Mechanisms of Adverse Drug Reactions to Biologics

  • Janet B. ClarkeEmail author
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 196)


Biologics encompass a broad range of therapeutics that include proteins and other products derived from living systems. Although the multiplicity of target organs often seen with new chemical entities is generally not seen with biologics, they can produce significant adverse reactions. Examples include IL-12 and an anti-CD28 antibody that resulted in patient deaths and/or long stays in intensive care units. Mechanisms of toxicities can be categorized as pharmacological or nonpharmacological, with most, excepting hypersensitivity reactions, associated with the interaction of the agent with its planned target. Unexpected toxicities generally arise as a result of previously unknown biology. Manufacturing quality is a significant issue relative to the toxicity of biologics. The development of recombinant technology represented the single biggest advance leading to humanized products with minimal or no contaminants in comparison to products purified from animal tissues. Nevertheless, the type of manufacturing process including choice of cell type, culture medium, and purification method can result in changes to the protein. For example, a change to the closure system for erythropoietin led to an increase in aplastic anemia as a result of changing the immunogenicity characteristics of the protein. Monoclonal antibodies represent a major class of successful biologics. Toxicities associated with these agents include those associated with the binding of the complementary determining region (CDR) with the target. First dose reactions or infusion reactions are generally thought to be mediated via the Fc region of the antibody activating cytokine release, and have been observed with several antibodies. Usually, these effects (flu-like symptoms, etc.) are transient with subsequent dosing. Although biologics can have nonpharmacologic toxicities, these are less common than with small molecule drugs.


Biologics Mechanisms Pharmacological Monoclonal antibodies Cardiotoxicity Superagonism 


