AI Article Synopsis
- Overexpression of the Axl receptor, which is part of the TAM family of receptor tyrosine kinases, is linked to tumor development, growth, metastasis, and resistance to cancer treatments.
- Researchers discovered new llama-derived variable heavy chain antibodies (VHs) that specifically target human Axl, identifying several high-affinity VHs that bind to different sites on Axl's structure.
- The modified VHs, when attached to human IgG1 Fc, were effective in binding to cancer cell lines and showed cytotoxic effects in vitro, suggesting potential for use in advanced therapies like antibody-drug conjugates.
Article Abstract
Overexpression of Axl, a TAM-family receptor tyrosine kinase, plays key roles in the formation, growth, and spread of tumors as well as resistance to targeted therapies and chemotherapies. We identified novel llama VHs against human Axl using multiple complementary phage display selection strategies and characterized a subset of high-affinity VHs. The VHs targeted multiple sites in Ig-like domains 1 and 2 of the Axl extracellular domain, including an immunodominant epitope overlapping the site of Gas6 interaction and two additional non-Gas6 competitive epitopes recognized by murine monoclonal antibodies. Only a subset of VHs cross-reacted with cynomolgus monkey Axl and none recognized mouse Axl. As fusions to human IgG1 Fc, VH-Fcs bound Axl tumor cell lines and mertansine-loaded VH-Fcs were cytotoxic in vitro against Axl cells in proportion to their binding affinities. Engineered biparatopic VH-VH heterodimers bound Axl avidly, and a subset of molecules showed dramatically enhanced association rates indicative of intramolecular binding. These VHs may have applications as modular elements of biologic drugs such as antibody-drug conjugates.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.bbrc.2021.05.030 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the virus that caused the Coronavirus Disease 2019 (COVID-19) pandemic, has a spike glycoprotein that is involved in recognizing and fusing to host cell receptors, such as angiotensin-converting enzyme 2 (ACE2), neuropilin-1 (NRP1), and AXL tyrosine-protein kinase. Since the major spike protein receptor is ACE2, an enzyme that regulates angiotensin II (1-8), this study tested the hypothesis that angiotensin II (1-8) influences the binding of the spike protein to its receptors. While angiotensin II (1-8) did not influence spike-ACE2 binding, we found that it significantly enhances spike-AXL binding.
View Article and Find Full Text PDFThe Discovery of a Novel AXL/Triple Angiokinase Inhibitor Based on 6-Chloro-Substituted Indolinone and Side Chain Methyl Substitution Inhibiting Pancreatic Cancer Growth and Metastasis.
J Med Chem
December 2024
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
In this study, we discovered and identified a novel AXL/triple angiokinase inhibitor by rational structural modification based on the structure of triple angiokinase inhibitor Nintedanib. We found that potently inhibited AXL expression with the IC value of 3.75 nM and possessed similar inhibitory activity on KDR as Nintedanib.
View Article and Find Full Text PDFIdentification of AXL as a novel positive regulator of lipid raft in gastric cancer.
Cell Signal
December 2024
Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China; Department of General Surgery, Drum Tower Clinical Medical College of Nanjing Medical University, Nanjing, China; Department of General Surgery, Taikang Xianlin DrumTower Hospital, Nanjing, China. Electronic address:
Lipid rafts are highly heterogeneous and dynamic microdomains involved in molecule trafficking and signaling transduction. This study investigates the role of lipid rafts in gastric cancer and their key regulators. Analyzing FFPE samples from 111 gastric cancer patients, we found that high lipid raft levels predict poor prognosis.
View Article and Find Full Text PDFImplications of myopia in diagnosis and screening of open angle glaucoma.
Curr Opin Ophthalmol
December 2024
Ophthalmology, Kanagawa Dental University, Yokohama.
Purpose Of Review: Rapid increase in the prevalence of myopia has been documented worldwide. Myopia, especially high myopia, is not only an important risk factor for having open angle glaucoma (OAG), but also has a strong linking with the progression of OAG. Since myopic axial length (AXL) elongation is associated with nonglaucomatous optic nerve head (ONH) and visual field abnormalities, myopia poses a challenge in differential diagnosis of OAG.
View Article and Find Full Text PDFChanges in AXL and/or MITF melanoma subpopulations in patients receiving immunotherapy.
Immunooncol Technol
December 2024
Department of Dermatology and Netherlands Institute for Pigment Disorders, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, Cancer Center Amsterdam, Amsterdam Institute for Immunology and Infectious Diseases, Amsterdam, The Netherlands.
Background: Tumor heterogeneity is a hurdle to effective therapy, as illustrated by the 'mixed responses' frequently seen in immunotherapy-treated patients. Previously, AXL+ tumor cells were identified to be highly resistant to targeted therapy, whereas more differentiated MITF+ tumor cells do respond to RAF and MEK inhibitors.
Patients And Methods: In this study, we analyzed tumor heterogeneity and explored the presence of the previously described AXL+ or MITF+ melanoma subpopulations in metastatic tissues by NanoString gene expression analysis, single-cell RNA sequencing and multiplex immunofluorescence.
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!