# US 11,028,158 B2 · Anti-transthyretin antibodies

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- Number: US 11,028,158 B2
- Document ID: US11028158B2
- Status: Granted
- Kind: B2
- Application number: 16/584,634
- Filed: 2019-09-26
- Published: 2020-03-19
- Granted: 2021-06-08
- Earliest claimed: 2015-01-28
- Assignees: Prothena Biosciences Limited; University Health Network
- Applicants: Prothena Biosciences Limited; University Health Network
- Inventors: Yue Liu; Tarlochan S. Nijjar; Avijit Chakrabartty; Jeffrey N. Higaki
- Web page: https://patentgrep.com/patent/US11028158B2

## CPC

- C07K 16/18: against material from animals or humans
- A61K 51/1018: {against material from animals or humans}
- 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 2317/41: Glycosylation, sialylation, or fucosylation
- C07K 2317/56: variable (Fv) region, i.e. VH and/or VL
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/567: Framework region [FR]
- C07K 2317/734: Complement-dependent cytotoxicity [CDC]
- 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: 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 invention provides antibodies that specifically bind transthyretin (TTR). The antibodies can be used for treating or effecting prophylaxis of diseases or disorders associated with TTR accumulation or accumulation of TTR deposits (e.g., TTR amyloidosis). The antibodies can also be used for diagnosing TTR amyloidosis and inhibiting or reducing aggregation of TTR, among other applications.

## Claims

### Claim 1

A vector comprising a nucleic acid encoding a mature heavy chain variable region and a mature light chain variable region operably linked to one or more regulatory sequences to effect expression in a mammalian cell of an antibody comprising the mature heavy chain variable region and mature light chain variable region that binds to human transthyretin, wherein the mature heavy chain variable region comprises three heavy chain CDRs having sequences comprising SEQ ID NOS:67-69, respectively, and the mature light chain variable region comprises three light chain CDRs having sequences comprising SEQ ID NOS:77-79, respectively, except that positions H52 and L26 by Kabat numbering are independently each N or S.

### Claim 2 (depends on 1)

The vector of claim 1 wherein the mature heavy chain variable region is encoded by a sequence comprising any one of SEQ ID NOS:44-51 and SEQ ID NOS:91-93 and the nucleic acid encoding the mature light chain variable region is encoded by a sequence comprising any one of SEQ ID NOS:52-56 and SEQ ID NOS:94-96.

### Claim 3 (depends on 1)

The vector of claim 1, wherein the mature heavy chain variable region has the amino acid sequence of any one of SEQ ID NOS:5-12 and the mature light chain variable region has the amino acid sequence of any one of SEQ ID NOS:19-23.

### Claim 4 (depends on 3)

The vector of claim 3, wherein the mature heavy chain variable region has the amino acid sequence of SEQ ID NO:11 and the mature light chain variable region has the amino acid sequence of SEQ ID NO:19.

### Claim 5 (depends on 1)

The vector of claim 1, wherein positions H47 and H108 in the mature heavy chain variable region are each occupied by L, and wherein position L36 in the mature light chain variable region is occupied by F, wherein positions are defined by Kabat numbering.

### Claim 6 (depends on 2)

The vector of claim 2 having a sequence comprising SEQ ID NO:50 encoding the mature heavy chain variable region and SEQ ID NO:52 encoding the mature light chain variable region.

### Claim 7 (depends on 1)

The vector of claim 1, wherein the mature heavy chain variable region has the amino acid sequence of any one of SEQ ID NOS:64-66, and the mature light chain variable region has the amino acid sequence of any one of SEQ ID NOS:74-76.

### Claim 8 (depends on 7)

The vector of claim 7, wherein the mature heavy chain variable region has the amino acid sequence of SEQ ID NO:65 and the mature light chain variable region has the amino acid sequence of SEQ ID NO:76.

### Claim 9 (depends on 1)

The vector of claim 1, wherein positions H1 and H47 in the mature heavy chain variable region are occupied by E and L, respectively, and wherein positions L36 and L60 in the mature light chain variable region are occupied by F and S, respectively, wherein positions are defined by Kabat numbering.

### Claim 10 (depends on 2)

The vector of claim 2 having a sequence comprising SEQ ID NO:92 encoding the mature heavy chain variable region and SEQ ID NO:96 encoding the mature light chain variable region.

### Claim 11 (depends on 1)

The vector of claim 1, wherein the nucleic acid further encodes a heavy chain constant region fused to the mature heavy chain variable region and a light chain constant region fused to the mature light chain variable region.

### Claim 12 (depends on 11)

The vector of claim 11, wherein the heavy chain constant region has the sequence of any one of SEQ ID NOS:101-103 with or without the C-terminal lysine and the light chain constant region has the sequence of any one of SEQ ID NOS:104-105.

### Claim 13 (depends on 11)

The vector of claim 11, wherein the heavy chain constant region is encoded by the sequence of SEQ ID NO:106 and the light chain constant region is encoded by the sequence of any one of SEQ ID NOS:107-108.

### Claim 14 (depends on 1)

The vector of claim 1, wherein the antibody is a scFv.

### Claim 15 (depends on 1)

The vector of claim 1, wherein the antibody is a Fab fragment.

### Claim 16 (depends on 1)

The vector of claim 1, wherein the one or more regulatory sequences include one or more of a promoter, enhancer, ribosome binding site, and transcription termination signal.

