Compositions for preventing or treating viral and other microbial infections

Abstract

The present application relates to compositions for preventing or treating viral and other microbial infections. In some embodiments, the present application provides chimeric proteins comprising a target-binding moiety that specifically binds to a pathogen that infects through a mucosa, and a positively charged mucoadhesive peptide fragment. Also provided are antibodies and constructs thereof that specifically binds to an S1 subunit of a spike protein of SARS-CoV-2. Compositions comprising the chimeric proteins, antibodies, or constructs described herein are useful for preventing or treating a microbial infection in an individual, such as a coronavirus infection.

1 . A chimeric protein comprising: (a) a target-binding moiety that specifically binds to a component of a pathogen that infects through a mucosa; and (b) a mucoadhesive peptide fragment comprising no more than about 5 contiguous positively charged amino acid residues, wherein the mucoadhesive peptide fragment facilitates attachment of the chimeric protein to the mucosa, and wherein the mucoadhesive peptide fragment has an isoelectric point (pI) higher than the pH of the mucosa. 
     
     
         2 . (canceled) 
     
     
         3 . The chimeric protein of  claim 1 , wherein the chimeric protein comprises two or more mucoadhesive peptide fragments. 
     
     
         4 . (canceled) 
     
     
         5 . The chimeric protein of  claim 1 , wherein the positively charged amino acid residues are selected from the group consisting of lysine, arginine, histidine, ornithine, and combinations thereof. 
     
     
         6 . The chimeric protein of  claim 5 , wherein the positively charged amino acid residues are lysines. 
     
     
         7 . The chimeric protein of  claim 5 , wherein the positively charged amino acid residues are histidines. 
     
     
         8 . The chimeric protein of  claim 1 , wherein the target-binding moiety comprises an inhibitory polypeptide that inhibits binding of the component of the pathogen to a receptor on a cell of the mucosa. 
     
     
         9 . The chimeric protein of  claim 8 , wherein the inhibitory polypeptide comprises a natural receptor of the component of the pathogen or a fragment derived from the natural receptor. 
     
     
         10 . The chimeric protein of  claim 9 , wherein the inhibitory polypeptidecomprises an extracellular binding domain (EBD) of ACE2. 
     
     
         11 . The chimeric protein of  claim 1 , wherein the target-binding moiety comprises an antibody moiety or an antigen binding fragment thereof that specifically binds the component of the pathogen. 
     
     
         12 . The chimeric protein of  claim 1 , wherein the pathogen is a virus that causes a respiratory infection, and wherein the virus is selected from the group consisting of coronaviruses, respiratory syncytial viruses, influenza viruses, and adenoviruses. 
     
     
         13 . The chimeric protein of  claim 12 , wherein the virus is a coronavirus selected from the group consisting of SARS-CoV, SARS-CoV-2, MERS-CoV, and variant thereof. 
     
     
         14 . The chimeric protein of  claim 13 , wherein the virus is SARS-CoV-2 or a variant thereof selected from the group consisting of WIV4, a B.1.1.7 variant, a B.1.351 variant, a B.1.526 variant, a B1.526.1 variant, a B1.617 variant, a B.1.617.1 variant, a B.1.617.2 variant, a B1.617.3 variant, a P.2 variant, a P.1 variant, an A.23.1 variant, a CAL.20C variant, a B.1.427 variant, a B.1.429 variant, a B.1.525 variant, and a P.1.351 variant. 
     
     
         15 . The chimeric protein of  claim 14 , wherein the component of the pathogen is a spike (S) protein. 
     
     
         16 . The chimeric protein of  claim 15 , wherein the target-binding_moiety comprises an antibody moiety or an antigen binding fragment thereof that specifically binds the S protein, wherein the antibody moiety or antigen binding fragment thereof comprises a heavy chain variable region (V H ) comprising a heavy chain complementarity determining region (HC-CDR)1 comprising the amino acid sequence of SEQ ID NO: 37, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 39; and a light chain variable region (V L)  comprising a light chain complementarity determining region (LC-CDR)1 comprising the amino acid sequence of SEQ ID NO: 40, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 41, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 42. 
     
     
         17 . The chimeric protein of  claim 16 , wherein the target-binding moiety comprises a V H  comprising an amino acid sequence having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 75, and a V L  comprising an amino acid sequence having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 76. 
     
     
         18 . A method of preventing or treating an infection caused by a pathogen that infects through a mucosa in an individual, comprising administering to the individual an effective amount of the chimeric protein of  claim 1 . 
     
     
         19 - 20 . (canceled) 
     
     
         21 . The chimeric protein of  claim 15 , wherein the target-binding moiety comprises an antibody moiety or an antigen binding fragment thereof that specifically binds the S protein, and wherein the antibody moiety or antigen binding fragment thereof comprises: 
 (1) a V H  comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 2, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 3; and a V L  comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 4, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 6;   (2) a V H  comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 7, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 8, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 9; and a V L  comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 10, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 11, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 12;   (3) a V H  comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 13, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 14, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 15; and a V L  comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 16, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 17, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 18;   (4) a V H  comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 19, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 20, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 21; and a V L  comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 22, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 23, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 24;   (5) a VH comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 25, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 27; and a V L  comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 28, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 29, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 30;   (6) a V H  comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 31, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 32, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 33; and a V L  comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 34, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 35, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 36;   (7) a V H  comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 37, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 39; and a V L  comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 40, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 41, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 42;   (8) a V H  comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 43, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 44, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 45; and a V L  comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 46, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 47, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 48;   (9) a V H  comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 49, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 50, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 51; and a V L  comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 52, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 53, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 54; or   (10) a V H  comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 55, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 56, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 57; and a V L  comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 58, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 59, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 60.   
     
     
         22 . (canceled) 
     
     
         23 . A pharmaceutical composition comprising the chimeric protein of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         24 . The pharmaceutical composition of  claim 23 , comprising a plurality of the chimeric proteins, and wherein the target-binding moieties of the chimeric proteins are different from each other. 
     
     
         25 . (canceled) 
     
     
         26 . The pharmaceutical composition of  claim 23 , wherein the pharmaceutical composition is for nasal administration. 
     
     
         27 . An isolated nucleic acid or a set of isolated nucleic acids encoding the chimeric protein of  claim 1 . 
     
     
         28 - 29 . (canceled) 
     
     
         30 . The chimeric protein of  claim 11 , wherein the antibody moiety is a full-length antibody. 
     
     
         31 . The chimeric protein of  claim 30 , wherein the full-length antibody is selected from the group consisting of an IgG, an IgA, an IgM, and an IgD. 
     
     
         32 . The chimeric protein of  claim 11 , wherein the target-binding moiety comprises an scFv comprising an amino acid sequence having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 87.