# US 2014/0154307 A1 · Inhibition of factor b, the alternative complement pathway and methods related thereto

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- Number: US 2014/0154307 A1
- Document ID: US20140154307A1
- Status: Published application
- Kind: A1
- Application number: 14/183,213
- Filed: 2014-02-18
- Published: 2014-06-05
- Earliest claimed: 2004-02-10
- Assignees: MUSC Foundation for Research Development; National Jewish Health; The Regents of the University of Colorado, a body corporate
- Applicants: MUSC Foundation for Research Development; National Jewish Health; The Regents of the University of Colorado, a body corporate
- Inventors: V. Michael HOLERS; Joshua M. Thurman; Christian Taube; Erwin W. Gelfand; Gary Steven Gilkeson
- Web page: https://patentgrep.com/patent/US20140154307A1

## CPC

- C07K 16/18: against material from animals or humans
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/02: Nasal agents, e.g. decongestants
- A61P 11/06: Antiasthmatics
- A61P 11/08: Bronchodilators
- A61P 27/16: Otologicals
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/12: Antivirals
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- A61K 2039/505: {comprising antibodies}
- A61K 2039/544: {to the airways}
- 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 2319/30: Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
- 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

## Abstract

Disclosed are novel inhibitors of the alternative complement pathway and particularly, novel anti-factor B antibodies. Also disclosed is the use of such inhibitors to reduce or prevent airway hyperresponsiveness and/or airway inflammation by selectively inhibiting the alternative complement pathway, thereby treating diseases in which such conditions play a role. Also disclosed is the use of such inhibitors to reduce or prevent other diseases and conditions, including ischemia-reperfusion injury, by inhibition of the alternative complement pathway.

## Claims

### Claim 1

An isolated antibody or antigen-binding fragment thereof that selectively binds to factor B within the third short consensus repeat (SCR) domain, wherein the antibody prevents formation of a C3bBb complex.

### Claim 2 (depends on 1)

The isolated antibody or antigen-binding fragment thereof of claim 1, wherein the antibody or antigen-binding fragment thereof binds to factor B and prevents or inhibits cleavage of factor B by factor D.

### Claim 3 (depends on 1)

The isolated antibody or antigen-binding fragment thereof of claim 1, wherein the antibody or antigen binding fragment bind to the third short consensus repeat (SCR) domain of human factor B.

### Claim 4 (depends on 1)

The isolated antibody or antigen-binding fragment thereof of claim 1, wherein the antibody or antigen binding fragment thereof selectively binds to an epitope in the third SCR domain of factor B selected from the group consisting of:
a) an epitope of factor B that includes at least a portion of human factor B (SEQ ID NO:2) comprising from about position Tyr139 to about position Ser185, or equivalent positions thereto in a non-human factor B sequence;
b) an epitope of factor B that includes at least a portion of human factor B (SEQ ID NO:2) comprising from about position Tyr139 to about position Ser141, or equivalent positions thereto in a non-human factor B sequence;
c) an epitope of factor B that includes at least a portion of human factor B (SEQ ID NO:2) comprising from about position Glu182 to about position Ser185, or equivalent positions thereto in a non-human factor B sequence; and
d) an epitope of factor B that includes at least a portion of human factor B (SEQ ID NO:2) comprising any one or more of the following positions or their equivalent positions in a non-human factor B sequence: Tyr139, Cys 140, Ser141, Glu182, Gly184, or Ser185.

### Claim 5 (depends on 1)

The isolated antibody or antigen-binding fragment thereof of claim 1, wherein the antibody or antigen binding fragment thereof selectively binds to an epitope in the third SCR domain of factor B (SEQ ID NO:2) comprising one or more of the following amino acid positions or their equivalent positions in a non-human factor B sequence: Ala137, Tyr139, Ser141, Glu182, Ser185, Thr189, Glu190, and Ser192.

### Claim 6 (depends on 1)

The isolated antibody or antigen-binding fragment thereof of claim 1, wherein the antibody or antigen binding fragment thereof selectively binds to an epitope in the third SCR domain of factor B (SEQ ID NO:2) comprising the following amino acid positions or their equivalent positions in a non-human factor B sequence: Ala137, Tyr139, Ser141, Glu182, Ser185, Thr189, Glu190, and Ser192.

### Claim 7 (depends on 1)

The isolated antibody or antigen-binding fragment thereof of claim 1, wherein the antibody or antigen binding fragment thereof selectively binds to an epitope in the third SCR domain of factor B (SEQ ID NO:2) consisting of the following amino acid positions or their equivalent positions in a non-human factor B sequence: Ala137, Tyr139, Ser141, Glu182, Ser185, Thr189, Glu190, and Ser192.

