Compositions and methods for preventing the spread of viruses

Abstract

The present application relates to compositions and methods for: (a) preventing or treating viral infections; and / or (b) preventing the transmission and / or spread of infections. In some embodiments, the present application provides chimeric proteins comprising a target-binding moiety that specifically binds to a virus, and a positively charged mucoadhesive peptide fragment. Compositions comprising the chimeric proteins described herein are useful for preventing or treating viral infections, preventing the transmission of a viral infection from an infected individual to a non-infected individual, and for preventing the spread of a viral infection within a population of individuals.

Description

COMPOSITIONS AND METHODS FOR PREVENTING THE SPREAD OF VIRUSESCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority benefit of U.S. Provisional Application No. 63 / 677378, filed July 30, 2024, the content of which is hereby incorporated by reference in its entirety.REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0002] The content of the electronic sequence listing (SeqListing-ETI-2024-02-WO-PCT-l.xml, 894,056 bytes; and Date of Creation: July 29,2025) is herein incorporated by reference in its entirety.I FIELD OF THE INVENTION

[0003] The invention relates to compositions and methods for: (a) preventing or treating viral infections; and / or (b) preventing transmission or spread of viruses. In particular, the invention relates to: (a) preventing or treating influenza, RSV, and / or coronavirus infections; and (b) preventing transmission of a virus from an individual infected with the virus to an individual not infected with the virus thereby preventing the spread of viruses within a vulnerable population of individuals.BACKGROUND

[0004] Respiratory microbial infections, including viral infections, are a leading cause of adult and pediatric illness and mortality worldwide. There is a large unmet need for novel methods that effectively prevent the transmission and spread of these viral infections. For example, infectious large droplets or aerosols of small droplets can mediate infection by respiratory viruses, including the three major pathogenic viruses affecting humans SARS-CoV-2, influenza, and respiratory syncytial virus (RSV). These viruses principally enter through the nose where initial replication occurs. The virus progressively spreads to the upper airwaysand finally penetrates into the lungs. Currently, facemasks provide an imperfect first line of defense primarily acting as a physical barrier to viral entry or exit. Discovery efforts are urgently needed on both the prevention and therapeutic fronts to halt the transmission of these viruses that carry high morbidity and mortality.

[0005] CDC initially estimated that, from October 1, 2023 - June 15, 2024, influenza would have caused 35-65 million illnesses (actual number about 40 million), 16-30 million medical visits (actual number about 18 million), 390,000-830,000 hospitalizations (actual number about 470,000), and 25,000-72,000 flu deaths (actual number about 28,000) in the U.S. CDC estimates that, from October 1, 2024 - May 17, 2025, influenza will have caused 47-82 million illnesses, 21-37 million medical visits, 610,000-1.3 million hospitalizations, and 27,000-130,000 flu deaths (www.cdc.gov / flu / about / burden / preliminary-in-season- estimates.htm). New data on SARS-CoV-2 is less complete as the virus has become endemic and reported testing has decreased, but the disease it caused, COVID-19, remains a serious public health issue, especially in people who are more than 65 years old, immunocompromised, or diabetic. SARS-CoV-2 is approximately 2.8 times as infectious as influenza, making it one of the most transmissible viruses known among humans. Rates of hospitalization for >65 year old individuals are nearly 10 times higher for SARS-CoV-2 than influenza and death rates are 3-4 times higher. Even in the post-pandemic period, roughly 500-600 people die of COVID-19 weekly in the United States, and approximately 10% of infected individuals develop symptoms of Long COVID (www.ahcancal.org / News-and- Communications / Blog / Pages / Flu-or-COVID-19 — Which-is-Worse.aspx; Lancet Infect Dis. 2020 Sep;20(9):e238-e244). RSV infections are a more common cause of death in children under 1 year of age than influenza infections, and RSV is more lethal in adults over the age of 65 than in children, causing roughly 11,000 deaths per year in the United States (Hansen CL, Chaves SS, Demont C, Viboud C. JAMA Netw Open. 2022;5(2):e220527).

[0006] Moreover, during the COVID-19 pandemic, an increased likelihood of co-infections of RSV and SARS-CoV-2 among children was also observed. In addition, influenza viruses were also identified as a significant risk in exacerbating pre-existing lung disease in older patients during the COVID-19 pandemic (Teluguakula N, et al. Viruses. 2024; 16(5):793).

[0007] While there are FDA approved vaccines against each of these three viral species, vaccines are not safe for certain patients (e.g., people with severe allergies or myocarditis) and can become obsolete quickly (within a year or even a few months) due to rapid viral antigen sequence mutations or incorrect prediction of prevalent viral strains. Safer, broader- spectrum, and more cost-effective protectives and administration methods are needed to prevent or reduce infections caused by influenza, RSV, and SARS-CoV2 or to prevent or reduce the transmission of these viruses among humans.BRIEF SUMMARYThe present application provides compositions and methods for: (a) preventing or treating viral infections; and / or (b) preventing transmission or spread of viruses.In some aspects, the present application provides compositions and methods for preventing the transmission or spread of an infection caused by a virus or a variant thereof. Thus, one aspect of the present application provides a method of preventing transmission of a virus from an individual infected with the virus to an individual not infected with the virus, comprising administering to the individual infected with the virus an effective amount of a chimeric protein, wherein the chimeric protein comprises: (a) a target-binding moiety that specifically binds to the virus; and (b) a mucoadhesive peptide fragment, wherein the mucoadhesive peptide fragment facilitates attachment of the chimeric protein to a mucosa, thereby preventing transmission of the virus to the individual not infected with the virus.In some aspects, there is provided a method of preventing spread of a virus within a population of individuals, wherein at least one of the individuals is infected with the virus, the method comprising administering to the at least one individual infected with the virus with an effective amount of a chimeric protein, wherein the chimeric protein comprises: (a) a target-binding moiety that specifically binds to the virus; and (b) a mucoadhesive peptide fragment, wherein the mucoadhesive peptide fragment facilitates attachment of the chimeric protein to a mucosa, thereby preventing transmission of the virus to another individual or individuals not infected with the virus in the population.In some embodiments according to (or as applied to) any of the embodiments above, the transmission is via small respiratory droplets.In some embodiments according to (or as applied to) any of the embodiments above, the transmission is via aerosol.In some embodiments according to (or as applied to) any of the embodiments above, the transmission is via large respiratory droplets.In some embodiments according to (or as applied to) any of the embodiments above, the administration is intranasal administration.In some embodiments according to (or as applied to) any of the embodiments above, the mucosa is selected from the group consisting of a nasal mucosa, nasopharyngeal mucosa, and posterior oropharyngeal mucosa.In some embodiments according to (or as applied to) any of the embodiments above, the individual infected with the virus or the at least one individual infected with the virus is a human, and the effective amount is between about 1 μg and about 500 ug per nostril. In some embodiments according to (or as applied to) any of the embodiments above, the effective amount is between about 10 μg and about 100 μg per nostril.In some embodiments according to (or as applied to) any of the embodiments above, the individual not infected with the virus is 50 years or older. In some embodiments according to (or as applied to) any of the embodiments above, the individual not infected with the virus is immunocompromised. In some embodiments according to (or as applied to) any of the embodiments above, the individual infected with the virus or the at least one individual infected with the virus shows no symptom of the infection. In some embodiments according to (or as applied to) any of the embodiments above, the individual infected with the virus or the at least one individual infected with the virus is under treatment for the virus infection before, concurrently with, or after the administration of the chimeric protein.In some embodiments according to (or as applied to) any of the embodiments above, the method further comprises identifying the individual infected with the virus or the at least one individual infected with the virus prior to the administration of the chimeric protein. In some embodiments according to (or as applied to) any of the embodiments above, the identification is via a screening process.In some embodiments according to (or as applied to) any of the embodiments above, the chimeric protein is administered within 14 days after a symptom is detected in the individual infected with the virus. In some embodiments according to (or as applied to) any of theembodiments above, the individual infected with the virus or the at least one individual infected with the virus has been vaccinated against the virus prior to infection, and where the chimeric protein is administered within 1, 2, 3, 4, 5, 6, or 7 days after a symptom is detected in the individual infected with the virus. In some embodiments according to (or as applied to) any of the embodiments above, the individual infected with the virus or the at least one individual infected with the virus has not been vaccinated against the virus prior to infection, and where the chimeric protein is administered within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days after a symptom is detected in the individual infected with the virus. In some embodiments according to (or as applied to) any of the embodiments above, the chimeric protein is administered within 4 days after a symptom is detected in the individual infected with the virus. In some embodiments according to (or as applied to) any of the embodiments above, the chimeric protein is administered within 3 days after a symptom is detected in the individual infected with the virus. In some embodiments according to (or as applied to) any of the embodiments above, the chimeric protein is administered within 2 days after a symptom is detected in the individual infected with the virus. In some embodiments according to (or as applied to) any of the embodiments above, the chimeric protein is administered within 1 day after a symptom is detected in the individual infected with the virus.In some embodiments according to (or as applied to) any of the embodiments above, the chimeric protein is administered within 14 days after identification of the individual infected with the virus. In some embodiments according to (or as applied to) any of the embodiments above, the individual infected with the virus or the at least one individual infected with the virus has been vaccinated against the virus prior to infection, and where the chimeric protein is administered within 1, 2, 3, 4, 5, 6, or 7 days after identification of the individual infected with the virus. In some embodiments according to (or as applied to) any of the embodiments above, the individual infected with the virus or the at least one individual infected with the virus has not been vaccinated against the virus prior to infection, and where the chimeric protein is administered within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days after identification of the individual infected with the virus. In some embodiments according to (or as applied to) any of the embodiments above, the chimeric protein is administered within 4 days after identification of the individual infected with the virus. In some embodiments according to (or as applied to) any of the embodiments above, the chimeric protein is administered within 3 days after identificationof the individual infected with the virus. In some embodiments according to (or as applied to) any of the embodiments above, the chimeric protein is administered within 2 days after identification of the individual infected with the virus. In some embodiments according to (or as applied to) any of the embodiments above, the chimeric protein is administered within 1 day after identification of the individual infected with the virus.In some embodiments according to (or as applied to) any of the embodiments above, the individual not infected with the virus is also administered with the chimeric protein. In some embodiments according to (or as applied to) any of the embodiments above, the individual not infected with the virus is not administered with the chimeric protein.In some embodiments according to (or as applied to) any of the embodiments above, the mucoadhesive peptide fragment comprises at least about 5 positively charged amino acid residues. In some embodiments according to (or as applied to) any of the embodiments above, the mucoadhesive peptide fragment comprises at least about 5 contiguous positively charged amino acids. In some embodiments according to (or as applied to) any of the embodiments above, the positively charged amino acid residues are interspersed with one or more non- positively charged amino acid residues. In some embodiments according to (or as applied to) any of the embodiments above, at least about 50% of the amino acid residues in the mucoadhesive peptide fragment are positively charged amino acid residues.In some embodiments according to (or as applied to) any of the embodiments above, the chimeric protein comprises a single polypeptide chain. In some embodiments according to (or as applied to) any of the embodiments above, the chimeric protein comprises two or more polypeptide chains. In some embodiments according to (or as applied to) any of the embodiments above, the chimeric protein comprises two or more mucoadhesive peptide fragments. In some embodiments according to (or as applied to) any of the embodiments above, each of the two or more mucoadhesive peptide fragments comprises at least about 5 positively charged amino acid residues. In some embodiments according to (or as applied to) any of the embodiments above, the positively charged amino acid residues are selected from the group consisting of lysine, arginine, histidine, ornithine, and combinations thereof.In some embodiments according to (or as applied to) any of the embodiments above, the mucoadhesive peptide fragment: (i) is no more than about 15 kDa; (ii) has an isoelectric point (pl) higher than the pH of the mucosa; (iii) does not facilitate penetration of the chimeric proteininto a cell of the mucosa; (iv) does not disrupt folding of the chimeric protein within a host cell expressing the chimeric protein; (v) does not block secretion of the chimeric protein from a host cell expressing the chimeric protein; and / or (vi) does not interfere with the binding between the target-binding moiety and the virus.In some embodiments according to (or as applied to) any of the embodiments above, the mucoadhesive peptide fragment is fused to the target-binding moiety via a peptide linker. In some embodiments according to (or as applied to) any of the embodiments above, the peptide linker comprises: (i) one or more oligomerization and / or multimerization domains; (ii) the constant region of a heavy chain of a full-length antibody or a fragment thereof, or the constant region of a light chain of a full-length antibody or a fragment thereof; (iii) an Fc region or a fragment thereof; (iv) a CHi, CH2, CH3, CPU, and / or CL domain or a fragment thereof; (v) an antibody hinge domain or a fragment thereof; (vi) a detectable enzymatic tag, optionally wherein the enzymatic tag is an alkaline phosphatase and / or a glutathione-s-transferase; (vii) a basic helix-loop-helix leucine zipper (bZIP) domain, bZIP isoleucine zipper domain, and / or bZIP- leucine / isoleucine zipper domain; (viii) a collagen-like peptide; (ix) a p53 tetramerization domain; (x) a streptavidin (SA) protein, optionally wherein the peptide linker further comprises a dextran scaffold or one or more maleimide polymers (DMGS); (xi) a bacteriophage T7 fibritin protein or a portion thereof; and / or (xii) a cartilage oligomeric matrix protein (COMP) protein. In some embodiments according to (or as applied to) any of the embodiments above, the mucoadhesive peptide fragment is fused to a C-terminus of the target-binding moiety.In some embodiments according to (or as applied to) any of the embodiments above, the virus is a virus that causes respiratory infection. In some embodiments according to (or as applied to) any of the embodiments above, the virus is selected from the group consisting of coronaviruses, respiratory syncytial viruses (RSV), and influenza viruses.In some embodiments according to (or as applied to) any of the embodiments above, the virus is a coronavirus selected from the group consisting of SARS-CoV, SARS-CoV-2, and a variant, subtype, or reassortant thereof. In some embodiments according to (or as applied to) any of the embodiments above, the virus is SARS-CoV-2 or a variant, subtype, or reassortant thereof, selected from the group consisting of WIV4, a B.1.1.7 variant, a B.1.351 variant, a Delta (B.1.617.1) variant, an A.23.1 variant, a B.1.525 variant, a BA.2 variant, a BA.5.1.1 variant, a BQ. l variant, an XBB.1.5 variant, a BA.2.86 variant, a JN.l variant, a KP.1.1 variant, aJN.1.13.1 variant, a JN.1.16 variant, a JN.1 .7 variant, a KQ.1 variant, a JN.1 .8.1 variant, a JN.1.11.1 variant, a JN.1.18 variant, a KP.2 (also known as JN.1.11.1.2) variant, a BA.1 variant, a KP.3 variant, an LB. l variant, an XEC variant, an LF.7 variant, an LP.8.1 variant, an NB.1.8.1 variant and an XFG variant . In some embodiments according to (or as applied to) any of the embodiments above, the target-binding moiety specifically binds to a spike (S) protein of SARS- CoV-2. In some embodiments according to (or as applied to) any of the embodiments above, the target-binding moiety comprises an inhibitory polypeptide that inhibits binding of the virus to a receptor on a cell of the mucosa. In some embodiments according to (or as applied to) any of the embodiments above, the target-binding moiety comprises a natural receptor of the virus or a variant derived from the natural receptor of the virus. In some embodiments according to (or as applied to) any of the embodiments above, the target-binding moiety comprises an extracellular binding domain (EBD) of an angiotensin-converting enzyme 2 (ACE2) protein or a variant thereof. In some embodiments according to (or as applied to) any of the embodiments above, the target-binding moiety comprises the EBD of a human ACE2 (hACE2) protein or a variant thereof. In some embodiments according to (or as applied to) any of the embodiments above, the target-binding moiety comprises: (i) amino acids 24-42 of a full-length hACE2 protein, or a variant thereof having at least about 90% sequence identity to amino acids 24-42 of a full-length hACE2 protein; and / or (ii) the amino acid sequence of SEQ ID NO: 254, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 254. In some embodiments according to (or as applied to) any of the embodiments above, the targetbinding moiety comprises the amino acid sequence of any one of SEQ ID NOs: 246-253 and 256-261, or a variant thereof having at least about 90% sequence identity the amino acid sequence of any one of SEQ ID NOs: 246-253 and 256-261. In some embodiments according to (or as applied to) any of the embodiments above, the chimeric protein comprises the amino acid sequence of any one of SEQ ID NOs: 1-10, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 1-10. In some embodiments according to (or as applied to) any of the embodiments above, the target-binding moiety comprises the EBD of an animal ACE2 protein or a variant thereof. In some embodiments according to (or as applied to) any of the embodiments above, the target-binding moiety comprises: (i) amino acids 30-41 of a full-length animal ACE2 protein, or a variant thereof having at least about 90% sequence identity to amino acids 30-41 of a full-length animalACE2 protein, wherein the full-length animal ACE2 protein is not a chicken or canine ACE2 protein; or (ii) amino acids 29-40 of a full-length animal ACE2 protein, or a variant thereof having at least about 90% sequence identity to amino acids 29-40 of a full-length animal ACE2 protein, wherein the full-length animal ACE2 protein is a chicken or canine ACE2 protein. In some embodiments according to (or as applied to) any of the embodiments above, the targetbinding moiety comprises the amino acid sequence of any one of SEQ ID NOs: 262-287, or a variant thereof having at least about 90% sequence identity to any one of SEQ ID NOs: 262-287. In some embodiments according to (or as applied to) any of the embodiments above, the chimeric protein comprises the amino acid sequence of any one of SEQ ID NOs: 11-15, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 11-15.In some embodiments according to (or as applied to) any of the embodiments above, the targetbinding moiety comprises an antibody moiety. In some embodiments according to (or as applied to) any of the embodiments above, the antibody moiety is: (i) a full-length antibody; or(ii) an antigen-binding fragment selected from the group consisting of a Fab, a Fab’, a (Fab’)2, an Fv, a single chain Fv (scFv), a disulfide stabilized Fv fragment (dsFv), a (dsFv)2, an scFv dimer, a domain antibody, a single domain antibody, a bivalent domain antibody, and a minibody.In some embodiments according to (or as applied to) any of the embodiments above, the targetbinding moiety comprises: (i) an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 192, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 193, an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 194, an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 195, an LC-CDR2 comprising the amino acid sequence of VSN, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 197; (ii) an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 156, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 157, an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 158, an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 159, an LC- CDR2 comprising the amino acid sequence of SNN, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 161; (iii) an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 162, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 163, an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 164, an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 165, an LC-CDR2 comprising the amino acid sequenceof EDK, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 167; (iv) an HC- CDR1 comprising the amino acid sequence of SEQ ID NO: 168, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 169, an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 170, an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 171, the HC-LDR2 comprises the amino acid sequence of RNN, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 173; (v) an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 174, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 175, an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 176, an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 177, an LC-CDR2 comprising the amino acid sequence of FND, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 179; (vi) an HC- CDR1 comprising the amino acid sequence of SEQ ID NO: 180, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 181, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 182, an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 183, an LC-CDR2 comprising the amino acid sequence of EVS, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 185; (vii) an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 186, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 187, an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 188, an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 189, an LC-CDR2 comprising the amino acid sequence of SNN, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 191; (viii) an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 198, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 199, an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 200, an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 201, an LC-CDR2 comprising the amino acid sequence of EVS, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 203; (viv) an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 204, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 205, an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 206, an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 207, an LC-CDR2 comprising the amino acid sequence of SNN, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 209; or (x) an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 210, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 211, an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 212, an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 213, anLC-CDR2 comprising the amino acid sequence of GND, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 215.In some embodiments according to (or as applied to) any of the embodiments above, the virus is an influenza virus selected from the group consisting of a Type A influenza virus (IAV), a Type B influenza virus (IBV), a Type C influenza virus (ICV), a Type D influenza virus (IDV), or a variant, subtype, or reassortant thereof. In some embodiments according to (or as applied to) any of the embodiments above, the influenza virus comprises a hemagglutinin (HA) antigen selected from the group consisting of Hl, H2, H3, H5, H6, H7, H9, and H10, or a variant or reassortant thereof. In some embodiments according to (or as applied to) any of the embodiments above, the influenza virus comprises a neuraminidase (NA) antigen selected from the group consisting of Nl, N2, N3, N7, N8, and N9, or a variant or reassortant thereof. In some embodiments according to (or as applied to) any of the embodiments above, the influenza virus is selected from the group consisting of H1N1, H1N2, H2N2, H3N2, H3N8, H5N1, H5N9, H6N1, H7N2, H7N3, H7N7, H7N9, H9N2, H10N7, or a variant or reassortant thereof.In some embodiments according to (or as applied to) any of the embodiments above, the targetbinding moiety specifically binds HA. In some embodiments according to (or as applied to) any of the embodiments above, the target-binding moiety comprises: (i) a heavy chain complementarity determining region (HC-CDR) 1 comprising the amino acid sequence of SEQ ID NO: 310, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 311, and an HC- CDR3 comprising the amino acid sequence of SEQ ID NO: 312, a light chain complementarity determining region (LC-CDR) 1 comprising the amino acid sequence of SEQ ID NO: 313, an LC-CDR2 comprising the amino acid sequence of WAS, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 315; (ii) an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 318, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 319, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 320, an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 321, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 322, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 323; (iii) an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 416, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 417, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 418, an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 419, an LC-CDR2 comprising the amino acid sequence of SND,and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 421 ; (iv) a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO: 308, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO:308, and a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO:309, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 309; (v) a VH comprising the amino acid sequence of SEQ ID NO: 316, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 316, and a VL comprising the amino acid sequence of SEQ ID NO: 317, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 317; (vi) a VH comprising the amino acid sequence of SEQ ID NO: 414, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 414, and a VL comprising the amino acid sequence of SEQ ID NO: 415, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 415; (vii) a heavy chain (HC) polypeptide comprising the amino acid sequence of SEQ ID NO: 659, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO:659, and a light chain (LC) polypeptide comprising the amino acid sequence of SEQ ID NO: 17, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 17; (viii) an HC polypeptide comprising the amino acid sequence of SEQ ID NO:660, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 660, and an LC polypeptide comprising the amino acid sequence of SEQ ID NO: 46, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 46; (ix) an HC polypeptide comprising the amino acid sequence of SEQ ID NO:661, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 661, and an LC polypeptide comprising the amino acid sequence of SEQ ID NO: 66, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 66; (x) a first and a second polypeptide chain each independently comprising the amino acid sequence of any one of SEQ ID NOs: 16 and 18-44, or a variant thereof comprising at least about 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 16 and 18-44, and a third and a fourth polypeptide chain each independently comprising the amino acid sequence of SEQ ID NO: 17, or a variant thereof comprising at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 17; (xi) a first and a second polypeptidechain each independently comprising the amino acid sequence of any one of SEQ ID NOs: 45 and 47-64, or a variant thereof comprising at least about 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 45 and 47-64, and a third and a fourth polypeptide chain each independently comprising the amino acid sequence of SEQ ID NO: 46, or a variant thereof comprising at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 46; or (xii) a first and a second polypeptide chain each independently comprising the amino acid sequence of any one of SEQ ID NOs: 65 and 67-104, or a variant thereof comprising at least about 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 65 and 67- 104, and a third and a fourth polypeptide chain each independently comprising the amino acid sequence of SEQ ID NO: 66, or a variant thereof comprising at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 66.In some embodiments according to (or as applied to) any of the embodiments above, the targetbinding moiety specifically binds NA. In some embodiments according to (or as applied to) any of the embodiments above, the target-binding moiety comprises: (i) an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 432, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 433, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 434, an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 435, an LC-CDR2 comprising the amino acid sequence of AAS, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 437; (ii) an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 440, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 441, and an HC- CDR3 comprising the amino acid sequence of SEQ ID NO: 442, an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 443, an LC-CDR2 comprising the amino acid sequence of GAS, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 445; (iii) a VH comprising the amino acid sequence of SEQ ID NO: 430, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 430, and a VL comprising the amino acid sequence of SEQ ID NO: 431, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 431; (iv) a VH comprising the amino acid sequence of SEQ ID NO: 438, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 438, and a VL comprising the amino acid sequence of SEQ ID NO: 439, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 439; (v) an HCpolypeptide comprising the amino acid sequence of SEQ ID NO: 657, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 657, and an LC polypeptide comprising the amino acid sequence of SEQ ID NO: 106, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 106; (vi) an HC polypeptide comprising the amino acid sequence of SEQ ID NO: 658, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 658, and an LC polypeptide comprising the amino acid sequence of SEQ ID NO: 126, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 126; (vii) a first and a second polypeptide chain each independently comprising the amino acid sequence of any one of SEQ ID NOs: 105 and 107-124, or a variant thereof comprising at least about 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 105 and 107-124, and a third and a fourth polypeptide chains each independently comprising the amino acid sequence of SEQ ID NO: 106, or a variant thereof comprising at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 106; or (viii) a first and a second polypeptide chain each independently comprising the amino acid sequence of any one of SEQ ID NOs: 125 and 127- 144, or a variant thereof comprising at least about 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 125 and 127-144, and a third and a fourth polypeptide chains each independently comprising the amino acid sequence of SEQ ID NO: 126, or a variant thereof comprising at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 126.In some embodiments according to (or as applied to) any of the embodiments above, the individual not infected with the virus or the individual(s) not infected with the virus in the population is / are not administered the chimeric protein. In some embodiments according to (or as applied to) any of the embodiments above, the individual not infected with the virus is administered the chimeric protein, or at least some of the individuals not infected with the virus in the population are administered the chimeric protein.In some embodiments according to (or as applied to) any of the embodiments above, the administering of the chimeric protein to the individual infected with the virus or the at least one individual infected with the virus lowers transmission of the virus by at least about 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% as compared to a reference. In some embodiments according to (or as applied to) any of the embodiments above, the administering of the chimericprotein to the individual infected with the virus or the at least one individual infected with the virus lowers transmission of the virus by at least about 50% as compared to the reference. In some embodiments according to (or as applied to) any of the embodiments above, the individual infected with the virus or the at least one individual infected with the virus does not transmit the virus to any other individuals after being administered the chimeric protein.In some embodiments according to (or as applied to) any of the embodiments above, wherein compared to a reference, the administering of the chimeric protein to the individual infected with the virus or the at least one individual infected with the virus: (i) lowers the chance of the virus being transmitted to the individual not infected with the virus or the individual(s) not infected with the virus in the population by at least about 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%; and / or (ii) lowers the proportion of individuals in the population becoming infected with the virus by at least about 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some embodiments according to (or as applied to) any of the embodiments above, wherein compared to the reference, the administering of the chimeric protein to the individual infected with the virus or the at least one individual infected with the virus: (i) lowers the chance of the virus being transmitted to the individual not infected with the virus or the individual(s) not infected with the virus in the population by at least about 50%; and / or (ii) lowers the proportion of individuals in the population becoming infected with the virus by at least about 50%. In some embodiments according to (or as applied to) any of the embodiments above, the individual infected with the virus or the at least one individual infected with the virus does not transmit the virus to any other individuals after being administered the chimeric protein. In some embodiments according to (or as applied to) any of the embodiments above, the reference is: (i) the same individual infected with the virus before the individual is administered the chimeric protein; (ii) another individual who is infected with the virus but is not administered the chimeric protein; (iii) not all of the at least one individual infected with the virus in the population is administered the chimeric protein; (iv) none of the at least one individual infected with the virus in the population is administered the chimeric protein; (v) a reference population, wherein the reference population has identical proportion, or no more than about 5% variation in the proportion, of individual(s) infected with the virus, wherein not all of the individual(s) infected with the virus is administered the chimeric protein, and optionally wherein the proportion of individual(s) in the reference population who is / are not infected with the virus but is / are administered the chimeric protein (uninfected butchimeric protein-administered proportion) is identical to or no more than about 5% variation from the uninfected but chimeric protein-administered proportion in the population recited in any one of the embodiments above; and / or (vi) a reference population, wherein the reference population has identical proportion, or no more than about 5% variation in the proportion, of individual(s) infected with the virus, wherein none of the individual(s) infected with the virus is administered the chimeric protein, and optionally wherein the uninfected but chimeric protein- administered proportion in the reference population is identical to or no more than about 5% variation from the uninfected but chimeric protein-administered proportion in the population recited in any one of the embodiments above.Also provided are kits and articles of manufacture (e.g., a nasal spray medicament) comprising any one of the compositions described above and instructions for any one of the methods described above.In some other aspects, the present application provides compositions and methods for preventing or treating influenza, RSV, and / or coronavirus infections.In some aspects, there is provided an antibody moiety that specifically binds to a component of an influenza virus or a variant thereof, wherein the antibody moiety comprises: (a) a HC- CDR1 comprising the amino acid sequence of SEQ ID NO: 754 ; (b) a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 755 ; (c) a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 756 ; (d) a LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 757 ; (e) a LC-CDR2 comprising the amino acid sequence VDS; and (f) a LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 759 .In some embodiments according to (or as applied to) any of the embodiments above, the antibody moiety comprises (a) a VH comprising the amino acid sequence of SEQ ID NO:730 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 730; and (b) a VL comprising the amino acid sequence of SEQ ID NO: 731 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 731.In some aspects, there is provided a chimeric protein comprising an antibody moiety according to any of the embodiments above, and a mucoadhesive peptide fragment comprising at leastabout 5 positively charged amino acid residues, wherein the mucoadhesive peptide fragment facilitates attachment of the chimeric protein to a mucosa.In some aspects, there is provided a chimeric protein comprising: (a) an antibody moiety that specifically binds to a component of a RSV or a variant thereof, the antibody moiety further comprising: (i) a HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 689 ; (ii) a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 690 ; (iii) a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 691 ; (iv) a LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 692 ; (v) a LC-CDR2 comprising the amino acid sequence DTS; and (vi) a LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 694 ; and the chimeric protein further comprising (b) a mucoadhesive peptide fragment comprising at least about 5 positively charged amino acid residues, wherein the mucoadhesive peptide fragment facilitates attachment of the chimeric protein to a mucosa.In some embodiments according to (or as applied to) any of the embodiments above, the chimeric protein according to above embodiments, wherein the antibody moiety comprises: (a) a VH comprising the amino acid sequence of SEQ ID NO: 687 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 687; and (b) a VL comprising the amino acid sequence of SEQ ID NO: 688 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 688.In some aspects, there is provided a trispecific target-binding moiety that comprises (i) an ACE2 fragment comprising the EBD of an ACE2 protein or a variant thereof; (ii) an antiinfluenza antibody moiety that specifically binds to a component of an influenza virus or a variant thereof; and (iii) an anti-RSV antibody moiety that specifically binds to a component of an RSV or a variant thereof.In some embodiments according to (or as applied to) any of the embodiments above, the trispecific target-binding moiety according to above embodiments, wherein the anti-influenza antibody moiety and the anti-RSV antibody moiety are located at the N-terminus of the trispecific target-binding moiety, optionally wherein the ACE2 EBD fragment is fused to the C-terminus of the anti-influenza antibody moiety and / or the anti-RSV antibody moiety, directly or indirectly.In some embodiments of the trispecific target-binding moiety, the ACE2 fragment comprises the EBD of a human ACE2 (hACE2) protein or a variant thereof, optionally: (a) wherein the target-binding moiety comprises: (i) amino acids 24-42 of a full-length hACE2 protein comprising the amino acid sequence of SEQ ID NO: 246, or a variant thereof having at least about 90% sequence identity to amino acids 24-42 of a full-length hACE2 protein comprising the amino acid sequence of SEQ ID NO:246; and / or (ii) the amino acid sequence of SEQ ID NO: 254, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 254; (b) wherein the target-binding moiety comprises the amino acid sequence of any one of SEQ ID NOs: 248,249,252,253,254, and 255, or a variant thereof having at least about 90% sequence identity the amino acid sequence of any one of SEQ ID NOs: 248, 249, 252, 253, 254, and 255; or (c) wherein the target-binding moiety comprises the amino acid sequence of any one of SEQ ID NOs: 246,247,250,251,256,257,258,259,260, and 261, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 246,247,250,251,256,257,258,259,260, and 261.In some embodiments of the tri specific target-binding moiety, the trispecific target-binding moiety comprises: (i) a first polypeptide chain which comprises an influenza-binding sequence, and (ii) a second polypeptide chain which comprises an RSV-binding sequence; optionally wherein the influenza-binding sequence comprises an influenza-binding VH and / or an influenza-binding VL, or optionally wherein the RSV-binding sequence comprises an RSV- binding VH and / or an RSV-binding VLIn some embodiments of the trispecific target-binding moiety, the trispecific target-binding moiety also comprises an immunoglobulin constant region, and (a) optionally wherein the immunoglobulin constant region comprises a heavy chain constant domain (CH) 1 and a light chain constant domain (CL); and / or (b) optionally wherein the immunoglobulin constant region comprises a CH2 domain and a CH3 domain. The trispecific target-binding moiety according to the above embodiment, wherein both the first and the second polypeptide chains comprise an ACE2 fragment, optionally wherein both the first and the second polypeptide chains comprise a CH2 domain and a CH3 domain.In some embodiments of the trispecific target-binding moiety, the anti -influenza antibody moiety comprises: (i) a HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 754 ;(ii) a HC-CDR2 comprising the amino acid sequence of SEQ ID NO:755 ; (iii) a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 756 ; (iv) a LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 757; (v) a LC-CDR2 comprising the amino acid sequence VDS; and (vi) a LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 759.In some embodiments of the trispecific target-binding moiety, the anti -influenza antibody moiety comprises (i) a VH comprising the amino acid sequence of SEQ ID NO: 730 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 730; and (ii) a VL comprising the amino acid sequence of SEQ ID NO: 731 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 731.In some embodiments of the tri specific target-binding moiety, the target-binding moiety comprises: (i) a first polypeptide chain comprising the amino acid sequence of SEQ ID NO: 745; (ii) a second polypeptide chain comprising the amino acid sequence of SEQ ID NO: 748;(iii) a third polypeptide chain comprising the amino acid sequence of SEQ ID NO: 747; and(iv) a fourth polypeptide chain comprising the amino acid sequence of SEQ ID NO: 749.In some embodiments of the trispecific target-binding moiety, the anti-RSV antibody moiety comprises: (i) a HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 689 ; (ii) a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 690; (iii) a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 691 ; (iv) a LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 692 ; (v) a LC-CDR2 comprising the amino acid sequence DTS; and (vi) a LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 694.In some embodiments of the trispecific target-binding moiety, the anti-RSV antibody moiety comprises: (i) a VH comprising the amino acid sequence of SEQ ID NO: 687 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 687; and (ii) a VL comprising the amino acid sequence of SEQ ID NO: 688 or a variantthereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 688.In some aspects, the current invention provides a chimeric protein comprising: (i) the trispecific target-binding moiety of any one of the above embodiments ; and (ii) a mucoadhesive peptide fragment comprising at least about 5 positively charged amino acid residues, wherein the mucoadhesive peptide fragment facilitates attachment of the chimeric protein to a mucosa.In some embodiments of the chimeric protein, the mucoadhesive peptide fragment comprises at least about 5 contiguous positively charged amino acids. In some embodiments, the chimeric protein comprises two or more polypeptide chains and wherein at least one of the polypeptide chains comprises two or more mucoadhesive peptide fragments, and optionally wherein each of the two or more mucoadhesive peptide fragments comprises at least about 5 positively charged amino acid residues.In some embodiments of the chimeric protein, the chimeric protein comprises two or more polypeptide chains and wherein at least one of the polypeptide chains comprises two or more mucoadhesive peptide fragments, and optionally wherein each of the two or more mucoadhesive peptide fragments comprises at least about 5 positively charged amino acid residues. In some embodiments, the positively charged amino acid residues are selected from the group consisting of lysine, arginine, histidine, and ornithine, optionally wherein the chimeric protein comprises a mucoadhesive peptide comprising 12 lysine amino acids bound to the antibody moiety.In some embodiments of the chimeric protein, the mucoadhesive peptide fragment is fused to the target-binding moiety via a peptide linker, optionally wherein the peptide linker comprises: (i) one or more oligomerization and / or multimerization domains; (ii) the constant region of a heavy chain of a full-length antibody or a fragment thereof, or the constant region of a light chain of a full-length antibody or a fragment thereof; (iii) an Fc region or a fragment thereof; (iv) a CHi, CH2, CH3, CH4, and / or CL domain or a fragment thereof; (v) an antibody hinge domain or a fragment thereof; (vi) a detectable enzymatic tag, optionally wherein the enzymatic tag is an alkaline phosphatase and / or a glutathione-s-transferase; (vii) a basic helix-loop-helix leucine zipper (bZIP) domain, bZIP isoleucine zipper domain, and / or bZIP- leucine / isoleucine zipper domain; (viii) a collagen-like peptide; (ix) a p53 tetramerization domain; (x) a streptavidin (SA) protein, optionally wherein the peptide linker further comprises a dextran scaffold or one or more maleimide polymers (DMGS); (xi) a bacteriophage T7 fibritin protein or a portion thereof; and / or (xii) a cartilage oligomeric matrix protein (COMP) protein. In some embodiments, the mucoadhesive peptide fragment is fused to a C-terminus of the target-binding moiety. In some embodiments, the mucoadhesive peptide fragment is fused to the antibody moiety.In some embodiments of the chimeric protein according to any of the above embodiments, the half-life of the chimeric protein on the mucosa is at least 12 hours.In some embodiments of the antibody moiety, the trispecific target-binding moiety, and / or the chimeric protein according to any of the above embodiments, the antibody moiety is an antigen-binding fragment selected from the group consisting of a Fab, a Fab’, a (Fab’)2, an Fv, a single chain Fv (scFv), an scFv-Fc, a disulfide stabilized Fv fragment (dsFv), a (dsFv)2, an scFv dimer, a domain antibody, a camelized single domain antibody (sdAb), a bivalent domain antibody, a minibody, and a VHH, optionally wherein the antibody moiety is an animal, human, humanized, camelid, or chimeric antibody moiety.In some aspects, the present application provides a pharmaceutical composition comprising the antibody moiety, the trispecific target-binding moiety, and / or the chimeric protein according to any of the above embodiments, and a pharmaceutically acceptable carrier, optionally wherein the pharmaceutically acceptable carrier is selected from the group consisting of methionine; citrate; NaCl; polysorbate 80; glycerin; and potassium sorbate.In some aspects, the present application provides 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 antibody moiety, the trispecific target-binding moiety, and / or the chimeric protein according to any of the above embodiments.In some aspects, the present application provides a method of preventing or treating respiratory infection in an individual, comprising administering to the individual an effective amount of the antibody moiety, the trispecific target-binding moiety, and / or the chimeric protein according to any of the above embodiments.In some aspects, the present application provides a method of preventing transmission of a virus causing a respiratory infection from an individual infected with the virus to an individual not infected with the virus, comprising administering to the individual an effective amount of the antibody moiety, the trispecific moiety , and / or the chimeric protein according to any of the above embodiments.In some aspects, the present application provides a method of preventing spread of a virus causing a respiratory infection, within a population of individuals, wherein at least one of the individuals is infected with the virus, the method comprising administering to the at least one individual infected with the virus with an effective amount of the antibody moiety, the trispecific moiety , and / or the chimeric protein according to any of the above embodiments, thereby preventing transmission of the virus to another individual or individuals not infected with the virus in the population.In some embodiments of the above methods, the virus is a virus that causes respiratory infection, optionally wherein the virus causing the respiratory infection is selected from the group consisting of coronaviruses, RSV, and influenza viruses, and further optionally wherein the virus is a coronavirus selected from the group consisting of SARS-CoV, SARS-CoV-2, and a variant, subtype, or reassortant thereof.In some embodiments of the above methods, the individual or the at least one individual is a human, and the effective amount is between about 1 μg and about 500 ug per nostril, optionally the effective amount is between 10 μg and 100 μg per nostril.In some embodiments of the above methods, the virus is a virus that causes respiratory infection, the transmission is via small respiratory droplets, and / or the transmission is via aerosol.In some embodiments of the above methods, the antibody moiety, the target-binding moiety or the chimeric protein is administered intranasally.BRIEF DESCRIPTION OF THE DRAWINGS

