AA-98(AA-98) - 药物靶点：Muc18_在研适应症：肿瘤_专利_临床

概要

基本信息

药物类型

单克隆抗体

别名

anti-CD146 antibody(Chinese Academy of Sciences)、AA-98

靶点

Muc18

作用方式

抑制剂、调节剂

作用机制

Muc18抑制剂(黑色素瘤细胞粘附分子抑制剂)、Surface antigens 调节剂(表面抗原调节剂)

治疗领域

肿瘤

在研适应症

肿瘤

非在研适应症-

原研机构

中国科学院

在研机构

北京迈康斯德医药技术有限公司

非在研机构-

权益机构-

最高研发阶段药物发现

首次获批日期-

最高研发阶段(中国)药物发现

特殊审评-

关联

100 项与 AA-98 相关的临床结果

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100 项与 AA-98 相关的转化医学

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100 项与 AA-98 相关的专利（医药）

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19

项与 AA-98 相关的文献（医药）

2025-05-13·INFECTION AND IMMUNITY

Involvement of CD146 in the Cryptococcus neoformans adhesion and infection of brain endothelial cells

Article

作者: Chen, Junhong ; Yan, Xiyun ; Duan, Hongxia ; Liu, Wei ; Wang, Ting ; Yang, Chen ; Li, Yuwei ; Wang, Xiaoming ; Zhang, Mingshun ; Gong, Ying

ABSTRACT:

Cryptococcal meningitis is a common and refractory central nervous system (CNS) infection with high mortality and disability. For Cryptococcus neoformans ( C. neoformans ) to penetrate the CNS, it first adheres to and breaches the blood‒brain barrier (BBB). Here, we explored the roles of CD146, an adhesion molecule expressed on the surface of brain microvascular endothelial cells (BMECs), in cryptococcal vascular adhesion and BBB invasion. Following cryptococcal infection, we observed a reduction in CD146 expression in BMECs, which was at least partially mediated by metalloproteinase-9. Once overexpressed on BMECs, CD146 increased C. neoformans adhesion; in contrast, CD146 knockout decreased the attachment of fungi to endothelial cells in vitro . Unexpectedly, CD146 knockout failed to reduce fungal infection in the brain following intravascular instillation of C. neoformans . However, the anti-CD146 antibody AA98 significantly increased the fungemia (spleen CFU), suggesting that CD146 may be involved in the early adhesion and invasion of Cryptococcus into cerebral vessels. AA98, however, failed to extend the survival of C. neoformans infected mice. These results suggest that CD146 may play dispensable roles in the C. neoformans brain infection.

2023-11-01·Cancer communications (London, England)

CD146 promotes malignant progression of breast phyllodes tumor through suppressing DCBLD2 degradation and activating the AKT pathway

Article

作者: Nie, Yan ; Huang, Hongyan ; Song, Erwei ; Xu, Qingji ; Liao, Jianyou ; Liu, Dan ; Lei, Rong ; Chen, Xuehui ; Saw, Phei Er ; Guo, Mingyan ; Yan, Xiyun ; Li, Wende ; Chen, Jiewen ; Li, Xun

Abstract:

Background:

As a rapid‐progressing tumor, breast malignant phyllodes tumors (PTs) are challenged by the lack of effective therapeutic strategies and suitable prognostic markers. This study aimed to clarify the role and mechanism of CD146 on promoting PTs malignant progression, and to identify a novel prognosis marker and treatment target of breast malignant PTs.

Methods:

The expression and prognostic significance of CD146 in PTs was detected through single‐cell RNA‐sequencing (scRNA‐seq), immunostaining, real‐time PCR and other methodologies. Functional experiments including proliferation assay, colony formation assay, transwell assay, and collagen contraction assay were conducted to validate the role of CD146 in malignant progression of PTs. The efficacy of anti‐CD146 monoclonal antibody AA98 against malignant PTs was corroborated by a malignant PT organoid model and a PT patient‐derived xenograft (PDX) model. Transcriptome sequencing, proteomic analysis, co‐immunoprecipitation, and pull‐down assay was employed to identify the modulating pathway and additional molecular mechanism.

Results:

In this study, the scRNA‐seq analysis of PTs disclosed a CD146‐positive characteristic in the α‐SMA+ fibroblast subset. Furthermore, a progressive elevation in the level of CD146 was observed with the malignant progression of PTs. More importantly, CD146 was found to serve as an independent predictor for recurrence in PT patients. Furthermore, CD146 was found to augment the viability and invasion of PTs. Mechanistically, CD146 acted as a protective “shield” to prevent the degradation of Discoidin, CUB, and LCCL domain‐containing protein 2 (DCBLD2), thereby activating the phosphoinositide 3‐kinase (PI3K)/protein kinase B (AKT) signaling pathway and enhancing malignant behaviors of PT cells. In the malignant PT organoid and PDX model, a significant suppression of malignant PT growth was observed after the application of AA98.

Conclusions:

These findings suggested that CD146 served as an efficacious marker for predicting PT malignant progression and showed promise as a prognosis marker and treatment target of breast malignant PTs. The study further unveiled the essential role of the CD146‐DCBLD2/PI3K/AKT axis in the malignant progression of PTs.

2022-08-01·Cellular oncology (Dordrecht)

Inhibition of CD146 lessens uveal melanoma progression through reducing angiogenesis and vasculogenic mimicry

Article

作者: Tang, Jiajia ; Tu, LiLi ; Chen, Feng ; Yan, Xiyun ; Chen, Xiaogang ; Lin, Yong ; Duan, Hongxia ; Hou, Qiang ; Chen, Shengwen ; Qu, Jia ; Zhang, Ronghan ; Reinach, Peter Sol

PURPOSE:

Anti-angiogenesis drug therapy is ineffective in treating uveal melanoma since it only targets angiogenesis leaving vasculogenic mimicry aside. There is no effective clinical strategy targeting vasculogenic mimicry, yet. We show here that CD146 is a novel target to inhibit uveal melanoma progression since it regulates both uveal melanoma angiogenesis and vasculogenic mimicry activity.

METHODS:

CD146 inhibition was achieved with its specific siRNAs or antibody AA98. Tube formation and migration of primary human retinal microvascular endothelial cells and tube-like structure formation, migration, invasion of uveal melanoma cells were evaluated after CD146 inhibition. The underlying mechanisms were investigated by Western blot and immunofluorescence. Finally, uveal melanoma cells were injected subretinally into the eyes of nude mice and AA98 was administrated. Tumor size was revealed by H&E staining, and angiogenesis and vasculogenic mimicry were evaluated with CD31-PAS staining.

RESULTS:

CD146 inhibition induced declines in tube formation and migration of primary human retinal microvascular endothelial cells and tube-like structure formation of uveal melanoma cells. CD146 mediated VEGFR/AKT/p38/NF-κB and FAK/VE-cadherin signal cascades were partially responsible for these biological effects. CD146 blockade by siRNA or AA98 also resulted in inhibition of migration and invasion as well as EMT process of uveal melanoma cells. The physiological relevance of such declines was confirmed by showing that AA98 treatment markedly suppressed the tumor growth, angiogenesis and vasculogenic mimicry induced by implantation of uveal melanoma cells into the eyes of nude mice.

CONCLUSIONS:

CD146 is a novel mediator of both angiogenesis and vasculogenic mimicry in uveal melanoma. Its antibody AA98 has the potency to be developed as a new antibody drug for treating uveal melanoma. Our results warrant further assessment of CD146 as a potential target to improve therapeutic management of uveal melanoma in a clinical setting.

100 项与 AA-98 相关的药物交易

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