Antitumor Activities by a Humanized Cancer-Specific Anti-Podoplanin Monoclonal Antibody humPMab-117 Against Human Tumors.

IF 5.7 2区 医学 Q1 Medicine
Cancer Science Pub Date : 2025-05-20 DOI:10.1111/cas.70103
Tomohiro Tanaka, Hiroyuki Suzuki, Tomokazu Ohishi, Manabu Kawada, Mika K Kaneko, Yukinari Kato
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引用次数: 0

Abstract

Podoplanin (PDPN), also referred to as T1α/Aggrus, is a type I transmembrane sialoglycoprotein that plays a crucial role in invasiveness, stemness, and epithelial-to-mesenchymal transition, all of which contribute to the malignant progression of tumors. Therefore, a monoclonal antibody (mAb) against PDPN has been evaluated in preclinical models as a promising tumor therapy strategy. However, PDPN plays an essential role in normal development, such as in the development of the lungs. On-target toxicity by anti-PDPN mAbs to normal cells should be avoided to minimize adverse effects. A cancer-specific mAb against PDPN, PMab-117 (rat IgM, kappa), was previously established. This study engineered the humanized IgG1 version (humPMab-117) to investigate antitumor activity. Flow cytometry analysis confirmed that humPMab-117 recognized PDPN-overexpressed glioma LN229 (LN229/PDPN) cells as well as PDPN-positive PC-10 (human lung squamous cell carcinoma) and LN319 (human glioblastoma) cells. In contrast, humPMab-117 did not react with normal epithelial cells from the lung bronchus, gingiva, mammary gland, corneal, and normal kidney podocytes, suggesting that humPMab-117 retains cancer-specific reactivity. Furthermore, humPMab-117 effectively induced antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity against LN229/PDPN, PC-10, and LN319 cells. In the xenograft tumor models, humPMab-117 demonstrated strong antitumor efficacy. These results suggest the potential of humPMab-117 as a therapeutic antibody for treating PDPN-positive malignant tumors.

人源化肿瘤特异性抗podoplanin单克隆抗体humPMab-117抗肿瘤活性研究
Podoplanin (PDPN),也被称为T1α/Aggrus,是一种I型跨膜唾液糖蛋白,在侵袭性、干性和上皮-间质转化中起关键作用,所有这些都有助于肿瘤的恶性进展。因此,针对PDPN的单克隆抗体(mAb)已在临床前模型中被评估为一种有前景的肿瘤治疗策略。然而,PDPN在正常发育中起着至关重要的作用,例如肺的发育。应避免抗pdpn单克隆抗体对正常细胞的靶毒性,以尽量减少不良反应。先前已经建立了一种针对PDPN的癌症特异性单抗,PMab-117(大鼠IgM, kappa)。本研究设计了人源化IgG1版本(humPMab-117)来研究抗肿瘤活性。流式细胞术分析证实,humPMab-117能够识别PDPN过表达的胶质瘤LN229 (LN229/PDPN)细胞以及PDPN阳性的PC-10(人肺鳞状细胞癌)和LN319(人胶质母细胞瘤)细胞。相比之下,humPMab-117与来自肺支气管、牙龈、乳腺、角膜和正常肾足细胞的正常上皮细胞没有反应,这表明humPMab-117保留了癌症特异性反应性。此外,humPMab-117可有效诱导针对LN229/PDPN、PC-10和LN319细胞的抗体依赖性细胞毒性和补体依赖性细胞毒性。在异种移植肿瘤模型中,humPMab-117显示出较强的抗肿瘤作用。这些结果提示humPMab-117有潜力作为治疗pdpn阳性恶性肿瘤的治疗性抗体。
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来源期刊
Cancer Science
Cancer Science ONCOLOGY-
CiteScore
9.90
自引率
3.50%
发文量
406
审稿时长
17 weeks
期刊介绍: Cancer Science (formerly Japanese Journal of Cancer Research) is a monthly publication of the Japanese Cancer Association. First published in 1907, the Journal continues to publish original articles, editorials, and letters to the editor, describing original research in the fields of basic, translational and clinical cancer research. The Journal also accepts reports and case reports. Cancer Science aims to present highly significant and timely findings that have a significant clinical impact on oncologists or that may alter the disease concept of a tumor. The Journal will not publish case reports that describe a rare tumor or condition without new findings to be added to previous reports; combination of different tumors without new suggestive findings for oncological research; remarkable effect of already known treatments without suggestive data to explain the exceptional result. Review articles may also be published.
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