immunoglobulin in the mouse. Nature 223:195–196PubMedCrossRefGoogle Scholar
  24. Gogishvili T, Langenhorst D, Luhder F, Elias F, Elflein K, Dennehy KM, Gold R, Hunig T (2009) Rapid regulatory T-cell response prevents cytokine storm in CD28 superagonist treated mice. PLoS One 4:e4634–e4643CrossRefGoogle Scholar
  25. Guan C, Ye C, Yang X, Gao J (2010) A review of current large-scale mouse knockout efforts. Genesis 48:73–85PubMedGoogle Scholar
  26. Hendrickx AG, Binkerd PE (1990) Nonhuman primates and teratological research. J Med Primatol 19:81–108PubMedGoogle Scholar
  27. Herzyk DJ, Gore ER, Polsky R, Nadwodny KL, Maier CC, Liu S, Hart TK, Harmsen AG, Bugelski PJ (2001) Immunomodulatory effects of anti-CD4 antibody in host resistance against infections and tumors in human CD4 transgenic mice. Infect Immun 69:1032–1043PubMedCrossRefGoogle Scholar
  28. Herzyk DJ, Bugelski PJ, Hart TK, Wier PJ (2002) Practical aspects of including functional endpoints in developmental toxicity studies. Case study: immune function in HuCD4 transgenic mice exposed to anti-CD4 MAb in utero. Hum Exp Toxicol 21:507–512PubMedCrossRefGoogle Scholar
  29. Hulett MD, Hogarth PM, Frank JD (1994) Molecular basis of Fc receptor function. In: Dixon FJ (ed) Advances in immunology, vol 57. Academic Press, San Diego, p 1–56, 56a, 57–127Google Scholar
  30. Jarvis P, Srivastav S, Vogelwedde E, Stewart J, Mitchard T, Weinbauer GF (2010) The cynomolgus monkey as a model for developmental toxicity studies: variability of pregnancy losses, statistical power estimates, and group size considerations. Birth Defects Res 89:175–187Google Scholar
  31. Jauniaux E, Gulbis B (2000) In vivo investigation of placental transfer early in human pregnancy. Eur J Obstet Gynecol Reprod Biol 92:45–49PubMedCrossRefGoogle Scholar
  32. Kon OM, Sihra BS, Compton CH, Leonard TB, Kay AB, Barnes NC (1998) Randomised, dose-ranging, placebo-controlled study of chimeric antibody to CD4 (keliximab) in chronic severe asthma. Lancet 352:1109–1113PubMedCrossRefGoogle Scholar
  33. Kon OM, Sihra BS, Loh LC, Barkans J, Compton CH, Barnes NC, Larche M, Kay AB (2001) The effects of an anti-CD4 monoclonal antibody, keliximab, on peripheral blood CD4 + T-cells in asthma. Eur Respir J 18:45–52PubMedCrossRefGoogle Scholar
  34. Leach MW, Halpern WG, Johnson CW, Rojko JL, MacLachlan TK, Chan CM, Galbreath EJ, Ndifor AM, Blanset DL, Polack E, Cavagnaro JA (2010) Use of tissue cross-reactivity studies in the development of antibody-based biopharmaceuticals: history, experience, methodology, and future directions. Toxicol Pathol 38:1138–1166PubMedCrossRefGoogle Scholar
  35. Lowe PJ, Tannenbaum S, Wu K, Lloyd P, Sims J (2009) On setting the first dose in man: quantitating biotherapeutic drug-target binding through pharmacokinetic and pharmacodynamic models. Basic Clin Pharmacol Toxicol 106:195–209PubMedCrossRefGoogle Scholar
  36. Lowe DC, Gerhardt S, Ward A, Hargreaves D, Anderson M, Ferraro F, Pauptit RA, Pattison DV, Buchanan C, Popovic B, Finch DK, Wilkinson T, Sleeman M, Vaughan TJ, Mallinder PR (2011) Engineering a high-affinity anti-IL-15 antibody: crystal structure reveals an alpha-helix in VH CDR3 as key component of paratope. J Mol Biol 406:160–175PubMedCrossRefGoogle Scholar
  37. Martin PL, Weinbauer GF (2010) Developmental toxicity testing of biopharmaceuticals in nonhuman primates: previous experience and future directions. Int J Toxicol 29:552–568PubMedCrossRefGoogle Scholar
  38. Martin PL, Breslin W, Rocca M, Wright D, Cavagnaro J (2009) Considerations in assessing the developmental and reproductive toxicity potential of biopharmaceuticals. Birth Defects Res 86:176–203CrossRefGoogle Scholar
  39. Martin PL, Zhou Z, Van den Bulck K, Kwok D, Powers G, Jiao Q, Schantz A, Treacy G (2010) Pharmacology and placental transfer of a human alphav integrin monoclonal antibody in rabbits. Birth Defects Res 89:116–123Google Scholar
  40. Masters CL, Bignold LP, Morgan EH (1969) Plasma protein metabolism and transfer to the fetus during pregnancy in the rat. Am J Physiol 216:876–883PubMedGoogle Scholar