[0008] The drawings illustrate certain embodiments of the features and advantages of this disclosure. These embodiments are not intended to limit the scope of the appended claims in any manner.

[0009] FIG. 1 is a schematic representation of the ACE614-Fcl-12K chimeric mucoadhesive protein.

[0010] FIG. 2A shows a schematic depicting the experimental design of a pre-exposure prophylaxis experiment . Two donor Syrian hamsters were intranasally infected with 103plaque-forming units (PFU) of the SARS-CoV-2 Delta variant. On the following day, separate groups of uninfected recipient hamsters were intranasally administered with either ACE614-Fcl-12K (5 pM, n=6) or IgG (5 pM, n=6). Thirty minutes (mins) postadministration, the recipient hamsters were co-housed with the donor hamsters for 2 hours, where the animals shared a common air supply, but no physical contact was possible. On days 2 and 3, all donor and recipient hamsters were euthanized, and their right lung and nasal tissues were collected and analyzed for infectious virus titers using a plaque assay. The left lung lobe and nasal tissue of these animals were used for histological analysis.

[0011] FIG. 2B shows viral titers of SARS-CoV-2-infected donor Syrian hamsters and ACE614-Fcl-12K- or IgG-administered recipient Syrian hamsters following the pre-exposure prevention of transmission assay described in FIG. 2A. Infectious virus particles were measured in the lungs and nasal wash of the donor and recipient Syrian hamsters. The data are shown as the mean ± s.e.m. and were analyzed using a two-tailed unpaired Student’ s Mann Whitney t-test (*p<0.05, ***p<0.001). Each dot represents the infectious virus titer of an individual Syrian hamster.

[0012] FIG. 2C shows representative images of immunohistochemistry of the SARS-CoV-2 Nucleocapsid (N) protein in nasal tissue. Scale bars represent 50 pm.

[0013] FIG. 2D shows representative images of immunohistochemistry of the SARS-CoV-2 Nucleocapsid (N) protein in left lung lobe. Scale bars represent 50 pm.

[0014] FIG. 3A shows a schematic depicting the experimental design of the post-infection transmission prevention assay. Four donor Syrian hamsters were intranasally infected with 103PFU of the SARS-CoV-2 Delta variant. The next day, the donor hamsters were divided into two groups (n=2 per group) and administered with either ACE614-Fcl-12K or IgG. Thirty mins post-administration, donors from both groups were separately co-housed with distinct groups of uninfected recipient hamsters (n=5 recipient hamsters per group). On days 2 and 3, all donor and recipient hamsters were euthanized, and their lung and nasal tissues were collected for virus titer analysis using a plaque assay. At the time of euthanasia (day 2), the donor animal’s viral titers were quite high at 108pfu / ml.

[0015] FIG. 3B shows viral titers of SARS-CoV-2-infected donor Syrian hamsters administered with ACE614-Fcl-12K or IgG and recipient Syrian hamsters following the donor- administered transmission assay described in FIG. 3A. Mature virus particles were measured from the lungs and nasal wash of donor and recipient Syrian hamsters. Data are presented as mean ± s.e.m. and were analyzed using a two-tailed unpaired Student’s Mann-Whitney t-test (**p<0.008). Each dot represents the infectious virus titer in an individual Syrian hamster.

[0016] FIG. 4 shows a comparative sequence analysis of the heavy and light variable regions of antibodies HA17, HA16, HA18, and HA15 using CLUSTAL Omega.

[0017] FIG. 5A shows the structural schematic of the chimeric antibody HA17-hIgG-12K, in which the mucoadhesive peptide 12K is fused to the C-terminal end of the HA17-hIgG heavy chain.

[0018] FIG. 5B illustrates the proposed mechanism of action of HA17-hIgG-12K. The chimeric antibody anchors to the respiratory mucosa via electrostatic interactions mediated by the 12K tail, while the antigen-binding domain of HA17 targets the hemagglutinin (HA) protein on the influenza virus surface. This dual interaction blocks viral attachment to host mucosal receptors, thereby preventing infection at the entry site.

[0019] FIG. 6 shows flow cytometry analysis of HA17-hIgG-12K binding to hemagglutinin (HA) antigens from nine distinct influenza A and B virus strains.

[0020] FIG. 7 demonstrates the binding kinetics of HA16-hIgG-12K and HA17-hIgG-12K to hemagglutinins from H1N1 and H5N1 influenza strains using surface plasmon resonance.

[0021] FIG. 8 demonstrates the ability of HA16-hIgG-12K and HA17-hIgG-12K chimeric proteins to neutralize infection in vitro by virus pseudotyped with influenza strain H5 hemagglutinin. Luciferase emission correlates with the degree of infection.

[0022] FIG. 9 shows the in vivo evaluation of the duration of the protective effect against H3N2 influenza infection following administration of HA16-hIgG-12K and HA17-hIgG-12K chimeric proteins into the nasal cavities of mice.

[0023] FIG. 10 shows the in vivo protective effect of intranasal application ACE2-12K and / or HA15-IgG-12K chimeric antibodies prior to inoculation of ACE2 transgenic mice with SARS-CoV-2 or influenza H3N2 pseudoviruses.

[0024] FIG. 11 demonstrates the in vivo protective effect of aRSV chimeric mucoadhesive antibody against RSV pseudovirus infection in mice, as measured by bioluminescence.

[0025] FIG. 12A-FIG. 12D show schematic representations of four tri specific chimeric antibody configurations (Trispecific Antibodies 1-4) designed to simultaneously target viral antigens from SARS-CoV-2, influenza, and respiratory syncytial virus (RSV).

[0026] FIG. 13A-FIG. 13C demonstrate the in vitro neutralization of SARS-CoV-2 XBB.1.5 isolate (A), RSV (B) or influenza H5N1(C) pseudoviral infection by Trispecific Antibodies 3 and 4 measures as relative infection by luciferase luminescence.

[0027] FIG. 14A-FIG. 14C show in vitro SARS-CoV-2 Omicron (A), influenza H5N1 (B) and RSV (C) pseudovirus neutralization assays comparing the efficacy of Trispecific Antibody 2 chimeric protein to its respective parental mucoadhesive monospecific antibodies. Relative infection is calculated from luciferase luminescence.

[0028] FIG. 15A-FIG. 15D show in vitro neutralization assay results evaluating the potency of Trispecific Antibody 1 chimeric protein against multiple viral pseudotypes, compared to corresponding monospecific antibodies independently or in combination. ECso values were calculated to quantify neutralization efficiency. Each panel represents a distinct viral target, with dose-response curves plotted for Trispecific Antibody 1 and its parental monospecific counterparts. Lower ECso values indicate higher neutralizing potency.DETAILED DESCRIPTION

[0029] The present application provides compositions and methods for: (a) preventing or treating viral infections; and / or (b) preventing transmission or spread of viruses.

[0030] In one aspect, the present application provides compositions and methods for preventing or treating influenza, RSV, and / or coronavirus infections.

[0031] In another aspect, the present application provides compositions and methods for preventing transmission of a virus from an individual infected with the virus to an individual not infected with the virus and preventing the spread of viruses within a population of individuals. The provided methods may comprise administering to one or more individuals infected with the virus an effective amount of a chimeric protein, wherein the chimeric protein comprises a target-binding moiety that specifically binds to the virus and a mucoadhesive peptide fragment that facilitates attachment of the chimeric protein to a mucosa.

[0032] The present application provides compositions and methods for preventing transmission of a virus from an individual infected with the virus to an individual not infected with the virus and preventing the spread of viruses within a population of individuals. The provided methods may comprise administering to one or more individuals infected with the virus an effective amount of a chimeric protein, wherein the chimeric protein comprises a targetbinding moiety that specifically binds to the virus and a mucoadhesive peptide fragment that facilitates attachment of the chimeric protein to a mucosa.

[0033] The present invention is based, at least in part, on the inventors’ surprising finding that, when administered to an individual infected with a virus, chimeric proteins (e.g., chimeric proteins comprising a target-binding moiety that specifically binds to a virus (such as a coronavirus, RSV, influenza virus, or a variant, subtype, or reassortant thereof) fused to a positively charged mucoadhesive peptide fragment, optionally via a peptide linker) prevent the transmission of the virus to an individual not infected with the virus. In particular, in vivo administration of an exemplary chimeric protein to hamsters infected with a virus reduced the transmission of a virus (i.e., coronavirus) to uninfected hamsters that were not administered the chimeric protein. Moreover, in vivo administration of the exemplary chimeric protein to uninfected hamsters provided protection against aerosol-mediated transmission of a virus (i.e., coronavirus) from hamsters infected with the virus, indicating these chimeric proteins can be administered as a precautionary and / or preventative measureto protect healthy individuals from viral infections. Protection against viral infection was documented as effective in both nasal and lung areas two days after viral exposure. These results are surprising because the inventors have demonstrated that the target-binding chimeric proteins can be used to intercept the transmission of virus by either treating the infected individual or treating the uninfected individual. For instance, using the provided methods, viral spread may be prevented by treating either an infected individual and / or an uninfected individual dwelling within the same household. Such agents also could be deployed in a pandemic situation to curb the spread of the viral pathogen across a large population.

[0034] Thus, one aspect of the present application provides a method of preventing transmission of a virus from an individual infected with the virus to an individual not infected with the virus, comprising administering to the individual infected with the virus an effective amount of a chimeric protein, wherein the chimeric protein comprises: (a) a target-binding moiety that specifically binds to the virus; and (b)a mucoadhesive peptide fragment, wherein the mucoadhesive peptide fragment facilitates attachment of the chimeric protein to the mucosa, thereby preventing transmission of the virus to the individual not infected with the virus. In another aspect, the present application provides a method of preventing spread of a virus within a population of individuals, wherein at least one of the individuals is infected with the virus, the method comprising administering to the at least one individual infected with the virus an effective amount of a chimeric protein, wherein the chimeric protein comprises: (a) a target-binding moiety that specifically binds to the virus; and (b) a mucoadhesive peptide fragment, wherein the mucoadhesive peptide fragment facilitates attachment of the chimeric protein to the mucosa, thereby preventing transmission of the virus to another individual or individuals not infected with the virus in the population.

[0035] The chimeric proteins for use in the method of the present invention can specifically bind to a variety of viruses. For example, in some embodiments, the chimeric protein may be a “coronavirus chimeric protein,” wherein the coronavirus chimeric protein comprises: (a) a target-binding moiety comprising an antibody moiety that specifically binds to a component of a coronavirus or a variant thereof (such as a spike protein of a coronavirus or a variant thereof); and (b) a mucoadhesive peptide fragment, wherein the mucoadhesive peptidefragment facilitates attachment of the chimeric protein to the mucosa. Tn other embodiments, the chimeric protein may be an “ACE2 chimeric protein,” wherein the ACE2 chimeric protein comprises: (a) a target-binding moiety comprising an extracellular binding domain (EBD) of an ACE2 protein or fragment thereof that specifically binds to a coronavirus or a variant thereof (such as a spike protein of a coronavirus or a variant thereof); and (b) a mucoadhesive peptide fragment, wherein the mucoadhesive peptide fragment facilitates attachment of the chimeric protein to the mucosa. In further embodiments, the chimeric protein may be an “influenza chimeric protein,” wherein the influenza chimeric protein comprises: (a) a target-binding moiety that specifically binds to a component of an influenza virus or a variant thereof (such as an HA or NA surface protein of an influenza virus or a variant thereof); and (b) a mucoadhesive peptide fragment, wherein the mucoadhesive peptide fragment facilitates attachment of the chimeric protein to the mucosa. In still further embodiments, the chimeric protein may be an “RSV chimeric protein,” wherein the RSV chimeric protein comprises: (a) a target-binding moiety that specifically binds to a component of an RSV or a variant thereof (such as an F glycoprotein or a G glycoprotein of an RSV or a variant thereof); and (b) a mucoadhesive peptide fragment, wherein the mucoadhesive peptide fragment facilitates attachment of the chimeric protein to the mucosa.

[0036] For example, the methods described herein may comprise administration of a chimeric protein comprising a target-binding moiety that specifically binds a coronavirus, respiratory syncytial virus (RSV), influenza virus, or a variant, subtype, or reassortant thereof, and is modified with a positively charged peptide that prevents the specifically targeted and bound virus from reaching its primary target cell population deeper in the respiratory tract (e.g., nasopharynx) mucosa for human or animal infection. The methods described herein may also comprise administration of a cocktail of different chimeric proteins, each comprising a target-binding moiety that targets the same virus and / or one or more variants thereof, such as a cocktail of different chimeric proteins each comprising a target-binding moiety that targets a coronavirus or a variant thereof, a cocktail of different chimeric proteins each comprising a target-binding moiety that targets an RSV or a variant thereof, or a cocktail of different chimeric proteins each comprising a target-binding moiety that targets an influenza virus or a variant thereof. The compositions can be administered via the nasal passages using an intranasal spray.

[0037] In one aspect, the present application provides a novel antibody moiety that specifically binds to a component of an influenza virus or a variant thereof. The anti -influenza antibody moiety has the surprising ability to bind to many strains / variants of influenza virus. Therefore, the anti -influenza antibody moiety can be a highly valuable tool for: (a) preventing or treating an infection caused by various influenza viruses; (b) preventing or reducing the transmission of various influenza viruses to a non-infected individual from an infected individual; and (c) diagnosis of influenza infection.

[0038] In one aspect, the present application provides a trispecific target binding moiety that comprises (i) an ACE2 fragment comprising the EBD of an ACE2 protein or a variant thereof; (ii) an anti-influenza antibody moiety that specifically binds to a component of an influenza virus or a variant thereof; and (iii) an anti-RSV antibody moiety that specifically binds to a component of an RSV or a variant thereof. Also, in some embodiments of the trispecific target-binding moiety described in the present application, the anti -influenza antibody moiety and the anti-RSV antibody moiety are located at the N-terminus of the trispecific target-binding moiety, or optionally the ACE2 EBD fragment is fused to the C- terminus of the anti-influenza antibody moiety and / or the anti-RSV antibody moiety, directly or indirectly.

[0039] The tri-specific target-binding moiety, in some embodiments of the present invention, can bind to three different types of respiratory infection-causing pathogens: coronaviruses, RSV, and influenza viruses. Hence these trispecific target-binding moieties can be highly valuable tools for: (a) preventing or treating an infection caused by any one of these viruses; (b) preventing or reducing the transmission of these viruses to a non-infected individual from an infected individual; and (c) diagnosis of RSV and influenza.

[0040] In another aspect, the present application also presents novel chimeric proteins comprising a mucoadhesive peptide fragment and an anti -influenza antibody moiety, an anti- RSV antibody moiety, or a trispecific target-binding moiety. These chimeric proteins can bind to the nasal mucosa effectively because of the presence of the mucoadhesive peptide fragment. The chimeric proteins are administered intranasally, and can help to pr event / reducetransmission of coronaviruses, RSV, or influenza viruses to a non-infected individual from an infected individual.

[0041] In another aspect, the present application provides a method of preventing or treating an infection caused by a pathogen that infects via a mucosa in an individual, comprising administering to the individual an effective amount of the anti -influenza antibody moiety, the trispecific target-binding moiety, or the chimeric protein comprising the anti-influenza antibody moiety, the trispecific target-binding moiety, or an anti-RSV antibody moiety.I. Definitions

[0042] The term “target-binding moiety” is used herein to refer to a molecule or a fragment thereof that is capable of specifically binding to a target. A target-binding moiety may have one or more target-binding sites.

[0043] As used herein, a “mucoadhesive peptide fragment” refers to a peptide that carries one or more positive charges and is capable of interacting with a mucosa, e.g., via electrostatic interactions.

[0044] As used herein, a “receptor” refers to a receptor on a host cell that facilitates or mediates microbial entry into the host cell. A receptor may be membrane-bound or a soluble receptor.

[0045] “ Transmission” as used herein, occurs when an organism (e.g., an individual, such as a human) infected with a pathogen, such as a virus, exposes another organism to the pathogen and causes the other organism to be infected with the pathogen. The transmission of the pathogen may occur when the infected organism exhales, emits, and / or secretes fluids (e.g., through sneezing, coughing, breathing, speaking, nose-blowing, and / or nose-wiping), such as large or small respiratory droplets, that contain the pathogen. Large respiratory droplets typically have diameters of greater than 5 Dm, while small respiratory droplets (also called droplet nuclei) typically have diameters of equal to or smaller than 5 Dm. Small respiratory droplets can be transmitted through aerosol. Transmission can occur before the organism is aware that it is infected with the pathogen. Transmission can be direct, such as via physical contact between an infected organism and another organism, or indirect, which requires nodirect organism-to-organism contact (e.g., inhaling respiratory droplets that contain the pathogen, or touching a surface that contains respiratory droplets containing the pathogen).

[0046] “Spread” as used herein, occurs when an organism (e.g., an individual, such as a human, “Organism A”) infected with a pathogen, such as a virus, transmits the pathogen to another organism within a population which was not previously infected (“Organism B”), and causes at least one other organism within the population to be infected with the pathogen (“Organism C”), through direct or indirect transmission.

[0047] “Preventing” as used herein, refers to stopping, lowering, and / or reducing transmission of a pathogen, such as a virus, from one organism (e.g., an individual, such as a human) infected with the pathogen to another organism. Such prevention may comprise preventing transmission of a pathogen between organisms or preventing the spread of a pathogen within a population. In some embodiments, the provided methods of preventing transmission or preventing spread of a pathogen may comprise lowering transmission (e.g., viral transmission) by at least about 20% (such as at least about 30%, 40%, 50%, 60%, 70%, 80%, or 90% or more) as compared to the transmission of the pathogen without performing the provided methods. In some embodiments, the provided methods of preventing transmission or preventing spread of a pathogen result in no transmission of the pathogen. Preventing may also include preventing a disease that is secondary to a transmitted pathogen.

[0048] An “effective amount” of an agent, such as one or more chimeric proteins or a composition thereof, refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prevention of transmission, including reduction in transmission rates (e.g., viral transmission rate) or to completely stop transmission. An effective amount herein may vary according to factors such as the disease state, age, sex, and weight of the patient, and the ability of the chimeric protein (e.g., the target-binding moiety) to elicit a desired response in the individual. An effective amount is also one in which any toxic or detrimental effects of the administration are outweighed by the beneficial effects. Beneficial or desired results include results such as eliminating or reducing the risk, lessening the severity, or delaying the onset of the disease, including biochemical, histological and / or behavioral symptoms of the disease, its complications and intermediate pathologicalphenotypes presenting during development of the disease. For purposes of this application, an effective amount of a drug, compound, or pharmaceutical composition is an amount sufficient to prevent transmission either directly or indirectly. As is understood in the clinical context, an effective amount of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition. Thus, an “effective amount” may be considered in the context of administering one or more chimeric proteins, and a single chimeric protein may be considered to be given in an effective amount if, in conjunction with one or more other chimeric proteins, or other agents, a desirable result may be or is achieved in an individual. The effective amount can be ascertained by measuring relevant physiological effects, and it can be adjusted in connection with the dosing regimen and diagnostic analysis of the individual’s condition, and the like.

[0049] The terms “individual,” “subject” and “patient” are used interchangeably herein to describe a mammal, including humans. In some embodiments, the individual is human. In some embodiments, an individual suffers from a respiratory infection. In some embodiments, the individual does not suffer from a respiratory infection. In some embodiments, the individual suffers from a viral infection.

[0050] The terms “polypeptide” and “protein” are used interchangeably to refer to a polymer of amino acid residues and are not limited to a minimum length. Such polymers of amino acid residues may contain natural or non-natural amino acid residues, and include, but are not limited to, peptides, oligopeptides, dimers, trimers, and multimers of amino acid residues. Both full-length proteins and fragments thereof are encompassed by the definition. The terms also include post-expression modifications of the polypeptide, for example, glycosylation, sialylation, acetylation, phosphorylation, and the like. Furthermore, for purposes of the present application, a “polypeptide” refers to a protein which includes modifications, such as deletions, additions, and substitutions (generally conservative in nature), to the native sequence, as long as the protein maintains the desired activity. These modifications may be deliberate, as through site-directed mutagenesis, or may be accidental, such as through PCR amplification errors or mutations that arise during transcription and / or translation in the host cell.

[0051] As use herein, the term “specifically binds,” “specifically recognizing,” or “is specific for” refers to measurable and reproducible interactions, such as binding between a target and a target-binding moiety that is determinative of the presence of the target in the presence of a heterogeneous population of molecules, including biological molecules. For example, targetbinding moiety that specifically recognizes a target (which can be an epitope) is targetbinding moiety that binds this target with greater affinity, avidity, more readily, and / or with greater duration than it binds to other targets. In some embodiments, the target-binding moiety that specifically recognizes an antigen reacts with one or more antigenic determinants of the antigen (such as SARS-CoV-2 S protein) with a binding affinity that far exceeds its binding affinity (e.g., is at least about lOx its binding affinity) for other untargeted viral components (such as MERS-CoV S protein, or a non-respiratory-pathogen protein).

[0052] As used herein, the term "trispecific antibody chimeric protein" refers to a protein molecule comprising three distinct binding specificities combined with a mucoadhesive peptide fragment. The trispecific antibody chimeric protein may include binding domains that recognize three different target antigens or epitopes.

[0053] As used herein, the term "trispecific target-binding moiety" refers to a molecule or a fragment thereof that is capable of specifically binding to three different targets. A targetbinding moiety may have one or more target-binding sites .comprising three distinct targetbinding domains capable of binding three different antigens or epitopes. The trispecific target-binding moiety may be composed of antibody fragments, receptor fragments, or other binding domains arranged to provide three separate binding specificities.

[0054] As used herein, the term "positively charged amino acid residues" refers to amino acids that carry a positive charge at physiological pH. Examples of positively charged amino acids include lysine, arginine, histidine, and ornithine.

[0055] As used herein, the term "neutralization assay" refers to methods used to evaluate the ability of antibodies or other proteins to inhibit viral infection. Pseudovirus neutralization assays may be used to assess the neutralizing activity of monospecific or trispecific antibody chimeric proteins against viral infection.

