# US 11,028,151 B2 · Monovalent, bivalent and trivalent anti human respiratory syncytial virus (HRSV) nanobody constructs for the prevention and/or treatment of respiratory tract infections

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- Number: US 11,028,151 B2
- Document ID: US11028151B2
- Status: Granted
- Kind: B2
- Application number: 15/712,247
- Filed: 2017-09-22
- Published: 2018-04-19
- Granted: 2021-06-08
- Earliest claimed: 2009-06-05
- Assignees: Ablynx N.V.
- Applicants: Ablynx N.V.
- Inventors: Erik Depla; Catelijne Stortelers; Stephanie Staelens
- Web page: https://patentgrep.com/patent/US11028151B2

## CPC

- C07K 16/11: Paramyxoviridae (F); Pneumoviridae (F), e.g. respiratory syncytial virus [RSV]
- A61M 11/00: Sprayers or atomisers specially adapted for therapeutic purposes (in general B05B; {aerosol containers B65D83/14})
- A61M 15/0065: {Inhalators with dosage or measuring devices (A61M15/0028 takes precedence; dosage devices incorporated in aerosol cans B65D83/52)}
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/04: for throat disorders
- A61P 11/06: Antiasthmatics
- A61P 11/14: Antitussive agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/14: for RNA viruses
- A61K 2039/505: {comprising antibodies}
- A61M 2202/064: Powder
- C07K 2317/22: from camelids, e.g. camel, llama or dromedary
- C07K 2317/34: Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
- C07K 2317/35: Valency
- C07K 2317/56: variable (Fv) region, i.e. VH and/or VL
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/567: Framework region [FR]
- C07K 2317/569: Single domain, e.g. dAb, sdAb, VHH, VNAR or nanobody®
- C07K 2317/626: Diabody or triabody
- 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: 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)
- A61M: DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY (introducing media into or onto the bodies of animals A61D7/00; means for inserting tampons A61F13/26; devices for administering food or medicines orally A61J; containers for collecting, storing or administering blood or medical fluids A61J1/05); DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY (surgery A61B; chemical aspects of surgical articles A61L); DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR {(Electrotherapy, e.g. producing anaesthesia by the use of alternating or intermittent currents A61N1/36021)}
- 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

Amino acid sequences are provided that are directed against/and or that can specifically bind protein F of hRSV, as well as to compounds or constructs, and in particular proteins and polypeptides, that comprise or essentially consist of one or more such amino acid sequences. The amino acid sequences, polypeptides and therapeutic compounds and compositions provided by the invention show an improved stability, less immunogenicity and/or improved affinity and/or avidity for protein F of hRSV. The invention also relates to the uses of such amino acid sequences, polypeptides, compounds or constructs for prophylactic and/or therapeutic purposes.

## Claims

### Claim 1

Polypeptide that specifically binds F protein of hRSV, comprising or essentially consisting of at least three amino acid sequences with SEQ ID NO: 5, in which in at least one of said amino acid sequences one or more (such as two, three, four, five, six, seven, eight or nine, ten, eleven, or twelve) amino acid residues have been mutated selected from the following: Val5Leu, Ala14Pro, Ser19Arg, Ile20Leu, Glu44Gly, Ala74Ser, Gly78Leu, Ala83Arg, Asp85Glu, Arg105Gln, Gln108Leu and Gly54Asp.

### Claim 2 (depends on 1)

Polypeptide according to claim 1, comprising or essentially consisting of at least three amino acid sequences with SEQ ID NO: 5, in which in at least one of said amino acid sequences the following amino acid residues have been mutated:
Val5Leu, Ala14Pro, Glu44Gly, Gly78Leu, Ala83Arg, Asp85Glu, Arg105Gln and Gln108Leu;
Ala83Arg, Asp85Glu, Arg105Gln and Gln108Leu;
Gly78Leu, Ala83Arg, Asp85Glu and Arg105Gln;
Val5Leu, Ala14Pro, Glu44Gly, Gly78Leu, Ala83Arg, Asp85Glu, Arg105Gln, Gln108Leu and Gly54Asp;
Ala83Arg, Asp85Glu, Arg105Gln, Gln108Leu and Gly54Asp;
Gly78Leu, Ala83Arg, Asp85Glu, Arg105Gln and Gly54Asp;
Gly54Asp;
Ala14Pro, Ser19Arg, Ile20Leu and Gln108Leu;
Ala14Pro, Ser19Arg, Ile20Leu, Gln108Leu and Ala83Arg;
Ala14Pro, Ser19Arg, Ile20Leu, Gln108Leu and Asp85Glu;
Ala14Pro, Ser19Arg, Ile20Leu, Gln108Leu and Arg105Gln;
Ala14Pro, Ser19Arg, Ile20Leu, Gln108Leu, Ala83Arg and Asp85Glu;
Ala14Pro, Ser19Arg, Ile20Leu, Gln108Leu, Ala83Arg and Arg105Gln;
Ala14Pro, Ser19Arg, Ile20Leu, Gln108Leu, Asp85Glu and Arg105Gln; or
Ala14Pro, Ser19Arg, Ile20Leu, Gln108Leu, Ala83Arg, Asp85Glu and Arg105Gln.

