PO.CL06.01 · 临床研究

一种B7-H3抗体药物偶联物在骨肉瘤患者来源模型和转移模型中的抗肿瘤活性

Antitumor activity of a B7-H3 antibody-drug conjugate in osteosarcoma patient-derived and metastatic models

编号 7813 展板 16 时间 4/22 09:00–12:00 区域 Section 44 主讲 Adil Bahadir, MD

分会场 Immunotherapies in Pediatric Cancers

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作者与单位 Authors & Affiliations

Wendong Zhang¹, Adil Bahadir¹, Zhongting Zhang¹, Yianhua Yi¹, Zhaohui Xu¹, Simon Olivares¹, Harjeet Singh¹, AMER NAJJAR¹, Caterina Longo¹, Xin Zhou¹, Jasbir Kaur², Hiroki Torikai², Chunhua Shi², Jonathan Gill¹, Michael Roth¹, Tim Heffernan², Richard Gorlick¹

¹UT MD Anderson Cancer Center, Houston, TX,²Oncology Research for Biologics and Immunotherapy Translation (ORBIT), MD Anderson Cancer Center, Houston, TX

摘要 Abstract

中文摘要

背景：骨肉瘤的预后在三十多年来未见改善，肺转移患者的预后仍然很差。B7-H3在骨肉瘤上高表达，而在正常组织中表达有限，使其成为一个有吸引力的治疗靶点。本研究评估了一种B7-H3靶向抗体药物偶联物（B7H3 ADC）在骨肉瘤PDX和转移模型中的抗肿瘤活性。方法：B7-H3抗体（由MD Anderson的ORBIT开发）与tesirine载荷SG3249偶联。在体外，使用Incucyte成像评估了六种PDX来源骨肉瘤细胞系在B7H3 ADC（10点稀释，起始1000 nM）处理120小时后的细胞活力。通过非线性回归计算IC₅₀值，并通过单因素方差分析（配合η²和Cohen's f）分析剂量反应效应。在体内，六个PDX模型接受单次1 mg/kg腹腔注射剂量的B7H3 ADC、同型对照ADC或PBS治疗。评估了肿瘤生长抑制和EFS。使用荧光素酶标记的SJSA LM7细胞在静脉注射和胫骨注射模型中评估了转移疗效，在约3 × 10⁶光子/秒时开始治疗。结果：B7H3 ADC在所有六种细胞系中均产生强烈的剂量依赖性细胞毒性（IC₅₀=0.0795-0.6703 nM），效应量大（η²=0.80-0.93；Cohen's f=2.01-3.65；p<0.001）。在体内，六个PDX模型中有三个实现了维持性完全缓解（MCR），两个显示部分缓解（PR），一个表现出疾病进展（PD）。在静脉转移模型中，对照组小鼠从第20天开始需要安乐死，而所有接受治疗的小鼠直到第93天仍无转移。在胫骨模型中，对照组小鼠在第25天前被安乐死，第22天检测到肺转移。接受治疗的小鼠在第17天时胫骨肿瘤完全消退，直到第64天仍无转移。结论：B7H3 ADC在骨肉瘤PDX和转移模型中表现出强效且可重复的抗肿瘤活性，诱导持久的肿瘤消退并阻止转移进展。这些发现支持B7-H3作为一个有前景的治疗靶点，并证明进一步开发B7H3 ADC用于原发性和转移性骨肉瘤是合理的。

查看英文原文 English abstract

Background: Osteosarcoma outcomes have not improved in over three decades, and prognosis remains poor for patients with pulmonary metastases. B7-H3 is highly expressed on osteosarcoma with limited normal-tissue expression, making it an attractive therapeutic target. This study evaluated the antitumor activity of a B7-H3-targeting antibody-drug conjugate (B7H3 ADC) in osteosarcoma PDX and metastatic models. Methods: The B7-H3 antibody (developed by ORBIT, MD Anderson) was conjugated to the tesirine payload SG3249. In vitro, cell viability was assessed in six PDX-derived osteosarcoma cell lines treated with B7H3 ADC (10-point dilution, 1000 nM start) over 120 h using Incucyte imaging. IC₅₀ values were calculated by nonlinear regression, and dose-response effects were analyzed by one-way ANOVA with η² and Cohen's f. In vivo, six PDX models were treated with a single 1 mg/kg IP dose of B7H3 ADC, isotype-ADC, or PBS. Tumor growth inhibition and EFS were evaluated. Metastatic efficacy was assessed in IV and tibial injection models using luciferase-labeled SJSA LM7 cells, with treatment initiated at ~3 × 10⁶ photons/sec. Results: B7H3 ADC produced strong, dose-dependent cytotoxicity across all six cell lines (IC₅₀ = 0.0795-0.6703 nM), with large effect sizes (η² = 0.80-0.93; Cohen's f = 2.01-3.65; p < 0.001). In vivo, three of six PDX models achieved maintained complete response (MCR), two showed partial response (PR), and one exhibited progressive disease (PD). In the IV metastasis model, control mice required euthanasia beginning on day 20, whereas all treated mice remained metastasis-free through day 93. In the tibial model, control mice were euthanized by day 25 with lung metastases detected by day 22. Treated mice showed complete tibial tumor regression by day 17 and remained metastasis-free through day 64. Conclusions: B7H3 ADC demonstrated potent and reproducible antitumor activity in osteosarcoma PDX and metastatic models, inducing durable tumor regression and preventing metastatic progression. These findings support B7-H3 as a promising therapeutic target and justify further development of B7H3 ADC for primary and metastatic osteosarcoma.

利益披露 Disclosure

W. Zhang, None.. A. Bahadir, None.. Z. Zhang, None.. Y. Yi, None.. Z. Xu, None.. S. Olivares, None.. H. Singh, None.. A. Najjar, None.. C. Longo, None.. X. Zhou, None.. J. Kaur, None.. H. Torikai, None.. C. Shi, None.. M. Roth, None.. T. Heffernan, None.

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