[0056] ‘ ‘Penetration,” as used herein, refers to the process by which inhaled particles including allergens and pathogens make their way through or into biological barriers. In the context of mucosal immunity, the nasal epithelium produces a physical glycoprotein barrier that prevents penetration to the epithelial surface of mucosal tissues. This barrier acts to obstruct the entry of airborne particles, thereby limiting their access to underlying cells and reducing the likelihood of infection or immune activation.

[0057] The “CHI domain” of a human IgG Fc region (also referred to as “Cl” of “Hl” domain) usually extends from about amino acid 118 to about amino acid 215 (EU numbering system, see also SEQ ID NO:629).

[0058] ‘ ‘Hinge region” is generally defined as stretching from Glu216 to Pro230 of human IgGl (Burton, Molec. Immunol.22: 161-206 (1985)). Hinge regions of other IgG isotypes may be aligned with the IgGl sequence by placing the first and last cysteine residues forming interheavy chain S-S bonds in the same positions.

[0059] The “CH2 domain” of a human IgG Fc region (also referred to as “C2” of “H2” domain) usually extends from about amino acid 231 to about amino acid 340 (see also SEQ ID NO:630). The CH2 domain is unique in that it is not closely paired with another domain. Rather, two N-linked branched carbohydrate chains are interposed between the two CH2 domains of an intact native IgG molecule. It has been speculated that the carbohydrate may provide a substitute for the domain-domain pairing and help stabilize the CH2 domain. Burton, Molec Immunol. 22: 161-206 (1985).

[0060] The “CH3 domain” (also referred to as “C2” or “H3” domain) comprises the stretch of residues C-terminal to a CH2 domain in an Fc region (i.e., from about amino acid residue 341 to the C-terminal end of an antibody sequence, typically at amino acid residue 446 or 447 of an IgG, see also SEQ ID NO:631).

[0061] The “CH4 domain” found in IgE and IgM molecules, is situated C-terminal to the CH3 domain, comprising residues 466-572 of human IgM and residues 323-427 of hlgE (see also SEQ ID NO:632). The term “substantially similar” or “substantially the same,” as used herein, denotes a sufficiently high degree of similarity between two or more numeric valuessuch that one of skill in the art would consider the difference between the two or more values to be of little or no biological and / or statistical significance within the context of the biological characteristic measured by said value. In some embodiments, the two or more substantially similar values differ by no more than about any one of 5%, 10%, 15%, 20%, 25%, or 50%. The term “substantially similar” or “substantially the same,” as used herein, denotes a sufficiently high degree of similarity between two or more numeric values such that one of skill in the art would consider the difference between the two or more values to be of little or no biological and / or statistical significance within the context of the biological characteristic measured by said value. In some embodiments, the two or more substantially similar values differ by no more than about any one of 5%, 10%, 15%, 20%, 25%, or 50%.

[0062] A polypeptide “variant” means a biologically active polypeptide having at least about 80% amino acid sequence identity and no more than 100% identity with the reference sequence polypeptide (e.g., native or non-native reference sequence) after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity. The variant may be a polypeptide fragment or a polypeptide mutant, so long as it has at least about 80% amino acid sequence identity and no more than 100% identity with the reference sequence polypeptide (e.g., native or non-native reference sequence) after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity. Such variants include, for instance, polypeptides wherein one or more amino acid residues are added, or deleted, at the N- or C-terminus of the polypeptide. In some embodiments, a variant has at least about 80% amino acid sequence identity. In some embodiments, a variant has at least about 90% amino acid sequence identity. In some embodiments, a variant has at least about 95% amino acid sequence identity with the native sequence polypeptide.

[0063] As used herein, “Percent (%) amino acid sequence identity” with respect to a peptide or polypeptide sequence are defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the specific peptide or polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acidsequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or MEGALIGNTM (DNASTAR) software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared.

[0064] The term “isolated nucleic acid” as used herein is intended to mean a nucleic acid of genomic, cDNA, or synthetic origin or some combination thereof, which by virtue of its origin the “isolated nucleic acid” (1) is not associated with all or a portion of a polynucleotide in which the “isolated nucleic acid” is found in nature, (2) is operably linked to a polynucleotide which it is not linked to in nature, or (3) does not occur in nature as part of a larger sequence.

[0065] Unless otherwise specified, a “nucleotide sequence encoding an amino acid sequence” includes all nucleotide sequences that are degenerate versions of each other and that encode the same amino acid sequence. The phrase nucleotide sequence that encodes a protein or an RNA may also include introns to the extent that the nucleotide sequence encoding the protein may in some versions contain an intron(s).

[0066] The term “operably linked” refers to functional linkage between a regulatory sequence and a heterologous nucleic acid sequence resulting in expression of the latter. For example, a first nucleic acid sequence is operably linked with a second nucleic acid sequence when the first nucleic acid sequence is placed in a functional relationship with the second nucleic acid sequence. For instance, a promoter is operably linked to a coding sequence if the promoter affects the transcription or expression of the coding sequence. Generally, operably linked DNA sequences are contiguous and, where necessary to join two protein coding regions, in the same reading frame.

[0067] The term “vector” is used to describe a polynucleotide that may be engineered to contain a cloned polynucleotide or polynucleotides that may be propagated in a host cell. A vector may include one or more of the following elements: an origin of replication, one or more regulatory sequences (such as, for example, promoters and / or enhancers) that regulate the expression of the polypeptide of interest, and / or one or more selectable marker genes (suchas, for example, antibiotic resistance genes and genes that may be used in colorimetric assays, e.g., P-galactosidase). The term “expression vector” refers to a vector that is used to express a polypeptide of interest in a host cell.

[0068] A “host cell” refers to a cell that may be or has been a recipient of a vector or isolated polynucleotide. Host cells may be prokaryotic cells or eukaryotic cells. Exemplary eukaryotic cells include mammalian cells, such as primate or non-primate animal cells; fungal cells, such as yeast; plant cells; and insect cells. Non-limiting exemplary mammalian cells include, but are not limited to, human ACE2 expressing 293T cells, A549 cells, NSO cells, PER.C6® cells (Crucell), and 293 and CHO cells and their derivatives, such as 293-6E and DG44 cells, respectively.

[0069] As used herein, a “variant” virus refers to an isolate of a virus whose genome sequence differs from that of a reference virus and the difference in the genome sequence confers new phenotypic properties such as increased fitness compared to the reference virus. When referring to a viral species in the present application, it is understood that the species encompasses variants as well as the reference virus that was first isolated and identified. In some embodiments, the variant virus described herein is a “variant of interest”, i.e., a variant with specific genetic markers that have been associated with changes to receptor binding, reduced neutralization by antibodies generated against previous infection or vaccination, reduced efficacy of treatments, potential diagnostic impact, and / or predicted increase in transmissibility and / or disease severity. In some embodiments, the variant virus described herein is a “variant of concern”, i.e., a variant for which there is evidence of an increase in transmissibility, more severe disease (e.g., increased hospitalizations and / or deaths), significant reduction in neutralization by antibodies generated during previous infection or vaccination, reduced effectiveness of treatments or vaccines, and / or diagnostic detection failures. In some embodiments, the variant virus described herein is a “variant of high consequence”, i.e., a variant of high consequence has clear evidence that prevention measures or medical countermeasures (MCMs) have significantly reduced effectiveness relative to previously circulating variants.

[0070] As used herein, by “pharmaceutically acceptable” or “pharmacologically compatible” is meant a material that is not biologically or otherwise undesirable, e.g., the material may be incorporated into a pharmaceutical composition administered to a patient without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. Pharmaceutically acceptable carriers or excipients have preferably met the required standards of toxicological and manufacturing testing and / or are included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration.

[0071] As used herein, “a pharmaceutically acceptable carrier” refers to a pharmaceutically acceptable substrate, composition or vehicle used in the process of drug delivery, which may have one or more ingredients including, but not limited to, excipient(s), binder(s), diluent(s), solvent(s), filler(s), and / or stabilizer(s).

[0072] It is understood that embodiments of the invention described herein include “consisting of’ and / or “consisting essentially of’ embodiments.

[0073] Reference to “about” a value or parameter herein includes (and describes) variations that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X”.

[0074] As used herein, reference to “not” a value or parameter generally means and describes “other than” a value or parameter.

[0075] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise.IL Methods of preventing viral transmission and spread

[0076] The present application provides methods of preventing viral transmission and spread. Thus, the present application provides methods of preventing transmission of a virus (e.g., a virus that causes a respiratory infection, such as a coronavirus, RSV, influenza virus, or a variant, subtype, or reassortant thereof) from an individual infected with the virus to an individual not infected with the virus. The present application further provides methods ofpreventing spread of a virus (e.g., a virus that causes a respiratory infection, such as a coronavirus, RSV, influenza virus, or a variant, subtype, or reassortant thereof) within a population of individuals, wherein at least one of the individuals is infected with the virus. In some embodiments, the methods prevent transmission of the virus to an individual not infected with the virus, and / or another individual not infected with the virus in the population. In some embodiments, the methods prevent aerosol-mediated transmission and spread of the virus.

[0077] The provided methods of preventing viral transmission and spread comprise administering to the individual infected with the virus or the at least one individual infected with the virus an effective amount of any one of the chimeric proteins described herein, or a cocktail composition of chimeric proteins targeting the same virus or a variant thereof, described herein. In some embodiments, the method comprises administering to the individual a pharmaceutical composition, such as any of the pharmaceutical compositions provided herein, comprising an effective amount of any one of the chimeric proteins described herein, or a cocktail composition of chimeric proteins targeting the same virus, or a variant thereof described herein. In some embodiments, the methods prevent transmission of the virus to an individual not infected with the virus, and / or another individual not infected with the virus in the population. In some embodiments, the method is for preventing the transmission and / or spread of a coronavirus, RSV, influenza virus, or a variant, subtype, or reassortant thereof. Use of the chimeric proteins in prevention of transmission or spread of an infection and use of the chimeric proteins in the preparation of a medicament for preventing transmission or spread of an infection are also provided. Methods of veterinary use are also contemplated herein.

[0078] In some embodiments, there is provided a method of preventing transmission of a virus from an individual infected with the virus to an individual not infected with the virus, comprising administering to the individual infected with the virus an effective amount of a chimeric protein, wherein the chimeric protein comprises: (a) a target-binding moiety that specifically binds to the virus; and (b) a mucoadhesive peptide fragment, wherein the mucoadhesive peptide fragment facilitates attachment of the chimeric protein to the mucosa, thereby preventing transmission of the virus to the individual not infected with the virus. Insome embodiments, the mucoadhesive peptide fragment comprises at least 5 positively charged amino acid residues interspersed with one or more non-positively charged amino acid residues.

[0079] In other embodiments, there is provided a method of preventing spread of a virus within a population of individuals, wherein at least one of the individuals is infected with the virus, the method comprising administering to the at least one individual infected with the virus with an effective amount of a chimeric protein, wherein the chimeric protein comprises: (a) a target-binding moiety that specifically binds to the virus; and (b) a mucoadhesive peptide fragment, wherein the mucoadhesive peptide fragment facilitates attachment of the chimeric protein to the mucosa, thereby preventing transmission of the virus to another individual or individuals not infected with the virus in the population. In some embodiments, the mucoadhesive peptide fragment comprises at least 5 positively charged amino acid residues interspersed with one or more non-positively charged amino acid residues.

[0080] In further embodiments, provided herein is a method of coating a virus in an individual infected with the virus, the method comprising administering to the individual infected with the virus an effective amount of a chimeric protein, wherein the chimeric protein comprises: (a) a target-binding moiety that specifically binds to the virus; and (b) a mucoadhesive peptide fragment, wherein the mucoadhesive peptide fragment facilitates attachment of the chimeric protein to the mucosa, thereby coating the virus in the individual. In some embodiments, the method prevents the transmission of the virus from the individual infected with the virus (e.g., to an individual not infected with the virus). In some embodiments, the mucoadhesive peptide fragment comprises at least 5 positively charged amino acid residues interspersed with one or more non-positively charged amino acid residues.

[0081] In additional embodiments, provided herein is a method of preventing outbreak of a virus within population of individuals, wherein at least one of the individuals is infected with the virus, the method comprising administering to the at least one individual infected with the virus with an effective amount of a chimeric protein, wherein the chimeric protein comprises: (a) a target-binding moiety that specifically binds to the virus; and (b) a mucoadhesive peptide fragment, wherein the mucoadhesive peptide fragment facilitates attachment of thechimeric protein to the mucosa, thereby preventing outbreak of the virus to individuals not infected with the virus in the population. In some embodiments, the mucoadhesive peptide fragment comprises at least 5 positively charged amino acid residues interspersed with one or more non-positively charged amino acid residues.

[0082] In other embodiments, provided herein is a method of preventing a pandemic of a virus within a population of individuals, wherein at least one of the individuals is infected with the virus, the method comprising administering to the at least one individual infected with the virus with an effective amount of a chimeric protein, wherein the chimeric protein comprises: (a) a target-binding moiety that specifically binds to the virus; and (b) a mucoadhesive peptide fragment, wherein the mucoadhesive peptide fragment facilitates attachment of the chimeric protein to the mucosa, thereby preventing a pandemic within the population. In some embodiments, the mucoadhesive peptide fragment comprises at least 5 positively charged amino acid residues interspersed with one or more non-positively charged amino acid residues.

[0083] In other embodiments, provided herein is a method of preventing a pandemic of a virus within a population of individuals, the method comprising administering to one or more individuals within the population an effective amount of a chimeric protein, wherein the chimeric protein comprises: (a) a target-binding moiety that specifically binds to the virus; and (b) a mucoadhesive peptide fragment, wherein the mucoadhesive peptide fragment facilitates attachment of the chimeric protein to the mucosa, thereby preventing the pandemic of the within the population. In some embodiments, the mucoadhesive peptide fragment comprises at least 5 positively charged amino acid residues interspersed with one or more non-positively charged amino acid residues. In some embodiments, the method comprises administering the chimeric protein to each of the individuals of the population. In some embodiments, none of the individuals of the population are infected with the virus.

[0084] In other embodiments, provided herein is a method of protecting healthy individuals from a virus within a population of individuals, the method comprising administering to one or more individuals not infected with the virus within the population an effective amount of a chimeric protein, wherein the chimeric protein comprises: (a) a target-binding moiety thatspecifically binds to the virus; and (b) a mucoadhesive peptide fragment, wherein the mucoadhesive peptide fragment facilitates attachment of the chimeric protein to the mucosa, thereby preventing the transmission of the virus within the population as a preventative and / or precautionary measure. In some embodiments, the mucoadhesive peptide fragment comprises at least 5 positively charged amino acid residues interspersed with one or more non-positively charged amino acid residues. In some embodiments, the method comprises administering the chimeric protein to both uninfected and infected individuals within the population. In some embodiments, the method comprises administering the chimeric protein to each of the individuals of the population. In some embodiments, one or more individuals of the population are known to be infected with the virus. In some embodiments, none of the individuals of the population are infected or known to be infected with the virus.

[0085] In some embodiments, the individual (such as the individual infected with the virus and / or the individual not infected with the virus) is a mammal (e.g., human, non-human primate, rat, mouse, cow, horse, pig, sheep, goat, dog, cat, chicken, etc.). In some embodiments, the individual is a human. In some embodiments, the individual is a clinical patient, a clinical trial volunteer, an experimental animal, etc. In some embodiments, the individual is younger than about 50 years old (including for example younger than about n years old, where n is selected from 50, 40, 30, 25, 20, 15, and 10). In some embodiments, the individual is about 50 years old or older (including for example older than about n years old, where n is selected from 60, 70, 80, 90, and 100).

[0086] In some embodiments, the virus or variant thereof is transmitted via airborne particles. In some embodiments, the virus or variant thereof is transmitted via respiratory droplets (e.g., aerosol droplets or aerosol particles). In some embodiments, the virus or variant thereof is transmitted via respiratory droplets from an individual infected with the virus to an individual not infected with the virus. In some embodiments, the virus or variant thereof is transmitted via large respiratory droplets (e.g., respiratory droplets with diameters > 5 pm). In some embodiments, the virus or variant thereof is transmitted via large respiratory droplets from an individual infected with the virus to an individual not infected with the virus. In some embodiments, the virus or variant thereof is transmitted via small respiratory droplets (e.g., respiratory droplets with diameters < 5 pm). In some embodiments, the virus or variantthereof is transmitted via small respiratory droplets from an individual infected with the virus to an individual not infected with the virus. In some embodiments, the virus or variant thereof is transmitted via aerosol. In some embodiments, the virus or variant thereof is transmitted via aerosol droplets. In some embodiments, the virus or variant thereof is transmitted via aerosol particles. In some embodiments, the virus or variant thereof is transmitted via breathing, speaking, coughing, sneezing, nose-blowing and / or nose-wiping. In some embodiments, the virus or variant thereof is transmitted via aerosol from an individual infected with the virus to an individual not infected with the virus.

[0087] In some embodiments, the individual not infected with the virus is at risk of developing severe symptoms of the viral infection. In some embodiments, the individual not infected with the virus has an underlying medical condition, such as cardiovascular disease, diabetes, chronic respiratory disease, and / or cancer. In some embodiments, the individual not infected with the virus is immunocompromised. In some embodiments, the individual not infected with the virus has not been previously infected with the virus. In some embodiments, the individual not infected with the virus has been previously infected with the virus.

[0088] In some embodiments, the individual infected with the virus shows no symptom of the infection. In some embodiments, the individual infected with the virus is not in need of treatment for the infection. In some embodiments, the individual infected with the virus has high viral titers. In some embodiments, the individual infected with the virus has tested positive for the virus. In some embodiments, the individual infected with the virus shows viral symptoms but has tested negative for the virus. In some embodiments, the individual infected with the virus has been diagnosed with a virus infection caused by the virus. In some embodiments, individual infected with the virus has been diagnosed with a coronavirus infection, an RSV infection, and / or an influenza infection.

[0089] In some embodiments, the individual not infected with the virus has tested negative for the virus. In some embodiments, the individual not infected with the virus has been in close contact with an individual infected with the virus, such as being in the same enclosed space as an infected individual (e.g., a room, home, automobile, store, restaurant, hospital, office, classroom, or recreation space). In some embodiments, the individual not infected with thevirus resides in the same residence as an individual infected with the virus, such as a residential home, senior home, or assisted living facility. In some embodiments, the individual not infected with the virus has not had known contact with an individual infected with the virus. In some embodiments, the individual not infected with the virus has had known contact with an individual infected with the virus.

[0090] In some embodiments, the methods comprise preventing the spread of a virus within a population of individuals, where the population of individuals comprises 2 or more individuals. For example, in some embodiments, the population of individuals comprises greater than about n individuals, where n is selected from 2, 5, 10, 20, 30, 40, 50, 100, 500, 1,000, 5,000, 10,000, 50,000, 100,000, 500,000, 1,000,000, 5,000,000, 10,000,000, or more. In some embodiments, the population of individuals comprises fewer than about n individuals, where n is selected from 10,000,000, 5,000,000, 1,000,000, 500,000, 100,000, 50,000, 10,000, 5,000, 1,000, 500, 100, 50, 40, 30, 20, 10, 5, or fewer. In some embodiments, the population of individuals are familiar with each other, such as family, friends, roommates, classmates, or colleagues. In some embodiments, the population of individuals are strangers.

[0091] In some embodiments, the individual infected with the virus is under treatment for the virus infection. In some embodiments, the individual infected with the virus was under treatment for the virus infection before administration of the chimeric protein. In some embodiments, the individual infected with the virus is under treatment for the virus infection concurrently with administration of the chimeric protein. In some embodiments, the individual infected with the virus begins treatment for the virus infection after the administration of the chimeric protein.

[0092] In some embodiments, the method further comprises identifying the individual infected with the virus. In some embodiments, the method further comprises identifying the individual infected with the virus to be administered the chimeric protein. In some embodiments, the identification is via a screening process. For example, the screening process may comprise, in some embodiments, testing individuals for viral infection using a nucleic acid amplification test (NAAT) (e.g., PCR test), an antigen test, a breath test, a nose or throat swab, urinesample, stool sample, tests identifying fluid around the brain and / or spinal cord, a blood sample, X-ray, ultrasound, MRI, and / or CT imaging.

[0093] In some embodiments, the provided methods of preventing transmission and / or spread of a virus comprise administering to an individual infected with the virus a composition (e.g., pharmaceutical compositions) comprising any one of the chimeric proteins described herein. In some embodiments, the provided methods of preventing transmission and / or spread of a virus comprise administering to an individual not infected with the virus a composition (e.g., pharmaceutical compositions) comprising any one of the chimeric proteins described herein. Further description surrounding the pharmaceutical compositions of the present invention is provided in Section VILA.

[0094] In some embodiments, the chimeric protein is present in a kit. For example, in some embodiments, the chimeric protein is present in a kit comprising a viral detection test, such as a coronavirus, influenza, or RSV infection detection test, and instructions for the same. Further description surrounding the kits of the present invention is provided in Section VII. B.

[0095] In some embodiments, the chimeric protein is administered by a human or a machine. In some embodiments, the chimeric protein is administered by the individual themself (e.g., the individual administers the chimeric protein to themself). In some embodiments, the chimeric protein is administered by a medical professional, such as a Doctor of Medicine, a Doctor of Osteopathy, a nurse, a nurse practitioner, a medical assistant, a hospice worker, an emergency medical technician, or another trained caretaker. In some embodiments, the chimeric protein is administered at a hospital, nursing home, or other care facility. In some embodiments, the chimeric protein is administered at a viral infection testing site, such as a coronavirus, influenza, or RSV infection testing site. In some embodiments, the chimeric protein is administered by an untrained individual. In some embodiments, the chimeric protein is administered in a non-medical location, such as a home, automobile, outside, or any other non-medical location.

[0096] In some embodiments, the chimeric protein is administered topically to the mucosa of the individual infected with the virus and / or the individual not infected with the virus. In someembodiments, the chimeric protein is administered via a nasal spray. In some embodiments, the chimeric protein is administered to both nostrils of the individual.

[0097] In some embodiments, the chimeric protein is administered once every two days, once daily, or twice daily. In some embodiments, the chimeric protein is administered more than once daily, such as twice daily, three times daily, four times daily, or more times daily. In some embodiments, the chimeric protein is administered once every two days, once every three days, once every four days, once every five days, once every six days, once a week, biweekly, once a month, once every two months, once every three months, once every four months, quarterly, once every five months, biannually, or once a year.

[0098] In some embodiments, the chimeric protein is administered within about n hours from exposure of the individual to the virus or variant thereof, where n is selected from 72, 48, 36, 24, 12, 6, 4, or less. The transmission potential of viruses, especially respiratory viruses, continues until there is an antibody response that neutralizes the virus, which typically peaks about 5-10 days in a vaccinated person, and about 10-20 days in an unvaccinated person. In some embodiments, the individual infected with the virus has been vaccinated against the virus prior to infection. In some embodiments, the individual infected with the virus has not been vaccinated against the virus prior to infection. In some embodiments, the chimeric protein is administered to the individual infected with the virus within about 14 days after a symptom is detected in the individual. In some embodiments, the individual infected with the virus has been vaccinated against the virus prior to infection, and the chimeric protein is administered to the individual infected with the virus within about n days after a symptom is detected in the individual infected with the virus, where n is selected from 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, or less. In some embodiments, the individual infected with the virus has not been vaccinated against the virus prior to infection, and the chimeric protein is administered to the individual infected with the virus within about n days after a symptom is detected in the individual infected with the virus, where n is selected from 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, or less. In some embodiments, the individual infected with the virus has been vaccinated against the virus prior to infection, and the chimeric protein is administered to the individual infected with the virus within about 3 days after a symptom is detected in the individual. In someembodiments, the individual infected with the virus has not been vaccinated against the virus prior to infection, and the chimeric protein is administered to the individual infected with the virus within about 3 days after a symptom is detected in the individual. In some embodiments, the individual infected with the virus has been vaccinated against the virus prior to infection, and the chimeric protein is administered to the individual infected with the virus within about 2 days after a symptom is detected in the individual. In some embodiments, the individual infected with the virus has not been vaccinated against the virus prior to infection, and the chimeric protein is administered to the individual infected with the virus within about 2 days after a symptom is detected in the individual. In some embodiments, the individual infected with the virus has been vaccinated against the virus prior to infection, and the chimeric protein is administered to the individual infected with the virus within about 1 day after a symptom is detected in the individual. In some embodiments, the individual infected with the virus has not been vaccinated against the virus prior to infection, and the chimeric protein is administered to the individual infected with the virus within about 1 day after a symptom is detected in the individual.

[0099] In some embodiments, the chimeric protein is administered to the individual within about n days after identification of the individual infected with the virus, where n is selected from 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, or less. In some embodiments, the individual infected with the virus has been vaccinated against the virus prior to infection. In some embodiments, the individual infected with the virus has not been vaccinated against the virus prior to infection. In some embodiments, the chimeric protein is administered to the individual infected with the virus within about 14 days after identification of the individual infected with the virus. In some embodiments, the individual infected with the virus has been vaccinated against the virus prior to infection, and where the chimeric protein is administered within about n days after identification of the individual infected with the virus, where n is selected from 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, or less. In some embodiments, the individual infected with the virus has not been vaccinated against the virus prior to infection, and where the chimeric protein is administered within about n days after identification of the individual infected with the virus, where n is selected from 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, or less. In some embodiments, the individual infected with the virus has been vaccinated against the virusprior to infection, and the chimeric protein is administered to the individual infected with the virus within about 4 days after identification of the individual infected with the virus. In some embodiments, the individual infected with the virus has not been vaccinated against the virus prior to infection, and the chimeric protein is administered to the individual infected with the virus within about 4 days after identification of the individual infected with the virus. In some embodiments, the individual infected with the virus has been vaccinated against the virus prior to infection, and the chimeric protein is administered to the individual infected with the virus within about 3 days after identification of the individual infected with the virus. In some embodiments, the individual infected with the virus has not been vaccinated against the virus prior to infection, and the chimeric protein is administered to the individual infected with the virus within about 3 days after identification of the individual infected with the virus. In some embodiments, the individual infected with the virus has been vaccinated against the virus prior to infection, and the chimeric protein is administered to the individual infected with the virus within about 2 days after identification of the individual infected with the virus. In some embodiments, the individual infected with the virus has not been vaccinated against the virus prior to infection, and the chimeric protein is administered to the individual infected with the virus within about 2 days after identification of the individual infected with the virus. In some embodiments, the individual infected with the virus has been vaccinated against the virus prior to infection, and the chimeric protein is administered to the individual infected with the virus within about 1 day after identification of the individual infected with the virus. In some embodiments, the individual infected with the virus has not been vaccinated against the virus prior to infection, and the chimeric protein is administered to the individual infected with the virus within about 1 day after identification of the individual infected with the virus. In some embodiments, the individual not infected with the virus is not administered with the chimeric protein administered to the individual infected with the virus. In some embodiments, the individual not infected with the virus is not administered with any chimeric protein.

[0100] In some embodiments, the individual not infected with the virus is also administered the chimeric protein. In some embodiments, the individual not infected with the virus is administered the same chimeric protein administered to the individual infected with the virus. In some embodiments, the individual not infected with the virus is administered a differentchimeric protein compared to the chimeric protein administered to the individual infected with the virus. For example, in some embodiments, the individual not infected with the virus is administered a chimeric protein that comprises a different target-binding moiety, a different mucoadhesive fragment, and / or a different linker compared to the chimeric protein administered to the individual infected with the virus.

[0101] In some embodiments, the individual not infected with the virus is administered with a cocktail of chimeric proteins comprising the same chimeric protein administered to the individual infected with the virus and one or more additional, different chimeric proteins targeting the same virus or a variant thereof.

[0102] In some embodiments, the individual not infected with the virus is administered the chimeric protein before the individual infected with the virus is administered the chimeric protein. In some embodiments, the individual not infected with the virus is administered the chimeric protein concurrently with the administration of the chimeric protein to the individual infected with the virus. In some embodiments, the individual not infected with the virus is administered the chimeric protein after the individual infected with the virus is administered the chimeric protein.

[0103] In some embodiments, the individual is administered an effective amount of the chimeric protein, such as any of the chimeric proteins provided herein comprising a targetbinding moiety and a mucoadhesive peptide fragment. In some embodiments, the effective amount of the chimeric protein is the dosage of chimeric protein administered to the individual over a period of time, which achieves the desired result of preventing the transmission or spread of an infection caused by a virus or a variant thereof. In some embodiments, the effective amount depends on the age, weight, sex, and / or other demographic characteristics of the individual.

[0104] In some embodiments, the effective amount for a human is between about 1 μg and about 1 mg per nostril, such as between about 10 μg and about 500 μg per nostril, between about 50 μg and about 100 μg per nostril, between about 300 μg and about 800 μg per nostril, or between about 500 μg and about 1 mg per nostril. In some embodiments, the effective amount for a human is greater than about n per nostril, where n is selected from 1μg, io μg , 20 gg, 30μg, 40μg, oμg, 60μg, 70μg, soμg, 90μg, iooμg, isoμg , 200μg, 250μg , 300μg, 350μg, 400μg, 450μg, sooμg, 550μg, 600μg, 650μg, 700μg, 750μg,800μg , 850μg, 900μg, 950μg, 1 mg, or greater. In some embodiments, the effective amount for a human is less than about n per nostril, where n is selected from 1 mg, 950μg, 900μg , 850μg, sooμg, 750μg, 700μg, 650μg, 600μg, 550μg, sooμg, 450μg, 400μg,350μg , 3ooμg, 250μg, 200μg, 150μg , 100μg, 90μg, soμg, 70μg, 60μg, soμg, 40μg,30μg, 20μg, 10μg, I μg, or less. In some embodiments, the effective amount for a human is any of about n per nostril, where n is selected from 1 μg, 10 μg, 20 μg, 30 μg, 40 μg, 50 μg, 60 μg, 70 μg, 80 μg, 90 μg, 100 μg, 150 μg, 200 μg, 250 μg, 300 μg, 350 μg, 400 μg, 450 μg, 500 μg, 550 μg, 600 μg, 650 μg, 700 μg, 750 μg, 800 μg, 850 μg, 900 μg, 950 μg, and 1 mg.

[0105] In some embodiments, the provided methods prevent the transmission and / or spread of viral infection by a virus or a variant thereof. In some embodiments, the methods prevent the transmission and / or spread of viral infection by a plurality (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) of variants of a virus.

[0106] Accordingly, there is provided a method of preventing transmission of a virus from an individual infected with the virus to an individual not infected with the virus, comprising administering to the individual infected with the virus an effective amount of a plurality of chimeric proteins, wherein each of the chimeric proteins of the plurality of chimeric proteins comprises: (a) a target-binding moiety that specifically binds to the virus; and (b) a mucoadhesive peptide fragment, wherein the mucoadhesive peptide fragment facilitates attachment of the chimeric protein to the mucosa, thereby preventing transmission of the virus to the individual not infected with the virus. In some embodiments, the mucoadhesive peptide fragment comprises at least 5 positively charged amino acid residues interspersed with one or more non-positively charged amino acid residues.

