Immunogenic peptide conjugate and method for inducing an anti-influenza therapeutic antibody response therewith

Patent metadata

Field	Value
Publication number	US-2017258902-A1
Application number	US-201715591386-A
Country	US
Kind code	A1
Filing date	May 10, 2017
Priority date	Mar 14, 2013
Publication date	Sep 14, 2017
Grant date	—

Abstract

Immunogenic influenza hemagglutinin-derived peptide conjugates described herein induce a specific therapeutic antibody response against influenza virus. The immunogenic peptide conjugates comprise a segment from the fusion initiation region (FIR) domain of an influenza hemagglutinin protein conjugated to an immunogenic carrier protein, such asbovine serum albumin (BSA), an influenza hemagglutinin (HA) protein (i.e., full length HA), and the like. The immunogenic peptide conjugates described herein can be utilized to treat or prevent influenza infection and to prepare influenza-specific therapeutic antibodies that interfere with influenza virus-host cell membrane fusion. The peptide conjugates can be formulated in pharmaceutical compositions useful for broad spectrum treatment or prevention of influenza infections.

First claim

We claim:

1 . An immunogenic peptide conjugate comprising a hemagglutinin fusion initiation region (FIR) peptide or a variant thereof, conjugated to an immunogenic carrier protein by a linking group; wherein the hemagglutinin FIR peptide has an amino acid sequence that consists of SEQ ID NO: 1 or a variant of SEQ ID NO: 1 sharing at least 50% sequence identity therewith and differing from SEQ ID NO: 1 by one or more amino acid substitutions selected from the group consisting of V1I, V1L, V1A, V1G, V1T, V1S, V1M, E2D, E2K, E2R, D3E, T4G, T4S, T4Q, T4A, K5F, K5M, K5I, K5V, K5L, K5A, I6L, I6V, I6A, I6T, I6S, I6Q, I6N, D7E, L8I, L8V, L8A, W9Y, S10T, S10G, S10A, S10M, and E14K; wherein the immunogenic carrier protein is selected from the group consisting of the outer membrane protein complex of Neiserria meningitidis (OMPC), tetanus toxoid protein, diphtheria toxin derivative CRM 197 , bovine serum albumin (BSA), cationized BSA, Concholepas concholepas hemocyanin (CCH), hepatitis B virus (HBV) surface antigen protein (HBsAg), HBV core antigen protein, a rotavirus capsid protein, bovine pappiloma virus (BPV) L1 protein, a human papilloma virus (HPV) L1 protein, ovalbumin, and a full-length influenza hemagglutinin protein.

2 . The peptide conjugate of claim 1 , wherein the immunogenic carrier protein is a full-length influenza hemagglutinin protein.

3 . The peptide conjugate of claim 2 , wherein the full-length influenza hemagglutinin protein is a hemagglutinin from an influenza A subtype selected from the group consisting of H1, H2, H3, H4, H5, H6, H7, H8,H9, H10, H11, H12, H13, H14, H15, H16 and H17.

4 . The peptide conjugate of claim 2 , wherein the full-length influenza hemagglutinin protein is an influenza B hemagglutinin protein.

5 . The peptide conjugate of claim 1 , wherein the linking group comprises a sulfide bond.

6 . The peptide conjugate of claim 1 , wherein the linking group comprises the peptide conjugate of any one of embodiments 1 to 6 wherein the linking group is a 4-(N-succinimidomethylcyclohexane-1-carbonyl group of Formula I:

wherein the Cys residue of Formula I is bound to the succinimido moiety through the sulfhydryl group thereof and is bound the N-terminus of the FIR peptide by a peptide bond, optionally with an additional spacer peptide of 1 to 5 residues between the Cys and the FIR peptide, and the 1-carbonyl group on the cyclohexyl moiety of Formula I is bound to an primary amine on the carrier protein by an amide bond.

7 . An immunogenic peptide conjugate comprising a hemagglutinin fusion initiation region (FIR) peptide having an amino acid sequence that consists of SEQ ID NO: 1, conjugated to an immunogenic carrier protein by a linking group; wherein the immunogenic carrier protein is selected from the group consisting of the outer membrane protein complex of Neiserria meningitidis (OMPC), tetanus toxoid protein, diphtheria toxin derivative CRM 197 , bovine serum albumin (BSA), cationized BSA, Concholepas concholepas hemocyanin (CCH), hepatitis B virus (HBV) surface antigen protein (HBsAg), HBV core antigen protein, a rotavirus capsid protein, bovine pappiloma virus (BPV) L1 protein, a human papilloma virus (HPV) L1 protein, ovalbumin, and a full-length influenza hemagglutinin protein.

8 . The peptide conjugate of claim 7 , wherein the immunogenic carrier protein is a full-length influenza hemagglutinin protein.

9 . The peptide conjugate of claim 8 , wherein the full-length influenza hemagglutinin protein is a hemagglutinin from an influenza A subtype selected from the group consisting of H1, H2, H3, H4, H5, H6, H7, H8,H9, H10, H11, H12, H13, H14, H15, H16 and H17.

10 . The peptide conjugate claim 8 , wherein the full-length influenza HA protein is an influenza B hemagglutinin protein.

11 . The peptide conjugate of claim 7 , wherein the linking group comprises the peptide conjugate of any one of embodiments 1 to 6 wherein the linking group is a 4-(N-succinimidomethylcyclohexane-1-carbonyl group of Formula I:

wherein the Cys residue of Formula I is bound to the succinimido moiety through the sulfhydryl group thereof and is bound the N-terminus of the FIR peptide by a peptide bond, and the 1-carbonyl group on the cyclohexyl moiety of Formula I is bound to an primary amine on the carrier protein by an amide bond.

12 . A pharmaceutical composition for treating or preventing an influenza infection comprising the immunogenic peptide conjugate of claim 1 in a pharmaceutically acceptable carrier.

13 . A method of treating or preventing an influenza infection comprising administering a therapeutically effective amount of the immunogenic peptide conjugate of claim 1 to a subject.

14 . A method of inducing a specific therapeutic antibody response in a subject comprising administering the immunogenic peptide conjugate of claim 1 to the subject.

15 . The method of claim 14 , wherein the specific therapeutic antibody response is inhibiting fusion of an influenza virus with the membrane of a host cell.

16 . A therapeutic monoclonal antibody capable of specifically binding to the FIR region of an influenza virus hemagglutinin, the monoclonal antibody comprising complementarity determining regions (CDRs) from an antibody that specifically binds to the FIR region of an influenza virus hemagglutinin produced in a host organism after being administered the immunogenic peptide conjugate of claim 1 .

17 . The therapeutic monoclonal antibody of claim 16 , wherein the therapeutic monoclonal antibody is a human, humanized, or chimeric monoclonal antibody.

18 . A method of treating or preventing an influenza infection comprising administering a therapeutically effective amount of the therapeutic monoclonal antibody of claim 16 to a subject.

Assignees

• The Administrators Of The Tulane Educational Fund
• Autoimmune Tech Llc
• Autoimmune Tech Llc

Inventors

• Garry Robert Francis
• Wilson Russell B

Classifications

• A61P31/16

  for influenza or rhinoviruses · CPC title

• C07K16/108

  Orthomyxoviridae (F), e.g. influenza virus · CPC title

• A61K2039/6081

  Albumin; Keyhole limpet haemocyanin [KLH] · CPC title

• C12N2760/16134

  Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein · CPC title

• C12N2760/16122

  New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes · CPC title