# US 12,491,245 B2 · Antibodies useful in passive influenza immunization, and compositions, combinations and methods for use thereof

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- Number: US 12,491,245 B2
- Document ID: US12491245B2
- Status: Granted
- Kind: B2
- Application number: 17/560,830
- Filed: 2021-12-23
- Published: 2022-04-14
- Granted: 2025-12-09
- Earliest claimed: 2014-02-04
- Assignees: Contrafect Corporation; Trellis Bioscience, LLC
- Applicants: Contrafect Corporation; Trellis Bioscience, Inc.
- Inventors: Angeles Estelles; Lawrence M. Kauvar; Adam Vigil; Michael Wittekind
- Web page: https://patentgrep.com/patent/US12491245B2

## CPC

- A61K 39/42: viral
- A61P 31/16: for influenza or rhinoviruses
- C07K 16/108: Orthomyxoviridae (F), e.g. influenza virus
- A61K 2039/505: {comprising antibodies}
- A61K 2039/507: {Comprising a combination of two or more separate antibodies}
- A61K 2039/543: {intranasal}
- A61K 2039/545: {characterised by the dose, timing or administration schedule}
- C07K 2317/21: from primates, e.g. man
- C07K 2317/33: Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
- C07K 2317/34: Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
- C07K 2317/55: Fab or Fab'
- 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
- 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
- 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)

## Abstract

Antibodies, compositions and methods are provided for treatment and prophylaxis of influenza virus. Antibodies and antigen-binding fragments are provided that bind near the HA0 maturation cleavage site consensus sequence of influenza hemagglutinin A. Antibody compositions, combinations and methods for effective passive immunization across influenza A and B strains are also provided.

## Claims

### Claim 1

A pharmaceutical composition formulated for intranasal or inhalation administration and effective for treatment or prophylaxis of influenza viral infection in a subject comprising:
(a) a first antibody or antigen-binding fragment thereof that binds to and/or inhibits influenza virus comprising:
a heavy chain amino acid sequence comprising a heavy chain variable region (HCVR) comprising a heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 11, a heavy chain complementarity determining region 2 (HCDR2) comprising the amino acid sequence of SEQ ID NO: 12 and a heavy chain complementarity determining region 3 (HCDR3) comprising the amino acid sequence of SEQ ID NO:13 and
a light chain amino acid sequence comprising a light chain variable region (LCVR) comprising a light chain complementarity determining region 1 (LCDR1) comprising the amino acid sequence of SEQ ID NO: 14, a light chain complementarity determining region 2 (LCDR2) comprising the amino acid sequence of SEQ ID NO: 15, and a light chain complementarity determining region 3 (LCDR3) comprising the amino acid sequence of SEQ ID NO: 16;
(b) a second antibody or antigen-binding fragment thereof that binds to and/or inhibits influenza virus comprising: a heavy chain amino acid sequence comprising HCVR comprising a HCDR1 comprising the amino acid sequence of SEQ ID NO: 21, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 22, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 23 and a light chain amino acid sequence comprising a LCVR comprising a LCDR1 comprising the amino acid sequence of SEQ ID NO: 24, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 25, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 26; and
(c) a third antibody or antigen-binding fragment thereof that binds to one or more strains of each of influenza B Yamagata and influenza B Victoria clades comprising: a heavy chain amino acid sequence comprising a HCVR comprising: a heavy chain amino acid sequence comprising a HCVR comprising: a HCDR1 comprising the amino acid sequence of SEQ ID NO:241, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 242, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 243 and a light chain amino acid sequence comprising a LCVR comprising: a LCDR1 comprising the amino acid sequence of SEQ ID NO: 244, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 245, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 246.

### Claim 2 (depends on 1)

The pharmaceutical composition of claim 1, wherein each antibody or antigen-binding fragment thereof is formulated in a dosage for administration of 1 mg/kg or less.

### Claim 3 (depends on 1)

The pharmaceutical composition of claim 1, wherein each antibody or antigen-binding fragment thereof is formulated in a dosage for administration of 0.5 mg/kg or less.

### Claim 4 (depends on 1)

The pharmaceutical composition of claim 1, wherein each antibody or antigen-binding fragment thereof is formulated in a dosage for administration of 0.1 mg/kg or less.

### Claim 5 (depends on 1)

The pharmaceutical composition of claim 1, wherein said first antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR)/light chain variable region (HCVR/LCVR) sequence pair of SEQ ID NOs: 19 and 20, said second antibody or antigen-binding fragment thereof comprises an HCVR/LCVR sequence pair of SEQ ID NOs: 29 and 30 and said third antibody or antigen-binding fragment thereof comprises a HCVR/LCVR pair of SEQ ID NOs.: 249-250.

### Claim 6 (depends on 1)

The pharmaceutical composition of claim 1, wherein said pharmaceutical composition is formulated for delivery with a nebulizer.

### Claim 7 (depends on 1)

The pharmaceutical composition of claim 1, wherein said pharmaceutical composition is formulated for delivery with a device selected from a metered dose inhaler, a metered spray pump, a hand-bulb atomizer, a small or large volume nebulizer, an ultrasonic nebulizer and/or a dry powder inhaler.

### Claim 8 (depends on 1)

The pharmaceutical composition of claim 1, wherein said first antibody is TRL053/Mab53 comprising heavy chain (HC)/light chain (LC) amino acid sequences of SEQ ID NOs: 17 and 18, said second antibody is antibody TRL579/Mab579 comprising a HC/LC amino acid sequences of SEQ ID NOs: 27 and 28, and said third antibody is TRL849 comprising HC/LC amino acid sequences of SEQ ID NOs: 247 and 248.

