# US 11,993,644 B2 · Antigen binding molecules targeting SARS-CoV-2

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- Number: US 11,993,644 B2
- Document ID: US11993644B2
- Status: Granted
- Kind: B2
- Application number: 18/313,306
- Filed: 2023-05-05
- Published: 2023-11-09
- Granted: 2024-05-28
- Earliest claimed: 2022-05-06
- Assignees: Generate Biomedicines, Inc.
- Applicants: Generate Biomedicines, Inc.
- Inventors: Francesco Borriello; Alexis Hiram Ramos
- Web page: https://patentgrep.com/patent/US11993644B2

## CPC

- C07K 16/104: Severe acute respiratory syndrome coronavirus 2 [SARS‐CoV‐2]
- A61K 31/13: Amines {(A61K31/04 takes precedence)}
- A61K 31/215: of carboxylic acids
- A61K 31/45: having oxo groups directly attached to the heterocyclic ring, e.g. cycloheximide
- A61K 31/4706: 4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
- A61K 31/4965: Non-condensed pyrazines
- A61K 31/675: having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
- A61K 31/7052: having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K 31/7068: having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K 31/7088: Compounds having three or more nucleosides or nucleotides
- A61K 39/215: Coronaviridae, e.g. avian infectious bronchitis virus
- A61K 39/42: viral
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 31/14: for RNA viruses
- A61K 2039/505: {comprising antibodies}
- A61K 2039/507: {Comprising a combination of two or more separate antibodies}
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- 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 2317/567: Framework region [FR]
- 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 2319/00: Fusion polypeptide
- 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

## Abstract

The disclosure provides, in various embodiments, polypeptides (e.g., antibodies and antigen binding fragments thereof) that specifically bind to S2 domains of betacoronavirus Spike glycoproteins, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Spike glycoproteins. The disclosure also provides, in various embodiments, fusion proteins comprising one or more of polypeptides, polynucleotides encoding polypeptides, vectors and host cells suitable for expressing polypeptides, and methods for treating viral infections (e.g., COVID-19).

## Claims

### Claim 1

A polypeptide that specifically binds a severe acute respiratory syndrome coronavirus 2 Spike glycoprotein (SARS-CoV-2-Spike) comprising:
a) a heavy chain variable domain (VH) that comprises a heavy chain complementarity-determining region (HCDR) 1 comprising the amino acid sequence of SEQ ID NO:77, a HCDR2 comprising the amino acid sequence of SEQ ID NO:80, and a HCDR3 comprising the amino acid sequence of SEQ ID NO:91; and
b) a light chain variable domain (VL) that comprises a light chain complementarity-determining region (LCDR) 1 comprising the amino acid sequence of SEQ ID NO:133, a LCDR2 comprising the amino acid sequence of SEQ ID NO:141, and a LCDR3 comprising the amino acid sequence of SEQ ID NO:144, wherein the polypeptide is an antibody or an antigen-binding fragment thereof.

### Claim 2

A polypeptide that specifically binds a severe acute respiratory syndrome coronavirus 2 Spike glycoprotein (SARS-CoV-2-Spike) comprising:
a) a heavy chain variable domain (VH) that comprises a heavy chain complementarity-determining region (HCDR) 1 consisting of the amino acid sequence of SEQ ID NO:77, a HCDR2 consisting of the amino acid sequence of SEQ ID NO:80, and a HCDR3 consisting of the amino acid sequence of SEQ ID NO:91; and
b) a light chain variable domain (VL) that comprises a light chain complementarity-determining region (LCDR) 1 consisting of the amino acid sequence of SEQ ID NO:133, a LCDR2 consisting of the amino acid sequence of SEQ ID NO:141, and a LCDR3 consisting of the amino acid sequence of SEQ ID NO:144, wherein the polypeptide is an antibody or an antigen-binding fragment thereof.

### Claim 3 (depends on 1)

The polypeptide of claim 1, comprising:
a) a heavy chain variable domain (VH) that is humanized, contains human framework regions, or a combination thereof,
b) a light chain variable domain (VL) that is humanized, contains human framework regions, or a combination thereof, or both a) and b).

### Claim 4 (depends on 1)

The polypeptide of claim 1, comprising a VH comprising the amino acid sequence of SEQ ID NO:4.

### Claim 5 (depends on 1)

The polypeptide of claim 1, comprising a VL comprising the amino acid sequence of SEQ ID NO:51.

### Claim 6 (depends on 1)

The polypeptide of claim 1, comprising a VH comprising the amino acid sequence of SEQ ID NO:4 and a VL comprising the amino acid sequence of SEQ ID NO:51.

### Claim 7 (depends on 1)

The polypeptide of claim 1, wherein the polypeptide is an antigen-binding fragment of an antibody, and wherein the antigen-binding fragment comprises a single-chain fragment variable (scFv), a fragment antigen-binding (Fab), a Fab′ or a F(ab′)2.

### Claim 8 (depends on 1)

The polypeptide of claim 1, comprising an antibody heavy chain constant domain, an antibody light chain constant domain, or both an antibody heavy chain constant domain and an antibody light chain constant domain.

### Claim 9 (depends on 8)

The polypeptide of claim 8, wherein the antibody heavy chain constant domain is an IgG1, IgG2, IgG3 or IgG4 constant domain.

### Claim 10 (depends on 8)

The polypeptide of claim 8, wherein the antibody heavy chain constant domain is an IgG1 constant domain.