[0107] In other embodiments, there is provided a method of preventing spread of a virus within a population of individuals, wherein at least one of the individuals is infected with the virus, the method comprising administering to the at least one individual infected with the virus with an effective amount of a plurality of chimeric proteins, wherein each of thechimeric proteins of the plurality of chimeric proteins comprises: (a) a target-binding moiety that specifically binds to the virus; and (b) a mucoadhesive peptide fragment, wherein the mucoadhesive peptide fragment facilitates attachment of the chimeric protein to the mucosa, thereby preventing transmission of the virus to another individual or individuals not infected with the virus in the population. In some embodiments, the mucoadhesive peptide fragment comprises at least 5 positively charged amino acid residues interspersed with one or more non-positively charged amino acid residues.

[0108] In some embodiments, the plurality of chimeric proteins each comprise a different target-binding moiety that specifically recognizes different variants of the same virus (e.g., a coronavirus, an influenza virus, or an RSV). For example, the individual infected with the virus may be administered a cocktail of chimeric proteins each comprising a target-binding fragment derived from different variants of the same virus, such as those described herein or known in the art. In some embodiments, the mucoadhesive peptide fragment comprises at least 5 positively charged amino acid residues interspersed with one or more non-positively charged amino acid residues. In some embodiments, the chimeric protein is administered via a nasal spray. In some embodiments, the chimeric protein, e.g., any of the chimeric proteins described herein, is administered as a single agent, or in combination with a second, third, or fourth agent (including, e.g., anti-viral drugs, convalescent plasma, anti-inflammatory drugs etc.) to prevent the transmission and / or spread of the virus. In some embodiments, the plurality of chimeric proteins each comprise a different target-binding moiety that specifically recognizes different components of the same virus (e.g., a coronavirus, an influenza virus, or an RSV). For example, the individual infected with the virus may be administered a cocktail of chimeric proteins each comprising a target-binding moiety that specifically binds a different component of the same virus (e.g., each chimeric protein comprises a different antibody moiety, where each antibody moiety targeting the same virus but a different component thereof), such as those described herein or known in the art. In some embodiments, the mucoadhesive peptide fragment comprises at least 5 positively charged amino acid residues interspersed with one or more non-positively charged amino acid residues. In some embodiments, the chimeric protein is administered via a nasal spray. In some embodiments, the chimeric protein, e.g., any of the chimeric proteins described herein, is administered as a single agent, or in combination with a second, third, or fourthagent (including, e.g., anti-viral drugs, convalescent plasma, anti-inflammatory drugs etc.) to prevent the transmission and / or spread of the virus. Efficacy of the prevention of transmission or spread of the virus can be evaluated, for example, by viral load (e.g., via detection of viral DNA), duration of survival, quality of life, viral protein expression and / or activity, detection of serological antibodies against the coronavirus or variant thereof, assessment of respiratory functions, and / or CT imaging.

[0109] In some embodiments, the individual not infected with the virus or the individual(s) not infected with the virus in the population is / are not administered the chimeric protein. In some embodiments, the individual not infected with the virus is administered the chimeric protein, or at least some of the individuals not infected with the virus in the population are administered the chimeric protein.

[0110] In some embodiments, the administering of the chimeric protein to the individual infected with the virus or the at least one individual infected with the virus lowers transmission of the virus by at least about 20% (such as at least about 30%, 40%, 50%, 60%, 70%, 80%, or 90% or more) as compared to a reference. In some embodiments, the administering of the chimeric protein to the individual infected with the virus or the at least one individual infected with the virus lowers transmission of the virus by at least about 50% as compared to a reference. In some embodiments, the individual infected with the virus or the at least one individual infected with the virus does not transmit the virus to any other individuals after being administered the chimeric protein.

[0111] In some embodiments, wherein compared to a reference, the administering of the chimeric protein to the individual infected with the virus or the at least one individual infected with the virus lowers the chance of the virus being transmitted to the individual not infected with the virus or the individual(s) not infected with the virus in the population by at least about 20% (such as at least about 30%, 40%, 50%, 60%, 70%, 80%, or 90% or more). In some embodiments, wherein compared to a reference, the administering of the chimeric protein to the individual infected with the virus or the at least one individual infected with the virus lowers the proportion of individuals in the population becoming infected with the virus by at least about 20% (such as at least about 30%, 40%, 50%, 60%, 70%, 80%, or 90% ormore). In some embodiments, wherein compared to a reference, the administering of the chimeric protein to the individual infected with the virus or the at least one individual infected with the virus lowers the chance of the virus being transmitted to the individual not infected with the virus or the individual(s) not infected with the virus in the population by at least about 50%. In some embodiments, wherein compared to a reference, the administering of the chimeric protein to the individual infected with the virus or the at least one individual infected with the virus lowers the number of individuals in the population becoming infected with the virus by at least about 50%. In some embodiments, the individual infected with the virus or the at least one individual infected with the virus does not transmit the virus to any other individuals after being administered the chimeric protein.

[0112] In some embodiments, the reference is the same individual infected with the virus before the individual is administered the chimeric protein. In some embodiments, the reference is another individual who is infected with the virus but is not administered the chimeric protein. In some embodiments, the reference is not all of the at least one individual infected with the virus in a population of individuals is administered the chimeric protein. In some embodiments, the reference is none of the at least one individual infected with the virus in a population of individuals is administered the chimeric protein. In some embodiments, the reference is a reference population, wherein the reference population has identical proportion, or no more than about 5% variation in the proportion, of individual(s) infected with the virus, wherein not all of the individual(s) infected with the virus is administered the chimeric protein. In some embodiments, the proportion of individual(s) in the reference population who is / are not infected with the virus but is / are administered the chimeric protein (uninfected but chimeric protein-administered proportion) is identical to or no more than about 5% variation from the uninfected but chimeric protein-administered proportion in the population. In some embodiments, the reference is a reference population, wherein the reference population has identical proportion, or no more than about 5% variation in the proportion, of individual(s) infected with the virus, wherein none of the individual(s) infected with the virus is administered the chimeric protein. In some embodiments, the uninfected but chimeric protein-administered proportion in the reference population is identical to or no more than about 5% variation from the uninfected but chimeric protein-administered proportion in the population.

[0113] In some embodiments, the reference is an individual with identical or similar demographics (e.g., age, race, vaccination status, and / or sex) as the individual infected with the virus administered the chimeric protein. In some embodiments, the reference is an individual with an identical or similar severity of infection (e.g., viral load and / or symptoms) as the individual infected with the virus administered the chimeric protein. In some embodiments, the reference is an individual infected with the same virus (e.g. viral variant) as the individual infected with the virus administered the chimeric protein.

[0114] In some embodiments, the reference is at least one individual with identical or similar demographics (e.g., age, race, vaccination status, and / or sex) as the at least one individual infected with the virus administered the chimeric protein. In some embodiments, the reference is at least one individual with identical or similar severity of infections (e g., viral load and / or symptoms) as the at least one individual infected with the virus administered the chimeric protein. In some embodiments, the reference is at least one individual infected with the same virus (e.g. viral variant) as the at least one individual infected with the virus administered the chimeric protein.

[0115] In some embodiments, the reference is a population with identical or similar demographics (e.g., population size, population density, age distribution, race, vaccination status, and / or sex ratio) as the population comprising the individual infected with the virus or the at least one individual infected with the virus administered the chimeric protein. In some embodiments, the reference is a population with identical or similar severity of infections (e.g., viral load and / or symptoms) as the population comprising the individual infected with the virus or the at least one individual infected with the virus administered the chimeric protein. In some embodiments, the reference is a population infected with the same virus (e.g. viral variant) as the population comprising the individual infected with the virus or the at least one individual infected with the virus administered the chimeric protein.

[0116] In some embodiments, compared to a reference, the administering of the chimeric protein to the individual infected with the virus or the at least one individual infected with the virus lowers the chance of the virus being transmitted to the individual not infected with the virus or the individual(s) not infected with the virus in the population by a statisticallysignificant amount. In some embodiments, compared to a reference, the administering of the chimeric protein to the individual infected with the virus or the at least one individual infected with the virus lowers the proportion of individuals in the population becoming infected with the virus by a statistically significant amount. In some embodiments, a statistically significant amount generally means a two standard deviation or greater difference. In some embodiments, a statistically significant amount generally means a p value of 5% or lower. In some embodiments, the individual infected with the virus or the at least one individual infected with the virus does not transmit the virus to any other individuals after being administered the chimeric protein.

[0117] In some embodiments, the present application provides a method described herein comprising administration of an antibody moiety for preventing transmission or spread of influenza virus, wherein the antibody moiety specifically binds to a component of an influenza virus or a variant thereof.III. Novel Antigen Binding MoietiesA. Anti-influenza

[0118] In some aspects, the present application provides an antibody moiety that specifically binds to a component of an influenza virus or a variant thereof, wherein the antibody moiety comprises: a HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 754, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 755, a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 756, a LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 757, a LC-CDR2 comprising the amino acid sequence VDS; and a LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 759 .

[0119] In some embodiments of the anti-influenza antibody moiety described above, the antibody moiety may comprise: (a) a VH comprising the amino acid sequence of SEQ ID NO: 730 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 730; and (b) a VL comprising the amino acid sequence of SEQ ID NO: 731 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 731.

[0120] In some embodiments of the anti -influenza antibody moiety described above, the antibody moiety comprises the amino acid sequence of SEQ ID NO: 730 and the amino acid sequence of SEQ ID NO: 731.

[0121] In some embodiments of the anti-influenza antibody moiety described above, the component of the influenza virus that the antibody moiety binds to is hemagglutinin (HA).

[0122] In additional embodiments of the anti -influenza antibody moiety described above, the antibody moiety comprises the variable domain of HA17-hIgG.

[0123] In some embodiments according to (or as applied to) any of the embodiments above, the virus is an influenza virus selected from the group consisting of a Type A influenza virus (IAV), a Type B influenza virus (IBV), a Type C influenza virus (ICV), a Type D influenza virus (IDV), or a variant, subtype, or reassortant thereof. In some embodiments according to (or as applied to) any of the embodiments above, the influenza virus comprises a hemagglutinin (HA) antigen selected from the group consisting of Hl, H2, H3, H5, H6, H7, H9, and H10, or a variant or reassortant thereof. In some embodiments according to (or as applied to) any of the embodiments above, the influenza virus comprises a neuraminidase (NA) antigen selected from the group consisting of Nl, N2, N3, N7, N8, and N9, or a variant or reassortant thereof. In some embodiments according to (or as applied to) any of the embodiments above, the influenza virus is selected from the group consisting of H1N1, H1N2, H2N2, H3N2, H3N8, H5N1, H5N9, H6N1, H7N2, H7N3, H7N7, H7N9, H9N2, H10N7, or a variant or reassortant thereof.B. Trispecifc Antibodies

[0124] In one aspect, the present application provides, a trispecific target- binding moiety that comprises an ACE2 fragment comprising the EBD of an ACE2 protein or variant thereof; an anti-influenza antibody moiety that specifically binds to a component of an influenza virus or a variant thereof; and an anti- RSV antibody moiety that specifically binds to a component of an RSV or a variant thereof.

[0125] In some embodiments according to any of the preceding embodiments of the trispecific target-binding moiety, the trispecific target-binding moiety comprises antibody fragments or domains that recognize viral surface proteins from different viruses.

[0126] In some embodiments according to any of the preceding embodiments of the tri specific target-binding moiety, the anti-influenza antibody moiety and the anti-RSV antibody moiety are located at the N-terminus of the trispecific target-binding moiety.

[0127] In some embodiments according to any of the preceding embodiments of the trispecific target-binding moiety, the ACE2 EBD fragment is fused to the C-terminus of the antiinfluenza antibody moiety and / or the anti-RSV antibody moiety, directly or indirectly. In some embodiments, the ACE2 fragment comprises the EBD of a human ACE2 (hACE2) protein or a variant thereof.

[0128] In some embodiments according to any of the preceding embodiments of the trispecific target-binding moiety, the trispecific target-binding moiety of claim 84 or 85, wherein the target-binding moiety comprises:(i) amino acids 24-42 of a full-length hACE2 protein comprising the amino acid sequence of SEQ ID NO: 246, or a variant thereof having at least about 90% sequence identity to amino acids 24-42 of a full-length hACE2 protein comprising the amino acid sequence of SEQ ID NO:246; and / or(ii) the amino acid sequence of SEQ ID NO: 254, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 254.

[0129] In some embodiments according to any of the preceding embodiments of the trispecific target-binding moiety, the trispecific target-binding moiety comprises the amino acid sequence of any one of SEQ ID NOs: 246-253 and 256-261, or a variant thereof having at least about 90% sequence identity the amino acid sequence of any one of SEQ ID NOs: 246- 253 and 256-261.

[0130] In some embodiments according to any of the preceding embodiments of the trispecific target-binding moiety, the trispecific target-binding moiety comprises: a first polypeptide chain which comprises an influenza-binding sequence, and a second polypeptide chain which comprises an RSV-binding sequence. In some embodiments, the influenza-binding sequence comprises an influenza-binding VH and / or an influenza-binding VL. In some embodiments, the influenza-binding sequence comprises both an influenza-binding VH and an influenza-binding VL. In some embodiments, the RSV-binding sequence comprises an RSV-binding VH and / or an RSV-binding VL. In some embodiments, the RSV-binding sequence comprises both an RSV-binding VH and an RSV-binding VL.

[0131] In some embodiments according to any of the preceding embodiments of the trispecific target-binding moiety, the influenza-binding sequence comprises an influenza-binding VH but not an influenza-binding VL, wherein the trispecific target-binding moiety comprises a third polypeptide chain which comprises an influenza-binding VL.

[0132] In some embodiments according to any of the preceding embodiments of the trispecific target-binding moiety, the RSV-binding sequence comprises an RSV-binding VH but not an RSV-binding VL, wherein the trispecific target-binding moiety comprises a fourth polypeptide chain which comprises an RSV-binding VL.

[0133] In some embodiments according to any of the preceding embodiments of the trispecific target-binding moiety, the trispecific target-binding moiety also comprises an immunoglobulin constant region. In some embodiments, the trispecific target-binding moiety comprises a heavy chain constant domain (CH) 1 and a light chain constant domain (CL). ISE1, the trispecific target-binding moiety comprises a CH2 domain and a CH3 domain.

[0134] In some embodiments according to any of the preceding embodiments of the trispecific target-binding moiety, the trispecific target-binding moiety does not comprise an immunoglobulin constant region.

[0135] In some embodiments according to any of the preceding embodiments of the trispecific target-binding moiety, both the first and the second polypeptide chains of the trispecific target-binding moiety comprise an ACE2 fragment. ISE1, both the first and the second polypeptide chains comprise a CH2 domain and a CH3 domain.

[0136] In some embodiments according to any of the preceding embodiments of the trispecific target-binding moiety, the anti-influenza antibody moiety comprises: a HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 754 ; a HC-CDR2 comprising the amino acid sequence of SEQ ID NO:755 ;a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 756 ; a LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 757 ; a LC-CDR2 comprising the amino acid sequence VDS; and a LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 759 .

[0137] In some embodiments according to any of the preceding embodiments of the trispecific target-binding moiety ,the anti-influenza antibody moiety comprises: (i) a VH comprising the amino acid sequence of SEQ ID NO: 730 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 730; and a VL comprising the amino acid sequence of SEQ ID NO: 731 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 731.

[0138] In some embodiments according to any of the preceding embodiments of the trispecific target-binding moiety, the anti-RSV antibody moiety comprises: a HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 689 ; a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 690; a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 691 ; a LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 692 ; a LC-CDR2 comprising the amino acid sequence DTS; and a LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 694 .

[0139] In some embodiments , the anti-RSV antibody moiety comprises: a VH comprising the amino acid sequence of SEQ ID NO: 687 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 687; and a VL comprising the amino acid sequence of SEQ ID NO: 688 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 688.

[0140] In one aspect, the present application provides, a trispecific target-binding moiety that comprises: a first polypeptide chain comprising the amino acid sequence of SEQ ID NO: 745; a second polypeptide chain comprising the amino acid sequence of SEQ ID NO: 748; a third polypeptide chain comprising the amino acid sequence of SEQ ID NO: 747; and a fourth polypeptide chain comprising the amino acid sequence of SEQ ID NO: 749.

[0141] In some embodiments, the viral pathogens are influenza and RSV, and the trispecific antibody chimeric protein encodes an anti-influenza antibody or fragment and an anti-RSV antibody or fragment. The trispecific target-binding moiety of the trispecific antibody chimeric protein may be animal, human, humanized, camelid, or chimeric. In some embodiments, the trispecific target binding moiety is a full-length antibody. In other embodiments, the binding moiety of an antibody can be selected from a group comprising a Fab, a Fab', a (Fab')2, an Fv, a single chain Fv (scFv), an scFv-Fc, a disulfide stabilized Fv fragment (dsFv), a (dsFv)2, an scFv dimer, a domain antibody, such as a camelized single domain antibody (sdAb), a nanobody, a bivalent domain antibody, a minibody, and a VHH. The anti-influenza antibody targets the HA protein of influenza strains and prevents the virus from initiating an infection. The anti-HA antibody can be any of the anti-HA antibodies listed in Table 2. The anti-HA antibodies can be any of the influenza antibodies disclosed in the Examples. The anti-influenza antibodies can be directed to the NA protein of influenza virus, such as those listed in Table 2. Suitable anti-influenza antibodies or antibody fragments can be derived from antibodies other than those listed in Table 2 or the Examples, a survey of the scientific literature can identify additional antibodies and antibody fragments.

[0142] In some embodiments, the trispecific target-binding moiety may comprise antibody moieties that specifically bind to components of influenza virus and respiratory syncytial virus (RSV). The antibody moieties may include an anti-influenza antibody moiety and an anti-RSV antibody moiety.

[0143] The anti-influenza antibody targets the HA protein of influenza strains and prevents the virus from initiating an infection. The anti-HA antibody can be any of the anti-HA antibodies listed in Table 2. The anti-HA antibodies can be any of the influenza antibodies disclosed in the Examples. The anti-influenza antibodies can be directed to the NA protein of influenza virus, such as those listed in Table 2. Suitable anti-influenza antibodies or antibody fragments can be derived from antibodies other than those listed in Table 2 or the Examples, a survey of the scientific literature can identify additional antibodies and antibody fragments.

[0144] In certain embodiments, the anti -influenza antibody moiety of the trispecific target binding moiety may comprise a heavy chain and a light chain. The heavy chain may include three complementarity determining regions (CDRs): HC-CDR1, HC-CDR2, and HC-CDR3. The light chain may include three CDRs: LC-CDR1, LC-CDR2, and LC-CDR3. These CDRs may be responsible for the specific binding of the antibody to influenza virus components.

[0145] In some embodiments, the anti -RS V antibody or fragment of the tri specific target binding moiety may target the RSV F protein, as described in the Examples or listed in Table C. The RSV F protein directs the fusion of viral and cellular membranes to promote viral penetration. Antibodies that target the RSV F protein block the viral F protein from encountering its cellular receptors (nucleolin and IGF1R) The anti-RSV antibodies can also be directed to the RSV G protein as listed in Table C; the RSV G protein promotes viral infection by binding its cellular receptor CX3CR1, which is enriched in cells of the airway epithelium. Other suitable antibodies or fragments that target the RSV G protein can be found in the scientific literature.

[0146] In some embodiments, the anti-RSV antibody moiety of the trispecifc target binding moiety may comprise a heavy chain and a light chain, each containing three CDRs. The heavy chain may include HC-CDR1, HC-CDR2, and HC-CDR3, while the light chain may include LC-CDR1, LC-CDR2, and LC-CDR3. These CDRs may confer specificity for binding to RSV components.IV. Chimeric Proteins

[0147] The present application provides chimeric proteins (such as fusion proteins, i.e., coronavirus chimeric proteins, ACE2 chimeric proteins, influenza chimeric proteins, andRSV chimeric proteins) comprising: (a) a target-binding moiety that specifically binds to a virus; and (b) a mucoadhesive peptide fragment, wherein the mucoadhesive peptide fragment facilitates attachment of the chimeric protein to the mucosa. In some embodiments, the mucoadhesive peptide fragment comprises at least about 5 (e.g., about 5 to about 30) positively charged amino acid residues. In some embodiments, the positively charged amino acid residues are selected from the group consisting of lysine, arginine, histidine, ornithine, and combinations thereof. In some embodiments, the positively charged amino acid residues are lysines. In some embodiments, the mucoadhesive peptide fragment is a polylysine peptide having at least about 5 (e.g., about 5 to about 30, such as about 12) lysines (including for example at least about 5 (e.g., about 5 to about 30, such as about 12) contiguous lysines). In some embodiments, the positively charged amino acid residues are histidines. In some embodiments, the mucoadhesive peptide fragment is a polyhistidine peptide having at least about 5 (e.g., about 5 to about 30, such as about 12) histidines (including for example at least about 5 (e.g., about 5 to about 30, such as about 12) contiguous histidines). In some embodiments, the positively charged amino acid residues are arginines. In some embodiments, the mucoadhesive peptide fragment is a polyarginine peptide having at least about 5 (e.g., about 5-30 such as 12) arginines (including for example at least about 5 (e.g., about 5-30 such as 12) contiguous arginines). In some embodiments, the positively charged amino acid residues are ornithines. In some embodiments, the mucoadhesive peptide fragment is a polyornithine peptide having at least about 5 (e.g., about 5 to about 30, such as about 12) ornithines (including for example at least about 5 (e.g., about 5 to about 30, such as about 12) contiguous ornithines). In some embodiments, the positively charged amino acid residues are contiguous with each other. In some embodiments, the positively charged amino acid residues are interspersed with non-positively charged amino acid residues. In some embodiments, the mucoadhesive peptide fragment is covalently fused to the target-binding moiety. In some embodiments, the mucoadhesive peptide fragment is non-covalently associated with the target-binding moiety, e.g., via an oligomerization and / or multimerization domain. In some embodiments, the virus causes a respiratory infection. In some embodiments, the virus is a coronavirus or variant thereof, respiratory syncytial virus (RSV) or variant thereof, or influenza virus or variant thereof. In some embodiments, the mucosa is selected from the group consisting of nasal mucosa, nasopharyngeal mucosa, posteriororopharyngeal mucosa, and combinations thereof. In some embodiments, the target-binding moiety is directly fused to the mucoadhesive peptide fragment. In some embodiments, the target-binding moiety is fused to the mucoadhesive peptide fragment via peptide linker. In some embodiments, the peptide linker comprises the amino acid sequence of any one of the peptide linkers described in Table 20.

[0148] In some embodiments, the chimeric protein (e.g., fusion protein) comprises: (a) an antibody moiety that specifically binds a component of a virus; and (b) a mucoadhesive peptide fragment, wherein the mucoadhesive peptide fragment facilitates attachment of the chimeric protein to the mucosa. In some embodiments, the antibody moiety is a full-length antibody (e.g., IgG, IgA, IgM or IgD). In some embodiments, the antibody moiety is an antigen-binding fragment selected from the group consisting of a Fab, a Fab’, a (Fab’) , an Fv, a single chain Fv (scFv), a disulfide stabilized Fv fragment (dsFv), a (dsFv)?, an scFv dimer, a domain antibody, a single domain antibody, a bivalent domain antibody, and a minibody. In some embodiments, the virus causes a respiratory infection. In some embodiments, the virus is a coronavirus or variant thereof, respiratory syncytial virus (RSV) or variant thereof, or influenza virus or variant thereof. In some embodiments, the virus is a coronavirus selected from the group consisting of SARS-CoV, SARS-CoV-2, and a variant, subtype, or reassortant thereof. In some embodiments, the virus is SARS-CoV-2 or a variant, subtype, or reassortant thereof, selected from the group consisting of WIV4, a B.1 .1 .7 variant, a B.1.351 variant, a Delta (B.1.617.1) variant, an A.23.1 variant, a B.1.525 variant, a BA.2 variant, a BA.5.1.1 variant, a BQ.1 variant, an XBB.1.5 variant, a BA.2.86 variant, a JN.1 variant, a KP.1.1 variant, a JN.1.13.1 variant, a JN.1.16 variant, a IN.1.7 variant, a KQ.1 variant, a JN.1.8.1 variant, a JN.1.11.1 variant, a JN.1.18 variant, a KP.2 (also known as JN.1.11.1.2) variant, a BA.1 variant, a KP.3 variant, and an LB. 1 variant. In some embodiments, the antibody moiety specifically binds to a spike (S) protein of SARS-CoV-2. In some embodiments, the virus is an influenza virus selected from the group consisting of a Type A influenza virus (IAV), a Type B influenza virus (IBV), a Type C influenza virus (ICV), a Type D influenza virus (IDV), or a variant, subtype, or reassortant thereof. In some embodiments, the influenza virus comprises a hemagglutinin (HA) antigen selected from the group consisting of Hl, H2, H3, H5, H6, H7, H9, and H10, or a variant or reassortant thereof. In some embodiments, the influenza virus comprises a neuraminidase (NA) antigen selectedfrom the group consisting of Nl, N2, N3, N7, N8, and N9, or a variant or reassortant thereof. In some embodiments, the influenza virus is selected from the group consisting of H1N1, H1N2, H2N2, H3N2, H3N8, H5N1, H5N9, H6N1, H7N2, H7N3, H7N7, H7N9, H9N2, H10N7, or a variant or reassortant thereof. In some embodiments, the antibody moiety specifically binds HA. In some embodiments, the antibody moiety specifically binds NA. In some embodiments, the mucosa is selected from the group consisting of nasal mucosa, nasopharyngeal mucosa, posterior oropharyngeal mucosa, and combinations thereof. In some embodiments, the mucoadhesive peptide fragment comprises the amino acid sequence of any one of the mucoadhesive peptide fragments described in Table 19. In some embodiments, the target-binding moiety is directly fused to the mucoadhesive peptide fragment. In some embodiments, the target-binding moiety is fused to the mucoadhesive peptide fragment via peptide linker. In some embodiments, the peptide linker comprises the amino acid sequence of any one of the peptide linkers described in Table 20.

[0149] In some embodiments, the chimeric protein (e.g., fusion protein) comprises: (a) a target-binding moiety comprising an inhibitory polypeptide that inhibits binding of a virus to a receptor on a cell of the mucosa; and (b) a mucoadhesive peptide fragment, wherein the mucoadhesive peptide fragment facilitates attachment of the chimeric protein to the mucosa. In some embodiments, the target-binding moiety comprises a natural receptor of the virus or a variant derived from the natural receptor of the virus. In some embodiments, the virus is a coronavirus selected from the group consisting of SARS-CoV, SARS-CoV-2, and a variant, subtype, or reassortant thereof. In some embodiments, the virus is SARS-CoV-2 or a variant, subtype, or reassortant thereof, selected from the group consisting of WIV4, a B.1.1.7 variant, a B.1.351 variant, a Delta (B.1.617.1) variant, an A.23.1 variant, a B.1.525 variant, a BA.2 variant, a BA.5.1. 1 variant, a BQ.1 variant, an XBB.1.5 variant, a BA.2.86 variant, a JN.1 variant, a KP.1.1 variant, a JN.1.13.1 variant, a JN.1.16 variant, a JN.1.7 variant, a KQ.1 variant, a JN.1.8.1 variant, a JN.1.11.1 variant, a JN.1.18 variant, a KP.2 (also known as JN.1.11.1.2) variant, a BA.1 variant, a KP.3 variant, and an LB.1 variant. In some embodiments, the target-binding moiety specifically binds to a spike (S) protein of SARS- CoV-2. In some embodiments, the target-binding moiety comprises an extracellular binding domain (EBD) of a human ACE2 (hACE2) protein or a fragment thereof that specifically binds to an S protein of a coronavirus. In some embodiments, the target-binding moietycomprises an EBD of an animal ACE2 protein or a fragment thereof that specifically binds to an S protein of a coronavirus. In some embodiments, the mucosa is selected from the group consisting of nasal mucosa, nasopharyngeal mucosa, posterior oropharyngeal mucosa, and combinations thereof In some embodiments, the mucoadhesive peptide fragment comprises the amino acid sequence of any one of the mucoadhesive peptide fragments described in Table 19. In some embodiments, the target-binding moiety is directly fused to the mucoadhesive peptide fragment. In some embodiments, the target-binding moiety is fused to the mucoadhesive peptide fragment via peptide linker. In some embodiments, the peptide linker comprises the amino acid sequence of any one of the peptide linkers described in Table 20.

[0150] In some embodiments, the half-life of the chimeric protein on the mucosa is at least about n hours, where n is selected from 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours 22 hours, 24 hours, 30 hours, 36 hours, 48 hours, or more. In some embodiments, the half-life of the chimeric protein on the mucosa is at least 12 hours. In some embodiments, the half-life of the chimeric protein on the mucosa is at least 24 hours.

[0151] The half-life of the chimeric protein on the mucosa may be determined using known in vitro assays in the art. In view of the size and polar properties of the chimeric protein, mucosal (e.g, nasal) absorption of the chimeric protein is minimal because of low membrane permeability of the chimeric protein. However, mucociliary clearance of the chimeric protein may play a role in the half-life of the chimeric proteins. The mucoadhesive peptide fragment can improve the retention time of the chimeric protein on the mucosa. For example, an in vitro model cell system, such as mucosal epithelial cells, may be used to determine the amount of the chimeric protein remaining on cell / mucin surface by FACS or immunofluorescence. As another example, mucosa related components, such as mucin, could be used to incubate with a chimeric protein and determine the amount of the chimeric protein associated with mucin by ELISA.

[0152] In some embodiments, the chimeric protein comprises: (a) a target-binding moiety that specifically binds to a coronavirus; and (b) a mucoadhesive peptide fragment comprising at least about 5 (e.g, about 5 to about 30) positively charged amino acid residues, wherein themucoadhesive peptide fragment facilitates attachment of the chimeric protein to a mucosa. In some embodiments, the coronavirus is SARS-CoV, SARS-CoV-2, a variant, subtype, or reassortant thereof. In some embodiments, the coronavirus is SARS-CoV-2, or a variant, subtype, or reassortant thereof. In some embodiments, the SARS-CoV-2 is WIV4, a B.1.1.7 variant, a B.1.351 variant, a Delta (B.1.617.1) variant, an A.23.1 variant, a B.1.525 variant, a BA.2 variant, a BA.5.1.1 variant, a BQ.1 variant, an XBB.1.5 variant, a BA.2.86 variant, a JN.1 variant, a KP.1.1 variant, a JN.1.13.1 variant, a JN.1.16 variant, a JN.1.7 variant, a KQ.1 variant, a JN.1.8.1 variant, a JN.1.11.1 variant, a JN.1.18 variant, a KP.2 (also known as JN.1.11.1.2) variant, a BA.1 variant, a KP.3 variant, or an LB.1 variant. In some embodiments, the target-binding moiety is an antibody moiety. In some embodiments, the antibody moiety is a full-length antibody (e.g., IgG, IgA, IgM or IgD). In some embodiments, the antibody moiety is an antigen-binding fragment selected from the group consisting of a Fab, a Fab’, a (Fab’)2, an Fv, a single chain Fv (scFv), a disulfide stabilized Fv fragment (dsFv), a (dsFv)2, an scFv dimer, a domain antibody, a single domain antibody, a bivalent domain antibody, and a minibody. In some embodiments, the mucoadhesive peptide fragment comprises the amino acid sequence of any one of the mucoadhesive peptide fragments described in Table 19. In some embodiments, the target-binding moiety is directly fused to the mucoadhesive peptide fragment. In some embodiments, the target-binding moiety is fused to the mucoadhesive peptide fragment via peptide linker. In some embodiments, the peptide linker comprises the amino acid sequence of any one of the peptide linkers described in Table 20.

