# US 12,216,129 B2 · Human antibody having high affinity to human IL-4 receptor alpha

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- Number: US 12,216,129 B2
- Document ID: US12216129B2
- Status: Granted
- Kind: B2
- Application number: 17/292,050
- Filed: 2019-11-07
- Published: 2021-12-30
- Granted: 2025-02-04
- Earliest claimed: 2018-11-09
- Assignees: Ajou University Industry-Academic Cooperation Foundation
- Applicants: Ajou University Industry-Academic Cooperation Foundation
- Inventors: Yong Sung Kim; Hae-Sim Park; Jung Eun Kim; Keunok Jung
- Web page: https://patentgrep.com/patent/US12216129B2

## CPC

- G01N 33/6869: {Interleukin}
- A61K 47/6845: {the antibody targeting a cytokine, e.g. growth factors, VEGF, TNF, a lymphokine or an interferon}
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- C07K 16/2866: {against receptors for cytokines, lymphokines, interferons}
- G01N 33/6893: {related to diseases not provided for elsewhere}
- C07K 2317/21: from primates, e.g. man
- 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 2317/55: Fab or Fab'
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/73: Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- 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
- G01N 2333/7155: for interleukins [IL]
- G01N 2800/24: Immunology or allergic disorders
- G01N 2800/7095: Inflammation
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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)

## Abstract

An antibody or antigen-binding fragment thereof, which binds with a high pM-level affinity to a human IL-4 receptor alpha chain that is a human IL-4 receptor, is provided. The antibody or antigen-binding fragment has a different epitope and a different antigen dissociation rate than existing antibodies. A nucleic acid encoding the antibody or antigen-binding fragment thereof, a vector including the nucleic acid, a cell transformed with the vector, a method for producing the antibody or antigen-binding fragment thereof, a conjugate comprising the antibody or antigen-binding fragment thereof, a composition for preventing or treating inflammatory diseases, and a composition for diagnosing inflammatory diseases are disclosed.

