# US 11,897,951 B2 · Polypeptides comprising immunoglobulin single variable domains targeting IL-6 and TNF-α

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- Number: US 11,897,951 B2
- Document ID: US11897951B2
- Status: Granted
- Kind: B2
- Application number: 17/553,916
- Filed: 2021-12-17
- Published: 2022-11-10
- Granted: 2024-02-13
- Earliest claimed: 2020-12-18
- Assignees: Ablynx N.V.; Sanofi
- Applicants: Ablynx N.V.; Sanofi
- Inventors: Heidi Rommelaere; Christian Asbrand; Nadine Biesemann; Ann Brigé; Sigrid Cornelis; Karen Heyninck; Eric Lorent; Shanna Van Zwam
- Web page: https://patentgrep.com/patent/US11897951B2

## CPC

- C07K 16/248: {IL-6}
- A61P 19/00: Drugs for skeletal disorders
- A61P 19/08: for bone diseases, e.g. rachitism, Paget's disease
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 37/02: Immunomodulators
- C07K 16/18: against material from animals or humans
- C07K 16/241: {Tumor Necrosis Factors}
- C07K 16/2875: {against the NGF/TNF superfamily, e.g. CD70, CD95L, CD153, CD154 (against NGF C07K16/22, against TNF C07K16/241)}
- A61K 2039/505: {comprising antibodies}
- A61K 2039/507: {Comprising a combination of two or more separate antibodies}
- A61K 2039/545: {characterised by the dose, timing or administration schedule}
- C07K 2317/31: multispecific
- C07K 2317/33: Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
- C07K 2317/35: Valency
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/569: Single domain, e.g. dAb, sdAb, VHH, VNAR or nanobody®
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- C07K 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
- C07K 2317/94: Stability, e.g. half-life, pH, temperature or enzyme-resistance
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

The present disclosure provides a novel type of drug for treating a subject suffering from an inflammatory and/or autoimmune disease, and specifically rheumatoid arthritis. Specifically, the disclosure provides polypeptides comprising at least three immunoglobulin single variable domains (ISVDs), characterized in that at least one ISVD binds to TNF-α and at least two ISVDs bind to IL-6. The present disclosure also provides nucleic acids, vectors and compositions.

## Claims

### Claim 1

A polypeptide, or a composition comprising the polypeptide, wherein the polypeptide comprises at least three immunoglobulin single variable domains (ISVDs), wherein each of said ISVDs comprises three complementarity determining regions (CDR1 to CDR3, respectively), optionally linked via one or more peptidic linkers; and wherein:
a) a first ISVD binds to IL-6 and comprises
i. a CDR1 which has the amino acid sequence of SEQ ID NO: 6;
ii. a CDR2 which has the amino acid sequence of SEQ ID NO: 10 amino acid difference(s) with SEQ ID NO: 10; and
iii. a CDR3 which has the amino acid sequence of SEQ ID NO: 14;
b) a second ISVD binds to IL-6 and comprises;
iv. a CDR1 which has the amino acid sequence of SEQ ID NO: 8
v. a CDR2 which has the amino acid sequence of SEQ ID NO: 12 amino acid difference(s) with SEQ ID NO: 12; and
vi. a CDR3 which has the amino acid sequence of SEQ ID NO: 16; and
c) a third ISVD binds to TNF-α and comprises
vii. a CDR1 which has the amino acid sequence of SEQ ID NO: 9;
viii. a CDR2 which has the amino acid sequence of SEQ ID NO: 13 amino acid difference(s) with SEQ ID NO: 13; and
ix. a CDR3 which has the amino acid sequence of SEQ ID NO: 17.

### Claim 2 (depends on 1)

The polypeptide or composition according to claim 1, which is a pharmaceutical composition which further comprises at least one pharmaceutically acceptable carrier, diluent or excipient and/or adjuvant, and optionally comprises one or more further polypeptides and/or compounds.

