# US 11,892,450 B2 · Evaluation, assays and treatment of pKal-mediated disorders

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- Number: US 11,892,450 B2
- Document ID: US11892450B2
- Status: Granted
- Kind: B2
- Application number: 16/881,911
- Filed: 2020-05-22
- Published: 2020-12-17
- Granted: 2024-02-06
- Earliest claimed: 2013-01-20
- Assignees: Takeda Pharmaceutical Company Limited
- Applicants: Takeda Pharmaceutical Company Limited
- Inventors: Kusumam Joseph; Allen P. Kaplan
- Web page: https://patentgrep.com/patent/US11892450B2

## CPC

- G01N 33/573: for enzymes or isoenzymes
- A61P 1/02: Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/14: Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A61P 7/04: Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
- A61P 7/10: Antioedematous agents; Diuretics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 9/14: Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 13/12: of the kidneys
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/06: Antigout agents, e.g. antihyperuricemic or uricosuric agents
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 27/00: Drugs for disorders of the senses
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 37/02: Immunomodulators
- C07K 14/435: from animals; from humans
- C07K 16/38: against protease inhibitors of peptide structure
- C07K 16/40: against enzymes
- C12Q 1/37: involving peptidase or proteinase
- G01N 33/6893: {related to diseases not provided for elsewhere}
- C07K 2317/21: from primates, e.g. man
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- G01N 2333/4706: stimulating, promoting or activating activity
- G01N 2333/8121: Serpins
- G01N 2333/96455: Kallikrein (3.4.21.34; 3.4.21.35)
- G01N 2333/96458: Factor XII (3.4.21.38)
- G01N 2800/32: Cardiovascular disorders
- G01N 2800/52: Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
- G01N 2800/70: Mechanisms involved in disease identification (G01N2800/02 - G01N2800/44 take precedence)
- 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)
- 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)
- C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES

## Abstract

The invention provides assay methods of detecting plasma protease CI inhibitor (C1-INH) that binds plasma kallikrein, Factor XII, or both, and uses thereof for identifying subjects at risk for or suffering from a pKal-me-diated or bradykinin-mediated disorder. Provided methods permit analysis of patients with plasma kallikrein-mediated angioedema (KMA), or other diseases mediated by pKal useful in the evaluation and treatment.

## Claims

### Claim 1

A method of treating a subject having a plasma kallikrein (pKal)-mediated disorder, the method comprising:
(i) contacting a sample obtained from the subject containing plasma protease C1 inhibitor (C1-INH) with a capture reagent; wherein the capture reagent comprises:
a) an active form of Factor XII, or a C1-INH binding fragment thereof,
b) an active form of pKal, or a C1-INH binding fragment thereof, or
c) a combination of a) and b);
(ii) measuring a level of the C1-INH in the sample that binds to the capture reagent,
(iii)—identifying the subject as having a pKal-mediated disorder, wherein the level of the C1-INH obtained in step (i) being reduced relative to the level of the C1-INH in a healthy subject is indicative of occurrence of the pKal-mediated disorder; and
(iv) administering an effective amount of a therapeutic agent to the subject identified in step (iii);
wherein the therapeutic agent is a plasma kallikrein inhibitor, a bradykinin B2 receptor antagonist or a C1-INH replacement agent; and
wherein the pKal-mediated disorder is selected from the group consisting of rheumatoid arthritis, Crohn's disease, brain ischemia/reperfusion injury, cerebral edema, macular edema, arterial or venous thrombosis, thrombosis associated with ventricular assist devices or stents, heparin-induced thrombocytopenia with thrombosis, thromboembolic disease, intestinal bowel disease, and hereditary angioedema (HAE).

### Claim 2 (depends on 1)

The method of claim 1, wherein the active form of pKal retains protease activity of a naturally occurring pKal and the active form of Factor XII retains blood coagulation activity of a naturally occurring Factor XII.