  1. Baumann H, Gauldie J (1994) The acute phase response. Immunol Today 15:74-80PubMedCrossRefGoogle Scholar
  2. Boven K, Stryker S, Knight J, Thomas A, van Regenmortel M, Kemeny DM, Power D, Rossert J, Casadevall N (2005) The increased incidence of pure red cell aplasia with an Eprex formulation in uncoated rubber stopper syringes. Kidney Int 67:2346-2353PubMedCrossRefGoogle Scholar
  3. Business wire (1998) Amgen discontinues MGDF platelet donation trialsGoogle Scholar
  4. Car BD, Eng VM, Lipman JM, Anderson TD (1999) The toxicology of interleukin-12: a review. Toxicol Pathol 27:58-63PubMedCrossRefGoogle Scholar
  5. Clark M (2000) Antibody humanization: a case of the Emperor’s new clothes'? Immunol Today 21:397-402PubMedCrossRefGoogle Scholar
  6. Covic A, Kuhlmann MK (2007) Biosimilars: recent developments. Int Urol Nephrol 39:261-266PubMedCrossRefGoogle Scholar
  7. Crone SA, Zhao YY, Fan L, Gu Y, Minamisawa S, Liu Y, Peterson KL, Chen J, Kahn R, Condorelli G, Ross J Jr, Chien KR, Lee KF (2002) ErbB2 is essential in the prevention of dilated cardiomyopathy. Nat Med 8:459-465PubMedCrossRefGoogle Scholar
  8. D'Arcy CA, Mannik M (2001) Serum sickness secondary to treatment with the murine-human chimeric antibody IDEC-C2B8 (rituximab). Arthritis Rheum 44:1717-1718PubMedCrossRefGoogle Scholar
  9. Del Vecchio M, Bajetta E, Canova S, Lotze MT, Wesa A, Parmiani G, Anichini A (2007) Interleukin-12: biological properties and clinical application. Clin Cancer Res 13:4677-4685PubMedCrossRefGoogle Scholar
  10. Farshid M, Taffs RE, Scott D, Asher DM, Brorson K (2005) The clearance of viruses and transmissible spongiform encephalopathy agents from biologicals. Curr Opin Biotechnol 16:561-567PubMedCrossRefGoogle Scholar
  11. Ferrara N, Hillan KJ, Gerber HP, Novotny W (2004) Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov 3:391-400PubMedCrossRefGoogle Scholar
  12. Gerber HP, Dixit V, Ferrara N (1998a) Vascular endothelial growth factor induces expression of the antiapoptotic proteins Bcl-2 and A1 in vascular endothelial cells. J Biol Chem 273:13313-13316PubMedCrossRefGoogle Scholar
  13. Gerber HP, McMurtrey A, Kowalski J, Yan M, Keyt BA, Dixit V, Ferrara N (1998b) Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3'-kinase/Akt signal transduction pathway. Requirement for Flk-1/KDR activation. J Biol Chem 273:30336-30343PubMedCrossRefGoogle Scholar
  14. Gollob JA, Mier JW, Veenstra K, McDermott DF, Clancy D, Clancy M, Atkins MB (2000) Phase I trial of twice-weekly intravenous interleukin 12 in patients with metastatic renal cell cancer or malignant melanoma: ability to maintain IFN-gamma induction is associated with clinical response. Clin Cancer Res 6:1678-1692PubMedGoogle Scholar
  15. Gribble E, Pallavar V, Ponce R, Hughes S (2007) Toxicity as a result of immunostimulation by biologics. Expert Opin Drug Metab Toxicol 3:209-234PubMedCrossRefGoogle Scholar
  16. Joensuu H, Kellokumpu-Lehtinen PL, Bono P, Alanko T, Kataja V, Asola R, Utriainen T, Kokko R, Hemminki A, Tarkkanen M, Turpeenniemi-Hujanen T, Jyrkkio S, Flander M, Helle L, Ingalsuo S, Johansson K, Jaaskelainen AS, Pajunen M, Rauhala M, Kaleva-Kerola J, Salminen T, Leinonen M, Elomaa I, Isola J (2006) Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med 354:809-820PubMedCrossRefGoogle Scholar
  17. Kohler G, Milstein C (1975) Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256:495-497PubMedCrossRefGoogle Scholar
  18. Kozak RW, Golker CF, Stadler P (1996) Transmissible spongiform encephalopathies (TSE): minimizing the risk of transmission by biological/biopharmaceutical products: an industry perspective. Dev Biol Stand 88:257-264PubMedGoogle Scholar
  19. Kromminga A, Schellekens H (2005) Antibodies against erythropoietin and other protein-based therapeutics: an overview. Ann N Y Acad Sci 1050:257-265PubMedCrossRefGoogle Scholar
  20. Leonard JP, Sherman ML, Fisher GL, Buchanan LJ, Larsen G, Atkins MB, Sosman JA, Dutcher JP, Vogelzang NJ, Ryan JL (1997) Effects of single-dose interleukin-12 exposure on interleukin-12-associated toxicity and interferon-gamma production. Blood 90:2541-2548PubMedGoogle Scholar
  21. Locatelli F, Del Vecchio L, Pozzoni P (2007) Pure red-cell aplasia “epidemic” - mystery completely revealed? Perit Dial Int 27(Suppl 2):S303-S307PubMedGoogle Scholar
  22. Moreau T, Coles A, Wing M, Isaacs J, Hale G, Waldmann H, Compston A (1996) Transient increase in symptoms associated with cytokine release in patients with multiple sclerosis. Brain 119(Pt 1):225-237Google Scholar
  23. Muller N, van den Brandt J, Odoardi F, Tischner D, Herath J, Flugel A, Reichardt HM (2008) A CD28 superagonistic antibody elicits 2 functionally distinct waves of T cell activation in rats. J Clin Invest 118:1405-1416PubMedCrossRefGoogle Scholar
  24. Presta LG (2006) Engineering of therapeutic antibodies to minimize immunogenicity and optimize function. Adv Drug Deliv Rev 58:640-656PubMedCrossRefGoogle Scholar
  25. Rohwer RG (1996) Analysis of risk to biomedical products developed from animal sources (with special emphasis on the spongiform encephalopathy agents, scrapie and BSE). Dev Biol Stand 88:247-256PubMedGoogle Scholar
  26. Ryan AM, Eppler DB, Hagler KE, Bruner RH, Thomford PJ, Hall RL, Shopp GM, O'Neill CA (1999) Preclinical safety evaluation of rhuMAbVEGF, an antiangiogenic humanized monoclonal antibody. Toxicol Pathol 27:78-86PubMedCrossRefGoogle Scholar
  27. Schellekens H (2002a) Bioequivalence and the immunogenicity of biopharmaceuticals. Nat Rev Drug Discov 1:457-462PubMedCrossRefGoogle Scholar
  28. Schellekens H (2002b) Immunogenicity of therapeutic proteins: clinical implications and future prospects. Clin Ther 24:1720-1740; discussion 1719Google Scholar
  29. Schraven B, Kalinke U (2008) CD28 superagonists: what makes the difference in humans? Immunity 28:591-595PubMedCrossRefGoogle Scholar
  30. Shankar G, Shores E, Wagner C, Mire-Sluis A (2006) Scientific and regulatory considerations on the immunogenicity of biologics. Trends Biotechnol 24:274-280PubMedCrossRefGoogle Scholar
  31. Siegrist CA (2007) Mechanisms underlying adverse reactions to vaccines. J Comp Pathol 137(Suppl 1):S46-S50PubMedCrossRefGoogle Scholar
  32. 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
  33. 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
  34. Trinchieri G (1993) Interleukin-12 and its role in the generation of TH1 cells. Immunol Today 14:335-338PubMedCrossRefGoogle Scholar
  35. Valabrega G, Montemurro F, Aglietta M (2007) Trastuzumab: mechanism of action, resistance and future perspectives in HER2-overexpressing breast cancer. Ann Oncol 18:977-984PubMedCrossRefGoogle Scholar
  36. Verheul HM, Pinedo HM (2007) Possible molecular mechanisms involved in the toxicity of angiogenesis inhibition. Nat Rev Cancer 7:475-485PubMedCrossRefGoogle Scholar
  37. Weiss JM, Subleski JJ, Wigginton JM, Wiltrout RH (2007) Immunotherapy of cancer by IL-12-based cytokine combinations. Expert Opin Biol Ther 7:1705-1721PubMedCrossRefGoogle Scholar
  38. Wing MG, Waldmann H, Isaacs J, Compston DA, Hale G (1995) Ex-vivo whole blood cultures for predicting cytokine-release syndrome: dependence on target antigen and antibody isotype. Ther Immunol 2:183-190PubMedGoogle Scholar
  39. Wing MG, Moreau T, Greenwood J, Smith RM, Hale G, Isaacs J, Waldmann H, Lachmann PJ, Compston A (1996) Mechanism of first-dose cytokine-release syndrome by CAMPATH 1-H: involvement of CD16 (FcgammaRIII) and CD11a/CD18 (LFA-1) on NK cells. J Clin Invest 98:2819-2826PubMedCrossRefGoogle Scholar
  40. Zelzer E, Mamluk R, Ferrara N, Johnson RS, Schipani E, Olsen BR (2004) VEGFA is necessary for chondrocyte survival during bone development. Development 131:2161-2171PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2010

Authors and Affiliations

  1. 1.Biogen Idec, Inc., 4 Cambridge CenterCambridgeUSA

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