PO.CT01.01 · 临床试验
靶向肿瘤胚胎性硫酸软骨素的同类首创泛癌抗体Vartumab的临床验证
Clinical validation of a first-in-class pan-cancer antibody Vartumab targeting oncofetal chondroitin sulfate
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
新型基于抗体的癌症疗法的开发因可作用靶点的稀缺而受到挑战。人类肿瘤合成并展示一种保守的肿瘤胚胎性硫酸软骨素(chondroitin sulfate, CS)糖胺聚糖，作为对肿瘤细胞表面、癌症相关成纤维细胞上所发现蛋白的修饰，并作为肿瘤微环境的结构成分。在非病理条件下，肿瘤胚胎性CS仅存在于胎儿组织中，出生后在正常组织中无/极少呈现。我们已鉴定出一种单克隆抗体(Vartumab C9)，对多种恶性肿瘤中的肿瘤胚胎性CS具有特异性，如黑色素瘤、肉瘤、AML、胰腺癌，以及肺癌、结直肠癌、乳腺癌和胃癌。动物体内生物分布研究证实，静脉给药后Vartumab C9特异性地在肿瘤中蓄积。Vartumab C9衍生的ADC在啮齿动物中耐受性良好，并在广泛的动物模型中显示出显著的抗肿瘤活性。为验证肿瘤胚胎性CS作为人类新型泛癌靶点的资格，我们启动了一项0期微剂量PET成像试验(VARTUTRACE)，纳入实体瘤全人群患者(n=32)(NCT06645808)。未分层的实体瘤患者接受单次微剂量静脉注射Zr89-Vartumab C9(VTP-01，1mg，15 MBq)，并在第1、2和4天通过PET/CT获得全身图像。所有注射均耐受性良好，未报告不良事件。截至投稿时，五例癌症患者(肺癌(n=2)、食管癌(n=2)和直肠癌(n=1)患者)接受了VTP-01给药。所有患者在第4天均观察到明确的肿瘤蓄积，脱靶结合有限。成像后病灶活检证实了靶点存在。迄今未观察到与产品相关的不良反应。
总体而言，这些发现支持Vartumab C9作为一种有前景的、经临床验证的同类首创肿瘤靶向抗体，具有跨越多种恶性肿瘤递送治疗药物的广泛潜力。用于1-2a期Vartumab C9衍生ADC试验的GMP生产正在进行中。
查看英文原文 English abstract
The development of novel antibody-based cancer therapies is challenged by the scarcity of actionable tumor targets. Human tumors make and display a conserved oncofetal chondroitin sulfate (CS) glycosaminoglycan as a modification to proteins found on the surface of tumor cells, cancer-associated fibroblasts, and as structural components of the tumor microenvironment. In non-pathological conditions, oncofetal CS is found exclusively in fetal tissues with absent/minimal presentation in normal tissues after birth. We have identified a monoclonal antibody (Vartumab C9) with specificity to oncofetal CS in diverse malignancies, such as melanoma, sarcoma, AML, pancreatic cancer, as well as lung, colorectal, breast, and gastric cancers. Biodistribution studies in animals confirmed specific Vartumab C9 tumor accumulation upon intravenous administration. Vartumab C9-derived ADCs are well tolerated in rodents and show profound antitumor activity across a wide range of animal models. To qualify oncofetal CS as a novel pan-cancer target in humans, we have initiated a phase 0 micro-dosing PET imaging trial (VARTUTRACE) in all-commers (n=32) with solid tumors (NCT06645808). Non-stratified patients with solid tumors received a single micro-dose IV of a Zr89-Vartumab C9 (VTP-01, 1mg, 15 MBq) and whole-body images were obtained with PET/CT at days 1, 2, and 4. All injections were well tolerated and no adverse events reported. At time of submission, five cancer patients (lung cancer (n=2), esophagus cancer (n=2), and rectal cancer (n=1) patients) were dosed with VTP-01. Clear tumor accumulation was observed in all patients by day 4, with limited off-target binding. Post-imaging lesion biopsies confirmed target presence. No product-related adverse reactions were observed to date.
Collectively, these findings support Vartumab C9 as a promising clinical validated first-in-class, tumor targeting antibody with broad potential to deliver therapeutics across diverse malignancies. GMP production for a phase I-IIa Vartumab C9-derived ADC trial is ongoing.
利益披露 Disclosure
M. Daugaard,
VAR2 Pharmaceuticals Employment, g., Board of Directors, non-salaried role), Stock.
Rakovina Therapeutics Employment, Independent Contractor, Stock, Stock Option, ).
SnapCyte Solutions g., Board of Directors, non-salaried role), Stock.
T. Gustavsson,
VAR2 Pharmaceuticals Employment.
E. E. Vidal-Calvo, None..
S. Choudhary, None..
R. Dagil, None.
A. S. Verhaar,
TRACER Europe BV Employment.
N. C. van Dijk,
TRACER Europe BV Employment.
H. H. B. Boersma, None..
A. W. Glaudemans, None..
D. J. Vugts, None..
D. Waagmeester, None.
Y. Janssen,
TRACER Europe BV Employment.
M. Brom,
TRACER Europe BV Employment.
F. M. Pimenta,
VAR2 Pharmaceuticals ApS Employment.
G. M. van Dam,
TRACER Europe BV Employment, g., Board of Directors, non-salaried role), Stock.
A. Salanti,
VAR2 Pharmaceuticals ApS Employment, g., Board of Directors, non-salaried role), Stock.