Unwanted Immunogenicity: Implications for Follow-on Biologicals

Abstract

The unexpected and unpredictable development of unwanted immunogenicity is a significant issue affecting therapeutic proteins, including follow-on biologicals. The development of antibodies against the therapeutic biological can cause allergic or anaphylactic reactions, reduction in efficacy, and, in some cases, severe adverse effects. The risk of inducing immune responses is largely dependent on the recipient as well as a number of product-related factors (eg, production process, formulation, and number of doses administered during the course of treatment). Consideration should be given to the evaluation of unwanted immunogenicity of follow-on biologicals from preclinical development, through clinical trials, and into the postregistration period to minimize the risks associated with immunogenicity in recipients of therapeutic products. Properly planned immunogenicity studies during phase I/II clinical trials using a range of carefully validated procedures are needed to assess unwanted immunogenicity of therapeutic products.

Keywords

Antibodies Neutralizing Assays Prediction Strategy

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References

Porter

. Human immune response to recombinant human proteins. J Pharm Sci. 2001;90:1–11.

Koren

Zuckerman

Mire-Sluis

. Immune responses to therapeutic proteins in humans—clinical significance, assessment and prediction. Curr Pharm Biotechnol 2002;3:349–360.

Jacquemin

Saint-Remy

. Factor VIII immunogenicity. Haemophilia. 1998;4:552–557.

Rosenberg

Kingma

Fitzpatrick

Richards

. Immunosurveillance of alglucerase enzyme therapy for Gaucher patients: induction of humoral tolerance in seroconverted patients after repeat administration. Blood. 1999;93:2081–2088.

Chance

Root

Galloway

. The immunogenicity of insulin preparations. Acta Endocrinol. 1976;205(suppl):185–198.

Antonelli

Currenti

Turriziani

Dianzani

. Neutralizing antibodies to interferon-α: relative frequency in patients treated with different interferon preparations. J Infect Dis. 1991;163:882–885.

Stein

. Immunogenicity: concepts/issues/concerns. Dev Biol. 2002;109:15–23.

Baert

Noman

Vermiere

Influence of immunogenicity on the long-term efficacy of infliximab in Crohn's disease. N Engl J Med. 2003;348:601–608.

Saint-Remy

. Immunology of factor VIII inhibitors. Semin Thromb Hemost. 2002;28:265–268.

10.

Steis

Smith

Urba

Resistance to recombinant interferon α-2a in hairy-cell leukaemia associated with neutralizing anti-interferon antibodies. N Engl J Med. 1988;318:1409–1413.

11.

Francis

Rice

Alsop

PRISMS Study Group

Interferon β-1a in MS: results following development of neutralizing antibodies in PRISMS. Neurology. 2005;65:48–55.

12.

Hjelm

AL Skog

Wadhwa

Hassan

Alteration of 1L-2 pharmacokinetics and function by 1L-2 antibodies induced following treatment of colorectal carcinoma patients with a combination of monoclonal antibody 17–1A, GM-CSF and 1L-2. Clin Can Res. 2001;7:1163–1170.

13.

Yang

Xia

Thrombocytopenia caused by the development of antibodies to thrombopoietin. Blood. 2001;98:3241–3248.

14.

Casadevall

Nataf

Viron

Pure red cell aplasia and anti-erythropoietin antibodies against human erythropoietin in patients treated with recombinant erythropoietin. N Engl J Med. 2002;346:469–475.

15.

Wadhwa

Skog

A-LH

Bird

Immunogenicity of granulocyte-macrophage colony stimulating factor (GM-CSF) products in patients undergoing combination therapy with GM-CSF. Clin Cancer Res. 1999;5:1353–1361.

16.

Schellekens

. Biosimilar therapeutic agents: issues with bioequivalence and immunogenic. Eur J Clin Invest. 2004;34:797–799.

17.

European Medicines Evaluation Agency. EMEA Guideline on Similar Biological Medicinal Products Containing Biotechnology-Derived Proteins as Active Substance—Non-clinical and Clinical Issues. EMEA/CHMP/BMWP/42832/2005.

18.

De Groot

Rayner

Martin

. Modelling the immunogenicity of therapeutic proteins using T cell epitope mapping. Dev Biol. 2003;112:71–80.

19.

Chirino

Ary

Marshall

. Minimizing the immunogenicity of protein therapeutics. Drug Discovery Today. 2004;9:82–90.

20.

Stickler

Rochanayon

Razo

An in vitro human cell-based assay to rank the relative immunogenicity of proteins. Toxicol Sci. 2004;77:280–289.

21.

Bussiere

. Animal models as indicators of immunogenicity of therapeutic proteins in humans. Dev Biol. 2003;112:135–139.

22.

Braun

Kwee

Labow

Alsenz

. Protein aggregates seem to play a key role among the parameters influencing the antigenicity of interferon α (IFN-α) in normal and transgenic mice. Pharm Res. 1997;14:1472–1478.

23.

Zwickl

Cocke

Tamura

Comparison of the immunogenicity of recombinant and pituitary human growth hormone in rhesus monkeys. Fundam Appl Toxicol. 1991;16:275–287.

24.

Hermeling

Jiskoot

Crommelin

Bornaes

Schellekens

. Development of a transgenic mouse model immune tolerant for human interferon β. Pharm Res. 2005;22:847–851.

25.

Wadhwa

Bird

Dilger

Gaines-Das

Thorpe

. Strategies for detection, measurement and characterization of unwanted antibodies induced by therapeutic biologicals. J Immunol Methods. 2003;278:1–17.

26.

Mire-Sluis

Barrett

Devanarayan

Recommendations for the design and optimization of immunoassays used in the detection of host antibodies against biotechnology products. J Immunol Methods. 2004;289:1–16.