### Claim 9 (depends on 1)

The pharmaceutical composition of claim 1, wherein said pharmaceutical composition further comprises a pharmaceutically acceptable carrier, said pharmaceutically acceptable carrier comprising a diluent and/or excipient for nasal or pulmonary delivery and/or
wherein the pharmaceutical composition further comprises an immunological mediator and/or stimulator of the immune response.

### Claim 10 (depends on 1)

The pharmaceutical composition of claim 1, wherein the pharmaceutical composition further comprises one or more of an antiviral therapeutic, viral replication inhibitor, protease inhibitor, polymerase inhibitor, hemagglutinin inhibitor, bronchodilator, immune modulator, or inhaled corticosteroid.

### Claim 11 (depends on 1)

The pharmaceutical composition of claim 1, wherein one or more of said antibodies or antigen binding fragments thereof is an antibody fragment selected from Fab, Fab′, and F(ab′)2, scFv, and/or dAb.

### Claim 12

A method for the treatment or prophylaxis of influenza infection in a subject which method comprises administering intranasally (IN) or via inhalation to a subject a pharmaceutical composition comprising:
(a) a first antibody or antigen-binding fragment thereof that binds to and/or inhibits influenza virus comprising: a heavy chain amino acid sequence comprising a heavy chain variable region (HCVR) comprising a heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 11, a heavy chain complementarity determining region 2 (HCDR2) comprising the amino acid sequence of SEQ ID NO: 12 and a heavy chain complementarity determining region 3 (HCDR3) comprising the amino acid sequence of SEQ ID NO:13 and a light chain amino acid sequence comprising a light chain variable region (LCVR) comprising a light chain complementarity determining region 1 (LCDR1) comprising the amino acid sequence of SEQ ID NO: 14, a light chain complementarity determining region 2 (LCDR2) comprising the amino acid sequence of SEQ ID NO: 15, and a light chain complementarity determining region 3 (LCDR3) comprising the amino acid sequence of SEQ ID NO: 16;
(b) a second antibody or antigen-binding fragment thereof that binds to and/or inhibits influenza virus comprising: a heavy chain amino acid sequence comprising HCVR comprising a HCDR1 comprising the amino acid sequence of SEQ ID NO: 21, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 22, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 23 and a light chain amino acid sequence comprising a LCVR comprising a LCDR1 comprising the amino acid sequence of SEQ ID NO: 24, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 25, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 26; and
(c) a third antibody or antigen-binding fragment thereof that binds to one or more strains of each of influenza B Yamagata and influenza B Victoria clades comprising: a heavy chain amino acid sequence comprising a HCVR comprising: a heavy chain amino acid sequence comprising a HCVR comprising: a HCDR1 comprising the amino acid sequence of SEQ ID NO:241, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 242, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 243 and a light chain amino acid sequence comprising a LCVR comprising: a LCDR1 comprising the amino acid sequence of SEQ ID NO: 244, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 245, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 246.

### Claim 13 (depends on 12)

The method of claim 12, wherein each antibody or antigen-binding fragment thereof of the pharmaceutical composition is formulated in a dosage for administration of 1 mg/kg or less.

### Claim 14 (depends on 12)

The method of claim 12, wherein each antibody or antigen-binding fragment thereof of the pharmaceutical composition is formulated in a dosage for administration of 0.5 mg/kg or less.

### Claim 15 (depends on 12)

The method of claim 12, wherein each antibody or antigen-binding fragment thereof of the pharmaceutical composition is formulated in a dosage for administration of 0.1 mg/kg or less.

### Claim 16 (depends on 12)

The method of claim 12, wherein the pharmaceutical composition is administered in a time period selected from the group consisting of (i) up to 24 hours post infection; (ii) up to 48 hours post infection and (iii) up to 72 hours post infection.

### Claim 17 (depends on 12)

The method of claim 12, wherein the pharmaceutical composition is administered in one or more doses before infection or exposure to virus.

### Claim 18 (depends on 12)

The method of claim 12, wherein the pharmaceutical composition is administered intranasally or via inhalation in multiple doses of less than 1 mg/kg per dose, wherein the multiple doses are administered at least 2 hours apart and first administered up to 72 hours after presumed infection or exposure to virus.

### Claim 19 (depends on 12)

The method of claim 12, wherein the method further comprises administering intraperitoneally (IP) or intravenously (IV) at least one virus specific monoclonal antibody,
wherein the additionally administered virus specific monoclonal antibody is a neutralizing or non-neutralizing antibody and is the same as or is different from at least one of the antibodies or antigen-binding fragments of the intranasally or via inhalation administered pharmaceutical composition.

### Claim 20 (depends on 19)

The method of claim 19, wherein the additionally administered virus specific monoclonal antibody is a non-neutralizing virus specific monoclonal antibody.

### Claim 21 (depends on 19)

The method of claim 19, wherein the additionally administered virus specific monoclonal antibody is at a dosage of at least 5 mg/kg and each of the antibodies or antigen-binding fragments of the intranasally or via inhalation administered pharmaceutical composition are administered at a dosage of 1 mg/kg or less.

### Claim 22 (depends on 19)

The method of claim 19, wherein the pharmaceutical composition is administered via a nebulizer.

### Claim 23 (depends on 19)

The method of claim 19, wherein the pharmaceutical composition is administered via a device selected from a metered dose inhaler, a metered spray pump, a hand-bulb atomizer, a small or large volume nebulizer, an ultrasonic nebulizer and/or a dry powder inhaler.