RESUMO
Monoclonal antibodies (mAbs) and mAb derivatives have become mainstay pharmaceutical modalites. A critical assessment is to ascertain the specificity of these molecules prior to human clinical trials. The primary technique for determining specificity has been the immunohistochemistry (IHC)-based "Tissue Cross-Reactivity" (TCR) assay, where the candidate molecule is applied to > 30 tissues to look for unexpected staining. In the last few years, however, non-IHC array-based platforms have emerged that allow for screening 75-80% of the human membrane proteome, indicating a viable alternative and/or addition to the IHC methods. The preclinical sciences subcommittee of the Biotechnology Innovation Organization (BIO), "BioSafe", conducted a survey of 26 BIO member companies to understand current sponsor experience with the IHC and array techniques. In the last ten years, respondents noted they have conducted more than 650 IHC TCR assays, largely on full length mAbs, with varying impacts on programs. Protein/cell arrays have been utilized by almost half of the companies and sponsors are gaining familiarity and comfort with the platform. Initial experience with recent versions of these arrays has been largely positive. While most sponsors are not prepared to eliminate the IHC TCR assay, growing experience with these alternatives allows them to confidently choose other approaches with or without TCR assays.
Assuntos
Anticorpos Monoclonais , Reações Cruzadas , Avaliação Pré-Clínica de Medicamentos/métodos , Animais , Biotecnologia , Indústria Farmacêutica , Humanos , Imuno-Histoquímica , Inquéritos e QuestionáriosRESUMO
Monoclonal antibodies (mAbs) are improving the quality of life for patients suffering from serious diseases due to their high specificity for their target and low potential for off-target toxicity. The toxicity of mAbs is primarily driven by their pharmacological activity, and therefore safety testing of these drugs prior to clinical testing is performed in species in which the mAb binds and engages the target to a similar extent to that anticipated in humans. For highly human-specific mAbs, this testing often requires the use of non-human primates (NHPs) as relevant species. It has been argued that the value of these NHP studies is limited because most of the adverse events can be predicted from the knowledge of the target, data from transgenic rodents or target-deficient humans, and other sources. However, many of the mAbs currently in development target novel pathways and may comprise novel scaffolds with multi-functional domains; hence, the pharmacological effects and potential safety risks are less predictable. Here, we present a total of 18 case studies, including some of these novel mAbs, with the aim of interrogating the value of NHP safety studies in human risk assessment. These studies have identified mAb candidate molecules and pharmacological pathways with severe safety risks, leading to candidate or target program termination, as well as highlighting that some pathways with theoretical safety concerns are amenable to safe modulation by mAbs. NHP studies have also informed the rational design of safer drug candidates suitable for human testing and informed human clinical trial design (route, dose and regimen, patient inclusion and exclusion criteria and safety monitoring), further protecting the safety of clinical trial participants.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Avaliação Pré-Clínica de Medicamentos/métodos , Primatas , Animais , Anticorpos Monoclonais/efeitos adversos , Qualidade de Produtos para o Consumidor , Humanos , Modelos Animais , Medição de Risco , Fatores de Risco , Especificidade da EspécieRESUMO
PEGylation (the covalent binding of one or more polyethylene glycol molecules to another molecule) is a technology frequently used to improve the half-life and other pharmaceutical or pharmacological properties of proteins, peptides, and aptamers. To date, 11 PEGylated biopharmaceuticals have been approved and there is indication that many more are in nonclinical or clinical development. Adverse effects seen with those in toxicology studies are mostly related to the active part of the drug molecule and not to polyethylene glycol (PEG). In 5 of the 11 approved and 10 of the 17 PEGylated biopharmaceuticals in a 2013 industry survey presented here, cellular vacuolation is histologically observed in toxicology studies in certain organs and tissues. No other effects attributed to PEG alone have been reported. Importantly, vacuolation, which occurs mainly in phagocytes, has not been linked with changes in organ function in these toxicology studies. This article was authored through collaborative efforts of industry toxicologists/nonclinical scientists to address the nonclinical safety of large PEG molecules (>10 kilo Dalton) in PEGylated biopharmaceuticals. The impact of the PEG molecule on overall nonclinical safety assessments of PEGylated biopharmaceuticals is discussed, and toxicological information from a 2013 industry survey on PEGylated biopharmaceuticals under development is summarized. Results will contribute to the database of toxicological information publicly available for PEG and PEGylated biopharmaceuticals.
