Composition for preventing or treating influenza infection

Abstract

The present application provides chimeric proteins comprising an antibody portion that specifically binds to a component of an influenza virus or variants thereof and a positively charged mucoadhesive peptide fragment. Compositions comprising the chimeric proteins described herein are useful for preventing or treating an infection caused by an influenza virus or variants thereof in an individual.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 331,100, filed April 14, 2022, the entire contents of which are incorporated herein by reference.

[0002] Reference to Electronic Sequence Listing

[0002] The contents of the electronic sequence listing (256442000240SEQLIST.xml, size: 503,568 bytes, created on: April 12, 2023) are incorporated herein by reference in their entirety.

[0003] FIELD OF THE INVENTION

[0003] The present invention relates to compositions and methods for preventing or treating infectious diseases caused by influenza viruses or variants thereof. [Background technology]

[0004] background Influenza, commonly known as influenza (flu), is a highly contagious respiratory disease caused by numerous RNA influenza viruses that infect humans. Influenza and its complications can cause significant morbidity and mortality. The World Health Organization (WHO) estimates that approximately 1 billion people are infected annually worldwide, with 3 to 5 million severe illnesses and 300,000 to 500,000 deaths. In the United States, the Centers for Disease Control and Prevention (CDC) estimated that between 2010 and 2020, influenza caused 9 to 41 million illnesses, 140,000 to 710,000 hospitalizations, and 12,000 to 52,000 deaths annually. (Krammer et al., Nat Rev Dis Primers, 4(1):1-21 (2018); Tyrrell et al., Medicine (Abingdon), 49(12):797-804 (2021)).

[0005]

[0005] There are three types of influenza viruses that infect humans: types A, B, and C. Type A influenza viruses are the most pathogenic and are most likely to cause epidemics and pandemics. Type A influenza viruses, also known as influenza A, can infect both humans and animals (e.g., cattle, horses, and birds). Influenza A viruses are classified into two groups based on two viral surface proteins, hemagglutinin (HA) and neuraminidase (NA). Eighteen different HAs and eleven different NAs have been found in various influenza A viruses, resulting in various subtypes and strains (e.g., H1N1, H5N1). Type B influenza viruses typically cause less severe disease than type A and are more commonly found in children, long-term care facilities, university campuses, and military bases. Influenza C viruses generally cause mild respiratory illness.

[0006]

[0006] People with viral influenza can spread the virus to others up to about 6 feet away, primarily through aerosolized droplets expelled when a person with influenza talks, coughs, or sneezes. These droplets can enter the mouth or nose of a nearby person and be inhaled into the lungs. A person can also become infected with the virus by touching a surface or object that has the influenza virus on it and then touching their own mouth, nose, or eyes. An infected person is contagious from one day before symptoms appear until five to seven days after symptoms appear. Even asymptomatic infected people can spread the virus.

[0007]

[0007] Most influenza infections can be prevented with an annual influenza vaccine. Historically, influenza vaccines have been produced by inoculating eggs, producing virus-inactivated allantoic fluid from the eggs, and purifying the relevant viral antigens. Currently, influenza vaccines are often produced in cell culture as either inactivated influenza vaccines (IIV) or live attenuated influenza vaccines (LAIV). IIVs are produced to protect against three (trivalent) or four (tetravalent) different strains of influenza virus; LAIVs are produced only as tetravalent vaccines.

[0008]

[0008] Additionally, four antiviral drugs have been approved by the Food and Drug Administration (FDA) for the treatment of influenza, including three neuraminidase inhibitors, oseltamivir (Tamiflu), peramivir (Rapivab), and zanamivir (Relenza), and the endonuclease inhibitor baloxavir marboxil (Xofluza). Baloxavir inhibits the endonuclease activity of the polymerase acidic protein contained in the influenza virus RNA polymerase complex, ultimately inhibiting viral replication.

[0009]

[0009] In most people, influenza causes a mild, self-limiting upper respiratory tract infection (e.g., cough, headache, chills, muscle aches, and fever), but it can also cause complications such as pneumonia, bronchitis, and sinus infections. Rarely, influenza infection can lead to severe viral pneumonia and acute respiratory distress syndrome (ARDS) with multiple organ failure, caused by exacerbation of underlying chronic conditions such as asthma, congestive heart failure, and chronic obstructive pulmonary disease. Individuals classified as at high risk for developing influenza complications include individuals aged 65 years or older or under 5 years, immunocompromised, pregnant, within 2 weeks of giving birth, or living in congregate settings (e.g., dormitories, military barracks, and nursing homes), and individuals with pre-existing chronic conditions (e.g., asthma, congestive heart failure, and diabetes) or obesity.

[0010] Influenza viruses are constantly evolving through a process called reassortment. The influenza A genome is composed of eight independent single-stranded RNA segments. When different viruses co-infect a cell, they can exchange genetic segments. The immense viral diversity generated by reassortment plays a key role in the global evolution of influenza viruses, making it difficult to predict which strains should be included in each year's influenza vaccine. To meet the need for global surveillance, the World Health Organization established National Influenza Centers in each region to collect and conduct preliminary analysis of influenza specimens, which are then sent to WHO Collaborating Centers for advanced evaluation. These analyses are used to inform the composition of influenza vaccines each year. This is a daunting task every year, and each season's vaccine composition does not necessarily provide protection for that season. In the 2018-2019 influenza season, the overall efficacy of the 2018 vaccine was low (only 29%), and the influenza vaccine for the 2020-2021 influenza season had to be modified to include many of the influenza strains predicted for 2020. (Xu et al., MMWR, 68(24):544-551(2019)). These factors make influenza infection prevention (currently mostly achieved through vaccination) costly (in terms of time and resources) and unpredictable (in terms of effectiveness). Furthermore, some patients are unable to or choose not to receive the influenza vaccine for various reasons, including those who experience severe adverse reactions to the vaccine. (Tyrrell et al., Dec;49(12):797-804(2021)). The influenza strains currently circulating (as of March 2023) are the influenza A H1N1pdm09 strain (the 2009 pandemic strain) and the H3N2 strain. The vaccine compositions for 2022-2023 were A / H1N1 / pdm09 and A / Darwin / 6 / 2021 (H3N2); for influenza B, the B / Yamagata and B / Austria / 1359417 / 2021 strains, which closely reflect current infections.

[0011]

[0011] Regarding medications, some patients cannot tolerate the adverse effects of commercially available influenza treatments or do not respond to the medications, and these medications are not readily available to many patients worldwide.

[0012]

[0012] There remains a great need for additional compositions and methods for preventing or treating influenza infections, particularly using cheaper, safer, more effective, and more flexible means. Summary of the Invention

[0013]

[0013] The present application provides compositions and methods for preventing or treating infectious diseases caused by influenza viruses or variants thereof. Accordingly, one aspect of the present application provides a chimeric protein comprising: (a) an antibody portion that specifically binds to a component of an influenza virus or variant thereof; and (b) a mucoadhesive peptide fragment comprising at least about five positively charged amino acid residues, wherein the mucoadhesive peptide fragment promotes adhesion of the chimeric protein to a mucosa.

[0014] In some embodiments, the chimeric protein comprises a single polypeptide chain.

[0015] In some embodiments, the chimeric protein comprises two or more polypeptide chains. In some embodiments, the chimeric protein comprises two or more mucoadhesive peptide fragments. In some embodiments, each of the two or more mucoadhesive peptide fragments comprises at least about five positively charged amino acid residues.

[0016] In some embodiments according to any of the foregoing embodiments of the chimeric protein, the mucoadhesive peptide fragment comprises at least about 6 positively charged amino acid residues.

[0017] In some embodiments according to any of the foregoing embodiments of the chimeric protein, the positively charged amino acid residue is selected from the group consisting of lysine, arginine, histidine, ornithine, and combinations thereof. In some embodiments, the positively charged amino acid residue comprises lysine. In some embodiments, the mucoadhesive peptide fragment comprises about 5, about 6, about 12, or about 30 lysines. In some embodiments, the positively charged amino acid residue comprises arginine. In some embodiments, the mucoadhesive peptide fragment comprises about 6, about 12, or about 30 arginines. In some embodiments, the positively charged amino acid residue comprises histidine. In some embodiments, the mucoadhesive peptide fragment comprises about 6, about 12, or about 30 histidines. In some embodiments, the positively charged amino acid residue comprises ornithine. In some embodiments, the mucoadhesive peptide fragment comprises about 6, about 12, or about 30 ornithines.

[0018] In some embodiments according to any of the foregoing embodiments of the chimeric protein, the mucoadhesive peptide fragment comprises at least 5 consecutive positively charged amino acids.

