Novel means and methods for treating hbv infection and associated conditions

Patent metadata

Field	Value
Publication number	US-2016200798-A1
Application number	US-201415021916-A
Country	US
Kind code	A1
Filing date	Sep 16, 2014
Priority date	Sep 16, 2013
Publication date	Jul 14, 2016
Grant date	—

Abstract

The present invention relates to a polypeptide comprising (a) a first set of six complementarity determining regions (CDRs) configured to bind a first antigen; and (b) (ba) a second set of six CDRs configured to bind a second antigen; or (bb) a ligand capable of binding to a second antigen; wherein (i) said first antigen is selected from Hepatitis B virus (HBV) small surface antigen; HBV medium surface antigen; and HBV large surface antigen; and (ii) said second antigen is selected from surface antigens presented by immune effector cells such as natural killer (NK) cells and cytotoxic T lymphocytes (CTLs). Also provided are compositions for use in a method of treating or preventing HBV infection and/or a condition caused by said HBV infection, said condition caused by said HBV infection being selected from liver cirrhosis and hepatocellular carcinoma.

First claim

1 . A polypeptide comprising:
(a) a first set of six complementarity determining regions (CDRs) configured to bind a first antigen; and (b) (ba) a second set of six CDRs configured to bind a second antigen; or (bb) a ligand capable of binding to a second antigen; wherein (i) said first antigen is selected from Hepatitis B virus (HBV) small surface antigen; HBV medium surface antigen; and HBV large surface antigen; and (ii) said second antigen is selected from surface antigens presented by immune effector cells such as natural killer (NK) cells and cytotoxic T lymphocytes (CTLs), and wherein said CDRs are part of immunoglobulin domains.

2 . The polypeptide of claim 1 , wherein
(a) said first set of six CDRs is comprised in a first scFv fragment; and/or (b) (ba) said second set of six CDRs is comprised in a second scFv fragment; or (bb) said ligand is an immunoligand.

3 . The polypeptide of claim 1 , wherein said first set of six CDRs binds an epitope of said first antigen which epitope is located
(a) in said HBV small surface antigen; (b) in the part of said HBV large surface antigen which is not comprised by said HBV small surface antigen; or (c) in a part of said HBV large surface antigen which part varies in structure from said HBV small surface antigen.

4 . The polypeptide of claim 1 , wherein said surface antigen presented by immune effector cells is selected from CD3, CD28, 4-1BB, OX40, CD16, CD56, NKG2D, and NKp30/NCR3.

5 . The polypeptide of claim 1 , wherein said polypeptide further comprises a dimerization region, wherein said dimerization region provides for covalent and/or non-covalent dimerization.

6 . The polypeptide of claim 2 , wherein said polypeptide further comprises a spacer region, said spacer region preferably comprising a CH2 domain and a CH3 domain, said spacer region being located between
(i) said first scFv fragment and (ii) said second scFv fragment or said ligand in the amino acid sequence of said polypeptide, and said CH2 domain and/or said CH3 domain preferably being mutated in one or more positions to diminish or abolish the binding to F c receptors.

7 . The polypeptide of claim 1 , wherein
(a) said first set of six CDRs has the sequences of SEQ ID NOs: 1 to 6, 7 to 12 or 13 to 18; and/or (b) said second set of six CDRs has the sequences of SEQ ID NOs: 19 to 24, 25 to 30, 31 to 36 or 37 to 42, wherein within each set of six CDRs the order of CDRs is as follows: CDR1 of heavy chain, CDR2 of heavy chain, CDR3 of heavy chain, CDR1 of light chain, CDR2 of light chain, and CDR3 of light chain.

8 . The polypeptide of claim 1 , wherein said polypeptide comprises the amino acid sequence of any one of SEQ ID NOs: 43 to 46 or an amino acid sequence which exhibits at least 80% identity to any one of SEQ ID NOs: 43 to 46, provided that the CDRs of said amino acid sequence exhibiting at least 80% identity are identical to SEQ ID NOs: 1 to 6, 7 to 12, 13 to 18, 19 to 24, 25 to 30, 31 to 36 or 37 to 42, respectively.

9 . A nucleic acid encoding the polypeptide of claim 1 .

10 . A complex comprising a first and a second polypeptide, said first and second polypeptides being as defined in claim 1 , wherein
(a) there is at least one covalent linkage between said first and said second polypeptide, preferably at least one disulfide bridge between a Cys residue of said first polypeptide and a Cys residue of said second polypeptide; or (b) said first and said second polypeptide are bound to each other non-covalently.

11 . A composition comprising one or more polypeptides according to claim 1 and/or one or more complexes according to claim 10 , provided that the composition comprises at least two polypeptides of which two polypeptides are-distinct from each other with regard to the first antigen and/or the second antigen to which they bind.

12 . The composition of claim 11 , wherein said two polypeptides are
(a) (i) a polypeptide binding to HBV small or large surface antigen and CD3; and (ii) a polypeptide binding to HBV small or large surface antigen and CD28; or (b) (i) a polypeptide binding to HBV small or large surface antigen and CD16; and (ii) a polypeptide binding to HBV small or large surface antigen and CD56.

13 . The complex of claim 10 or the composition of claim 11 , wherein said complex and said composition comprise or consist of a tetravalent antibody which is bispecific, trispecific or tetraspecific.

14 . A pharmaceutical composition comprising one or more polypeptides of claim 1 , one or more complexes of claim 10 and/or one or more compositions of claim 11 .

15 . (canceled)

16 . An in vitro or ex vivo immune effector cell comprising a polypeptide of claim 1 or a complex according to claim 10 bound to a surface antigen of said immune effector cell.

17 . A method of treating or preventing HBV infection and/or a condition caused by said HBV infection in a subject, comprising administering a polypeptide of claim 1 , a complex of claim 10 , or a composition of claim 11 to said subject, wherein the condition is selected from liver cirrhosis, hepatocellular carcinoma, and liver cancer, said liver cancer being characterized by the expression of one or more HBV surface antigens.

Assignees

• Helmholtz Zentrum München Deutsches Forschungszentrum Für Gesundheit Und Umwelt Gmbh
• Deutsches Krebsforsch

Inventors

• Protzer Ulrike
• Bohne Felix
• Momburg Frank
• Moldenhauer Gerhard

Classifications

• A61P31/20

  for DNA viruses · CPC title

• A61P37/04

  Immunostimulants · CPC title

• A61P1/16

  for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics · CPC title

• C07K16/082 Primary

  Hepadnaviridae (F), e.g. hepatitis B virus · CPC title

• C07K16/2809 Primary

  against the T-cell receptor (TcR)-CD3 complex · CPC title