  41. Milton MN, Horvath CJ (2009) The EMEA guideline on first-in-human clinical trials and its impact on pharmaceutical development. Toxicol Pathol 37:363–371PubMedCrossRefGoogle Scholar
  42. Morphis LG, Gitlin D (1970) Maturation of the maternofoetal transport system for human gamma-globulin in the mouse. Nature 228:573PubMedCrossRefGoogle Scholar
  43. Mould DR, Davis CB, Minthorn EA, Kwok DC, Elliott MJ, Luggen ME, Totoritis MC (1999) A population pharmacokinetic–pharmacodynamic analysis of single doses of clenoliximab in patients with rheumatoid arthritis. Clin Pharmacol Ther 66:246–257PubMedCrossRefGoogle Scholar
  44. Muller PY, Brennan FR (2009) Safety assessment and dose selection for first-in-human clinical trials with immunomodulatory monoclonal antibodies. Clin Pharmacol Ther 85:247–258PubMedCrossRefGoogle Scholar
  45. Muller PY, Milton M, Lloyd P, Sims J, Brennan FR (2009) The minimum anticipated biological effect level (MABEL) for selection of first human dose in clinical trials with monoclonal antibodies. Curr Opin Biotechnol 20:722–729PubMedCrossRefGoogle Scholar
  46. Nada A, Somberg J (2007) First-in-Man (FIM) clinical trials post-TeGenero: a review of the impact of the TeGenero trial on the design, conduct, and ethics of FIM trials. Am J Ther 14:594–604PubMedCrossRefGoogle Scholar
  47. Newman R, Hariharan K, Reff M, Anderson DR, Braslawsky G, Santoro D, Hanna N, Bugelski PJ, Brigham-Burke M, Crysler C, Gagnon RC, Dal Monte P, Doyle ML, Hensley PC, Reddy MP, Sweet RW, Truneh A (2001) Modification of the Fc region of a primatized IgG antibody to human CD4 retains its ability to modulate CD4 receptors but does not deplete CD4(+) T cells in chimpanzees. Clin Immunol 98:164–174PubMedCrossRefGoogle Scholar
  48. Olson H, Betton G, Robinson D, Thomas K, Monro A, Kolaja G, Lilly P, Sanders J, Sipes G, Bracken W, Dorato M, Van Deun K, Smith P, Berger B, Heller A (2000) Concordance of the toxicity of pharmaceuticals in humans and in animals. Reg Toxicol Pharmacol 32:56–67CrossRefGoogle Scholar
  49. Palfi M, Selbing A (1998) Placental transport of maternal immunoglobulin G. Am J Reprod Immunol 39:24–26PubMedCrossRefGoogle Scholar
  50. Pallardy M, Hunig T (2010) Primate testing of TGN1412: right target, wrong cell. Br J Pharmacol 161:509–511PubMedCrossRefGoogle Scholar
  51. Pentsuk N, van der Laan JW (2009) An interspecies comparison of placental antibody transfer: new insights into developmental toxicity testing of monoclonal antibodies. Birth Defects Res 86:328–344CrossRefGoogle Scholar
  52. Podolin PL, Webb EF, Reddy M, Truneh A, Griswold DE (2000) Inhibition of contact sensitivity in human CD4+ transgenic mice by human CD4-specific monoclonal antibodies: CD4+ T-cell depletion is not required. Immunology 99:287–295PubMedCrossRefGoogle Scholar
  53. Probert L, Keffer J, Corbella P, Cazlaris H, Patsavoudi E, Stephens S, Kaslaris E, Kioussis D, Kollias G (1993) Wasting, ischemia, and lymphoid abnormalities in mice expressing T cell-targeted human tumor necrosis factor transgenes. J Immunol 151:1894–1906PubMedGoogle Scholar
  54. Reddy MP, Kinney CA, Chaikin MA, Payne A, Fishman-Lobell J, Tsui P, Dal Monte PR, Doyle ML, Brigham-Burke MR, Anderson D, Reff M, Newman R, Hanna N, Sweet RW, Truneh A (2000) Elimination of Fc receptor-dependent effector functions of a modified IgG4 monoclonal antibody to human CD4. J Immunol 164:1925–1933PubMedGoogle Scholar
  55. Robinson S, Delongeas JL, Donald E, Dreher D, Festag M, Kervyn S, Lampo A, Nahas K, Nogues V, Ockert D, Quinn K, Old S, Pickersgill N, Somers K, Stark C, Stei P, Waterson L, Chapman K (2008) A European pharmaceutical company initiative challenging the regulatory requirement for acute toxicity studies in pharmaceutical drug development. Reg Toxicol Pharmacol 50:345–352CrossRefGoogle Scholar
  56. Sharma A, Davis CB, Tobia LA, Kwok DC, Tucci MG, Gore ER, Herzyk DJ, Hart TK (2000) Comparative pharmacodynamics of keliximab and clenoliximab in transgenic mice bearing human CD4. J Pharmacol Exp Ther 293:33–41PubMedGoogle Scholar
  57. Simister NE (2003) Placental transport of immunoglobulin G. Vaccine 21:3365–3369PubMedCrossRefGoogle Scholar