[0153] In some embodiments, the chimeric protein comprises: (a) an antibody moiety that specifically binds to an S protein of a coronavirus; and (b) a mucoadhesive peptide fragment comprising at least about 5 (e.g., about 5 to about 30) positively charged amino acid residues, wherein the mucoadhesive peptide fragment facilitates attachment of the chimeric protein to a mucosa. In some embodiments, the target-binding moiety specifically binds an SI subunit of the S protein of the coronavirus. In some embodiments, the S protein is any one of the S proteins described in Table 4. In some embodiments, the coronavirus is SARS-CoV-2 or a variant thereof. In some embodiments, the antibody moiety is a full-length antibody (e.g., IgG, IgA, IgM or IgD). In some embodiments, the antibody moiety is an antigen-binding fragment selected from the group consisting of a Fab, a Fab’, a (Fab’)2, an Fv, a single chainFv (scFv), a disulfide stabilized Fv fragment (dsFv), a (dsFv)2, an scFv dimer, a domain antibody, a single domain antibody, a bivalent domain antibody, and a minibody. In some embodiments, the antibody moiety comprises the amino acid sequence of any one of the SARS-CoV-2 antibody CDR sequences described in Table 5, e.g.. in some embodiments, the antibody moiety comprises an HC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 156, 162, 168, 174, 180, 186, 192, 198, 204, 210, and 681, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 157, 163, 169, 175, 181, 187, 193, 199, 205, 211, and 682, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 158, 164, 170, 176, 182, 188, 194, 200, 206, 212, and 683, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, an LC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 159, 165, 171, 177, 183, 189, 195, 201, 207, 213, and 684, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, an LC-CDR2 comprising the amino acid sequence of any one of SNN, EDK, RNN, FND, EVS, VSN, GND, and GSS, or a variant thereof comprising about 1 or about 2 amino acid substitutions, and an LC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 161, 167, 173, 179, 185, 191, 197, 203, 209, 215, and 686, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions. In some embodiments, the antibody moiety comprises the amino acid sequence of any one of the SARS-CoV-2 antibody VH and / or VL sequences described in Table 6, e.g., in some embodiments, the antibody moiety comprises a VH comprising the amino acid sequence of any one of SEQ ID NOs: 216, 218, 220, 222, 224, 226, 228, 230, 232, 234, and 679, or a variant thereof having at least about 90% (such as about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) sequence identity to the amino acid sequence of any one of SEQ ID NOs: 216, 218, 220, 222, 224, 226, 228, 230, 232, 234, and 679, and / or the target-binding moiety comprises a VL comprising the amino acid sequence of any one of SEQ ID NOs: 217, 219, 221, 223, 225, 227, 229, 231, 233, 235, and 680, or a variant thereof having at least about 90% (such as about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%)sequence identity to the amino acid sequence of any one of SEQ ID NOs: 217, 219, 221, 223, 225, 227, 229, 231, 233, 235, and 680. In some embodiments, the antibody moiety comprises the amino acid sequence of any one of the SARS-CoV-2 antibody scFv described in Table 7, e.g.. in some embodiments, the antibody moiety comprises the amino acid sequence of any one of SEQ ID NOs: 236-245 or a variant thereof having at least about 90% (such as about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) sequence identity to the amino acid sequence of any one of SEQ ID NOs: 236-245. In some embodiments, the chimeric protein comprises the amino acid sequence of SEQ ID NO: 652, or a variant thereof having at least about 90% (such as about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) sequence identity to the amino acid sequence of SEQ ID NO: 652. In some embodiments, the chimeric protein comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 653, or a variant thereof having at least about 90% (such as about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) sequence identity to the amino acid sequence of SEQ ID NO: 653, and a second polypeptide comprising the amino acid sequence of SEQ ID NO: 654, or a variant thereof having at least about 90% (such as about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) sequence identity to the amino acid sequence of SEQ ID NO: 654. In some embodiments, the chimeric protein comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 655, or a variant thereof having at least about 90% (such as about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) sequence identity to the amino acid sequence of SEQ ID NO: 655, and a second polypeptide comprising the amino acid sequence of SEQ ID NO: 654, or a variant thereof having at least about 90% (such as about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) sequence identity to the amino acid sequence of SEQ ID NO: 654. In some embodiments, the chimeric protein comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 656, or a variant thereof having at least about 90% (such as about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) sequence identity to the amino acid sequence of SEQ ID NO: 656, and a second polypeptide comprising the amino acid sequence of SEQ ID NO: 654, or a variant thereof having at leastabout 90% (such as about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) sequence identity to the amino acid sequence of SEQ ID NO: 654. In some embodiments, the mucoadhesive peptide fragment comprises the amino acid sequence of any one of the mucoadhesive peptide fragments described in Table 19. In some embodiments, the antibody moiety is directly fused to the mucoadhesive peptide fragment. In some embodiments, the antibody moiety is fused to the mucoadhesive peptide fragment via peptide linker. In some embodiments, the peptide linker comprises the amino acid sequence of any one of the peptide linkers described in Table 20. Additional exemplary SARS-CoV-2 chimeric proteins, and anti-SARS-CoV-2 antibody moieties, are described in WO2022 / 082217A1, which is hereby incorporated by reference in its entirety.

[0154] In some embodiments, the chimeric protein comprises a target-binding moiety comprising between about 12 amino acids (aa) and about 805 aa of a full-length hACE2 protein or a fragment thereof (e.g., an EBD of an ACE2 protein or a fragment thereof, such as SEQ ID NO: 246), such as between about 12 aa and about 700 aa, between about 15 aa and about 500 aa, between about 100 aa and about 300 aa, between about 200 aa and about 400 aa, between about 300 aa and about 500 aa, between about 400 aa and about 600 aa, between about 500 aa and about 700 aa, between about 600 aa and about 805 aa, between about 12 aa and about 20 aa, between about 15 aa and about 20 aa, between about 21 aa and about 42 aa, between about 30 aa and about 41 aa, or between about 500 aa and about 805 aa. In some embodiments, the chimeric protein comprises a target-binding moiety comprising greater than about 12 aa of a full-length hACE2 protein or a fragment thereof, such any greater than about n, where n is selected from 13 aa, 14 aa, 15 aa, 16 aa, 17 aa, 18 aa, 19, aa, 20 aa, 30 aa, 40 aa, 50 aa, 100 aa, 150 aa, 200 aa, 250 aa, 300 aa, 350 aa, 400 aa, 450 aa, 500 aa, 550 aa, 600 aa, 650 aa, 700 aa, 750 aa, 800 aa, 850 aa, or more. In some embodiments, the chimeric protein comprises a target-binding moiety comprising less than about 805 aa of a full-length hACE2 protein or a variant thereof, such as less than about n, where n is selected from 800 aa, 750 aa, 700 aa, 650 aa, 600 aa, 550 aa, 500 aa, 450 aa, 400 aa, 350 aa, 300 aa, 250 aa, 200 aa, 150 aa, 100 aa, 50 aa, 40 aa, 30 aa, 20 aa, 19aa, 18aa, 17aa, 16aa, 15 aa, 14 aa, 13 aa, 12 aa, or less. In some embodiments, the chimeric protein comprises a target-binding moiety comprising any of about 805 aa, about 714 aa, about 596 aa, about 380aa, about 342 aa, about 331 aa, about 182 aa, about 19 aa, or about 12 aa, of a full-length hACE2 protein or a variant thereof.

[0155] In some embodiments, the chimeric protein comprises a target-binding moiety comprising between about 12 aa and about 805 aa of a full-length animal ACE2 protein or a variant thereof, such as between about 12 aa and about 700 aa, between about 15 aa and about 500 aa, between about 100 aa and about 300 aa, between about 200 aa and about 400 aa, between about 300 aa and about 500 aa, between about 400 aa and about 600 aa, between about 500 aa and about 700 aa, between about 600 aa and about 805 aa, between about 15 aa and about 20 aa, between about 12 aa and about 20 aa, between about 21 aa and about 42 aa, between about 30 aa and about 41 aa, or between about 500 aa and about 805 aa, of a full- length animal ACE2 protein or a variant thereof. In some embodiments, the chimeric protein comprises a target-binding moiety comprising greater than about 12 aa of a full-length animal ACE2 protein or a variant thereof, such any greater than about n, where n is selected from 13 aa, 14 aa, 15 aa, 16 aa, 17 aa, 18 aa, 19, aa, 20 aa, 30 aa, 40 aa, 50 aa, 100 aa, 150 aa, 200 aa, 250 aa, 300 aa, 350 aa, 400 aa, 450 aa, 500 aa, 550 aa, 600 aa, 650 aa, 700 aa, 750 aa, 800 aa, 850 aa, or more, of a full-length animal ACE2 protein or a variant thereof. In some embodiments, the chimeric protein comprises a target-binding moiety comprising less than about 805 aa of a full-length animal ACE2 protein or a variant thereof, such as less than about n, where n is selected from 800 aa, 750 aa, 700 aa, 650 aa, 600 aa, 550 aa, 500 aa, 450 aa, 400 aa, 350 aa, 300 aa, 250 aa, 200 aa, 150 aa, 100 aa, 40 aa, 30 aa, 50 aa, 20 aa, 19aa, 18aa, 17aa, 16aa, 15 aa, 14 aa, 13 aa, 12 aa, or less, of a full-length animal ACE2 protein or a variant thereof. In some embodiments, the chimeric protein comprises a target-binding moiety comprising any of about 805 aa, about 714 aa, about 596 aa, about 380 aa, about 342 aa, about 331 aa, about 182 aa, about 19 aa, or about 12 aa, of a full-length animal ACE2 protein or a variant thereof.

[0156] In some embodiments, the chimeric protein comprises a target-binding moiety comprising a fragment that selectively recognizes an SI subunit of the S protein and is capable of interfering with SI binding to a full-length ACE2. In some embodiments, the chimeric protein comprises a target-binding moiety comprising amino acids 24-42 of a full- length ACE2 protein (e.g., a full-length hACE2 protein) or a variant thereof. In someembodiments, the chimeric protein comprises a target-binding moiety comprising between about 12 aa and about 19 aa, such as between about 12 aa and about 14 aa, between about 13 aa and about 15 aa, between about 14 aa and about 16 aa, between about 15 aa and about 17 aa, between about 16 aa and about 18 aa, between about 17 aa and about 19 aa, or between about 18 aa and about 19 aa of amino acids 24-42, of a full-length ACE2 protein or a variant thereof. In some embodiments, the chimeric protein comprises a target-binding moiety comprising at least about 12 aa, such as at least about n, where n is selected from 13aa, 14 aa, 15 aa, 16 aa, 17 aa, and 18 aa, of SEQ ID NO: 254. In some embodiments, the chimeric protein comprises a target-binding moiety comprising greater than about 12 aa, such as greater than about n, where n is selected from 13 aa, 14 aa, 15 aa, 16 aa, 17 aa, and 18 aa, of SEQ ID NO: 254. In some embodiments, the chimeric protein comprises a target-binding moiety comprising less than about 20 aa, such as at less than about n, where n is selected from 19 aa, 18 aa, 17 aa, 16 aa, 15 aa, 14 aa, 13 aa, 12 aa, or fewer, of SEQ ID NO: 254. In some embodiments, the chimeric protein comprises a target-binding moiety comprising about 19 aa of SEQ ID NO: 254. In some embodiments, the chimeric protein comprises a targetbinding moiety comprising the amino acid sequence of SEQ ID NO: 254, or a variant thereof comprising at least about 90% (such as about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) sequence identity to the amino acid sequence of SEQ ID NO: 254.

[0157] In some embodiments, the chimeric protein comprises a target-binding moiety comprising amino acids 30-41 of a full-length ACE2 protein (e.g., a full-length hACE2 protein or a full-length animal ACE2 protein) or a variant thereof. In some embodiments, the chimeric protein comprises a target-binding moiety comprising the amino acid sequence of any one of SEQ ID NOs: 255, 276-285, and 287, or a variant thereof comprising at least about 90% (such as about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) sequence identity to any one of SEQ ID NOs: 255, 276-285, and 287. In some embodiments, the full-length ACE2 protein or a variant thereof is a hACE2 protein or variant thereof. In some embodiments, the full-length ACE2 protein or variant thereof is not a canine or a chicken full-length ACE2 protein or variant thereof.

[0158] In some embodiments, the chimeric protein comprises a target-binding moiety comprising amino acids 29-40 of a full-length ACE2 protein (e.g., a full-length animal ACE2 protein) or a variant thereof. In some embodiments, the chimeric protein comprises a targetbinding moiety comprising the amino acid sequence of SEQ ID NO: 275 or 286, or a variant thereof comprising at least about 90% (such as about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) sequence identity to SEQ ID NO: 275 or 286. In some embodiments, the full-length ACE2 protein or variant thereof is a canine or a chicken ACE2 protein or a variant thereof.

[0159] In some embodiments, the chimeric protein comprises: (a) a target-binding moiety comprising an EBD of a hACE2 protein or a fragment thereof that specifically binds to an S protein of a coronavirus; and (b) a mucoadhesive peptide fragment comprising at least about 5 (e.g., about 5 to about 30) positively charged amino acid residues, wherein the mucoadhesive peptide fragment facilitates attachment of the chimeric protein to a mucosa. In some embodiments, the target-binding moiety specifically binds an SI subunit of the S protein of the coronavirus. In some embodiments, the S protein is any one of the S proteins described in Table 4. In some embodiments, the coronavirus is SARS-CoV-2 or a variant thereof. In some embodiments, the target-binding moiety comprises the amino acid sequence of any one of the hACE2 proteins or fragments thereof described in Table 8, e.g., in some embodiments, the target-binding moiety comprises the amino acid sequence of any one of SEQ ID NOs: 246-253 and 256-261, or a variant thereof having at least about 90% (such as about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) sequence identity to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NOs: 246-253 and 256-261. In some embodiments, the target-binding moiety comprises the amino acid sequence of SEQ ID NO: 254, or a variant thereof comprising at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 254. In some embodiments, the target-binding moiety comprises the amino acid sequence of SEQ ID NO: 255, or a variant thereof comprising at least about 90% (such as about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) sequence identity to the amino acid sequence of SEQ ID NO: 255. In some embodiments, the chimeric protein comprises the amino acid sequence of any one of the hACE2 chimeric proteins described in Table 1, e.g., in some embodiments, the chimeric protein comprises the aminoacid sequence of any one of SEQ TD NOs: 1-10, or a variant thereof having at least about 90% (such as about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) sequence identity to the amino acid sequence of any one of SEQ ID NOs: 1-10.

[0160] In some embodiments, the chimeric protein comprises: (a) a target-binding moiety comprising an EBD of an animal ACE2 protein or a fragment thereof that specifically binds to an S protein of a coronavirus; and (b) a mucoadhesive peptide fragment comprising at least about 5 (e.g., about 5 to about 30) positively charged amino acid residues, wherein the mucoadhesive peptide fragment facilitates attachment of the chimeric protein to a mucosa. In some embodiments, the target-binding moiety specifically binds an SI subunit of the S protein of the coronavirus. In some embodiments, the S protein is any one of the S proteins described in Table 4. In some embodiments, the coronavirus is SARS-CoV-2 or a variant thereof. In some embodiments, the target-binding moiety comprises the amino acid sequence of any one of the animal ACE2 proteins or fragments thereof described in Table 9, e.g., in some embodiments, the target-binding moiety comprises the amino acid sequence of any one of SEQ ID NOs: 262-274, or a variant thereof having at least about 90% (such as about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) sequence identity to the amino acid sequence of any one of SEQ ID NOs: 262-274. In some embodiments, the chimeric protein comprises the amino acid sequence of any one of the animal ACE2 chimeric proteins described in Table 1, e.g., in some embodiments, the chimeric protein comprises the amino acid sequence of any one of SEQ ID NOs: 11-15, or a variant thereof having at least about 90% (such as about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) sequence identity to the amino acid sequence of any one of SEQ ID NOs: 11-15.

[0161] Table 1 describes the sequences of the exemplary ACE2 chimeric proteins provided herein. Additional exemplary ACE2 chimeric proteins, and hACE2 and animal ACE2 targetbinding moieties, are described in W02023 / 201304A2, which is hereby incorporated by reference in its entirety.

[0162] Additional ACE2 chimeric proteins comprising any of the anti-ACE2 moieties or variants thereof, the mucoadhesive peptide fragments, and / or linkers provided herein are also contemplated. It should be understood that various other chimeric proteins comprising targetbinding moieties comprising an EBD of known ACE2 proteins or fragments thereof (e.g., hACE2 or animal ACE2 proteins, or fragments thereof), such as those described in Tables 8 and 9, or variants known in the art, fused with any of the mucoadhesive peptide fragments, such as those described in Table 19, and / or linkers, such as those described in Table 20, provided herein may be encompassed by the scope of this invention.

[0163] Using the hACE2 protein sequences disclosed in Table 8, and fragments thereof, exemplary human-derived hACE2 chimeric proteins and chimeric protein fragments may be designed. In some embodiments, the chimeric protein comprises: (a) a target-binding moiety comprising the amino acid sequence of any one of SEQ ID NOs: 246-261, i.e. described inTable 8; and (b) a mucoadhesive peptide fragment comprising at least about 5 (e.g., about 5 to about 30) positively charged amino acid residues, wherein the mucoadhesive peptide fragment facilitates attachment of the chimeric protein to a mucosa. In some embodiments, the chimeric protein comprises a target-binding moiety comprising an EBD of a hACE2 protein or a fragment thereof and one or more of the mucoadhesive peptide fragments described herein, such as any of the chimeric proteins comprising a hACE2 protein provided in Table 1 above, e.g., ACE740-Fcl-5H, ACE740-Fcl-6H, ACE740-Fcl-7X-l, ACE740- Fcl-12X-7, ACE740-Fcl-12X-8, ACE614-Fcl-12K, ACE614-Fcl-12H, ACE200-bIZIP- 35X-1, ACE200-CH2-CH2-12X-4, and ACE19-SA-50X-1. In some embodiments, the chimeric protein comprises an amino acid sequence having at least about 90% sequence identity (such as about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of any one of SEQ ID NOs: 1-10. In some embodiments, the chimeric protein comprises the amino acid sequence of any one of SEQ ID NOs: 1-10.

[0164] Using the animal ACE2 protein sequences disclosed in Table 9, and fragments thereof, exemplary animal-derived hACE2 chimeric proteins and chimeric protein fragments may be designed. In some embodiments, the chimeric protein comprises: (a) a target-binding moiety comprising the amino acid sequence of any one of SEQ ID NOs: 262-287, i.e., described in Table 9; and (b) a mucoadhesive peptide fragment comprising at least about 5 (e.g., about 5 to about 30) positively charged amino acid residues, wherein the mucoadhesive peptide fragment facilitates attachment of the chimeric protein to a mucosa. In some embodiments, the chimeric protein comprises a target-binding moiety comprising an EBD of an animal ACE2 protein or a fragment thereof and one or more of the mucoadhesive peptide fragments described herein, such as any of the chimeric proteins comprising an animal ACE2 protein provided in Table 1 above, e.g., cACE614-Fcl-12H, cACE200-(GPP)10-40X-2, mACE614- COMP-6X-5, gACEA360-FC 1-120, and nACEA420-T4F-12X-l. In some embodiments, the chimeric protein comprises an amino acid sequence having at least about 90% sequence identity (such as about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of any one of SEQ ID NOs: 11-15. In some embodiments, the chimeric protein comprises the amino acid sequence of any one of SEQ ID NOs: 11-15.

[0165] The present application provides chimeric proteins (such as fusion proteins) comprising: (a) an antibody moiety that specifically binds to a component of an influenza virus or a variant thereof; and (b) a mucoadhesive peptide fragment comprising at least about 5 positively charged amino acid residues (e.g., about 5 to about 30 positively charged amino acid residues), wherein the mucoadhesive peptide fragment facilitates attachment of the chimeric protein to a mucosa. In some embodiments, the antibody moiety is a full-length antibody (e.g., IgG, IgA, IgM or IgD). In some embodiments, the antibody moiety is an antigen-binding fragment selected from the group consisting of a Fab, a Fab’, a (Fab’)2, an Fv, a single chain Fv (scFv), a disulfide stabilized Fv fragment (dsFv), a (dsFv)2, an scFv dimer, a domain antibody, a single domain antibody, a bivalent domain antibody, and a minibody. In some embodiments, the influenza virus is an IAV, an IBV, an ICV, an IDV, or a variant, subtype, or reassortant thereof. In some embodiments, the influenza virus comprises an HA antigen selected from the group consisting of Hl, H2, H3, H5, H6, H7, H9, and H 10, or a variant or reassortant thereof. In some embodiments, the influenza virus comprises a NA antigen selected from the group consisting of Nl, N2, N3, N7, N8, and N9, or a variant or reassortant thereof. In some embodiments, the influenza virus is selected from the group consisting of H1N1, H1N2, H2N2, H3N2, H3N8, H5N1, H5N9, H6N1, H7N2, H7N3, H7N7, H7N9, H9N2, H10N7, or a variant or reassortant thereof. In some embodiments, the component of the influenza virus or variant thereof is a viral surface protein. In some embodiments, the viral surface protein is HA. In some embodiments, the viral surface protein is NA. In some embodiments, the influenza virus or variant thereof causes a respiratory infection. In some embodiments, the mucosa is selected from the group consisting of nasal mucosa, nasopharyngeal mucosa, posterior oropharyngeal mucosa, and combinations thereof. In some embodiments, the mucoadhesive peptide fragment comprises the amino acid sequence of any one of the mucoadhesive peptide fragments described in Table 19. In some embodiments, the target-binding moiety is directly fused to the mucoadhesive peptide fragment. In some embodiments, the target-binding moiety is fused to the mucoadhesive peptide fragment via peptide linker. In some embodiments, the peptide linker comprises the amino acid sequence of any one of the peptide linkers described in Table 20.

[0166] In some embodiments, the chimeric protein (e.g., fusion protein) comprises: (a) an antibody moiety that specifically binds to a HA protein of an influenza virus or a variant thereof; and (b) a mucoadhesive peptide fragment comprising at least about 5 positively charged amino acid residues (e.g., about 5 to about 30 positively charged amino acid residues), wherein the mucoadhesive peptide fragment facilitates attachment of the chimeric protein to a mucosa. In some embodiments, the antibody moiety binds to an HA antigen, such as an HA antigen selected from the group consisting of Hl, H2, H3, H5, H6, H7, H9, and H10, or a variant or reassortant thereof. In some embodiments, the influenza virus is selected from the group consisting of H1N1, H1N2, H2N2, H3N2, H3N8, H5N1, H5N9, H6N1, H7N2, H7N3, H7N7, H7N9, H9N2, H10N7, or a variant or reassortant thereof. In some embodiments, the antibody moiety specifically binds to a human HA antigen and comprises any one of the antibodies or antigen binding fragments thereof as described in Table 13. In some embodiments, the antibody moiety specifically binds to an animal HA antigen and comprises any one of the antibodies or antigen binding fragments thereof as described in Table 16. In some embodiments, the mucosa is selected from the group consisting of nasal mucosa, nasopharyngeal mucosa, posterior oropharyngeal mucosa, and combinations thereof. In some embodiments, the mucoadhesive peptide fragment comprises the amino acid sequence of any one of the mucoadhesive peptide fragments described in Table 19. In some embodiments, the target-binding moiety is directly fused to the mucoadhesive peptide fragment. In some embodiments, the target-binding moiety is fused to the mucoadhesive peptide fragment via peptide linker. In some embodiments, the peptide linker comprises the amino acid sequence of any one of the peptide linkers described in Table 20.

[0100] In some embodiments, the chimeric protein (e.g., fusion protein) comprises a full-length antibody comprising: a first antibody heavy chain, a second antibody heavy chain, a first antibody light chain, and a second antibody light chain (e.g., a first, second, third, and fourth polypeptide chain, respectively), wherein the antibody specifically binds to a HA protein, wherein the chimeric protein comprises: (a) a first polypeptide chain comprising the first antibody heavy chain fused to a first mucoadhesive peptide fragment; (b) a second polypeptide chain comprising the second antibody heavy chain fused to a second mucoadhesive peptide fragment; (c) a third polypeptide chain comprising the first antibody light chain; and (d) thefourth polypeptide chain comprising a second antibody light chain, wherein the first and second mucoadhesive peptide fragments each comprise about at least about 5 positively charged amino acid residues (e.g., about 5 to about 30 positively charged amino acid residues), wherein the first and second mucoadhesive peptide fragments facilitate attachment of the chimeric protein to a mucosa. In some embodiments, the chimeric protein comprises: (1) a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of any one of SEQ ID NOs: 16 and 18-44, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 17; (2) a first and a second polypeptide chain each independently having at least about 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 45 and 47-64, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 46; or (3) a first and a second polypeptide chain each independently having at least about 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 65 and 67-104, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 66.

[0101] In some embodiments, the chimeric protein (e. , fusion protein) comprises: (a) an antibody moiety that specifically binds to a NA protein of an influenza virus or a variant thereof; and (b) a mucoadhesive peptide fragment comprising at least about 5 positively charged amino acid residues (e.g., about 5 to about 30 positively charged amino acid residues), wherein the mucoadhesive peptide fragment facilitates attachment of the chimeric protein to a mucosa. In some embodiments, the antibody moiety binds with a NA antigen, such as an NA antigen selected from the group consisting of Nl, N2, N3, N7, N8, and N9, or a variant or reassortant thereof. In some embodiments, the influenza virus is selected from the group consisting of H1N1, H1N2, H2N2, H3N2, H3N8, H5N1, H5N9, H6N1, H7N2, H7N3, H7N7, H7N9, H9N2, H10N7, or a variant or reassortant thereof. In some embodiments, the antibody moietyspecifically binds to a human NA antigen and comprises any one of the antibodies or antigen binding fragments thereof as described in Table 14. In some embodiments, the mucosa is selected from the group consisting of nasal mucosa, nasopharyngeal mucosa, posterior oropharyngeal mucosa, and combinations thereof.

[0102] In some embodiments, the chimeric protein (e.g., fusion protein) comprises a full-length antibody comprising: a first antibody heavy chain, a second antibody heavy chain, a first antibody light chain, and a second antibody light chain (e.g., a first, second, third, and fourth polypeptide chain, respectively), wherein the antibody specifically binds to a NA protein, wherein the chimeric protein comprises: (a) a first polypeptide chain comprising the first antibody heavy chain fused to a first mucoadhesive peptide fragment; (b) a second polypeptide chain comprising the second antibody heavy chain fused to a second mucoadhesive peptide fragment; (c) a third polypeptide chain comprising the first antibody light chain; and (d) the fourth polypeptide chain comprising a second antibody light chain, wherein the first and second mucoadhesive peptide fragments each comprise about at least about 5 positively charged amino acid residues (e.g., about 5 to about 30 positively charged amino acid residues), wherein the first and second mucoadhesive peptide fragments facilitate attachment of the chimeric protein to a mucosa. In some embodiments, the chimeric protein comprises: (1) a first and a second polypeptide chains each independently having at least about 90% sequence identity (such as at least about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of any one of SEQ ID NOs: 105 and 107-124, and a third and a fourth polypeptide chains each having at least about 90% sequence identity (such as at least about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 106; or (2) a first and a second polypeptide chains each independently having at least about 90% sequence identity (such as at least about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of any one of SEQ ID NOs: 125 and 127-144, and a third and a fourth polypeptide chains each having at least about 90% sequence identity (such as at least about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 126.

[0103] Exemplary chimeric proteins comprising an antibody moiety that specifically binds to a component of an influenza virus or a variant thereof, and a mucoadhesive peptide fragment comprising at least about 5 (e. , about 5 to about 30 positively charged amino acid residues) positively charged amino acid residues are provided herein. Table 2 provides the sequences of some exemplary chimeric proteins which comprise antibody light chain (“LC”) polypeptides as well as antibody heavy chain (“HC”) polypeptides fused to mucoadhesive peptide fragments. Additional exemplary influenza chimeric proteins, and anti -influenza antibody moieties, are described in W02023201306A1, which is hereby incorporated by reference in its entirety.II.Ill

[0104] Additional influenza chimeric proteins comprising any of the anti-influenza virus (e.g., anti-HA or anti-NA) antibody moieties or variants thereof, the mucoadhesive peptide fragments, and / or linkers provided herein are also contemplated. It should be understood that various other chimeric proteins comprising anti-influenza virus antibody moieties or variants known in the art fused with any of the mucoadhesive peptide fragments and / or linkers provided herein may be encompassed by the scope of this invention.

[0105] In some embodiments, the chimeric protein comprises an anti-HA antibody moiety and one or more of the mucoadhesive peptide fragments described herein. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently comprising a heavy chain of a full-length anti-HA antibody, and a third and fourth polypeptide chain each independently comprising a light chain of a full-length anti-HA antibody, such as any of the chimeric proteins provided in Table 1 above, e.g., HAl-hIgG-6H; HAl-hIgG-12H; HAl-hlgG- 30H; HAl-hIgG-6K; HAl-hIgG-12K; HAl-hIgG-30K; HAl-hIgG-6R; HAl-hIgG-12R; HA1- hIgG-30R; HAl-hIgG-60; HAl-hIgG-120; HAl-hIgG-300; HAl-hIgG-6X-l; HAl-hIgG-6X- 2; HAl-hIgG-6X-3; HAl-hIgG-6X-4; HAl-hIgG-12X-l; HAl-hIgG-30X-l; HAl-hIgG-6X-2; HAl-hIgG-12X-2; HAl-hIgG-30X-2; HAl-hIgG-6X-3; HAl-hIgG-12X-3; HAl-hIgG-30X-3; HAl-hIgG-12X-4; HAl-hIgG-30X-4; HA2-hIgG-6H; HA2-hIgG-12H; HA2-hIgG-30H; HA2- hIgG-6K; HA2-hIgG-12K; HA2-hIgG-30K; HA2-hIgG-6R; HA2-hIgG-12R; HA2-hIgG-30R; HA2-hIgG-6O; HA2-hIgG-12O; HA2-hIgG-30O; HA2-hIgG-6X-7; HA2-hIgG-12X-5; HA2-h!gG-30X-l; HAl -hIgG-5H; HAl-hIgG-7X-l; HAl-hIgG-12X-7; HAl-hIgG-12X-8; HA2- hIgG-5H ;HA2-hIgG-7X-l; HA2-hIgG-12X-7; HA2-hIgG-12X-8; HA15-hIgG-5H; HA15-hIgG- 6H; HA15-hIgG-12H; HA15-hIgG-30H; HA15-hIgG-6K; HA15-hIgG-12K; HA15-hIgG-30K; HA15-hIgG-6R; HA15-hIgG-12R; HA15-hIgG-30R; HA15-hIgG-6O; HA15-hIgG-12O; HA15- hIgG-300; HA15-hIgG-6X-l; HA15-hIgG-6X-2; HA15-hIgG-6X-3; HA15-hIgG-6X-4; HA15- h!gG-6X-5; HA15-hIgG-6X-6; HA15-hIgG-6X-7; HA15-hIgG-7X-l; HA15-hIgG-12X-l; HA15-hIgG-12X-2; HA15-hIgG-12X-3; HA15-hIgG-12X-4; HA15-hIgG-12X-5; HA15-hIgG- 12X-6; HA15-hIgG-12X-7; HA15-hIgG-12X-8; HA15-hIgG-30X-l; HA15-hIgG-30X-2; HA15- h!gG-30X-3; HA15-hIgG-30X-4; HA15-hIgG-35X-l; HA15-hIgG-40X-2; HA15-hIgG-42X-l; HA15-hIgG-45X-l; HA15-hIgG-50X-l; and HA 15 -hlgG- 5 OX-2.

