Mezagitamab in systemic lupus erythematosus: clinical and mechanistic findings of CD38 inhibition in an autoimmune disease

Abstract

Objective: To evaluate safety and mechanism of action of mezagitamab (TAK-079), an anti-CD38 monoclonal antibody, in patients with moderate to severe systemic lupus erythematosus (SLE).

Methods: A phase 1b double-blind, placebo-controlled, multicentre study was conducted in patients with SLE receiving standard background therapy. Eligible patients were adults who met the 2012 SLICC or ACR criteria for diagnosis, had a baseline SLE Disease Activity Index 2000 (SLEDAI-2K) score of ≥6 and were positive for anti-double-stranded DNA antibodies and/or anti-extractable nuclear antigens antibodies. Patients received 45 mg, 90 mg or 135 mg of mezagitamab or placebo every 3 weeks over 12 weeks. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics and pharmacodynamics. Exploratory assessments included disease activity scales, deep immune profiling and interferon pathway analysis.

Results: 22 patients received at least one dose of either mezagitamab or placebo. In patients exposed to mezagitamab (n=17), drug was well tolerated. Adverse event (AEs) were balanced across treatment groups, with no treatment emergent AEs exceeding grade 2. Responder analyses for Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) and SLEDAI-2K did not reveal any observable differences across treatment groups. However, there was a trend for more profound skin responses among patients with higher CLASI scores (>10) at baseline. Pharmacodynamic analysis showed median CD38 receptor occupancy up to 88.4% on CD38+ natural killer cells with concurrent depletion of these cells up to 90% in the 135 mg group. Mean reductions in IgG and autoantibodies were less than 20% in all dose groups. Cytometry by time of flight and type 1 interferon gene analysis revealed unique fingerprints that are indicative of a broad immune landscape shift following CD38 targeting.

Conclusions: Mezagitamab had a favourable safety profile in patients with moderate to severe SLE and elicited a pharmacodynamic effect consistent with CD38+ cell depletion. These findings reveal novel insights into the drug's mechanism of action and support the continued investigation of mezagitamab in autoimmune diseases.

Keywords: B-lymphocytes; antibodies; biological products; interferon type I; systemic lupus erythematosus.

Figure 1

Pharmacodynamics of mezagitamab in patients with SLE. Receptor occupancy and population change in NK cells (A) and plasmablasts (B) isolated from patient blood. Data expressed as median % change from pretreatment baseline. (C) Dose-dependent, longitudinal alterations in serum IgG levels, expressed as mean % change from pretreatment baseline±SD. SLE, systemic lupus erythematosus.

Figure 2

Mezagitamab depleted populations in a roughly CD38-dependent fashion. (A) Depletion of selected CD38 positive cell populations (labelled) plotted against baseline CD38 expression. (B) 20-cluster TSNE cluster mapping identified following CyTOF analysis reveals discrete populations (described in online supplemental figure 5) that are maintained over the course of study. (C) CD38 heatmap expression throughout study. CM, classical monocytes; mDC, myeloid dendritic cells; NK, natural killer; pDCs, plasmacytoid dendritic cells; TSNE, t-distributed stochastic neighbour embedding.

Figure 3

Mezagitamab decreased type 1 interferon responsive genes. A subset of placebo and 135 mg patients had available samples analysed for inflammation-associated RNA gene expression by Nanostring. Data from selected type 1 interferon genes are presented as heatmaps normalised to the baseline expression of each gene for each patient. CLASI, Cutaneous Lupus Erythematosus Disease Area and Severity Index; SLEDAI-2K, SLE Disease Activity Index 2000.