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Update on new regulatory guidelines on immunogenicity
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Abstracts / Toxicology Letters 221S (2013) S4–S30
Symposium 6: Challenges with immunogenicity of biologics
S06-1 Challenges with immunogenicity of biologics Cecilia Tami Laboratory of Immunology, Division of Therapeutic Proteins, CDER, FDA, Bethesda, MD, USA Protein immunogenicity plays a key role in the safety and efficacy of therapeutic proteins. This talk will review critical product attributes that impact on immunogenicity, highlight critical elements of the recently released FDA guidelines, and present a few case studies. http://dx.doi.org/10.1016/j.toxlet.2013.06.043
S06-2 Update on new regulatory guidelines on immunogenicity Gaby Reichmann Paul-Ehrlich-Institute, Federal Institute for Vaccines and Biomedicines, Langen, Germany Often an unwanted immune response is generated against therapeutic proteins. While such immune response can comprise both cellular and humoral elements, most adverse effects appear to be mediated by humoral mechanisms (i.e. anti-drug antibodies, ADA). Unwanted immunogenicity to therapeutic proteins can affect product efficacy. ADA may lead to enhanced clearance of the drug or directly neutralize the biological activity of the drug, both resulting in a loss of efficacy. Such ADA may also cross-react with an endogenous version of the therapeutic protein and inhibit the activity of the endogenous factor. In addition, unwanted immune responses to a therapeutic protein can affect patient safety. Acute effects such as anaphylaxis, cytokine-release syndrome and infusion reactions as well as non-acute effects such as immune complex disease have been observed. The development of an unwanted immune response against therapeutic proteins is dependent on patient-, disease- and product-related factors. However, it is not possible to predict if and to what extent an anti-therapeutic response will occur. Therefore, it is essential to assess unwanted immunogenicity against therapeutic proteins during clinical development and an appropriate assay strategy has to be developed. This should usually include a screening assay for identification of antibody-positive samples, a confirmatory assay and an assay to detect the neutralizing capacity of ADA. Since immune responses to therapeutic proteins can range from no apparent effect to serious adverse events a risk-based approach in the evaluation of unwanted immunogenicity may be recommended. http://dx.doi.org/10.1016/j.toxlet.2013.06.044
S06-4 Drug hypersensitivity and stimulation of the immune system: beyond the hapten concept Werner J. Pichler Allergology, Inselspital, University of Bern & ADR-AC, Bern, Switzerland Small molecular compounds like most drugs (<1000 D) are too small per se to act as antigen and require covalent binding to protein to become antigenic. However, drugs fit often into a small pocket of a particular protein, and thereby may activate or block their function without covalent interactions (only van der Waals). One assumes there are >1011 different antibodies or T-cell receptors for antigen (TCR)/individual and >7400 HLA alleles in the population, thus “immune receptors” offer an endless possibility of drug binding structures. Under certain circumstances this interaction may lead to functional consequences like immune stimulation. This concept is called “pharmacological interaction with immune receptors” (p-i concept) and may explain the majority of severe drug hypersensitivity reactions. The p-i concept is best investigated in T-cell reactions to drugs, which account for the majority of severe drug reactions. One differentiates p-i HLA, where the drug binds first to a certain HLA molecule: e.g. abacavir binds to HLA-B*57:01 and make it look like an allo-allele. Similar features may play a role in other HLA-allele linked hypersensitivity reactions (allopurinol, carbamazepine, flucloxacillin, etc). In p-i TCR, a direct binding of a drug to a certain TCR region occurs and leads to T cell activation. Examples might be sulfonamide hypersensitivity, which is not HLA allele linked. Off target activities of drugs with immune receptors have an enormous impact on understanding drug hypersensitivity, autoimmunity and immune suppression and tools need to be developed to consider the p-i concept for risk assessment. http://dx.doi.org/10.1016/j.toxlet.2013.06.045
S06-5 Assessing immunogenicity of therapeutic antibodies in transgenic mice Antonio Iglesias Non-clinical Safety, F. Hoffmann-La Roche AG, Basel, Switzerland Therapeutic antibodies (Abs), being humanized or fully human proteins, are not expected to provoke immune responses in treated humans. However, the Ab therapy often causes an anti-drug Ab response (ADA) leading to altered PK and efficacy and resulting in safety concerns. Thus, predictive tools for assessment of the immunogenic properties of therapeutic Abs are highly desired. To this end transgenic mice have been constructed capable of expressing a large recombinatorial repertoire of human heavy and light chain immunoglobulins (huIgG). The germline, unrearraged human Ig transgenes are allowed to rearrange along with the endogenous mouse Ig genes during normal B cell development in the transgenic mice. These huIgG-transgenic mice display immunological tolerance to a broad range of human antibodies (Abs). Therefore, they can sense immunogenic modifications, e.g. aggregates, as imposed to therapeutic Abs by different stress conditions. The breakage of tolerance in this system is indicative of immunogenic properties intrinsic to the Abs, or introduced to them during manufacture or storage processes. This transgenic system is suited to distinguish immunogenic from non-immunogenic Ab modifications and thus represents a useful instrument for the assessment
