# US 2019/0315840 A1 · Anti-dengue virus antibodies, polypeptides containing variant fc regions, and methods of use

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- Number: US 2019/0315840 A1
- Document ID: US20190315840A1
- Status: Published application
- Kind: A1
- Application number: 16/435,979
- Filed: 2019-06-10
- Published: 2019-10-17
- Earliest claimed: 2016-09-16
- Assignees: Chugai Seiyaku Kabushiki Kaisha; Agency for Science, Technology and Research
- Applicants: Chugai Seiyaku Kabushiki Kaisha; Agency for Science, Technology and Research
- Inventors: Zenjiro SAMPEI; Xing'er Christine KOO; Katja FINK; Roland ZUEST
- Web page: https://patentgrep.com/patent/US20190315840A1

## CPC

- C07K 16/116: Togaviridae (F); Matonaviridae (F); Flaviviridae (F)
- A61P 31/12: Antivirals
- A61K 2039/505: {comprising antibodies}
- C07K 2317/52: Constant or Fc region; Isotype
- C07K 2317/56: variable (Fv) region, i.e. VH and/or VL
- C07K 2317/734: Complement-dependent cytotoxicity [CDC]
- 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
- 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
- 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)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

The disclosure provides anti-DENV antibodies and methods of making and using the same. Nucleic acids encoding anti-DENV antibodies and host cells comprising the nucleic acids are also provided. The anti-DENV antibodies have uses that include treating DENV infection. The disclosure also provided polypeptides containing a variant Fc region and methods of making the same. Nucleic acids encoding polypeptides and host cells comprising the nucleic acids are also provided. The polypeptides have uses that include treating a viral infection. Also claimed is a polypeptide comprising a Fc variant comprising at least one amino acid alteration in Sa parent Fc region, wherein the variant Fc region has a substantially decreased FcYR-binding activity and does not have a substantially decreased C1q-binding activity when compared to the parent Fc region.

## Claims

### Claim at position 1

1-17. (canceled)

### Claim 18

An isolated antibody that binds to dengue virus (DENV) E protein, wherein the antibody comprises:
(i) (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 11,
(b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 14,
(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 17,
(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 21,
(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 24 and
(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 27;
(ii) (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 11,
(b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 15,
(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 17,
(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 21,
(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 24 and
(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 27;
(iii) (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 11,
(b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 15,
(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 18,
(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 21,
(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 24 and
(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 27;
(iv) (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 11,
(b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 15,
(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 19,
(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 21,
(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 24 and
(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 27;
(v) (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 11,
(b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 15,
(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 17,
(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 21,
(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25 and
(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28;
(vi) (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 11,
(b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 15,
(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 17,
(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 22,
(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25 and
(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 29;
(vii) (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 12,
(b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 15,
(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 20,
(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 23,
(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26 and
(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 30; or
(viii) (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 12,
(b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 15,
(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 20,
(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 21,
(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 24 and
(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 27.

### Claim 19

An isolated antibody, comprising a VH sequence of any one of SEQ ID NOs: 2-6 and a VL sequence of any one of SEQ ID NOs: 7-10.

### Claim 20 (depends on 18)

The antibody of claim 18, wherein the antibody comprises a variant Fc region of a human IgG comprising Ala at position 234, and Ala at position 235 and further amino acid alterations of any one of the following:
(i) positions 267, 268, and 324;
(ii) positions 236, 267, 268, 324, and 332; and
(iii) positions 326 and 333;
(iv) according to EU numbering.

### Claim 21 (depends on 19)

The antibody of claim 19, wherein the antibody comprises a variant human Fc gamma region comprising Ala at position 234, and Ala at position 235, according to EU numbering.

### Claim 22 (depends on 20)

The antibody of claim 20, wherein the variant Fc region further comprises amino acids selected from the group consisting of:
(i) Glu at position 267;
(ii) Phe at position 268;
(iii) Thr at position 324;
(iv) Ala at position 236;
(v) Glu at position 332;
(vi) Ala, Asp, Glu, Met, or Trp at position 326; and
(vii) Ser at position 333;
according to EU numbering.

### Claim 23 (depends on 21)

The antibody of claim 21, wherein the variant Fc region further comprises amino acids selected from the group consisting of:
(i) Glu at position 267;
(ii) Phe at position 268;
(iii) Thr at position 324;
(iv) Ala at position 236;
(v) Glu at position 332;
(vi) Ala, Asp, Glu, Met, or Trp at position 326; and
(vii) Ser at position 333;
according to EU numbering.

