Fda regulatory perspectives on therapeutic protein immunogenicity. Jul 09, 2011 immunogenicity of therapeutic proteins lowers patient wellbeing and drastically increases therapeutic costs. These potentially lead to reduced efficacy through rapid clearance or neutralisation of the drug or toxicity due to crossreaction with proteins in the body. Immunogenicity assessment of therapeutic proteins european. The fast growing number of therapeutic proteins and related immunogenicity data shows that most of them. Product and hostspecific factors can influence immunogenicity healthy vs. Immunogenicity in protein and peptide basedtherapeutics. Immunogenicity in clinical practice and drug development. The consequences of such immune reactions to a therapeutic protein, range from transient appearance.
The findings from these measurements impact dose selection and the safety profile of the drug. The measurement of unwanted immunogenicity of therapeutic proteins and peptides is a key scientific expertise of eurofins biopharma product testing munich gmbh. Typically, immunogenicity is characterised by measuring the production of antidrug antibodies ada against the protein therapeutic. Proteins are susceptible to glycation and it is the protein structure that determines to what extent given protein will accumulate ages.
Immunogenicity testing of the biosimilar and the reference product should be. Preventing immunogenicity is an important issue to consider when developing novel therapeutic proteins and applying them in the clinic. Immunogenicity is the immune response a host mounts against an antigen, such as a protein therapeutic. Implications of immunogenicity in drug development covance. Therapeutic proteins rmabs, if they dont mimic the naturally occurring protein, can also produce an immune response, with the body seeing it as an invader.
The guideline advocates a risk and sciencebased multidisciplinary approach to immunogenicity and serves as a roadmap for developers of therapeutic proteins and regulators. Guideline on immunogenicity assessment of therapeutic. A successful, robust formulation depends on the understanding of the physical and chemical nature of the active substance and the excipients alone and their interaction. Immunogenicity testing in clinical practice is typically performed as reflex testing based on druglevel monitoring or clinical suspicion. Immunogenicity assessment for therapeutic protein products. Many therapeutic protein products intended to address unmet medical needs are being developed worldwide, including in japan, and therefore, ensuring their safety and efficacy is of paramount importance. Antibodies health aspects biological products biomedical laboratories enzymelinked immunosorbent assay evidencebased medicine medical laboratories patient compliance tumor necrosis factor tumors viral antibodies. Aug 27, 20 the immunogenicity of therapeutic proteins is a commonly occurring phenomenon.
During drug development, regulatory agencies require pharmaceutical companies to test biological drugs so that they are safe for patients. Faqi, in reproductive and developmental toxicology, 2011. One of the major challenges in the utilization of information on immunogenicity for biologics in drug development and clinical practice is related to the analytical methodologies used to assess the incidence of. The prediction of immunogenicity in patients based on physicochemical characterization and animal studies is not easy. And for the purposes of this guidance, immunogenicity is defined as the propensity of a therapeutic protein product to generate immune responses to itself and to related proteins or to induce immunologically related adverse clinical events. This is exemplified by clinical immunogenicity testing for the antitnf biologics. Taking immunogenicity assessment of therapeutic proteins to the. Analysis of regulatory guidance on antidrug antibody. Federal register assay development and validation for. Immunogenicity testing of therapeutic protein products fda. Principles of immunogenicity testing during product development. May 09, 2012 therapeutic proteins rmabs, if they dont mimic the naturally occurring protein, can also produce an immune response, with the body seeing it as an invader. Guideline on immunogenicity assessment of therapeutic proteins.
Such differences may reflect disparate bioanalytical methods and interpretation approaches 7, 8, as well as a plethora of product. Assessing the immunogenicity of protein therapeutics. Many of the protein therapeutics elicit immune response when administered to patients schellekens, 2002. Therefore, the appropriate immunogenicity assays and. Preclinical immunogenicity testing for recombinant. One of the major challenges in the utilization of information on immunogenicity for biologics in drug development and clinical practice is related to the analytical methodologies used to assess the incidence of ada formation and the impact of immune reactions. Importantly, the incidence of ada can vary greatly between same. Assay development for immunogenicity testing of therapeutic. During drug development, regulatory agencies require pharmaceutical companies to. The measurement of unwanted immunogenicity of therapeutic proteins and peptides is a key scientific expertise of eurofins munich. Similarly as human proteins are foreign to animals, it is common for animals to develop anti.
