Translational PK/PD Modeling of Tumor Growth Inhibition and Target Inhibition to Support Dose Range Selection of the LMP7 Inhibitor M3258 in Relapsed/Refractory Multiple Myeloma.

M3258 is an orally bioavailable, potent, selective, reversible inhibitor of the large multifunctional peptidase 7 (LMP7, 5i, PSMB8) proteolytic subunit of the immunoproteasome, a component of the cellular protein degradation machinery, highly expressed in malignant hematopoietic cells including multiple myeloma. Here we describe the fit-for-purpose pharmacokinetic (PK)/pharmacodynamic (PD)/efficacy modeling of M3258 based on preclinical data from several species. The inhibition of LMP7 activity (PD) and tumor growth (efficacy) were tested in human multiple myeloma xenografts in mice.

Pharmacodynamic biomarkers of long-term interferon beta-1a therapy in REFLEX and REFLEXION.

This post-hoc analysis evaluated candidate biomarkers of long-term efficacy of subcutaneous interferon beta-1a (sc IFN β-1a) in REFLEX/REFLEXION studies of clinically isolated syndrome. Samples from 507 REFLEX and 287 REFLEXION study participants were analyzed. All investigated biomarkers were significantly upregulated 1.

Improved production of A40926 by Nonomuraea sp. through deletion of a pathway-specific acetyltransferase.

Nonomuraea strain ATCC 39727 produces the glycopeptide A40926, used for manufacturing dalbavancin, currently in advanced clinical trials. From the gene cluster involved in A40926 biosynthesis, a strain deleted in dbv23 was constructed. This mutant can produce only the glycopeptides lacking the O-linked acetyl residue at position 6 of the mannose moiety, while, under identical fermentation conditions, the wild-type strain produces mostly glycopeptides carrying an acetylated mannose.

A derivative of the glycopeptide A40926 produced by inactivation of the beta-hydroxylase gene in Nonomuraea sp. ATCC39727.

The actinomycete Nonomuraea sp. ATCC39727 produces the glycopeptide A40926. In the corresponding dbv cluster, ORF28 encodes a putative hydroxylase.

A gene transfer system for the glycopeptide producer Nonomuraea sp. ATCC39727.

The filamentous actinomycete Nonomuraea sp. ATCC39727 produces the industrially important glycopeptide antibiotic A40926. We developed a gene transfer system based on intergeneric conjugation from Escherichia coli.

The gene cluster for the biosynthesis of the glycopeptide antibiotic A40926 by nonomuraea species.

The glycopeptide A40926 is the precursor of dalbavancin, a second-generation glycopeptide currently under clinical development. The dbv gene cluster, devoted to A40926 biosynthesis, was isolated and characterized from the actinomycete Nonomuraea species ATCC39727. From sequence analysis, 37 open reading frames (ORFs) participate in A40926 biosynthesis, regulation, resistance, and export.