Cheng Yezhe, Yuan Xiaoxi, Tian Qiang, Huang Xiuying, Chen Yang, Pu Yuzhi, Long Hu, Xu Mingyu, Ji Yafei, Xie Jia, Tan Yuping, Zhao Xi, Song Hongmei
Center of Translational Medicine, Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd., Chengdu, China.
Front Oncol. 2022 Dec 23;12:951589. doi: 10.3389/fonc.2022.951589. eCollection 2022.
The aim of this study was to improve the intratumoral accumulation of an antibody-drug conjugate (ADC) and minimize its off-target toxicity, SKB264, a novel anti-trophoblast antigen 2 (TROP2) ADC that was developed using 2-methylsulfonyl pyrimidine as the linker to conjugate its payload (KL610023), a belotecan-derivative topoisomerase I inhibitor. The preclinical pharmacologic profiles of SKB264 were assessed in this study.
The and pharmacologic profiles of SKB264, including efficacy, pharmacokinetics-pharmacodynamics (PK-PD), safety, and tissue distribution, were investigated using TROP2-positive cell lines, cell-derived xenograft (CDX), patient-derived xenograft (PDX) models, and cynomolgus monkeys. Moreover, some profiles were compared with IMMU-132.
, SKB264 and SKB264 monoclonal antibody (mAb) had similar internalization abilities and binding affinities to TROP2. After cellular internalization, KL610023 was released and inhibited tumor cell survival. , SKB264 significantly inhibited tumor growth in a dose-dependent manner in both CDX and PDX models. After SKB264 administration, the serum or plasma concentration/exposure of SKB264 (conjugated ADC, number of payload units ≥1), total antibody (Tab, unconjugated and conjugated mAb regardless of the number of the payload units), and KL610023 in cynomolgus monkeys increased proportionally with increasing dosage from 1 to 10 mg/kg. The linker stability of SKB264 was significantly enhanced as shown by prolonged payload half-life (SKB264 . IMMU-132, 56.3 h . 15.5 h). At the same dose, SKB264's exposure in tumor tissue was 4.6-fold higher than that of IMMU-132.
Compared with IMMU-132, the longer half-life of SKB264 had a stronger targeting effect and better antitumor activity, suggesting the better therapeutic potential of SKB264 for treating TROP2-positive tumors.
本研究旨在提高抗体药物偶联物（ADC）SKB264在肿瘤内的蓄积，并将其脱靶毒性降至最低。SKB264是一种新型抗滋养层抗原2（TROP2）ADC，它以2-甲基磺酰嘧啶为连接子，偶联其有效载荷（KL610023），一种喜树碱衍生物拓扑异构酶I抑制剂。本研究评估了SKB264的临床前药理学特征。
使用TROP2阳性细胞系、细胞源异种移植（CDX）模型、患者源异种移植（PDX）模型和食蟹猴研究了SKB264的药效学、药代动力学-药效学（PK-PD）、安全性和组织分布等药理学特征。此外，还将部分特征与IMMU-132进行了比较。
首先，SKB264及其单克隆抗体（mAb）对TROP2具有相似的内化能力和结合亲和力。细胞内化后，KL610023被释放并抑制肿瘤细胞存活。其次，SKB264在CDX和PDX模型中均以剂量依赖性方式显著抑制肿瘤生长。给予SKB264后，食蟹猴血清或血浆中SKB264（偶联ADC，有效载荷单元数≥1）、总抗体（Tab，未偶联和偶联的mAb，无论有效载荷单元数）和KL610023的浓度/暴露量随剂量从1 mg/kg增加到10 mg/kg成比例增加。SKB264的连接子稳定性显著增强，表现为有效载荷半衰期延长（SKB264对IMMU-132，56.3小时对15.5小时）。在相同剂量下，SKB264在肿瘤组织中的暴露量比IMMU-132高4.6倍。
与IMMU-132相比，SKB264更长的半衰期具有更强的靶向作用和更好的抗肿瘤活性，表明SKB264在治疗TROP2阳性肿瘤方面具有更好的治疗潜力。