[0019] In some embodiments according to any of the foregoing embodiments of the chimeric protein, the positively charged amino acid residues are interspersed with one or more non-positively charged amino acid residues. In some embodiments, the non-positively charged amino acid residues are non-polar amino acids or polar non-charged amino acids. In some embodiments, the non-positively charged amino acid residues are selected from the group consisting of isoleucine, valine, alanine, tryptophan, leucine, glycine, methionine, proline, phenylalanine, threonine, cysteine, tyrosine, glutamine, serine, and asparagine, and combinations thereof. In some embodiments, at least 50% of the amino acid residues in the mucoadhesive peptide fragment are positively charged amino acid residues.

[0020] In some embodiments according to any of the foregoing embodiments of the chimeric protein, the mucoadhesive peptide fragment is about 15 kD or less. In some embodiments, the mucoadhesive peptide fragment has an isoelectric point (pI) higher than the pH of the mucosa. In some embodiments according to any of the foregoing embodiments of the chimeric protein, the half-life of the chimeric protein on the mucosa is at least 12 hours. In some embodiments, the mucoadhesive peptide fragment does not promote penetration of the chimeric protein into mucosal cells. In some embodiments, the mucoadhesive peptide fragment does not disrupt folding of the chimeric protein in host cells expressing the chimeric protein. In some embodiments, the mucoadhesive peptide fragment does not block secretion of the chimeric protein from host cells expressing the chimeric protein. In some embodiments, the mucoadhesive peptide fragment does not interfere with binding between the antibody moiety and a component of an influenza virus or variant thereof.

[0021]

[0021] In some embodiments according to any of the above embodiments of the chimeric protein, the mucoadhesive peptide fragment comprises an amino acid sequence of any one of SEQ ID NOs: 291-325 and 407-413, or a variant thereof comprising up to about three amino acid substitutions.

[0022] In some embodiments according to any of the foregoing embodiments of the chimeric protein, the mucoadhesive peptide fragment is fused to an antibody moiety.

[0023] In some embodiments according to any of the foregoing embodiments of the chimeric protein, the mucoadhesive peptide fragment is fused to the antibody portion via a bond.

[0024] In some embodiments according to any of the foregoing embodiments of the chimeric protein, the mucoadhesive peptide fragment is fused to the antibody portion via a peptide linker. In some embodiments, the peptide linker comprises one or more oligomerization domains and / or multimerization domains. In some embodiments, the peptide linker comprises a constant region of the heavy chain of a full-length antibody or a fragment thereof. In some embodiments, the peptide linker comprises a constant region of the light chain of a full-length antibody or a fragment thereof. In some embodiments, the linker comprises a constant region of CH1, CH2, CH3, CH4, and / or C L domain or a fragment thereof. In some embodiments, the linker comprises an Fc region or a fragment thereof. In some embodiments, the linker comprises a detectable enzyme tag. In some embodiments, the enzyme tag is alkaline phosphatase. In some embodiments, the enzyme tag is glutathione-S-transferase. In some embodiments, the peptide linker comprises a basic helix-loop-helix leucine zipper (bZIP) domain. In some embodiments, the peptide linker comprises a bZIP isoleucine zipper domain. In some embodiments, the peptide linker comprises a bZIP-leucine / isoleucine zipper domain. In some embodiments, the peptide linker comprises a collagen-like peptide. In some embodiments, the peptide linker comprises a p53 tetramerization domain. In some embodiments, the peptide linker comprises a streptavidin (SA) protein. In some embodiments, the peptide linker comprises an SA protein and a dextran scaffold. In some embodiments, the peptide linker comprises an SA protein and one or more maleimide polymers (DMGS). In some embodiments, the peptide linker comprises a bacteriophage T7 fibritin protein or a portion thereof. In some embodiments, the peptide linker comprises a cartilage oligomeric matrix protein (COMP) protein.

[0025] In some embodiments according to any of the foregoing embodiments of the chimeric protein, the antibody portion is a full-length antibody. In some embodiments, the antibody portion is selected from the group consisting of IgG, IgA, IgM, and IgD.

[0026] In some embodiments according to any of the foregoing embodiments of the chimeric protein, the antibody portion is selected from the group consisting of Fab, Fab', (Fab')2, Fv, single chain Fv (scFv), scFv-Fc, disulfide stabilized Fv fragment (dsFv), (dsFv)2, scFv dimer, domain antibody, camelid single domain antibody (sdAb), bivalent domain antibody, minibody, and V H H.

[0027] In some embodiments according to any of the foregoing embodiments of the chimeric protein, the antibody portion is animal, human, humanized, camelid, or chimeric.

[0028] In some embodiments according to any of the foregoing embodiments of the chimeric protein, the mucoadhesive peptide fragment is fused to the C-terminus of the antibody moiety.

[0029] In some embodiments of the chimeric protein, the antibody portion is a full-length antibody and the mucoadhesive peptide fragment is fused to the C-terminus of the heavy chain of the full-length antibody via a first optional peptide linker. In some embodiments, the antibody portion is a full-length antibody and the mucoadhesive peptide fragment is fused to the C-terminus of the light chain of the full-length antibody via a second optional peptide linker. In some embodiments, the antibody portion is a full-length antibody and (1) the mucoadhesive peptide fragment is fused to the C-terminus of the heavy chain of the full-length antibody via a first optional peptide linker, and (2) the mucoadhesive peptide fragment is fused to the C-terminus of the light chain of the full-length antibody via a second optional peptide linker. In some embodiments, the chimeric protein comprises i) first and second polypeptide chains, each comprising, from N-terminus to C-terminus, a heavy chain of a full-length antibody, a first optional peptide linker, and a mucoadhesive peptide fragment; and ii) third and fourth polypeptide chains, each comprising a light chain of a full-length antibody.

[0030] In some embodiments according to any of the foregoing embodiments of the chimeric protein, the influenza virus is influenza A virus (IAV), influenza B virus (IBV), influenza C virus (ICV), influenza D 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 H1, 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 selected from the group consisting of N1, 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 variants or reassortant thereof.

[0031]

[0031] In some embodiments according to any of the foregoing embodiments of the chimeric protein, the component of an influenza virus or variant thereof is a viral surface protein or a fragment thereof.

[0032] In some embodiments according to any of the foregoing embodiments of the chimeric protein, the viral surface protein is HA. In some embodiments, the chimeric protein comprises a heavy chain complementarity determining region (HC-CDR)1 comprising the amino acid sequence of SEQ ID NO:1, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO:2, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO:3, a light chain complementarity determining region (LC-CDR)1 comprising the amino acid sequence of SEQ ID NO:4, a LC-CDR2 comprising the amino acid sequence WAS, and a LC-CDR3 comprising the amino acid sequence of SEQ ID NO:6. In some embodiments, the chimeric protein comprises a HC-CDR1 comprising the amino acid sequence of SEQ ID NO:7, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO:8, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO:9, a LC-CDR1 comprising the amino acid sequence of SEQ ID NO:235, a LC-CDR2 comprising the amino acid sequence of SEQ ID NO:238, and a LC-CDR3 comprising the amino acid sequence of SEQ ID NO:415. In some embodiments, the chimeric protein comprises: (i) a heavy chain variable domain (V) comprising the amino acid sequence of SEQ ID NO: 76; (ii) a heavy chain variable domain (V) comprising the amino acid sequence of SEQ ID NO: 77; H ), or a variant thereof having at least about 90% sequence identity with the amino acid sequence of SEQ ID NO: 76, and a light chain variable domain (V) comprising the amino acid sequence of SEQ ID NO: 77. L ), or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 77. In some embodiments, the chimeric protein comprises a V comprising the amino acid sequence of SEQ ID NO: 78.H or a variant thereof having at least about 90% sequence identity with the amino acid sequence of SEQ ID NO: 78, and V comprising the amino acid sequence of SEQ ID NO: 79. L or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 79. In some embodiments, the chimeric protein comprises a V comprising the amino acid sequence of SEQ ID NO: 438. H or a variant thereof having at least about 90% sequence identity with the amino acid sequence of SEQ ID NO: 438, and V comprising the amino acid sequence of SEQ ID NO: 442. Lor a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 442. In some embodiments, the chimeric protein comprises a heavy chain (HC) polypeptide 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 light chain (LC) polypeptide comprising the amino acid sequence of SEQ ID NO: 217, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein comprises an HC polypeptide comprising the amino acid sequence of SEQ ID NO: 420, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 420, and an LC polypeptide comprising the amino acid sequence of SEQ ID NO: 244, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 244. In some embodiments, the chimeric protein comprises an HC polypeptide comprising the amino acid sequence of SEQ ID NO: 446, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 446, and an LC polypeptide comprising the amino acid sequence of SEQ ID NO: 447, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 216, 218-234, 236, 237, 239-242, and 416-419, and third and fourth polypeptide chains, each having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 243, 245-258, and 422-425, and third and fourth polypeptide chains, each having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 244.In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently comprising the amino acid sequence of any one of SEQ ID NOs: 448-468 or a variant thereof comprising at least about 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 448-468, and third and fourth polypeptide chains, each independently comprising the amino acid sequence of SEQ ID NO: 447 or a variant thereof comprising at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 447.

