# US 11,999,797 B2 · Methods of treating initial episode of TTP with immunoglobulin single variable domains

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- Number: US 11,999,797 B2
- Document ID: US11999797B2
- Status: Granted
- Kind: B2
- Application number: 16/967,514
- Filed: 2019-02-06
- Published: 2021-07-22
- Granted: 2024-06-04
- Earliest claimed: 2018-02-06
- Assignees: Ablynx N.V.
- Applicants: Ablynx N.V.
- Inventors: Filip Callewaert; Hilde De Winter
- Web page: https://patentgrep.com/patent/US11999797B2

## CPC

- C07K 16/36: against blood coagulation factors
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A61K 2039/505: {comprising antibodies}
- A61K 2039/545: {characterised by the dose, timing or administration schedule}
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/35: Valency
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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)

## Abstract

The present invention is based on the finding that administration of polypeptides comprising two immunoglobulin single variable domains (ISVD) against von Willebrand Factor (vWF) to human patients with an initial episode of thrombotic thrombocytopenic purpura (TTP) episode results in improved outcomes, including a faster time to platelet count response lower proportion of patients with either death, recurrence or a major thromboembolic event (TE) during the treatment period, lower recurrence rate, and prevention of refractoriness. The invention provides a polypeptide comprising two ISVD against vWF for use in treating a vWF-related disease, preferably TTP, in a human in need thereof. The invention further relates to dosage unit forms, kits and medical uses for treating TTP.

## Claims

### Claim 1

A method of treating an initial episode of a von Willebrand Factor (vWF)-related disease comprising administering to a human experiencing an initial episode of the vWF-related disease a polypeptide comprising two anti-human vWF immunoglobulin single variable domains (ISVDs),
wherein the human is 2-18 years old and has a body weight of <40 kg,
wherein the polypeptide is administered in a dose of 5 mg,
wherein each of the anti-human vWF ISVDs consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), and
wherein at least one of the anti-human vWF ISVDs is represented by SEQ ID NO: 19.

### Claim 2 (depends on 1)

The method according to claim 1, wherein said step of administering the polypeptide is repeated for at least 1 day.

### Claim 3 (depends on 2)

The method according to claim 2, wherein said treatment results in a faster time to platelet count response, lower proportion of patients with either death, recurrence or a major thromboembolic event (TE) event during the treatment period, lower recurrence rate, and/or prevention of refractoriness.

### Claim 4 (depends on 1)

The method according to claim 1, wherein said polypeptide comprises at least one ISVD binding SEQ ID NO: 20.

### Claim 5 (depends on 1)

The method according to claim 1, wherein each of the anti-human vWF ISVDs comprises:
a) a CDR1 comprising or consisting essentially of the amino acid sequence YNPMG (SEQ ID NO: 21);
b) a CDR2 comprising or consisting essentially of the amino acid sequence AISRTGGSTYYPDSVEG (SEQ ID NO: 22); and
c) a CDR3 comprising or consisting essentially of the amino acid sequence AGVRAEDGRVRTLPSEYTF (SEQ ID NO: 23).

### Claim 6 (depends on 1)

The method according to claim 1, wherein said polypeptide is at least 90% identical to SEQ ID NO: 1.

### Claim 7 (depends on 1)

The method according to claim 1, wherein said polypeptide is ALX 0081 (SEQ ID NO: 1) or ALX 0081-A (SEQ ID NO: 24).

### Claim 8 (depends on 1)

The method according to claim 1, wherein said dose is administered 1 time per day or two times per day.

### Claim 9 (depends on 1)

The method according to claim 1, comprising repeating administering said polypeptide until the platelet number in said human is at least 150,000/μl.

### Claim 10 (depends on 9)

The method according to claim 9, comprising repeating administering said polypeptide until the platelet number in said human is at least 150,000/μl on at least 2 consecutive measurements.

### Claim 11 (depends on 10)

The method according to claim 10, wherein said step of administering the polypeptide is repeated for at least 1 day after said platelet number is at least 150,000/μl on at least 2 consecutive measurements.

### Claim 12 (depends on 10)

The method according to claim 10, wherein said 2 consecutive measurements are at least 24 h apart.

### Claim 13 (depends on 1)

The method according to claim 1, comprising repeating administering said polypeptide until the ADAMTS13 activity in said human is at least 10% of an ADAMTS13 reference activity.

### Claim 14 (depends on 1)

The method according to claim 1, comprising repeating administering said polypeptide until the level of an organ damage marker in said human returns to at least 40% of normal levels.

### Claim 15 (depends on 1)

The method according to claim 1, comprising performing a Plasma Exchange.

### Claim 16 (depends on 1)

The method according to claim 1, wherein said vWF-related disease is acute coronary syndrome (ACS), transient cerebral ischemic attack, unstable or stable angina pectoris, stroke, myocardial infarction or thrombotic thrombocytopenic purpura (TTP).

### Claim 17 (depends on 1)

The method according to claim 1, comprising using a kit or an article of manufacture, comprising a container containing the polypeptide, and instructions for use.

### Claim 18 (depends on 1)

The method of claim 1, further comprising performing a Plasma Exchange within 5 hours following administration of the polypeptide.

### Claim 19 (depends on 14)

The method according to claim 14, wherein the organ damage marker is LDH level, troponin T level, troponin I level, and/or creatinine level.

### Claim 20 (depends on 1)

The method according to claim 1, wherein said vWF-related disease is thrombotic thrombocytopenic purpura (TTP).