# US 11,028,153 B2 · Targeting immunological functions to the site of bacterial infections using cell wall targeting domains of bacteriolysins

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- Number: US 11,028,153 B2
- Document ID: US11028153B2
- Status: Granted
- Kind: B2
- Application number: 16/691,923
- Filed: 2019-11-22
- Published: 2020-07-09
- Granted: 2021-06-08
- Earliest claimed: 2014-01-14
- Assignees: Integrated Biotherapeutics, Inc.
- Applicants: Integrated Biotherapeutics, Inc.
- Inventors: Mohammad Javad Aman; Rajan Prasad Adhikari
- Web page: https://patentgrep.com/patent/US11028153B2

## CPC

- C07K 16/1271: Micrococcaceae (F); Staphylococcaceae (F), e.g. Staphylococcus (G)
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 31/04: Antibacterial agents
- C07K 14/195: from bacteria
- C12N 9/52: derived from bacteria {or Archaea}
- C12Y 304/24075: Lysostaphin (3.4.24.75)
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- C07K 2319/00: Fusion polypeptide
- C07K 2319/70: containing domain for protein-protein interaction
- 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
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- C12Y: ENZYMES
- 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

This disclosure provides a comprehensive approach to specifically target various immune functions to the site of infection by a variety of fusion proteins that consist of a bacteriolysin cell wall targeting domain (CWT) and an immune function mediating component (IFMC). The CWT targets the fusion protein to the bacterial surface leading to accumulation at the site of infection. The IFMC mediates various immune functions such as toxin neutralization or recruitment of immune cells that can clear the bacteria.

## Claims

### Claim 1

A method for treating a bacterial infection, disease, or disorder, comprising administering to a subject in need of treatment an effective amount of a therapeutic polypeptide comprising a cell wall targeting (CWT) domain of a bacteriolysin fused to an immune function mediating component (IFMC) through a peptide linker:
wherein the bacteriolysin is a bacteriocin selected from the group consisting of: Lysostaphin, Bacteriocin AS-48, Bacteriocin ColE9, adherence binding domain DSL peptides of the pilin protein, an E-colicin, Autolysin, and the FyuA binding domain of pesticin fused to the N-terminus of T4 lysozyme, or
wherein the bacteriolysin is a phage encoded lysin selected from the group consisting of: Phage phiKZ gp144 lysin, ϕNM3 lysin, ϕ11 lysin, ϕ68 P17 lysin, ϕB30 lysin, OK LysK lysin, ϕ MR11 MV-L lysin, ϕSs2 PlySs2bacteriophage lysin, OBPgp279 endolysin, PVP-SE1gp146 lysin, E201φ2-1gp229 lysin, Endolysin PlyL, Endolysin PlyG, LambdaSa2 cpl-7 lysin, bacteriophage SM1 lysin, Endolysin CD27L, and mycobacteriophage Ms6 lysin,
wherein the IFMC comprises an antibody or antigen binding fragment thereof to a bacterial toxin or toxoid, or a fragment thereof, wherein the antibody or antigen binding fragment thereof lacks the ability to recognize a bacterial cell wall, and wherein the CWT domain of the therapeutic polypeptide can target the IFMC to a bacterial target.

### Claim 2 (depends on 1)

The method of claim 1, wherein the disease is a respiratory disease.

### Claim 3 (depends on 2)

The method of claim 2, wherein the respiratory disease is pneumonia.

### Claim 4 (depends on 1)

The method of claim 1, wherein the disease is sepsis.

### Claim 5 (depends on 1)

The method of claim 1, wherein the subject is a human.

### Claim 6 (depends on 1)

The method of claim 1, wherein the therapeutic polypeptide or composition is administered via intramuscular injection, intradermal injection, intraperitoneal injection, subcutaneous injection, intravenous injection, oral administration, mucosal administration, intranasal administration, or pulmonary administration.

### Claim 7 (depends on 1)

The method of claim 1, wherein the bacterial toxin or toxoid comprises a Staphylococcus aureus toxin, a Clostridium difficile toxin A (TcdA), a Clostridium difficile toxin B (TcdB), a Clostridium perfringens toxin, a Bacillus anthracis toxin, a Clostridium diphtheria toxin, an E. coli toxin, a Pseudomonas exoprotein A (EPA) or other Pseudomonas aeruginosa toxin, a Vibrio cholerae toxin, a Klebsiella pneumoniae toxin, a pneumolysin or other Streptococcus pneumoniae toxin, a streptolysin, an Enterococcus faecalis toxin, a tetanus toxoid, a pertussis toxoid, a diphtheria toxoid, or a fragment thereof.

### Claim 8 (depends on 7)

The method of claim 7, wherein the Staphylococcus aureus toxin comprises a superantigen, a staphylococcal enterotoxin, a toxic shock syndrome toxin 1 (TSST-1), an alpha hemolysin, a gamma hemolysin, a leukocidin, or any fragment thereof.

### Claim 9 (depends on 1)

The method of claim 1 wherein the therapeutic peptide further comprises a heterologous amino acid sequence.

### Claim 10 (depends on 9)

The method of claim 9, wherein the heterologous amino acid sequence encodes an immunogen, a T-cell epitope, a B-cell epitope, a fragment of any of said heterologous peptides, and a combination of two or more of said heterologous peptides.

### Claim 11 (depends on 1)

The method of claim 1, comprising administering the therapeutic polypeptide and a carrier.

### Claim 12 (depends on 1)

The method of claim 1, wherein the bacteriolysin is the bacteriocin Lysostaphin and the bacterial toxin is a Staphylococcus aureus alpha hemolysin toxin, or a toxoid and/or fragment thereof.

### Claim 13 (depends on 1)

The method of claim 1, wherein the bacteriolysin is the phage encoded lysin Endolysin PlyL and the bacterial toxin is a Bacillus anthracis toxin, or a toxoid and/or fragment thereof.

### Claim 14 (depends on 1)

The method of claim 1, wherein the bacteriolysin is the phage encoded Endolysin CD27L and the bacterial toxin is a Clostridium difficile toxin A (TcdA), or a toxoid and/or fragment of TcdA.

### Claim 15 (depends on 1)

The method of claim 1, wherein the bacteriolysin is the phage encoded lysin Endolysin PlyG and the bacterial toxin is a Bacillus anthracis toxin, or a toxoid and/or fragment thereof.

### Claim 16 (depends on 1)

The method of claim 1, wherein the bacteriolysin is the phage encoded Endolysin CD27L and the bacterial toxin is a Clostridium difficile toxin B (TcdB), or a toxoid and/or fragment of TcdB.

### Claim 17 (depends on 1)

The method of claim 1, wherein the bacteriolysin is the phage encoded ϕSs2 PlySs2bacteriophage lysin, and the bacterial toxin is a pneumolysin, or a toxoid and/or fragment thereof.

### Claim 18 (depends on 1)

The method of claim 1, wherein the bacteriolysin is the phage encoded bacteriophage SM1 lysin, and the bacterial toxin is a pneumolysin, or a toxoid and/or fragment thereof.

### Claim 19 (depends on 1)

The method of claim 1, wherein the bacteriolysin is the phage encoded ϕSs2 PlySs2bacteriophage lysin, and the bacterial toxin is a Streptococcus pneumoniae toxin other than a pneumolysin, or a toxoid and/or fragment thereof.

### Claim 20 (depends on 1)

The method of claim 1, wherein the bacteriolysin is the phage encoded bacteriophage SM1 lysin, and the bacterial toxin is a Streptococcus pneumoniae toxin other than a pneumolysin, or a toxoid and/or fragment thereof.