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  • Review Article
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Challenges and approaches for the development of safer immunomodulatory biologics

Nature Reviews Drug Discovery volume 12, pages 306–324 (2013)Cite this article

Subjects

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.

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.

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Figure 1: Complex interactions among the disease, the immune system and immunomodulatory biologics that influence safety and efficacy.
Figure 2: Pathways for the development of safer immunomodulatory biologics.

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Acknowledgements

The authors thank F. Brennan for his helpful discussions.

Author information

Author notes

  1. Jean G. Sathish and Swaminathan Sethu: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular and Clinical Pharmacology, MRC Centre for Drug Safety Science and Institute of Translational Medicine, University of Liverpool, Sherrington Buildings, Liverpool, L69 3GE, UK

    Jean G. Sathish, Swaminathan Sethu, Neil S. French, Karthik Govindappa, Dean J. Naisbitt, Munir Pirmohamed & B. Kevin Park

  2. Medicines and Healthcare products Regulatory Agency (MHRA), 151 Buckingham Palace Road, London, SW1W 9SZ, UK

    Marie-Christine Bielsky & David Jones

  3. Medimmune, Aaron Klug Building, Granta Park, Cambridge, CB21 6GH, UK

    Lolke de Haan

  4. Boehringer-Ingelheim, 4 Kato Summit, Sudbury, 01776, Massachusetts, USA

    James Green

  5. Dermatology Centre, University of Manchester, Manchester Academic Health Science Centre, Manchester, M6 8HD, UK

    Christopher E. M. Griffiths

  6. Faculty of Medicine, Clinical and Experimental Sciences, Level F, South Block, MP810, Southampton General Hospital, Tremona Road, Southampton, SO16 6YD, Hampshire, UK

    Stephen Holgate

  7. MRC Centre for Drug Safety Science and Faculty of Life Sciences, University of Manchester, Manchester, M13 9PT, UK

    Ian Kimber

  8. Translational Sciences, Preclinical Safety and Investigative Toxicology, Novartis Institutes for BioMedical Research, WSH-2881.1.29, Auhafenstrasse, Muttenz, CH-4132, Switzerland

    Jonathan Moggs

  9. Paul-Ehrlich-Institute, Federal Institute for Vaccines and Biomedicines, Paul-Ehrlich Strasse, 51–59, Langen, 63225, Germany

    Gabriele Reichmann

  10. Integrated Biologix, Basel, 4056, Switzerland

    Jennifer Sims

  11. Translational Medicine, Biogen Idec, 14 Cambridge Center, Cambridge, 02142, Massachusetts, USA

    Meena Subramanyam

  12. Pfizer, La Jolla Laboratories, 10646 Science Center Drive, San Diego, 92121, California, USA

    Marque D. Todd

  13. Section on Pharmacology, Toxicology and Biotechnology (FTBB), Medicines Evaluation Board, Graadt van Roggenweg 500, Utrecht, 3531 AH, The Netherlands

    Jan Willem Van Der Laan

  14. Drug Safety Assessment Centre, Biologie Servier, 45520, Gidy, France

    Richard J. Weaver

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Correspondence to B. Kevin Park.

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Competing interests

Lolke de Haan is an employee of Medimmune, Cambridge, UK.

James Green is an employee of Boehringer-Ingelheim, Sudbury, USA.

Jonathan Moggs is an employee of Novartis, Basel, Switzerland.

Jennifer Sims is an employee of Integrated Biologix, Basel, Switzerland.

Meena Subramanyam is an employee of Biogen Idec, Cambridge, Massachusetts, USA.

Marque Todd is an employee of Pfizer, California, USA.

Richard Weaver is an employee of Biologie Servier, Gidy, France.

All other authors declare no competing financial interests.

Supplementary information

Supplementary information Box S1

Pharmacovigilance and the role of regulators (PDF 241 kb)

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FURTHER INFORMATION

Citizens For Responsible Care and Research (CIRCARE) — Tegenero AG TGN1412 clinical trial

CRACK IT 2011 challenge 4 (“Improving the predictive capacity of in vitro cytokine release”)

Drugs@FDA — FDA-approved drug products

European public assessment reports

University of Liverpool — Centre for Drug Safety Science

Glossary

Immunomodulatory biologics

Biotechnology-derived pharmaceutical agents (recombinant proteins and therapeutic monoclonal antibodies) that render their therapeutic effect primarily through modulating (augmenting or reducing) immune responses by targeting immune-relevant molecules.

