Background/Purpose: Toll-like receptor (TLR)7 is a pattern recognition receptor, whose ligands include nucleic acids and whose activation is part of the pathogenesis of systemic lupus erythematosus (SLE).In mice, TLR7 overexpression worsens lupus models, while TLR7 deficiency ameliorates them.In humans, TLR7 gain-of-function mutations confer susceptibility to SLE.DS-7011a is an anti-TLR7 monoclonal antibody (mAb), which prevents TLR7 from signaling.DS-7011a inhibits in vitro production of cytokines stimulated by TLR7.A surrogate anti-TLR7 mAb effectively treats mouse lupus models, improving survival and decreasing autoantibody production.The aim of this first-in-human, single ascending intravenous (IV) and subcutaneous (SC) dose study was to evaluate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of DS-7011a in human volunteers (HV), including HV of Japanese descent [NCT05203692].

Methods: This study was a double-blind, randomized, and placebo-controlled trial. Eighty HV were enrolled in 3 stages and assigned to receive DS-7011a or placebo 6:2 in 10 cohorts of 8 each.Non-Japanese HV were enrolled in Stage 1 in 6 ascending IV dose (0.1, 0.3, 1, 3, 10, and 20 mg/kg) cohorts and in Stage 2 in 3 ascending SC dose (100, 300, and 600 mg) cohorts; Japanese HV were enrolled in Stage 3 in 1 IV dose (3 mg/kg) cohort.HV received a single DS-7011a dose on Day 1 and were followed for 8 weeks until Day 57 for safety, PK, and PD assessments. PK exposure was evaluated by measuring DS-7011a in plasma by ligand-binding assay.PD response was evaluated ex vivo in blood using TruCulture® tubes containing gardiquimod, which is a TLR7-specific stimulant, and measuring interleukin (IL)-6 by ligand-binding assay.

Results: DS-7011a was generally safe and well tolerated across all cohorts given by either IV (up to the dose of 20 mg/kg) or SC (up to the dose of 600 mg) administration to either non-Japanese or Japanese HV. The treatment emergent adverse events (TEAE) observed during the study were mostly mild in severity and not drug-related (one TEAE of hospitalization for bone fractures was considered severe and reported as serious but not drug-related).DS-7011a exposure (AUClast and Clast) generally increased with dose increment.PK linearity started at 3 mg/kg following IV administration and at 300 mg following SC, while the elimination of lower doses was noticeably accelerated probably by target-mediated disposition. Mean terminal half-life was about 17 days (within dose range of PK linearity) and mean Tmax upon SC administration was about 5 days. PK exposure in non-Japanese HV was slightly higher than Japanese, reflecting difference in body weight.DS-7011a showed ex vivo inhibition of TLR7-stimulated IL-6 production that was of large extent, early onset, and lasting duration.

Conclusion: DS-7011a, a mAb that specifically antagonizes TLR7, was generally safe and well tolerated and showed appealing PK and PD properties that support its development for the treatment of SLE.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/first-in-human-safety-tolerability-pharmacokinetics-and-pharmacodynamics-study-of-ds-7011a-an-anti-tlr7-antagonistic-monoclonal-antibody-for-the-treatment-of-systemic-lupus-erythematosus/