Abstracts / Toxicology Letters 221S (2013) S4–S30
Symposium 6: Challenges with immunogenicity of biologics
S06-1 Challenges with immunogenicity of biologics Cecilia Tami Laboratory of Immunology, Division of Therapeutic Proteins, CDER, FDA, Bethesda, MD, USA Protein immunogenicity plays a key role in the safety and efficacy of therapeutic proteins. This talk will review critical product attributes that impact on immunogenicity, highlight critical elements of the recently released FDA guidelines, and present a few case studies. http://dx.doi.org/10.1016/j.toxlet.2013.06.043
S06-2 Update on new regulatory guidelines on immunogenicity Gaby Reichmann Paul-Ehrlich-Institute, Federal Institute for Vaccines and Biomedicines, Langen, Germany Often an unwanted immune response is generated against therapeutic proteins. While such immune response can comprise both cellular and humoral elements, most adverse effects appear to be mediated by humoral mechanisms (i.e. anti-drug antibodies, ADA). Unwanted immunogenicity to therapeutic proteins can affect product efficacy. ADA may lead to enhanced clearance of the drug or directly neutralize the biological activity of the drug, both resulting in a loss of efficacy. Such ADA may also cross-react with an endogenous version of the therapeutic protein and inhibit the activity of the endogenous factor. In addition, unwanted immune responses to a therapeutic protein can affect patient safety. Acute effects such as anaphylaxis, cytokine-release syndrome and infusion reactions as well as non-acute effects such as immune complex disease have been observed. The development of an unwanted immune response against therapeutic proteins is dependent on patient-, disease- and product-related factors. However, it is not possible to predict if and to what extent an anti-therapeutic response will occur. Therefore, it is essential to assess unwanted immunogenicity against therapeutic proteins during clinical development and an appropriate assay strategy has to be developed. This should usually include a screening assay for identification of antibody-positive samples, a confirmatory assay and an assay to detect the neutralizing capacity of ADA. Since immune responses to therapeutic proteins can range from no apparent effect to serious adverse events a risk-based approach in the evaluation of unwanted immunogenicity may be recommended. http://dx.doi.org/10.1016/j.toxlet.2013.06.044
S06-4 Drug hypersensitivity and stimulation of the immune system: beyond the hapten concept Werner J. Pichler Allergology, Inselspital, University of Bern & ADR-AC, Bern, Switzerland Small molecular compounds like most drugs (<1000 D) are too small per se to act as antigen and require covalent binding to protein to become antigenic. However, drugs fit often into a small pocket of a particular protein, and thereby may activate or block their function without covalent interactions (only van der Waals). One assumes there are >1011 different antibodies or T-cell receptors for antigen (TCR)/individual and >7400 HLA alleles in the population, thus “immune receptors” offer an endless possibility of drug binding structures. Under certain circumstances this interaction may lead to functional consequences like immune stimulation. This concept is called “pharmacological interaction with immune receptors” (p-i concept) and may explain the majority of severe drug hypersensitivity reactions. The p-i concept is best investigated in T-cell reactions to drugs, which account for the majority of severe drug reactions. One differentiates p-i HLA, where the drug binds first to a certain HLA molecule: e.g. abacavir binds to HLA-B*57:01 and make it look like an allo-allele. Similar features may play a role in other HLA-allele linked hypersensitivity reactions (allopurinol, carbamazepine, flucloxacillin, etc). In p-i TCR, a direct binding of a drug to a certain TCR region occurs and leads to T cell activation. Examples might be sulfonamide hypersensitivity, which is not HLA allele linked. Off target activities of drugs with immune receptors have an enormous impact on understanding drug hypersensitivity, autoimmunity and immune suppression and tools need to be developed to consider the p-i concept for risk assessment. http://dx.doi.org/10.1016/j.toxlet.2013.06.045
S06-5 Assessing immunogenicity of therapeutic antibodies in transgenic mice Antonio Iglesias Non-clinical Safety, F. Hoffmann-La Roche AG, Basel, Switzerland Therapeutic antibodies (Abs), being humanized or fully human proteins, are not expected to provoke immune responses in treated humans. However, the Ab therapy often causes an anti-drug Ab response (ADA) leading to altered PK and efficacy and resulting in safety concerns. Thus, predictive tools for assessment of the immunogenic properties of therapeutic Abs are highly desired. To this end transgenic mice have been constructed capable of expressing a large recombinatorial repertoire of human heavy and light chain immunoglobulins (huIgG). The germline, unrearraged human Ig transgenes are allowed to rearrange along with the endogenous mouse Ig genes during normal B cell development in the transgenic mice. These huIgG-transgenic mice display immunological tolerance to a broad range of human antibodies (Abs). Therefore, they can sense immunogenic modifications, e.g. aggregates, as imposed to therapeutic Abs by different stress conditions. The breakage of tolerance in this system is indicative of immunogenic properties intrinsic to the Abs, or introduced to them during manufacture or storage processes. This transgenic system is suited to distinguish immunogenic from non-immunogenic Ab modifications and thus represents a useful instrument for the assessment