# US 11,077,187 B2 · Epitope of optimized humanized monoclonal antibodies against activated protein C and uses thereof

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- Number: US 11,077,187 B2
- Document ID: US11077187B2
- Status: Granted
- Kind: B2
- Application number: 15/775,056
- Filed: 2016-11-15
- Published: 2018-11-15
- Granted: 2021-08-03
- Earliest claimed: 2015-11-17
- Assignees: Oklahoma Medical Research Foundation
- Applicants: Oklahoma Medical Research Foundation
- Inventors: Xiao-Yan Zhao; Andreas Wilmen; Christoph Freiberg; Lars Linden; Ji-Yun Kim; Subramanian Yegneswaran; Karin Regnstrom; Ursula Egner; Xinquan Wang
- Web page: https://patentgrep.com/patent/US11077187B2

## CPC

- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61K 39/00: Medicinal preparations containing antigens or antibodies (materials for immunoassay G01N33/53)
- A61P 7/04: Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
- C07K 16/40: against enzymes
- A61K 2039/505: {comprising antibodies}
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- 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 2317/55: Fab or Fab'
- C07K 2317/567: Framework region [FR]
- 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
- 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
- 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)

## Abstract

Provided are optimized humanized antibodies that selectively bind to and inhibit activated protein C without binding to or inhibiting unactivated protein C. In particular, the antibodies bind to particular epitopes outside the catalytic triad of the active site of human activated protein C. Methods of treatment employing these antibodies are described herein.

## Claims

### Claim 1

A human or humanized monoclonal antibody or human or humanized antibody fragment that is capable of specifically binding activated human protein C, but not unactivated human protein C, wherein said antibody or antibody fragment comprise a variable light chain of SEQ ID NO: 19 but with an N→D substitution at position 85 and a variable heavy chain of SEQ ID NO: 15.

### Claim 2 (depends on 1)

The antibody or antibody fragment of claim 1, wherein the antibody is a diabody or minibody.

### Claim 3 (depends on 1)

The antibody or antibody fragment of claim 1, wherein the antibody is germ-lined, affinity matured or framework shuffled antibody.

### Claim 4 (depends on 1)

The antibody or antibody fragment of claim 1, wherein the antibody is a bispecific antibody or a chimeric antibody.

### Claim 5 (depends on 1)

The antibody or antibody fragment of claim 1, wherein the antibody is a humanized or antibody.

### Claim 6 (depends on 1)

The antibody or antibody fragment of claim 1, wherein said antibody is a single chain antibody.

### Claim 7 (depends on 1)

The antibody or antibody fragment of claim 1, wherein said antibody fragment is an Fab′.

### Claim 8 (depends on 1)

The antibody or antibody fragment of claim 1, wherein said antibody is capable of specifically binding an epitope in the autolysis lysis loop of the human activated protein C.

### Claim 9 (depends on 1)

A pharmaceutical composition comprising an antibody or antibody fragment according to claim 1 and a pharmaceutically acceptable carrier or diluent.

### Claim 10

A method of treating a subject in need of coagulation comprising administering to said subject an human or humanized antibody or human or humanized antibody fragment that is capable of specifically binding activated human protein C, but not unactivated human protein C, wherein said antibody or antibody fragment comprise a variable light chain of SEQ ID NO: 19 but with an N→D substitution at position 85 and a variable heavy chain of SEQ ID NO: 15.

### Claim 11 (depends on 10)

The method of claim 10, wherein the antibody is a diabody or minibody.

### Claim 12 (depends on 10)

The method of claim 10, wherein the antibody is a single chain antibody, a bispecific antibody or a chimeric antibody.

### Claim 13 (depends on 10)

The method of claim 10, wherein the antibody is a humanized antibody.

### Claim 14 (depends on 10)

The method of claim 10, wherein said antibody fragment is an Fab′.

### Claim 15 (depends on 10)

The method of claim 10, wherein said antibody is capable of specifically binding an epitope in the autolysis lysis loop of the human activated protein C.

### Claim 16 (depends on 10)

The method of claim 10, wherein said subject suffers from hemophilia or other bleeding diseases.

### Claim 17 (depends on 16)

The method of claim 16, wherein the disease is including acute bleeding and/or bleeding associated with traumatic coagulopathy (endogenous acute coagulopathy EAC).