PO.ET07.01 · 实验与分子治疗
CS5006的临床前疗效与安全性，一种搭载拓扑异构酶1抑制剂载荷的新型整合素beta4靶向抗体药物偶联物
Preclinical efficacy and safety of CS5006, a novel integrin beta4-targeting antibody-drug conjugate with a topoisomerase 1 inhibitor payload
该海报暂无可下载的资料
AACR 官方页面
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：整合素beta4（ITGB4）在结直肠癌（CRC）、非小细胞肺癌（NSCLC）、头颈部鳞状细胞癌（SCCHN）、食管鳞状细胞癌（ESCC）及其他实体瘤中高度表达。CS5006是一款新型ITGB4靶向抗体药物偶联物（ADC），由一种ITGB4特异性人源化IgG1抗体（H86.2）通过高度稳定、亲水性的串联可裂解CSL接头与经临床验证的exatecan（Exa）载荷偶联而成，抗体载药比（DAR）值为4。
方法：在一组ITGB4表达水平各异的癌细胞系中，通过活力试验评价了CS5006的效力。在细胞来源异种移植（CDX）小鼠模型中评价了其抗肿瘤疗效。体外和体内研究所用肿瘤细胞系上的ITGB4表达水平通过定量流式细胞术和免疫组织化学（IHC）测定。在10、30、50 mg/kg三个剂量水平评估了其NHP安全性和药代动力学（PK）。在加速条件下（40°C持续2周及5个冻融循环）的物理稳定性通过SEC-HPLC测定纯度、通过RP-HPLC测定DAR值进行评估。
结果：CS5006表现出对ITGB4阳性癌细胞系强效、靶点依赖性的杀伤，其效力与抗原表达水平呈正相关（对高表达细胞的IC50处于纳摩尔范围）。单次10 mg/kg剂量的CS5006在全部9个CDX模型中诱导了肿瘤消退，这些模型代表NSCLC（n=4）、CRC、SCCHN、尿路上皮癌（UC）、胃癌（GC）和乳腺癌（BC）。在一项重复给药毒性研究中，CS5006在研究期间对食蟹猴耐受性良好。ADC的全身暴露与总抗体相当，并呈剂量比例增加，提示CS5006具有显著的循环稳定性。CS5006表现出优异的可开发性，在五个冻融循环后及40°C下2周后仍保持稳定。
结论：CS5006在临床前研究中表现出高效力、强健的抗肿瘤活性、可控的安全性特征以及优异的可开发性，支持其临床转化。计划于2026年下半年提交CS5006的IND申请，以支持在晚期实体瘤患者中的临床开发。
查看英文原文 English abstract
Background: Integrin beta4 (ITGB4) is highly expressed in colorectal carcinoma (CRC), non-small cell lung cancer (NSCLC), squamous cell carcinoma of the head and neck (SCCHN), esophageal squamous cell carcinoma (ESCC), and other solid tumors. CS5006 is a novel ITGB4-targeting antibody-drug conjugate (ADC) composed of an ITGB4-specific humanized IgG1 antibody (H86.2) conjugated to the clinically validated exatecan (Exa) payload via a highly stable, hydrophilic tandem-cleavage CSL linker, with a drug-to-antibody (DAR) value of 4.
Methods: The potency of CS5006 was evaluated in viability assays across a panel of cancer cell lines with varied ITGB4 expression levels. Its antitumor efficacy was evaluated in cell-derived xenograft (CDX) mouse models. ITGB4 expression level on tumor cell lines applied in vitro and in vivo studies was determined by quantitative flow cytometry and immunohistochemistry (IHC) assays. Its NHP safety and pharmacokinetics (PK) were assessed at three dose levels including 10, 30, 50 mg/kg. The physical stability under accelerated conditions (40°C for 2 weeks and freeze-thaw for 5 cycles) was assessed by SEC-HPLC for purity and by RP-HPLC for DAR value.
Results: CS5006 demonstrated potent, target-dependent killing of ITGB4-positive cancer cell lines with potency positively correlating with antigen expression levels (nanomolar range IC50 against high-expressing cells). A single 10 mg/kg dose of CS5006 induced tumor regression across all 9 CDX models, representing NSCLC (n=4), CRC, SCCHN, urothelial carcinoma (UC), gastric cancer (GC) and breast cancer (BC). In a repeat-dose toxicity study, CS5006 was well tolerated in cynomolgus monkeys during the study. Systemic exposure of the ADC was comparable to the total antibody, and increased dose-proportionally, suggesting CS5006's remarkable circulating stability. CS5006 exhibited excellent developability, maintaining stable after five freeze-thaw cycles and after 2 weeks at 40°C.
Conclusions: CS5006 demonstrates high potency, robust antitumor activity, a manageable safety profile, and excellent developability in preclinical studies, supporting its clinical translation. An IND application for CS5006 is planned for H2 2026 to support clinical development in patients with advanced solid tumors.
利益披露 Disclosure
C. Wang,
CStone Pharmaceuticals Employment.
X. Zhang,
CStone Pharmaceuticals Employment.
N. Zhang,
CStone Pharmaceuticals Employment.
Y. Wang,
CStone Pharmaceuticals Employment.
Y. Li,
CStone Pharmaceuticals Employment.
M. Zhu,
CStone Pharmaceuticals Employment.
X. Liu,
CStone Pharmaceuticals Employment.
Y. Chen,
CStone Pharmaceuticals Employment.
Y. Qian,
CStone Pharmaceuticals Employment.
Y. Yang,
CStone Pharmaceuticals Employment.
J. Sun,
CStone Pharmaceuticals Employment.
F. Ma,
CStone Pharmaceuticals Employment.
J. Yang,
CStone Pharmaceuticals Employment, Stock, Stock Option.