Assuntos
Avaliação Pré-Clínica de Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Polietilenoglicóis/toxicidade , Animais , Humanos , Polietilenoglicóis/químicaRESUMO
The utility of animal models of disease for assessing the safety of novel therapeutic modalities has become an increasingly important topic of discussion as research and development efforts focus on improving the predictive value of animal studies to support accelerated clinical development. Medicines are approved for marketing based upon a determination that their benefits outweigh foreseeable risks in specific indications, specific populations, and at specific dosages and regimens. No medicine is 100% safe. A medicine is less safe if the actual risks are greater than the predicted risks. The purpose of preclinical safety assessment is to understand the potential risks to aid clinical decision-making. Ideally preclinical studies should identify potential adverse effects and design clinical studies that will minimize their occurrence. Most regulatory documents delineate the utilization of conventional "normal" animal species to evaluate the safety risk of new medicines (i.e., new chemical entities and new biological entities). Animal models of human disease are commonly utilized to gain insight into the pathogenesis of disease and to evaluate efficacy but less frequently utilized in preclinical safety assessment. An understanding of the limitations of the animal disease models together with a better understanding of the disease and how toxicity may be impacted by the disease condition should allow for a better prediction of risk in the intended patient population. Importantly, regulatory authorities are becoming more willing to accept and even recommend data from experimental animal disease models that combine efficacy and safety to support clinical development.
Assuntos
Ensaios Clínicos como Assunto/métodos , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos/métodos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Regulamentação Governamental , Pesquisa Translacional Biomédica/métodos , Alternativas ao Uso de Animais , Animais , Ensaios Clínicos como Assunto/legislação & jurisprudência , Europa (Continente) , Guias como Assunto , Humanos , Especificidade da Espécie , Testes de Toxicidade , Pesquisa Translacional Biomédica/legislação & jurisprudência , Estados UnidosRESUMO
This white paper summarizes the current consensus of the Reproductive Subcommittee of the Oligonucleotide Safety Working Group on strategies to assess potential reproductive and/or developmental toxicities of therapeutic oligonucleotides (ONs). The unique product characteristics of ONs require considerations when planning developmental and reproductive toxicology studies, including (a) chemical characteristics, (b) assessment of intended and unintended mechanism of action, and (c) the optimal exposure, including dosing regimen. Because experience across the various classes of ONs as defined by their chemical backbone is relatively limited, best practices cannot be defined. Rather, points to consider are provided to help in the design of science-based reproductive safety evaluation programs based upon product attributes.
Assuntos
Aptidão Genética/efeitos dos fármacos , Guias como Assunto , Oligonucleotídeos/farmacocinética , Reprodução/efeitos dos fármacos , Animais , Biomarcadores Farmacológicos/análise , Vias de Administração de Medicamentos , Esquema de Medicação , Cálculos da Dosagem de Medicamento , Avaliação Pré-Clínica de Medicamentos , Humanos , Modelos Animais , Oligonucleotídeos/administração & dosagem , Oligonucleotídeos/toxicidadeRESUMO
Oligonucleotides (ONs) are an emerging class of drugs being developed for the treatment of a wide variety of diseases including the treatment of respiratory diseases by the inhalation route. As a class, their toxicity on human lungs has not been fully characterized, and predictive toxicity biomarkers have not been identified. To that end, identification of sensitive methods and biomarkers that can detect toxicity in humans before any long term and/or irreversible side effects occur would be helpful. In light of the public's greater interests, the Inhalation Subcommittee of the Oligonucleotide Safety Working Group (OSWG) held expert panel discussions focusing on the potential toxicity of inhaled ONs and assessing the strengths and weaknesses of different monitoring techniques for use during the clinical evaluation of inhaled ON candidates. This white paper summarizes the key discussions and captures the panelists' perspectives and recommendations which, we propose, could be used as a framework to guide both industry and regulatory scientists in future clinical research to characterize and monitor the short and long term lung response to inhaled ONs.
Assuntos
Pulmão/efeitos dos fármacos , Oligonucleotídeos/toxicidade , Administração por Inalação , Animais , Biomarcadores/sangue , Avaliação Pré-Clínica de Medicamentos , Humanos , Pulmão/fisiopatologia , Oligonucleotídeos/administração & dosagem , Guias de Prática Clínica como Assunto , Testes de Função RespiratóriaRESUMO
Tissue cross-reactivity (TCR) studies are screening assays recommended for antibody and antibody-like molecules that contain a complementarity-determining region (CDR), primarily to identify off-target binding and, secondarily, to identify sites of on-target binding that were not previously identified. At the present time, TCR studies involve the ex vivo immunohistochemical (IHC) staining of a panel of frozen tissues from humans and animals, are conducted prior to dosing humans, and results are filed with the initial IND/CTA to support first-in-human clinical trials. In some cases, a robust TCR assay cannot be developed, and in these cases the lack of a TCR assay should not prevent a program from moving forward. The TCR assay by itself has variable correlation with toxicity or efficacy. Therefore, any findings of interest should be further evaluated and interpreted in the context of the overall pharmacology and safety assessment data package. TCR studies are generally not recommended for surrogate molecules or for comparability assessments in the context of manufacturing/cell line changes. Overall, the design, implementation, and interpretation of TCR studies should follow a case-by-case approach.