[0033] In some embodiments according to any of the foregoing embodiments of the chimeric protein, the viral surface protein is NA. In some embodiments, the chimeric protein comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 104, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 105, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 106, an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 107, an LC-CDR2 comprising the amino acid sequence of AAS, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 109. In some embodiments, the chimeric protein comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 110, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 111, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 112, an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 113, an LC-CDR2 comprising the amino acid sequence of GAS, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 115. In some embodiments, the chimeric protein comprises a V-CDR1 comprising the amino acid sequence of SEQ ID NO: 188. H or a variant thereof having at least about 90% sequence identity with the amino acid sequence of SEQ ID NO: 188, and V comprising the amino acid sequence of SEQ ID NO: 189. L or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 189. In some embodiments, the chimeric protein comprises a V comprising the amino acid sequence of SEQ ID NO: 190. Hor a variant thereof having at least about 90% sequence identity with the amino acid sequence of SEQ ID NO: 190, and V comprising the amino acid sequence of SEQ ID NO: 191. L or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 191. In some embodiments, the chimeric protein comprises an HC polypeptide comprising the amino acid sequence of SEQ ID NO: 426, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 426, and an LC polypeptide comprising the amino acid sequence of SEQ ID NO: 260, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 260. In some embodiments, the chimeric protein comprises an HC polypeptide comprising the amino acid sequence of SEQ ID NO: 432, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 432, and an LC polypeptide comprising the amino acid sequence of SEQ ID NO: 276, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 276. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 259, 261-274, and 428-431, and third and fourth polypeptide chains, each having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 260. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 275, 277-290, and 434-437, and third and fourth polypeptide chains, each having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 276.

[0034]

[0034] In some embodiments of any of the above-mentioned embodiments of the chimeric protein, the mucosa is selected from the group consisting of nasal mucosa, laryngeal mucosa, tracheal mucosa, bronchial mucosa, pulmonary mucosa, ocular mucosa, and combinations thereof.

[0035]

[0035] In some aspects, provided herein is a pharmaceutical composition comprising the chimeric protein of any one of the preceding embodiments and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises a plurality of chimeric proteins, wherein at least two of the plurality of chimeric proteins are different from one another. In some embodiments, the pharmaceutically acceptable carrier comprises about 0.05% to about 0.2% (w / w) methionine. In some embodiments, the pharmaceutically acceptable carrier has a pH of about 4.5 to about 7.5. In some embodiments, the pharmaceutically acceptable carrier comprises about 20 mM to about 50 mM citric acid. In some embodiments, the pharmaceutically acceptable carrier comprises about 100 mM to about 150 mM NaCl. In some embodiments, the pharmaceutically acceptable carrier comprises about 0.01% to about 0.1% (w / w) polysorbate 80. In some embodiments, the pharmaceutically acceptable carrier comprises about 1% to about 10% (w / w) glycerin. In some embodiments, the pharmaceutically acceptable carrier comprises about 0.05% to about 0.2% (w / w) potassium sorbate. In some embodiments, the pharmaceutically acceptable carrier (i) comprises about 0.05% to about 0.2% (w / w) methionine; (ii) has a pH of about 4.5 to about 7.5; (iii) comprises about 20 mM to about 50 mM citric acid; (iv) comprises about 100 mM to about 150 mM NaCl; (v) comprises about 0.01% to about 0.1% (w / w) polysorbate 80; (vi) comprises about 1% to about 10% (w / w) glycerin; and (vii) comprises about 0.05% to about 0.2% (w / w) potassium sorbate. In some embodiments, the pharmaceutical compositions are formulated for intranasal, intraocular, and / or intrabronchial administration.

[0036]

[0036] In another aspect, provided herein is an isolated nucleic acid or set of isolated nucleic acids encoding a chimeric protein described in any one of the preceding embodiments.

[0037]

[0037] In some aspects, provided herein is a vector or set of vectors comprising a nucleic acid or set of nucleic acids described in the preceding embodiments.

[0038]

[0038] In a further aspect, provided herein is a host cell comprising a chimeric protein described in any one of the preceding embodiments, a nucleic acid or set of nucleic acids described in the preceding embodiments, or a vector or set of vectors described in the preceding embodiments.

[0039]

[0039] In a further aspect, provided herein is a method for preparing a chimeric protein, the method comprising: (a) culturing a host cell described in the preceding embodiment under conditions effective to express the chimeric protein; and (b) obtaining the expressed chimeric protein from the host cell.

[0040] In a further aspect, provided herein are methods for preventing or treating an infection caused by an influenza virus or a variant thereof in an individual, the method comprising administering to the individual an effective amount of any one of the chimeric proteins disclosed herein. In some embodiments, the chimeric protein or pharmaceutical composition is administered to the individual before the individual is exposed to an influenza virus or a variant thereof. In some embodiments, the chimeric protein or pharmaceutical composition is administered to the individual within about 72 hours after the individual is exposed to an influenza virus or a variant thereof. In some embodiments, the chimeric protein or pharmaceutical composition is administered topically onto a mucous membrane. In some embodiments, the chimeric protein or pharmaceutical composition is administered via nasal spray, inhaler, nebulizer, or eye drops. In some embodiments, the chimeric protein or pharmaceutical composition is administered once daily.

[0041] In other aspects, provided herein are in vitro methods of killing or neutralizing a virus, comprising contacting the virus with a chimeric protein described in any of the preceding embodiments in the presence of at least one component of the complement system, optionally wherein the at least one component of the complement system is C1, C4, or the membrane attack complex (MAC). In some aspects, provided herein are methods of killing or neutralizing a virus in an individual, comprising administering to the individual an effective amount of a chimeric protein described in any one of the preceding embodiments or a pharmaceutical composition described in any one of the preceding embodiments. In some aspects, provided herein are methods of activating the complement pathway in an individual, comprising administering to the individual an effective amount of a chimeric protein described in any one of the preceding embodiments or a pharmaceutical composition described in any one of the preceding embodiments. In some embodiments, at least one virus is killed or neutralized on the mucosa. In some aspects, provided herein are methods for preventing, treating, or alleviating an infectious disease caused by a virus in an individual, comprising administering to the individual an effective amount of a chimeric protein described in any one of the preceding embodiments or a pharmaceutical composition described in any one of the preceding embodiments, wherein at least one virus is killed or neutralized on the mucosa. In some embodiments, the chimeric protein activates the complement pathway in the individual. In some embodiments, the killing or neutralization is achieved via activation of the complement pathway. In some embodiments, the virus is an influenza virus. In some embodiments, the influenza virus is selected from the group consisting of influenza A virus (IAV), influenza B virus (IBV), influenza C virus (ICV), influenza D virus (IDV), or variants, subtypes, or reassortants thereof.In some embodiments, the influenza virus comprises an HA antigen selected from the group consisting of H1, H2, H3, H5, H6, H7, H9, and H10, or a variant or reassortant thereof. In some embodiments, the influenza virus comprises an NA antigen selected from the group consisting of N1, 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.

[0042]

[0042] The drawings illustrate certain embodiments of the features and advantages of the present disclosure. These embodiments are not intended to limit the scope of the appended claims in any way. [Brief explanation of the drawings]

[0043] [Figure 1] Figure 1 shows that the exemplary mucoadhesive chimeric human antibody HA1-IgG-12K binds well to hemagglutinin (His-tagged) from influenza A H1N1 (A / Wisconsin / 588 / 2019) / (A / Victoria / 2570 / 2019). Binding was not affected by the presence of polycationic moieties. All steps were aligned by the position of the step sensor. [Figure 2]

[0044] Figure 2 shows that the exemplary mucoadhesive chimeric human antibody HA2-IgG-12K binds well to hemagglutinin (ECD, His-tagged) from influenza A H3N2 (A / Aichi / 2 / 1968) strain. Binding was not affected by the presence of polycationic moieties. All steps were aligned by the position of the step sensor. [Figure 3]

[0045] Figure 3 shows that the exemplary mucoadhesive chimeric human antibody NA1-IgG-12K binds well to the neuraminidase protein (His-tagged) from influenza B (B / PHUKET / 3073 / 2013) strain. Binding was not affected by the presence of polycationic moieties. All steps were aligned by the position of the step sensor. [Figure 4]

[0046] Figure 4 shows that the modified chimeric human antibodies HA1-IgG-12K and HA15-IgG-12K bind to mucin in vitro significantly better than their unmodified counterparts. HRP-anti-human IgG fluorescence at 450 nM measures binding of the HA-IgG mucoadhesive antibody compared to the HA-IgG antibody alone. [Figure 5A-5B]

