Maio Michele, Moreno Victor, Martin-Liberal Juan, Opdam Frans, Hansen Aaron, Bauer Todd M, Le Tourneau Christophe, Italiano Antoine, Rischin Danny, Ellis Catherine, Turner David, Yadavilli Sapna, Zhou Helen, Hirschfeld Steven, Ballas Marc, Diaz-Padilla Ivan, Angevin Eric
University of Siena, Siena, Italy.
Medical Oncology and Immunotherapy, Center for Immuno-Oncology, Siena University Hospital, Siena, Italy.
J Immunother Cancer. 2025 Aug 11;13(8):e011475. doi: 10.1136/jitc-2025-011475.
Inducible costimulator (ICOS) receptor belongs to the CD28/CTLA immunoglobulin super family, whose expression is restricted to T cells and is weakly expressed on resting TH17, follicular helper T cells, and regulatory T cells, but is highly induced on CD4+ and CD8+ T cells on activation by T-cell receptors. ICOS stimulation downstream effects include activation of conventional CD4+cells and cytotoxic CD8+cells, resulting in a durable antitumor response in preclinical models.
As part of a larger first-in-human study (GSK Study 204691), this study focused on 2 cohorts of 25 and 67 participants enrolled in a dose escalation and pharmacokinetic/pharmacodynamic (PK/PD) analysis of the ICOS agonist feladilimab (GSK3359609) as monotherapy. For these cohorts, the objectives were to determine the safety, tolerability, maximum tolerated dose (MTD) or maximum administered dose of feladilimab. Additional objectives included determining the recommended dose of feladilimab for further exploration, characterizing the PK properties, and immunogenicity.
Feladilimab was examined over a range of 4 logs from 0.001 mg/kg to 10 mg/kg, and no MTD was established. Adverse events were manageable and consistent with those observed with other immunomodulatory treatments; fatigue, fever, and anemia were the most common events. PK showed a peak value 1 hour following infusion. Accumulation ratio ranged from 1.4 to 2.5 and was generally consistent with expected patterns of accumulation for a monoclonal antibody, and the drug showed linear dose proportionality. ICOS receptor occupancy was maximal at doses>0.1 mg/kg. Based on the collected data, doses of 0.3 and 1.0 mg/kg were selected for further exploration.
This study showed the feasibility of a modified Toxicity Proportion Interval design and PK/PD analysis to determine a recommended dose for a compound without a dose-limiting toxicity and a tolerable and manageable safety profile.
诱导性共刺激分子（ICOS）受体属于CD28/CTLA免疫球蛋白超家族，其表达仅限于T细胞，在静息的TH17细胞、滤泡辅助性T细胞和调节性T细胞上弱表达，但在T细胞受体激活后，CD4⁺和CD8⁺T细胞上会高度诱导表达。ICOS刺激的下游效应包括激活常规CD4⁺细胞和细胞毒性CD8⁺细胞，在临床前模型中产生持久的抗肿瘤反应。
作为一项更大规模的首次人体研究（GSK研究204691）的一部分，本研究聚焦于两组分别有25名和67名参与者的队列，这些参与者参与了ICOS激动剂费拉地利单抗（GSK3359609）作为单一疗法的剂量递增及药代动力学/药效学（PK/PD）分析。对于这些队列，目标是确定费拉地利单抗的安全性、耐受性、最大耐受剂量（MTD）或最大给药剂量。其他目标包括确定用于进一步探索的费拉地利单抗推荐剂量、表征其PK特性以及免疫原性。
在0.001mg/kg至10mg/kg的4个对数范围内对费拉地利单抗进行了研究，未确定MTD。不良事件可控，与其他免疫调节治疗中观察到的事件一致；疲劳、发热和贫血是最常见的事件。PK显示输注后1小时达到峰值。蓄积比在1.4至2.5之间，总体上与单克隆抗体预期的蓄积模式一致，且该药物显示出线性剂量比例关系。ICOS受体占有率在剂量>0.1mg/kg时最大。根据收集的数据，选择0.3mg/kg和1.0mg/kg的剂量进行进一步探索。
本研究显示了改良的毒性比例区间设计和PK/PD分析用于确定一种无剂量限制毒性且具有可耐受和可控安全性的化合物推荐剂量的可行性。
