# US 10,441,531 B2 · Protein stabilizing factors

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- Number: US 10,441,531 B2
- Document ID: US10441531B2
- Status: Granted
- Kind: B2
- Application number: 14/442,387
- Filed: 2013-11-12
- Published: 2015-11-12
- Granted: 2019-10-15
- Earliest claimed: 2012-11-09
- Assignees: Bloodworks
- Applicants: Bloodworks
- Inventors: Dominic Chung; Jose Aron Lopez; Minhua Ling; Junmei Chen; Xiaoyun Fu
- Web page: https://patentgrep.com/patent/US10441531B2

## CPC

- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 47/42: Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein (oligopeptides having up to five amino acids {A61K47/183}; polyamino acids A61K47/34)
- A61L 29/048: {Other specific proteins or polypeptides not covered by A61L29/045 - A61L29/047}
- A61L 29/085: {Macromolecular materials}
- A61L 29/143: {Stabilizers}
- A61L 29/16: Biologically active materials, e.g. therapeutic substances {(A61L29/048 takes precedence)}
- A61L 31/10: Macromolecular materials
- A61L 31/143: {Stabilizers}
- A61L 31/16: Biologically active materials, e.g. therapeutic substances {(A61L31/047 takes precedence)}
- C07K 14/755: Factors VIII {, e.g. factor VIII C (AHF), factor VIII Ag (VWF)}
- C07K 14/775: Apolipopeptides
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- A61L 2300/424: Anti-adhesion agents
- A61L 2400/18: Modification of implant surfaces in order to improve biocompatibility, cell growth, fixation of biomolecules, e.g. plasma treatment
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- 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)
- A61L: METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES (preservation of bodies or disinfecting characterised by the agents employed A01N; preserving, e.g. sterilising, food or foodstuffs A23; preparations for medical, dental or toiletry purposes A61K)
- 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)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

Compositions and methods are described for preventing or reducing protein loss due to protein aggregation, denaturation, and adsorption to surfaces. Also described are compositions and methods for preventing or reducing the fouling or clogging of medical devices that come into contact with blood, such as catheters. Also described are methods to treat diseases caused by activation of the microvasculature.

## Claims

### Claim 1

A method of reducing or preventing loss of an in vitro protein by adsorption to an in vitro surface or by self-association, wherein the in vitro protein is selected from the group consisting of Von Willebrand Factor (VWF), Factor VIII, ADAMTS13, and Factor IX, the method comprising:
a. exposing the in vitro protein to an amount of Apolipoprotein A1 (ApoA-1), high density lipoprotein (HDL), or ApoA-1 and HDL; and
b. maintaining the in vitro protein in the presence of the amount of ApoA-1, HDL, or ApoA-1 and HDL and thereby reducing or preventing loss of the in vitro protein by adsorption to the in vitro surface or by self-association.

### Claim 2 (depends on 1)

The method of claim 1, wherein the in vitro protein is a recombinant purified protein.

### Claim 3 (depends on 1)

The method of claim 1, wherein the in vitro protein is non-recombinant.

### Claim 4 (depends on 1)

The method of claim 1, wherein the concentration of ApoA-1 is at least 40 μg/mL, and the concentration of HDL is at least 80 μg/mL.

### Claim 5 (depends on 1)

The method of claim 1, wherein the surface is an in vitro medical device surface.

### Claim 6 (depends on 1)

The method of claim 1, wherein the in vitro protein is maintained in the presence of the amount of ApoA-1, HDL, or ApoA-1 and HDL within an in vitro medical device.

### Claim 7 (depends on 1)

The method of claim 1, wherein the method reduces or prevents fouling or clogging of an in vitro medical device.

### Claim 8 (depends on 1)

The method of claim 1, wherein the amount of ApoA-1, HDL, or ApoA-1 and HDL is retained in a transport fluid or a flush solution.

### Claim 9 (depends on 6)

The method of claim 6, wherein the medical device is an in vitro catheter, port, or ventricular assist device.

