Scholarlink

<p>Blocking CD154 (CD40L) has the potential to prolong transplanted solid organ graft survival and treat autoimmune diseases. However, first-generation anti-CD154 IgG1 monoclonal antibodies (mAbs) were associated with an increased risk of thrombosis linked to Fc binding to FcγRIIa (CD32A). Here, we describe a first-in-human, phase 1 clinical trial of TNX-1500, a novel Fc-modified IgG4 anti-CD154 mAb designed to decrease binding to FcγRIIa. Healthy volunteers (<i>N</i> = 26) were enrolled into single-ascending dose (3, 10, and 30&#xa0;mg/kg) cohorts and received TNX-1500 intravenously. TNX-1500 was generally well tolerated. Among participants receiving TNX-1500 3, 10, and 30&#xa0;mg/kg, 1 (25%), 3 (38%), and 3 (38%) participants, respectively, reported ≥ 1 treatment-emergent adverse event; all were mild or moderate in severity, and none resulted in study discontinuation. There were no thromboembolic events. Pharmacokinetic analyses of TNX-1500 demonstrated a mean half-life of 37.8 and 33.8 days for 10 and 30&#xa0;mg/kg, respectively, supportive of monthly dosing; dose-proportional exposure was suggested over the 3 to 30&#xa0;mg/kg range. TNX-1500 blocked the primary T cell–dependent antibody response to keyhole limpet hemocyanin (KLH) at all doses and blocked the secondary response at the 10 and 30&#xa0;mg/kg doses. At 3&#xa0;mg/kg, TNX-1500 reduced peak secondary response to KLH by ~ 70% relative to placebo. TNX-1500 administration was associated with immediate and sustained reduction in soluble CD154. Overall, TNX-1500 demonstrated a safety profile and pharmacologic properties that support further development as an agent with potential for prevention of organ transplant rejection and treatment for autoimmune conditions.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

First-in-Human, Phase 1, Randomized, Double-Blind, Placebo-Controlled Study of TNX-1500, an Fc-Modified anti-CD154 Monoclonal Antibody, Evaluating the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single-Ascending Doses in Healthy Adults

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月29日

查看全文
  • Seth Lederman,
  • Bruce L. Daugherty,
  • Nancy Herje,
  • Gregory M. Sullivan

摘要

Blocking CD154 (CD40L) has the potential to prolong transplanted solid organ graft survival and treat autoimmune diseases. However, first-generation anti-CD154 IgG1 monoclonal antibodies (mAbs) were associated with an increased risk of thrombosis linked to Fc binding to FcγRIIa (CD32A). Here, we describe a first-in-human, phase 1 clinical trial of TNX-1500, a novel Fc-modified IgG4 anti-CD154 mAb designed to decrease binding to FcγRIIa. Healthy volunteers (N = 26) were enrolled into single-ascending dose (3, 10, and 30 mg/kg) cohorts and received TNX-1500 intravenously. TNX-1500 was generally well tolerated. Among participants receiving TNX-1500 3, 10, and 30 mg/kg, 1 (25%), 3 (38%), and 3 (38%) participants, respectively, reported ≥ 1 treatment-emergent adverse event; all were mild or moderate in severity, and none resulted in study discontinuation. There were no thromboembolic events. Pharmacokinetic analyses of TNX-1500 demonstrated a mean half-life of 37.8 and 33.8 days for 10 and 30 mg/kg, respectively, supportive of monthly dosing; dose-proportional exposure was suggested over the 3 to 30 mg/kg range. TNX-1500 blocked the primary T cell–dependent antibody response to keyhole limpet hemocyanin (KLH) at all doses and blocked the secondary response at the 10 and 30 mg/kg doses. At 3 mg/kg, TNX-1500 reduced peak secondary response to KLH by ~ 70% relative to placebo. TNX-1500 administration was associated with immediate and sustained reduction in soluble CD154. Overall, TNX-1500 demonstrated a safety profile and pharmacologic properties that support further development as an agent with potential for prevention of organ transplant rejection and treatment for autoimmune conditions.