Abstract
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.
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References
Baumann H, Gauldie J (1994) The acute phase response. Immunol Today 15:74-80
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 67:2346-2353
Business wire (1998) Amgen discontinues MGDF platelet donation trials
Car BD, Eng VM, Lipman JM, Anderson TD (1999) The toxicology of interleukin-12: a review. Toxicol Pathol 27:58-63
Clark M (2000) Antibody humanization: a case of the Emperor’s new clothes'? Immunol Today 21:397-402
Covic A, Kuhlmann MK (2007) Biosimilars: recent developments. Int Urol Nephrol 39:261-266
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 8:459-465
D'Arcy CA, Mannik M (2001) Serum sickness secondary to treatment with the murine-human chimeric antibody IDEC-C2B8 (rituximab). Arthritis Rheum 44:1717-1718
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 13:4677-4685
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 16:561-567
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 3:391-400
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 273:13313-13316
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 273:30336-30343
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 6:1678-1692
Gribble E, Pallavar V, Ponce R, Hughes S (2007) Toxicity as a result of immunostimulation by biologics. Expert Opin Drug Metab Toxicol 3:209-234
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 354:809-820
Kohler G, Milstein C (1975) Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256:495-497
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 88:257-264
Kromminga A, Schellekens H (2005) Antibodies against erythropoietin and other protein-based therapeutics: an overview. Ann N Y Acad Sci 1050:257-265
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 90:2541-2548
Locatelli F, Del Vecchio L, Pozzoni P (2007) Pure red-cell aplasia “epidemic” - mystery completely revealed? Perit Dial Int 27(Suppl 2):S303-S307
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):225-237
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 118:1405-1416
Presta LG (2006) Engineering of therapeutic antibodies to minimize immunogenicity and optimize function. Adv Drug Deliv Rev 58:640-656
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 88:247-256
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 27:78-86
Schellekens H (2002a) Bioequivalence and the immunogenicity of biopharmaceuticals. Nat Rev Drug Discov 1:457-462
Schellekens H (2002b) Immunogenicity of therapeutic proteins: clinical implications and future prospects. Clin Ther 24:1720-1740; discussion 1719
Schraven B, Kalinke U (2008) CD28 superagonists: what makes the difference in humans? Immunity 28:591-595
Shankar G, Shores E, Wagner C, Mire-Sluis A (2006) Scientific and regulatory considerations on the immunogenicity of biologics. Trends Biotechnol 24:274-280
Siegrist CA (2007) Mechanisms underlying adverse reactions to vaccines. J Comp Pathol 137(Suppl 1):S46-S50
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 179:3325-3331
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 355:1018-1028
Trinchieri G (1993) Interleukin-12 and its role in the generation of TH1 cells. Immunol Today 14:335-338
Valabrega G, Montemurro F, Aglietta M (2007) Trastuzumab: mechanism of action, resistance and future perspectives in HER2-overexpressing breast cancer. Ann Oncol 18:977-984
Verheul HM, Pinedo HM (2007) Possible molecular mechanisms involved in the toxicity of angiogenesis inhibition. Nat Rev Cancer 7:475-485
Weiss JM, Subleski JJ, Wigginton JM, Wiltrout RH (2007) Immunotherapy of cancer by IL-12-based cytokine combinations. Expert Opin Biol Ther 7:1705-1721
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 2:183-190
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 98:2819-2826
Zelzer E, Mamluk R, Ferrara N, Johnson RS, Schipani E, Olsen BR (2004) VEGFA is necessary for chondrocyte survival during bone development. Development 131:2161-2171
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Clarke, J.B. (2010). Mechanisms of Adverse Drug Reactions to Biologics. In: Uetrecht, J. (eds) Adverse Drug Reactions. Handbook of Experimental Pharmacology, vol 196. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-00663-0_16
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