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Abstract：
Lunsekimig is a novel, bispecific NANOBODY® molecule that inhibits both thymic stromal lymphopoietin (TSLP) and interleukin (IL)-13, two key mediators of asthma pathophysiology. In this first-in-human study, we evaluated the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of lunsekimig in healthy adult participants. Participants received single ascending doses (SAD) of lunsekimig (10-400 mg intravenous [IV] or 400 mg subcutaneous [SC]) (SAD part) or multiple ascending doses (MAD part) of lunsekimig (100 or 200 mg, every 2 weeks [Q2W] for three SC doses), or placebo. Overall, 48 participants were randomized 3:1 in the SAD part and 4:1 in the MAD part for lunsekimig or placebo. The primary endpoint was safety and tolerability. The secondary endpoints included PK, antidrug antibodies (ADAs) and total target measurement. Lunsekimig was well tolerated and common treatment-emergent adverse events were COVID-19, nasopharyngitis, injection site reactions, and headache. Lunsekimig showed dose-proportional increases in exposure and linear elimination. Mean t1/2z of lunsekimig was around 10 days across all IV and SC doses of the SAD and MAD parts of the study. Increases in the serum concentration of total TSLP and IL-13 for lunsekimig versus placebo indicated target engagement. ADA of low titers were detected in four (11.1%) participants who received lunsekimig in the SAD, and seven (43.8%) in the MAD. In conclusion, lunsekimig was well tolerated in healthy participants with a linear PK profile up to single 400 mg IV and SC dose and multiple doses of 100 and 200 mg SC Q2W, with low immunogenicity.
摘要：
Lunsekimig是一部小说，双特异性NANOBODY®分子，抑制胸腺基质淋巴细胞生成素（TSLP）和白细胞介素（IL）-13，哮喘病理生理学的两个关键介质。在这项首次人类研究中，我们评估了安全性，耐受性,药代动力学（PK），药效学（PD），和lunsekimig在健康成人参与者中的免疫原性。参与者接受单次递增剂量（SAD）的lunsekimig（静脉注射10-400mg[IV]或皮下400mg[SC]）（SAD部分）或多次递增剂量（MAD部分）的lunsekimig（100或200mg，每2周[Q2W]三次SC剂量)，或安慰剂。总的来说,48名参与者在SAD部分随机分为3：1，在MAD部分随机分为4：1，用于lunsekimig或安慰剂。主要终点是安全性和耐受性。次要终点包括PK，抗药物抗体(ADAs)和总目标测量。Lunsekimig的耐受性良好，常见的治疗引起的不良事件包括COVID-19，鼻咽炎，注射部位反应,和头痛。Lunsekimig在暴露和线性消除方面显示出剂量成比例的增加。在研究的SAD和MAD部分的所有IV和SC剂量中，lunsekimig的平均t1/2z约为10天。与安慰剂相比，lunsekimig的总TSLP和IL-13的血清浓度增加表明目标参与。在SAD中接受lunsekimig的四名（11.1％）参与者中检测到低滴度的ADA，MAD中有7人(43.8%)。总之,lunsekimig在健康参与者中具有良好的耐受性，其线性PK曲线高达400mgIV和SC剂量以及100和200mgSCQ2W的多剂量，免疫原性低。
