Merck Patent Gmbh

Euro-celtique S.a.

John Watkins

Matthew Baker

Francis Joseph Carr

Graham Carter

Stephen D Gillies

Anita Anne Hamilton

Stephen Williams

Tim Jones

Marian Hanlon

Jones Tim

Jeffrey Charles Way

Kevin John Smith

Alexander Oksche

Heikki Mansikka

Paul Bailey

Jeffrey C Way

The present invention provides a method of providing pain relief in a human subject in need thereof comprising administering (R)-dihydroetorphine to said subject, wherein said (R)-dihydroetorphine is administered in a dose of at least 0.01 &#x3bc;g/kg, preferably at least 0.05 &#x3bc;g/kg, and the level of respiratory depression in said subject is 65 or less % relative to the baseline level pre-administration of (R)-dihydroetorphine.

Dihydroetorphine for the provision of pain relief and anaesthesia

The invention relates to artificial modified proteins, preferably fusion proteins, having a reduced immunogenicity compared to the parent non-modified molecule when exposed to a species in vivo. The invention relates, above all, to novel immunoglobulin fusion proteins which essentially consist of an immunoglobulin molecule or a fragment thereof covalently fused via its C-terminus to the N-terminus of a biologically active non-immunoglobulin molecule, preferably a polypeptide or protein or a biologically active fragment thereof. In a specific embodiment, the invention relates to fusion proteins consisting of an Fc portion of an antibody which is fused as mentioned to the non-immunological target molecule which elicits biological or pharmacological efficacy. The molecules of the invention have amino acid sequences which are altered in one or more amino acid residue positions but have in principal the same biological activity as compared with the non-altered molecules. The changes are made in regions of the molecules which are identified as T-cell epitopes, which contribute to an immune reaction in a living host. Thus, the invention also relates to a novel method of making such fusion proteins by identifying said epitopes comprising calculation of T-cell epitope values for MHC Class II molecule binding sites in a peptide by computer-aided methods.

Artificial proteins with reduced immunogenicity

The present invention relates a modified human interferon beta (INF&#x3b2;) which is less immunogenic than human INF&#x3b2; (SEQ ID NO: 1) when administered in vivo to a human. The modified human INF&#x3b2; comprises an amino acid residue sequence that differs from SEQ ID NO: 1 by an amino acid residue substitution selected from the group consisting of L57A, L57C, L57D L57E, L57G, L57H, L57K, L57N, L57P, L57Q, L57R, L57S, and L57T and an additional substitution selected from the group consisting of the H140A, H140C, H140G, and H140P.

Modified interferon beta with reduced immunogenicity

The invention concerns human thrombopoietin and in particular modified forms of thrombopoietin (TPO) with improved properties. The improved proteins contain amino acid substitutions at specific positions within the TPO molecule. The invention provides modified TPO molecules, preferably fusion proteins comprising immunoglobulin constant regions and modified human TPO, with improved biological activity concomitant with reduced immunogenic potential in the protein. The improved proteins are intended for therapeutic use in the treatment of diseases in humans.

Thrombopoietin proteins with improved properties

Modified forms of hirudin having improved properties are disclosed. The modified hirudin compounds are hirudin variants comprising amino acid substitutions in the sequence of hirudin. Peptide molecules consisting of the amino acid residue sequence CILGSDGEKNQCVTGEGTPKPESHNDGDFE (SEQ ID NO: 1) or a sequence consisting of at least 9 consecutive amino acid residues of SEQ ID NO: 1 having a potential MHC class II binding activity are disclosed. The peptide has a stimulation index of &#x3e;1.8 in a biological assay of cellular proliferation, in which the index is defined as the value of cellular proliferation scored following stimulation by the peptide and divided by the value of cellular proliferation scored in control cells that have not been exposed to the peptide.

Modified hirudin proteins and T-cell epitopes in hirudin

A modified interferon beta (INF&#x3b2;) is provided, which is less immunogenic than human INF&#x3b2; (SEQ ID NO: 1) when administered to a human in vivo. The modified INF&#x3b2; comprises an amino acid residue sequence that differs from SEQ ID NO: 1 by a substitution at one or more residues of SEQ ID NO: 1. Preferred substitutions are at residues selected from the group consisting of residue 50, 59, 60, 62, 63, 66, 67, 69, 70, 125, 126, 129, 130, 132, 133, and 138. Examples of suitable substitutions include F50A, L57A, I59A, Y60N, M62A, L63A, I66T, F67H, I69A, F70A, Y125A, Y126A, I129A, L130A, Y132S, L133A, Y138H, and Y138A.

Anti-KSA/IL-2 fusion proteins with reduced immunogenicity

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Girton, United Kingdom

John Watkins