[0047] Figures 5A-5B show the association of chimeric antibodies to HA, as examined by BLI using a ForteBio Octet KQ equipped with an anti-hFC capture biosensor. Influenza A H1N1 (A / Wisconsin / 588 / 2019) / (A / Victoria / 2570 / 2019) His-tagged HA protein binding was unaffected by the presence of cationic peptides in the HA-1-IgG (Figure 5A) and HA15-IgG (Figure 5B) mucoadhesive antibodies. [Figures 6A-6B]

[0048] Figures 6A-6B show the association of chimeric antibodies to HA examined by BLI using a ForteBio Octet KQ equipped with an anti-hFC capture biosensor. Influenza A H3N2 (A / Aichi / 2 / 1968) His-tagged HA antigen binding was unaffected by the presence of cationic peptides in the HA-1-IgG (Figure 6A) and HA15-IgG (Figure 6B) mucoadhesive antibodies. [Figures 7A-7B]

[0049] Figures 7A-7B show in vitro neutralization of pseudovirus infection of HEK293F cells using luciferase bioluminescence. Relative infection values ​​determined using bioluminescence intensity demonstrate that viral infection levels of transduced cells are inhibited by HA1-IgG-12K (Figure 7A) and HA15-IgG-12K (Figure 7B) mucoadhesive antibodies that bind to H1N1 (left panel) or H3N2 (right panel) pseudoviruses. [Figure 8A-8B]

[0050] Figures 8A-8B show neutralization of pseudovirus infection in a mouse model. Pretreatment with mucoadhesive HA1-IgG-12K antibody attenuated H3N2 pseudovirus infection compared with pretreatment without antibody (vehicle). Bioluminescence imaging of mice (Figure 8A) and the corresponding graph (Figure 8B) show protection by HA1-IgG-12K antibody from pseudovirus infection on days 5 and 7 after pretreatment (day -1). [Figure 9A-9B]

[0051] Figures 9A-9B show neutralization of pseudovirus infection in a mouse model. H3N2 pseudovirus infection was attenuated by pretreatment with mucoadhesive HA15-IgG-6K / HA15-IgG-12K antibodies compared with pretreatment with unmodified HA15-IgG antibodies or no antibodies (vehicle). Bioluminescence imaging of mice (Figure 9A) and the corresponding graph (Figure 9B) show protection by HA15-IgG-6K / 12K antibodies from pseudovirus infection on days 5 and 7 after pretreatment (day -1). [Figure 10]

[0052] Figure 10 shows that the addition of various mucoadhesive peptides increases the attraction of different viral antigen-binding chimeric proteins, ACE2-Fc1, to mucin proteins. To compare the mucin-binding ability of various ACE2-Fc1 mucoadhesive chimeric proteins with that of ACE2-Fc1 without mucoadhesive peptides, an ELISA assay using mucin-coated plates was performed. Binding was detected using horseradish peroxidase (HRP)-conjugated goat anti-human IgG, and staining was detected at OD450. DETAILED DESCRIPTION OF THE INVENTION

[0044]

[0053] The present application provides compositions and methods for preventing or treating infections caused by influenza viruses or their variants that transmit through the mucosa of an individual by targeting the influenza virus or its variants with chimeric proteins having positively charged mucoadhesive peptide fragments. For example, the compositions described herein may include a chimeric protein or a cocktail of different chimeric proteins comprising an antibody moiety modified with a positively charged peptide that targets a viral surface protein (e.g., hemagglutinin (HA) or neuraminidase (NA) protein) and prevents the influenza virus or its variants from reaching the primary target cell population in the respiratory tract (e.g., nasal) mucosa for human infection. The compositions can be administered via the nasal cavity using a respiratory spray.

[0045]

[0054] The inventors of the present application have developed antibodies (e.g., human and animal) that recognize the HA or NA viral surface proteins of influenza viruses or their variants ("anti-HA antibodies" and "anti-NA antibodies"), as well as chimeric proteins comprising the anti-HA and anti-NA antibodies fused to positively charged mucoadhesive peptide fragments. These chimeric proteins exhibit significantly improved affinity for mucin molecules compared to unmodified anti-HA or anti-NA antibodies, resulting in improved stability in respiratory mucosa. These chimeric proteins demonstrated improved efficacy in blocking influenza infection compared to unmodified anti-HA or anti-NA antibodies in cell-based assays. Protection against influenza viruses is effective in both the nasal and pulmonary regions. Furthermore, the chimeric proteins may activate innate immune functions and kill influenza viruses through activation of the complement pathway. The exemplary chimeric proteins were highly stable and maintained influenza virus-neutralizing activity in nasal spray formulations. The chimeric protein nasal spray could potentially be developed as an affordable and effective preventative product to protect people from infection due to airborne (e.g., nasal) exposure to influenza viruses.

[0046]

[0055] Compared to other methods of blocking microbial infections, which involve the systemic administration of antibodies without positively charged mucoadhesive peptide fragments, the methods described herein require the administration of much less protein, leading to significant cost savings that are important in any pandemic situation. The compositions can also be self-administered, which would significantly reduce the burden on overwhelmed healthcare systems. Importantly, the methods described herein avoid the potential problems of antibody-dependent enhancement (ADE) that arise from traditional antibody therapy or vaccination.

[0047]

[0056] Thus, one aspect of the present application provides a chimeric protein comprising: (a) an antibody portion that specifically binds to a component of an influenza virus or variant thereof; and (b) a mucoadhesive peptide fragment comprising at least about five positively charged amino acid residues, wherein the mucoadhesive peptide fragment promotes adhesion of the chimeric protein to a mucosa. In some embodiments, the positively charged amino acid residues are interspersed with non-positively charged amino acid residues.

[0048]

[0057] The chimeric proteins provided herein are useful for treating or preventing infection by a virus (e.g., influenza virus or variants thereof) in an individual. The chimeric proteins provided herein can be useful for killing or neutralizing a virus (e.g., influenza virus or variants thereof) in an individual through activation of the complement pathway.

[0049] I. Definition

[0058] As used herein, a "mucoadhesive peptide fragment" refers to a peptide that has one or more positive charges and is capable of interacting with a mucosa, for example, via electrostatic interactions.

[0050]

[0059] As used herein, "receptor" refers to a receptor on a host cell that facilitates or mediates microbial entry into the host cell. The receptor may be a membrane-bound or soluble receptor.

[0051]

[0060] As used herein, "treatment" or "treating" is an approach to obtaining beneficial or desired results, including clinical results. For purposes of this application, beneficial or desired clinical results include, but are not limited to, one or more of the following: alleviating one or more symptoms attributable to a disease, reducing the extent of the disease, stabilizing the disease (e.g., preventing or slowing the worsening of the disease), preventing or slowing the spread of the disease, preventing or slowing the onset or recurrence of the disease, slowing or mitigating the progression of the disease, ameliorating the disease state, causing remission (partial or complete) of the disease, reducing the dosage of one or more other drugs required to treat the disease, slowing the progression of the disease, improving quality of life, and / or prolonging survival. "Treatment" also includes alleviating the pathological consequences of a disease. The methods of the present application contemplate any one or more of these aspects of treatment.

[0052]

[0061] As used herein, "prevention" includes providing protection against the occurrence or recurrence of a disease in a subject who may be susceptible to the disease but has not yet been diagnosed with the disease.

[0053]

[0062] An "effective amount" of a drug refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or prophylactic result. The effective amount herein may vary depending on factors such as the patient's condition, age, sex, and weight, and the ability of the antibody to elicit a desired response in the individual. An effective amount is also one in which any toxic or adverse effects of the treatment outweigh the therapeutically beneficial effects. For prophylactic use, beneficial or desired results include eliminating or reducing the risk, reducing the severity, or delaying the onset of disease, including the biochemical, histological, and / or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes manifested during the development of the disease. For therapeutic use, beneficial or desired results include clinical results such as alleviating one or more symptoms caused by the disease, improving the quality of life of affected individuals, reducing the dosage of other drugs required to treat the disease, enhancing the effectiveness of other drugs, such as by targeting, slowing disease progression, and / or prolonging survival. For purposes of this application, an effective amount of a drug, compound, or pharmaceutical composition refers to an amount sufficient to directly or indirectly achieve prophylactic or therapeutic treatment. As understood in a clinical context, an effective amount of a drug, compound, or pharmaceutical composition may or may not be achieved in combination with another drug, compound, or pharmaceutical composition. Thus, an "effective amount" can be considered in the context of administering one or more therapeutic agents, and an agent can be considered to be administered in an effective amount if a desired result is likely or actually achieved in combination with one or more other agents. An effective amount can be ascertained by measuring the relevant physiological effect and can be adjusted in conjunction with dosing regimens, diagnostic analysis of the subject's condition, and the like.

[0054]

[0063] The terms "individual," "subject," and "patient" are used interchangeably herein to describe a mammal, including a human. In some embodiments, the individual is a human. In some embodiments, the individual is suffering from a respiratory infection. In some embodiments, the individual is in need of treatment.