### Claim 24 (depends on 20)

The antibody of claim 20, wherein the variant Fc region further comprises amino acids selected from the group consisting of:
(i) Ala at position 434;
(ii) Ala at position 434, Thr at position 436, Arg at position 438, and Glu at position 440;
(iii) Leu at position 428, Ala at position 434, Thr at position 436, Arg at position 438, and Glu at position 440; and
(iv) Leu at position 428, Ala at position 434, Arg at position 438, and Glu at position 440;
according to EU numbering.

### Claim 25 (depends on 21)

The antibody of claim 21, wherein the variant Fc region further comprises amino acids selected from the group consisting of:
(i) Ala at position 434;
(ii) Ala at position 434, Thr at position 436, Arg at position 438, and Glu at position 440;
(iii) Leu at position 428, Ala at position 434, Thr at position 436, Arg at position 438, and Glu at position 440; and
(iv) Leu at position 428, Ala at position 434, Arg at position 438, and Glu at position 440;
according to EU numbering.

### Claim 26 (depends on 18)

The antibody of claim 18, wherein the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 11,
(i) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 14,
(ii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 17,
(iii) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 21,
(iv) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 24 and
(v) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 27.

### Claim 27 (depends on 18)

The antibody of claim 18, wherein the antibody comprises
(i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 11,
(ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 15,
(iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 17,
(iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 21,
(v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 24 and
(vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 27.

### Claim 28 (depends on 18)

The antibody of claim 18, wherein the antibody comprises
(i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 11,
(ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 15,
(iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 18,
(iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 21,
(v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 24 and
(vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 27.

### Claim 29 (depends on 18)

The antibody of claim 18, wherein the antibody comprises
(i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 11,
(ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 15,
(iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 19,
(iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 21,
(v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 24 and
(vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 27.

### Claim 30 (depends on 18)

The antibody of claim 18, wherein the antibody comprises
(i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 11,
(ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 15,
(iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 17,
(iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 21,
(v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25 and
(vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28.

### Claim 31 (depends on 18)

The antibody of claim 18, wherein the antibody comprises
(i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 11,
(ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 15,
(iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 17,
(iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 22,
(v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25 and
(vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 29.

### Claim 32 (depends on 18)

The antibody of claim 18, wherein the antibody comprises
(i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 12,
(ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 15,
(iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 20,
(iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 23,
(v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26 and
(vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 30.

### Claim 33 (depends on 18)

The antibody of claim 18, wherein the antibody comprises
(i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 12,
(ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 15,
(iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 20,
(iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 21,
(v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 24 and
(vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 27.