## Claims

### Claim 1

An isolated antibody or antigen-binding fragment thereof binding to human interleukin-4 receptor alpha (hIL-4Rα) comprising:
a heavy-chain complementarity-determining region (CDR) 1 of SEQ ID NO:11, a heavy-chain CDR2 of SEQ ID NO: 14, a heavy-chain CDR3 of SEQ ID NO: 23, a light-chain CDR1 of SEQ ID NO: 43, a light-chain CDR2 SEQ ID NO: 53; and a light-chain CDR3 of SEQ ID NO: 61;
a heavy-chain CDR1 of SEQ ID NO: 12, a heavy-chain CDR2 of SEQ ID NO: 15, a heavy-chain CDR3 of SEQ ID NO: 24, a light-chain CDR1 of SEQ ID NO: 44, a light-chain CDR2 SEQ ID NO: 54; and a light-chain CDR3 of SEQ ID NO: 62;
a heavy-chain CDR1 of SEQ ID NO:11, a heavy-chain CDR2 of SEQ ID NO: 16, a heavy-chain CDR3 of SEQ ID NO: 25, a light-chain CDR1 of SEQ ID NO: 45, a light-chain CDR2 SEQ ID NO: 55; and a light-chain CDR3 of SEQ ID NO: 63;
a heavy-chain CDR1 of SEQ ID NO: 13, a heavy-chain CDR2 of SEQ ID NO: 17, a heavy-chain CDR3 of SEQ ID NO: 26, a light-chain CDR1 of SEQ ID NO: 46, a light-chain CDR2 SEQ ID NO: 56; and a light-chain CDR3 of SEQ ID NO: 64;
a heavy-chain CDR1 of SEQ ID NO: 11, a heavy-chain CDR2 of SEQ ID NO: 18, a heavy-chain CDR3 of SEQ ID NO: 27, a light-chain CDR1 of SEQ ID NO: 47, a light-chain CDR2 SEQ ID NO: 57; and a light-chain CDR3 of SEQ ID NO: 65;
a heavy-chain CDR1 of SEQ ID NO: 11, a heavy-chain CDR2 of SEQ ID NO: 19, a heavy-chain CDR3 of SEQ ID NO: 28, a light-chain CDR1 of SEQ ID NO: 48, a light-chain CDR2 SEQ ID NO: 53; and a light-chain CDR3 of SEQ ID NO: 65;
a heavy-chain CDR1 of SEQ ID NO:11, a heavy-chain CDR2 of SEQ ID NO: 20, a heavy-chain CDR3 of SEQ ID NO: 29, a light-chain CDR1 of SEQ ID NO: 49, a light-chain CDR2 SEQ ID NO: 58; and a light-chain CDR3 of SEQ ID NO: 66;
a heavy-chain CDR1 of SEQ ID NO:11, a heavy-chain CDR2 of SEQ ID NO: 21, a heavy-chain CDR3 of SEQ ID NO: 30, a light-chain CDR1 of SEQ ID NO: 50, a light-chain CDR2 SEQ ID NO: 59; and a light-chain CDR3 of SEQ ID NO: 67;
a heavy-chain CDR1 of SEQ ID NO:11, a heavy-chain CDR2 of SEQ ID NO: 22, a heavy-chain CDR3 of SEQ ID NO: 31, a light-chain CDR1 of SEQ ID NO: 51, a light-chain CDR2 SEQ ID NO: 55; and a light-chain CDR3 of SEQ ID NO: 65;
a heavy-chain CDR1 of SEQ ID NO: 11, a heavy-chain CDR2 of SEQ ID NO: 14, a heavy-chain CDR3 of SEQ ID NO: 32, a light-chain CDR1 of SEQ ID NO: 52, a light-chain CDR2 SEQ ID NO: 60; and a light-chain CDR3 of SEQ ID NO: 68;
a heavy-chain CDR1 of SEQ ID NO: 11, a heavy-chain CDR2 of SEQ ID NO: 73, a heavy-chain CDR3 of SEQ ID NO: 32, a light-chain CDR1 of SEQ ID NO: 52, a light-chain CDR2 SEQ ID NO: 60; and a light-chain CDR3 of SEQ ID NO: 68;
a heavy-chain CDR1 of SEQ ID NO:11, a heavy-chain CDR2 of SEQ ID NO: 74, a heavy-chain CDR3 of SEQ ID NO: 32, a light-chain CDR1 of SEQ ID NO: 52, a light-chain CDR2 SEQ ID NO: 60; and a light-chain CDR3 of SEQ ID NO: 81;
a heavy-chain CDR1 of SEQ ID NO:11, a heavy-chain CDR2 of SEQ ID NO: 75, a heavy-chain CDR3 of SEQ ID NO: 32, a light-chain CDR1 of SEQ ID NO: 52, a light-chain CDR2 SEQ ID NO: 60; and a light-chain CDR3 of SEQ ID NO: 82;
a heavy-chain CDR1 of SEQ ID NO:11, a heavy-chain CDR2 of SEQ ID NO: 76, a heavy-chain CDR3 of SEQ ID NO: 32, a light-chain CDR1 of SEQ ID NO: 52, a light-chain CDR2 SEQ ID NO: 60; and a light-chain CDR3 of SEQ ID NO: 68;
a heavy-chain CDR1 of SEQ ID NO:84, a heavy-chain CDR2 of SEQ ID NO: 85, a heavy-chain CDR3 of SEQ ID NO: 32, a light-chain CDR1 of SEQ ID NO: 92, a light-chain CDR2 SEQ ID NO: 60; and a light-chain CDR3 of SEQ ID NO: 68;
a heavy-chain CDR1 of SEQ ID NO:84, a heavy-chain CDR2 of SEQ ID NO: 85, a heavy-chain CDR3 of SEQ ID NO: 32, a light-chain CDR1 of SEQ ID NO: 93, a light-chain CDR2 SEQ ID NO: 60; and a light-chain CDR3 of SEQ ID NO: 68;
a heavy-chain CDR1 of SEQ ID NO:84, a heavy-chain CDR2 of SEQ ID NO: 85, a heavy-chain CDR3 of SEQ ID NO: 32, a light-chain CDR1 of SEQ ID NO: 94, a light-chain CDR2 SEQ ID NO: 60; and a light-chain CDR3 of SEQ ID NO: 68;
a heavy-chain CDR1 of SEQ ID NO:84, a heavy-chain CDR2 of SEQ ID NO: 85, a heavy-chain CDR3 of SEQ ID NO: 32, a light-chain CDR1 of SEQ ID NO: 95, a light-chain CDR2 SEQ ID NO: 60; and a light-chain CDR3 of SEQ ID NO: 68;
a heavy-chain CDR1 of SEQ ID NO:84, a heavy-chain CDR2 of SEQ ID NO: 85, a heavy-chain CDR3 of SEQ ID NO: 32, a light-chain CDR1 of SEQ ID NO: 96, a light-chain CDR2 SEQ ID NO: 60; and a light-chain CDR3 of SEQ ID NO: 68; or
a heavy-chain CDR1 of SEQ ID NO:84, a heavy-chain CDR2 of SEQ ID NO: 85, a heavy-chain CDR3 of SEQ ID NO: 32, a light-chain CDR1 of SEQ ID NO: 97, a light-chain CDR2 SEQ ID NO: 60; and a light-chain CDR3 of SEQ ID NO: 68.

