# US 10,870,709 B2 · Specific murine and humanized monoclonal antibodies detecting pathology associated secondary structure changes in proteins and peptides

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- Number: US 10,870,709 B2
- Document ID: US10870709B2
- Status: Granted
- Kind: B2
- Application number: 16/319,682
- Filed: 2017-07-22
- Published: 2019-08-22
- Granted: 2020-12-22
- Earliest claimed: 2016-07-22
- Assignees: New York University
- Applicants: New York University
- Inventors: Thomas M. Wisniewski; Fernando Goni
- Web page: https://patentgrep.com/patent/US10870709B2

## CPC

- C07K 16/44: against material not provided for elsewhere {, e.g. haptens, metals, DNA, RNA, amino acids}
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- C07K 7/06: having 5 to 11 amino acids
- C07K 14/00: Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K 16/18: against material from animals or humans
- A61K 2039/505: {comprising antibodies}
- C07K 2317/30: characterized by aspects of specificity or valency
- C07K 2317/33: Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
- 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: 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 relates to antibodies and binding fragments thereof that bind the β-sheet secondary structure of a pathological monomeric or oligomeric non-fibrillar proteins without binding to the non-toxic, non-pathological forms of these proteins or peptides These antibodies and binding fragments thereof are suitable for the diagnosis, prevention, and treatment of protein conformational disorders including all amyloid diseases.

## Claims

### Claim 1

An antibody or binding fragment thereof that binds β-sheet secondary structure of pathologic monomeric or oligomeric non-fibrillar proteins/peptides, said antibody or binding fragment thereof comprising:
(a) a heavy chain variable region, wherein said heavy chain variable region comprises a complementarity-determining region 1 (H-CDR1) comprising the amino acid sequence of SEQ ID NO: 23, a complementarity-determining region 2 (H-CDR2) comprising the amino acid sequence of SEQ ID NO: 27, and a complementarity-determining region 3 (H-CDR3) comprising the amino acid sequence of SEQ ID NO: 31; and a light chain variable region, wherein said light chain variable region comprises a complementarity-determining region 1 (L-CDR1) comprising the amino acid sequence of SEQ ID NO: 35, a complementarity-determining region 2 (L-CDR2) comprising the amino acid sequence of SEQ ID NO: 40, and a complementarity-determining region 3 (L-CDR3) comprising the amino acid sequence of SEQ ID NO: 45;
(b) a heavy chain variable region, wherein said heavy chain variable region comprises a H-CDR1 comprising the amino acid sequence of SEQ ID NO: 24, a H-CDR2 comprising the amino acid sequence of SEQ ID NO: 28, and a H-CDR3 comprising the amino acid sequence of SEQ ID NO: 32; and a light chain variable region, wherein said light chain variable region comprises a L-CDR1 comprising the amino acid sequence of SEQ ID NO: 36, a L-CDR2 comprising the amino acid sequence of SEQ ID NO: 41, and a L-CDR3 comprising the amino acid sequence of SEQ ID NO: 46;
(c) a heavy chain variable region, wherein said heavy chain variable region comprises a H-CDR1 comprising the amino acid sequence of SEQ ID NO: 25, a H-CDR2 comprising the amino acid sequence of SEQ ID NO: 29, and a H-CDR3 comprising the amino acid sequence of SEQ ID NO: 33; and a light chain variable region, wherein said light chain variable region comprises a L-CDR1 comprising the amino acid sequence of SEQ ID NO: 37, a L-CDR2 comprising the amino acid sequence of SEQ ID NO: 42, and a L-CDR3 comprising the amino acid sequence of SEQ ID NO: 47;
(d) a heavy chain variable region, wherein said heavy chain variable region comprises a H-CDR1 comprising the amino acid sequence of SEQ ID NO: 26, a H-CDR2 comprising the amino acid sequence of SEQ ID NO: 30, and a H-CDR3 comprising the amino acid sequence of SEQ ID NO: 34; and a light chain variable region, wherein said light chain variable region comprises a L-CDR1 comprising the amino acid sequence of SEQ ID NO: 39, a L-CDR2 comprising the amino acid sequence of SEQ ID NO: 44, and a L-CDR3 comprising the amino acid sequence of SEQ ID NO: 49;
(e) a heavy chain variable region, wherein said heavy chain variable region comprises a H-CDR1 comprising the amino acid sequence of SEQ ID NO: 50, a H-CDR2 comprising the amino acid sequence of SEQ ID NO: 51, and a H-CDR3 comprising the amino acid sequence of SEQ ID NO: 52; and a light chain variable region, wherein said light chain variable region comprises a L-CDR1 comprising the amino acid sequence of SEQ ID NO: 53, a L-CDR2 comprising the amino acid sequence of SEQ ID NO: 54, and a L-CDR3 comprising the amino acid sequence of SEQ ID NO: 55;
(f) a heavy chain variable region comprising the H-CDR1 comprises the amino acid sequence of SEQ ID NO: 23, the H-CDR2 comprising the amino acid sequence of SEQ ID NO: 27, and the H-CDR3 comprising the amino acid sequence of SEQ ID NO: 31; a light chain variable region, wherein said light chain variable region comprises a L-CDR1 comprising the amino acid sequence of SEQ ID NO: 38, a L-CDR2 comprising the amino acid sequence of SEQ ID NO: 43, and a L-CDR3 comprising the amino acid sequence of SEQ ID NO: 48; and
(g) a heavy chain variable region, wherein said heavy chain variable region comprises a H-CDR1 comprising the amino acid sequence of SEQ ID NO: 50, a H-CDR2 comprising the amino acid sequence of SEQ ID NO: 51, and a H-CDR3 comprising the amino acid sequence of SEQ ID NO: 52; and a light chain variable region, wherein said light chain variable region comprises a L-CDR1 comprising the amino acid sequence of SEQ ID NO: 53, a L-CDR2 comprising the amino acid sequence of SEQ ID NO: 112, and a L-CDR3 comprising the amino acid sequence of SEQ ID NO: 55.

