Challenges and approaches for the development of safer immunomodulatory biologics

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.

Figure 1. Complex interactions among the disease, the immune system and immunomodulatory biologics that influence safety and efficacy.

The interaction of the immunomodulatory biologic with the immune system and immune processes results in either the required (or intended) on-target therapeutic effect or unwanted reactions. Adverse reactions such as unwanted immunosuppression or immune activation are usually associated with the on-target exaggerated pharmacology of the biologic (for example, immunosuppression from a tumour necrosis factor (TNF)-specific therapy increases the risk of reactivation of tuberculosis or there is the risk of inducing cytokine release syndrome through the excessive activation of T cells with muromonab-CD3 therapy). The biologic also has the potential to induce a host immune response (termed immunogenicity), which results in the formation of drug-targeting antibodies that in turn can impede the therapeutic efficacy of the immunomodulatory biologic. The disease type and status of the patient can also influence the functional state of the immune system and thereby determine whether the interaction with the biologic leads to a therapeutic effect or unwanted adverse reactions (for example, chronic inflammation associated with diseases such as rheumatoid arthritis exposes the patient to an increased risk of malignancy). Other patient-specific factors such as human leukocyte antigen (HLA) type as well as the route and frequency of administration have a bearing on the propensity to develop immunogenicity to the biologic, as these factors contribute to antigen processing and presentation of immunogenic epitopes. Factors that are intrinsic to the property of the biologic (biologic-specific factors), such as the presence of immunogenic epitopes, glycosylation and aggregation, also affect the generation of an immunogenic response. The prevention and mitigation of these unwanted adverse reactions is predicated on a detailed knowledge and understanding of the mechanisms and risk factors that drive the adverse reactions and the use of effective biomarkers and diagnostic tests. For example, knowledge of the association of the John Cunningham virus (JCV) in the aetiopathology of progressive multifocal leukoencephalopathy (PML) observed in patients receiving natalizumab (Tysabri; Biogen Idec/Elan) led to the recognition of the presence of JCV as a risk factor for PML. Consequently, a diagnostic test for JCV seropositivity is now used to stratify patients before initiating natalizumab therapy.

Figure 2. Pathways for the development of safer immunomodulatory biologics.

The iterative cycle for the development of safer immunomodulatory biologics incorporates two key pathways and depends on the collective knowledge obtained from adverse reactions observed in first-in-human studies, clinical trials and postmarketing pharmacovigilance analyses. These data provide the basis for understanding the frequency and nature of the adverse reactions associated with immunomodulatory biologic therapy, as well as the potential mechanisms by which these adverse reactions are induced. The next step in this process is the identification and characterization of hazards associated with the immunomodulatory biologic (for example, characterizing excessive Fc-mediated effector functions that result in cytokine release syndrome (CRS), overt or global immunosuppression leading to serious infections or the presence of immunogenic structures within the biologic that trigger immunogenicity). Pathways 1 and 2 are two different trajectories that utilize the understanding of the mechanism of adverse reactions to inform the design of safer and potentially more effective immunomodulatory biologics. Pathway 1 is followed when the adverse reaction cannot be dissociated from the target biology, and involves generating a biologic that engages an alternative target or mechanism to produce the desired pharmacodynamic effect without the associated adverse reaction. Pathway 2 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. New immunomodulatory biologics from both of these pathways (and any other lead drug candidates) need to go through a panel of predictive tests until a safer biologic emerges. The selection of the predictive tests to be used is on a case-by-case basis, as it should take into account the nature of the target biology, the effector mechanisms that are engaged and any other factor or factors that influence the intended pharmacological effect and the risk of adverse reactions. Currently available tests that are suitable for determining the CRS-inducing risk of a new biologic with immunostimulatory properties could include whole-blood assays, peripheral blood mononuclear cell (PBMC)-based assays and biomimetic cell models. Predicting the risk of serious infections and malignancies for a new immunomodulatory biologic still remains a challenge, and limitations in T cell-dependent antibody response (TDAR) assays and host resistance models are due to species-specific variations both in target biology and in exposure to risk factors. Preclinical tools for predicting the risk of immunogenicity involve the use of in silico models (immunogenic epitope mapping), in vitro or ex vivo models (T cell assays, antigen-presenting cell (APC)–T cell assays and major histocompatibility complex (MHC)-associated peptide proteomics (MAPPs)) and in vivo models (humanized animals). The integration of in silico and in vitro or ex vivo assays increases the predictive value of these preclinical tools. A new or redesigned immunomodulatory biologic that is considered to be safe based on predictive preclinical assessments enters the cycle of testing in first-in-human studies and clinical trials, and then moves to the clinic with necessary safety precautions in place and with continuous monitoring for any potential adverse reaction. By contrast, any new immunomodulatory biologic that is flagged using predictive tests for its potential to cause adverse reactions (or observed to cause adverse reactions in clinical studies) will be passed through this iterative cycle again for the design and development of a safer immunomodulatory biologic.