更新于：2024-11-01

CD51 x αvβ8

更新于：2024-11-01

基本信息

关联

项与 CD51 x αvβ8 相关的药物

PF-06940434

靶点

CD51 x αvβ8

作用机制

CD51拮抗剂 [+1]

在研机构

Pfizer Inc.

原研机构

Pfizer Inc.

在研适应症

胆管癌 [+12]

非在研适应症-

最高研发阶段临床1期

首次获批国家/地区-

首次获批日期1800-01-20

项与 CD51 x αvβ8 相关的临床试验

NCT04152018 / Active, not recruiting临床1期

A PHASE 1 STUDY TO EVALUATE THE SAFETY, PHARMACOKINETICS, AND PHARMACODYNAMICS OF ESCALATING DOSES OF PF-06940434 IN PATIENTS WITH ADVANCED OR METASTATIC SOLID TUMORS

Open-label, multi-center, non-randomized, multiple dose, safety, tolerability, pharmacokinetic, and pharmacodynamics and clinical activity study of PF-06940434 (Integrin alpha-V/beta-8 Antagonist) in patients with SCCHN (Squamous Cell Carcinoma of the Head and Neck), renal cell carcinoma (RCC - clear cell and papillary), ovarian, gastric, esophageal, esophageal (adeno and squamous), lung squamous cell, pancreatic and biliary duct, endometrial, melanoma and urothelial tumors. This study contains two parts, single agent dose escalation (Part 1A), dose finding of PF 06940434 in combination with anti-PD-1 (Part 1B) and dose expansion (Part 2). Part 2 Dose Combination Expansion will enroll participants into 3 cohorts at doses determined from Part 1B in order to further evaluate the safety of PF-06940434 in combination with anti-PD-1.

开始日期2019-11-13

申办/合作机构

Pfizer Inc.

100 项与 CD51 x αvβ8 相关的临床结果

登录后查看更多信息

100 项与 CD51 x αvβ8 相关的转化医学

登录后查看更多信息

0 项与 CD51 x αvβ8 相关的专利（医药）

登录后查看更多信息

项与 CD51 x αvβ8 相关的文献（医药）

2024-01-01·Clinical and Translational Medicine

Inhibition of TGFβ1 activation prevents radiation‐induced lung fibrosis

Article

作者: Liu, Bo ; Liao, Xin ; Yi, Minxiao ; Ma, Li ; Qin, Wan ; Li, Long ; Yuan, Ye ; Hu, Guangyuan ; Zheng, Bolong ; Wu, Bili

AbstractBackgroundRadiotherapy is the main treatment modality for thoracic tumours, but it may induce pulmonary fibrosis. Currently, the pathogenesis of radiation‐induced pulmonary fibrosis (RIPF) is unclear, and effective treatments are lacking. Transforming growth factor beta 1 (TGFβ1) plays a central role in RIPF. We found that activated TGFβ1 had better performance for radiation pneumonitis (RP) risk prediction by detecting activated and total TGFβ1 levels in patient serum. αv integrin plays key roles in TGFβ1 activation, but the role of αv integrin‐mediated TGFβ1 activation in RIPF is unclear. Here, we investigated the role of αv integrin‐mediated TGFβ1 activation in RIPF and the application of the integrin antagonist cilengitide to prevent RIPF.MethodsItgavloxP/loxP;Pdgfrb‐Cre mice were generated by conditionally knocking out Itgav in myofibroblasts, and wild‐type mice were treated with cilengitide or placebo. All mice received 16 Gy of radiation or underwent a sham radiation procedure. Lung fibrosis was measured by a modified Ashcroft score and microcomputed tomography (CT). An enzyme‐linked immunosorbent assay (ELISA) was used to measure the serum TGFβ1 concentration, and total Smad2/3 and p‐Smad2/3 levels were determined via Western blotting.ResultsConditional Itgav knockout significantly attenuated RIPF (p < .01). Hounsfield units (HUs) in the lungs were reduced in the knockout mice compared with the control mice (p < .001). Conditional Itgav knockout decreased active TGFβ1 secretion and inhibited fibroblast p‐Smad2/3 expression. Exogenous active TGFβ1, but not latent TGFβ1, reversed these reductions. Furthermore, cilengitide treatment elicited similar results and prevented RIPF.ConclusionsThe present study revealed that conditional Itgav knockout and cilengitide treatment both significantly attenuated RIPF in mice by inhibiting αv integrin‐mediated TGFβ1 activation.Highlights

Activated TGFβ1 has a superior capacity in predicting radiation pneumonitis (RP) risk and plays a vital role in the development of radiation‐induced pulmonary fibrosis (RIPF).

Conditional knock out Itgav in myofibroblasts prevented mice from developing RIPF.

Cilengitide alleviated the development of RIPF by inhibiting αv integrin‐mediated TGFβ1 activation and may be used in targeted approaches for preventing RIPF.

2020-08-01·Stem Cell Reports1区 · 医学

The Periostin/Integrin-αv Axis Regulates the Size of Hematopoietic Stem Cell Pool in the Fetal Liver

1区 · 医学

ArticleOA

作者: Schouteden, Sarah ; Roy, Irene M ; Khurana, Satish ; Biswas, Atreyi ; Anto, Ruby John ; Huelsken, Joerg ; Babu, Prathibha C ; Manesia, Javed ; Vijayakurup, Vinod ; Lacy-Hulbert, Adam ; Verfaillie, Catherine M

We earlier showed that outside-in integrin signaling through POSTN-ITGAV interaction plays an important role in regulating adult hematopoietic stem cell (HSC) quiescence. Here, we show that Itgav deletion results in increased frequency of phenotypic HSCs in fetal liver (FL) due to faster proliferation. Systemic deletion of Postn led to increased proliferation of FL HSCs, albeit without any loss of stemness, unlike Vav-Itgav^-/- HSCs. Based on RNA sequencing analysis of FL and bone marrow HSCs, we predicted the involvement of DNA damage response pathways in this dichotomy. Indeed, proliferative HSCs from Postn-deficient FL tissues showed increased levels of DNA repair, resulting in lesser double-strand breaks. Thus POSTN, with its expression majorly localized in the vascular endothelium of FL tissue, acts as a regulator of stem cell pool size during development. Overall, we demonstrate that the duality of response to proliferation in HSCs is developmental stage dependent and can be correlated with DNA damage responses.

2020-06-01·Immunology3区 · 医学

Regulation of barrier immunity and homeostasis by integrin‐mediated transforming growth factor β activation

3区 · 医学

Review

作者: Travis, Mark A. ; Gunaltay, Sezin ; McEntee, Craig P.

SummaryTransforming growth factor β (TGF‐β) is a multifunctional cytokine that regulates cell growth, differentiation, adhesion, migration and death dependent on cell type, developmental stage, or tissue conditions. Various cell types secrete TGF‐β, but always as an inactive complex. Hence, for TGF‐β to function, this latent complex must somehow be activated. Work in recent years has highlighted a critical role for members of the αv integrin family, including αvβ1, αvβ3, αvβ5, αvβ6 and αvβ8 that are involved in TGF‐β activation in various contexts, particularly at barrier sites such as the gut, lung and skin. The integrins facilitating this context‐ and location‐specific regulation can be dysregulated in certain diseases, so are potential therapeutic targets in a number of disorders. In this review, we discuss the role of TGF‐β at these barrier sites with a focus on how integrin‐mediated TGF‐β activation regulates tissue and immune homeostasis, and how this is altered in disease.