Compositions for preventing or treating viral and other microbial infections
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) an antibody or antigen binding fragment thereof that specifically binds to a SARS-CoV-2 spike (S) protein; and
(b) a mucoadhesive peptide fragment comprising about 5 to about 50 contiguous positively charged amino acid residues, wherein the mucoadhesive peptide fragment facilitates attachment of the chimeric protein to a mucosa.
2. The chimeric protein of claim 1 , wherein the mucoadhesive peptide fragment comprises at least about 6 contiguous positively charged amino acid residues.
3. The chimeric protein of claim 1 , wherein the chimeric protein comprises two or more mucoadhesive peptide fragments.
4. The chimeric protein of claim 3 , wherein each of the two or more mucoadhesive peptide fragments comprises about 11 to about 15 positively charged amino acid residues.
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 antibody or antigen binding fragment thereof inhibits binding of the SARS-CoV-2 S protein to a receptor of the SARS-CoV-2 S protein on a cell of the mucosa.
9. The chimeric protein of claim 1 , wherein the SARS-CoV-2 S protein is from SARS-CoV-2 or a variant thereof.
10. The chimeric protein of claim 9 , wherein the SARS-CoV-2 or variant thereof is 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.
11. The chimeric protein of claim 1 , wherein the antibody or antigen binding fragment thereof comprises 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, an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 39, 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.
12. The chimeric protein of claim 1 , wherein the antibody or antigen binding fragment thereof comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 75, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 76.
13. The chimeric protein of claim 1 , wherein the antibody or antigen binding fragment thereof comprises:
(1) 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, an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 3, 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) 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, an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 9, 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) 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, an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 15, an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 16, the HC-LDR2 comprises the amino acid sequence of SEQ ID NO: 17, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 18;
(4) 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, an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 21, 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) 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 HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 27, 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) 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, an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 33, 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) 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, an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 45, 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;
(8) 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, an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 51, 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
(9) 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, an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 57, 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.
14. A pharmaceutical composition comprising the chimeric protein of claim 1 and a pharmaceutically acceptable carrier.
15. The pharmaceutical composition of claim 14 , comprising a plurality of chimeric proteins, wherein the antibodies or antigen binding fragments thereof of the chimeric proteins are different from each other.
16. The pharmaceutical composition of claim 14 , wherein the pharmaceutical composition is for nasal administration.
17. An isolated nucleic acid or a set of isolated nucleic acids encoding the chimeric protein of claim 1 .
18. The chimeric protein of claim 1 , wherein the antibody or antigen binding fragment thereof specifically binds an S1 subunit of the S protein of SARS-CoV-2.
19. The chimeric protein of claim 1 , wherein the antibody or antigen binding fragment thereof is a human antibody or antigen binding fragment thereof.
20. The chimeric protein of claim 1 , wherein the antibody is a full-length antibody.
21. The chimeric protein of claim 20 , wherein the full-length antibody is selected from the group consisting of an IgG, an IgA, an IgM, and an IgD.
22. The chimeric protein of claim 1 , wherein the antibody or antigen binding fragment thereof comprises an scFv comprising the amino acid sequence of SEQ ID NO: 87.