PO.ET01.06 · 实验与分子治疗
ATL-024，一种靶向肿瘤特异性糖肽表位CA242（CanAg）的新型拓扑异构酶I类ADC，在结直肠癌和胰腺癌模型中展现出强效活性和优异的安全性特征
ATL-024, a novel topoisomerase I-based ADC targeting the tumor-specific glycopepitope CA242 (CanAg), demonstrates potent activity in colorectal and pancreatic cancer models, and excellent safety profile
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摘要 Abstract
中文摘要
CA242（也称CanAg）是一种肿瘤相关碳水化合物抗原，在胃肠道实体瘤中异常表达，但在正常组织中几乎不存在。特别是，该糖肽表位在结直肠、胰腺和胃肿瘤中高表达（高流行率且每个肿瘤细胞的拷贝数升高）。21世纪初的既往临床试验表明，CA242可通过抗体-药物偶联物（ADC）安全靶向，因为未报告显著的CA242相关脱靶毒性。微管抑制剂载荷所见的适度临床获益表明，替代载荷（如拓扑异构酶I抑制剂）可能改善CA242阳性肿瘤的治疗结果。为利用CA242的差异化表达，我们开发了一种名为ATL-024的新型CA242靶向ADC，它由一种抗CA242人源化Fc沉默单克隆抗体经二肽可切割连接子与拓扑异构酶I抑制剂exatecan偶联而成。该ADC是一个药物抗体比（DAR）为4的均质构建体。ATL-024在多个显示均质或异质CA242表达模式（经IHC测定）的结直肠癌和胰腺癌PDX模型中展现出强效抗肿瘤疗效，在低至3-6mg/kg的剂量下即有效。与既往基于cantuzumab-DM4的ADC（微管抑制剂载荷）相比，ATL-024在结直肠癌PDX模型中表现出显著更强的体内抗肿瘤活性。在食蟹猴的初步毒理学研究中，ATL-024在高达80 mg/kg（Q3W）的剂量下耐受良好，该剂量被确立为最高非严重毒性剂量（HNSTD）。在此剂量下，发现仅限于一只动物的轻度且可逆的血液学改变，临床化学参数正常，无严重临床体征，也未观察到器官毒性。药代动力学分析显示线性剂量依赖性暴露，与偶联物的全身稳定性一致。总体而言，ATL-024的临床前表征显示出非常有利的治疗指数，支持对患有CA242表达的胃肠道肿瘤（如结直肠或胰腺肿瘤）的患者进行人体临床评估。ATL-024目前正在进行IND申报支持开发。
查看英文原文 English abstract
CA242 (also known as CanAg) is a tumor-associated carbohydrate antigen that is aberrantly expressed by gastrointestinal solid tumors but is virtually absent from normal tissue. In particular, this glycopepitope is highly expressed in colorectal, pancreatic and gastric tumors (high prevalence and elevated number of copies per tumor cell). Previous clinical trials in the early 2000s showed that CA242 can be safely targeted with an antibody-drug conjugate (ADC), as no significant CA242-related off-tumor toxicities were reported. The modest clinical benefit seen with microtubule inhibitor payloads indicates that alternative payloads, such as topoisomerase-I inhibitors, may enhance therapeutic outcomes in CA242-positive tumors.To exploit CA242 differential expression, we developed a novel CA242-targeting ADC called ATL-024, which is comprised of an anti-CA242 humanized Fc-silenced monoclonal antibody conjugated to the topoisomerase I inhibitor exatecan via a dipeptide cleavable linker. This ADC is a homogeneous construct with a drug-to-antibody ratio (DAR) of 4.ATL-024 demonstrated potent antitumor efficacy in multiple colorectal and pancreatic cancer PDX models showing homogeneous or heterogeneous CA242 expression patterns (as determined by IHC), being effective at doses as low as 3-6mg/kg. Compared to previous cantuzumab-DM4 based ADC (microtubule inhibitor payload), ATL-024 exhibits significantly stronger in vivo anti-tumor activity in colorectal PDX models.In a pilot toxicology study in cynomolgus monkeys, ATL-024 was well tolerated up to 80 mg/kg (Q3W), which was established as the highest non-severely toxic dose (HNSTD). At this dose, findings were limited to mild and reversible hematologic changes in one animal, with normal clinical chemistry parameters, no severe clinical signs and no observed organ toxicities. Pharmacokinetic profiling showed linear dose-dependent exposure and is consistent with systemic stability of the conjugate.Overall, the preclinical characterization of ATL-024 shows a very favorable therapeutic index and support human clinical evaluation for patients with CA242-expressing gastrointestinal tumors such as colorectal or pancreatic tumors. ATL-024 is currently undergoing IND-enabling development.
利益披露 Disclosure
W. Viricel,
Eli Lilly Other, M&A transaction.
E. Leroy,
Eli Lilly Other, M&A transaction.