[0106] In some embodiments, the chimeric protein comprises a heavy chain (HC) polypeptide comprising the amino acid sequence of any one of SEQ ID NOs: 659, 660, and 661, or a variant thereof comprising at least about 90% sequence identity (such as at least about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of any one of SEQ ID NOs: 659, 660, and 661, and a light chain (LC) polypeptide comprising the amino acid sequence of any one of SEQ ID NOs: 17, 46, and 66, or a variant thereof comprising at least about 90% sequence identity (such as at least about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of any one of SEQ ID NOs: 17, 46, and 66.

[0107] In some embodiments, the chimeric protein comprises an HC polypeptide comprising the amino acid sequence of SEQ ID NO: 659, or a variant thereof comprising at least about 90% sequence identity (such as at least about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 659, and an LC polypeptide comprising the amino acid sequence of SEQ ID NO: 17, or a variant thereof comprising at least about 90% sequence identity (such as at least about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 17.

[0108] In some embodiments, the chimeric protein comprises an HC polypeptide comprising the amino acid sequence of SEQ ID NO: 660, or a variant thereof comprising at least about 90% sequence identity (such as at least about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO:660, and an LC polypeptide comprising the amino acid sequence of SEQ ID NO: 46, or a variant thereof comprising at least about 90% sequence identity (such as at least about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 46.

[0109] In some embodiments, the chimeric protein comprises an HC polypeptide comprising the amino acid sequence of SEQ ID NO: 661, or a variant thereof comprising at least about 90% sequence identity (such as at least about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO:661, and an LC polypeptide comprising the amino acid sequence of SEQ ID NO: 66, or a variant thereof comprising at least about 90% sequence identity (such as at least about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 66.

[0110] In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently comprising a VH of a fulLlength anti -NA antibody, and a third and fourth polypeptide chain each independently comprising a VL of a full-length anti-NA antibody, such as any of the chimeric proteins provided in Table 1 above, e.g., NAl-hIgG-6H; NAl-hlgG- 12H; NAl-hIgG-30H; NAl-hIgG-6K; NAl-hIgG-12K; NAl-hIgG-30K; NAl-hIgG-6R; NA1- hIgG-12R; NAl-hIgG-30R; NAl-hIgG-6O; NAl-hIgG-12O; NAl-hIgG-30O; NAl-hIgG-6X-5; NAl-hIgG-12X-5; NAl-hIgG-30X-l; NA2-hIgG-6H; NA2-hIgG-12H; NA2-hIgG-30H; NA2- hIgG-6K; NA2-hIgG-12K; NA2-hIgG-30K; NA2-hIgG-6R; NA2-hIgG-12R; NA2-hIgG-30R; NA2-hIgG-6O; NA2-hIgG-12O; NA2-hIgG-30O; NA2-hIgG-6X-6; NA2-hIgG-12X-6; NA2- hIgG-30X-l; NAl-hIgG-5H; NAl-hIgG-7X-l; NAl-hIgG-12X-7; NAl-hIgG-12X-8; NA2- hIgG-5H; NA2-hIgG-7X-l; NA2-hIgG-12X-7; and NA2-hIgG-12X-8.[0U1] In some embodiments, the chimeric protein comprises an HC polypeptide comprising the amino acid sequence of SEQ ID NO: 657 or 658, or a variant thereof comprising at least about 90% sequence identity (such as at least about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 657 or 658, an LC polypeptide comprising the amino acid sequence of SEQ ID NO: 106 or 126, or a variant thereof comprising at least about 90% sequence identity (such as at least about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 106 or 126.

[0112] In some embodiments, the chimeric protein comprises an HC polypeptide comprising the amino acid sequence of SEQ ID NO: 657, or a variant thereof comprising at least about 90% sequence identity (such as at least about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO:657, and an LC polypeptide comprising the amino acid sequence of SEQ ID NO: 106, or a variant thereof comprising at least about 90% sequence identity (such as at least about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 106.

[0113] In some embodiments, the chimeric protein comprises an HC polypeptide comprising the amino acid sequence of SEQ ID NO: 658, or a variant thereof comprising at least about 90% sequence identity (such as at least about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO:658, and an LC polypeptide comprising the amino acid sequence of SEQ ID NO: 126, or a variant thereof comprising at least about 90% sequence identity (such as at least about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 126.

[0114] In some embodiments, the chimeric protein comprises: (a) a target-binding moiety that specifically binds to an RSV; and (b) a mucoadhesive peptide fragment comprising at least about 5 (e.g., about 5 to about 30) positively charged amino acid residues, wherein the mucoadhesive peptide fragment facilitates attachment of the chimeric protein to a mucosa. In some embodiments, the RSV is RSV-A or RSV-B. In some embodiments, the target-binding moiety is an antibody moiety. In some embodiments, the antibody moiety is a full-length antibody (e.g., IgG, IgA, IgM or IgD). In some embodiments, the antibody moiety is an antigen-binding fragment selected from the group consisting of a Fab, a Fab’, a (Fab’)2, an Fv, a single chain Fv (scFv), a disulfide stabilized Fv fragment (dsFv), a (dsFv)2, an scFv dimer, a domain antibody, a single domain antibody, a bivalent domain antibody, and a minibody. In some embodiments, the antibody moiety specifically binds to an F glycoprotein and / or a G glycoprotein on the RSV or variant thereof. In some embodiments, the mucoadhesive peptide fragment comprises the amino acid sequence of any one of the mucoadhesive peptide fragments described in Table 19. In some embodiments, the target-binding moiety is directly fused to the mucoadhesive peptide fragment. In some embodiments, the target-binding moiety is fused to the mucoadhesive peptide fragmentvia peptide linker. In some embodiments, the peptide linker comprises the amino acid sequence of any one of the peptide linkers described in Table 20.

[0115] Without being bound by any theory or hypothesis, respiratory virus infection occurs mainly through respiratory droplets and possible airborne transmission. Upper respiratory surfaces are the dominant and initial sites for coronavirus infection. The nasal epithelium produces a physical glycoprotein barrier to inhaled particles including allergens and pathogens, preventing penetration to the epithelial surface of mucosal tissues. One major component of the mucosal layer of nasal and respiratory tract are mucins, a family of large glycoproteins that coat the surface of the respiratory epithelium. Mucins, the primary non-aqueous component of mucus, are a complex and heterogeneous structure, which carry a highly negative charge. The inventors of the present application, in some embodiments, engineered a peptide comprising at least 5 positively charged amino acids (e g., lysines, histidines, arginines, ornithines, or combinations thereof) which, when covalently linked to a target-binding moiety, confers to the conjugate (z.e., chimeric protein) positive charges. The target-binding moiety with its positively charged C- terminal peptide can form a layer of coronavirus-binding moieties that can line the nasal / respiratory tract and prevent the virus from binding to the viral receptor-expressing epithelial cells. A positively charged target-binding moiety could also bind the phospholipid bilayer of cell membranes, also negatively charged. This “sticky” property of the polymeric positively charged amino acid chain imparts to the target-binding moiety a longer half-life in the respiratory mucosal epithelium, providing a lengthened period of protection. Therefore, the engineered target-binding moiety-mucoadhesive polymer conjugate can block coronavirus entry into the cells of the respiratory cavity, even if the virus might penetrate the mucosal barrier and reach viral receptor-positive epithelial cells. In other embodiments, the positively charged mucoadhesive amino acids can be interspersed with non-positively charged amino acids without disrupting the mucoadhesive properties of the chimeric protein. Furthermore, the target-binding moiety of the chimeric protein may be fused to the mucoadhesive peptide fragment via a peptide linker.

[0116] The different aspects and embodiments are discussed in various sections below in further detail.A. Target-binding moieties

[0117] The chimeric proteins described herein comprise a target-binding moiety that specifically binds to a virus, e.g., a virus that causes a respiratory infection, such as a coronavirus, RSV, or influenza virus. Contemplated target-binding moieties include antibody moieties that specifically bind to the virus, as well as inhibitory polypeptides that inhibit binding of the virus to a receptor on a cell of the mucosa.

[0118] In some embodiments, the target-binding moiety is an antibody moiety. Contemplated antibody moieties include, for example, scFv, Fab, Fc fusion protein (e.g., scFv-Fc), full-length antibodies, and multi-specific antibodies.

[0119] In some embodiments, the antibody moiety comprises one or more (e.g., 2, 3, 4 or more) polypeptide chains. These one or more polypeptide chains may be bound together, for example, via a disulfide bond (z.e., S-S bond) or multimerization domains.

[0120] In some embodiments, the antibody moiety is a full-length antibody or any suitable antigen binding fragments thereof. In some embodiments, the antibody moiety is a full-length antibody. In some embodiments, the antibody moiety is selected from the group consisting of an IgG, an IgA, an IgM, and an IgD. In some embodiments, the antibody moiety is an antigenbinding fragment selected from the group consisting of a Fab, a Fab’, a (Fab’)2, an Fv, a single chain Fv (scFv), a disulfide stabilized Fv fragment (dsFv), a (dsFv)2, an scFv dimer, a domain antibody, a single domain antibody, a bivalent domain antibody, and a minibody. In some embodiments, the antibody moiety is an animal, human, humanized, camelid, or chimeric antibody or an antigen-binding fragment thereof.

[0121] In some embodiments, the antibody moiety comprises a scFv. In some embodiments, the antibody moiety is a scFv. In some embodiments, the antibody moiety is a scFv-Fc fusion protein. In some embodiments, the antibody moiety is a scFv-CHs fusion protein. In some embodiments, the scFv comprises a VH fused to a VL via a flexible peptide linker, such as (GGGS)n, or similar peptides disclosed in Table 20, SEQ ID NOs: 642-647. In some embodiments, the scFv comprises a VL fused to a VH via a peptide linker.

[0122] In humans, IgA is the major antibody isotype secreted in the upper airways; its presence there correlates with resistance to infection by some respiratory viruses, such as influenza viruses or variants thereof. Antibody delivery to the upper airway mucosal surface, mimicking naturally secreted antibody, can prevent virus from reaching its target or directly neutralize infectiousvirus, and may prove a very useful strategy for prophylaxis. Indeed, antibodies have been shown to provide protection of the respiratory tract from viral infection when given prophylactically. IgA antibodies have a unique structure and glycosylation pattern that enables binding to mucin molecules in the airway epithelium, resulting in extension of their half-lives in the mucosa. While secretory IgA antibodies are more efficient than IgG antibodies in providing effective viral protection, IgG antibodies have a well-established modality for large-scale manufacturing and characterization, both of which are essential for providing an affordable and scalable source of antibodies for a prophylactic approach.

[0123] In some embodiments, the target-binding moiety comprises an inhibitory polypeptide, i.e., an EBD of an ACE2 protein (such as SEQ ID NO: 650) or a fragment thereof that specifically binds to an S protein. In some embodiments, the target-binding moiety comprises an inhibitory polypeptide that inhibits binding of the S protein to a receptor on a cell of a mucosa. In some embodiments, the target-binding moiety comprises a natural receptor of the S protein or a fragment derived from the natural receptor. In some embodiments, the target-binding moiety comprises an EBD of the natural receptor, e.g., ACE2, or a fragment thereof. In some embodiments, the ACE2 is a hACE2 protein. In some embodiments, the ACE2 is an animal ACE2 protein. In some embodiments, the S protein is from a virus, such as a coronavirus.

[0124] In some embodiments, the target-binding moiety comprises a purification tag, e.g., a His tag, such as DYKDDDDKHHHHHH (Flag-His(6), SEQ ID NO: 649).

[0125] Exemplary viruses, targets, and target-binding moieties are further described below.

[0126] In some aspects, the chimeric proteins described herein comprise a target-binding moiety (e.g., an antibody moiety or an EBD of an ACE2 protein or a fragment thereof) that specifically binds to a spike protein (also referred to as spike glycoprotein, or S protein) of a virus. In some embodiments, the virus is a coronavirus. In some embodiments, the virus is selected from the group consisting of SARS-CoV, SARS-CoV-2, and HCoV-NL63, including variants thereof. In some embodiments, the virus is SARS-CoV-2. In some embodiments, the virus is a reference coronavirus or a coronavirus having substantially the same genomic sequence (e.g, fewer than any one of 200, 100, 50, 20, 10, 5, 4, 3, 2, or 1 mutation(s)) and phenotypes as the reference coronavirus. In some embodiments, the virus is a variant coronavirus that has one or moremutations in the genomic sequence compared to the reference coronavirus, wherein the one or more mutations contribute to phenotypic differences, such as increased viral fitness, including for example, infectivity, virulence, and / or drug resistance.

[0127] Coronaviruses are a group of related viruses that cause diseases in mammals and birds. In humans, coronaviruses cause respiratory tract infections that can range from mild to lethal. Mild illnesses include some cases of the common cold (e.g., with symptoms such as fever, sore throat), while more lethal varieties can cause SARS and COVID-19. Coronaviruses can cause pneumonia (either direct viral pneumonia with ensuing cytokine storm and acute respiratory distress syndrome or secondary bacterial pneumonia) and bronchitis (either direct viral bronchitis or secondary bacterial bronchitis).

[0128] Coronaviruses have been recognized as causing pathological conditions in veterinary medicine since the 1930s. Coronaviruses primarily infect the upper respiratory and gastrointestinal tract of mammals and birds. They also cause a range of diseases in farm animals and domesticated pets, some of which can be serious and are a threat to the farming industry. Exemplary coronaviruses that infect animals include the Infectious Bronchitis Virus (IBV) for chickens, porcine coronavirus (Transmissible Gastroenteritis Coronavirus, TGEV), Porcine Respiratory Coronavirus (PEDV), bovine coronavirus (BCoV), feline enteric coronavirus, Feline Infectious Peritonitis Virus (FIPV), ferret enteric coronavirus, ferret systemic coronavirus, Canine Coronavirus (CCoV), mouse hepatitis virus (MHV), Sialodacryoadenitis Virus (SDAV), and Swine Acute Diarrhea Syndrome Coronavirus (SADS-CoV).

[0129] Coronaviruses are large pleomorphic spherical particles with bulbous surface projections. The average diameter of the virus particles is around 120 nm (.12 pm). The diameter of the envelope is ~80 nm (.08 pm) and the spikes are ~20 nm (.02 pm) long. The viral envelope consists of a lipid bilayer where the membrane (M), envelope (E) and spike (S) structural proteins are anchored. A subset of coronaviruses (specifically the members of betacoronavirus subgroup A) also have a shorter spike-like surface protein called hemagglutinin esterase (HE). Inside the envelope, there is the nucleocapsid, which is formed from multiple copies of the nucleocapsid (N) protein, which are bound to the positive-sense single- stranded RNA genome in a continuous beads-on-a-string type conformation. The lipid bilayer envelope, membrane proteins, and nucleocapsid protect the virus when it is outside the host cell.

[0130] Infection begins when the viral S glycoprotein attaches to its complementary host cell receptor. After attachment, a protease of the host cell cleaves and activates the receptor-attached spike protein. Depending on the host cell protease available, cleavage and activation allows the virus to enter the host cell by endocytosis or direct fusion of the viral envelope with the host membrane. On entry into the host cell, the virus particle is uncoated, and its genome enters the cell cytoplasm. The coronavirus RNA genome has a 5' methylated cap and a 3' polyadenylated tail, which allows the RNA to attach to the host cell's ribosome for translation. The host ribosome translates the initial overlapping open reading frame of the virus genome and forms a long polyprotein. The polyprotein has its own proteases, which cleave the polyprotein into multiple nonstructural proteins.

[0131] The coronaviruses can be classified into five genera: Alpha, Beta, Gamma, Delta, and Omicron CoVs (Woo etal, 2009). Previously identified human CoVs that cause human disease include the aCoVs hCoV-NL63 and hCoV-229E and the PCOVS HCoV-OC43, HKU1, Severe Acute Respiratory Syndrome CoV (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV- 19; previously known as 2019-nCoV (Lu et al., 2015; Wevers and van der Hoek, 2009; Zhu et al., 2020). HCoV-OC43, HCoV-HKUl, HCoV-229E and HCoV-NL63 continually circulate in the human population and produce generally mild symptoms of the common cold in adults and children worldwide.

[0132] SARS-CoV is a zoonotic pathogen originating in animals. Detailed investigations indicate that SARS-CoV is transmitted from civet cats to humans (Azhar et al., 2014; Ge et al., 2013; Guan et al., 2003). Bats and birds, as warm-blooded flying vertebrates, are an ideal natural reservoir for the coronavirus gene pool (bats the reservoir for alphacoronavirus and betacoronavirus - and birds the reservoir for gammacoronavirus and deltacoronavirus). The large number of host bat and avian species, and their global range, has enabled extensive evolution and dissemination of coronaviruses.

[0133] SARS-CoV-2 is a betacoronavirus from Group 2B with approximately 70% genetic similarity to the SARS-CoV. The virus has a 96% similarity to a bat coronavirus (SARSr- CoV_RaTG13), so it is widely suspected to originate from bats as well.

[0134] A naturally occurring S protein of a coronavirus forms homotrimers protruding from the viral surface. The S protein comprises two functional subunits responsible for binding to the hostcell receptor (SI subunit), and fusion of the viral and cellular membranes (S2 subunit). For many CoVs, S is cleaved at the boundary between the SI and S2 subunits, which remain non- covalently bound in the pre-fusion conformation of the CoV. The distal SI subunit comprises the RBD(s) and contributes to stabilization of the prefusion state of the membrane-anchored S2 subunit that contains the fusion machinery. For all CoVs, S is further cleaved by host proteases at the so-called S2’ site located immediately upstream of the fusion peptide. This cleavage has been proposed to activate the protein for membrane fusion via extensive irreversible conformational changes. As a result, coronavirus entry into susceptible cells is a complex process that requires the concerted action of receptor-binding and proteolytic processing of the S protein to promote virus-cell fusion. See, Walls et al., Cell 180, 281-292 (2020).

[0135] For example, the S protein of SARS-CoV could be cleaved by trypsin at two distinct sites, one located at the boundary of SI and S2, the “classical” S1 / S2 site (R667 Pl residue), and the S2’ site (R797 Pl residue). Protease cleavage of SARS-CoV S is thought to be sequential, with the S1 / S2 cleavage occurring first and enhancing subsequent cleavage at S2’. It is the second cleavage event, at S2’, that is believed to be crucial for fusion activation of S. The S1 / S2 cleavage appears dispensable for syncytia formation and virus-cell fusion. See, Millet, Virus Research 202: 120-134 (2015).

[0136] The spike protein of SARS-CoV-2 can be cleaved by both furin at the S1 / S2 site and the transmembrane protease / serine (TMPRSS) protease 2, TMPRSS2, at the S2’ site. See, Hoffman et al., Cell 181, 271-280, 2020. The furin cleavage site of SARS-CoV-2 is located between amino acids 685 and 686 of the S protein. SARS-CoV-2 and SARS-CoV both use ACE2 as the receptor to enter human cells. See, Zhou et al., Nature 579: 270 (2020).

[0137] SI of the S protein can be further divided into an N-terminal domain (NTD) and a C- terminal domain (CTD), both of which can function as a receptor-binding entity (e.g., SARS- CoV utilizes the S I CTD to recognize the receptor (also called receptor binding domain [RBD]) (Li et al., 2005; Lu et al., 2013).

[0138] In nature, the S protein of coronaviruses mediates viral entry into the host cells. Table 3 below shows identified viral receptors for various coronaviruses. See, also, Raj VS et al. Chapter 15 of H. J. Maier et al. (eds.), Coronaviruses: Methods and Protocols, Methods in Molecular Biology, vol. 1282, Springer Science + Business Media New York 2015; Li F. Annu Rev Virol.,3(1): 237-261 (2016); Hulswit 2019 and Zhou et al., Nature 579: 270 (2020), which are incorporated herein by reference in their entirety.

[0139] Exemplary coronavirus S proteins and variants thereof are provided in Table 4.SARS-CoV-2 variants emergent July 2024-July 2025 include XEC (PV241966), LF.7 (PV602117), LP.8.1 (PV412564), NB1.8.1 (PV712625), and XFG (PV917192). All of tire ACE chimeric proteins described herein are expected to recognize the spike proteins of the newly emerged variants.

[0140] In some embodiments, the virus is SARS-CoV-2. In some embodiments, the virus is a reference SARS-CoV-2 e.g., WIV4, i.e., hCoV-19 / WIV04 / 2019 or BetaCoV / WIV04 / 2019) or a SARS-CoV-2 virus having substantially the same genomic sequence (e. , fewer than any one of 200, 100, 50, 20, 10, 5, 4, 3, 2, or 1 mutations) and phenotypes as the reference SARS-CoV-2. The genome sequence of the reference SARS-CoV-2 WIV4 can be found on Genbank (NCBI Reference Sequence: NC_045512.2), which is also known as 2019-nCoV. In some embodiments, the SARS-CoV-2 is a variant, such as a variant of interest, a variant of concern, or a variant of high consequence. In some embodiments, the SARS-CoV-2 is a variant selected from the group consisting of a B. l .1 .7 variant, a B.l .351 variant, a Delta (B.l .617.1) variant, an A.23.1 variant, a B.1.525 variant, a BA.2 variant, a BA.5.1.1 variant, a BQ. l variant, an XBB.1.5 variant, a BA.2.86 variant, a JN.l variant, a KP.1.1 variant, a JN.1.13.1 variant, a JN.1.16 variant, a JN.1.7 variant, a KQ.l variant, a JN.1.8.1 variant, a JN.1.11.1 variant, a JN.1.18 variant, a KP.2 (also known as JN.1.11.1.2) variant, a BA.1 variant, a KP.3 variant, and an LB.1 variant. In some embodiments, the SARS-CoV-2 variant is a B. l.1.7 variant. In some embodiments, the SARS- CoV-2 variant is a B.l.351 variant. In some embodiments, the SARS-CoV-2 variant is a KP.2 variant. In some embodiments, the SARS-CoV-2 variant is a KP.3 variant. In some embodiments, the SARS-CoV-2 variant is a LB.1 variant. Other variants of SARS-CoV-2 are known in the art. For example, See, Gomez et al., Vaccines 9(3): 243, 2021 and Tang et al., Journal of Infection 82: e27-e28 (2021), which are incorporated herein by reference in their entirety. In some embodiments, the SARS-CoV-2 variant has one or more mutations (e.g., insertion, deletion, and / or substitution) in the S protein. In some embodiments, the one or more mutations in the S protein may affect viral fitness, such as infectivity, virulence, and / or drug resistance (e.g., resistance to neutralizing antibodies and / or resistance to a vaccine). For example, the SARS-CoV-2 variant may have L452R and / or E484K substitutions in the S protein. In some embodiments, the one or more mutations in the S protein do not substantially alter viral fitness. In some embodiments, the SARS-CoV-2 variant does not have a mutation in the S protein.

[0141] In some embodiments, the S protein is an S protein of a coronavirus. In some embodiments, the target-binding moiety specifically binds the SI subunit of the S protein. In some embodiments, the target-binding moiety specifically binds the S2 subunit of the S protein.

[0142] Exemplary antibodies against SARS-CoV-2 (e. ., SARS-CoV-2 monoclonal antibodies that specifically bind to spike protein) are known in the art, including, for example, pemivibart, casirivimab, imdevimab, sotrovimab, bamlanivimab, etesevimab, TY027, BRII-196, BRII-198, ABBV-47D11, COVI-GUARD (STI-1499), MW33, HFB30132A, ADM03820, HLX70 DZIF- 10c, COVI-AMG (STI-2020), BGB DXP593, SCTA01, AZD7442 (AZD8895 and AZD1061), CT-P59, ADG20, C144-LS and C-135-LS, MAD0004J08, DXP593, LY-CoV1404, LY3853113, VIR-7832, COR-101, ZRC-3308, DXP604, LY-CovMab, JMB2002, XVR011, and biosimilars thereof. Exemplary SARS-CoV-2 antibodies are described in, for example, Taylor, P.C. et al. Neutralizing monoclonal antibodies for treatment of COVID-19. Nat Rev Immunol 21, 382- 393 (2021), US2021 / 0292392 Al, US2021 / 0277092A1, US2021 / 0300999A1,US2021 / 0292393 Al, US2021 / 0261650A1, US10975139B1, US10954289B1, US10787501B1, WO2021 / 195326A1, WO2021 / 195485A1, WO2021 / 158521A1, and WO2021 / 168305A1, the contents of which are herein incorporated by reference in their entirety. A list of known SARS- CoV-2 antibodies can be found at world wide web. antibodysociety.org / covid-19-biologics- tracker / .

[0143] In some embodiments, the chimeric proteins described herein may comprise the heavy chain and light chain CDRs, VH, and VL, and / or scFv of any one of the SARS-CoV-2 antibodies described herein, including antibody sequences in Tables 5-7.

[0144] In some embodiments, the target-binding moiety is an antibody that specifically binds to the SI protein of SARS-CoV, or an antigen-binding fragment thereof. In some embodiments, the antibody inhibits the binding of SARS-CoV spike protein SI to the cell surface. In some embodiments, the target-binding moiety is an antibody that binds within the receptor-binding domain of the S protein of SARS-CoV, or an antigen-binding fragment thereof. In some embodiments, the antibody specifically binds to amino acid residues 318-510 of the SI protein, wherein the numbering is based on SEQ ID NO: 651. In some embodiments, the antibody is a neutralizing human monoclonal antibody that blocks the binding of SI protein to its receptor angiotensin-converting enzyme 2 (ACE2) on host cells. In some embodiments, the antibody specifically binds to amino acid residues 261-672 of the SI protein, wherein the numbering isbased on SEQ ID NO: 651 . In some embodiments, the antibody is able to cross-neutralize several SARS-CoV isolates. In some embodiments, the antibody is raised to the different conformational epitopes of the receptor-binding domain of the SI protein. In some embodiments, SARS-CoV human isolates (e.g., Tor2, GD03T0013) or palm civet (Paguma larvata) isolate fusion proteins (e.g., Sz3 Sl-Fc) may be used as immunogens to induce high titers of crossneutralizing antibodies.

[0145] Exemplary antibodies against the SI protein of SARS-CoV are known in the art, including, for example, CR3041, CR3001, CR3002, CR3009, CR3013, and CR3018, reported in van den Brink, et al. Journal of Virology 79.3 (2005): 1635-1644; 80R, as reported in Sui, et al. 101.8 (2004): 2536-2541; m396 and S230.15 reported in Zhu, et al. PNAS 104.29 (2007): 12123- 12129; Conf I- VI monoclonal antibodies reported in He, et al. The Journal of Immunology 176 (2006): 6085-6092, which are incorporated by reference in their entirety. Exemplary antibody sequences against SI of SARS-CoV are shown in Tables A-B. In some embodiments, the targetbinding moiety is a derivative of any one of the antibodies against the SI protein of SARS-CoV described herein. In some embodiments, the antibodies that compete with any of these art- recognized antibodies for binding to the SI protein of SARS-CoV can be used.

[0146] In some embodiments, the target-binding moiety is an antibody or antigen-binding fragment derived from CR3041, including biosimilars thereof. In some embodiments, the anti-Sl antibody comprises a VH and a VL, wherein the VH comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 662, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 663, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 664; and wherein the VL comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 665, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 666, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 667. In some embodiments, the anti-Sl antibody comprises a VH comprising the amino acid sequence of SEQ ID NO: 674, and / or a VL comprising the amino acid sequence of SEQ ID NO: 675.

[0147] In some embodiments, the target-binding moiety is an antibody or antigen-binding fragment derived from 80R, including biosimilars thereof. In some embodiments, the anti-Sl antibody comprises a VH and a VL, wherein the VH comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 668, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 669, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 670;and wherein the VL comprises a LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 671, a LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 672, and a LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 673. In some embodiments, the anti-Sl antibody comprises a VH comprising the amino acid sequence of SEQ ID NO: 676, and / or a VL comprising the amino acid sequence of SEQ ID NO: 677.Table B. Exemplary SARS-CoV antibody VH / VL sequences

[0148] The spike (S) protein of SARS-CoV mediates receptor binding and viral entry (z.e., viral infection) of host cells, and is therefore an attractive target for vaccine design. The S protein is a type I transmembrane glycoprotein possessing an SI domain, comprising amino acid residues 1 to 672 of the S protein. A fragment located in the central region of the SI domain, amino acid residues 318-510, is defined as the receptor-binding domain. The receptor-binding domain of the SI protein is a major determinant of SARS-CoV neutralization. Antibodies targeting the SI protein, and in particular the receptor binding domain, represent a large class of useful therapeutics for prevention and treatment of SARS-CoV infection.

[0149] In some embodiments, the present application provides chimeric proteins comprising antibodies and antigen binding fragments thereof (also referred to as “anti-Sl antibodies”) that specifically binds to a SI protein of SARS-CoV-2 (including SARS-CoV-2 variants). The anti- Sl antibodies described herein can be of any suitable full-length antibody or antigen-binding fragment format. Any of the anti-Sl antibodies or antigen binding fragment thereof may be used as the target-binding moiety in a chimeric protein described herein.

[0150] In some embodiments, the anti-Sl antibody is a full-length antibody or an immunoglobulin derivative. In some embodiments, the anti-Sl antibody is an IgG, an IgA, an IgD, an IgE, or an IgM. In some embodiments, the anti-Sl antibody is an antigen-binding fragment, for example, an antigen-binding fragment selected from the group consisting of a Fab, a Fab’, a (Fab’)2, an Fv, a single chain Fv (scFv), a disulfide stabilized Fv fragment (dsFv), a (dsFv)2, an scFv dimer, a domain antibody, a single domain antibody, a bivalent domain antibody, and a minibody. In some embodiments, the anti-Sl antibody is a scFv. In some embodiments, the anti-Sl antibody is a fusion protein comprising a scFv fused to an Fc region.In some embodiments, the anti-Sl antibody is a fusion protein comprising a scFv fused to a CH3 domain.