### Claim 3

Polypeptide that specifically binds F protein of hRSV comprising or essentially consisting of at least three amino acid sequence with SEQ ID NO: 5, in which in at least one of said amino acid sequences optionally one or more (such as two, three, four, five, six, seven, eight or nine, ten, eleven or twelve) amino acid residues have been mutated selected from the following: Val5Leu, Ala14Pro, Ser19Arg, Ile20Leu, Glu44Gly, Ala74Ser, Gly78Leu, Ala83Arg, Asp85Glu, Arg105Gln, Gln108Leu and Gly54Asp and wherein the first Glutamic acid of said polypeptide has been changed into Aspartic acid.

### Claim 4 (depends on 3)

Polypeptide according to claim 3, comprising or essentially consisting of at least three amino acid sequences with SEQ ID NO: 5, in which in at least one of said amino acid sequences the following amino acid residues have been mutated:
Val5Leu, Ala14Pro, Glu44Gly, Gly78Leu, Ala83Arg, Asp85Glu, Arg105Gln and Gln108Leu;
Ala83Arg, Asp85Glu, Arg105Gln and Gln108Leu;
Gly78Leu, Ala83Arg, Asp85Glu and Arg105Gln;
Val5Leu, Ala14Pro, Glu44Gly, Gly78Leu, Ala83Arg, Asp85Glu, Arg105Gln, Gln108Leu and Gly54Asp;
Ala83Arg, Asp85Glu, Arg105Gln, Gln108Leu and Gly54Asp;
Gly78Leu, Ala83Arg, Asp85Glu, Arg105Gln and Gly54Asp;
Gly54Asp;
Ala14Pro, Ser19Arg, Ile20Leu and Gln108Leu;
Ala14Pro, Ser19Arg, Ile20Leu, Gln108Leu and Ala83Arg;
Ala14Pro, Ser19Arg, Ile20Leu, Gln108Leu and Asp85Glu;
Ala14Pro, Ser19Arg, Ile20Leu, Gln108Leu and Arg105Gln;
Ala14Pro, Ser19Arg, Ile20Leu, Gln108Leu, Ala83Arg and Asp85Glu;
Ala14Pro, Ser19Arg, Ile20Leu, Gln108Leu, Ala83Arg and Arg105Gln;
Ala14Pro, Ser19Arg, Ile20Leu, Gln108Leu, Asp85Glu and Arg105Gln;
Ala14Pro, Ser19Arg, Ile20Leu, Gln108Leu, Ala83Arg, Asp85Glu and Arg105Gln;
Glu1Asp, Val5Leu, Ala14Pro, Glu44Gly, Gly78Leu, Ala83Arg, Asp85Glu, Arg105Gln and Gln108Leu;
Glu1Asp, Ala83Arg, Asp85Glu, Arg105Gln and Gln108Leu;
Glu1Asp, Gly78Leu, Ala83Arg, Asp85Glu and Arg105Gln;
Glu1Asp, Val5Leu, Ala14Pro, Glu44Gly, Gly78Leu, Ala83Arg, Asp85Glu, Arg105Gln, Gln108Leu and Gly54Asp;
Glu1Asp, Ala83Arg, Asp85Glu, Arg105Gln, Gln108Leu and Gly54Asp;
Glu1Asp, Gly78Leu, Ala83Arg, Asp85Glu, Arg105Gln and Gly54Asp;
Glu1Asp and Gly54Asp;
Glu1Asp, Ala14Pro, Ser19Arg, Ile20Leu and Gln108Leu;
Glu1Asp, Ala14Pro, Ser19Arg, Ile20Leu, Gln108Leu and Ala83Arg;
Glu1Asp, Ala14Pro, Ser19Arg, Ile20Leu, Gln108Leu and Asp85Glu;
Glu1Asp, Ala14Pro, Ser19Arg, Ile20Leu, Gln108Leu and Arg105Gln;
Glu1Asp, Ala14Pro, Ser19Arg, Ile20Leu, Gln108Leu, Ala83Arg and Asp85Glu;
Glu1Asp, Ala14Pro, Ser19Arg, Ile20Leu, Gln108Leu, Ala83Arg, Arg105Gln;
Glu1Asp, Ala14Pro, Ser19Arg, Ile20Leu, Gln108Leu, Asp85Glu and Arg105Gln; or
Glu1Asp, Ala14Pro, Ser19Arg, Ile20Leu, Gln108Leu, Ala83Arg, Asp85Glu and Arg105Gln.

### Claim 5 (depends on 1)

Nucleic acid that encodes a polypeptide according to claim 1.

### Claim 6 (depends on 1)

Composition comprising at least one polypeptide according to claim 1.

### Claim 7 (depends on 6)

Composition according to claim 6, which is a pharmaceutical composition.

### Claim 8 (depends on 1)

Pharmaceutical composition comprising a polypeptide according to claim 1 and a carrier suitable for pulmonary delivery.

### Claim 9 (depends on 1)

Pharmaceutical device suitable for the pulmonary delivery comprising a polypeptide according to claim 1 and/or a composition comprising the same.

### Claim 10 (depends on 9)

Pharmaceutical device according to claim 9 that is an inhaler for liquids (e.g. a suspension of fine solid particles or droplets), an aerosol or a dry powder inhaler.

### Claim 11 (depends on 1)

Method for the prevention and/or treatment of hRSV infection, said method comprising administering, to a subject in need thereof, a pharmaceutically active amount of at least one polypeptide according to claim 1 and/or a composition comprising the same.