LBPO.CH01 · 化学 · Late-Breaking
LN019，一种新型HER2靶向亲和体-药物偶联物，在异种移植模型中展现出优于T-DXd的抗肿瘤疗效
LN019, a novel HER2-targeting affibody-drug conjugate, demonstrates superior antitumor efficacy compared to T-DXd in xenograft models
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摘要 Abstract
中文摘要
亲和体（Affibody）以其紧凑的三螺旋结构为特点，相较传统单克隆抗体具有显著优势，如更优的组织穿透动力学、皮摩尔级结合亲和力以及可通过原核表达高效生产。利用这些有利特性，我们开发了LN019，一种表现出卓越临床前疗效的新型亲和体-药物偶联物。在体外，LN019对HER2阳性细胞系表现出强效的剂量依赖性细胞毒性，在SKOV-3（卵巢癌）中IC50为3.6 nM，在BT474（乳腺癌）中为8.1 nM。体内生物分布试验显示出优异的动力学特性，LN019在注射后10分钟内即在肿瘤部位显著蓄积，验证了快速靶组织穿透的假说。在异种移植模型中，LN019在更低剂量下展现出显著的抗肿瘤疗效。在SKOV-3卵巢癌和N87胃癌异种移植模型中，4.8 mg/kg的LN019分别诱导了肿瘤完全消退，肿瘤生长抑制率（TGI）分别为105.2%和122.3%，大幅超越了高达8 mg/kg剂量的DS-8201所观察到的90.1%和115.3%的TGI。值得注意的是，在BT474乳腺癌模型中，低剂量2.4 mg/kg的LN019产生了112.0%的TGI，优于高剂量DS-8201组（8 mg/kg，105.1% TGI）。这些发现提示，LN019利用亲和体骨架的独特特性实现了快速的肿瘤摄取和强效的疗效。因此，LN019代表了一种颇具前景的下一代治疗候选药物，用于HER2过表达的恶性肿瘤，有可能在组织穿透为限制因素的实体瘤中提供更优的安全性特征和疗效。本研究获得上海市自然科学基金（25ZR1402262）、上海交通大学化学生物学协同创新国家重点实验室（sklscbs202547）的资助。
肿瘤生长抑制率（TGI） 乳腺癌肿瘤模型（BT474） 卵巢癌肿瘤模型（SKOV-3） 胃癌肿瘤模型（N87） DS-8201（8 mg/kg） 105.1 90.1 115.3 LN019（1.2 mg/kg） 94.0 N/A N/A LN019（2.4 mg/kg） 112.0 N/A N/A LN019（4.8 mg/kg） 118.1 105.2 122.3 LN019（7.2 mg/kg） N/A 107.7 123.2 LN019（9.6 mg/kg） N/A 108.6 124.1 TGI (%) = [1-(Ti-T0)/(Ci-C0)] × 100%，Ti为治疗组第i天的平均肿瘤体积，T0为治疗组第0天的平均肿瘤体积；Ci为对照组第i天的平均肿瘤体积，C0为对照组第0天的平均肿瘤体积。
查看英文原文 English abstract
Affibody, distinguished by its compact three-helix structure, offers significant advantages over conventional monoclonal antibodies, such as superior tissue penetration kinetics, picomolar binding affinity, and efficient production via prokaryotic expression. Leveraging these favorable properties, we developed LN019, a novel affibody-drug conjugate exhibited exceptional preclinical efficacy. In vitro, LN019 exhibited potent dose-dependent cytotoxicity against HER2-positive cell lines,with IC 50 of 3.6 nM in SKOV-3 (ovarian cancer) and 8.1 nM in BT474 (breast caner). In vivo biodistribution assays revealed the excellent kinetics, LN019 achieving significant accumulation at the tumor sites within 10 min post-injection, validating the hypothesis of rapid target-tissue penetration. In xenograft models, LN019 showed remarkable antitumor efficacy at reduced dose. In SKOV-3 ovarian and N87 gastric cancer xenograft models, LN019 at 4.8 mg/kg induced complete tumor regression with a tumor growth inhibition (TGI) of 105.2% and 122.3% respectively, dramatically surpassing the 90.1% and 115.3% TGI observed with DS-8201 at such high-dose 8 mg/kg. Notably, in BT474 breast cancer models, a low dose of 2.4 mg/kg LN019 yielded a TGI of 112.0%, outperforming the high-dose DS-8201 group (8 mg/kg, 105.1% TGI). These findings suggest that LN019 leverages the unique properties of the affibody scaffold to achieve rapid tumor uptake and potent efficacy. Consequently,LN019 represents a promising next-generation therapeutic candidate for HER2-overexpressing malignancies , potentially offering an improved safety profile and efficacy in solid tumors where tissue penetration is a limiting factor. This work was supported by the Natural Science Foundation of Shanghai (25ZR1402262), the State Key Laboratory of Synergistic Chem-Bio Synthesis, Shanghai Jiao Tong University (sklscbs202547)
Tumor Growth Inhibition (TGI) Breast cancer tumor models (BT474) Ovary cancer tumor models (SKOV-3) Gastric cancer tumor models (N87) DS-8201(8 mg/kg) 105.1 90.1 115.3 LN019(1.2 mg/kg) 94.0 N/A N/A LN019(2.4 mg/kg) 112.0 N/A N/A LN019(4.8 mg/kg) 118.1 105.2 122.3 LN019(7.2 mg/kg) N/A 107.7 123.2 LN019(9.6 mg/kg) N/A 108.6 124.1 TGI (%) = [1-(Ti-T0)/ (Ci-C0)] × 100%, Ti is average tumor volume of treatment group on day i，T0 is average tumor volume of treatment group on day 0；Ci is average tumor volume of control group on day i, C0 is average tumor volume of control group on day0.
利益披露 Disclosure
X. Xia, None..
N. Sun, None..
W. Huang, None..
Z. Yan, None..
Z. Sun, None..
Y. Liu, None..
W. Li, None..
X. Li, None..
X. Xia, None..
D. Yan, None.