The objective of this study was to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of PF‑06835375, a potent selective afucosyl immunoglobulin G1 antibody targeting C-X-C chemokine receptor type 5 (CXCR5) that potentially depletes B cells, follicular T helper (Tfh) cells, and circulating Tfh-like (cTfh) cells, in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). This first-in-human, multicenter, double-blind, sponsor-open, placebo-controlled Phase 1 study recruited patients aged 18–70 years with SLE or RA. In Part A, patients received single doses of intravenous PF-06835375 (dose range: 0.03–6 mg) or placebo in six sequential single ascending dose (SAD) cohorts. In Part B, patients received repeat doses of subcutaneous PF-06835375 (dose range: 0.3–10 mg) or placebo on Days 1 and 29 in five multiple ascending dose (MAD) cohorts. Tetanus/Diphtheria (Td) and Meningococcal B (MenB/Trumenba™) vaccines were administered at Day 4 (Td and MenB) and Week 8 (MenB only) to assess PF-06835375 functional effects. Endpoints included treatment-emergent adverse events (TEAEs), pharmacokinetic parameters, pharmacodynamic effects on B and cTfh cells, and biomarker counts, vaccine response, and exploratory differential gene expression analysis. Safety, pharmacokinetic, and pharmacodynamic endpoints are summarized descriptively. The change from baseline of B and Tfh cell-specific genes over time was calculated using a prespecified mixed-effects model, with a false discovery rate < 0.05 considered statistically significant. In total, 73 patients were treated (SAD cohorts: SLE, n = 17; RA, n = 14; MAD cohorts: SLE, n = 22; RA, n = 20). Mean age was 53.3 years. Sixty-two (84.9%) patients experienced TEAEs (placebo n = 17; PF-06835375 n = 45); most were mild or moderate. Three (9.7%) patients experienced serious adverse events. Mean t1/2 ranged from 3.4–121.4 h (SAD cohorts) and 162.0–234.0 h (MAD cohorts, Day 29). B and cTfh cell counts generally showed dose-dependent reductions across cohorts (range of mean maximum depletion: 67.3–99.3%/62.4–98.7% [SAD] and 91.1–99.6%/89.5–98.1% [MAD], respectively). B cell-related genes and pathways were significantly downregulated in patients treated with PF-06835375. These data support further development of PF-06835375 to assess the clinical potential for B and Tfh cell depletion as a treatment for autoimmune diseases. ClinicalTrials.gov identifier: NCT03334851.

中文翻译：

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一项随机、双盲、安慰剂对照、单剂量和多剂量递增研究的 1 期研究，旨在评估 PF-06835375（一种 C-X-C 趋化因子受体 5 型定向抗体）在系统性红斑狼疮患者中的安全性和药代动力学/药效学或类风湿性关节炎


本研究的目的是评估 PF-06835375 的安全性、耐受性、药代动力学和药效学，PF-06835375 是一种有效的选择性无岩藻糖基免疫球蛋白 G1 抗体，靶向 C-X-C 趋化因子受体 5 型 (CXCR5)，可能消耗 B 细胞、滤泡 T 辅助细胞 (Tfh)系统性红斑狼疮 (SLE) 和类风湿性关节炎 (RA) 患者体内的 Tfh 细胞和循环 Tfh 样 (cTfh) 细胞。这项首次人体、多中心、双盲、赞助商开放、安慰剂对照的 1 期研究招募了 18-70 岁的 SLE 或 RA 患者。在 A 部分中，患者在六个连续单剂量递增 (SAD) 队列中接受单剂量静脉注射 PF-06835375（剂量范围：0.03–6 mg）或安慰剂。在 B 部分中，患者在第 1 天和第 29 天在五个多剂量递增 (MAD) 队列中接受重复剂量的皮下 PF-06835375（剂量范围：0.3–10 mg）或安慰剂。在第 4 天（Td 和 MenB）和第 8 周（仅 MenB）接种破伤风/白喉 (Td) 和 B 型脑膜炎球菌 (MenB/Trumenba™) 疫苗，以评估 PF-06835375 的功能效果。终点包括治疗引起的不良事件 (TEAE)、药代动力学参数、对 B 和 cTfh 细胞的药效学影响、生物标志物计数、疫苗反应和探索性差异基因表达分析。对安全性、药代动力学和药效学终点进行了描述性总结。使用预先指定的混合效应模型计算 B 和 Tfh 细胞特异性基因随时间相对于基线的变化，错误发现率 < 0.05 被认为具有统计显着性。总共有 73 名患者接受了治疗（SAD 队列：SLE，n = 17；RA，n = 14；MAD 队列：SLE，n = 22；RA，n = 20）。平均年龄为 53.3 岁。六十二（84.9%) 患者经历过 TEAE（安慰剂 n = 17；PF-06835375 n = 45）；大多数是轻度或中度。三名（9.7%）患者经历了严重的不良事件。平均 t1/2 范围为 3.4–121.4 小时（SAD 队列）和 162.0–234.0 小时（MAD 队列，第 29 天）。 B 和 cTfh 细胞计数在各队列中通常表现出剂量依赖性减少（平均最大消耗范围：分别为 67.3–99.3%/62.4–98.7% [SAD] 和 91.1–99.6%/89.5–98.1% [MAD]）。在接受 PF-06835375 治疗的患者中，B 细胞相关基因和通路显着下调。这些数据支持进一步开发 PF-06835375，以评估 B 和 Tfh 细胞耗竭作为自身免疫性疾病治疗的临床潜力。 ClinicalTrials.gov 标识符：NCT03334851。