# US 11,111,293 B2 · IL-18 binding molecules

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- Number: US 11,111,293 B2
- Document ID: US11111293B2
- Status: Granted
- Kind: B2
- Application number: 16/111,659
- Filed: 2018-08-24
- Published: 2019-03-21
- Granted: 2021-09-07
- Earliest claimed: 2012-09-07
- Assignees: Novartis AG
- Applicants: Novartis AG
- Inventors: Michael Otto Bardroff; Barbara Brannetti; Emma Michelle Campbell; Beate Diefenbach-Streiber; Adina Eberth; Christian Carsten Silverster Kunz; Sylwia Marshall; Jean-Michel Rene Rondeau; Jean-Marc Alfred Schlaeppi; Gino Anselmus Van Heeke
- Web page: https://patentgrep.com/patent/US11111293B2

## CPC

- C07K 16/244: {Interleukins [IL]}
- G01N 33/6854: {Immunoglobulins}
- C07K 2299/00: Coordinates from 3D structures of peptides, e.g. proteins or enzymes
- 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 2317/76: 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
- C12P 21/005: {Glycopeptides, glycoproteins}
- G01N 2333/54: Interleukins [IL]
- 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)
- 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)
- C12P: FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE {(brewing of beer C12C; producing vinegar C12J; producing specific peptides or proteins C07K; producing enzymes C12N9/00; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; measuring or testing processes involving enzymes or microorganisms C12Q; measuring or testing processes involving nucleic acid amplification reactions C12Q1/6844; fermentation processes to form a food composition, A21 or A23; compounds in general, see the relevant compound class, e.g. C01, C07)}

## Abstract

Interleukin-18 (IL-18) participates in both innate and acquired immunity. The bioactivity of IL-18 is negatively regulated by the IL-18 binding protein (IL18BP), a naturally occurring and highly specific inhibitor. This soluble protein forms a complex with free IL-18 preventing its interaction with the IL-18 receptor, thus neutralizing and inhibiting its biological activity. The present invention discloses binding molecules, in particular antibodies or fragments thereof, which bind IL-18 and do not bind IL-18 bound to IL-18BP (IL-18/IL-18BP complex). Apart from its physiological role, IL-18 has been shown to mediate a variety of autoimmune and inflammatory diseases. The binding molecules of the inventions may be used as therapeutic molecules for treating IL-18-related autoimmune and inflammatory diseases or as diagnostic tools for characterizing, detecting and/or measuring IL-18 not bound to IL-18BP as component of the total IL-18 pool.

## Claims

### Claim 1

A method of inhibiting IL-18 biological activity in a mammalian patient in need thereof, which method comprises administering to the mammalian patient a therapeutically effective amount of an isolated antibody or fragment thereof that specifically binds IL-18 comprising:
(i) a heavy chain variable region H-CDR1 comprising SEQ ID NO: 3 and
(ii) a heavy chain variable region H-CDR2 comprising SEQ ID NO: 4 or SEQ ID NO: 9 or SEQ ID NO: 10 or SEQ ID NO: 11 or SEQ ID NO: 12 or SEQ ID NO: 13 and
(iii) a heavy chain variable region H-CDR3 comprising SEQ ID NO: 5 and
(iv) a light chain variable region L-CDR1 comprising SEQ ID NO: 6 and
(v) a light chain variable region L-CDR2 comprising SEQ ID NO: 7 and
(vi) a light chain variable region L-CDR3 comprising SEQ ID NO: 8.

### Claim 2 (depends on 1)

The method according to claim 1, wherein the mammalian patient is a human patient.

### Claim 3 (depends on 1)

The method of claim 1 wherein the patient suffers from pulmonary sarcoidosis.

### Claim 4 (depends on 1)

The method of claim 1, wherein the antibody or fragment thereof comprises a heavy chain variable region H-CDR2 comprising SEQ ID NO: 9.

### Claim 5 (depends on 1)

The method of claim 1, wherein the antibody or fragment thereof comprises a heavy chain variable region H-CDR2 comprising SEQ ID NO: 13.

