Immunogenicity to Therapeutic Proteins: Impact on PK/PD and Efficacy

The development of therapeutic proteins requires the understanding of the relationship between the dose, exposure, efficacy, and toxicity of these molecules. Several intrinsic and extrinsic factors contribute to the challenges for measuring therapeutic proteins in a precise and accurate manner. In addition, induction of an immune response to therapeutic protein results in additional complexities in the analysis of the pharmacokinetic profile, toxicity, safety, and efficacy of this class of molecules. Assessment of immunogenicity of therapeutic proteins is a required aspect of regulatory filings for a licensing application and for the safe and efficacious use of these compounds. A systematic strategy and well-defined criteria for measuring anti-drug antibodies (ADA) have been established, to a large extent, through coordinated efforts. These recommendations are based on risk assessment and include the determination of ADA content (concentration/titer), affinity, immunoglobulin isotype/subtype, and neutralization capacity. This manuscript reviews the requirements necessary for understanding the nature of an ADA response in order to discern the impact of immunogenicity on pharmacokinetics/pharmacodynamics and efficacy.

[1]  Ami C Bautista,et al.  Impact of matrix-associated soluble factors on the specificity of the immunogenicity assessment. , 2010, Bioanalysis.

[2]  J. Vielmetter,et al.  Clinical link between MHC class II haplotype and interferon-beta (IFN-beta) immunogenicity. , 2006, Clinical immunology.

[3]  N. Barois,et al.  Receptor-mediated endocytosis of immune complexes in rat liver sinusoidal endothelial cells is mediated by FcgammaRIIb2. , 2007, Hepatology.

[4]  Patrick G. Swann,et al.  Considerations for the development of therapeutic monoclonal antibodies. , 2008, Current opinion in immunology.

[5]  A. Millonig,et al.  High-dose intravenous interferon beta in patients with neutralizing antibodies (HINABS): a pilot study , 2009, Multiple sclerosis.

[6]  N. Barois,et al.  Receptor‐mediated endocytosis of immune complexes in rat liver sinusoidal endothelial cells is mediated by FcγRIIb2 , 2007 .

[7]  Jean W. Lee,et al.  Novel approaches using alkaline or acid/guanidine treatment to eliminate therapeutic antibody interference in the measurement of total target ligand. , 2010, Journal of pharmaceutical and biomedical analysis.

[8]  A. Mire-Sluis,et al.  Meeting report on protein particles and immunogenicity of therapeutic proteins: filling in the gaps in risk evaluation and mitigation. , 2010, Biologicals : journal of the International Association of Biological Standardization.

[9]  B. Meibohm,et al.  Population Pharmacokinetics of Therapeutic Monoclonal Antibodies , 2010, Clinical pharmacokinetics.

[10]  Eugen Koren,et al.  An acid dissociation bridging ELISA for detection of antibodies directed against therapeutic proteins in the presence of antigen. , 2005, Journal of immunological methods.

[11]  M. Tabrizi,et al.  Preclinical and clinical safety of monoclonal antibodies. , 2007, Drug discovery today.

[12]  Thomas Singer,et al.  The safety and side effects of monoclonal antibodies , 2010, Nature Reviews Drug Discovery.

[13]  Robin Thorpe,et al.  Assays for detecting and diagnosing antibody-mediated pure red cell aplasia (PRCA): an assessment of available procedures. , 2005, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[14]  Bruce N. Rehlaender,et al.  Antibodies as Carrier Proteins , 1998, Pharmaceutical Research.

[15]  A. Rathore,et al.  Quality by design for biopharmaceuticals , 2009, Nature Biotechnology.

[16]  Heather Myler,et al.  Bioanalytical Approaches to Quantify “Total” and “Free” Therapeutic Antibodies and Their Targets: Technical Challenges and PK/PD Applications Over the Course of Drug Development , 2011, The AAPS Journal.

[17]  An Carbonez,et al.  Influence of immunogenicity on the long-term efficacy of infliximab in Crohn's disease. , 2003, The New England journal of medicine.

[18]  Yuan-Tsong Chen,et al.  The impact of antibodies on clinical outcomes in diseases treated with therapeutic protein: Lessons learned from infantile Pompe disease , 2011, Genetics in Medicine.

[19]  L. Gibiansky,et al.  Population PK and IgE Pharmacodynamic Analysis of a Fully Human Monoclonal Antibody Against IL4 Receptor , 2011, Pharmaceutical Research.

