PO.IM01.13 · 免疫学
ADCE-T02——一种靶向组织因子的临床阶段抗体药物偶联物在头颈部鳞状细胞癌临床前模型中展现出强效疗效
ADCE-T02 - A clinical stage antibody drug conjugate targeting tissue factor demonstrates strong efficacy in preclinical models of head and neck squamous cell carcinoma
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
组织因子（TF、F3、凝血因子III、凝血活酶或CD142）是一种参与血液凝固的膜蛋白，在健康组织中局限表达于血管周围区室，但在许多实体瘤中过度表达，使其成为抗体药物偶联物（ADC）的一个有吸引力的靶点。TF靶向ADC Tisotumab vedotin已获批用于治疗宫颈癌，并在头颈部鳞状细胞癌（HNSCC）中展现出疗效¹，但治疗受限于包括眼部毒性、周围神经病变和出血在内的重大副作用，因此有必要开发一种更有效且耐受性更好的治疗模式。
ADCE-T02是一种临床阶段的TF靶向ADC，由专门设计以限制对血液凝固影响的人源化抗TF抗体组成，通过一种新型T1000连接子部分以约4的药物抗体比偶联至拓扑异构酶-1抑制剂Exatecan载荷。
在HNSCC患者中评估了TF的表达水平，证实无论人乳头瘤病毒（HPV）状态如何，大多数肿瘤中均有广泛且高水平的TF表达。在体外，在一组具有不同TF表达水平的HNSCC肿瘤细胞系中评估并证实了ADCE-T02的疗效。在体内，ADCE-T02在具有不同TF表达的细胞系和患者来源的HNSCC异种移植模型中也展现出强效的抗肿瘤活性。耐人寻味的是，在表达高水平表皮生长因子受体（EGFR）但对抗EGFR治疗反应有限的HNSCC肿瘤中，观察到ADCE-T02（起始剂量1 mg/kg）的强效疗效。此外，向携带大肿瘤（≥1000mm³）的小鼠单次给予ADCE-T02导致显著的肿瘤缩小，常常带来肿瘤的完全根除。另外，在抗EGFR治疗后长出的大肿瘤中，观察到单次剂量ADCE-T02的强效抗肿瘤反应。
总之，ADCE-T02在具有不同TF表达水平的HNSCC模型（包括对EGFR靶向药物耐药的模型）中展现出广泛的疗效。ADCE-T02在晚期实体瘤患者中的I期临床研究目前正在进行并积极招募（临床试验ID NCT06597721）。
¹ Sun等，J. Clin. Oncol.；42（16增刊）；2024
查看英文原文 English abstract
Tissue Factor (TF, F3, coagulation factor III, thromboplastin, or CD142), a membrane protein involved in blood coagulation, demonstrates confined expression to the perivascular compartment in healthy tissues but is over-expressed in many solid tumors, making it an attractive target for Antibody Drug Conjugates (ADC). The TF-targeted ADC Tisotumab vedotin is approved for treatment of cervical cancer and has demonstrated efficacy in Head and Neck Squamous Cell Carcinoma (HNSCC) 1 , but treatment is limited by substantial side effects including ocular toxicities, peripheral neuropathy, and bleeding warranting development of a more efficacious and better tolerated modality.
ADCE-T02 is a clinical stage TF-targeted ADC composed of a humanized anti-TF antibody specifically designed to limit the impact on blood coagulation, conjugated via a novel T1000 linker moiety to the Topoisomerase-1 inhibitor Exatecan payload at a drug-to-antibody ratio of ~4.
The expression level of TF was evaluated in patients with HNSCC, confirming broad and high TF expression in the majority of tumors, regardless of Human Papilloma Virus (HPV) status. In vitro, the efficacy of ADCE-T02 was evaluated and confirmed in a panel of HNSCC tumor cell lines with varying TF expression levels. In vivo, ADCE-T02 also demonstrated strong anti-tumor activity in both cell line and patient derived HNSCC xenograft models with varying TF expressions. Intriguingly, strong efficacy of ADCE-T02 (dosed from 1 mg/kg) was observed in HNSCC tumors expressing high levels of Epidermal Growth Factor Receptor (EGFR) but with limited response to anti-EGFR therapy. Furthermore, administration of a single dose of ADCE-T02 to mice bearing large tumors (≥1000mm 3 ) caused remarkable tumor shrinkage often resulting in complete tumor eradication. In addition, strong antitumor responses of a single dose of ADCE-T02 were observed in large tumors growing out following anti-EGFR therapy.
In summary, ADCE-T02 demonstrates broad efficacy in HNSCC models with varying levels of TF expression including models resistant to EGFR targeted agents. A phase I clinical study of ADCE-T02 in patients with advanced solid tumors is currently ongoing and actively recruiting (Clinical Trial ID NCT06597721).
1 Sun et al., J. Clin. Oncol.; 42 (16 suppl.); 2024
利益披露 Disclosure
T. T. Poulsen, None..
O. Ilina, None..
P. Barkholt, None..
D. Pontieri, None..
J. B. Lange, None..
J. H. Wardman, None..
C. Côme, None..
C. Hjæresen, None..
S. Liu, None..
X. Meng, None..
Y. Zhang, None..
D. Mumberg, None.