### Claim 10 (depends on 1)

The method of claim 1, wherein the surface is an in vitro synthetic microvessel surface.

### Claim 11 (depends on 5)

The method of claim 5, wherein the in vitro medical device surface further comprises a coating, and wherein the amount of ApoA-1, HDL, or ApoA-1 and HDL is in the coating.

### Claim 12 (depends on 1)

The method of claim 1, wherein the in vitro protein is VWF.

### Claim 13 (depends on 1)

The method of claim 1, wherein the in vitro protein is Factor VIII.

### Claim 14 (depends on 1)

The method of claim 1, wherein the in vitro protein is ADAMSTS13.

### Claim 15 (depends on 1)

The method of claim 1, wherein the maintaining comprises maintaining the in vitro protein in an amount of ApoA-1 but not HDL.

### Claim 16 (depends on 1)

The method of claim 1, wherein the in vitro protein is human.

### Claim 17 (depends on 12)

The method of claim 12, wherein the VWF is a VWF fragment corresponding to a processed VWF fragment selected from the group consisting of: a proteolytically cleaved VWF fragment, a furin processed VWF fragment, an ADAMTS13 processed VWF fragment, and a thrombospondin-1 processed VWF fragment.

### Claim 18 (depends on 12)

The method of claim 12, wherein the VWF is a VWF fragment corresponding to a A1A2A3 region of VWF.

### Claim 19

A method of reducing or preventing loss of in vitro Von Willebrand Factor (VWF) by adsorption to an in vitro surface or by self-association, the method comprising:
a. exposing the in vitro VWF to an amount of Apolipoprotein A1 (ApoA-1), high density lipoprotein (HDL), or ApoA-1 and HDL; and
b. maintaining the in vitro VWF in the presence of the amount of ApoA-1, HDL, or ApoA-1 and HDL and thereby reducing or preventing loss of the in vitro VWF by adsorption to the in vitro surface or by self-association.

### Claim 20

A method of reducing or preventing loss of in vitro Factor VIII by adsorption to an in vitro surface or by self-association, the method comprising:
a. exposing the in vitro Factor VIII to an amount of Apolipoprotein A1 (ApoA-1), high density lipoprotein (HDL), or ApoA-1 and HDL; and
b. maintaining the in vitro Factor VIII in the presence of the amount of ApoA-1, HDL, or ApoA-1 and HDL and thereby reducing or preventing loss of the in vitro Factor VIII by adsorption to the in vitro surface or by self-association.

### Claim 21

A method of reducing or preventing loss of in vitro ADAMTS13 by adsorption to an in vitro surface or by self-association, the method comprising:
a. exposing the in vitro ADAMTS13 to an amount of Apolipoprotein A1 (ApoA-1), high density lipoprotein (HDL), or ApoA-1 and HDL; and
b. maintaining the in vitro ADAMTS13 in the presence of the amount of ApoA-1, HDL, or ApoA-1 and HDL and thereby reducing or preventing loss of the in vitro ADAMTS13 by adsorption to the in vitro surface or by self-association.

### Claim 22

A method of reducing or preventing loss of in vitro Factor IX by adsorption to an in vitro surface or by self-association, the method comprising:
a. exposing the in vitro Factor IX to an amount of Apolipoprotein A1 (ApoA-1), high density lipoprotein (HDL), or ApoA-1 and HDL; and
b. maintaining the in vitro Factor IX in the presence of the amount of ApoA-1, HDL, or ApoA-1 and HDL and thereby reducing or preventing loss of the in vitro Factor IX by adsorption to the in vitro surface or by self-association.

### Claim 23 (depends on 1)

The method of claim 1, wherein the in vitro protein is Factor IX.

### Claim 24 (depends on 1)

The method of claim 1, wherein the method comprises reducing or preventing loss of the in vitro protein by adsorption to the in vitro surface.

### Claim 25 (depends on 1)

The method of claim 1, wherein the method comprises reducing or preventing loss of the in vitro protein by self-association.