Alkermes, Inc.

Alkermes Pharma Ireland Limited

Juan C Alvarez

Demetri Theodore Moustakas

Heather C Losey

John Adams Lowe, Iii

Laura Cook Blumberg

Tarek A Zeidan

Orn Almarsson

Leslie A McSweeney

Jean Chamoun

Thomas Andrew Wynn

Lewis D Pennington

Markus Haeberlein

Mark N Namchuk

Heather R Brodkin

The invention provides compositions and methods for modulating the immunostimulatory properties and/or anti-inflammatory properties of IL-10. The present invention provides scIL-10 polypeptides of Formula 1. The polypeptides of the invention are optionally linked to a fusion partner. The polypeptides of Formula 1 are referred to herein as 'scIL-10' polypeptides and comprise an amino acid sequence arrangement from N-terminus to C-terminus in accordance with Formula 1:(first monomer subunit)-LINKER-(second monomer subunit)&#x2003;&#x2003; Formula 1wherein the first monomer subunit, the second monomer subunit or both the first and second monomer subunits may be independently selected from: an unsubstituted IL-10 monomer subunit; or a substituted IL-10 monomer subunit comprising at least one amino acid substitution; and wherein LINKER is any amino acid linker of at least 1-100 amino acids in length.

Compositions and methods for modulating IL-10 immunostimulatory and anti-inflammatory properties

The present invention relates to compounds of Formula I: 

Prodrugs of secondary amine compounds

Provided herein are compounds that are useful in the treatment of pain in a subject.

Compounds for the treatment of pain

The present invention provides novel, single chain Fc fusion proteins having improved properties. The invention provides single chain fusions of soluble proteins fused to the Fc region of an immunoglobulin via a novel linker comprising a constant region of an immunoglobulin light chain linked to a CH1 constant region of an immunoglobulin heavy chain. This novel linker confers favorable properties on the Fc fusion proteins of the invention such as improved bioactivity and increased half-life as compared to non-Fc fusion counterparts or as compared to prior art Fc fusion proteins. The novel Fc fusion protein scaffold as described herein may be designed to include soluble proteins of interest capable of binding or interacting with any target of interest. Preferably, the Fc fusion protein of the invention is a dimer. The dimer preferably forms via a disulfide bond between free cysteine residues in the hinge region of two monomeric Fc fusion proteins of the invention.

Single chain Fc fusion proteins

The present invention provides fusion polypeptides comprising polypeptide ligands that are modified by circular permutation and fused to at least one polypeptide fusion partner wherein such fusion polypeptides have new, improved or enhanced biological functions or activities. Such improvements include, but are not limited to, increased binding affinity, increased activity, increased agonist activity (super agonist), antagonist activity, increased accessibility, increased flexibility of the active site, increased stability, broader and/or changed substrate specificity, and combinations thereof.

Ligands modified by circular permutation as agonists and antagonists

The invention provides compositions and methods for modulating the immunostimulatory properties and/or anti-inflammatory properties of IL-10. The present invention provides scIL-10 polypeptides of Formula 1. The polypeptides of the invention are optionally linked to a fusion partner. The polypeptides of Formula 1 are referred to herein as 'scIL-10' polypeptides and comprise an amino acid sequence arrangement from N-terminus to C-terminus in accordance with Formula 1:(first monomer subunit)-LINKER-(second monomer subunit)&#x2003;&#x2003; Formula 1

Compositions for modulating IL-10 immunostimulatory and anti-inflammatory properties

The invention provides fusion proteins having improved bioactivity comprising a first polypeptide fusion partner and a second polypeptide fusion partner wherein the first fusion partner is linked to the second fusion partner by a mucin-domain polypeptide linker and wherein the bioactivity of the fusion protein of the invention is improved as compared to fusion of the first polypeptide fusion partner and the second polypeptide fusion partner in the absence of the mucin-domain polypeptide linker. Mucin-domain polypeptide linkers comprise a mucin domain that is rich in potential glycosylation sites, and has a high content of serine and/or threonine and proline, which can represent greater than 40% of the amino acids within the mucin domain and further comprise at least about 60% of its mass due to the glycans.

Fusion polypeptides comprising mucin-domain polypeptide linkers

The present invention provides fusion proteins comprising a mucin-domain polypeptide covalently linked to an active protein that has improved properties (e.g. pharmacokinetic and/or physicochemical properties) compared to the same active protein not linked to mucin-domain polypeptide, as well as methods for making and using the fusion proteins of the invention.

Growing community of inventors

Lincoln, MA, United States of America

Juan C Alvarez