Anti-inflammatory pharmaceutical products

Inventors

Consalvo, Angelo P. • Mehta, Nozer M. • Perretti, Mauro • DALLI, JESMOND

Assignees

Resother Pharma AS

Abstract

Polypeptides having homology to regions of the N-terminal 50 residues of human Annexin 1 are provided for medical use as anti-inflammatory agents. Some of the polypeptides have homology to the N-terminal 48 residues of human Annexin 1, especially to residues 2-48 and 11-48 thereof. In some embodiments, properties of these compounds are improved by at least one modification at residues corresponding to residues 11, 22, 25 and/or 36 of human Annexin 1, and/or by C-terminal amidation of the polypeptide. Analogs of amino acids 2-26 of human Annexin 1, especially acetylated at the N-terminus and/or amidated at the C-terminus and having modifications at 11 and/or 22 are also disclosed for medical use as anti-inflammatory agents.

Core Innovation

The disclosure provides Annexin 1 N-terminal homology polypeptides as anti-inflammatory agents. The polypeptides are defined by amino acid sequences including SEQ ID NO: 5 and SEQ ID NO: 6, and are described as N-terminal homology polypeptides with short peptide lengths corresponding to Annexin 1 N-terminal residues. Structural definition is provided by defined percent identity or homology to Annexin 1 residues 2–48 or 2–26 and by specific residue substitutions within these N-terminal regions.

The disclosure further describes specific residue substitutions and N-terminal and C-terminal modifications of the Annexin 1 N-terminal homology polypeptides. For 2–26 analogs, N-terminal acetylation is described, and C-terminal amidation is described as a modification, including amidated forms and Leu-substituted variants.

The disclosure reports that the amidated and Leu-substituted variants show improved stability against proteases including PR3 and FINE. It also reports increased potency in inhibiting neutrophil–endothelium interaction through an FPR2-mediated mechanism and pro-resolving activity, including efferocytosis and phagocytosis of apoptotic cells.

In vivo, anti-inflammatory effects are reported, including reduced leukocyte infiltration in a mouse air-pouch inflammation model and tissue protection in acute myocardial reperfusion injury models, including reduced infarct size.

Claims Coverage

The partial content includes two independent claims. Both independent claims cover methods of treating inflammation by administering therapeutically effective amounts of isolated polypeptides corresponding to SEQ ID NO: 5 and SEQ ID NO: 6, with one claim directed to direct isolated polypeptide administration and the other directed to a pharmaceutical composition containing the isolated polypeptide.

Across the independent claims, the core inventive subject matter is the administration of therapeutically effective amounts of isolated polypeptides defined by SEQ ID NO: 5 and SEQ ID NO: 6 for treating inflammation, either as isolated polypeptides or within a pharmaceutical composition.

Stated Advantages

Documented Applications