[0055]

[0064] The terms "polypeptide" and "protein" are used interchangeably to refer to polymers of amino acid residues and are not limited to a minimum length. Such polymers of amino acid residues can contain natural or unnatural 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 this definition. The term also includes post-expression modifications of the polypeptide, such as glycosylation, sialylation, acetylation, phosphorylation, and the like. Furthermore, for purposes of this application, "polypeptide" refers to proteins containing modifications, such as deletions, additions, and substitutions (generally conservative in nature), to the native sequence, so long as the protein maintains the desired activity. Such modifications may be deliberate, such as by site-directed mutagenesis, or accidental, such as by mutations of hosts producing the protein or errors due to PCR amplification.

[0056]

[0065] As used herein, the term "antibody" or "antibody portion" includes full-length antibodies (including full-length four-chain antibodies having an immunoglobulin Fc region or full-length heavy-chain antibodies) and antigen-binding fragments thereof.

[0057]

[0066] As used herein, a "neutralizing antibody" refers to an antibody that protects host cells from an infectious pathogen by neutralizing any biological effects (e.g., cytotoxicity) that the infectious pathogen has. A "non-neutralizing antibody" refers to an antibody that specifically binds to an infectious pathogen but is unable to ameliorate the biological effects of the infectious pathogen on host cells. A "sub-neutralizing antibody" refers to an antibody that can partially neutralize the biological effects of an infectious pathogen on host cells. A sub-neutralizing antibody can ameliorate one or more biological effects of an infectious pathogen on host cells by about n% or less compared to a neutralizing antibody, where n% is selected from 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, or less.

[0058]

[0067] A full-length four-chain antibody is composed of two heavy chains and two light chains. The variable regions of the light and heavy chains are responsible for antigen binding. The variable regions of both chains generally contain three highly variable loops called complementarity-determining regions (CDRs): light chain (LC) CDRs including LC-CDR1, LC-CDR2, and LC-CDR3; heavy chain (HC) CDRs including HC-CDR1, HC-CDR2, and HC-CDR3. The CDR boundaries of the antibodies and antigen-binding fragments disclosed herein can be defined or identified according to the conventions of Kabat, Chothia, or Al-Lazikani (Al-Lazikani 1997; Chothia 1985; Chothia 1987; Chothia 1989; Kabat 1987; Kabat 1991). The three CDRs of a heavy or light chain are sandwiched between adjacent stretches known as framework regions (FRs), which are more highly conserved than the CDRs and form a scaffold supporting the hypervariable loops. The constant regions of the heavy and light chains are not involved in antigen binding but exhibit various effector functions. Antibodies are assigned to classes based on the amino acid sequence of the constant region of their heavy chains. The five major antibody classes or isotypes are IgA, IgD, IgE, IgG, and IgM, characterized by the presence of α, δ, ε, γ, and μ heavy chains, respectively. Some of the major antibody classes are divided into subclasses, such as IgG1 (γ1 heavy chain), IgG2 (γ2 heavy chain), IgG3 (γ3 heavy chain), IgG4 (γ4 heavy chain), IgG1 (α1 heavy chain), or IgG2 (α2 heavy chain).

[0059]

[0068] The term "heavy chain-only antibody" or "HCAb" refers to a functional antibody that contains heavy chains but lacks the light chains typically found in four-chain antibodies. Camelids (such as camels, llamas, or alpacas) are known to produce HCAbs. The variable regions of heavy chain-only antibodies are referred to herein as "V H It is called "H". H H is a type of single domain antibody. A "single domain antibody" or "sdAb" refers to a single antigen-binding polypeptide having three complementarity-determining regions (CDRs). An sdAb alone can bind to an antigen without pairing with a corresponding CDR-containing polypeptide. Some V HH is sometimes known as a nanobody. H H is one of the smallest known antigen-binding antibody fragments (see, e.g., Hamers-Casterman et al., Nature 363:446-8 (1993); Greenberg et al., Nature 374:168-73 (1995); Hassanzadeh-Ghassabeh et al., Nanomedicine (Lond), 8:1013-26 (2013)). H H has the following structure from the N-terminus to the C-terminus: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4, where FR1 to FR4 refer to framework regions 1 to 4, respectively, and CDR1 to CDR3 refer to complementarity-determining regions 1 to 3.

[0060]

[0069] The term "antigen-binding fragment" as used herein refers to, for example, a diabody, Fab, Fab', F(ab'), Fv fragment, disulfide-stabilized Fv fragment (dsFv), (dsFv), bispecific dsFv (dsFv-dsFv'), disulfide-stabilized diabody (ds diabody), single-chain antibody molecule (scFv), scFv dimer (bivalent diabody), scFv-Fc fusion protein, minibody (i.e., scFv-CH3 fusion protein), multispecific antibody formed from a portion of an antibody comprising one or more CDRs, VHH, camelid single domain antibody, nanobody, domain antibody, bivalent domain antibody, or any other antibody fragment that binds to an antigen but does not constitute a complete antibody structure. An antigen-binding fragment can bind to the same antigen as the parent antibody or parent antibody fragment (e.g., the parent scFv). In some embodiments, an antigen-binding fragment may comprise one or more CDRs from a particular human antibody grafted onto the framework regions of one or more different human antibodies.

[0061]

[0070] As used herein, the term "epitope" refers to the specific grouping of atoms or amino acids on an antigen to which an antibody or antibody portion binds. Two antibodies or antibody portions may bind to the same epitope within an antigen if they exhibit competitive binding to the antigen.

[0062]

[0071] As used herein, a first antibody portion "competes" with a second antibody portion for binding to a target (e.g., an influenza virus surface protein) if the first antibody portion inhibits target binding of the second antibody portion by at least about 50% (e.g., at least about n%, where n% is selected from 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, and 99%) in the presence of an equimolar concentration of the first antibody portion, or vice versa. A high-throughput process for "binning" antibodies based on antibody cross-competition is described in PCT Publication No. WO 03 / 48731.

[0063]

[0072] As used herein, the terms "specifically bind," "specifically recognize," or "specific" refer to a measurable and reproducible interaction, such as binding between a target and an antibody or antibody portion, that determines the presence of the target in the presence of a heterogeneous population of molecules, including biological molecules. For example, an antibody or antibody portion that specifically recognizes a target (which may be an epitope) is an antibody or antibody portion that binds to this target with higher affinity, avidity, more readily, and / or with a longer duration than its binding to other targets. In some embodiments, an antibody or antibody portion that specifically recognizes an antigen reacts with one or more antigenic determinants of the antigen (e.g., influenza virus surface proteins) with a binding affinity that is at least about 10-fold greater than its binding affinity to other targets (e.g., non-respiratory pathogen proteins).

[0064]

[0073] As used herein, the term "CDR" or "complementarity determining region" is intended to mean the non-contiguous antigen-binding sites found within the variable regions of both heavy and light chain polypeptides. These specific regions were identified by Kabat et al., J.Biol.Chem.252:6609-6616(1977);Kabat et al.,USDept.of Health and Human Services,“Sequences of proteins of immunological interest”(1991);Chothia et al.,J.Mol.Biol.196:901-917(1987);Al-Lazikani B.et al., J.Mol.Biol.,273:927-948(1997);MacCallum et al.,J.Mol.Biol.,262:732-745(1996);Abhinandan and Martin,Mol.Immunol.,45:3832-3839(2008);Lefranc MPet al., Dev. Comp. Immunol., 27:55-77 (2003); and Honegger and Plueckthun, J. Mol. Biol., 309:657-670 (2001), where the definitions include overlapping or subsets of amino acid residues when compared with each other. Nevertheless, application of either definition to refer to the CDRs of an antibody or grafted antibody or variants thereof is intended to be within the scope of the term as defined and used herein. The amino acid residues that encompass the CDRs as defined by each of the above-cited references are set forth below in Table A for comparison. CDR prediction algorithms and interfaces are known in the art, including, for example, Abhinandan and Martin, Mol. Immunol., 45:3832-3839 (2008); Ehrenmann F. et al., Nucleic Acids Res., 38:D301-D307 (2010); and Adolf-Bryfogle J. et al., Nucleic Acids Res., 43:D432-D438 (2015).The contents of the references cited in this paragraph are incorporated herein by reference in their entirety for use in the present invention and for inclusion in one or more claims herein. TIFF2025512515000002.tif39170 1 Residue numbering follows the nomenclature of Kabat et al., supra. 2 Residue numbering follows the nomenclature of Chothia et al., supra. 3 Residue numbering follows the nomenclature of MacCallum et al., supra. 4 Residue numbering follows the nomenclature of Lefranc et al., supra. 5 Residue numbering follows the nomenclature of Honegger and Plueckthun, supra.