### Claim 3 (depends on 1)

The polypeptide or composition according to claim 1, wherein the polypeptide consists of three ISVDs, wherein:
a) said first ISVD comprises a CDR1 having the amino acid sequence of SEQ ID NO:6, a CDR2 having the amino acid sequence of SEQ ID NO: 10 and a CDR3 having the amino acid sequence of SEQ ID NO: 14;
b) said second ISVD comprises a CDR1 having the amino acid sequence of SEQ ID NO:8, a CDR2 having the amino acid sequence of SEQ ID NO: 12 and a CDR3 having the amino acid sequence of SEQ ID NO: 16; and
c) said third ISVD comprises a CDR1 having the amino acid sequence of SEQ ID NO:9, a CDR2 having the amino acid sequence of SEQ ID NO: 13 and a CDR3 having the amino acid sequence of SEQ ID NO: 17.

### Claim 4 (depends on 1)

The polypeptide or composition according to claim 1, wherein:
a) the amino acid sequence of said first ISVD has a sequence identity of more than 90% with SEQ ID NO: 2;
b) the amino acid sequence of said second ISVD has a sequence identity of more than 90% with SEQ ID NO: 4; and
c) the amino acid sequence of said third ISVD has a sequence identity of more than 90% identity with SEQ ID NO: 5.

### Claim 5 (depends on 1)

The polypeptide or composition according to claim 1, wherein:
a)said first ISVD has the amino acid sequence of SEQ ID NO: 2;
b) said second ISVD has the amino acid sequence of SEQ ID NO: 4; and
c) said third ISVD has the amino acid sequence of SEQ ID NO: 5.

### Claim 6 (depends on 1)

The polypeptide or composition according to claim 1, wherein said polypeptide further comprises one or more other groups, residues, moieties or binding units, optionally linked via one or more peptidic linkers, in which said one or more other groups, residues, moieties or binding units provide the polypeptide with increased half-life, compared to the corresponding polypeptide without said one or more other groups, residues, moieties or binding units.

### Claim 7 (depends on 6)

The polypeptide or composition according to claim 6, in which said one or more other groups, residues, moieties or binding units that provide the polypeptide with increased half-life is chosen from the group consisting of binding units that can bind to serum albumin or and binding units that can bind to a serum immunoglobulin.

### Claim 8 (depends on 7)

The polypeptide or composition according to claim 7, wherein the binding units that can bind to serum albumin are binding units that can bind to human serum albumin.

### Claim 9 (depends on 7)

The polypeptide or composition according to claim 7, wherein the binding units that can bind to a serum immunoglobulin are binding units that can bind to IgG.

### Claim 10 (depends on 7)

The polypeptide or composition according to claim 7, in which said binding unit that provides the polypeptide with increased half-life is an ISVD that can bind to human serum albumin.

### Claim 11 (depends on 10)

The polypeptide or composition according to claim 10, wherein the ISVD binding to human serum albumin comprises
i. a CDR1 which has the amino acid sequence of SEQ ID NO: 7 amino;
ii. a CDR2 which has the amino acid sequence of SEQ ID NO: 11; and
iii. a CDR3 which has the amino acid sequence of SEQ ID NO: 15.

### Claim 12 (depends on 11)

The polypeptide or composition according to claim 11, wherein the amino acid sequence of said ISVD binding to human serum albumin has a sequence identity of more than 90% with SEQ ID NO: 3.

### Claim 13 (depends on 1)

The polypeptide or composition according to claim 1, wherein the polypeptide comprises or consists of an amino acid sequence having a sequence identity of more than 90% with SEQ ID NO: 1.

### Claim 14 (depends on 1)

A nucleic acid comprising a nucleotide sequence that encodes a polypeptide according to claim 1.

### Claim 15 (depends on 14)

A non-human host or host cell comprising a nucleic acid according to claim 14.

### Claim 16 (depends on 14)

A method for producing a polypeptide, said method at least comprising the steps of:
a) expressing a nucleic acid according to claim 14; optionally followed by:
b) isolating and/or purifying the polypeptide.

### Claim 17 (depends on 1)

A method of treating an inflammatory and/or autoimmune disease, wherein said method comprises administering, to a subject in need thereof, an effective amount of a polypeptide according to claim 1.

### Claim 18 (depends on 17)

The method according to claim 17, wherein the inflammatory and/or autoimmune disease is rheumatoid arthritis.