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Immunogenicity of Anti-TNF-α Biotherapies: II. Clinical Relevance of Methods Used for Anti-Drug Antibody Detection.

Bendtzen K - Front Immunol (2015)

Bottom Line: This paper discusses immunogenicity of genetically engineered immunoglobulins directed against tumor-necrosis factor-α (TNF).Emphasis will be on commonly used methods for detection of ADA in human serum including issues that question the clinical applicability of these methodologies.The use of dubious assays for ADA in a clinical context may not only contribute to confusion as to the importance of drug immunogenicity but may also prevent development of safe and cost-effective ways of using biological TNF-antagonists.

View Article: PubMed Central - PubMed

Affiliation: Institute for Inflammation Research (IIR 7521), Rigshospitalet University Hospital , Copenhagen , Denmark.

ABSTRACT
Immunogenicity of biopharmaceuticals is complex and influenced by both structural and pharmacological factors, and by patient-related conditions such as disease being treated, previous and concomitant therapies, and individual immune responsiveness. Essential for tailored therapeutic strategies based on immunopharmacological evidence from individual patients (personalized medicine) is the use of assays for anti-drug antibodies (ADA) that are accurate and relevant in the clinical setting. This paper discusses immunogenicity of genetically engineered immunoglobulins directed against tumor-necrosis factor-α (TNF). Emphasis will be on commonly used methods for detection of ADA in human serum including issues that question the clinical applicability of these methodologies. The use of dubious assays for ADA in a clinical context may not only contribute to confusion as to the importance of drug immunogenicity but may also prevent development of safe and cost-effective ways of using biological TNF-antagonists.

No MeSH data available.


Related in: MedlinePlus

Putative immunogenic sites on anti-TNF antibody constructs. Antibody constructs, drugs, and drug fragments with “human” aminoacid sequences, are depicted in red. Mouse sequences are shown in black/gray. ADA, anti-drug antibody; CDR, complementarity- determining variable region of antibody; CH1, CH3, CL, constant regions of IgG on light- and heavy-chains, respectively; Fab, antigen-binding region of antibody; Fc, crystallizable region of antibody; FR, framework region of antibody; TNF, tumor-necrosis factor; TNF-R2, TNF type 2, p75 receptor; VH, VL, variable regions of IgG on heavy and light chains, respectively.
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Figure 1: Putative immunogenic sites on anti-TNF antibody constructs. Antibody constructs, drugs, and drug fragments with “human” aminoacid sequences, are depicted in red. Mouse sequences are shown in black/gray. ADA, anti-drug antibody; CDR, complementarity- determining variable region of antibody; CH1, CH3, CL, constant regions of IgG on light- and heavy-chains, respectively; Fab, antigen-binding region of antibody; Fc, crystallizable region of antibody; FR, framework region of antibody; TNF, tumor-necrosis factor; TNF-R2, TNF type 2, p75 receptor; VH, VL, variable regions of IgG on heavy and light chains, respectively.

Mentions: Immunogenicity is a risk associated with all genetically engineered proteins, and repeated injections of humanized biopharmaceuticals may generate anti-drug antibodies (ADA), which can be related to drug failure and side effects (1). Examples are swine and human insulin, growth hormone, factor VIII, factor IX, erythropoietin, type I interferons, and a host of more or less “humanized” antibody constructs (2). The latter include biopharmaceuticals that target the inflammatory cytokine, tumor-necrosis factor-α (TNF) (Figure 1) (3–5). It has, for example, been documented repeatedly that the appearance of ADA against biological TNF-antagonists is a frequent occurrence, and that this is closely associated with disappearance of drug in the circulation, and response failure (2, 6, 7).


Immunogenicity of Anti-TNF-α Biotherapies: II. Clinical Relevance of Methods Used for Anti-Drug Antibody Detection.

Bendtzen K - Front Immunol (2015)

Putative immunogenic sites on anti-TNF antibody constructs. Antibody constructs, drugs, and drug fragments with “human” aminoacid sequences, are depicted in red. Mouse sequences are shown in black/gray. ADA, anti-drug antibody; CDR, complementarity- determining variable region of antibody; CH1, CH3, CL, constant regions of IgG on light- and heavy-chains, respectively; Fab, antigen-binding region of antibody; Fc, crystallizable region of antibody; FR, framework region of antibody; TNF, tumor-necrosis factor; TNF-R2, TNF type 2, p75 receptor; VH, VL, variable regions of IgG on heavy and light chains, respectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4389574&req=5

Figure 1: Putative immunogenic sites on anti-TNF antibody constructs. Antibody constructs, drugs, and drug fragments with “human” aminoacid sequences, are depicted in red. Mouse sequences are shown in black/gray. ADA, anti-drug antibody; CDR, complementarity- determining variable region of antibody; CH1, CH3, CL, constant regions of IgG on light- and heavy-chains, respectively; Fab, antigen-binding region of antibody; Fc, crystallizable region of antibody; FR, framework region of antibody; TNF, tumor-necrosis factor; TNF-R2, TNF type 2, p75 receptor; VH, VL, variable regions of IgG on heavy and light chains, respectively.
Mentions: Immunogenicity is a risk associated with all genetically engineered proteins, and repeated injections of humanized biopharmaceuticals may generate anti-drug antibodies (ADA), which can be related to drug failure and side effects (1). Examples are swine and human insulin, growth hormone, factor VIII, factor IX, erythropoietin, type I interferons, and a host of more or less “humanized” antibody constructs (2). The latter include biopharmaceuticals that target the inflammatory cytokine, tumor-necrosis factor-α (TNF) (Figure 1) (3–5). It has, for example, been documented repeatedly that the appearance of ADA against biological TNF-antagonists is a frequent occurrence, and that this is closely associated with disappearance of drug in the circulation, and response failure (2, 6, 7).

Bottom Line: This paper discusses immunogenicity of genetically engineered immunoglobulins directed against tumor-necrosis factor-α (TNF).Emphasis will be on commonly used methods for detection of ADA in human serum including issues that question the clinical applicability of these methodologies.The use of dubious assays for ADA in a clinical context may not only contribute to confusion as to the importance of drug immunogenicity but may also prevent development of safe and cost-effective ways of using biological TNF-antagonists.

View Article: PubMed Central - PubMed

Affiliation: Institute for Inflammation Research (IIR 7521), Rigshospitalet University Hospital , Copenhagen , Denmark.

ABSTRACT
Immunogenicity of biopharmaceuticals is complex and influenced by both structural and pharmacological factors, and by patient-related conditions such as disease being treated, previous and concomitant therapies, and individual immune responsiveness. Essential for tailored therapeutic strategies based on immunopharmacological evidence from individual patients (personalized medicine) is the use of assays for anti-drug antibodies (ADA) that are accurate and relevant in the clinical setting. This paper discusses immunogenicity of genetically engineered immunoglobulins directed against tumor-necrosis factor-α (TNF). Emphasis will be on commonly used methods for detection of ADA in human serum including issues that question the clinical applicability of these methodologies. The use of dubious assays for ADA in a clinical context may not only contribute to confusion as to the importance of drug immunogenicity but may also prevent development of safe and cost-effective ways of using biological TNF-antagonists.

No MeSH data available.


Related in: MedlinePlus