[0065]

[0074] The term "chimeric antibody" refers to antibodies in which a portion of the heavy and / or light chain is identical to or homologous to corresponding sequences in antibodies from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain is identical to or homologous to corresponding sequences in antibodies from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the biological activity of the invention (see, e.g., U.S. Pat. No. 4,816,567; and Morrison et al., Proc. Natl. Acad. Sci. USA, 81:6851-6855 (1984)).

[0066]

[0075] The term "semi-synthetic" with respect to an antibody or antibody portion means that the antibody or antibody portion has one or more naturally occurring sequences and one or more non-naturally occurring (i.e., synthetic) sequences.

[0067]

[0076] An "Fv" is the minimum antibody fragment that contains a complete antigen-recognition and antigen-binding site. This fragment consists of a dimer of one heavy-chain and one light-chain variable domain in tight, non-covalent association. Folding of these two domains results in six hypervariable loops (three loops from the heavy chain and three loops from the light chain) that contribute antigen-binding amino acid residues and confer antigen-binding specificity to the antibody. However, even a single variable domain (or half of an Fv containing only three CDRs specific for an antigen) has the ability to recognize and bind antigen, albeit with lower affinity than the entire binding site.

[0068]

[0077] "Single-chain Fv," also abbreviated as "sFv" or "scFv," is an antibody fragment comprising the VH and VL antibody domains connected in a single polypeptide chain. In some embodiments, the scFv polypeptide further comprises a polypeptide linker between the VH and VL domains, which enables the scFv to form the desired structure for antigen binding. For a review of scFvs, see, e.g., Pluckthun, The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., Springer-Verlag, New York, pp. 269-315 (1994).

[0069]

[0078] The term "diabody" refers to small antibody fragments prepared by constructing scFv fragments (see previous paragraph) using a short linker (about 5-10 residues) between the VH and VL domains, achieving interchain rather than intrachain pairing of the V domains, thereby creating a bivalent fragment, i.e., a fragment with two antigen-binding sites. Bispecific diabodies are fragments that combine the VH and VL domains of two antibodies. H Domains and V LDiabodies are heterodimers of two "crossover" scFv fragments whose domains are present on different polypeptide chains. Diabodies are described in further detail in, for example, EP 404,097; WO 93 / 011161; and Hollinger et al., Proc. Natl. Acad. Sci. USA, 90:6444-6448 (1993).

[0070]

[0079] "Humanized" forms of non-human (e.g., rodent) antibodies are chimeric antibodies that contain minimal sequence derived from the non-human antibody. Most often, humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a hypervariable region (HVR) of the recipient are replaced by residues from a hypervariable region of a non-human species (donor antibody) such as mouse, rat, rabbit, or non-human primate that possesses the desired antibody specificity, affinity, and capacity. In some instances, framework region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, humanized antibodies can comprise residues that are not found in the recipient antibody or the donor antibody. These modifications are made to further refine antibody performance. In general, humanized antibodies comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin and all or substantially all of the FRs are those of a human immunoglobulin sequence. The humanized antibody optionally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. For further details, see Jones et al., Nature 321:522-525 (1986); Riechmann et al., Nature 332:323-329 (1988); and Presta, Curr. Op. Struct. Biol. 2:593-596 (1992).

[0071]

[0080] The "CH1 domain" (also called "C1" for "H1" domain) of the human IgG Fc region typically extends from about amino acid 118 to about amino acid 215 (EU numbering system).

[0072]

[0081] The "hinge region" is generally defined as extending from Glu216 to Pro230 of human IgG1 (Burton, Molec. Immunol. 22:161-206 (1985)). Hinge regions of other IgG isotypes can be aligned with the IgG1 sequence by placing the first and last cysteine ​​residues that form inter-heavy chain S—S bonds in the same positions.

[0073]

[0082] The "CH2 domain" (also called "C2" for "H2" domain) of the human IgG Fc region typically extends from approximately amino acid 231 to approximately amino acid 340. The CH2 domain is unique in that it is not tightly paired with other domains. Rather, two N-linked branched carbohydrate chains are inserted between the two CH2 domains in intact native IgG molecules. It has been speculated that the carbohydrate chains may act as a surrogate for domain-domain pairing and help stabilize the CH2 domains. Burton, Molec Immunol. 22:161-206 (1985).

[0074]

[0083] The "CH3 domain" (also called the "C2" or "H3" domain) comprises the stretch of residues C-terminal to the CH2 domain of the Fc region (i.e., from about amino acid residue 341 to the C-terminus of the antibody sequence, typically to amino acid residue 446 or 447 for IgG).

[0075]

[0084] The "CH4 domain" found in IgE and IgM molecules is located C-terminal to the CH3 domain and comprises residues 466-572 of human IgM and residues 323-427 of hIgE. As used herein, the terms "substantially similar" or "substantially identical" refer to a sufficiently high degree of similarity between two or more values ​​such that one of skill in the art would consider the difference between the two or more values ​​to have little or no biological and / or statistical significance in the context of the biological property measured by the values. In some embodiments, two or more substantially similar values ​​differ by about n% or less, where n% is selected from 5%, 10%, 15%, 20%, 25%, and 50%.

[0076]

[0085] A polypeptide "variant" refers to a biologically active polypeptide having at least about 80% amino acid sequence identity with a native sequence polypeptide, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and having up to 100% identity. Such variants include, for example, polypeptides in which 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 (e.g., at least about n% amino acid sequence identity, where n% is selected from 80%, 85%, 90%, 95%, and 99%). In some embodiments, a variant has at least about 90% amino acid sequence identity (e.g., at least about n% amino acid sequence identity, where n% is selected from 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%). In some embodiments, a variant has at least about 95% amino acid sequence identity with a native sequence polypeptide (e.g., at least about n% amino acid sequence identity, where n% is selected from 95%, 96%, 97%, 98%, and 99%).

[0077]

[0086] As used herein, "percent (%) amino acid sequence identity" with respect to a peptide, polypeptide, or antibody sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical to amino acid residues in a particular peptide or polypeptide sequence after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, without considering conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in a variety of ways that are within the skill of those in the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN, or MEGALIGN™ (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.

[0078]

[0087] As used herein, the term "label" refers to a detectable compound or composition that can be directly or indirectly conjugated to an antibody moiety (e.g., an anti-HA antibody or an anti-NA antibody). The label may be detectable in itself (e.g., a radioisotope label or a fluorescent label) or, in the case of an enzymatic label, may catalyze chemical alteration of a substrate compound or composition that is detectable.

[0079]

[0088] As used herein, the term "isolated nucleic acid" is intended to mean a nucleic acid of genomic, cDNA, or synthetic origin, or a combination thereof, and by virtue of its origin, an "isolated nucleic acid" is one in which: (1) it is not associated with all or part of a polynucleotide with which it is found in nature; (2) it is operably linked to a polynucleotide with which it is not linked in nature; or (3) it is not found in nature as part of a larger sequence.

[0080]

[0089] 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 encoding a protein or RNA can also include introns, to the extent that some versions of a nucleotide sequence encoding a protein may contain introns.

[0081]

[0090] The term "operably linked" refers to a functional linkage between a regulatory sequence and a heterologous nucleic acid sequence that results 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 into a functional relationship with the second nucleic acid sequence. For example, a promoter is operably linked to a coding sequence if it 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.

[0082]

[0091] The term "vector" is used to describe a cloned polynucleotide that can be propagated in a host cell or a polynucleotide that can be engineered to contain multiple polynucleotides. A vector can contain one or more of the following elements: an origin of replication, one or more regulatory sequences (such as, for example, a promoter and / or enhancer) that control the expression of a polypeptide of interest, and / or one or more selectable marker genes (e.g., antibiotic resistance genes and genes that can be used in colorimetric assays, e.g., β-galactosidase). The term "expression vector" refers to a vector used to express a polypeptide of interest in a host cell.

[0083]

[0092] "Host cell" refers to a cell that can be or has been a recipient of a vector or isolated polynucleotide. Host cells can be prokaryotic or eukaryotic. Exemplary eukaryotic cells include mammalian cells, such as primate or non-primate cells; fungal cells, such as yeast cells; plant cells; and insect cells. Non-limiting exemplary mammalian cells include, but are not limited to, NSO cells, PER.C6® cells (Crucell), 293 cells, and CHO cells, and their derivatives, such as 293-6E cells and DG44 cells, respectively.

[0084]

[0093] As used herein, a "variant" virus refers to a virus isolate whose genomic sequence differs from that of a reference virus, and the difference in genomic sequence confers new phenotypic characteristics, such as increased fitness, compared to the reference virus. In this application, when a viral species, such as influenza virus, is referred to, it is understood that the species includes variants as well as the reference virus that was originally isolated and identified.