### Claim 8 (depends on 1)

The isolated antibody or antigen-binding fragment thereof of claim 1, wherein the antibody or antigen binding fragment thereof selectively binds to a non-linear epitope within the three-dimensional structure of a portion of the third SCR domain of factor B, wherein the portion is defined by at least amino acid positions Ala137-Ser192 of SEQ ID NO:2 or equivalent positions in a non-human factor B sequence.

### Claim 9 (depends on 1)

The isolated antibody or antigen-binding fragment thereof of claim 1, wherein the antibody or antigen binding fragment thereof selectively binds to factor B from multiple mammalian species.

### Claim 10 (depends on 1)

The isolated antibody or antigen-binding fragment thereof of claim 1, wherein the antibody or antigen binding fragment thereof selectively binds to factor B from human and an animal selected from the group consisting of non-human primate, mouse, rat, pig, horse and rabbit.

### Claim 11 (depends on 1)

The isolated antibody or antigen-binding fragment thereof of claim 1, wherein the antibody is of a non-complement activating isotype or subclass.

### Claim 12 (depends on 1)

The isolated antibody or antigen-binding fragment thereof of claim 1, wherein the antibody is a monoclonal antibody.

### Claim 13 (depends on 1)

The isolated antibody or antigen-binding fragment thereof of claim 1, wherein the antigen binding fragment is an Fab fragment.

### Claim 14 (depends on 1)

The isolated antibody or antigen-binding fragment thereof of claim 1, wherein the antibody is a humanized antibody.

### Claim 15 (depends on 1)

The isolated antibody or antigen-binding fragment thereof of claim 1, wherein the antibody is a bispecific antibody.

### Claim 16 (depends on 1)

The isolated antibody or antigen-binding fragment thereof of claim 1, wherein the antibody is a monovalent antibody.

### Claim 17 (depends on 1)

The isolated antibody or antigen-binding fragment thereof of claim 1, wherein the antibody is the monoclonal antibody 1379 (produced by ATCC Deposit No. PTA-6230).

### Claim 18 (depends on 1)

A composition comprising the isolated antibody or antigen binding fragment thereof, of claim 1.

### Claim 19

An isolated antibody or antigen-binding fragment thereof that selectively binds to factor B from multiple mammalian species, wherein the antibody prevents formation of a C3bBb complex.

### Claim 20 (depends on 19)

The isolated antibody or antigen-binding fragment thereof of claim 19, wherein the antibody or antigen binding fragment thereof selectively binds to factor B from human and an animal selected from the group consisting of non-human primate, mouse, rat, pig, horse and rabbit.

### Claim 21 (depends on 19)

The isolated antibody or antigen-binding fragment thereof of claim 19, wherein the antibody is of a non-complement activating isotype or subclass.

### Claim 22 (depends on 19)

The isolated antibody or antigen-binding fragment thereof of claim 19, wherein the antibody is a monoclonal antibody.

### Claim 23 (depends on 19)

The isolated antibody or antigen-binding fragment thereof of claim 19, wherein the antigen binding fragment is an Fab fragment.

### Claim 24 (depends on 19)

A composition comprising the isolated antibody or antigen binding fragment thereof, of claim 19.

### Claim 25

An antigen binding polypeptide that selectively binds to factor B within the third short consensus repeat (SCR) domain, wherein the antigen binding polypeptide prevents formation of a C3bBb complex.

### Claim 26

An antigen binding polypeptide that selectively binds to factor B from multiple mammalian species, wherein the antigen binding polypeptide prevents formation of a C3bBb complex.

### Claim 27 (depends on 25)

A composition comprising the antigen binding polypeptide of claim 25.

### Claim 28 (depends on 26)

A composition comprising the antigen binding polypeptide of claim 26.

### Claim 29

An isolated antibody or antigen binding fragment thereof that selectively binds to factor B, wherein the antibody or fragment thereof competitively inhibits the specific binding of the monoclonal antibody 1379 (produced by ATCC Deposit No. PTA-6230) to human factor B, and wherein, when the antibody or antigen binding fragment thereof binds to human factor B, the ability of monoclonal antibody 1379 to inhibit the alternative complement pathway is inhibited.