Assuntos
Anticorpos Monoclonais/imunologia , Reações Cruzadas/imunologia , Avaliação Pré-Clínica de Medicamentos/métodos , Animais , Anticorpos Monoclonais/farmacologia , Sítios de Ligação de Anticorpos , Desenho de Fármacos , Descoberta de Drogas , Humanos , Imuno-Histoquímica/métodosRESUMO
The ICH S6 guidance was developed to describe a rational science-based flexible approach to the preclinical evaluation for biotechnology-derived pharmaceutical products. It also suggested that some of the principles described may be suitable for plasma-derived therapeutics. Some of the specific concerns unique to protein-based therapeutics include complexity in structure and potential immunogenicity. S6 has been interpreted by some industry and regulatory authorities, often due to lack of experience with these types of products, as encouraging a broader or more conventional toxicology program similar to that normally conducted for small molecules. The guidance does encourage important and necessary preclinical evaluations but also recognizes the limitations of studies in non-relevant animal species because they are without pharmacological interaction with the biologic. In addition, studies of human proteins are often limited in useful chronic, reproductive and carcinogenic toxicity evaluations by the immunological response in animals. Thus the safety evaluation of biopharmaceuticals and plasma derivatives in animals has limitations that cannot be adequately addressed by the use of testing paradigms used for small molecule pharmaceuticals. S6 focuses evaluations on well-designed studies in relevant species for reasonable time periods to make the best use of available resources and enable clinical trials.
Assuntos
Produtos Biológicos/farmacologia , Avaliação Pré-Clínica de Medicamentos/normas , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Guias como Assunto/normas , Animais , Produtos Biológicos/sangue , Proteínas Sanguíneas/farmacologia , Ensaios Clínicos como Assunto/métodos , Ensaios Clínicos como Assunto/normas , Congressos como Assunto , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Agências Internacionais , Cooperação Internacional , Farmacopeias como Assunto/normas , Reprodutibilidade dos Testes , Tecnologia Farmacêutica/métodos , Tecnologia Farmacêutica/normasRESUMO
This report discusses the principles of developmental and reproductive toxicity (DART) testing for biopharmaceuticals. Biopharmaceuticals are large-molecular-weight proteins or peptides produced by modern biotechnology techniques incorporating genetic engineering and hybridoma technologies. The principles of DART testing for biopharmaceuticals are similar to those for small-molecule pharmaceuticals and in general follow the regulatory guidance outlined in International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) document S5(R2). However, because many biopharmaceuticals are species-specific, alternate approaches may be needed to evaluate DART potential as outlined in ICH S6. For molecules that show species-specific cross-reactivity restricted to non-human primates (NHP), some aspects of DART may require NHP testing. For biopharmaceuticals that are uniquely specific and only active on intended human targets or human and chimpanzee targets, surrogate molecules that cross-react with the more traditional rodent species may need to be developed and used for DART testing. Alternatively, genetically modified transgenic animals may also need to be considered. Surrogate molecules and transgenic animals may also be considered for DART testing even if the biopharmaceutical is active in NHPs in order to reduce the use of NHPs. Because of the unique properties of biopharmaceuticals, a case-by-case approach is needed for DART and general toxicity evaluation, which requires consideration of specific product attributes including biochemical and biophysical characteristics, pharmacological activity, and intended clinical indication.
Assuntos
Biofarmácia/métodos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Desenvolvimento Embrionário/efeitos dos fármacos , Reprodução/efeitos dos fármacos , Algoritmos , Animais , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Placenta/efeitos dos fármacos , Placenta/metabolismo , Gravidez , Medição de Risco , Testes de Toxicidade/métodosRESUMO
For chronic use biotechnology-derived pharmaceuticals, toxicity studies of 6 months have generally been accepted for regulatory approval. This review assessed the data for 23 approved biotechnology-derived pharmaceuticals to determine whether the studies conducted were predictive of human safety and whether there is new data from approved products indicating that longer than 6 months is necessary. This assessment involved three approaches; whether new toxicities were identified at >6 months, similarity of findings between 6 months and shorter studies and predictivity of clinical adverse events. In two cases there were apparently new findings in studies >6 months. On examination however, one of these cases was a well established risk with foreign protein administration to animals (adalimumab). For insulin aspart, the 12 month study identified tumors not seen in shorter term studies, however, determination of carcinogenic potential is not a goal of chronic toxicity studies and is addressed by separate studies. In most cases the toxicology studies were predictive of common clinical adverse reactions, but were poorly predictive of rare clinical events or some serious adverse reactions. Although specific circumstances may require a longer study, this review indicates no new data is available to refute the utility of 6 month studies to support chronic clinical dosing with biotechnology-derived pharmaceuticals.