### Claim 3 (depends on 1)

The method of claim 1, wherein the C1-INH binding fragment of Factor XII or the C1-INH binding fragment of pKal is prepared by
(a) generating fragments of the full length Factor XII or the full length plasma kallikrein, and
(b) selecting therefrom a fragment of the full length Factor XII or a fragment of the full length plasma kallikrein that binds C1-INH.

### Claim 4 (depends on 1)

The method of claim 1, wherein the capture reagent is immobilized on a substrate.

### Claim 5 (depends on 1)

The method of claim 1, wherein the sample is a blood sample or a plasma sample.

### Claim 6 (depends on 1)

The method of claim 1, wherein the level of the C1-INH is measured using a detection agent that binds C1-INH.

### Claim 7 (depends on 6)

The method of claim 6, wherein the detection agent is an antibody that binds C1-INH.

### Claim 8 (depends on 1)

The method of claim 1, wherein the level of the C1-INH is measured by an immunoassay.

### Claim 9 (depends on 8)

The method of claim 8, wherein the immunoassay is a Western blot assay, an enzyme linked immunosorbent assay (ELISA), a radioimmunoassay, or an electrochemiluminescence-based detection assay.

### Claim 10 (depends on 1)

The method of claim 1, wherein the pKal-mediated disorder is hereditary angioedema (HAE).

### Claim 11 (depends on 1)

The method of claim 1, wherein the pKal inhibitor is an anti-pKal antibody.

### Claim 12 (depends on 11)

The method of claim 11, wherein the anti-pKal antibody is DX-2930.

### Claim 13 (depends on 1)

The method of claim 1, wherein the pKal inhibitor is DX-88 or EPIKAL-2.

### Claim 14 (depends on 1)

The method of claim 1, further comprising evaluating effectiveness of the therapeutic agent based on the levels of the C1-INH, wherein an increase of the C1-INH level after the administering of the therapeutic agent or over the course of the administering of the therapeutic agent indicates that the therapeutic agent is effective.

### Claim 15 (depends on 1)

The method of claim 1, wherein the subject is resistant to an anti-histamine therapy, a corticosteroid therapy, or both.

### Claim 16 (depends on 1)

The method of claim 1, wherein the subject has a symptom of the pKal-mediated disorder.

### Claim 17 (depends on 16)

The method of claim 16, wherein the symptom is edema; recurrent attacks of swelling; swelling wherein said swelling is completely or predominantly peripheral; hives; redness, pain, and swelling in the absence of evidence of infection; or non-histamine-mediated edema.

### Claim 18 (depends on 1)

The method of claim 1, wherein the subject has no symptoms of the pKal-mediated disorder at the time the sample is collected, has no history of symptoms of the pKal-mediated disorder, or no history of the pKal-mediated disorder.

### Claim 19 (depends on 1)

The method of claim 1, wherein the active form of Factor XII is of a naturally-occurring Factor XII and the active form of plasma kallikrein is of a naturally-occurring plasma kallikrein.

### Claim 20

A method for treating a subject having a plasma kallikrein (pKal)-mediated disorder, the method comprising administering to the subject an effective amount of a therapeutic agent,
wherein the subject has a reduced level of plasma protease C1 inhibitor (C1-INH) that is capable of binding to a capture reagent as compared to a reference value, and
wherein the capture reagent comprises:
i) an active form of Factor XII, or a C1-INH-binding fragment thereof;
ii) an active form of pKal, or a C1-INH-binding fragment thereof, or
iii) a combination of i) and ii);
wherein the therapeutic agent is a plasma kallikrein inhibitor, a bradykinin B2 receptor antagonist or a C1-INH replacement agent; and
wherein the pKal-mediated disorder is selected from the group consisting of rheumatoid arthritis, Crohn's disease, brain ischemia/reperfusion injury, cerebral edema, macular edema, arterial or venous thrombosis, thrombosis associated with ventricular assist devices or stents, heparin-induced thrombocytopenia with thrombosis, thromboembolic disease, intestinal bowel disease, and hereditary angioedema (HAE).