### Claim 2 (depends on 1)

The antibody or binding fragment thereof of claim 1 comprising:
the heavy chain variable region comprising the H-CDR1 comprising the amino acid sequence of SEQ ID NO: 23, the H-CDR2 comprising the amino acid sequence of SEQ ID NO: 27, and the H-CDR3 comprising the amino acid sequence of SEQ ID NO: 31 and the light chain variable region comprising the complementarity-determining region 1 (L-CDR1) comprising the amino acid sequence of SEQ ID NO: 35, the complementarity-determining region 2 (L-CDR2) comprising the amino acid sequence of SEQ ID NO: 40, and the complementarity-determining region 3 (L-CDR3) comprising the amino acid sequence of SEQ ID NO: 45.

### Claim 3 (depends on 1)

The antibody or binding fragment thereof of claim 1 comprising:
the heavy chain variable region comprising the H-CDR1 comprising the amino acid sequence of SEQ ID NO: 23, the H-CDR2 comprising the amino acid sequence of SEQ ID NO: 27, and the H-CDR3 comprising the amino acid sequence of SEQ ID NO: 31, and the light chain variable region comprising the L-CDR1 comprising the amino acid sequence of SEQ ID NO: 38, the L-CDR2 comprising the amino acid sequence of SEQ ID NO: 43, and the L-CDR3 comprising the amino acid sequence of SEQ ID NO: 48.

### Claim 4 (depends on 1)

The antibody or binding fragment thereof of claim 1 comprising:
the heavy chain variable region comprising the H-CDR1 comprising the amino acid sequence of SEQ ID NO: 24, the H-CDR2 comprising the amino acid sequence of SEQ ID NO: 28, and the H-CDR3 comprising the amino acid sequence of SEQ ID NO: 32, and the light chain variable region comprising the L-CDR1 comprising the amino acid sequence of SEQ ID NO: 36, the L-CDR2 comprising the amino acid sequence of SEQ ID NO: 41, and the L-CDR3 comprising the amino acid sequence of SEQ ID NO: 46.

