PO.CL07.05 · 临床研究
DB-1323是一种新一代靶向间皮素的抗体药物偶联物，在临床前模型中展现出抗肿瘤活性和良好的安全性特征
DB-1323, a next-generation mesothelin targeting antibody-drug conjugate, demonstrated anti-tumor activity and favorable safety profile in pre-clinical models
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：间皮素（MSLN）在许多难治性实体瘤中高表达，并与转移、较差的无进展生存期和较低的总生存期相关。尽管25年来跨多种模态开展了药物研发工作，但由于靶上/靶外毒性、瘤内抗原异质性、MSLN-抗体复合物内化不良以及可溶性MSLN“陷阱（sink）”效应等因素的阻碍，尚无靶向MSLN的疗法获批。DB-1323是一种MSLN-ADC，由一种新型全人源抗MSLN免疫球蛋白G1（IgG1）单克隆抗体经马来酰亚胺-四肽可切割连接子共价偶联一种专有的DNA拓扑异构酶I抑制剂组成。在本研究中，我们在全面的临床前模型中评估了DB-1323的疗效和安全性。
方法：通过流式细胞术定量抗MSLN抗体与MSLN表达细胞的结合亲和力。在MSLN阳性胰腺癌细胞中评估细胞毒性。在MSLN阳性胰腺癌和卵巢癌异种移植模型中检测抗肿瘤活性，并与anetumab ravtansine及其他MSLN ADC进行比较。同时在食蟹猴中评估药代动力学和安全性特征。
结果：DB-1323对人和食蟹猴MSLN均表现出高亲和力，且无可检测的靶外结合。DB-1323具有独特的MSLN结合特性（快速的结合/解离动力学），使其能够规避可溶性MSLN，同时对肿瘤细胞表面的MSLN保持高亲合力。DB-1323的内化较anetumab ravtansine更快、更广泛，尤其是在存在生理相关浓度可溶性MSLN的情况下。在体外，DB-1323在存在可溶性MSLN时仍保留对MSLN表达胰腺癌细胞的细胞毒性。它还在胰腺癌异种移植模型和卵巢癌患者来源异种移植模型中表现出剂量依赖的抗肿瘤活性。此外，在相同剂量下DB-1323表现出比anetumab ravtansine更强的肿瘤生长抑制作用。DB-1323及总抗体的全身暴露量AUC0-last和Cmax在1 mg/kg至10 mg/kg范围内随剂量成比例增加，血清中游离载荷较低。DB-1323在食蟹猴中也表现出良好的安全性特征，最高非严重毒性剂量（HNSTD）为60 mg/kg。
结论：DB-1323通过独特的快速结合/解离、高效内化和强效拓扑异构酶I抑制，克服了MSLN靶向的历史性缺陷，在耐受良好的剂量下实现了更优的肿瘤根除。这些数据支持对MSLN表达肿瘤患者进行DB-1323的临床评估。
查看英文原文 English abstract
Background: Mesothelin (MSLN) is highly expressed in many hard-to-treat solid tumors and is associated with metastasis, poor progression-free survival and lower overall survival. Despite 25 years of drug- development efforts across modalities, no MSLN-directed therapy has been approved, hampered by on-/off-target toxicities, intra-tumoral antigen heterogeneity, poor internalization of MSLN-antibody complexes, and soluble MSLN “sink” effects. DB-1323 is a MSLN-ADC composed of a novel fully human anti-MSLN immunoglobulin G1 (IgG1) monoclonal antibody, covalently conjugated to a proprietary DNA topoisomerase I inhibitor via a maleimide-tetrapeptide cleavable linker. In the present study, we evaluated the efficacy and safety of DB-1323 in comprehensive preclinical models.
Methods: Binding affinity of the anti-MSLN antibody to MSLN-expressing cells was quantified by flow cytometry. Cytotoxicity was assessed in MSLN-positive pancreatic cancer cells. Anti-tumor activity was tested in MSLN-positive pancreatic and ovarian cancer xenograft models compared to that of anetumab ravtansine and other MSLN ADCs. The pharmacokinetics and safety profile were also evaluated in cynomolgus monkeys.
Results: DB-1323 showed high affinity to both Human and Cyno MSLN without detectable off-target binding. DB-1323 has unique MSLN binding characteristics (fast on/off kinetics) that allow it to evade soluble MSLN while maintaining high avidity for MSLN on the surface of tumor cells. DB-1323 has faster and more extensive internalization than anetumab ravtansine, especially in the presence of physiologically relevant soluble MSLN concentrations. In vitro, DB-1323 retained cytotoxicity towards MSLN-expressing pancreatic cancer cells in the presence of soluble MSLN. It also showed dose-dependent anti-tumor activity in a pancreatic cancer xenograft model and ovarian cancer patient-derived xenograft model. Moreover, DB-1323 showed stronger tumor growth inhibition than that of anetumab ravtansine at the same dose. The systemic exposure AUC0-last and Cmax of DB-1323 and total antibody increased dose proportionally from 1mg/kg to 10mg/kg with low free payload in serum. DB-1323 also showed good safety profile with highest non-severely toxic dose (HNSTD) of 60mg/kg in cynomolgus monkeys.
Conclusions: DB-1323 overcomes historical MSLN-targeting liabilities through unique rapid-on/off binding, efficient internalization, and potent topoisomerase I inhibition, delivering superior tumor eradication versus at well-tolerated doses. These data support clinical evaluation of DB-1323 for patients with MSLN expressing tumors.
利益披露 Disclosure
H. Hua, None..
T. Cheng, None..
J. Yang, None..
X. Chen, None..
S. Lee, None..
J. Shin, None..
Y. Choi, None..
G. Baek, None..
A. Joyeux, None..
J. Lim, None.