# US 11,078,284 B2 · Antibodies specific for LOX1 and use in treatment of cardiovascular disorders

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- Number: US 11,078,284 B2
- Document ID: US11078284B2
- Status: Granted
- Kind: B2
- Application number: 16/179,135
- Filed: 2018-11-02
- Published: 2019-08-29
- Granted: 2021-08-03
- Earliest claimed: 2014-10-01
- Assignees: MedImmune, LLC
- Applicants: MedImmune Limited
- Inventors: Andrew Buchanan; Matthieu Chodorge; Peter Cariuk; Johanna Husmark; Clare Balendran; Deepesh Pandey; Fumin Chang; Daniel E. Berkowitz; Lewis H. Romer
- Web page: https://patentgrep.com/patent/US11078284B2

## CPC

- C07K 16/2851: {against the lectin superfamily, e.g. CD23, CD72}
- A61K 39/395: Antibodies (agglutinins A61K38/36 {; as drug carriers A61K47/50}); Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- 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 9/12: Antihypertensives
- C07K 14/705: Receptors; Cell surface antigens; Cell surface determinants {(tumour specific antigens C07K14/4748)}
- C07K 16/28: against receptors, cell surface antigens or cell surface determinants
- C12N 15/09: Recombinant DNA-technology
- C12N 15/11: DNA or RNA fragments; Modified forms thereof (DNA or RNA not used in recombinant technology, C07H21/00); {Non-coding nucleic acids having a biological activity}
- C12N 15/63: Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- A61K 31/7068: having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K 2039/505: {comprising antibodies}
- C07K 14/47: from mammals
- C07K 16/30: from tumour cells
- C07K 2317/21: from primates, e.g. man
- C07K 2317/33: Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
- 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
- C07K 2317/94: Stability, e.g. half-life, pH, temperature or enzyme-resistance
- C07K 2318/00: Antibody mimetics or scaffolds
- C12N 5/00: Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor; (plant reproduction by tissue culture techniques A01H4/00)
- C12N 5/0695: {Stem cells; Progenitor cells; Precursor cells}
- C12N 15/1138: {against receptors or cell surface proteins}
- C12N 2310/14: interfering nucleic acids [NA]
- C12N 2310/531: Stem-loop; Hairpin
- C12N 2800/10: Plasmid DNA
- G01N 33/00: Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N 33/575: for cancer
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- 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)

## Abstract

This disclosure provides LOX1 (LOX1) binding proteins such as anti-LOX1 antibodies, and compositions and methods for making these binding proteins. In certain aspects the LOX1-binding proteins provided herein, inhibit, or antagonize LOX1 activity. In addition, the disclosure provides compositions and methods for diagnosing and treating conditions associated with atherosclerosis, thrombosis, coronary artery disease (CAD), ischemia (e.g., myocardial ischemia), infarction (e.g., myocardial infarction), acute coronary syndrome (ACS), stroke, reperfusion injury, restenosis, peripheral vascular disease, hypertension, heart failure, inflammation (e.g., chronic inflammation), angiogenesis, preeclampsia, cancer and other LOX1-mediated diseases and conditions.

## Claims

### Claim 1

An isolated Lectin-like oxidized low density lipoprotein receptor-1 (LOX1) antibody comprising a heavy chain variable region (VH) having at least 95, 97, 98 or 99% sequence identity to SEQ ID NOs:4, 19-29, 41, or 48-54; and a light chain variable region (VL) having at least 95, 97, 98 or 99% sequence identity to SEQ ID NOs:33, 36, 37, 58 or 65-70.

### Claim 2

An isolated Lectin-like oxidized low density lipoprotein receptor-1 (LOX1) antibody comprising a heavy chain variable region (VH) selected from the group consisting of: a VH comprising SEQ ID NO:4, 19-29, 41, or 48-54 and a light chain variable region (VL) selected from the group consisting of a VL comprising SEQ ID NO:33, 36, 37, 58 or 65-70.