### Claim 5 (depends on 1)

The antibody or binding fragment thereof of claim 1 comprising:
the heavy chain variable region comprising the H-CDR1 comprising the amino acid sequence of SEQ ID NO: 25, the H-CDR2 comprising the amino acid sequence of SEQ ID NO: 29, and the H-CDR3 comprising the amino acid sequence of SEQ ID NO: 33, and the light chain variable region comprising the L-CDR1 comprising the amino acid sequence of SEQ ID NO: 37, the L-CDR2 comprising the amino acid sequence of SEQ ID NO: 42, and the L-CDR3 comprising the amino acid sequence of SEQ ID NO: 47.

### Claim 6 (depends on 1)

The antibody or binding fragment thereof of claim 1 comprising:
the heavy chain variable region comprising the H-CDR1 comprising the amino acid sequence of SEQ ID NO: 26, the H-CDR2 comprising the amino acid sequence of SEQ ID NO: 30, and the H-CDR3 comprising the amino acid sequence of SEQ ID NO: 34, and the light chain variable region comprising the L-CDR1 comprising the amino acid sequence of SEQ ID NO: 39, the L-CDR2 comprising the amino acid sequence of SEQ ID NO: 44, and the L-CDR3 comprising the amino acid sequence of SEQ ID NO: 49.

### Claim 7 (depends on 1)

The antibody or binding fragment thereof of claim 1 comprising:
the heavy chain variable region comprising the H-CDR1 comprising the amino acid sequence of SEQ ID NO: 50, the H-CDR2 comprising the amino acid sequence of SEQ ID NO: 51, and the H-CDR3 comprising the amino acid sequence of SEQ ID NO: 52, and the light chain variable region comprising the L-CDR1 comprising the amino acid sequence of SEQ ID NO: 53, the L-CDR2 comprising the amino acid sequence of SEQ ID NO: 54, and the L-CDR3 comprising the amino acid sequence of SEQ ID NO: 55.

### Claim 8 (depends on 1)

The antibody or binding fragment thereof of claim 1 comprising:
the heavy chain variable region comprising the H-CDR1 comprising the amino acid sequence of SEQ ID NO: 50, the H-CDR2 comprising the amino acid sequence of SEQ ID NO: 51, and the H-CDR3 comprising the amino acid sequence of SEQ ID NO: 52, and the light chain variable region comprising the L-CDR1 comprising the amino acid sequence of SEQ ID NO: 53, the L-CDR2 comprising the amino acid sequence of SEQ ID NO: 112, and the L-CDR3 comprising the amino acid sequence of SEQ ID NO: 55.

### Claim 9 (depends on 1)

The antibody or binding fragment thereof of claim 1, wherein said antibody or binding fragment thereof comprises
(a) a heavy chain variable region comprising an amino acid sequence that is at least 80% identical to SEQ ID NO: 2 and a light chain variable region comprising an amino acid sequence that is at least 80% identical to SEQ ID NO: 4;
(b) a heavy chain variable region comprising an amino acid sequence that is at least 80% identical to SEQ ID NO: 6 and a light chain variable region comprising an amino acid sequence that is at least 80% identical to SEQ ID NO: 8;
(c) a heavy chain variable region comprising an amino acid sequence that is at least 80% identical to SEQ ID NO: 10 and a light chain variable region comprising an amino acid sequence that is at least 80% identical to SEQ ID NO: 12;
(d) a heavy chain variable region comprising an amino acid sequence that is at least 80% identical to SEQ ID NO: 2 and a light chain variable region comprising an amino acid sequence that is at least 80% identical to SEQ ID NO: 18;
(e) a heavy chain variable region comprising an amino acid sequence that is at least 80% identical to SEQ ID NO: 20 and a light chain variable region comprising an amino acid sequence that is at least 80% identical to SEQ ID NO: 22;
(f) a heavy chain variable region comprising an amino acid sequence that is at least 80% identical to SEQ ID NO: 14 and a light chain variable region comprising an amino acid sequence that is at least 80% identical to SEQ ID NO: 16; or
(g) a heavy chain variable region comprising an amino acid sequence that is at least 80% identical to SEQ ID NO: 14 and a light chain variable region comprising an amino acid sequence that is at least 80% identical to SEQ ID NO: 109.