[0085]

[0094] As used herein, "pharmaceutically acceptable" or "pharmacologically compatible" means that the substance is not biologically or otherwise undesirable, e.g., the substance can be incorporated into a pharmaceutical composition administered to a patient without causing significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is included. A pharmaceutically acceptable carrier or excipient desirably has met the required standards of toxicology and manufacturing testing and / or is included in the Inactive Ingredients Guide prepared by the U.S. Food and Drug Administration.

[0086]

[0095] As used herein, "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable substance, composition, or vehicle used in the process of drug delivery, which may have one or more components including, but not limited to, excipients, binders, diluents, solvents, fillers, and / or stabilizers.

[0087]

[0096] It is understood that embodiments of the invention described herein include "consisting of" and / or "consisting essentially of" embodiments.

[0088]

[0097] Reference herein to "about" a value or parameter includes (and describes) variations on that value or parameter itself. For example, reference to "about X" includes reference to "X."

[0089]

[0098] As used herein, a reference to "not" a value or parameter generally means and describes "other than" the value or parameter.

[0090]

[0099] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0091] II. Chimeric Proteins

[0100] The present application provides a chimeric protein (e.g., a fusion protein) comprising: (a) an antibody portion that specifically binds to a component of an influenza virus or a variant thereof; and (b) a mucoadhesive peptide fragment comprising at least about five positively charged amino acid residues (e.g., about 5 to about 30 positively charged amino acid residues), wherein the mucoadhesive peptide fragment promotes adhesion of the chimeric protein to a mucosa. In some embodiments, the positively charged amino acid residue is selected from the group consisting of lysine, arginine, histidine, ornithine, and combinations thereof. In some embodiments, the positively charged amino acid residue is lysine. In some embodiments, the mucoadhesive peptide fragment is a polylysine peptide having at least about five (e.g., about 5 to about 30, e.g., about 12) lysines (e.g., comprising at least about five (e.g., about 5 to about 30, e.g., about 12) consecutive lysines). In some embodiments, the positively charged amino acid residue is histidine. In some embodiments, the mucoadhesive peptide fragment is a polyhistidine peptide having at least about five (e.g., about 5 to about 30, e.g., about 12) histidines (e.g., comprising at least about five (e.g., about 5 to about 30, e.g., about 12) consecutive histidines). In some embodiments, the positively charged amino acid residue is arginine. In some embodiments, the mucoadhesive peptide fragment is a polyarginine peptide having at least about five (e.g., about 5 to about 30, e.g., about 12) arginines (e.g., comprising at least about five (e.g., about 5 to about 30, e.g., about 12) consecutive arginines). In some embodiments, the positively charged amino acid residue is ornithine. In some embodiments, the mucoadhesive peptide fragment is a polyornithine peptide having at least about 5 (e.g., about 5 to about 30, e.g., about 12) ornithines (e.g., comprising at least about 5 (e.g., about 5 to about 30, e.g., about 12) consecutive ornithines). In some embodiments, the positively charged amino acid residues are contiguous. 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 antibody portion. In some embodiments, the mucoadhesive peptide fragment is non-covalently associated with the antibody portion, e.g., via an oligomerization and / or multimerization domain. In some embodiments, the influenza virus is influenza A virus (IAV), influenza B virus (IBV), influenza C virus (ICV), influenza D virus (IDV), or a variant, subtype, 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, laryngeal mucosa, tracheal mucosa, bronchial mucosa, pulmonary mucosa, ocular mucosa, and combinations thereof.

[0092]

[0101] In some embodiments, a chimeric protein (e.g., a fusion protein) is provided that includes: (a) an antibody portion that specifically binds to the HA protein of an influenza virus or a variant thereof; and (b) a mucoadhesive peptide fragment comprising at least about five positively charged amino acid residues (e.g., about 5 to about 30 positively charged amino acid residues), wherein the mucoadhesive peptide fragment promotes adhesion of the chimeric protein to a mucosa. In some embodiments, the positively charged amino acid residue is selected from the group consisting of lysine, arginine, histidine, ornithine, and combinations thereof. In some embodiments, the positively charged amino acid residue is lysine. In some embodiments, the mucoadhesive peptide fragment is a polylysine peptide having at least about five (e.g., about 5 to about 30, e.g., about 12) lysines (e.g., comprising at least about five (e.g., about 5 to about 30, e.g., about 12) consecutive lysines). In some embodiments, the positively charged amino acid residue is histidine. In some embodiments, the mucoadhesive peptide fragment is a polyhistidine peptide having at least about five (e.g., about 5 to about 30, e.g., about 12) histidines (e.g., comprising at least about five (e.g., about 5 to about 30, e.g., about 12) consecutive histidines). In some embodiments, the positively charged amino acid residue is arginine. In some embodiments, the mucoadhesive peptide fragment is a polyarginine peptide having at least about five (e.g., about 5 to about 30, e.g., about 12) arginines (e.g., comprising at least about five (e.g., about 5 to about 30, e.g., about 12) consecutive arginines). In some embodiments, the positively charged amino acid residue is ornithine. In some embodiments, the mucoadhesive peptide fragment is a polyornithine peptide having at least about 5 (e.g., about 5 to about 30, e.g., about 12) ornithines (e.g., containing at least about 5 (e.g., about 5 to about 30, e.g., about 12) consecutive ornithines). In some embodiments, the positively charged amino acid residues are consecutive to one another.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 antibody moiety. In some embodiments, the mucoadhesive peptide fragment is non-covalently associated with the antibody moiety, for example, via an oligomerization and / or multimerization domain. In some embodiments, the influenza virus is an influenza A virus (IAV), an influenza B virus (IBV), an influenza C virus (ICV), an influenza D virus (IDV), or a variant, subtype, or reassortant thereof. In some embodiments, the influenza virus comprises a hemagglutinin (HA) antigen, e.g., an HA antigen selected from the group consisting of H1, 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 variants or reassortant thereof. In some embodiments, the mucosa is selected from the group consisting of nasal mucosa, laryngeal mucosa, tracheal mucosa, bronchial mucosa, pulmonary mucosa, ocular mucosa, and combinations thereof. In some embodiments, the antibody portion is a full-length antibody (e.g., IgG, IgA, IgM, IgE, or IgD). In some embodiments, the antibody portion is a Fab, Fab', (Fab')2, Fv, single chain Fv (scFv), scFv-Fc, disulfide stabilized Fv fragment (dsFv), (dsFv)2, scFv dimer, domain antibody, camelid single domain antibody, bivalent domain antibody, minibody, and V. H H.

[0093]

[0102] In some embodiments, provided are chimeric proteins (e.g., fusion proteins) comprising: (a) an antibody portion that specifically binds to an HA protein of an influenza virus or a variant thereof; and (b) a mucoadhesive peptide fragment comprising at least about five positively charged amino acid residues (e.g., about 5 to about 30 positively charged amino acid residues), wherein the mucoadhesive peptide fragment promotes attachment of the chimeric protein to a mucosa, and wherein the antibody portion comprises any one of the antibodies or antigen-binding fragments thereof listed in Table 4A or the antibody portion comprises any one of the antibodies or antigen-binding fragments thereof listed in Table 6. In some embodiments, the antibody portion binds to an HA antigen, e.g., an HA antigen selected from the group consisting of H1, H2, H3, H5, H6, H7, H9, and H10, or a variant or reassortant thereof. In some embodiments, the mucoadhesive peptide comprises any one of the mucoadhesive peptide fragments listed in Table 8.

[0094]