### Claim 3

An isolated Lectin-like oxidized low density lipoprotein receptor-1 (LOX1) antibody comprising a set of complementary determining regions (CDRs): heavy chain variable region (VH)-CDR1, VH-CDR2, VH-CDR3, and light chain variable region (VL)-CDR1, VL-CDR2 and VL-CDR3 wherein:
(a) VH-CDR1 comprises the amino acid sequence:
(SEQ ID NO: 1)
E L S M H;
(b) VH-CDR2 comprises the amino acid sequence:
(SEQ ID NO: 71)
G F D P E D HX1 HX2 HX3 HX4 HX5 HX6 Q K F Q G;
wherein HX1 is selected from the group consisting of G, W, Y and F,
HX2 is selected from the group consisting of E, T, Q, K, A, and S,
HX3 is selected from the group consisting of T, Y, I, and N,
HX4 is selected from the group consisting of I, A, R and H,
HX5 is selected from the group consisting of Y, V, T, L and Q, and
HX6 is selected from the group consisting of A, D, G, S and H;
(c) VH-CDR3 comprises the amino acid sequence:
(SEQ ID NO: 72)
HX7 HX8 G HX9 HX10 HX11 HX12 G V R G W D Y Y Y G M D V;
wherein HX7 is selected from the group consisting of P, S and V,
HX8 is selected from the group consisting of N, W, D, and T,
HX9 is selected from the group consisting of Q, R and T,
HX10 is selected from the group consisting of Q and H,
HX11 is selected from the group consisting of G and Q, and
HX12 is selected from the group consisting of K and G;
(d) VL-CDR1 comprises the amino acid sequence:
(SEQ ID NO: 30)
T G S S S N I G A G Y D V H;
(e) VL-CDR2 comprises the amino acid sequence:
(SEQ ID NO: 31)
G N S N R P S;
and
(f) VL-CDR3 comprises the amino acid sequence:
(SEQ ID NO: 73)
Q S Y D S LX1 LX2 LX3 LX4 LX5 LX6;
wherein LX1 is selected from the group consisting of M and S,
LX2 is selected from the group consisting of L, Y and H,
LX3 is selected from the group consisting of S and R,
LX4 is selected from the group consisting of A and G or is omitted (no amino acid),
LX5 is selected from the group consisting of W and F, and
LX6 is selected from the group consisting of V, G and A;
and wherein the LOX1 antibody reduces, inhibits or antagonizes LOX1 activity.

### Claim 4 (depends on 3)

The isolated LOX1 antibody of claim 3, wherein the antibody is a monoclonal antibody, a recombinant antibody, a human antibody, a humanized antibody, a chimeric antibody, a bi-specific antibody, a multi-specific antibody, or a LOX1-binding antibody fragment.

### Claim 5 (depends on 4)

The isolated LOX1 antibody of claim 4, wherein the LOX1-binding antibody fragment is selected from the group consisting of a Fab fragment, a Fab′ fragment, a F(ab′)2 fragment, a Fv fragment, a diabody, or a single chain antibody molecule.

### Claim 6 (depends on 4)

The isolated LOX1 antibody of claim 4, wherein the antibody further comprises a heavy chain immunoglobulin constant domain selected from the group consisting of:
(a) a human IgA constant domain
(b) a human IgD constant domain;
(c) a human IgE constant domain;
(d) a human IgG1 constant domain;
(e) a human IgG2 constant domain;
(f) a human IgG3 constant domain;
(g) a human IgG4 constant domain; and
(h) a human IgM constant domain.

### Claim 7 (depends on 4)

The isolated LOX1 antibody of claim 4, wherein the antibody further comprises a light chain immunoglobulin constant domain selected from the group consisting of:
(a) a human Ig kappa constant domain; and
(b) a human Ig lambda constant domain.

### Claim 8 (depends on 3)

The isolated LOX1 antibody of claim 3, wherein the LOX1 antibody further comprises a human IgG1 heavy chain constant domain and a human lambda light chain constant domain.

### Claim 9 (depends on 8)

The isolated LOX1 antibody of claim 8, wherein the IgG1 heavy chain constant domain contains a mutation at positions 234, 235 and 331, wherein the position numbering is according to the EU index as in Kabat.

### Claim 10 (depends on 9)

The isolated LOX1 antibody of claim 9, wherein the IgG1 heavy chain constant domain contains the mutations L234F, L235E and P331S, wherein the position numbering is according to the EU index as in Kabat.

### Claim 11 (depends on 3)

A pharmaceutical composition comprising a LOX1 binding protein LOX1 antibody of claim 3 and a pharmaceutically acceptable carrier.

### Claim 12 (depends on 3)

An isolated nucleic acid molecule or set of nucleic acid molecules encoding a LOX1 antibody according to claim 3.

### Claim 13 (depends on 12)

A vector comprising the nucleic acid molecule of claim 12.

### Claim 14 (depends on 12)

A host cell transformed with the nucleic acid molecule of claim 12.

### Claim 15 (depends on 1)

A method of reducing or inhibiting LOX1 activity in a subject having a cardiovascular disease or condition associated with LOX1 comprising administering an effective amount of a LOX1 antibody according to claim 1.

### Claim 16 (depends on 2)

A method of reducing or inhibiting LOX1 activity in a subject having a cardiovascular disease or condition associated with LOX1 comprising administering an effective amount of a LOX1 antibody according to claim 2.

### Claim 17 (depends on 3)

A method for treating, preventing and/or ameliorating a cardiovascular disease or condition associated with LOX1 in a subject, comprising administering to a subject in need thereof an effective amount of a composition comprising a LOX1 antibody of claim 3.

### Claim 18 (depends on 17)

The method of claim 17, wherein the cardiovascular disease or condition is selected from the group consisting of atherosclerosis, thrombosis, coronary artery disease (CAD), ischemia, infarction, acute coronary syndrome (ACS), stroke, reperfusion injury, restenosis, peripheral vascular disease, hypertension, heart failure, and angiogenesis.

### Claim 19 (depends on 3)

A method of reducing or inhibiting LOX1 activity in a subject having a cardiovascular disease or condition associated with LOX1 comprising administering an effective amount of a LOX1 antibody according to claim 3.