### Claim 10 (depends on 9)

The antibody or binding fragment thereof of claim 9, wherein said antibody or binding fragment thereof comprises:
(a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 2 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 4;
(b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 6 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8;
(c) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 10 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 12;
(d) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 2 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 18;
(e) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 20 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 22;
(f) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 14 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 16; or
(g) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 14 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 109.

### Claim 11 (depends on 1)

The antibody or binding fragment thereof of claim 1, wherein said antibody or binding fragment thereof is a murine antibody or a humanized antibody.

### Claim 12 (depends on 1)

The antibody or binding fragment thereof of claim 1, wherein said antibody or binding fragment thereof is selected from the group consisting of a disulfide linked Fv, a scFv, a CDR-grafted antibody, a diabody, a multispecific antibody, a Fab, a Fab′, a bispecific antibody, a F(ab′)2, and a Fv.

### Claim 13 (depends on 1)

An isolated polynucleotide encoding the antibody or binding fragment thereof of claim 1.

### Claim 14 (depends on 1)

A pharmaceutical composition comprising:
the antibody or binding fragment thereof of claim 1, and
a pharmaceutical carrier.

### Claim 15 (depends on 14)

A method of binding pathological oligomeric proteins or peptides having a β-sheet secondary structure in a subject, said method comprising:
administering to the subject the pharmaceutical composition of claim 14, wherein said composition is administered in an amount effective to bind pathological oligomeric proteins or peptides having β-sheet secondary structure in the subject.

### Claim 16 (depends on 15)

The method of claim 15, wherein the subject has a condition selected from the group consisting of Alzheimer's disease (AD), preclinical AD, Down syndrome (DS), fronto-temporal dementia (FTD), Lewy Body Dementia (LBD), Parkinson's disease (PD), hereditary cerebral hemorrhage with amyloidosis (HCHWA), kuru, Creutzfeldt-Jakob disease (CJD), chronic wasting disease (CWD), Gerstmann-Straussler-Scheinker disease (GSS), spongiform encephalopathy, Scrapie (Sc), Huntington's disease (HD), fatal familial insomnia, British familial dementia, Danish familial dementia, frontotemporal lobar degeneration associated with protein tau (FTLD-tau), frontotemporal lobar degeneration associated with protein FUS (FTLD-FUS), Amyotrophic lateral sclerosis (ALS), Mild Cognitive Impairment (MCI), familial corneal amyloidosis, Familial corneal dystrophies, medullary thyroid carcinoma, insulinoma, type 2 diabetes, isolated atrial amyloidosis, pituitary amyloidosis, aortic amyloidosis, plasma cell disorders, familial amyloidosis, senile cardiac amyloidosis, inflammation-associated amyloidosis, familial Mediterranean fever (FMF), dialysis-associated amyloidosis, systemic amyloidosis, familial systemic amyloidosis, motor neuron disease, traumatic brain injury (TBI), and chronic traumatic encephalopathy.

### Claim 17 (depends on 1)

A method of diagnosing an amyloid disease in a subject, said method comprising:
detecting, in the subject, the presence of an amyloidogenic protein or peptide using a diagnostic reagent, wherein the diagnostic reagent comprises the antibody or binding fragment thereof of claim 1, and
diagnosing the amyloid disease in the subject based on said detecting.

### Claim 18 (depends on 1)

A method of identifying a subject's risk for developing a condition mediated by an amyloidogenic protein or peptide, said method comprising:
detecting, in the subject, the presence of an amyloidogenic protein or peptide using a diagnostic reagent, wherein the diagnostic reagent comprises the antibody or binding fragment thereof of claim 1, and
identifying the subject's risk of developing the condition mediated by the amyloidogenic protein or peptide based on said detecting.

### Claim 19 (depends on 1)

A diagnostic kit comprising:
the antibody or binding fragment thereof of claim 1 and a detectable label.