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Challenges and Approaches for the Development of Safer Immunomodulatory Biologics

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Challenges and Approaches for the Development of Safer Immunomodulatory Biologics REVIEWS Challenges and approaches for the development of safer immunomodulatory biologics Jean G. Sathish1*, Swaminathan Sethu1*, Marie-Christine Bielsky2, Lolke de Haan3, Neil S. French1, Karthik Govindappa1, James Green4, Christopher E. M. Griffiths5, Stephen Holgate6, David Jones2, Ian Kimber7, Jonathan Moggs8, Dean J. Naisbitt1, Munir Pirmohamed1, Gabriele Reichmann9, Jennifer Sims10, Meena Subramanyam11, Marque D. Todd12, Jan Willem Van Der Laan13, Richard J. Weaver14 and B. Kevin Park1 Abstract | 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. Immunomodulatory Biologics currently represent more than 30% of licensed The high specificity of the interactions of immu- biologics pharmaceutical products and have expanded the thera- nomodulatory biologics with their relevant immune Biotechnology-derived peutic options available for a broad range of diseases, targets — the on‑target effects — should theoretically pharmaceutical agents including immune-mediated inflammatory diseases and abrogate off-target effects. Despite the generally superior (recombinant proteins and 1,2 therapeutic monoclonal malignancies . Between 1993 and 2011, 174 new biolog- safety profiles of immunomodulatory biologics com- antibodies) that render their ics (that are not vaccines or blood products) were author- pared with small-molecules, several clinical concerns therapeutic effect primarily ized by the European Medicines Agency (EMA) (see the have emerged relating to unwanted effects or adverse through modulating European public assessment reports on the EMA website) reactions associated with the use of immunomodulatory (augmenting or reducing) (TABLES 1–3) immune responses by targeting and/or the US Food and Drug Administration (FDA) (see biologics . These adverse reactions can be immune-relevant molecules. the Drugs@FDA page on the FDA website). A large pro- broadly categorized into two groups. The first category portion of these are immunomodulatory biologics, which can includes adverse reactions that are due to on‑target be grouped into three main categories according to their interactions (that is, exaggerated pharmacology). These mode of action: cytokine immunomodulatory biologics include serious infections, malignancies, cytokine that mimic, replace or augment endogenous cytokines release syndrome (CRS), tumour lysis syndrome and 1MRC Centre for Drug Safety (for example, granulocyte colony-stimulating factor autoimmunity. The second category includes adverse Science and Institute of (G‑CSF) and interferon-β (IFNβ)) and are recombinant reactions that are due to the inherent property of the Translational Medicine, Department of Molecular human proteins; antibody-based triggering immunomod- biologic, such as immunogenicity. Adverse reactions that and Clinical Pharmacology, ulatory biologics that bind to relevant targets and trigger are due to the inherent property of the biologic can result University of Liverpool, immune cell signalling pathways (for example, rituximab in the generation of neutralizing anti-drug antibodies Sherrington Buildings, (Rituxan/Mabthera; Biogen Idec/Genentech/Roche) and (ADAs) and hypersensitivity reactions. Liverpool L69 3GE, UK. muromonab‑CD3); and blocking immunomodulatory Understanding the complex interactions among dis- Correspondence to B.K.P. e-mail: biologics that bind to immune-relevant targets and block ease states, the host immune system, the target of immu- [email protected] their function (for example, etanercept (Enbrel; Amgen/ nomodulation and the immunomodulatory biologic is doi:10.1038/nrd3974 Pfizer) and omalizumab (Zolair; Genentech/Novartis)). vital to predicting and mitigating the risk of unwanted 306 | APRIL 2013 | VOLUME 12 www.nature.com/reviews/drugdisc © 2013 Macmillan Publishers Limited. All rights reserved REVIEWS Author addresses Immunomodulation leading to serious infections and malignancies. A major adverse reaction associated 2Medicines and Healthcare products Regulatory Agency (MHRA), 151 Buckingham with immunomodulation is the occurrence of serious Palace Road, London SW1W 9SZ, UK. infections that result in mortality or in hospitalization, 3Medimmune, Aaron Klug Building, Granta Park, Cambridge CB21 6GH, UK. requiring management with intravenously administered 4Boehringer-Ingelheim, 4 Kato