PO.CT01.01 · 临床试验
BGB-24714（一种第二线粒体来源的半胱天冬酶激活剂（SMAC）模拟物）在实体瘤首次人体研究中的药效动力学（PD）特征分析
Pharmacodynamic (PD) characterization of BGB-24714, a second mitochondrial-derived activator of caspases (SMAC) mimetic, in a first-in-human study in solid tumors
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摘要 Abstract
中文摘要
背景：凋亡蛋白抑制因子（IAP）是抑制程序性细胞死亡的关键调控因子，在癌症中常过表达，促成肿瘤存活、耐药和不良预后。抑制IAP可恢复凋亡敏感性并激活NF-κB通路，导致炎性细胞因子和趋化因子的诱导。SMAC从线粒体释放时可天然拮抗IAP。BGB-24714是一种强效、选择性的SMAC模拟物，可结合并抑制IAP，在多种异种移植模型中展现出强劲的抗肿瘤活性。本研究呈现了BGB-24714在实体瘤患者中的首次转化性PD生物标志物评估；安全性和疗效结果另行报告。
方法：在临床前模型中开发并验证PD生物标志物，以评估靶点结合和下游通路调节。在BGB-24714首次人体研究（NCT05381909）的单药剂量递增队列中，于基线（第1周期第1天给药前）和给药后系列时间点采集血样。定量测定PBMC中的细胞IAP1（cIAP1）水平以评估靶点结合。测定半胱天冬酶切割的细胞角蛋白-18（ccCK18）作为凋亡的循环标志物，并分析细胞因子/趋化因子谱以评估炎性信号传导。
结果：在人乳腺癌异种移植模型中，BGB-24714诱导剂量依赖性抗肿瘤活性，伴随cIAP1的快速和持续降解，在100 mg/kg时效应最大。cIAP1抑制在给药后1小时内发生并持续至少24小时，表明快速且持久的cIAP1降解是最佳疗效所必需的。在临床相关剂量下，小鼠PBMC和肿瘤组织中观察到相似的cIAP1降解水平和动力学，验证了PBMC作为PD评估的合适替代指标。在1期研究中，BGB-24714在PBMC中诱导快速、持续和剂量依赖性的cIAP1降解。在60 mg剂量下，第2天观察到约50%降解；在≥200 mg剂量下，第2天实现近乎完全的cIAP1降解并在此后维持。从200 mg起，第15天ccCK18的剂量依赖性增加表明凋亡诱导，而从200 mg或300 mg起，第15天循环细胞因子和趋化因子的剂量依赖性升高（在450 mg及以上趋势更为明显）与NF-κB通路激活一致。总体而言，这些PD发现证实了BGB-24714的机制内生物学活性。
结论：BGB-24714展现出强效、持续的靶点结合、凋亡诱导以及与其SMAC模拟物作用机制一致的免疫-炎症调节。这些转化性PD结果支持BGB-24714在实体瘤患者中的生物学活性。
查看英文原文 English abstract
Background: Inhibitor of apoptosis proteins (IAPs) are key regulators that suppress programmed cell death and are frequently overexpressed in cancer, contributing to tumor survival, drug resistance, and poor prognosis. Inhibition of IAPs restores apoptotic sensitivity and activates the NF-κB pathway, leading to induction of inflammatory cytokines and chemokines. SMACs, when released from mitochondria, naturally antagonize IAPs. BGB-24714 is a potent and selective SMAC mimetic that binds and inhibits IAPs, demonstrating robust antitumor activity across multiple xenograft models. This study presents the first translational PD biomarker evaluation of BGB-24714 in patients with solid tumors; safety and efficacy outcomes are reported separately.
Methods: PD biomarkers were developed and validated in preclinical models to assess target engagement and downstream pathway modulation. In the monotherapy dose escalation cohorts of BGB-24714 first-in-human study (NCT05381909), blood samples were collected at baseline (pre-dose on cycle 1 day 1) and at serial post-dose timepoints. Cellular IAP1 (cIAP1) levels in PBMCs were quantified to assess target engagement. Caspase-cleaved cytokeratin-18 (ccCK18) was measured as a circulating marker of apoptosis, and cytokine/chemokine profiles were analyzed to evaluate inflammatory signaling.
