Characterization of the robust humoral immune response to GSK2618960, a humanized anti-IL-7 receptor monoclonal antibody, observed in healthy subjects in a Phase 1 study

Karen Liao,Stephen L Dewall,Andrew Gehman,George R Gunn,Keguan Chen,Ann M Schwartz,Sara Brett,Aftab A Ansari

doi:10.1371/journal.pone.0249049

Karen Liao, Stephen L Dewall + Show 6 more

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https://doi.org/10.1371/journal.pone.0249049

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Journal: PloS one	Publication Date: Mar 23, 2021
Citations: 6	License type: CC BY 4.0

Affiliation: GlaxoSmithKline (United States)

Abstract

Interleukin-7 (IL-7) signaling modulates T cell activity and is implicated in numerous autoimmune diseases. An anti-IL-7 receptor monoclonal antibody (GSK2618960) biotherapeutic was evaluated in healthy subjects for safety, pharmacokinetics (PK), pharmacodynamics (PD) and immunogenicity in a single-dose escalation phase I study. We found that antibodies against GSK2618960 (i.e., anti-drug antibodies or ADA) developed in 83% and 100% of GSK2618960-treated subjects in the 0.6 and 2.0 mg/kg dose cohorts, respectively. Of the ADA positive subjects, 64% (7 of 11) had detectable neutralizing activity. Further investigation revealed the presence of GSK2618960-specific memory B cells, indicating the development of immunological memory for the ADAs. Ex vivo stimulation of peripheral blood mononuclear cell (PBMC) samples demonstrated a relatively strong CD4+ T cell proliferation response to GSK2618960 as compared to the control anti-RSV antibody (which is known to have only low immunogenic potential), confirming the high immunogenic potential of GSK2618960. Furthermore, GSK2618960 was found to bind in vitro monocyte-derived dendritic cells (DCs). GSK2618960 treatment of PBMCs increased the proportion of DC cells showing an increase in expression of CD83, CD86 and CD209, which indicated enhanced DC differentiation and activation relative to the isotype control anti-β amyloid antibody. Collectively, the evidence supports that the high incidence of observed clinical immunogenicity was likely related to the receptor-mediated activity by GSK2618960.

Highlights

Clinical immunogenicity data for approved therapeutic monoclonal antibody (mAb) indicate that most humanized or human antibodies generally have a relatively lower risk of immunogenicity in both incidence and consequence compared to non-human and chimeric antibodies [1]
Because there are reports that IL-7Rα expression can be induced in ex vivo cultured dendritic cells (DCs) [26,27,28], we evaluated whether GSK2618960 binds to ex vivo generated monocyte-derived DCs
We report that GSK2618960, a humanized anti-IL7Rα therapeutic monoclonal antibody was found to have a high incidence of immunogenicity in clinical study 200902

Summary

Introduction

Clinical immunogenicity data for approved therapeutic mAbs indicate that most humanized or human antibodies generally have a relatively lower risk of immunogenicity in both incidence and consequence compared to non-human and chimeric antibodies [1]. Adalimumab, a fully human monoclonal antibody (mAb) demonstrated a relatively high incidence of immunogenicity, with ADAs and neutralizing antibodies detected in 5% to 89% patients depending on the disease and concomitant medications [3]. Intrinsic factors may include the primary sequence (e.g., non-human sequences pose increased immunogenic risk) and structural/chemical modifications to the biotherapeutic (e.g., pegylation). Another key factor that can contribute to the immunogenicity risk is the mechanism of action (MoA) of the biotherapeutic. Target-mediated immunogenicity, believed to be related to the MoA of a biotherapeutic, has not been well characterized or understood, and, it remains difficult to predict even for biotherapeutics that target immune cells

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