[0151] In some embodiments, the anti-Sl antibody is chimeric, human, partially humanized, fully humanized, or semi-synthetic. In some embodiments, the anti-Sl antibody is a semisynthetic antibody comprising fully human sequences and one or more synthetic regions. In some embodiments, the anti-Sl antibody is a semi-synthetic antibody comprising a fully human light chain variable domain and a semi -synthetic heavy chain variable domain comprising fully human FR1, HC-CDR1, FR2, HC-CDR2, FR3, and FR4 regions and a synthetic HC-CDR3. In some embodiments, the semi -synthetic heavy chain variable domain comprises a fully synthetic HC-CDR3 having a sequence from about 5 to about 25 (such as about any of 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25) amino acids in length. In some embodiments, the semi-synthetic heavy chain variable domain or the synthetic HC-CDR3 is obtained from a semi-synthetic library (such as a semi-synthetic human library) comprising fully synthetic HC-CDR3s having a sequence from about 5 to about 25 (such as about any of 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25) amino acids in length, wherein each amino acid in the sequence is randomly selected from the standard human amino acids, minus cysteine. In some embodiments, the synthetic HC-CDR3 is from about 5 to about 19 (such as about any of 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19) amino acids in length. In some embodiments, the anti-Sl antibody is a semi-synthetic antibody comprising human CDRs and non-human framework sequences. Non-human framework sequences include, in some embodiments, any sequence that can be used for generating synthetic heavy and / or light chain variable regions using one or more human CDR sequences as described herein, including, e.g., mammals, such as mouse, rat, rabbit, pig, bovine (e.g., cow, bull, buffalo), deer, sheep, goat, chicken, cat, dog, ferret, primate (e.g., marmoset, rhesus monkey), etc. In some embodiments, the anti-S l antibody is generated by grafting one or more human CDR sequences as described herein onto a non-human framework sequence (e.g., a mouse or chicken framework sequence).

[0152] The anti-Sl antibodies in some embodiments comprise specific sequences or certain variants of such sequences. In some embodiments, the amino acid substitutions in the variant sequences do not substantially reduce the ability of the anti-Sl antibody to specifically recognize an SI subunit of a Spike protein of SARS-CoV-2. For example, alterations that do not substantially reduce SI binding affinity may be made. Alterations that substantially improve SIbinding affinity or affect some other property, such as specificity and / or cross-reactivity with related variants of the SI protein, are also contemplated.

[0153] Exemplary anti-Sl antibody sequences are shown in Tables 5-7. The exemplary CDR sequences in Table 5 are predicted using the IgBLAST algorithm. See, for example, Ye J. et al. Nucleic Acids Research, 4EW34-W40 (2013), the disclosure of which is incorporated herein by reference in its entirety. Those skilled in the art will recognize that many algorithms are known for prediction of CDR positions in antibody heavy chain and light chain variable regions, and antibody agents comprising CDRs from antibodies described herein, but based on prediction algorithms other than IgBLAST, are within the scope of this invention.

[0154] The exemplary anti-Sl antibody heavy chain and light chain variable region sequences in Table 6 are delimited according to the INTERNATIONAL IMMUNOGENETICS INFORMATION SYSTEM® (IMGT). See, for example, Lefranc, M.-P. et al., Nucleic Acids Res., 43:D413-422 (2015), the disclosure of which is incorporated herein by reference in its entirety. Those skilled in the art will recognize that antibody agents comprising VH or VL sequences from antibodies described herein, but based on algorithms other than IMGT, are within the scope of this invention.

[0155] In some embodiments, the anti-Sl antibody or antigen binding fragment thereof comprises an HC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 156, 162, 168, 174, 180, 186, 192, 198, 204, 210, and 681, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 157, 163, 169, 175, 181, 187, 193, 199, 205, 211, and 682, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 158, 164, 170, 176, 182, 188, 194, 200, 206, 212, and 683, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, an LC- CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 159, 165, 171, 177, 183, 189, 195, 201, 207, 213, and 684, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, an LC-CDR2 comprising the amino acid sequence of any one of SNN, EDK, RNN, FND, EVS, VSN, GND, and GSS, or a variant thereof comprising about 1 or about 2 amino acid substitutions, and an LC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 161, 167, 173, 179, 185, 191, 197, 203, 209, 215, and686, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions.

[0156] In some embodiments, the anti-Sl antibody or antigen binding fragment thereof comprises: a) a Vu comprising the amino acid sequence of any one of SEQ ID NOs: 216, 218, 220, 222, 224, 226, 228, 230, 232, and 234, or a variant thereof having at least about 80% (including for example at least about any of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to any one of SEQ ID NOs: 216, 218, 220, 222, 224, 226, 228, 230, 232, and 234; and b) a VL comprising the amino acid sequence of any one of SEQ ID NOs: 217, 219, 221, 223, 225, 227, 229, 231, 233, and 235, or a variant thereof having at least about 80% (including for example at least about any of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to any one of SEQ ID NOs: 217, 219, 221, 223, 225, 227, 229, 231, 233, and 235.

[0157] The heavy and light chain variable domains can be combined in various pair-wise combinations to generate a number of anti-Sl antibody moi eties.

[0158] Exemplary anti-Sl antibodies are provided in Tables 5-7.XIII.Table 6. VH / VL sequences of exemplary SARS-CoV-2 (anti-Sl) antibodiesTable 7. scFv sequences based on exemplary SARS-CoV-2 (anti-Sl) antibodies

[0159] In some embodiments, there is provided an anti-Sl antibody or antigen binding fragment thereof comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 156, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) aminoacid substitutions, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 157, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 158, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 159, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, an LC-CDR2 comprising the amino acid sequence of SNN, or a variant thereof comprising about 1 or about 2 amino acid substitutions, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 161, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions. In some embodiments, there is provided an anti- S1 antibody or antigen binding fragment thereof comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 156, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 157, an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 158, an LC- CDR1 comprising the amino acid sequence of SEQ ID NO: 159, an LC-CDR2 comprising the amino acid sequence of SNN, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 161. In some embodiments, the anti-Sl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 216, or a variant thereof having at least about 90% (such as about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) sequence identity to the amino acid sequence of SEQ ID NO: 216, and a VL comprising the amino acid sequence of SEQ ID NO: 217, or a variant thereof having at least about 90% (such as about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) sequence identity to the amino acid sequence of SEQ ID NO: 217. In some embodiments, the anti-Sl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 216 and a VL comprising the amino acid sequence of SEQ ID NO: 217. In some embodiments, the anti-Sl antibody or antigen binding thereof comprises an scFv comprising the amino acid sequence of SEQ ID NO: 236, or a variant thereof having at least about 80% (such as about n% sequence identity, where n% is selected from 80%, 85%, 90%, 95%, 96%, 97%, 98%, and 99%) sequence identity sequence identity to SEQ ID NO: 236. In some embodiments, the anti-Sl antibody or antigen binding thereof comprises an scFv comprising the amino acid sequence of SEQ ID NO: 236.

[0160] In some embodiments, there is provided an anti-Sl antibody or antigen binding fragment thereof comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 162, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 163, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 164, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 165, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, an LC-CDR2 comprising the amino acid sequence of EDK, or a variant thereof comprising about 1 or about 2 amino acid substitutions, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 167, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions. In some embodiments, there is provided an anti- Sl antibody or antigen binding fragment thereof comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 162, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 163, an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 164, an LC- CDR1 comprising the amino acid sequence of SEQ ID NO: 165, an LC-CDR2 comprising the amino acid sequence of EDK, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 167. In some embodiments, the anti-Sl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 218, or a variant thereof having at least about 90% (such as about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) sequence identity to the amino acid sequence of SEQ ID NO: 218, and a VL comprising the amino acid sequence of SEQ ID NO: 219, or a variant thereof having at least about 90% (such as about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) sequence identity to the amino acid sequence of SEQ ID NO: 219. In some embodiments, the anti-Sl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 218 and a VL comprising the amino acid sequence of SEQ ID NO: 219. In some embodiments, the anti-Sl antibody or antigen binding thereof comprises an scFv comprising the amino acid sequence of SEQ ID NO: 237, or a variant thereof having at least about 80% (such as about n% sequence identity, where n% is selected from 80%, 85%, 90%, 95%, 96%, 97%, 98%, and 99%)sequence identity sequence identity to SEQ ID NO: 237. In some embodiments, the anti-Sl antibody or antigen binding thereof comprises an scFv comprising the amino acid sequence of SEQ ID NO: 237.

[0161] In some embodiments, there is provided an anti-Sl antibody or antigen binding fragment thereof comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 168, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 169, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 170, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 171, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, an LC-CDR2 comprising the amino acid sequence of RNN, or a variant thereof comprising about 1 or about 2 amino acid substitutions, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 173, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions. In some embodiments, there is provided an anti- Sl antibody or antigen binding fragment thereof comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 168, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 169, an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 170, an LC- CDR1 comprising the amino acid sequence of SEQ ID NO: 171, an LC-CDR2 comprising the amino acid sequence of RNN, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 173. In some embodiments, the anti-Sl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 220, or a variant thereof having at least about 90% (such as about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) sequence identity to the amino acid sequence of SEQ ID NO: 220, and a VL comprising the amino acid sequence of SEQ ID NO: 221, or a variant thereof having at least about 90% (such as about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) sequence identity to the amino acid sequence of SEQ ID NO: 221. In some embodiments, the anti-Sl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 220 and a VL comprising the amino acid sequence of SEQ ID NO: 221. In some embodiments,the anti-Sl antibody or antigen binding thereof comprises an scFv comprising the amino acid sequence of SEQ ID NO: 238, or a variant thereof having at least about 80% (such as about n% sequence identity, where n% is selected from 80%, 85%, 90%, 95%, 96%, 97%, 98%, and 99%) sequence identity sequence identity to SEQ ID NO: 238. In some embodiments, the anti-Sl antibody or antigen binding thereof comprises an scFv comprising the amino acid sequence of SEQ ID NO: 238.

[0162] In some embodiments, there is provided an anti-Sl antibody or antigen binding fragment thereof comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 174, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 175, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 176, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 177, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, an LC-CDR2 comprising the amino acid sequence of FND, or a variant thereof comprising about 1 or about 2 amino acid substitutions, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 179, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions. In some embodiments, there is provided an anti- Sl antibody or antigen binding fragment thereof comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 174, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 175, an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 176, an LC- CDR1 comprising the amino acid sequence of SEQ ID NO: 177, an LC-CDR2 comprising the amino acid sequence of FND, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 179. In some embodiments, the anti-S l antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 222, or a variant thereof having at least about 90% (such as about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) sequence identity to the amino acid sequence of SEQ ID NO: 222, and a VL comprising the amino acid sequence of SEQ ID NO: 223, or a variant thereof having at least about 90% (such as about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) sequence identity to theamino acid sequence of SEQ ID NO: 223. In some embodiments, the anti-Sl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 222 and a VL comprising the amino acid sequence of SEQ ID NO: 223. In some embodiments, the anti-Sl antibody or antigen binding thereof comprises an scFv comprising the amino acid sequence of SEQ ID NO: 239, or a variant thereof having at least about 80% (such as about n% sequence identity, where n% is selected from 80%, 85%, 90%, 95%, 96%, 97%, 98%, and 99%) sequence identity sequence identity to SEQ ID NO: 239. In some embodiments, the anti-Sl antibody or antigen binding thereof comprises an scFv comprising the amino acid sequence of SEQ ID NO: 239.

[0163] In some embodiments, there is provided an anti-Sl antibody or antigen binding fragment thereof comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 180, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 181, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 182, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 183, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, an LC-CDR2 comprising the amino acid sequence of EVS, or a variant thereof comprising about 1 or about 2 amino acid substitutions, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 185, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions. In some embodiments, there is provided an anti- Sl antibody or antigen binding fragment thereof comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 180, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 181, an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 182, an LC- CDR1 comprising the amino acid sequence of SEQ ID NO: 183, an LC-CDR2 comprising the amino acid sequence of EVS, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 185. In some embodiments, the anti-Sl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 224, or a variant thereof having at least about 90% (such as about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) sequence identity to the amino acid sequenceof SEQ ID NO: 224, and a VL comprising the amino acid sequence of SEQ ID NO: 225, or a variant thereof having at least about 90% (such as about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) sequence identity to the amino acid sequence of SEQ ID NO: 225. In some embodiments, the anti-Sl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 224 and a VL comprising the amino acid sequence of SEQ ID NO: 225. In some embodiments, the anti-Sl antibody or antigen binding thereof comprises an scFv comprising the amino acid sequence of SEQ ID NO: 240, or a variant thereof having at least about 80% (such as about n% sequence identity, where n% is selected from 80%, 85%, 90%, 95%, 96%, 97%, 98%, and 99%) sequence identity sequence identity to SEQ ID NO: 240. In some embodiments, the anti-Sl antibody or antigen binding thereof comprises an scFv comprising the amino acid sequence of SEQ ID NO: 240.

[0164] In some embodiments, there is provided an anti-Sl antibody or antigen binding fragment thereof comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 186, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 187, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 188, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 189, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, an LC-CDR2 comprising the amino acid sequence of SNN, or a variant thereof comprising about 1 or about 2 amino acid substitutions, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 191, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions. In some embodiments, there is provided an anti- Sl antibody or antigen binding fragment thereof comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 186, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 187, an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 188, an LC- CDR1 comprising the amino acid sequence of SEQ ID NO: 189, an LC-CDR2 comprising the amino acid sequence of SNN, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 191. In some embodiments, the anti-Sl antibody or antigen binding fragment thereofcomprises a VH comprising the amino acid sequence of SEQ ID NO: 226, or a variant thereof having at least about 90% (such as about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) sequence identity to the amino acid sequence of SEQ ID NO: 226, and a VL comprising the amino acid sequence of SEQ ID NO: 227, or a variant thereof having at least about 90% (such as about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) sequence identity to the amino acid sequence of SEQ ID NO: 227. In some embodiments, the anti-Sl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 226 and a Vi, comprising the amino acid sequence of SEQ ID NO: 227. In some embodiments, the anti-Sl antibody or antigen binding thereof comprises an scFv comprising the amino acid sequence of SEQ ID NO: 241, or a variant thereof having at least about 80% (such as about n% sequence identity, where n% is selected from 80%, 85%, 90%, 95%, 96%, 97%, 98%, and 99%) sequence identity sequence identity to SEQ ID NO: 241. In some embodiments, the anti-Sl antibody or antigen binding thereof comprises an scFv comprising the amino acid sequence of SEQ ID NO: 241.

[0165] In some embodiments, there is provided an anti-Sl antibody or antigen binding fragment thereof comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 192, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 193, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 194, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 195, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, an LC-CDR2 comprising the amino acid sequence of VSN, or a variant thereof comprising about 1 or about 2 amino acid substitutions, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 197, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions. In some embodiments, there is provided an anti- Sl antibody or antigen binding fragment thereof comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 192, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 193, an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 194, an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 195, an LC-CDR2 comprising the amino acid sequence of VSN, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 197. In some embodiments, the anti-Sl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 228, or a variant thereof having at least about 90% (such as about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) sequence identity to the amino acid sequence of SEQ ID NO: 228, and a VL comprising the amino acid sequence of SEQ ID NO: 229, or a variant thereof having at least about 90% (such as about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) sequence identity to the amino acid sequence of SEQ ID NO: 229. In some embodiments, the anti-Sl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 228 and a VL comprising the amino acid sequence of SEQ ID NO: 229. In some embodiments, the anti-Sl antibody or antigen binding thereof comprises an scFv comprising the amino acid sequence of SEQ ID NO: 242, or a variant thereof having at least about 80% (such as about n% sequence identity, where n% is selected from 80%, 85%, 90%, 95%, 96%, 97%, 98%, and 99%) sequence identity sequence identity to SEQ ID NO: 242. In some embodiments, the anti-Sl antibody or antigen binding thereof comprises an scFv comprising the amino acid sequence of SEQ ID NO: 242.

[0166] In some embodiments, there is provided an anti-Sl antibody or antigen binding fragment thereof comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 198, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 199, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 200, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 201, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, an LC-CDR2 comprising the amino acid sequence of EVS, or a variant thereof comprising about 1 or about 2 amino acid substitutions, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 203, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions. In some embodiments, there is provided an anti-SI antibody or antigen binding fragment thereof comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 198, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 199, an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 200, an LC- CDR1 comprising the amino acid sequence of SEQ ID NO: 201, an LC-CDR2 comprising the amino acid sequence of EVS, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 203. In some embodiments, the anti-Sl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 230, or a variant thereof having at least about 90% (such as about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) sequence identity to the amino acid sequence of SEQ ID NO: 230, and a VL comprising the amino acid sequence of SEQ ID NO: 231, or a variant thereof having at least about 90% (such as about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) sequence identity to the amino acid sequence of SEQ ID NO : 231. In some embodiments, the anti-S 1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 230 and a VL comprising the amino acid sequence of SEQ ID NO: 231. In some embodiments, the anti-Sl antibody or antigen binding thereof comprises an scFv comprising the amino acid sequence of SEQ ID NO: 243, or a variant thereof having at least about 80% (such as about n% sequence identity, where n% is selected from 80%, 85%, 90%, 95%, 96%, 97%, 98%, and 99%) sequence identity sequence identity to SEQ ID NO: 243. In some embodiments, the anti-Sl antibody or antigen binding thereof comprises an scFv comprising the amino acid sequence of SEQ ID NO: 243.

[0167] In some embodiments, there is provided an anti-Sl antibody or antigen binding fragment thereof comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 204, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 205, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 206 or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 207, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, an LC- CDR2 comprising the amino acid sequence of SNN, or a variant thereof comprising about 1 orabout 2 amino acid substitutions, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 209, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions. In some embodiments, there is provided an anti-Sl antibody or antigen binding fragment thereof comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 204, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 205, an HC- CDR3 comprising the amino acid sequence of SEQ ID NO: 206, an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 207, an LC-CDR2 comprising the amino acid sequence of SNN, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 209. In some embodiments, the anti-Sl antibody or antigen binding fragment thereof comprises a Vu comprising the amino acid sequence of SEQ ID NO: 232, or a variant thereof having at least about 90% (such as about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) sequence identity to the amino acid sequence of SEQ ID NO: 232, and a VL comprising the amino acid sequence of SEQ ID NO: 233, or a variant thereof having at least about 90% (such as about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) sequence identity to the amino acid sequence of SEQ ID NO: 233. In some embodiments, the anti-Sl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 232 and a VL comprising the amino acid sequence of SEQ ID NO: 233. In some embodiments, the anti-Sl antibody or antigen binding thereof comprises an scFv comprising the amino acid sequence of SEQ ID NO: 244, or a variant thereof having at least about 80% (such as about n% sequence identity, where n% is selected from 80%, 85%, 90%, 95%, 96%, 97%, 98%, and 99%) sequence identity sequence identity to SEQ ID NO: 244. In some embodiments, the anti-Sl antibody or antigen binding thereof comprises an scFv comprising the amino acid sequence of SEQ ID NO: 244.

[0168] In some embodiments, there is provided an anti-Sl antibody or antigen binding fragment thereof comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 210, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 211, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 212 or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions,an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 213, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, an LC- CDR2 comprising the amino acid sequence of GND or a variant thereof comprising about 1 or about 2 amino acid substitutions, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 215, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions. In some embodiments, there is provided an anti-Sl antibody or antigen binding fragment thereof comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 210, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 211, an HC- CDR3 comprising the amino acid sequence of SEQ ID NO: 212, an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 213, an LC-CDR2 comprising the amino acid sequence of GND, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 215. In some embodiments, the anti-Sl antibody or antigen binding fragment thereof comprises a Vu comprising the amino acid sequence of SEQ ID NO: 234, or a variant thereof having at least about 90% (such as about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) sequence identity to the amino acid sequence of SEQ ID NO: 234, and a VL comprising the amino acid sequence of SEQ ID NO: 235, or a variant thereof having at least about 90% (such as about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) sequence identity to the amino acid sequence of SEQ ID NO: 235. In some embodiments, the anti-Sl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 234 and a VL comprising the amino acid sequence of SEQ ID NO: 235. In some embodiments, the anti-Sl antibody or antigen binding thereof comprises an scFv comprising the amino acid sequence of SEQ ID NO: 245, or a variant thereof having at least about 80% (such as about n% sequence identity, where n% is selected from 80%, 85%, 90%, 95%, 96%, 97%, 98%, and 99%) sequence identity sequence identity to SEQ ID NO: 245. In some embodiments, the anti-Sl antibody or antigen binding thereof comprises an scFv comprising the amino acid sequence of SEQ ID NO: 245.

[0169] In some embodiments, there is provided an anti-Sl antibody or antigen binding fragment thereof comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 681, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 682, or avariant thereof comprising up to about 5 (such as about any of 1 , 2, 3, 4, or 5) amino acid substitutions, an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 683 or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 684, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, an LC- CDR2 comprising the amino acid sequence of GSS or a variant thereof comprising about 1 or about 2 amino acid substitutions, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 686, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions. In some embodiments, there is provided an anti-Sl antibody or antigen binding fragment thereof comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 681, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 682, an HC- CDR3 comprising the amino acid sequence of SEQ ID NO: 683, an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 684, an LC-CDR2 comprising the amino acid sequence of GSS, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 686. In some embodiments, the anti-Sl antibody or antigen binding fragment thereof comprises a Vu comprising the amino acid sequence of SEQ ID NO: 679, or a variant thereof having at least about 90% (such as about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) sequence identity to the amino acid sequence of SEQ ID NO: 679, and a VL comprising the amino acid sequence of SEQ ID NO: 680, or a variant thereof having at least about 90% (such as about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) sequence identity to the amino acid sequence of SEQ ID NO: 680. In some embodiments, the anti-Sl antibody or antigen binding fragment thereof comprises a Vu comprising the amino acid sequence of SEQ ID NO: 679 and a VL comprising the amino acid sequence of SEQ ID NO: 680.

[0170] In some embodiments, the anti-S l antibody or antigen binding fragment thereof specifically binds to the SI protein of SARS-CoV-2. In some embodiments, the anti-Sl antibody or antigen binding fragment thereof specifically binds to the non-RBD region of the SI protein of SARS-CoV-2. In some embodiments, the anti-Sl antibody or antigen binding fragment thereof specifically binds to the RED of the SI protein of SARS-CoV-2. In some embodiments, the anti-Sl antibody or antigen binding fragment thereof is a neutralizing antibody. In some embodiments, the anti-Sl antibody or antigen binding fragment thereof specifically blocksbinding of the RBD of the SI protein of SARS-CoV-2 to human ACE2 (huACE2). In some embodiments, the anti-Sl antibody or antigen binding fragment thereof specifically blocks huACE2 binding of a wildtype SI protein of SARS-CoV-2 (e.g., SEQ ID NO: 678), or a variant of the SI protein of SARS-CoV-2, such as an SI protein comprising one or more mutations selected from the group consisting of D614G, V367F, N439K, A435S, V483A, K458R, G476S, R408I, V503F, A522V, Y508H, L452R, A520S, I472V, T478I, F490S, and / or P384L. In some embodiments, the anti-Sl antibody or antigen binding fragment thereof specifically blocks huACE2 binding of an SI protein of SARS-CoV-2 comprising the D614G mutation. In some embodiments, the anti-Sl antibody or antigen binding fragment thereof does not specifically bind to an SI protein of another coronavirus, such as SARS-CoV, MERS-CoV, HCoV-HKUl, HCoV-NL63, HCoV-229E, or HCoV-OC43. In some embodiments, the anti-Sl antibody or antigen binding fragment thereof does not block huACE2 binding of an SI protein of another coronavirus, such as SARS-CoV, HCoV-HKUl, HCoV-NL63, HCoV-229E, or HCoV-OC43.

[0171] In some embodiments, the anti-Sl antibody or antigen binding fragment thereof specifically binds to the SI protein of SARS-CoV-2 with a KD of no more than about any one of 100 nM, 50 nM, 20 nM, 10 nM, 5 nM, 4 nM, 3 nM, 2 nM, 1 nM, 0.75 nM, 0.5 nM, 0.2 nM, 0.1 nM, 0.05 nM, 0.01 nM, or less, including any values and ranges in between these values. In some embodiments, anti-Sl antibody or antigen binding fragment thereof specifically binds to the SI protein of SARS-CoV-2 with a KD of about any one of 0.01 nM to 0.1 nM, 0.1 nM to 1 nM, 1 nM to 5 nM, 5 nM to 10 nM, 10 nM-100 nM, 0.01 nM to 1 nM, 0.5 nM to 10 nM, 0.1 nM to 1 nM, 0.1 nM to 10 nM, or 0.01 nM to 100 nM.

[0172] In some embodiments, there is provided an anti-Sl antibody competes for binding to an SI subunit of a spike protein of SARS-CoV-2 with a second anti-Sl antibody according to any of the anti-Sl antibodies described herein. In some embodiments, the anti-Sl antibody binds to the same, or substantially the same, epitope as the second anti-Sl antibody. In some embodiments, binding of the anti-Sl antibody to an SI subunit of a spike protein of SARS-CoV-2 inhibits the binding of a second anti-Sl antibody to the same SI subunit of the spike protein of SARS-CoV-2 by at least about 70% (such as by at least about any of 75%, 80%, 85%, 90%, 95%, 98% or 99%), or vice versa. In some embodiments, the anti-Sl antibody and the second anti-Sl antibody cross-compete for binding to the SI subunit of the spike protein of SARS-CoV-2, i.e., each of theanti-Sl antibody moi eties competes with the other for binding to the SI subunit of the spike protein of SARS-CoV-2.ACE2 TARGET BINDING

[0173] In some embodiments, the target-binding moiety is an inhibitory polypeptide that inhibits binding of the S protein to a receptor on a cell of the mucosa. In some embodiments, the targetbinding moiety comprises a natural receptor of the S protein or a fragment derived from the natural receptor of a coronavirus. In some embodiments, the target-binding moiety comprises an EBD of the natural receptor of a coronavirus. In some embodiments, the target-binding moiety comprises an EBD of ACE2 or a fragment thereof. In some embodiments, the target-binding moiety comprises a truncated version of ACE2.

[0174] In some embodiments, provided herein are chimeric proteins comprising target-binding moi eties comprising an EBD of an ACE2 host viral receptor, or a fragment thereof, of a coronavirus. The ACE2 protein or a fragment thereof may be derived from any coronavirus comprising an ACE2 viral receptor. Chimeric proteins based on these host receptors are contemplated herein (see, Table 1). In some embodiments, the coronavirus is SARS-CoV-2, SARS-CoV, or HCoV-NL63, or a variant thereof.

[0175] ACE2 is the cellular receptor for coronavirus infection (e.g., SARS-CoV-2 infection) and mediates binding of the viral S protein present on the surface of viral particles, enabling viral entry into susceptible host cells of the respiratory tract. ACE2 is a metallocarboxyl peptidase of 805 amino acids and is comprised of an extracellular catalytic domain (e.g., an EBD), a transmembrane region, and a short intracellular domain, that is highly conserved among vertebrates. A catalytically active fragment of ACE2 membrane-bound protein can be released from its membrane tether by the action of the ADAM10 / ADAM17 metalloproteinases or cleaved by the transmembrane protease TMPRSS2 at the cell membrane. ADAM17 and TMPRSS2 are expressed in cells in the lung and play an important role in coronavirus entry into cells of the respiratory tract. ACE2 and TMPRSS2 are co-expressed in many tissues throughout the body and can be easily detected in the respiratory system (e.g., expression occurs in type II pneumocytes and enterocytes, alveolar cells, bronchial transient epithelial secretory cells, respiratory epithelial cells, and in the oral cavity and tongue (Beyerstedt et al. 2021; Heurich etal. 2014)). In cells of the nasal epithelium, ACE2 is highly expressed in adults, with lower expression shown in children.

[0176] A 19 amino-acid ACE2 fragment QAKTFLDKFNHEAEDLFYQ (“ACE19”, SEQ ID NO: 254 in Table 8), comprising the SI binding site DKFNHEAEDLFY (SEQ ID NO: 255; underlined portion of the above ACE 19), was found to selectively recognize the SARS-CoV-2 virus S protein S 1 subunit and interfere with S 1 binding (Kuznetsov et al. Ini J P ept Res Ther. 28:7, 2022; Mohebbi et al. Future Virol. 10:2217-2235 (2020)).

[0177] Provided herein are target-binding moieties comprising an EBD of an ACE2 protein or a fragment thereof. In some embodiments, the ACE2 protein is a hACE2 protein or a fragment thereof. In some embodiments, the ACE2 protein is an animal ACE2 protein or a fragment thereof. hACE2 and animal ACE2 proteins are known in the art. Tables 8-9 show exemplary hACE2 (Table 8) and animal ACE2 (Table 9) proteins and fragments thereof.Table 8. Exemplary hACE2 proteins and fragments and variants thereofTable 9. Exemplary animal ACE2 proteins and fragments and variants thereofan SI subunit of an S protein) of a coronavirus or variant thereof using art-known techniques, and the sequences of such proteins, or a fragment thereof, may be used as the target-binding moiety of a chimeric protein of the present disclosure. In some embodiments, the coronavirus is a known coronavirus. In some embodiments, the coronavirus is a variant of a known coronavirus. In some embodiments, the coronavirus is a future coronavirus. In some embodiments, the coronavirus is a variant of a future coronavirus. In some embodiments, the target-binding moiety comprises a derivative of any one of the hACE2 or animal ACE2 proteins described herein (e.g, a fragment of any one of the hACE2 or animal ACE2 proteins described herein, or a variant of any one of the hACE2 or animal ACE2 proteins described herein).

[0179] In some embodiments, the target-binding moiety comprises between about 12 amino acids (aa) and about 805 aa of a full-length hACE2 protein or a fragment or variant thereof (e.g,an EBD of an ACE2 protein or a fragment or variant thereof, such as SEQ ID NO: 246), such as between about 12 aa and about 700 aa, between about 15 aa and about 500 aa, between about 100 aa and about 300 aa, between about 200 aa and about 400 aa, between about 300 aa and about 500 aa, between about 400 aa and about 600 aa, between about 500 aa and about 700 aa, between about 600 aa and about 805 aa, between about 12 aa and about 20 aa, between about 15 aa and about 20 aa, between about 21 aa and about 42 aa, between about 30 aa and about 41 aa, or between about 500 aa and about 805 aa, of a full-length hACE2 protein or a fragment or variant thereof. In some embodiments, the target-binding moiety comprises greater than about 12 aa of a full-length hACE2 protein or a fragment or variant thereof, such any greater than about n, where n is selected from 13 aa, 14 aa, 15 aa, 16 aa, 17 aa, 18 aa, 19, aa, 20 aa, 30 aa, 40 aa, 50 aa, 100 aa, 150 aa, 200 aa, 250 aa, 300 aa, 350 aa, 400 aa, 450 aa, 500 aa, 550 aa, 600 aa, 650 aa, 700 aa, 750 aa, 800 aa, 850 aa, or more, of a full-length hACE2 protein or a fragment thereof. In some embodiments, the target-binding moiety comprises less than about 805 aa of a full-length hACE2 protein or a fragment or variant thereof, such as less than about n, where n is selected from 800 aa, 750 aa, 700 aa, 650 aa, 600 aa, 550 aa, 500 aa, 450 aa, 400 aa, 350 aa, 300 aa, 250 aa, 200 aa, 150 aa, 100 aa, 50 aa, 40 aa, 30 aa, 20 aa, 19aa, 18aa, 17aa, 16aa, 15 aa, 14 aa, 13 aa, 12 aa, or less, of a full-length hACE2 protein or a fragment or variant thereof. In some embodiments, the target-binding moiety comprises any of about 805 aa, about 722 aa, about 714 aa, about 596 aa, about 380 aa, about 342 aa, about 331 aa, about 182 aa, about 19 aa, or about 12 aa of a full-length hACE2 protein or a fragment or variant thereof.