Fusion proteins composed of a foreign and selfprotein, as well as chimeric proteins, may be of concern, especially because of the potential of the foreign moiety to provoke an immune response to the selfprotein epitope spreading. Analysis of regulatory guidance on antidrug antibody testing. Moreover, the role of treg in the development of autoimmune disease may be instructive for better understanding their contributions to the immunogenicity of therapeutic proteins. In support of preclinical and clinical trials the immunoanalytics department of eurofins munich contributes to. The development of adequate screening and confirmatory assays to measure immune responses against a therapeutic. However, given the sophistication and highthroughput capacity of existing in silico tools and the availability of precise in vitro validation assays, accurate prediction of immunogenicity for therapeutic protein products. Maillard reaction and immunogenicity of protein therapeutics. Emerging approaches to predict, reduce or reverse biotherapeutic immunogenicity. Prediction of immunogenicity for therapeutic proteins. Fda2009d0539 draft guidance for industry on assay development for immunogenicity testing of therapeutic proteins. Engineering of therapeutic proteins 157 posttranslational modification, protein fusions, and genetic engineering, as illustrated in figure 7. Characterization of antibodies to a therapeutic protein.
The recommendations apply to assays that detect one or more antidrug antibodies adas and may also apply, on a casebycase basis, to certain peptides, oligonucleotides and combination products, the agency said. Therapeutic proteins are known to elicit immune responses whether they are therapeutic counterparts of endogenous proteins or foreign proteins with little human homology. In order to provide context to the bioanalytical strategies used to support the pegylated therapeutics presented here, a. High resolution analytical techniques reveal structural microheterogeneity within endogenous proteins, however, they are seen as self molecules by the immune system and. Understanding the mechanism of the immune response and factors influencing immunogenicity of therapeutic proteins will allow us to design safer drugs and prevent immunogenicity. Immunogenicity is the development of immune responses, usually measured by antibodies, to therapeutic proteins. Immunogenicity testing of therapeutic protein products developing and validating assays for antidrug antibody detection guidance for. Although the reliability of the antidrug antibody ada assay is one of the key points, there are some difficulties in assessing its validity because the analytes are polyclonal antibodies with variable and unknown characteristics. Immunogenicity assessment of tumor necrosis factor. Jan 28, 2020 the objective of this manuscript is to provide the reader with two examples on how to present an immunogenicity risk assessment for a pegylated therapeutic as part of investigational new drug ind application or during other stages of the drug development process. Federal register draft guidance for industry on assay. Immunogenicity of therapeutic proteins springerlink. Fda issues guidance on therapeutic protein immunogenicity.
Animal models are increasingly used to study immunogenicity of therapeutic proteins. The information in this guidance has been reorganized for clarity and. Assay development for immunogenicity testing of therapeutic proteins 30 issued in december 2009. Immunogenicity testing of therapeutic protein products developing and validating assays for antidrug antibody detection january 2019. This guidance revises the draft guidance for industry entitled assay development for immunogenicity testing of therapeutic proteins issued in december 2009. These responses can adversely affect the safety and efficacy of the therapeutic agent and may have the following consequences. Pembrolizumab is a potent, humanized, monoclonal antiprogrammed death 1 antibody that has demonstrated effective antitumor activity and acceptable safety in multiple tumor types.
What you should know about immunogenicity testing of. Immunogenicity of pembrolizumab in patients with advanced. This guidance was created by a working group that consisted of staff from the center for drug evaluation and research cder and the center for biologics evaluation and research cber. The measurement of adverse immune reactions is complex as it depends on many drug and diseasespecific aspects.
Assay development and validation for immunogenicity testing. Draft guidance for industry on assay development for. Immunogenicity testing of therapeutic protein products. The objective of this manuscript is to provide the reader with two examples on how to present an immunogenicity risk assessment for a pegylated therapeutic as part of investigational new drug ind application or during other stages of the drug development process. Scaling up the studies by including other therapeutic proteins will reveal the magnitude of ages as a causal factor of drugs immunogenicity. Immunogenicity of therapeutic proteins manifests as the development of ada and hypersensitivity reactions. Testing munich gmbh contributes to biomarker analyses, pharmacokinetic studies, and the assessment of immunotoxicity and immunogenicity. Immunogenicity of therapeutic proteins lowers patient wellbeing and drastically increases therapeutic costs. Figures 1a and 1b property of meso scale diagnostics, llc and used with permission. Therapeutic antibodies and proteins can induce an immune response in patients leading to the development of antidrug antibodies adas.
