# US 8,540,986 B2 · Toll-like receptor 3 antagonists

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- Number: US 8,540,986 B2
- Document ID: US8540986B2
- Status: Granted
- Kind: B2
- Application number: 12/770,147
- Filed: 2010-04-29
- Published: 2011-01-13
- Granted: 2013-09-24
- Earliest claimed: 2008-10-31
- Assignees: Janssen Biotech, Inc.
- Applicants: Mark Cunningham; Yiqing Feng; Katharine Heeringa; Jinquan Luo; Robert Rauchenberger; Mark Rutz; Lani San Mateo; Robert Sarisky; Raymond Sweet; Fang Teng; Alexey Teplyakov; Sheng-Jiun Wu
- Inventors: Mark Cunningham; Yiqing Feng; Katharine Heeringa; Jinquan Luo; Robert Rauchenberger; Mark Rutz; Lani San Mateo; Robert Sarisky; Raymond Sweet; Fang Teng; Alexey Teplyakov; Sheng-Jiun Wu
- Web page: https://patentgrep.com/patent/US8540986B2

## CPC

- C07K 16/2896: {against molecules with a "CD"-designation, not provided for elsewhere}
- A61K 39/39533: {against materials from animals}
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/02: Nasal agents, e.g. decongestants
- A61P 11/06: Antiasthmatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/12: Antivirals
- A61P 31/16: for influenza or rhinoviruses
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- C07H 21/04: with deoxyribosyl as saccharide radical
- C07K 16/28: against receptors, cell surface antigens or cell surface determinants
- C12N 15/117: Nucleic acids having immunomodulatory properties, e.g. containing CpG-motifs
- A61K 2039/505: {comprising antibodies}
- C07K 14/705: Receptors; Cell surface antigens; Cell surface determinants {(tumour specific antigens C07K14/4748)}
- C07K 16/18: against material from animals or humans
- C07K 16/2863: {against receptors for growth factors, growth regulators}
- C07K 2317/21: from primates, e.g. man
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/33: Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
- 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 2317/51: Complete heavy chain or Fd fragment, i.e. VH + CH1
- C07K 2317/515: Complete light chain, i.e. VL + CL
- C07K 2317/52: Constant or Fc region; Isotype
- C07K 2317/55: Fab or Fab'
- C07K 2317/56: variable (Fv) region, i.e. VH and/or VL
- C07K 2317/565: Complementarity determining region [CDR]
- 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
- C12N 5/10: Cells modified by introduction of foreign genetic material
- C12N 5/12: Fused cells, e.g. hybridomas
- C12N 15/63: Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- C12N 2310/17: Immunomodulatory nucleic acids
- 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)
- 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
- C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

Toll Like Receptor 3 (TLR3) antibody antagonists, polynucleotides encoding TLR3 antibody antagonists or fragments thereof, and methods of making and using the foregoing are disclosed.

## Claims

### Claim 1

An isolated antibody or fragment thereof, wherein the antibody binds toll-like receptor 3 (TLR3) amino acid residues K416, K418, L440, N441, E442, Y465, N466, K467, Y468, R488, R489, A491, K493, N515, N516, N517, H539, N541, S571, L595, and K619 of SEQ ID NO: 2.

### Claim 2

An isolated antibody comprising a heavy chain variable region and a light chain variable region or fragment thereof, wherein the isolated antibody heavy chain variable region Chothia residues W33, F50, D52, D54, Y56, N58, P61, E95, Y97, Y100, and D100b and the isolated antibody light chain variable region Chothia residues Q27, Y32, N92, T93, L94, and S95 bind toll-like receptor 3 (TLR3) that has the amino acid sequence shown in SEQ ID NO: 2.

### Claim 3 (depends on 2)

The isolated antibody of claim 2, wherein the antibody has at least one of the following properties:
a. binds to human TLR3 with a Kd of <10 nM;
b. reduces human TLR3 biological activity in an in vitro poly(I:C) NF-κB reporter gene assay >50% at 1 μg/ml;
c. inhibits >60% of IL-6 or CXCL10/IP-10 production from BEAS-2B cells stimulated with <100 ng/ml poly(I:C) at 10 μg/ml;
d. inhibits >50% of IL-6 or CXCL10/IP-10 production from BEAS-2B cells stimulated with <100 ng/ml poly(I:C) at 0.4 μg/ml;
e. inhibits >50% of IL-6 production from NHBE cells stimulated with 62.5 ng/ml poly(I:C) at 5 μg/ml;
f. inhibits >50% of IL-6 production from NHBE cells stimulated with 62.5 ng/ml poly(I:C) at 1 μg/ml;
g. inhibits >20% of poly(I:C)-induced IFN-γ, IL-6 or IL-12 production by PBMC at 1 μg/ml;
h. inhibits cynomologus TLR3 biological activity in an in vitro NF-kB reporter gene assay with IC50<10 μg/ml; or
i. inhibits cynomologus TLR3 biological activity in an in vitro ISRE reporter gene assay with IC50<5 μg/ml.

### Claim 4 (depends on 2)

The isolated antibody of claim 2, wherein the antibody comprises a heavy chain complementarity determining region (CDR) 3 (HCDR3) that is 12 amino acids in length.

### Claim 5 (depends on 2)

The isolated antibody of claim 2, wherein the antibody comprises the heavy chain complementarity determining regions (CDR) 1, 2 and 3 (HCDR1, HCDR2, HCDR3) having the amino acid sequences shown in SEQ ID NOs: 82, 86 and 84, respectively, and the light chain complementarity determining regions 1, 2 and 3 (LCDR1, LCDR2, LCDR3) having the amino acid sequences shown in SEQ ID NOs: 79, 80 and 87, respectively.

### Claim 6 (depends on 2)

The isolated antibody of claim 2 comprising a light chain framework which is at least 90% identical to the amino acid sequence of a light chain variable region kappa 1 framework (VK1) and a heavy chain framework which is at least 90% identical to the amino acid sequence of a heavy chain variable region Vh5 framework (Vh5).

### Claim 7 (depends on 6)

The isolated antibody of claim 6, wherein the Vk1 framework is encoded by IGKV1-39*01 having the amino acid sequence shown in SEQ ID NO: 221, and the Vh5 framework is encoded by IGHV5-51*01 having the amino acid sequence shown in SEQ ID NO: 222.

### Claim 8 (depends on 1, 2)

The isolated antibody or fragment of claim 1 or 2, wherein the antibody
a. is fully human;
b. is human-adapted;
c. is conjugated to polyethylene glycol;
d. is of an IgG4 isotype; or
e. Fc domain comprises S229P, P235A or L236A mutations.

### Claim 9 (depends on 1, 2)

A pharmaceutical composition comprising the isolated antibody or fragment of claim 1 or 2 and a pharmaceutically acceptable carrier.