Results: In a human breast cancer xenograft model, BGB-24714 induced dose-dependent antitumor activity accompanied by rapid and sustained degradation of cIAP1, with maximal effects at 100 mg/kg. cIAP1 inhibition occurred within 1 hour post-dose and persisted at least for 24 hours, indicating that rapid and durable cIAP1 degradation is required for optimal efficacy. Similar levels and kinetics of cIAP1 degradation were observed in PBMCs and tumor tissue in mice at a clinically relevant dose, validating PBMCs as a suitable surrogate for PD assessment. In the phase 1 study, BGB-24714 induced rapid, sustained, and dose-dependent cIAP1 degradation in PBMCs. Approximately 50% degradation was observed on Day 2 at the 60 mg dose, near complete cIAP1 degradation was achieved by Day 2 and maintained thereafter at doses ≥ 200 mg. Dose-dependent increases in ccCK18 at Day 15 from 200 mg onward indicated apoptosis induction, while dose-dependent elevations in circulating cytokines and chemokines at Day 15 from doses 200 mg or 300 mg, with a more pronounced trend at 450 mg and above, were consistent with NF-κB pathway activation. Collectively, these PD findings confirm the on-mechanism biological activity of BGB-24714.
Conclusion: BGB-24714 demonstrated potent, sustained target engagement, apoptosis induction, and immune-inflammatory modulation consistent with its SMAC mimetic mechanism of action. These translational PD results support the biological activity of BGB-24714 in patients with solid tumors.
利益披露 Disclosure
J. Zhang,
BeOne Medicines Employment, Stock.
M. Deng,
BeOne Medicines Employment.
B. Jiang,
BeOne Medicines Employment.
J. Li,
BeOne Medicines Employment.
J. Wang,
Boehringer Ingelheim Travel.
NGM Bio Travel.
AbbVie; Abdera Therapeutics; Accent Therapeutics; Accutar Biotech; Acrivon Therapeutics; Adagene; Allorion Therapeutics; Alterome Therapeutics; Apollo; Artios; Astellas Pharma; Avenzo; BeiGene ).
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Kura Oncology; Loxo/Lilly; MabSpace Biosciences; Macrogenics; MBQ Pharma; Medikine; MediLink Therapeutics; Stemline/Menarini; Merck KGaA; Mersana; Moderna Therapeutics; NGM Biopharmaceuticals; NiKang ).
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E. Hamilton,
AbbVie; Accutar Biotechnology; Artios; Arvinas; AstraZeneca; AtlasMedx; BeiGene; BeOne Medicines; Bicycle Therapeutics; Biohaven Pharmaceuticals; BioNTech; Compugen; Cullinan; Daiichi Sankyo; Dantari ).
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Jacobio; Jazz Pharmaceuticals; K-Group Beta; Kind Pharmaceuticals; Lilly; Loxo Oncology; Mabspace Biosciences; Mabwell Bioscience; Marengo Therapeutics; MediLink Therapeutics; Merck; Mersana ).
Novartis; Olema; Orinove; Orum Therapeutics; Pfizer; Pionyr Immunotherapeutics; Prelude Therapeutics; Profound Bio; Regeneron; Relay Therapeutics; Rgenix; Roche/Genentech; SeaGen; Shattuck Labs ).
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Arvinas; AstraZeneca; BeOne Medicines; BioNTech; Boehringer Ingelheim; Boundless Bio; Bristol-Myers Squibb; Circle Pharma; Daiichi Sankyo; Gilead Sciences; Halda Therapeutics; Incyclix Bio; IQVIA Other, Consulting paid to institution.
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Stemline Therapeutics; Tempus Labs Other, Consulting paid to institution.
H. Gao,
BeOne Medicines Employment, Stock, Patent.
X. Song,
BeOne Medicines Employment.
Z. Shen,
BeOne Medicines Employment.
W. Jin,
BeOne Medicines Employment.
F. Doñate,
BeOne Medicines Employment.