### Claim 34

An isolated antibody that binds to dengue virus (DENV) E protein, wherein the antibody comprises:
(i) VH comprising the amino acid sequence of SEQ ID NO: 2, VL comprising the amino acid sequence of SEQ ID NO: 7, CH comprising the amino acid sequence of SEQ ID NO: 46 and CL comprising the amino acid sequence of SEQ ID NO: 60,
(ii) VH comprising the amino acid sequence of SEQ ID NO: 3, VL comprising the amino acid sequence of SEQ ID NO: 7, CH comprising the amino acid sequence of SEQ ID NO: 46 and CL comprising the amino acid sequence of SEQ ID NO: 60,
(iii) VH comprising the amino acid sequence of SEQ ID NO: 3, VL comprising the amino acid sequence of SEQ ID NO: 7, CH comprising the amino acid sequence of SEQ ID NO: 54 and CL comprising the amino acid sequence of SEQ ID NO: 60,
(iv) VH comprising the amino acid sequence of SEQ ID NO: 3, VL comprising the amino acid sequence of SEQ ID NO: 7, CH comprising the amino acid sequence of SEQ ID NO: 59 and CL comprising the amino acid sequence of SEQ ID NO: 60,
(v) VH comprising the amino acid sequence of SEQ ID NO: 4, VL comprising the amino acid sequence of SEQ ID NO: 7, CH comprising the amino acid sequence of SEQ ID NO: 46 and CL comprising the amino acid sequence of SEQ ID NO: 60,
(vi) VH comprising the amino acid sequence of SEQ ID NO: 5, VL comprising the amino acid sequence of SEQ ID NO: 7, CH comprising the amino acid sequence of SEQ ID NO: 46 and CL comprising the amino acid sequence of SEQ ID NO: 60,
(vii) VH comprising the amino acid sequence of SEQ ID NO: 3, VL comprising the amino acid sequence of SEQ ID NO: 8, CH comprising the amino acid sequence of SEQ ID NO: 46 and CL comprising the amino acid sequence of SEQ ID NO: 60,
(viii) VH comprising the amino acid sequence of SEQ ID NO: 3, VL comprising the amino acid sequence of SEQ ID NO: 9, CH comprising the amino acid sequence of SEQ ID NO: 46 and CL comprising the amino acid sequence of SEQ ID NO: 60,
(ix) VH comprising the amino acid sequence of SEQ ID NO: 6, VL comprising the amino acid sequence of SEQ ID NO: 10, CH comprising the amino acid sequence of SEQ ID NO: 46 and CL comprising the amino acid sequence of SEQ ID NO: 60,
(x) VH comprising the amino acid sequence of SEQ ID NO: 6, VL comprising the amino acid sequence of SEQ ID NO: 10, CH comprising the amino acid sequence of SEQ ID NO: 59 and CL comprising the amino acid sequence of SEQ ID NO: 60,
(xi) VH comprising the amino acid sequence of SEQ ID NO: 6, VL comprising the amino acid sequence of SEQ ID NO: 7, CH comprising the amino acid sequence of SEQ ID NO: 46 and CL comprising the amino acid sequence of SEQ ID NO: 60,
(xii) VH comprising the amino acid sequence of SEQ ID NO: 6, VL comprising the amino acid sequence of SEQ ID NO: 7, CH comprising the amino acid sequence of SEQ ID NO: 54 and CL comprising the amino acid sequence of SEQ ID NO: 60, or
(xiii) VH comprising the amino acid sequence of SEQ ID NO: 6, VL comprising the amino acid sequence of SEQ ID NO: 7, CH comprising the amino acid sequence of SEQ ID NO: 59 and CL comprising the amino acid sequence of SEQ ID NO: 60.

### Claim 35 (depends on 18)

A pharmaceutical composition comprising the antibody of claim 18.

### Claim 36 (depends on 18)

A method of treating an individual having a DENV infection, comprising administering to the individual in need thereof an effective amount of the antibody of claim 18.

### Claim 37 (depends on 18)

An isolated polynucleotide encoding of the antibody of claim 18.

### Claim 38 (depends on 37)

A host cell comprising the polynucleotide of claim 37.

### Claim 39 (depends on 38)

A method of producing an antibody comprising culturing the host cell of claim 38 so that the antibody is produced.

### Claim 40 (depends on 18)

A method of detecting the presence of DENV and/or DENV E protein in a biological sample using the antibody of claim 18.

### Claim 41 (depends on 18)

A method of selecting subjects eligible for therapy with an anti-DENV antibody using the antibody of claim 18, wherein DENV or DENV E protein is a biomarker of selection for patients.

### Claim 42 (depends on 18)

A method of treating an individual having a DENV infection, comprising administering to the individual in need thereof an effective amount of the antibody of claim 18, further comprising administering to the individual an effective amount of at least one additional therapeutic agent.

### Claim 43 (depends on 18)

A method of blocking binding of DENV E protein to and/or DENV entry into a host cell, comprising administering to the individual in need thereof an effective amount of the antibody of claim 18.

### Claim 44 (depends on 18)

A antibody comprising a variant Fc region of a human IgG comprising at least one amino acid alteration in a parent Fc region, wherein the variant Fc region has a substantially decreased FcgR binding activity and does not have a substantially decreased C1q binding activity when compared to the parent Fc region, wherein the antibody comprises HVR-H1, H2 and H3 and HVR-L1, L2 and L3 recited in claim 18.

### Claim 45

A polypeptide comprising a variant Fc region comprising at least one amino acid alteration in a parent Fc region, wherein the variant Fc region has a substantially decreased FcgR-binding activity and does not have a substantially decreased C1q-binding activity when compared to the parent Fc region.

### Claim 46 (depends on 45)

The polypeptide of claim 45, comprising the amino acid sequence of any one of SEQ ID NOs: 51-59.