  58. Simister NE, Story CM (1997) Human placental Fc receptors and the transmission of antibodies from mother to fetus. J Reprod Immunol 37:1–23PubMedCrossRefGoogle Scholar
  59. Small MF (1982) Reproductive failure in macaques. Am J Primatol 2:137–147CrossRefGoogle Scholar
  60. Stebbings R, Findlay L, Edwards C, Eastwood D, Bird C, North D, Mistry Y, Dilger P, Liefooghe E, Cludts I, Fox B, Tarrant G, Robinson J, Meager T, Dolman C, Thorpe SJ, Bristow A, Wadhwa M, Thorpe R, Poole S (2007) “Cytokine storm” in the Phase I trial of monoclonal antibody TGN1412: better understanding the causes to improve preclinical testing of immunotherapeutics. J Immunol 179:3325–3331PubMedGoogle Scholar
  61. Stewart J (2009) Developmental toxicity testing of monoclonal antibodies: an enhanced pre- and postnatal study design option. Reprod Toxicol 28:220–225PubMedCrossRefGoogle Scholar
  62. Suntharalingam G, Perry MR, Ward S, Brett SJ, Castello-Cortes A, Brunner MD, Panoskaltsis N (2006) Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med 355:1018–1028PubMedCrossRefGoogle Scholar
  63. Swann PG, Tolnay M, Muthukkumar S, Shapiro MA, Rellahan BL, Clouse KA (2008) Considerations for the development of therapeutic monoclonal antibodies. Curr Opin Immunol 20:493–499PubMedCrossRefGoogle Scholar
  64. Tabrizi MA, Tseng CM, Roskos LK (2006) Elimination mechanisms of therapeutic monoclonal antibodies. Drug Discov Today 11:81–88PubMedCrossRefGoogle Scholar
  65. Tabrizi MA, Bornstein GG, Klakamp SL, Drake A, Knight R, Roskos L (2009) Translational strategies for development of monoclonal antibodies from discovery to the clinic. Drug Discov Today 14:298–305PubMedCrossRefGoogle Scholar
  66. Treacy G (2000) Using an analogous monoclonal antibody to evaluate the reproductive and chronic toxicity potential for a humanized anti-TNFalpha monoclonal antibody. Hum Exp Toxicol 19:226–228PubMedCrossRefGoogle Scholar
  67. Vahle JL, Finch GL, Heidel SM, Hovland DN Jr, Ivens I, Parker S, Ponce RA, Sachs C, Steigerwalt R, Short B, Todd MD (2010) Carcinogenicity assessments of biotechnology-derived pharmaceuticals: a review of approved molecules and best practice recommendations. Toxicol Pathol 38:522–553PubMedCrossRefGoogle Scholar
  68. Vargas HM, Bass AS, Breidenbach A, Feldman HS, Gintant GA, Harmer AR, Heath B, Hoffmann P, Lagrutta A, Leishman D, McMahon N, Mittelstadt S, Polonchuk L, Pugsley MK, Salata JJ, Valentin JP (2008) Scientific review and recommendations on preclinical cardiovascular safety evaluation of biologics. J Pharmacol Toxicol Methods 58:72–76PubMedCrossRefGoogle Scholar
  69. Waibler Z, Sender LY, Kamp C, Muller-Berghaus J, Liedert B, Schneider CK, Lower J, Kalinke U (2008) Toward experimental assessment of receptor occupancy: TGN1412 revisited. J Allergy Clin Immunol 122:890–892PubMedCrossRefGoogle Scholar
  70. Wallis RS (2009) Infectious complications of tumor necrosis factor blockade. Curr Opin Infect Dis 22:403–409PubMedCrossRefGoogle Scholar
  71. Wehner NG, Shopp G, Oneda S, Clarke J (2009a) Embryo/fetal development in cynomolgus monkeys exposed to natalizumab, an alpha4 integrin inhibitor. Birth Defects Res 86:117–130CrossRefGoogle Scholar
  72. Wehner NG, Shopp G, Osterburg I, Fuchs A, Buse E, Clarke J (2009b) Postnatal development in cynomolgus monkeys following prenatal exposure to natalizumab, an alpha4 integrin inhibitor. Birth Defects Res 86:144–156CrossRefGoogle Scholar
  73. Wehner NG, Shopp G, Rocca MS, Clarke J (2009c) Effects of natalizumab, an alpha4 integrin inhibitor, on the development of Hartley guinea pigs. Birth Defects Res 86:98–107CrossRefGoogle Scholar
  74. Wehner NG, Skov M, Shopp G, Rocca MS, Clarke J (2009d) Effects of natalizumab, an alpha4 integrin inhibitor, on fertility in male and female guinea pigs. Birth Defects Res 86:108–116CrossRefGoogle Scholar
  75. Wu B, Joshi A, Ren S, Ng C (2006) The application of mechanism-based PK/PD modeling in pharmacodynamic-based dose selection of muM17, a surrogate monoclonal antibody for efalizumab. J Pharm Sci 95:1258–1268PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  1. 1.MedImmuneCambridgeUK

Personalised recommendations