血管内皮生长因子受体2（VEGFR2）在抗血管生成中发挥关键作用，这是癌症治疗的基本策略。我们报道了AK109的人体首次研究，它是一种新型的抗VEGFR2单克隆抗体，旨在表征其安全性和药代动力学/药效学（PK/PD）特性，并探索合并实体瘤患者的初步抗肿瘤功效。这是一个多中心、开放标签的Ⅰ期研究，包括剂量递增和扩大剂量（NCT04547205）。晚期癌症患者接受逐渐递增的AK109治疗，每2周和每3周1次。使用3+3设计确定最大耐受剂量。血液样本用于PK/PD分析。主要终点是安全性和建议的Ⅱ期剂量（RP2D）。共招募了40名患者。未观察到剂量限制性毒性。但是，38名患者报告了治疗相关的不良事件（TRAEs）；10名患者出现了≥3级TRAEs。最常见的TRAEs是蛋白尿（n = 24，60％），高血压（n = 13，32.5％），谷草转氨酶升高（n = 11，27.5％），血小板减少（n = 10，25％）和贫血（n = 10，25％）。共有28名患者（70％）报告了特殊关注的不良事件（AESIs）。最常见的AESI是蛋白尿（60％）、高血压（32.5％）和出血（32.5％），主要包括牙龈出血和尿道出血。AK109在2-12 mg/kg的剂量递增中表现出了近似线性的PK曝露。PD分析显示快速的靶向作用。在40名患者中，有4名患者实现了部分缓解，21名患者实现了稳定疾病，客观缓解率为10％，疾病控制率为62.5％。根据安全性、PK/PD特性和初步的抗肿瘤活性，选定12 mg/kg Q2W和15 mg/kg Q3W作为RP2D。AK109表现出可管理的安全性和有前途的抗肿瘤作用，支持在大人群中进行进一步的临床开发。版权所有 © 2023 The Authors。由Elsevier Ltd.发布。保留所有权利。

Vascular endothelial growth factor receptor 2 (VEGFR2) plays a key role in antiangiogenesis which has been an essential strategy for cancer treatment. We report the first-in-human study of AK109, a novel anti-VEGFR2 monoclonal antibody, to characterize the safety profile and pharmacokinetics/pharmacodynamics (PK/PD) properties, and explore the preliminary antitumor efficacy in patients with solid tumors.This was a multicenter, open-label, phase I study, including dose escalation and dose expansion (NCT04547205). Patients with advanced cancers were treated 2 and 3 weekly with escalating doses of AK109. A 3 + 3 design was used to determine the maximum tolerated dose. Blood was sampled for PK/PD analysis. The primary endpoint was safety and recommended phase II dose (RP2D).A total of 40 patients were enrolled. No dose-limiting toxicity was observed. However, 38 patients reported treatment-related adverse events (TRAEs); grade ≥3 TRAEs occurred in 10 patients. The most common TRAEs were proteinuria (n = 24, 60%), hypertension (n = 13, 32.5%), increased aspartate transaminase (n = 11, 27.5%), thrombopenia (n = 10, 25%), and anemia (n = 10, 25%). A total of 28 patients (70%) reported adverse events of special interest (AESIs). The most common AESIs were proteinuria (60%), hypertension (32.5%), and hemorrhage (32.5%), mainly including gum bleeding and urethrorrhagia. AK109 exhibited an approximately linear PK exposure with dose escalation at 2-12 mg/kg. PD analyses showed rapid target engagement. Among the 40 patients, 4 achieved partial response and 21 achieved stable disease with an objective response rate of 10% and a disease control rate of 62.5%. Based on the safety profile, the PK/PD profile, and preliminary antitumor activities, 12 mg/kg Q2W and 15 mg/kg Q3W were selected as RP2D.AK109 showed manageable safety profile and promising antitumor activity, supporting further clinical development in a large population.Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.