### Claim 30 (depends on 29)

The antibody or antigen binding fragment thereof according to claim 29, wherein the antibody or antigen binding fragment thereof competitively inhibits the binding of monoclonal antibody 1379 to human factor B, where comparative binding specificity is determined by antibody-antibody competition assay in the presence of human factor B.

### Claim 31

An isolated antibody or fragment thereof that selectively binds to human factor B, wherein the isolated antibody or fragment thereof competitively inhibits the specific binding of a second antibody or antigen binding fragment thereof to human factor B, and wherein the second antibody or antigen binding fragment thereof binds to the third SCR domain of human factor B.

### Claim 32 (depends on 1)

A method to reduce or prevent airway hyperresponsiveness (AHR) or airway inflammation in an animal, comprising administering an antibody or antigen binding fragment thereof according to claim 1 to an animal that has, or is at risk of developing, airway hyperresponsiveness associated with inflammation or airway inflammation.

### Claim 33 (depends on 32)

The method of claim 32, wherein the antibody or antigen binding fragment is administered by a route selected from the group consisting of oral, nasal, topical, inhaled, intratracheal, transdermal, rectal and parenteral routes.

### Claim 34 (depends on 32)

The method of claim 32, wherein the antibody or antigen binding fragment is administered to the animal in an amount effective to measurably reduce airway hyperresponsiveness in the animal as compared to prior to administration of the antibody or antigen binding fragment.

### Claim 35 (depends on 32)

The method of claim 32, wherein the antibody or antigen binding fragment is administered to the animal in an amount effective to measurably reduce airway hyperresponsiveness in the animal as compared to a level of airway hyperresponsiveness in a population of animals having inflammation wherein the antibody or antigen binding fragment was not administered.

### Claim 36 (depends on 32)

The method of claim 32, wherein administration of the antibody or antigen binding fragment decreases the animal's responsiveness to methacholine or to histamine.

### Claim 37 (depends on 32)

The method of claim 32, wherein the antibody or antigen binding fragment is administered with a pharmaceutically acceptable carrier selected from the group consisting of: a dry, dispersible powder; anhydrous ethanol; small capsules; liposomes; a nebulized spray; and an injectable excipient.

### Claim 38 (depends on 32)

The method of claim 32, wherein the antibody or antigen binding fragment is administered in a carrier or device selected from the group consisting of: anhydrous ethanol; a dry powder inhalation system; ultrasonic inhalation system; a pressurized metered dose inhaler; and a metered solution device.

### Claim 39 (depends on 32)

The method of claim 32, wherein said antibody or antigen binding fragment is administered to said mammal in conjunction with an agent selected from the group consisting of: corticosteroids, β-agonists (long or short acting), leukotriene modifiers, antihistamines, phosphodiesterase inhibitors, sodium cromoglycate, Nedocromil, theophylline, cytokine antagonists, cytokine receptor antagonists, anti-IgE, and inhibitors of T cell function.

### Claim 40 (depends on 32)

The method of claim 32, wherein said airway hyperresponsiveness or airway inflammation is associated with a disease selected from the group consisting of asthma, chronic obstructive pulmonary disease (COPD), allergic bronchopulmonary aspergillosis, hypersensitivity pneumonia, eosinophilic pneumonia, emphysema, bronchitis, allergic bronchitis bronchiectasis, cystic fibrosis, tuberculosis, hypersensitivity pneumonitis, occupational asthma, sarcoid, reactive airway disease syndrome, interstitial lung disease, hyper-eosinophilic syndrome, rhinitis, sinusitis, exercise-induced asthma, pollution-induced asthma, cough variant asthma, parasitic lung disease, respiratory syncytial virus (RSV) infection, parainfluenza virus (PTV) infection, rhinovirus (RV) infection and adenovirus infection.

### Claim 41 (depends on 32)

The method of claim 32, wherein the airway hyperresponsiveness is associated with allergic inflammation.

### Claim 42 (depends on 32)

The method of claim 32, wherein the (AHR) or airway inflammation is associated with asthma.

### Claim 43 (depends on 32)

The method of claim 32, wherein the (AHR) or airway inflammation is associated with COPD.

### Claim 44 (depends on 32)

The method of claim 32, wherein the animal is a mammal.

### Claim 45 (depends on 32)

The method of claim 32, wherein the animal is a human.

### Claim 46

A method to reduce or prevent airway hyperresponsiveness (AHR) or airway inflammation in an animal, comprising administering a reagent that selectively inhibits the alternative complement pathway to an animal that has, or is at risk of developing, airway hyperresponsiveness associated with inflammation or airway inflammation.