[20]  B. Meibohm,et al.  Pharmacokinetic aspects of biotechnology products. , 2004, Journal of pharmaceutical sciences.

[21]  Meina Liang,et al.  Detection of high- and low-affinity antibodies against a human monoclonal antibody using various technology platforms. , 2007, Assay and drug development technologies.

[22]  V. Quarmby,et al.  Clinical immunogenicity specificity assessments: a platform evaluation. , 2011, Journal of pharmaceutical and biomedical analysis.

[23]  N. Chirmule,et al.  Assessment of immunogenicity of romiplostim in clinical studies with ITP subjects , 2010, Annals of Hematology.

[24]  B. Dijkmans,et al.  The presence or absence of antibodies to infliximab or adalimumab determines the outcome of switching to etanercept , 2010, Annals of the rheumatic diseases.

[25]  B. Dijkmans,et al.  Inefficacy of infliximab in ankylosing spondylitis is correlated with antibody formation , 2006, Annals of the rheumatic diseases.

[26]  G. Walsh.  Pharmaceutical Biotechnology: Concepts and Applications , 2007 .

[27]  K. Knight,et al.  Somatic hypermutation: mutations 3' of rabbit VDJ H-chain genes. , 1997, Journal of immunology.

[28]  Arunan Kaliyaperumal,et al.  Comparing ELISA and Surface Plasmon Resonance for Assessing Clinical Immunogenicity of Panitumumab , 2007, The Journal of Immunology.

[29]  S. Quataert,et al.  Assignment of weight-based antibody units to a human antipneumococcal standard reference serum, lot 89-S , 1995, Clinical and diagnostic laboratory immunology.

[30]  Viswanath Devanarayan,et al.  Recommendations for the validation of cell-based assays used for the detection of neutralizing antibody immune responses elicited against biological therapeutics. , 2011, Journal of pharmaceutical and biomedical analysis.

[31]  R Seitz,et al.  Taking immunogenicity assessment of therapeutic proteins to the next level. , 2011, Biologicals : journal of the International Association of Biological Standardization.

[32]  M. Allez.  L’immunisation contre l’infliximab, associée à des réactions d’intolérance et à une perte d’efficacité, peut être prévenue par l’utilisation d’immunosuppresseurs , 2004 .

[33]  Jos H. Beijnen,et al.  Clinical Pharmacokinetics of Therapeutic Monoclonal Antibodies , 2010, Clinical pharmacokinetics.

[34]  D. Salinger,et al.  Quantitative Prediction of Human Pharmacokinetics for Monoclonal Antibodies , 2011, Clinical pharmacokinetics.

[35]  C. Gegg,et al.  Ligand-Binding Mass Spectrometry to Study Biotransformation of Fusion Protein Drugs and Guide Immunoassay Development: Strategic Approach and Application to Peptibodies Targeting the Thrombopoietin Receptor , 2010, The AAPS Journal.

[36]  Huub Schellekens,et al.  Bioequivalence and the immunogenicity of biopharmaceuticals , 2002, Nature Reviews Drug Discovery.

[37]  H. Mandel,et al.  Cross-reactive immunologic material status affects treatment outcomes in Pompe disease infants. , 2010, Molecular genetics and metabolism.

[38]  M. Carcao,et al.  Current and future approaches to inhibitor management and aversion. , 2006, Seminars in thrombosis and hemostasis.

[39]  Viswanath Devanarayan,et al.  Recommendations for the validation of immunoassays used for detection of host antibodies against biotechnology products. , 2008, Journal of pharmaceutical and biomedical analysis.

[40]  George Scott,et al.  Recommendations for the design and optimization of immunoassays used in the detection of host antibodies against biotechnology products. , 2004, Journal of immunological methods.

[41]  B. Klein,et al.  Pharmacokinetic study of anti-interleukin-6 (IL-6) therapy with monoclonal antibodies: enhancement of IL-6 clearance by cocktails of anti-IL-6 antibodies. , 1995, Blood.

[42]  R. Keenan,et al.  Rituximab and immune tolerance in severe hemophilia A: a consecutive national cohort , 2009, Journal of thrombosis and haemostasis : JTH.

[43]  E. D. De Jong,et al.  Extent and clinical consequences of antibody formation against adalimumab in patients with plaque psoriasis. , 2010, Archives of dermatology.

[44]  B. Dijkmans,et al.  Development of antidrug antibodies against adalimumab and association with disease activity and treatment failure during long-term follow-up. , 2011, JAMA.