Amino acid sequences directed against il-6r and polypeptides comprising the same for the treatment of il-6r related diseases and disorders

Patent metadata

Field	Value
Publication number	US-2016333099-A1
Application number	US-201615042316-A
Country	US
Kind code	A1
Filing date	Feb 12, 2016
Priority date	Apr 10, 2009
Publication date	Nov 17, 2016
Grant date	—

Abstract

The present invention relates to amino acid sequences that are directed against/and or that can specifically bind Interleukin-6 Receptor (IL-6R) with improved affinity and/or avidity, and/or that have an improved efficacy and/or potency, and which are capable of (partially, or preferably totally) blocking the IL-6/IL-6R interaction and/or inhibit signalization through IL-6, IL-6R and/or the IL-6/IL-6R complex. The invention further relates to compounds or constructs, and in particular proteins and polypeptides, that comprise or essentially consist of one or more such amino acid sequences.
The invention also relates to nucleic acids encoding such amino acid sequences and polypeptides, to methods for preparing such amino acid sequences and polypeptides, to host cells expressing or capable of expressing such amino acid sequences or polypeptides, to compositions, and in particular to pharmaceutical compositions, that comprise such amino acid sequences, polypeptides, nucleic acids and/or host cells, and to uses of such amino acid sequences or polypeptides, nucleic acids, host cells and/or compositions, in particular for prophylactic, therapeutic or diagnostic purposes.

First claim

1 . Amino acid sequence directed against IL-6R, that comprises one or more stretches of amino acid residues chosen from the following:
a) SEQ ID NO's: 80-82; or b) a stretch of amino acid residues that has no more than 2, preferably no more than 1 amino acid difference with one of SEQ ID NO's: 80-82, provided that the amino acid sequence comprising said stretch of amino acid residues binds IL-6R with about the same or a higher affinity compared to the amino acid sequence comprising said stretch of amino acid residues without the 2 or 1 amino acid difference, said affinity as measured by surface plasmon resonance;
and/or
c) SEQ ID NO's: 84-91; or
d) a stretch of amino acid residues that has no more than 2, preferably no more than 1 amino acid difference with one of SEQ ID NO's: 84-91, provided that the amino acid sequence comprising said stretch of amino acid residues binds IL-6R with about the same or a higher affinity compared to the amino acid sequence comprising said stretch of amino acid residues without the 2 or 1 amino acid difference, said affinity as measured by surface plasmon resonance;

and/or
e) SEQ ID NO's: 93-95; or
f) a stretch of amino acid residues that has no more than 2, preferably no more than 1 amino acid difference with one of SEQ ID NO's: 93-95, provided that the amino acid sequence comprising said stretch of amino acid residues binds IL-6R with about the same or a higher affinity compared to the amino acid sequence comprising said stretch of amino acid residues without the 1 or 2 amino acid difference, said affinity as measured by surface plasmon resonance.

2 . Amino acid sequence according to claim 1 , which comprises SEQ ID NO: 80, SEQ ID NO: 84 and SEQ ID NO: 93.

3 . Amino acid sequence according to claim 1 selected from the group consisting of:
a) SEQ ID NO's: 60-69;
b) a sequence that has no more than 2, preferably no more than 1 amino acid difference in one, two or all of its CDRs with one of SEQ ID NO's 60-69, provided that the amino acid sequence with no more than 2, preferably no more than 1 amino acid difference in one, two or all of its CDRs binds IL-6R with about the same or a higher affinity compared to the binding by the one of SEQ ID NO's 60-69, said affinity as measured by surface plasmon resonance;
c) a sequence that has no more than 2, preferably no more than 1 amino acid difference with one of SEQ ID NO's 60-69, provided that the amino acid sequence with no more than 2, preferably no more than 1 amino acid difference with one of SEQ ID NO's 60-69 binds IL-6R with about the same or a higher affinity compared to the binding by the one of SEQ ID NO's 60-69, said affinity as measured by surface plasmon resonance.

4 . Compound or construct, that comprises or essentially consists of one or more amino acid sequences according to claim 1 , and optionally further comprises one or more other groups, residues, moieties or binding units, optionally linked via one or more linkers.