### Claim 2 (depends on 1)

The antibody or antigen-binding fragment thereof according to claim 1, wherein the antibody recognizes an epitope including an amino acid residue selected from the group consisting of Leu67, Leu68, Asp92, Val93 and Asp97 in hIL-4Rα of SEQ ID NO: 98.

### Claim 3 (depends on 1)

The antibody or antigen-binding fragment thereof according to claim 1, wherein the antibody binds to an epitope including amino acid residues of Leu67, Leu68, Asp92, Val93 and Asp97 in hIL-4Rα of SEQ ID NO: 98, and binds to hIL-4Rα competitively with human interleukin-4 (hIL-4) and human interleukin-13 (hIL-13).

### Claim 4 (depends on 1)

The antibody or antigen-binding fragment thereof according to claim 1, wherein the antibody has a higher antigen dissociation rate (off-rate) than other antibodies such that it has lower antigen-mediated antibody clearance in vivo to increase the serum half-life in vivo.

### Claim 5 (depends on 1)

The antibody or antigen-binding fragment thereof according to claim 1, wherein the antibody or antigen-binding fragment thereof comprises a heavy-chain variable region comprising a sequence selected from the group consisting of SEQ ID NOs: 1 to 10, 69 to 72, and 83.

### Claim 6 (depends on 1)

The antibody or antigen-binding fragment thereof according to claim 1, wherein the antibody or antigen-binding fragment thereof comprises a light-chain variable region comprising a sequence selected from the group consisting of SEQ ID NOs: 33 to 42, 77 to 80, and 86 to 91.

### Claim 7 (depends on 1)

A method of producing an isolated antibody or antigen-binding fragment thereof binding to human interleukin-4 receptor alpha (hIL-4Rα) with an equilibrium dissociation constant (KD) of less than 150 pM, as measured by surface plasmon resonance (SPR), the method comprising:
a) culturing a cell transformed with a vector comprising a nucleic acid, said nucleic acid coding for the antibody or antigen-binding fragment thereof according to claim 1; and
(b) recovering an antibody or antigen-binding fragment thereof from the cultured cell.

### Claim 8 (depends on 1)

A conjugate of the antibody or antigen-binding fragment thereof according to claim 1, and a bioactive molecule selected from the group consisting of a peptide, a protein, a small-molecule drug, a nucleic acid, a nanoparticle, a liposome, and a combination thereof, wherein the antibody or antigen-binding fragment is genetically fused or chemically conjugated with the bioactive molecule.