It is widely accepted in the scientific literature that protein aggregation can augment a proteinspecific immune response, and lead to formation of ada in the case of protein therapeutics rosenberg, 2006. Immunogenicity assessment during the development of. Preclinical immunogenicity testing for recombinant therapeutic proteins article in journal of immunotoxicology 24. Formulation the composition of a formulation is chosen in order to best maintain the native conformation of therapeutic proteins. Immunogenicity assessment of tumor necrosis factor antagonists in the clinical laboratory. A riskbased approach to immunogenicity concerns of therapeutic protein products part 1 considering consequences of the immune response to a protein. Recombinant therapeutic proteins can be immunogenic antibodies to therapeutic proteins can cause difficulties in preclinical animal studies and occasionally, serious side effects in humans antibody testing method can greatly impact the results careful antibody monitoring with appropriate assays is necessary throughout preclinical and clinical. Immunogenicity has the potential to be a significant obstacle in the development of successful biological drugs. Guideline on immunogenicity assessment of biotechnology. Although immunoassays represent the most common analytical platform, other methodologies demonstrate similar performance. Therapeutic proteins provide interventions for some of the most complex and intractable diseases and are an essential part of modern medicine.
Immunogenicity risk assessment immunogenicity prediction. Product testing immunogenicity testing eurofins biopharma product testing is an internationally active contract research organization cro offering comprehensive services in biological safety and activity testing. Evaluating and mitigating the immunogenicity of therapeutic. These tests also measure the various antidrug antibodies ada and soluble protein biomarkers. The fda released guidance for sponsors of therapeutic proteins on developing tests to assess immunogenicity during clinical trials. They can be considered to be patient, disease or productrelated. Immunogenicity refers to the ability of therapeutic protein products to stimulate an immune response, specifically, the development of antidrug antibodies adas. Therapeutic biologics can result in the development of antidrug antibodies adas, which may alter drug clearance and neutralize target binding, potentially reducing drug efficacy. Immunogenicity risk assessment for pegylated therapeutics. It does not create or confer any rights for or on any person and does not operate to 8 bind fda or the public.
Taking immunogenicity assessment of therapeutic proteins to. The immunogenicity of therapeutic proteins is a commonly occurring phenomenon. This guidance provides recommendations to facilitate industrys development and validation of assays for assessment of the immunogenicity of therapeutic protein products during. The information in the draft guidance has been reorganized for clarity, and the revised draft guidance includes new information on titering and confirmatory assays. Immunogenicity testing of therapeutic protein products fda have issued a new draft guidance for developing and validating assays for antidrug antibody detection. When final, this guidance will reflect the agencys current thinking on this topic. Dec 15, 2017 therapeutic proteins such as monoclonal antibodies are currently essential in the treatment of cancer, autoimmune disease and other diseases. Fda for some therapeutic protein products, the sponsor may need to investigate the ada to specific. These antibodies act by neutralizing or binding to therapeutic protein products, and their presence is often concerning for impending biologic failure. Validation for immunogenicity testing of therapeutic. Immunogenicity of protein pharmaceuticals sciencedirect. Many factors may influence the immunogenicity of therapeutic proteins. The importance of immunogenicity to patient safety and drug efficacy has resulted in a number of guidance documents prepared by the regulatory community, the most recent of which is fdas draft guidance for industry on assay development for immunogenicity testing of therapeutic proteins released december 2009.
In order to provide context to the bioanalytical strategies used to support the pegylated therapeutics presented here, a brief. Taking immunogenicity assessment of therapeutic proteins. Preventing immunogenicity is an important issue to consider when developing novel. Immunogenicity, biosensor, peptide, biological drugs, antidrugs antibodies, adas. Immunogenicity is defined as the ability of a substance protein or chemical to provoke an immune response. Clinical immunogenicity of therapeutic proteins is a growing issue that threatens to undermine the development of potent protein drugs. Immunogenicity assessment during the development of protein. Validated detection systems are essential to study the immunogenicity of therapeutic proteins. Immunogenicity, therapeutic proteins, antidrug antibodies ada, assays, assay strategy, binding antibodies, neutralising antibodies, risk factors, safety, efficacy. Fda is announcing the availability of a draft guidance for industry entitled assay development for immunogenicity testing of therapeutic proteins. Fda guidance on immunogenicity of therapeutic proteins 2014immunogenicity assessment for therapeutic protein products 2016assay development and validation for immunogenicity testing of therapeutic protein products draft final version expected 2018. Immunogenicity assessment is an important issue for ensuring the safety and efficacy of therapeutic protein products.