德帕妥珠单抗马福多汀(ABT-414)在头颈癌临床前模型中的疗效。

IF 3.3 3区 医学 Q2 ONCOLOGY
Lucas Mani, Abdullah Naveed, Ashtyn McAdoo, Eben Rosenthal, Marisa Hom
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引用次数: 0

摘要

表皮生长因子受体(EGFR)在80-90%的头颈部鳞状细胞癌(HNSCC)中高度表达,因此成为抗体药物共轭物(ADC)的理想靶点。Depatuxizumab mafodotin(ABT-414)是一种表皮生长因子受体靶向ADC,由单克隆抗体(mAb)ABT-806与单甲基auristatin F(一种微管蛋白聚合抑制剂)结合而成。本研究评估了ABT-414在HNSCC中的体内疗效。ABT-414对HNSCC的影响是通过体外细胞毒性试验和体内侧腹异种移植小鼠模型确定的。利用ABT-414与近红外药剂IRDye800的共轭物,通过光学成像方法评估了ABT-414在体内外的分布情况。用ABT-414(0-3.38 nM)体外处理高表皮生长因子受体表达的人类HNSCC细胞系(UMSCC47和FaDu)会导致剂量依赖性细胞死亡(IC50值分别为0.213 nM和0.167 nM)。ABT-414治疗FaDu小鼠异种移植显示了抗肿瘤活性(p= 0.023),但体重没有变化(p= 0.1335),而治疗UMSCC47则没有产生显著反应(p= 0.1761)。荧光成像显示,ABT-414-IRDye800在FaDu和UMSCC47细胞系的肿瘤中均有积累,信噪比大于10。ABT-414治疗在FaDu肿瘤中产生了抗肿瘤活性,但在UMSCC47中却没有,这凸显了ABT-414在表皮生长因子受体高表达肿瘤中的潜在疗效。虽然ABT-414-IRDye800在两种细胞系中都能定位肿瘤,但不同的抗肿瘤反应突显了进一步研究肿瘤微环境在给药中的作用的必要性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Efficacy of depatuxizumab mafodotin (ABT-414) in preclinical models of head and neck cancer.

Epidermal growth factor receptor (EGFR) is highly expressed in 80-90% of head and neck squamous cell carcinomas (HNSCCs), making it an ideal target for antibody-drug conjugates. Depatuxizumab mafodotin (ABT-414), is an EGFR-targeting ADC comprised of the monoclonal antibody ABT-806 conjugated to monomethyl auristatin F, a tubulin polymerization inhibitor. This study assessed the in vivo efficacy of ABT-414 in HNSCC. The effects of ABT-414 on HNSCCs were determined using in vitro cytotoxicity assays and in vivo flank xenograft mouse models. The distribution of ABT-414 was assessed ex vivo via optical imaging methods using a conjugate of ABT-414 to the near-infrared agent IRDye800. In vitro treatment of high EGFR-expressing human HNSCC cell lines (UMSCC47 and FaDu) with ABT-414 (0-3.38 nM) resulted in dose-dependent cell death (IC50 values of 0.213 nM and 0.167 nM, respectively). ABT-414 treatment of the FaDu mouse xenografts displayed antitumor activity (P = 0.023) without a change in body mass (P = 0.1335), whereas treatment of UMSCC47 did not generate a significant response (P = 0.1761). Fluorescence imaging revealed ABT-414-IRDye800 accumulation in the tumors of both FaDu and UMSCC47 cell lines, with a signal-to-background ratio of >10. ABT-414 treatment yielded antitumor activity in FaDu tumors, but not in UMSCC47, highlighting the potential for ABT-414 efficacy in high EGFR-expressing tumors. Although ABT-414-IRDye800 localized tumors in both cell lines, the differing antitumor responses highlight the need for further investigation into the role of the tumor microenvironment in drug delivery.

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来源期刊
Carcinogenesis
Carcinogenesis 医学-肿瘤学
CiteScore
9.20
自引率
2.10%
发文量
95
审稿时长
1 months
期刊介绍: Carcinogenesis: Integrative Cancer Research is a multi-disciplinary journal that brings together all the varied aspects of research that will ultimately lead to the prevention of cancer in man. The journal publishes papers that warrant prompt publication in the areas of Biology, Genetics and Epigenetics (including the processes of promotion, progression, signal transduction, apoptosis, genomic instability, growth factors, cell and molecular biology, mutation, DNA repair, genetics, etc.), Cancer Biomarkers and Molecular Epidemiology (including genetic predisposition to cancer, and epidemiology), Inflammation, Microenvironment and Prevention (including molecular dosimetry, chemoprevention, nutrition and cancer, etc.), and Carcinogenesis (including oncogenes and tumor suppressor genes in carcinogenesis, therapy resistance of solid tumors, cancer mouse models, apoptosis and senescence, novel therapeutic targets and cancer drugs).
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