[0180] In some embodiments, the target-binding moiety comprises between about 12 aa and about 805 aa of a full-length animal ACE2 protein or a fragment or a variant thereof, such as between about 12 aa and about 700 aa, between about 15 aa and about 500 aa, between about 100 aa and about 300 aa, between about 200 aa and about 400 aa, between about 300 aa and about 500 aa, between about 400 aa and about 600 aa, between about 500 aa and about 700 aa, between about 600 aa and about 805 aa, between about 15 aa and about 20 aa, between about 12 aa and about 20 aa, between about 21 aa and about 42 aa, between about 30 aa and about 41 aa, or between about 500 aa and about 805 aa, of a full-length animal ACE2 protein or a fragment or a variant thereof. In some embodiments, the target-binding moiety comprises greater than about 12 aa of a full-length animal ACE2 protein or a fragment or variant thereof, such any greater than about n, where n is selected from 13 aa, 14 aa, 15 aa, 16 aa, 17 aa, 18 aa, 19, aa, 20 aa, 30aa, 40 aa, 50 aa, 100 aa, 150 aa, 200 aa, 250 aa, 300 aa, 350 aa, 400 aa, 450 aa, 500 aa, 550 aa, 600 aa, 650 aa, 700 aa, 750 aa, 800 aa, 850 aa, or more, of a full-length animal ACE2 protein or a fragment or variant thereof. In some embodiments, the target-binding moiety comprises less than about 805 aa of a full-length animal ACE2 protein or a fragment or variant thereof, such as less than about n, where n is selected from 800 aa, 750 aa, 700 aa, 650 aa, 600 aa, 550 aa, 500 aa, 450 aa, 400 aa, 350 aa, 300 aa, 250 aa, 200 aa, 150 aa, 100 aa, 40 aa, 30 aa, 50 aa, 20 aa, 19aa, 18aa, 17aa, 16aa, 15 aa, 14 aa, 13 aa, 12 aa, or less, of a full-length animal ACE2 protein or a fragment or variant thereof. In some embodiments, the target-binding moiety comprises any of about 805 aa, about 722 aa, about 714 aa, about 596 aa, about 380 aa, about 342 aa, about 331 aa, about 182 aa, 19 aa, or about 12 aa, of a full-length animal ACE2 protein or a fragment or variant thereof.

[0181] In some embodiments, the target-binding moiety comprises a fragment that selectively recognizes an SI subunit of the S protein and is capable of interfering with SI binding to a full- length ACE2. In some embodiments, the target-binding moiety comprises amino acids 24-42 of a full-length ACE2 protein (e. , a full-length hACE2 protein) or a variant thereof. In some embodiments, the target-binding moiety comprises between about 12 aa and about 19 aa, such as between about 12 aa and about 14 aa, between about 13 aa and about 15 aa, between about 14 aa and about 16 aa, between about 15 aa and about 17 aa, between about 16 aa and about 18 aa, between about 17 aa and about 19 aa, or between about 18 aa and about 19 aa of amino acids 24- 42, of a full-length ACE2 protein or a variant thereof. In some embodiments, the target-binding moiety comprises at least about 12 aa, such as at least about n, where n is selected from 13 aa, 14 aa, 15 aa, 16 aa, 17 aa, and 18 aa, of SEQ ID NO: 254. In some embodiments, the target-binding moiety comprises greater than about 12 aa, such as greater than about n, where n is selected from 13 aa, 14 aa, 15 aa, 16 aa, 17 aa, and 18 aa, of SEQ ID NO: 254. In some embodiments, the target-binding moiety comprises less than about 20 aa, such as less than about n, where n is selected from 19 aa, 18 aa, 17 aa, 16 aa, 15 aa, 14 aa, 13 aa, 12 aa, or fewer, of SEQ ID NO: 254. In some embodiments, the target-binding moiety comprises about 19 aa of SEQ ID NO: 254. In some embodiments, the chimeric protein comprises a target-binding moiety comprising the amino acid sequence of SEQ ID NO: 254, or a variant thereof comprising at least about 90% (such as about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) sequence identity to the amino acid sequence of SEQ ID NO: 254.

[0182] In some embodiments, the target-binding moiety comprises amino acids 30-41 of a full- length ACE2 protein (e.g., a full-length hACE2 protein or a full-length animal ACE2 protein) or a variant thereof. In some embodiments, the chimeric protein comprises a target-binding moiety comprising the amino acid sequence of any one of SEQ ID NOs: 255, 276-285, and 287, or a variant thereof comprising at least about 90% (such as about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) sequence identity to any one of SEQ ID NOs: 255, 276-285, and 287. In some embodiments, the full-length ACE2 protein or a variant thereof is a hACE2 protein or variant thereof. In some embodiments, the full-length ACE2 protein or variant thereof is not a canine or a chicken full-length ACE2 protein or variant thereof.

[0183] In some embodiments, the target-binding moiety comprises amino acids 29-40 of a full- length ACE2 protein (e.g., a full-length animal ACE2 protein) or a variant thereof. In some embodiments, the chimeric protein comprises a target-binding moiety comprising the amino acid sequence of SEQ ID NO: 275 or 286, or a variant thereof comprising at least about 90% (such as about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) sequence identity to SEQ ID NO: 275 or 286. In some embodiments, the full- length ACE2 protein or variant thereof is a canine or a chicken ACE2 protein or a variant thereof.

[0184] In some embodiments, the target-binding moiety comprises at least about 90% sequence identity (such as about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to amino acids 24-42 of a full-length hACE2 protein. In some embodiments, the target-binding moiety comprises amino acids 24-42 of a full-length hACE2 protein. In some embodiments, the target-binding moiety comprises an amino acid sequence having at least about 90% sequence identity (such as about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 254. In some embodiments, the target-binding moiety comprises the amino acid sequence of SEQ ID NO: 254. In some embodiments, the target-binding moiety comprises ACE19, as described in Table 8.

[0185] In some embodiments, the target-binding moiety comprises at least about 90% sequence identity (such as about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to amino acids 30-41 of a full-length hACE2 protein. In someembodiments, the target-binding moiety comprises amino acids 30-41 of a full-length hACE2 protein. In some embodiments, the target-binding moiety comprises an amino acid sequence having at least about 90% sequence identity (such as about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 255. In some embodiments, the target-binding moiety comprises the amino acid sequence of SEQ ID NO: 255. In some embodiments, the target-binding moiety comprises ACE12, as described in Table 8.

[0186] In some embodiments, the chimeric protein comprises a target-binding moiety comprising an EBD of a hACE2 protein that specifically binds to an S protein, or a fragment thereof. Exemplary hACE2 proteins are provided in Table 8 above. In some embodiments, the target-binding moiety comprises an amino acid sequence having at least about 90% sequence identity (such as about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of any one of SEQ ID NOs: 246- 253 and 256-261. In some embodiments, the target-binding moiety comprises the amino acid sequence of any one of SEQ ID NOs: 246-253 and 256-261.

[0187] In some embodiments, the target-binding moiety comprises an amino acid sequence having at least about 90% sequence identity (such as about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 246. In some embodiments, the target-binding moiety comprises the amino acid sequence of SEQ ID NO: 246. In some embodiments, the target-binding moiety comprises a full-length hACE2 protein, as described in Table 8.

[0188] In some embodiments, the target-binding moiety comprises amino acids 19-614 of hACE2 (e.g., SEQ ID NO: 246). In some embodiments, the target-binding moiety comprises an amino acid sequence having at least about 90% sequence identity (such as about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 247. In some embodiments, the target-binding moiety comprises the amino acid sequence of SEQ ID NO: 247. In some embodiments, the targetbinding moiety comprises ACE614, as described in Table 8.

[0189] In some embodiments, the target-binding moiety comprises amino acids 19-360 of hACE2 (e.g., SEQ ID NO: 246). In some embodiments, the target-binding moiety comprises an amino acid sequence having at least about 90% sequence identity (such as about n% sequenceidentity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 248. In some embodiments, the target-binding moiety comprises the amino acid sequence of SEQ ID NO: 248. In some embodiments, the targetbinding moiety comprises ACE360, as described in Table 8.

[0190] In some embodiments, the target-binding moiety comprises amino acids 30-360 of hACE2 (e.g., SEQ ID NO: 246). In some embodiments, the target-binding moiety comprises an amino acid sequence having at least about 90% sequence identity (such as about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 249. In some embodiments, the target-binding moiety comprises the amino acid sequence of SEQ ID NO: 249. In some embodiments, the targetbinding moiety comprises ACEA360, as described in Table 8.

[0191] In some embodiments, the target-binding moiety comprises amino acids 19-732 of hACE2 (e.g., SEQ ID NO: 246). In some embodiments, the target-binding moiety comprises an amino acid sequence having at least about 90% sequence identity (such as about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 250. In some embodiments, the target-binding moiety comprises the amino acid sequence of SEQ ID NO: 250. In some embodiments, the targetbinding moiety comprises ACE732, as described in Table 8.

[0192] In some embodiments, the target-binding moiety comprises amino acids 19-740 of hACE2 (e.g., SEQ ID NO: 246). In some embodiments, the target-binding moiety comprises an amino acid sequence having at least about 90% sequence identity (such as about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 251. In some embodiments, the target-binding moiety comprises the amino acid sequence of SEQ ID NO: 251. In some embodiments, the targetbinding moiety comprises ACE740, as described in Table 8.

[0193] In some embodiments, the target-binding moiety comprises amino acids 19-200 of hACE2 (e.g., SEQ ID NO: 246). In some embodiments, the target-binding moiety comprises an amino acid sequence having at least about 90% sequence identity (such as about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 252. In some embodiments, the target-binding moietycomprises the amino acid sequence of SEQ ID NO: 252. In some embodiments, the targetbinding moiety comprises ACE200, as described in Table 8.

[0194] In some embodiments, the target-binding moiety comprises amino acids 42-420 of hACE2 (e.g., SEQ ID NO: 246). In some embodiments, the target-binding moiety comprises an amino acid sequence having at least about 90% sequence identity (such as about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 253. In some embodiments, the target-binding moiety comprises the amino acid sequence of SEQ ID NO: 253. In some embodiments, the targetbinding moiety comprises ACEA420, as described in Table 8.

[0195] In some embodiments, the target-binding moiety comprises a K26R point mutation at amino acid 26 in hACE2 (e.g., SEQ ID NO: 246). In some embodiments, the target-binding moiety comprises an amino acid sequence having at least about 90% sequence identity (such as about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 256. In some embodiments, the target-binding moiety comprises the amino acid sequence of SEQ ID NO: 256. In some embodiments, the target-binding moiety comprises ACE2 K26R, as described in Table 8.

[0196] In some embodiments, the target-binding moiety comprises an I468V point mutation at amino acid 468 in hACE2 e.g., SEQ ID NO: 246). In some embodiments, the target-binding moiety comprises an amino acid sequence having at least about 90% sequence identity (such as about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 257. In some embodiments, the target-binding moiety comprises the amino acid sequence of SEQ ID NO: 257. In some embodiments, the target-binding moiety comprises ACE2 I468V, as described in Table 8.

[0197] In some embodiments, the hACE2 protein or a fragment thereof comprises an hACE2 fusion fragment comprising a N638S point mutation at amino acid 638 in hACE2 (e.g., SEQ ID NO: 246). In some embodiments, the target-binding moiety comprises an amino acid sequence having at least about 90% sequence identity (such as about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 258. In some embodiments, the target-binding moiety comprises the amino acid sequence of SEQ ID NO: 258. In some embodiments, the target-binding moiety comprises ACE2 N638S, as described in Table 8.

[0198] In some embodiments, the target-binding moiety comprises a N720D point mutation at amino acid 720 in hACE2 (e.g., SEQ ID NO: 246). In some embodiments, the target-binding moiety comprises an amino acid sequence having at least about 90% sequence identity (such as about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 259. In some embodiments, the target-binding moiety comprises the amino acid sequence of SEQ ID NO: 259. In some embodiments, the target-binding moiety comprises ACE2 N720D, as described in Table 8.

[0199] In some embodiments, the target-binding moiety comprises a hACE2 fragment comprising a H374N point mutation at amino acid 374, and a H378N point mutation at amino acid 378 in hACE2 (e.g, SEQ ID NO: 246). In some embodiments, the target-binding moiety comprises an amino acid sequence having at least about 90% sequence identity (such as about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 260. In some embodiments, the targetbinding moiety comprises the amino acid sequence of SEQ ID NO: 260. In some embodiments, the target-binding moiety comprises ACE2 HN-HN, as described in Table 8.

[0200] In some embodiments, the target-binding moiety comprises a hACE2 fragment comprising a T27Y point mutation at amino acid 27, and a H34A point mutation at amino acid 34 in hACE2 (e.g., SEQ ID NO: 246). In some embodiments, the target-binding moiety comprises an amino acid sequence having at least about 90% sequence identity (such as about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 261. In some embodiments, the targetbinding moiety comprises the amino acid sequence of SEQ ID NO: 261. In some embodiments, the target-binding moiety comprises ACE2 TY-HA, as described in Table 8.

[0201] In some embodiments, the chimeric protein comprises a target-binding moiety comprising an EBD of an animal ACE2 protein that specifically binds to an S protein, or a fragment thereof. In some embodiments, the target-binding moiety comprising an animal ACE2 protein described herein is a murine, guinea pig, equine, ferret, macaque, chimpanzee, swine, canine, feline, bovine, rabbit, mink, or chicken ACE2 protein or a fragment or variant thereof. Exemplary animal ACE2 proteins and fragments thereof are provided in Table 9 above.

[0202] In some embodiments, the target-binding moiety comprises an amino acid sequence having at least about 90% sequence identity (such as about n% sequence identity, where n% isselected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to amino acids 30-41 of a full-length animal ACE2 protein. In some embodiments, the target-binding moiety comprises amino acids 30-41 of a full-length animal ACE2 protein. In some embodiments, the full-length animal ACE2 protein is a murine, guinea pig, equine, ferret, macaque, chimpanzee, swine, feline, bovine, rabbit, or mink ACE2 protein. In some embodiments, the full-length animal ACE2 protein comprises an amino acid sequence having at least about 90% sequence identity (such as about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to any one of SEQ ID NOs: 262-267 and 269-273. In some embodiments, the target-binding moiety...

Claims

1. CLAIMSWhat is claimed is:

1. A method of preventing transmission of a virus from an individual infected with the virus to an individual not infected with the virus, comprising administering to the individual infected with the virus an effective amount of a chimeric protein, wherein the chimeric protein comprises:(a) a target-binding moiety that specifically binds to the virus; and(b) a mucoadhesive peptide fragment, wherein the mucoadhesive peptide fragment facilitates attachment of the chimeric protein to a mucosa, thereby preventing transmission of the virus to the individual not infected with the virus.

2. A method of preventing spread of a virus within a population of individuals, wherein at least one of the individuals is infected with the virus, the method comprising administering to the at least one individual infected with the virus with an effective amount of a chimeric protein, wherein the chimeric protein comprises:(a) a target-binding moiety that specifically binds to the virus; and(b) a mucoadhesive peptide fragment, wherein the mucoadhesive peptide fragment facilitates attachment of the chimeric protein to a mucosa, thereby preventing transmission of the virus to another individual or individuals not infected with the virus in the population.

3. The method of any one of claims 1-2, wherein the individual infected with the virus or the at least one individual infected with the virus is under treatment for the virus infection before, concurrently with, or after the administration of the chimeric protein, or optionally, has been vaccinated against the virus prior to infection.

4. The method of any one of claims 1-3, wherein the chimeric protein is administered within 14 days after a symptom is detected in the individual infected with the virus.

5. The method of any one of claims 1-4, wherein the mucoadhesive peptide fragment comprises at least about 5 positively charged amino acid residues.

6. The method of any of the claims 1-5, wherein the chimeric protein comprises two or more mucoadhesive peptide fragments, and optionally wherein each of the two or more mucoadhesive peptide fragments comprises at least about 5 positively charged amino acid residues.

7. The method of claims 5 or 6, wherein the positively charged amino acid residues are selected from the group consisting of lysine, arginine, histidine, ornithine, and combinations thereof.

8. The method of any one of claims 1-7, wherein the mucoadhesive peptide fragment is fused to the target-binding moiety via a peptide linker, and optionally wherein the peptide linker comprises:(i) one or more oligomerization and / or multimerization domains;(ii) the constant region of a heavy chain of a full-length antibody or a fragment thereof, or the constant region of a light chain of a full-length antibody or a fragment thereof;(iii) an Fc region or a fragment thereof;(iv) a CHi, CH2, CH3, CH4, and / or CL domain or a fragment thereof;(v) an antibody hinge domain or a fragment thereof;(vi) a detectable enzymatic tag, optionally wherein the enzymatic tag is an alkaline phosphatase and / or a glutathione-s-transferase;(vii) a basic helix-loop-helix leucine zipper (bZIP) domain, bZIP isoleucine zipper domain, and / or bZIP-leucine / i sol eucine zipper domain;(viii) a collagen-like peptide;(ix) a p53 tetramerization domain;(x) a streptavidin (SA) protein, optionally wherein the peptide linker further comprises a dextran scaffold or one or more maleimide polymers (DMGS);(xi) a bacteriophage T7 fibritin protein or a portion thereof; and / or(xii) a cartilage oligomeric matrix protein (COMP) protein.

9. The method of any one of claims 1-8, wherein the mucoadhesive peptide fragment is fused to a C-terminus of the target-binding moiety.

10. The method of any one of claims 1-9, wherein the target-binding moiety specifically binds to a spike (S) protein of SARS-CoV-2, optionally wherein the target-binding moiety comprises a natural receptor of the virus or a variant derived from the natural receptor of the virus, and further optionally wherein the target-binding moiety comprises an extracellular binding domain (EBD) of an angiotensin-converting enzyme 2 (ACE2) protein or a variant thereof.

11. The method of claim 10, wherein the target-binding moiety comprises the EBD of a human ACE2 (hACE2) protein or a variant thereof, optionally:(a) wherein the target-binding moiety comprises:(i) amino acids 24-42 of a full-length hACE2 protein comprising the amino acid sequence of SEQ ID NO: 246, or a variant thereof having at least about 90% sequence identity to amino acids 24-42 of a full-length hACE2 protein comprising the amino acid sequence of SEQ ID NO: 246; and / or(ii) the amino acid sequence of SEQ ID NO: 254, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 254;(b) wherein the target-binding moiety comprises the amino acid sequence of any one of SEQ ID NOs: 248, 249, 252, 253, 254, and 255, or a variant thereof having at least about 90% sequence identity the amino acid sequence of any one of SEQ ID NOs: 248, 249, 252, 253, 254, and 255; or(c) wherein the target-binding moiety comprises the amino acid sequence of any one of SEQ ID NOs: 246, 247, 250, 251, 256, 257, 258, 259, 260, and 261, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 246, 247, 250, 251, 256, 257, 258, 259, 260, and 261.

12. The method of any one of claims 1-9, wherein the virus is an influenza virus, optionally wherein the virus is selected from the group consisting of a Type A influenza virus (IAV), a Type B influenza virus (IBV), a Type C influenza virus (ICV), a Type D influenza virus (IDV), or a variant, subtype, or reassortant thereof, and optionally wherein the targetbinding moiety specifically binds an hemagglutinin (HA) antigen or a neuraminidase (NA) antigen.

13. An antibody moiety that specifically binds to a component of an influenza virus or a variant thereof, wherein the antibody moiety comprises:(a) a HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 754 ;(b) a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 755 ;(c) a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 756 ;(d) a LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 757 ;(e) a LC-CDR2 comprising the amino acid sequence VDS; and(f) a LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 759.

14. The antibody moiety of claim 13, comprising:(a) a VH comprising the amino acid sequence of SEQ ID NO: 730 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 730; and(b) a VL comprising the amino acid sequence of SEQ ID NO: 731 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 731.

15. A chimeric protein comprising:(a) the antibody moiety of claims 13 or 14; and(b) a mucoadhesive peptide fragment comprising at least about 5 positively charged amino acid residues, wherein the mucoadhesive peptide fragment facilitates attachment of the chimeric protein to a mucosa.

16. A chimeric protein comprising:(a) an antibody moiety that specifically binds to a component of a RSV or a variant thereof, comprising: i. a HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 689 ; ii. a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 690 ; iii. a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 691 ; iv. a LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 692 ; v. a LC-CDR2 comprising the amino acid sequence DTS; and vii. a LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 694 ; and(b) a mucoadhesive peptide fragment comprising at least about 5 positively charged amino acid residues, wherein the mucoadhesive peptide fragment facilitates attachment of the chimeric protein to a mucosa.

17. The chimeric protein of claim 16, wherein the antibody moiety comprises:(c) a VH comprising the amino acid sequence of SEQ ID NO: 687 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 687; and(d) a VL comprising the amino acid sequence of SEQ ID NO: 688 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 688.

18. A trispecific target-binding moiety that comprises:(iv)an ACE2 fragment comprising the EBD of an ACE2 protein or a variant thereof;(v) an anti-influenza antibody moiety that specifically binds to a component of an influenza virus or a variant thereof; and(vi) an anti-RSV antibody moiety that specifically binds to a component of an RSV or a variant thereof.

19. The trispecific target-binding moiety of claim 18, wherein the anti -influenza antibody moiety and the anti-RSV antibody moiety are located at the N-terminus of the trispecific target-binding moiety, optionally wherein the ACE2 EBD fragment is fused to the C-terminus of the anti-influenza antibody moiety and / or the anti-RSV antibody moiety, directly or indirectly.

20. The trispecific target-binding moiety of any one of claims 18 or 19, wherein the ACE2 fragment comprises the EBD of a human ACE2 (hACE2) protein or a variant thereof, optionally:(a)wherein the target-binding moiety comprises:(i) amino acids 24-42 of a full-length hACE2 protein comprising the amino acid sequence of SEQ ID NO: 246, or a variant thereof having at least about 90% sequence identity to amino acids 24-42 of a full-length hACE2 protein comprising the amino acid sequence of SEQ ID NO:246; and / or(ii) the amino acid sequence of SEQ ID NO: 254, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 254;(b) wherein the target-binding moiety comprises the amino acid sequence of any one of SEQ ID NOs: 246-253 and 256-261, or a variant thereof having at least about 90% sequence identity the amino acid sequence of any one of SEQ ID NOs: 246-253 and 256-261; or(c) wherein the chimeric protein comprises the amino acid sequence of any one of SEQ ID NOs: 1-10, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 1-10.

21. The trispecific target-binding moiety of any one of claims 18-20, comprising:(iii)a first polypeptide chain which comprises an influenza-binding sequence, and(iv)a second polypeptide chain which comprises an RSV-binding sequence; optionally wherein the influenza-binding sequence comprises an influenza-binding Vn and / or an influenza-binding VL, or optionally wherein the RSV-binding sequence comprises an RSV-binding VH and / or an RSV- binding VL.

22. The trispecific target-binding moiety of any one of claims 18-21, wherein the trispecific target-binding moiety also comprises an immunoglobulin constant region, and:(a) optionally wherein the immunoglobulin constant region comprises a heavy chain constant domain (CH) 1 and a light chain constant domain (CL); and / or(b) optionally wherein the immunoglobulin constant region comprises a CH2 and a CH3.

23. The trispecific target-binding moiety of any one of claims 18-22, wherein both the first and the second polypeptide chains comprise an ACE2 fragment, optionally wherein both the first and the second polypeptide chains comprise a CH2 and a CH3.

24. The trispecific target-binding moiety of any one of claims 18-23, wherein the anti -influenza antibody moiety comprises:(i) a HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 754 ;(ii) a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 755 ;(iii) a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 756 ;(iv) a LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 757 ;(v) a LC-CDR2 comprising the amino acid sequence VDS; and(vi) a LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 759;25. The trispecific target-binding moiety of claim 24, wherein the anti-influenza antibody moiety comprises:(i) a VH comprising the amino acid sequence of SEQ ID NO: 730 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 730; and(ii) a VL comprising the amino acid sequence of SEQ ID NO: 731 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 731.

26. The trispecific target-binding moiety of any one of claims 18-25, wherein the anti-RSV antibody moiety comprises:(i) a HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 689 ;(ii) a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 690;(iii) a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 691 ;(iv) a LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 692 ;(v) a LC-CDR2 comprising the amino acid sequence DTS; and(vi) a LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 694 .

27. The trispecific target-binding moiety of claim 26, wherein the anti-RSV antibody moiety comprises:(i) a VH comprising the amino acid sequence of SEQ ID NO: 687 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 687; and(ii) a VL comprising the amino acid sequence of SEQ ID NO: 688 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 688.

28. A trispecific target-binding moiety that comprises:(i) a first polypeptide chain comprising the amino acid sequence of SEQ ID NO: 745;(ii) a second polypeptide chain comprising the amino acid sequence of SEQ ID NO: 748;(iii) a third polypeptide chain comprising the amino acid sequence of SEQ ID NO: 747; and(iv) a fourth polypeptide chain comprising the amino acid sequence of SEQ ID NO: 749.

29. A chimeric protein comprising:(iii) the trispecific target-binding moiety of any one of claims 18-28; and(i) a mucoadhesive peptide fragment comprising at least about 5 positively charged amino acid residues, wherein the mucoadhesive peptide fragment facilitates attachment of the chimeric protein to a mucosa.

30. The chimeric protein of any one of claims 15-17 and 29, wherein the mucoadhesive peptide fragment comprises at least about 5 contiguous positively charged amino acids.

31. The chimeric protein of any one of claims 15-17 and 29-30, wherein the chimeric protein comprises two or more polypeptide chains and wherein at least one of the polypeptide chains comprises two or more mucoadhesive peptide fragments, and optionally wherein each of the two or more mucoadhesive peptide fragments comprises at least about 5 positively charged amino acid residues.

32. The chimeric protein of any one of claims 15-17 and 29-31, wherein the mucoadhesive peptide fragment is fused to the target-binding moiety via a peptide linker, optionally wherein the peptide linker comprises:(1) one or more oligomerization and / or multimerization domains;(ii) the constant region of a heavy chain of a full-length antibody or a fragment thereof, or the constant region of a light chain of a full-length antibody or a fragment thereof;(iii) an Fc region or a fragment thereof;(iv) a CHi, CH2, CH3, CH4, and / or CLdomain or a fragment thereof;(v) an antibody hinge domain or a fragment thereof;(vi) a detectable enzymatic tag, optionally wherein the enzymatic tag is an alkaline phosphatase and / or a glutathione-s-transferase;(vii) a basic helix-loop-helix leucine zipper (bZIP) domain, bZIP isoleucine zipper domain, and / or bZIP-leucine / isoleucine zipper domain;(viii) a collagen-like peptide;(ix) a p53 tetramerization domain;(x) a streptavidin (SA) protein, optionally wherein the peptide linker further comprises a dextran scaffold or one or more maleimide polymers (DMGS);(xi) a bacteriophage T7 fibritin protein or a portion thereof; and / or(xii) a cartilage oligomeric matrix protein (COMP) protein.

33. The chimeric protein of any one of claims 15-17 and 29-32, wherein the mucoadhesive peptide fragment is fused to a C-terminus of the target-binding moiety.

34. The chimeric protein of claim 15-17 and 29-33, wherein the positively charged amino acid residues are selected from the group consisting of lysine, arginine, histidine, and ornithine, optionally wherein the chimeric protein comprises a mucoadhesive peptide comprising 12 lysine amino acids bound to the antibody moiety.

35. The chimeric protein of claim 15-17 and 29-34, wherein the half-life of the chimeric protein on the mucosa is at least 12 hours.

36. The chimeric protein of claim 15-17 and 29-35, wherein the mucoadhesive peptide fragment is fused to the antibody moiety.

37. The antibody moiety of claims 13 or 14 the trispecific target-binding moiety of any one of claims 18-28, or the chimeric protein of any one of claims 15-17 and 29-36 wherein the antibody moiety is an antigen-binding fragment selected from the group consisting of a Fab, a Fab’, a (Fab’)2, an Fv, a single chain Fv (scFv), an scFv-Fc, a disulfide stabilized Fv fragment (dsFv), a (dsFv)2, an scFv dimer, a domain antibody, a camelized single domain antibody (sdAb), a bivalent domain antibody, a minibody, and a VHH, optionally wherein the antibody moiety is an animal, human, humanized, camelid, or chimeric antibody moiety.

38. A pharmaceutical composition comprising the antibody moiety of claims 13 or 14, the trispecific target-binding moiety of any one of claims 18-28, or the chimeric protein of any one of claims 15-17 and 29-36, and a pharmaceutically acceptable carrier, optionally wherein the pharmaceutically acceptable carrier is selected from the group consisting of methionine; citrate; NaCl; polysorbate 80; glycerin; and potassium sorbate.

39. 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 antibody moiety of any one of the claims 13 or 14, the trispecific target-binding moiety of any one of claims 18-28, or the chimeric protein of any one of claims 15-17 and 29-36.

40. A method of preventing or treating respiratory infection in an individual, comprising administering to the individual an effective amount of the antibody moiety of any one of the claims 13 or 14, the trispecific target-binding moiety of any one of claims 18-28, or the chimeric protein of any one of claims 15-17 and 29-36.

41. A method of preventing transmission of a virus causing a respiratory infection from an individual infected with the virus to an individual not infected with the virus, comprising administering to the individual an effective amount of the antibody moiety of any one of the claims 13 or 14, the trispecific target-binding moiety of any one of claims 18-28, or the chimeric protein of any one of claims 15-17 and 29-36.

42. A method of preventing spread of a virus causing a respiratory infection, within a population of individuals, wherein at least one of the individuals is infected with the virus, the method comprising administering to the at least one individual infected with the virus with an effective amount of antibody moiety of any one of the claims 13 or 14, the tri specific targetbinding moiety of any one of claims 18-28, or the chimeric protein of any one of claims 15- 17 and 29-36, thereby preventing transmission of the virus to another individual or individuals not infected with the virus in the population.

43. The method of any one of claims 1- 12 and 39-42, wherein the virus is a virus that causes respiratory infection, optionally wherein the virus causing the respiratory infection is selected from the group consisting of coronaviruses, RSV, and influenza viruses, and further optionally wherein the virus is a coronavirus selected from the group consisting of SARS- CoV, SARS-CoV-2, and a variant, subtype, or reassortant thereof.

44. The method of any one of claims 1-12 and 39-43, wherein the individual or the at least one individual is a human, and the effective amount is between about 1 μg and about 500 ug per nostril, optionally the effective amount is between 10 μg and 100 μg per nostril.

45. The method of any one of claims 1 -12 and 39-44, wherein the virus is a virus that causes respiratory infection, the transmission is via small respiratory droplets, and / or the transmission is via aerosol .

46. The method of any of the claims 1-12 and 39-45, wherein the antibody moiety, the targetbinding moiety or the chimeric protein is administered intranasally.

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