### Claim 6 (depends on 1)

The method of claim 1, wherein the isolated antibody or fragment comprises a light chain variable domain comprising SEQ ID NO: 16 or SEQ ID NO: 20.

### Claim 7 (depends on 1)

The method of claim 1, wherein the isolated antibody or fragment thereof comprises:
(i) a heavy chain variable domain comprising SEQ ID NO: 14 or SEQ ID NO: 22 or SEQ ID NO: 25 or SEQ ID NO: 28 or SEQ ID NO: 31 or SEQ ID NO: 34 and a light chain variable domain comprising SEQ ID NO: 16 or conservative variants thereof or
(ii) a heavy chain variable domain comprising SEQ ID NO: 18 or SEQ ID NO: 37 or SEQ ID NO: 40 and a light chain variable domain comprising SEQ ID NO: 20.

### Claim 8 (depends on 1)

The method of claim 1, wherein the isolated antibody or fragment thereof comprises a heavy chain variable domain comprising SEQ ID NO: 14 and a light chain variable domain comprising SEQ ID NO: 16.

### Claim 9 (depends on 1)

The method of claim 1, wherein the isolated antibody or fragment thereof comprises a light chain variable domain comprising SEQ ID NO: 16 and a heavy chain variable domain comprising SEQ ID NO: 14 that is modified to have amino acid lysine (Lys; K) in position 30 replaced by an amino acid selected from asparagine (Asn; N) or serine (Ser; S) or threonine (Thr; T) or alanine (Ala; A) or glutamate (Glu; E) or histidine (His; H) or leucine (Leu; L) or glutamine (Gin; Q) or arginine (Arg; R) or valine (Val; V) or tyrosine (Tyr; Y) or isoleucine (Ile; I).

### Claim 10 (depends on 7)

The method of claim 7, wherein the isolated antibody or fragment thereof comprises a heavy chain variable domain comprising SEQ ID NO: 18 and a light chain variable domain comprising SEQ ID NO: 20.

### Claim 11 (depends on 1)

The method of claim 1, wherein the isolated antibody comprises:
(i) a heavy chain comprising SEQ ID NO: 43 or SEQ ID NO: 47 or SEQ ID NO: 50 or SEQ ID NO: 56 and a light chain comprising of SEQ ID NO: 45 or
(ii) a heavy chain comprising SEQ ID NO: 53 or SEQ ID NO: 100 or SEQ ID NO: 158 thereof and a light chain comprising SEQ ID NO: 160.

### Claim 12 (depends on 11)

The method of claim 11, wherein the isolated antibody comprises:
(i) a heavy chain comprising SEQ ID NO: 43 thereof and a light chain comprising of SEQ ID NO: 45 or
(ii) a heavy chain comprising SEQ ID NO: 158 and a light chain comprising SEQ ID NO: 160.

### Claim 13

A method of inhibiting IL-18 biological activity in a mammalian patient in need thereof, which method comprises administering to the mammalian patient a therapeutically effective amount of a pharmaceutical composition comprising an isolated antibody or fragment thereof that specifically binds IL-18 comprising:
(i) a heavy chain variable region H-CDR1 comprising SEQ ID NO: 3 and
(ii) a heavy chain variable region H-CDR2 comprising SEQ ID NO: 4 or SEQ ID NO: 9 or SEQ ID NO: 10 or SEQ ID NO: 11 or SEQ ID NO: 12 or SEQ ID NO: 13 and
(iii) a heavy chain variable region H-CDR3 comprising SEQ ID NO: 5 and
(iv) a light chain variable region L-CDR1 comprising SEQ ID NO: 6 and
(v) a light chain variable region L-CDR2 comprising SEQ ID NO: 7 and
(vi) a light chain variable region L-CDR3 comprising SEQ ID NO: 8.

### Claim 14 (depends on 13)

The method according to claim 13, wherein the mammalian patient is a human patient.

### Claim 15 (depends on 13)

The method of claim 13 wherein the patient suffers from pulmonary sarcoidosis.