5 . Compound or construct according to claim 4 , in which said one or more other groups, residues, moieties or binding units provide the compound or construct with increased half-life and in which said one or more other groups, residues, moieties or binding units are chosen from the group consisting of domain antibodies, amino acid sequences that are suitable for use as a domain antibody, single domain antibodies, amino acid sequences that are suitable for use as a single domain antibody, “dAb”'s, amino acid sequences that are suitable for use as a dAb, or Nanobodies that can bind to serum albumin (such as human serum albumin) or a serum immunoglobulin (such as IgG).

6 . Compound or construct according to claim 4 , selected from the following polypeptide sequences:
a) SEQ ID NO's 70-72; b) a polypeptide sequence that has no more than 2, preferably no more than 1 amino acid difference in one, two or all of its CDRs of the invention with one of SEQ ID NO's: 70-72, provided that the polypeptide sequence with no more than 2, preferably no more than 1 amino acid difference in one, two or all of its CDRs of the invention binds IL-6R with about the same or a higher affinity compared to the binding by the one of SEQ ID NO's: 70-72, said affinity as measured by surface plasmon resonance; c) a polypeptide sequence that has no more than 2, preferably no more than 1 amino acid difference with one of SEQ ID NO's: 70-72, provided that the amino acid sequence with no more than 2, preferably no more than 1 amino acid difference with one of SEQ ID NO's: 70-72 binds IL-6R with about the same or a higher affinity compared to the binding by the one of SEQ ID NO's: 70-72, said affinity as measured by surface plasmon resonance.

7 . Compound or construct according to claim 4 , that has or essentially consists of the amino acid sequence of SEQ ID NO: 70 or the amino acid sequence of SEQ ID NO: 71.

8 . Compound or construct according to claim 4 , that specifically binds to hIL-6R with a dissociation constant (KD) of 1 nM to 1 pM moles/litre or less, preferably 500 pM to 1 pM moles/litre or less, more preferably 100 pM to 1 pM moles/litre or less, or even more preferably about 50 pM to 1 pM or less.

9 . Monovalent construct, comprising or essentially consisting of one amino acid sequence according to claim 1 .

10 . Method for the preparation of a multivalent compound or construct, comprising the linking of an amino acid sequence according to claim 1 to one or more groups, residues, moieties or binding units.

11 . Nucleic acid or nucleotide sequence, that encodes an amino acid sequence according to claim 1 , said nucleic acid optionally in the form of a genetic construct.

12 . Host or host cell that expresses, or that under suitable circumstances is capable of expressing, an amino acid sequence according to claim 1 .

13 . Method for producing an amino acid sequence, said method at least comprising the steps of:
a) expressing, in a suitable host cell or host organism or in another suitable expression system, a nucleic acid or nucleotide sequence or a genetic construct;
or
cultivating and/or maintaining a host or host cell under conditions that are such that said host or host cell expresses and/or produces at least one amino acid sequence according to claim 1 ,
optionally followed by:
b) isolating and/or purifying the amino acid sequence according to claim 1 thus obtained.

14 . Composition, such as a pharmaceutical composition, comprising at least one amino acid sequence according to claim 1 .

15 . Method for the prevention and/or treatment of at least one of the diseases and disorders associated with IL-6, with IL-6R, with the IL-6/IL-6R complex and/or with the signalling pathways and/or the biological functions and responses in which IL-6, IL-6R and/or the IL-6/IL-6R complex are involved chosen from the group consisting of sepsis, various forms of cancer, bone resorption, osteoporosis, cachexia, psoriasis, mesangial proliferative glomerulonephritis, Kaposi's sarcoma, AIDS-related lymphoma, and inflammatory diseases, said method comprising administering, to a subject in need thereof, a pharmaceutically active amount of at least one amino acid sequence according to claim 1 .

Assignees

• Ablynx Nv

Inventors

• Beirnaert Els Anna Alice
• Ververken Cedric Jozef Neotere
• Kolkman Joost Alexander
• Van Roy Maarten

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title