Challenges and approaches for the development of safer immunomodulatory biologics
| Autor: | Jan Willem van der Laan, Ian Kimber, Dean J. Naisbitt, Meena Subramanyam, Swaminathan Sethu, Marque Todd, Karthik Govindappa, Jennifer Sims, David Jones, Richard J. Weaver, Stephen T. Holgate, B. Kevin Park, Neil French, Lolke de Haan, Jean G. Sathish, Christopher E.M. Griffiths, James D. Green, Marie Christine Bielsky, Gabriele Reichmann, Jonathan G. Moggs, Munir Pirmohamed |
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| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
medicine.medical_specialty
Immunologic Factors Biologics Toxicology Risk Assessment Article Autoimmune Diseases SAFER Neoplasms Drug Discovery Medicine Animals Humans Drug discovery and development Intensive care medicine Drug safety Immunological disorders Pharmacology Inflammation Risk Management business.industry Pharmaceutics General Medicine medicine.disease Cytokine release syndrome Drug Design Immunology Screening business |
| Zdroj: | Nature Reviews. Drug Discovery |
| ISSN: | 1474-1784 1474-1776 |
| Popis: | Key Points Immunomodulatory biologics are a class of biotechnology-derived therapeutic products that are designed to engage immune-relevant targets and are indicated in the treatment and management of a range of diseases, including immune-mediated inflammatory diseases and malignancies.Despite their high specificity and therapeutic advantages, immmunomodulatory biologics have been associated with adverse reactions such as serious infections, malignancies and cytokine release syndrome, which arise owing to the on-target or exaggerated pharmacological effects of these drugs. Immunogenicity resulting in the generation of antidrug antibodies is another unwanted effect that leads to loss of efficacy and — rarely — hypersensitivity reactions.For some adverse reactions, mitigating and preventive strategies are in place, such as stratifying patients on the basis of responsiveness to therapy and the risk of developing adverse reactions. These strategies depend on the availability of robust biomarkers for therapeutic efficacy and the risk of adverse reactions: for example, seropositivity for John Cunningham virus is a risk factor for progressive multifocal leukoencephalopathy. The development of effective biomarkers will greatly aid these strategies.The development and design of safer immunomodulatory biologics is reliant on a detailed understanding of the nature of the disease, target biology, the interaction of the target with the immunomodulatory biologic and the inherent properties of the biologic that elicit unwanted effects.The availability of in vitro and in vivo models that can be used to predict adverse reactions associated with immunomodulatory biologics is central to the development of safer immunomodulatory biologics. Some progress has been made in developing in vitro and in silico tests for predicting cytokine release syndrome and immunogenicity, but there is still a lack of models for effectively predicting infections and malignancies.Two pathways can be followed in designing and developing safer immunomodulatory biologics. The first pathway involves generating a biologic that engages an alternative target or mechanism to produce the desired pharmacodynamic effect without the associated adverse reaction, and is followed when the adverse reaction cannot be dissociated from the target biology. The second pathway involves redesigning the biologic to 'engineer out' components within the biologic structure that trigger adverse effects or to alter the nature of the target–biologic interactions. Supplementary information The online version of this article (doi:10.1038/nrd3974) contains supplementary material, which is available to authorized users. Owing to their specificity, immunomodulatory biologics generally have better safety profiles than small-molecule drugs. However, adverse effects such as an increased risk of infections or cytokine release syndrome are of concern. Here, Park and colleagues discuss the current strategies used to predict and mitigate these adverse effects and consider how they can be used to inform the development of safer immunomodulatory biologics. Supplementary information The online version of this article (doi:10.1038/nrd3974) contains supplementary material, which is available to authorized users. Immunomodulatory biologics, which render their therapeutic effects by modulating or harnessing immune responses, have proven their therapeutic utility in several complex conditions including cancer and autoimmune diseases. However, unwanted adverse reactions — including serious infections, malignancy, cytokine release syndrome, anaphylaxis and hypersensitivity as well as immunogenicity — pose a challenge to the development of new (and safer) immunomodulatory biologics. In this article, we assess the safety issues associated with immunomodulatory biologics and discuss the current approaches for predicting and mitigating adverse reactions associated with their use. We also outline how these approaches can inform the development of safer immunomodulatory biologics. Supplementary information The online version of this article (doi:10.1038/nrd3974) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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