Adverse reactions

Any adverse events occurring in temporal association with a therapeutic for which causality (possible, probable or definite) has been determined.

Boxed warnings

Warnings on a pharmaceutical product label indicating the risk of a serious or life-threatening adverse reaction (or reactions) associated with the use of the therapeutic agent.

Post-transplant lymphoproliferative disease

A disorder characterized by the neoplastic proliferation of lymphocytes that usually occurs as a result of therapeutic immunosuppression induced to prevent transplant rejection.

Fc region

A non-antigen-binding region of an antibody molecule that is involved in the binding of the antibody to Fc receptors and to the complement component C1q, which can lead to antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity.

Antibody-dependent cellular cytotoxicity

(ADCC). An effector function mediated by the Fc region of an antibody that involves the death of a target cell owing to the interaction of the Fc region of the therapeutic antibody with activatory Fcγ receptors on phagocytic cells (such as neutrophils and macrophages) and natural killer cells. Target cell death is induced through either ingestion by phagocytic cells or via the secretion of cytotoxic molecules by natural killer cells.

Complement-dependent cytotoxicity

(CDC). An effector function mediated by the Fc region of an antibody that involves complement activation induced by the engagement of C1q (a complement component) with the Fc region of the therapeutic antibody (which is bound to the target cell). This leads to the formation of a membrane attack complex, resulting in the destruction of the target cell membrane and cell death.

Fc-mediated effector functions

A collective term referring to antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity; these processes result in target cell destruction but they may also result in adverse reactions such as cytokine release syndrome and tumour lysis syndrome.

Neonatal Fc receptor

(FcRn). A type of Fc receptor that is structurally related to major histocompatibility complex (MHC) class 1 molecules and is involved in binding to and recycling circulating immunoglobulin G, thereby increasing the serum half-life of these immunoglobulins.

Biomarkers

Readouts (usually biochemical in nature) obtained through measurements performed on humans or preclinical models that can report on and allow quantitative assessments to be made on one or a combination of the following: the disease state, immune status, pharmacological efficacy, pharmacological safety and the onset of adverse reactions.

Human leukocyte antigen

(HLA). The human major histocompatibility complex (MHC) molecule involved in the presentation of antigenic peptides derived from intracellular (in the case of HLA class I) or extracellular (in the case of HLA class II) sources. The recognition of specific HLA–peptide complexes by antigen-specific T lymphocytes initiates the immune response.

Humanized monoclonal antibody

An antibody that contains only the antigen-binding region derived from a non-human species (such as mice); the remaining regions of the antibody are of human origin.

Primary immunological responses

The initial humoral immune responses that are generated following the exposure of naive B lymphocytes to antigens for the first time. This is a relatively weak response and it is predominantly associated with the production of the immunoglobulin M class of antibodies against the antigen.

Secondary immunological responses

Rapid humoral immune responses that are triggered following the secondary or repeated exposure of antigen-experienced B lymphocytes to antigens. These responses are predominantly associated with the production of the immunoglobulin G class of antibodies with improved specificity and affinity for the antigens.

Syngeneic

A term referring to animal models being genetically identical to the tumours or cells that they are to be transplanted with. This ensures that the immune system of the host animal does not react towards the transplanted cells.

Minimal anticipated biological effect level

(MABEL). The anticipated dose level leading to a minimum biological effect level that can be ascribed to the pharmacological action of the immunomodulatory biologic. It is calculated using information obtained from all in vitro (using target cells from humans and relevant animal species) and in vivo (from relevant animal species) pharmacokinetic/pharmacodynamic (PK/PD) studies.

B cell tolerance

Immunological processes (such as clonal deletion and anergy induction) that operate to prevent B cells from responding to self antigens.

NOD-SCID-Il2rg-null mice

Non-obese diabetic (NOD) severe combined immunodeficient (SCID) mice lacking the gene encoding the γ-chain of the interleukin-2 receptor (Il2rg).

Chimeric mAb

An antibody that contains regions derived from different species. For example, an antibody composed of an antigen-binding region of mouse origin and a constant region (Fc) of human origin.

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Sathish, J., Sethu, S., Bielsky, MC. et al. Challenges and approaches for the development of safer immunomodulatory biologics. Nat Rev Drug Discov 12, 306–324 (2013). https://doi.org/10.1038/nrd3974

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