### Claim 11 (depends on 10)

The polypeptide of claim 10, wherein the antibody heavy chain constant domain comprises one or more mutations which increase serum half-life of the antibody or antigen-binding fragment thereof in humans.

### Claim 12 (depends on 1)

The polypeptide of claim 1, comprising an antibody heavy chain (HC) constant domain comprising the amino acid sequence of SEQ ID NO:194.

### Claim 13 (depends on 1)

The polypeptide of claim 1, comprising an antibody light chain (LC) constant domain comprising the amino acid sequence of SEQ ID NO:195.

### Claim 14 (depends on 1)

The polypeptide of claim 1, comprising an antibody light chain (LC) constant domain comprising the amino acid sequence of SEQ ID NO:196.

### Claim 15 (depends on 1)

A composition comprising the polypeptide of claim 1 and one or more pharmaceutical excipients, diluents, or carriers.

### Claim 16 (depends on 15)

A method of treating a subject in need thereof, comprising administering an effective amount of the composition of claim 15 to the subject.

### Claim 17 (depends on 16)

The method of claim 16, further comprising administering a therapeutically effective amount of an additional therapeutic or prophylactic agent to the subject.

### Claim 18 (depends on 17)

The method of claim 17, wherein the additional therapeutic agent is selected from the group consisting of an antiviral agent, an ACE2 inhibitors, an additional SARS-CoV-2-Spike-binding antibody, an antibiotic, an antimalarial agent, a vaccine, and combinations thereof.

### Claim 19 (depends on 18)

The method of claim 18, wherein:
a) the additional SARS-CoV-2-Spike-binding antibody is selected from the group consisting of bamlanivimab, etesevimab, bebtelovimab, casirivimab, imdevimab, Cilgavimab, Tixagevimab, AZD7442, Regdanvimab, Sotrovimab and combinations thereof;
b) the antiviral agent is selected from the group consisting of Molnupiravir, PF-07817883, STI-1558, PBI-0451, EDP-235, oseltamivir, favipiravir, amantadine, remdesivir, rimantadine, pleconaril, an anti-sense RNA to SARS-CoV-2, a siRNA to SARS-CoV-2, and combinations thereof;
c) the ACE2 inhibitor is selected from the group consisting of an RNAi to ACE2, a siRNA to ACE2, CRISPR-based inhibitor of ACE2, a soluble ACE2, a soluble ACE2 variant, an anti-ACE2 antibody, and combinations thereof;
d) the antibiotic comprises azithromycin;
e) the antimalarial agent comprises a chloroquine;
f) the vaccine is a nucleic acid vaccine or an inactivated virus vaccine; or
g) a combination thereof.

### Claim 20 (depends on 16)

The method of claim 16, wherein the subject has COVID-19, is suspected of having COVID-19, or is at risk of developing COVID-19.

### Claim 21 (depends on 16)

The method of claim 16, wherein the subject has a heart disease, diabetes, a lung disease, is immune comprised, is on immunosuppressive therapy, or any combination thereof.

### Claim 22 (depends on 15)

A method of reducing infectivity of a betacoronavirus in a subject in need thereof, comprising administering an effective amount of the composition of claim 15 to the subject.

### Claim 23 (depends on 22)

The method of claim 22, further comprising administering a therapeutically effective amount of an additional therapeutic or prophylactic agent to the subject.

### Claim 24 (depends on 23)

The method of claim 23, wherein the additional therapeutic agent is selected from the group consisting of an antiviral agent, an ACE2 inhibitors, an additional SARS-CoV-2-Spike-binding antibody, an antibiotic, an antimalarial agent, a vaccine, and combinations thereof.

### Claim 25 (depends on 24)

The method of claim 24, wherein:
a) the additional SARS-CoV-2-Spike-binding antibody is selected from the group consisting of bamlanivimab, etesevimab, bebtelovimab, casirivimab, imdevimab, Cilgavimab, Tixagevimab, AZD7442, Regdanvimab, Sotrovimab and combinations thereof;
b) the antiviral agent is selected from the group consisting of Molnupiravir, PF-07817883, STI-1558, PBI-0451, EDP-235, oseltamivir, favipiravir, amantadine, remdesivir, rimantadine, pleconaril, an anti-sense RNA to SARS-CoV-2, a siRNA to SARS-CoV-2, and combinations thereof;
c) the ACE2 inhibitor is selected from the group consisting of an RNAi to ACE2, a siRNA to ACE2, CRISPR-based inhibitor of ACE2, a soluble ACE2, a soluble ACE2 variant, an anti-ACE2 antibody, and combinations thereof;
d) the antibiotic comprises azithromycin;
e) the antimalarial agent comprises a chloroquine;
f) the vaccine is a nucleic acid vaccine or an inactivated virus vaccine; or
g) a combination thereof.

### Claim 26 (depends on 22)

The method of claim 22, wherein the subject has COVID-19, is suspected of having COVID-19, or is at risk of developing COVID-19.

### Claim 27 (depends on 22)

The method of claim 22, wherein the subject has a heart disease, diabetes, a lung disease, is immune comprised, is on immunosuppressive therapy, or any combination thereof.

### Claim 28 (depends on 1)

A polynucleotide comprising a nucleotide sequence encoding the polypeptide of claim 1.

### Claim 29 (depends on 28)

A host cell comprising the polynucleotide of claim 28.

### Claim 30 (depends on 1)

A method of making the polypeptide of claim 1, comprising culturing a host cell comprising a nucleotide sequence encoding the polypeptide under conditions where the polypeptide is expressed in the host cell.