Author: Jeziorski, Jacob J ; Herai, Roberto H ; LaRock, Christopher N ; Trujillo, Cleber A ; Ferrasa, Adriano ; Muotri, Alysson R ; Snethlage, Cedric E ; Goldberg, Gabriela ; Nakashima, Hideyuki ; Nizet, Victor ; Ozaki, Tomoka ; Chermont, Natalia ; Sanchez, Sandra ; Saleh, Aurian ; Mesci, Pinar ; Nakashima, Kinichi

Although microglia are macrophages of the central nervous system, their involvement is not limited to immune functions. The roles of microglia during development in humans remain poorly understood due to limited access to fetal tissue. To understand how microglia can impact human neurodevelopment, the methyl-CpG binding protein 2 (MECP2) gene was knocked out in human microglia-like cells (MGLs). Disruption of the MECP2 in MGLs led to transcriptional and functional perturbations, including impaired phagocytosis. The co-culture of healthy MGLs with MECP2-knockout (KO) neurons rescued synaptogenesis defects, suggesting a microglial role in synapse formation. A targeted drug screening identified ADH-503, a CD11b agonist, restored phagocytosis and synapse formation in spheroid-MGL co-cultures, significantly improved disease progression, and increased survival in MeCP2-null mice. These results unveil a MECP2-specific regulation of human microglial phagocytosis and identify a novel therapeutic treatment for MECP2-related conditions.

01 Sep 2019·Nature Reviews Gastroenterology & HepatologyQ1 · MEDICINE

CD11b agonism overcomes PDAC immunotherapy resistance

Q1 · MEDICINE

Article

Author: Dickson, Iain

A new study has shown that immunotherapeutic responses in pancreatic ductal adenocarcinoma (PDAC) can be improved by agonism of integrin mol. expressed on cell surface of myeloid cell subsets.CD11b (integrin αM) is expressed on most myeloid cells and plays important part in myeloid cell migration and function, but to achieve CD11b blockade requires antagonist doses not tolerable in humans.To overcome this limitation, small mol., allosteric agonist of CD11b were developed.This agonist(ADH-503) results in a partially active CD11b conformation upon binding and suppresses myeloid cell infiltration by increasing adhesion to endothelium.Using various mouse models and ex vivo assays, effect of treatment with ADH-503 on immune responses and potential for immunotherapeutic synergy were assessed.CD11b agonism rapidly repolarizes TAMs to support antitumor immunity without compensatory mechanisms seen from other myeloid-targeting agents.The combination of CD11b-agonists with checkpoint immunotherapy leads to tumor regression, long-term survival and immunol. memory in PDAC models that are otherwise resistant to immunotherapy.This work identifies CD11b agonism as an alternative approach for reprograming innate immunity in PDAC.These studies have led to the development of ADH-503 for planned testing in human patients, although more studies are also needed to understand if the novel mechanisms of action observed in animals are similar in humans.

03 Jul 2019·Science Translational MedicineQ1 · MEDICINE

Agonism of CD11b reprograms innate immunity to sensitize pancreatic cancer to immunotherapies

Q1 · MEDICINE

Article

Author: Breden, Marcus A. ; Krisnawan, Varintra E. ; Knolhoff, Brett L. ; Hogg, Graham D. ; Zuo, Chong ; Schwarz, Julie K. ; DeNardo, David G. ; Fields, Ryan C. ; Hawkins, William G. ; Khan, Samia Q. ; Hegde, Samarth ; Gupta, Vineet ; Rogers, Buck E. ; Herndon, John M. ; Li, Xiaobo ; Panni, Roheena Z.

Agonism of CD11b overcomes myeloid cell–induced immunosuppression to render pancreatic cancer models responsive to checkpoint immunotherapy.

100 Deals associated with ADH-503

R&D Status

10 top R&D records.

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Pancreatic Ductal Adenocarcinoma	Phase 2	United States	University of Washington	03 Jul 2019
Nervous System Diseases	Preclinical	United States	University of California	25 Jul 2024

Clinical Result

Indication

Phase

Evaluation

View All Results

Translational Medicine

Boost your research with our translational medicine data.

view full example data

Deal

Boost your decision using our deal data.

view full example data

Core Patent

Boost your research with our Core Patent data.

view full example data

Clinical Trial

Identify the latest clinical trials across global registries.

view full example data

Approval

Accelerate your research with the latest regulatory approval information.

view full example data

Regulation

Understand key drug designations in just a few clicks with Synapse.

view full example data

AI Agents Built for Biopharma Breakthroughs

Accelerate discovery. Empower decisions. Transform outcomes.

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis


No Data

ADH-503

Overview

Basic Info

Structure/Sequence

Related

R&D Status

Clinical Result

Translational Medicine

Deal

Core Patent

Clinical Trial

Approval

Regulation