### Claim 17 (depends on 1)

The vector of claim 1, wherein the nucleic acid further encodes signal peptides fused to the mature heavy and light chain variable regions.

### Claim 18 (depends on 1)

The vector of claim 1, wherein the nucleic acid is codon-optimized for expression in a host cell.

### Claim 19 (depends on 1)

The vector of claim 1, wherein the one or more regulatory sequences include a eukaryotic promoter.

### Claim 20 (depends on 1)

The vector of claim 1, wherein the nucleic acid further encodes a selection marker.

### Claim 21 (depends on 1)

A host cell comprising the nucleic acid of claim 1.

### Claim 22 (depends on 1)

A method of expressing an antibody in a mammalian cell comprising incorporating the nucleic acid of claim 1 into the genome of a transgenic animal, whereby the antibody is expressed.

### Claim 23

A host cell comprising first and second nucleic acids respectively encoding a mature heavy chain variable region and a mature light chain variable region, each operably linked to one or more regulatory sequences to effect expression of an antibody comprising the mature heavy chain variable region and mature light chain variable region, wherein the mature heavy chain variable region comprises three heavy chain CDRs having sequences comprising SEQ ID NOS:67-69, respectively, and the mature light chain variable region comprises three light chain CDRs having sequences comprising SEQ ID NOS:77-79, respectively, except that positions H52 and L26 by Kabat numbering are independently each N or S.

### Claim 24 (depends on 23)

The host cell of claim 23, wherein the mature heavy chain variable region is encoded by a sequence comprising any one of SEQ ID NOS:44-51 and SEQ ID NOS:91-93 and the nucleic acid encoding the mature light chain variable region is encoded by a sequence comprising any one of SEQ ID NOS:52-56 and SEQ ID NOS:94-96.

### Claim 25 (depends on 23)

The host cell of claim 23, wherein the mature heavy chain variable region has the amino acid sequence of any one of SEQ ID NOS:5-12 and the mature light chain variable region has the amino acid sequence of any one of SEQ ID NOS:19-23.

### Claim 26 (depends on 25)

The host cell of claim 25, wherein the mature heavy chain variable region has the amino acid sequence of SEQ ID NO:11 and the mature light chain variable region has the amino acid sequence of SEQ ID NO:19.

### Claim 27 (depends on 23)

The host cell of claim 23, wherein positions H47 and H108 in the mature heavy chain variable region are each occupied by L, and wherein position L36 in the mature light chain variable region is occupied by F, wherein positions are defined by Kabat numbering.

### Claim 28 (depends on 24)

The host cell of claim 24, wherein the nucleic acid encoding the mature heavy chain variable region has a sequence comprising SEQ ID NO:50 and the nucleic acid encoding the mature light chain variable region has a sequence comprising SEQ ID NO:52.

### Claim 29 (depends on 23)

The host cell of claim 23, wherein the mature heavy chain variable region has the amino acid sequence of any one of SEQ ID NOS:64-66, and the mature light chain variable region has the amino acid sequence of any one of SEQ ID NOS:74-76.

### Claim 30 (depends on 29)

The host cell of claim 29, wherein the mature heavy chain variable region has the amino acid sequence of SEQ ID NO:65 and the mature light chain variable region has the amino acid sequence of SEQ ID NO:76.

### Claim 31 (depends on 23)

The host cell of claim 23, wherein positions H1 and H47 in the mature heavy chain variable region are occupied by E and L, respectively, and wherein positions L36 and L60 in the mature light chain variable region are occupied by F and S, respectively, wherein positions are defined by Kabat numbering.

### Claim 32 (depends on 24)

The host cell of claim 24, wherein the nucleic acid encoding the mature heavy chain variable region has a sequence comprising SEQ ID NO:92 and the nucleic acid encoding the mature light chain variable region has a sequence comprising SEQ ID NO:96.

### Claim 33 (depends on 23)

The host cell of claim 23, wherein the nucleic acids respectively further encode a heavy chain constant region fused to the mature heavy chain variable region and a light chain constant region fused to the mature light chain variable region.

### Claim 34 (depends on 33)

The host cell of claim 33, wherein the heavy chain constant region has the sequence of any one of SEQ ID NOS:101-103 with or without the C-terminal lysine and the light chain constant region has the sequence of any one of SEQ ID NOS:104-105.

### Claim 35 (depends on 33)

The host cell of claim 33, wherein the heavy chain constant region is encoded by the sequence of SEQ ID NO:106 and the light chain constant region is encoded by the sequence of any one of SEQ ID NOS:107-108.

### Claim 36

A method of expressing an antibody in a mammalian cell comprising incorporating first and second nucleic acids respectively encoding a mature heavy chain variable region and a mature light chain variable region, each operably linked to one or more regulatory sequences to effect expression of an antibody comprising the mature heavy chain variable region and mature light chain variable region, wherein the mature heavy chain variable region comprises three heavy chain CDRs having sequences comprising SEQ ID NOS:67-69, respectively, and the mature light chain variable region comprises three light chain CDRs having sequences comprising SEQ ID NOS:77-79, respectively, except that positions H52 and L26 by Kabat numbering are independently each N or S into the genome of a transgenic animal, whereby the antibody is expressed.