# US 11,897,969 B2 · Inhibition of oxidation-specific epitopes to treat ischemic reperfusion injury

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- Number: US 11,897,969 B2
- Document ID: US11897969B2
- Status: Granted
- Kind: B2
- Application number: 16/759,331
- Filed: 2018-10-26
- Published: 2021-07-22
- Granted: 2024-02-13
- Earliest claimed: 2017-10-26
- Assignees: The Regents of the University of California
- Applicants: The Regents of the University of California
- Inventors: Sotirios Tsimikas; Joseph L. Witztum; Xuchu Que
- Web page: https://patentgrep.com/patent/US11897969B2

## CPC

- A61P 9/12: Antihypertensives
- C07K 16/44: against material not provided for elsewhere {, e.g. haptens, metals, DNA, RNA, amino acids}
- 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 39/39583: {against materials not provided for elsewhere, e.g. haptens, coenzymes}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A61P 7/10: Antioedematous agents; Diuretics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- A61P 9/06: Antiarrhythmics
- 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 39/06: Free radical scavengers or antioxidants
- C07K 16/18: against material from animals or humans
- A61K 2039/505: {comprising antibodies}
- A61K 2039/54: {characterised by the route of administration}
- A61K 2039/545: {characterised by the dose, timing or administration schedule}
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/622: Single chain antibody (scFv)
- 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
- 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)
- 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 disclosure provides for methods and treatments of ischemic injury, reperfusion injury, stroke and myocardial infarctions by administering within minutes to hours an antibody or antibody fragment that bind to and inhibits the biological activity of OxPL in an affected tissue.

## Claims

### Claim 1

A method of reducing cardiomyocyte death associated with reperfusion-dependent oxidized phospholipid (OxPL) generation in a subject at risk thereof following a cardiac ischemic event, comprising
administering a therapeutically effective amount of an antibody or antibody fragment that specifically binds to a phosphocholine headgroup of an oxidized phospholipid to the subject, wherein the antibody or antibody fragment comprises: a variable heavy chain domain (VH) that includes complementarity determining regions (CDRs) comprising amino acid sequences that are at least 95% identical to each of SEQ ID NO:6, 7, and 8; and a variable light chain domain (VL) that includes CDRs comprising amino acid sequences that are at least 95% identical to each of SEQ ID NO:9 or 12, 10, and 11, wherein the antibody or antibody fragment is administered within 10 hours after the ischemic event.

### Claim 2 (depends on 1)

The method of claim 1, wherein the antibody or antibody fragment is administered after the cardiac ischemic event and at the time of reperfusion.

### Claim 3 (depends on 1)

The method of claim 1, wherein the antibody or antibody fragment is administered after the cardiac ischemic event and before reperfusion.

### Claim 4 (depends on 1)

The method of claim 1, wherein the cardiac ischemic event is associated with a condition selected from the group consisting of cardiovascular ischemia, myocardial ischemia associated with myocardial infarction; and myocardial ischemia associated with congestive heart failure (CHF).

### Claim 5 (depends on 1)

The method of claim 1, wherein the cardiac ischemic event is the result of an induced injury.

### Claim 6 (depends on 5)

The method of claim 5, wherein the induced injury is the result of surgery, transplantation, accidental trauma, or application of a mechanical support device.

### Claim 7 (depends on 6)

The method of claim 6, wherein the surgery is selected from the group consisting of heart surgery, kidney surgery, brain surgery, liver surgery, and bypass surgery.

### Claim 8 (depends on 1)

The method of claim 1, wherein the antibody or antibody fragment lacks complement activation or inflammatory cell recruitment activity.

### Claim 9 (depends on 1)

The method of claim 1, wherein the antibody or antibody fragment has the same or substantially the same binding affinity as an E06 antibody.

### Claim 10 (depends on 1)

The method of claim 1, wherein the antibody or antibody fragment is administered continuously after the ischemic event.

### Claim 11 (depends on 1)

The method of claim 1, wherein the administering results in a reduction in the severity of ischemic-reperfusion injury or inflammation arising from the ischemic event.

### Claim 12 (depends on 1)

The method of claim 1, further comprising administering one or more additional agents useful to treat ischemia.

### Claim 13 (depends on 12)

The method of claim 12, wherein the one or more additional agents are selected from the group consisting of a reperfusion agent, a free-radical scavenger agent, and a spin trap agent, a neuroprotective agent, an anticoagulant, an antiplatelet agent, nimodipine and naloxone.

### Claim 14 (depends on 1)

The method of claim 1, further comprising administering one or more agents useful to treat a thrombotic disorder.

### Claim 15 (depends on 14)

The method of claim 14, wherein the one or more agents useful to treat a thrombotic disorder are selected from the group consisting of an anticoagulant, heparin, a vitamin K antagonist, 4-hydroxycoumarin derivatives, warfarin, acenocoumarol, dicumarol, ethyl biscoumacetate, phenprocoumon, streptokinase, urokinase, tissue plasminogen activator (tPA), alteplase (recombinant tPA), reteplase, tenecteplase and argatroban.

### Claim 16 (depends on 1)

The method of claim 1, wherein the antibody or antibody fragment is administered intravascularly or by an intracoronary route.

### Claim 17 (depends on 1)

The method of claim 1, wherein the antibody fragment is a single chain variable fragment (scFv).

### Claim 18 (depends on 1)

The method of claim 1, wherein: the VH domain comprises the CDR amino acid sequences set forth in SEQ ID NO:6, 7 and 8; and the VL domain comprises the CDR amino acid sequences set forth in SEQ ID NO:9, 10 and 11.

### Claim 19 (depends on 18)

The method of claim 18, wherein: the VH comprises an amino acid sequence that is at least 95% identical to the VH amino acid sequence set forth in SEQ ID NO:2; and the VL comprises an amino acid sequence that is at least 95% identical to the VL amino acid sequence set forth in SEQ ID NO:2.

### Claim 20 (depends on 18)

The method of claim 18, wherein: the VH comprises the VH amino acid set forth in SEQ ID NO:2; and the VL comprises the VL amino acid sequence set forth in SEQ ID NO:2.

### Claim 21 (depends on 1)

The method of claim 1, wherein: the VH domain comprises the CDR amino acid sequences set forth in SEQ ID NO:6, 7 and 8; and the VL domain comprises the CDR amino acid sequences set forth in SEQ ID NO: 12, 10 and 11.

### Claim 22 (depends on 21)

The method of claim 21, wherein: the VH comprises an amino acid sequence that is at least 95% identical to the VH amino acid sequence set forth in SEQ ID NO:4; and the VL comprises an amino acid sequence that is at least 95% identical to the VL amino acid sequence set forth in SEQ ID NO:4.

### Claim 23 (depends on 21)

The method of claim 21, wherein: the VH comprises the VH amino acid set forth in SEQ ID NO:4; and the VL comprises the VL amino acid sequence set forth in SEQ ID NO:4.