Summit, Sudbury, Massachusetts 01776, USA. 5Dermatology Centre, University of Manchester, Manchester Academic Health Science antibiotics. Out of the 40 licensed immunomodulatory Centre, Manchester M6 8HD, UK. biologics, 18 have been associated with serious infections, 6Faculty of Medicine, Clinical and Experimental Sciences, Level F, South Block, including reactivation of bacterial infections (for example, MP810, Southampton General Hospital, Tremona Road, Southampton, Hampshire mycobacterial, streptococcal, listerial or meningococcal SO16 6YD, UK. infections), viral infections (for example, hepatitis B virus 7MRC Centre for Drug Safety Science and Faculty of Life Sciences, University of (HBV) or HCV), fungal infections (for example, histo- Manchester, Manchester M13 9PT, UK. plasmosis) or opportunistic infections (for example, John 8Translational Sciences, Preclinical Safety and Investigative Toxicology, Novartis Cunningham virus (JCV) or Pseudomonas aeruginosa) Institutes for BioMedical Research, WSH-2881.1.29, Auhafenstrasse, CH-4132 (TABLES 1–3). Muttenz, Switzerland. The significance of these adverse reactions has been 9Paul-Ehrlich-Institute, Federal Institute for Vaccines and Biomedicines Paul-Ehrlich Strasse, 51–59, 63225 Langen, Germany. recognized by regulatory authorities (the FDA and the 10Integrated Biologix, Basel 4056, Switzerland. EMA) and is reflected in product labels that state this 11Translational Medicine, Biogen Idec, 14 Cambridge Center, Cambridge, risk. For some of these biologics, there is a clear cause Massachusetts 02142, USA. and effect, and with this knowledge (BOX 1) it is possible 12Pfizer, La Jolla Laboratories, 10646 Science Center Drive, San Diego, California to implement mitigating strategies. However, for other 92121, USA. biologics the causes of the increased susceptibility to 13Section on Pharmacology, Toxicology and Biotechnology (FTBB), Medicines infections are less obvious and therefore further analyses Evaluation Board, Graadt van Roggenweg 500, 3531 AH Utrecht, The Netherlands. are necessary before preventive strategies can be formu- 14 Drug Safety Assessment Centre, Biologie Servier, Gidy 45520, France. lated (BOX 1). *These authors contributed equally to this work. Natalizumab (Tysabri; Biogen Idec/Elan) is an exam- ple of an immunomodulatory biologic that has a clear cause and effect, and for which the implementation of a risk management strategy was possible. Natalizumab effects (FIG. 1). Furthermore, such detailed understanding is indicated for the treatment of multiple sclerosis and can contribute to the design and development of immu- Crohn’s disease, and it exerts its therapeutic effects nomodulatory biologics with a reduced risk of unwanted by binding to the α4 integrin subunit to interfere with effects. T cell trafficking. However, it has been associated with In this Review, we first focus on the current under- progressive multifocal leukoencephalopathy (PML), a standing regarding immunomodulation leading to seri- progressive sub-acute demyelinating neurological con- ous infections, malignancies and CRS, as well as the dition4 that is caused by the reactivation of latent JCV immunogenicity of immunomodulatory biologics. We infection. The reduced T cell trafficking to the central also outline strategies that are being pursued to prevent, nervous system (CNS) compromises the immune sur- minimize or mitigate these unwanted effects. We dis- veillance and control of JCV in susceptible patients, thus cuss the current state of available tools to predict these increasing the risk of developing PML. Indeed, up to 11 adverse reactions. Finally, we present a scheme out- out of every 1,000 patients receiving natalizumab therapy lining how an increased understanding of target biol- may develop PML if they have all of the following risk ogy and the mechanisms that drive unwanted effects, factors: prior infection with JCV, presence of JCV anti- along with predictive tools, can be used for developing bodies and clinical factors such as increased duration of immunomodulatory biologics that have improved safety treatment and concomitant immunosuppressant ther- profiles. apy5. These risk factors have been formally taken into account by regulatory agencies and are recognized by Current knowledge of adverse reactions boxed warnings. Moreover, the product label for natali- A comprehensive understanding of the nature and zumab recommends testing patients for JCV-specific Adverse reactions mechanisms of the adverse reactions associated with antibody
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