Merck Sharp + Dohme Corp.

Research Development Foundation

Ambrx, Inc.

Ambryx, Inc.

Dennis P Gately

Nick Knudsen

Robert M Garbaccio

Anthony Manibusan

Ying Sun

Elisabetta Bianchi

Linda Liang

Stephen B Howell

Jeffrey Curtis Kern

Federica Orvieto

Wolfgang Seghezzi

Philip E Brandish

Jianing Wang

Paul E Carrington

Grigori Ermakov

Andrew Beck

Sanjiv Shah

Xinjian Lin

Gerrit Los

Dennis Zaller

Described are antibody peptide conjugates (APCs) comprising an antibody conjugated to a peptide analog of glucagon, which have been modified to be resistant to cleavage and inactivation by dipeptidyl peptidase IV (DPP-IV) and to increase in vivo half-life of the peptide analog while enabling the peptide analog to have agonist activity at the glucagon (GCG) receptor and the glucagon-like peptide 1 (GLP-1) receptor and the use of such APCs for treatment of metabolic disorders such as diabetes, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and obesity.

Antibody peptide conjugates that have agonist activity at both the glucagon and glucagon-like peptide 1 receptors

Antibody drug conjugates (ADCs) comprising an antibody conjugated to an anti-inflammatory therapeutic agent via a phosphate-based linker with tunable extracellular and intracellular stability are described.

Antibody drug conjugate for anti-inflammatory applications

Phosphate-based linkers with tunable stability for intracellular delivery of drug conjugates are described. The phosphate-based linkers comprise a monophosphate, diphosphate, triphosphate, or tetraphosphate group (phosphate group) and a linker arm comprising a tuning element and optionally a spacer. A payload is covalently linked to the phosphate group at the distal end of the linker arm and the functional group at the proximal end of the linker arm is covalently linked to a cell-specific targeting ligand such as an antibody. These phosphate-based linkers have a differentiated and tunable stability in blood vs. an intracellular environment (e.g. lysosomal compartment).

Phosphate based linkers for intracellular delivery of drug conjugates

The GADD153 gene is used herein as a molecular marker for in vivo tumor cell injury which occurs in response to chemotherapy. A GADD153-based prognostic method for tumor clinical response in a patient undergoing chemotherapy is provided. By determination of the magnitude of increase, above baseline, in GADD153 mRNA in a sample derived from a tumor in a patient after administration of a chemotherapeutic agent, the method is able to predict the tumor clinical response and, thus, the patient therapeutic response. This method is advantageous over known prognostic methods for tumor clinical response in that it can accurately and rapidly predict therapeutic responses including tumor progression, partial regression and complete regression for a wide range of tumors and chemotherapeutic agents.

Gene coding for GADD153 as a clinical diagnostic and prognostic in cancer therapy

The present invention features a novel cellular injury reporter system in which a chimeric gene containing the GADD153 promoter linked to the coding region of an enhanced green fluorescent protein (EGFP) gene was stably integrated into the genome of carcinoma cells. Activation of the GADD153 promoter was quantified using flow cytometric measurement of EGFP expression following drug exposure. This reporter system is suitable for high. throughput in vitro and in vivo screening for agents capable of producing cytotoxicity via a wide variety of different mechanisms, and can be utilized to investigate the relative potency of structurally related DNA adducts.

Quantification of cellular injury using expression of a fluorescent protein under the control of the GADD153 promoter

The present invention provides a vector with a DNA sequence coding for a cellular injury element promoter from nucleotides -74 to -35 of the GADD153 promoter, relative to the start of transcription. The vector includes an origin of replication in operable linkage with a DNA sequence coding for the promoter. Also, a host cell is transfected with the vector and expresses the cellular injury response element promoter.

Cellular injury response element and uses thereof

Growing community of inventors

Elkins Park, PA, United States of America

Dennis P Gately