[0103] In some embodiments, a chimeric protein (e.g., a fusion protein) is provided that includes: (a) an antibody portion that specifically binds to the NA protein of an influenza virus or a variant thereof; and (b) a mucoadhesive peptide fragment comprising at least about five positively charged amino acid residues (e.g., about 5 to about 30 positively charged amino acid residues), wherein the mucoadhesive peptide fragment promotes adhesion of the chimeric protein to a mucosa. In some embodiments, the positively charged amino acid residue is selected from the group consisting of lysine, arginine, histidine, ornithine, and combinations thereof. In some embodiments, the positively charged amino acid residue is lysine. In some embodiments, the mucoadhesive peptide fragment is a polylysine peptide having at least about five (e.g., about 5 to about 30, e.g., about 12) lysines (e.g., comprising at least about five (e.g., about 5 to about 30, e.g., about 12) consecutive lysines). In some embodiments, the positively charged amino acid residue is histidine. In some embodiments, the mucoadhesive peptide fragment is a polyhistidine peptide having at least about five (e.g., about 5 to about 30, e.g., about 12) histidines (e.g., comprising at least about five (e.g., about 5 to about 30, e.g., about 12) consecutive histidines). In some embodiments, the positively charged amino acid residue is arginine. In some embodiments, the mucoadhesive peptide fragment is a polyarginine peptide having at least about five (e.g., about 5 to about 30, e.g., about 12) arginines (e.g., comprising at least about five (e.g., about 5 to about 30, e.g., about 12) consecutive arginines). In some embodiments, the positively charged amino acid residue is ornithine. In some embodiments, the mucoadhesive peptide fragment is a polyornithine peptide having at least about 5 (e.g., about 5 to about 30, e.g., about 12) ornithines (e.g., containing at least about 5 (e.g., about 5 to about 30, e.g., about 12) consecutive ornithines). In some embodiments, the positively charged amino acid residues are consecutive to one another.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 antibody moiety. In some embodiments, the mucoadhesive peptide fragment is non-covalently associated with the antibody moiety, for example, via an oligomerization and / or multimerization domain. In some embodiments, the influenza virus is influenza A virus (IAV), influenza B virus (IBV), influenza C virus (ICV), influenza D virus (IDV), or a variant, subtype, or reassortant thereof. In some embodiments, the influenza virus comprises a neuraminidase (NA) antigen, e.g., an NA antigen selected from the group consisting of N1, 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 variants or reassortant thereof. In some embodiments, the mucosa is selected from the group consisting of nasal mucosa, laryngeal mucosa, tracheal mucosa, bronchial mucosa, pulmonary mucosa, ocular mucosa, and combinations thereof. In some embodiments, the antibody portion is a full-length antibody (e.g., IgG, IgA, IgM, IgE, or IgD). In some embodiments, the antibody portion is a Fab, Fab', (Fab')2, Fv, single chain Fv (scFv), scFv-Fc, disulfide stabilized Fv fragment (dsFv), (dsFv)2, scFv dimer, domain antibody, camelid single domain antibody, bivalent domain antibody, minibody, and V. H H.

[0095]

[0104] In some embodiments, provided are chimeric proteins (e.g., fusion proteins) comprising: (a) an antibody portion that specifically binds to the NA protein of an influenza virus or a variant thereof; and (b) a mucoadhesive peptide fragment comprising at least about five positively charged amino acid residues (e.g., about 5 to about 30 positively charged amino acid residues), wherein the mucoadhesive peptide fragment promotes attachment of the chimeric protein to a mucosa, and wherein the antibody portion comprises any one of the antibodies or antigen-binding fragments thereof listed in Table 4B, or the antibody portion comprises any one of the antibodies or antigen-binding fragments thereof listed in Table 6. In some embodiments, the antibody portion binds to an NA antigen, e.g., an NA antigen selected from the group consisting of N1, N2, N3, N7, N8, and N9, or a variant or reassortant thereof. In some embodiments, the mucoadhesive peptide comprises any one of the mucoadhesive peptide fragments listed in Table 8.

[0096]

[0105] In some embodiments, a chimeric protein (e.g., a fusion protein) comprising 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 chains, respectively), wherein the antibody specifically binds to a component of an influenza virus or a variant thereof, 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 first antibody heavy chain fused to a second mucoadhesive peptide fragment; (c) a second polypeptide chain comprising a second antibody heavy chain; (c) a third polypeptide chain comprising a first antibody light chain; and (d) a fourth polypeptide chain comprising a second antibody light chain, wherein the first and second mucoadhesive peptide fragments each comprise at least about five positively charged amino acid residues (e.g., about 5 to about 30 positively charged amino acid residues), and the first and second mucoadhesive peptide fragments promote adhesion of the chimeric protein to a mucosa. In some embodiments, the first polypeptide chain comprises, from N-terminus to C-terminus, the first antibody heavy chain, an optional peptide linker, and the first mucoadhesive peptide fragment. In some embodiments, the second polypeptide chain comprises, from N-terminus to C-terminus, the second antibody heavy chain, an optional peptide linker, and the second mucoadhesive peptide fragment. In some embodiments, the first mucoadhesive peptide fragment is identical to the second mucoadhesive peptide fragment. In some embodiments, the first mucoadhesive peptide fragment is different from the second mucoadhesive peptide fragment. In some embodiments, any linker of the first and second polypeptide chains is the same. In some embodiments, any linker of the first and second polypeptide chains is different. In some embodiments, the third polypeptide chain and the fourth polypeptide comprise an antibody light chain. In some embodiments, the full-length antibody is a monospecific antibody. In some embodiments, the full-length antibody is a multispecific antibody (e.g., a bispecific antibody). In some embodiments, the influenza virus or variants thereof cause a respiratory infection.In some embodiments, the influenza virus is an influenza A virus (IAV), an influenza B virus (IBV), an influenza C virus (ICV), an influenza D virus (IDV), or a variant, subtype, or reassortant thereof. In some embodiments, the influenza virus comprises an HA antigen, e.g., an HA antigen selected from the group consisting of H1, H2, H3, H5, H6, H7, H9, and H10, or a variant or reassortant thereof. In some embodiments, the influenza virus comprises an NA antigen, e.g., an NA antigen selected from the group consisting of N1, 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 variants or reassortant thereof. In some embodiments, the mucosa is selected from the group consisting of nasal mucosa, laryngeal mucosa, tracheal mucosa, bronchial mucosa, pulmonary mucosa, ocular mucosa, and combinations thereof. In some embodiments, the full-length antibody is IgG, IgA, IgM, IgE, or IgD.

[0097]

[0106] In some embodiments, a chimeric protein (e.g., a fusion protein) comprising 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 chains, respectively), wherein the antibody specifically binds to an HA protein, the chimeric protein comprising: (a) a first polypeptide chain comprising the first antibody heavy chain fused to a first mucoadhesive peptide fragment; (b) a second antibody heavy chain fused to a second mucoadhesive peptide fragment; (c) a second polypeptide chain comprising a first antibody light chain; and (d) a fourth polypeptide chain comprising a second antibody light chain, wherein the first and second mucoadhesive peptide fragments each comprise at least about 5 positively charged amino acid residues (e.g., about 5 to about 30 positively charged amino acid residues), and the first and second mucoadhesive peptide fragments promote adhesion of the chimeric protein to mucosa.In some embodiments, the chimeric protein comprises: (1) first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 216, 218-242, and 416-419; and (2) third and fourth polypeptide chains. (1) a third and fourth polypeptide chain, each having at least about 90% sequence identity (e.g., 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: 217; (2) a first and second polypeptide chain, each independently having at least about n% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 243, 245 to 258, and 422 to 425; (3) first and second polypeptide chains having at least about 90% sequence identity, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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:244; or (3) first and second polypeptide chains, each independently and a first and second polypeptide chain having at least about 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 448 to 486, and a third and fourth polypeptide chain, each of which has at least about 90% sequence identity (e.g., 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: 447.

[0098]

[0107] In some embodiments, a chimeric protein (e.g., a fusion protein) comprising 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 chains, respectively), wherein the antibody specifically binds to an NA protein, the chimeric protein comprising: (a) a first polypeptide chain comprising the first antibody heavy chain fused to a first mucoadhesive peptide fragment; (b) a second antibody heavy chain fused to a second mucoadhesive peptide fragment; (c) a second polypeptide chain comprising a first antibody light chain; and (d) a fourth polypeptide chain comprising a second antibody light chain, wherein the first and second mucoadhesive peptide fragments each comprise at least about 5 positively charged amino acid residues (e.g., about 5 to about 30 positively charged amino acid residues), and the first and second mucoadhesive peptide fragments promote adhesion of the chimeric protein to mucosa.In some embodiments, the chimeric protein comprises: (1) first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 259, 261-274, and 428-431; and (2) third and fourth polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 260. and a fourth polypeptide chain; or (2) a first and second polypeptide chain, each independently having at least about 90% sequence identity (e.g., 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: 275, 277-290, and 434-437, and a third and fourth polypeptide chain, each having at least about 90% sequence identity (e.g., 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: 276.

[0099]

[0108] In some embodiments, chimeric proteins (e.g., fusion proteins) are provided that include: (a) an scFv that specifically binds to a component of an influenza virus or variant thereof; and (b) a mucoadhesive peptide fragment, wherein the mucoadhesive peptide fragment comprises at least about five positively charged amino acid residues (e.g., about 5 to about 30 positively charged amino acid residues), and the mucoadhesive peptide fragment promotes adhesion of the chimeric protein to a mucosa. In some embodiments, the chimeric protein comprises, from N- to C-terminus, a polypeptide comprising an scFv, an optional peptide linker, and the mucoadhesive peptide fragment. In some embodiments, the scFv comprises, from N- to C-terminus, a V H , an optional linker, and V L In some embodiments, the scFv comprises, from the N-terminus to the C-terminus, V L , an optional linker, and V H In some embodiments, the chimeric protein comprises one or more constant domains of an antibody, e.g., CH1, C L, CH2, CH3, and / or CH4. In some embodiments, the chimeric protein further comprises an Fc. In some embodiments, the positively charged amino acid residue is selected from the group consisting of lysine, arginine, histidine, ornithine, and combinations thereof. In some embodiments, the positively charged amino acid residue is lysine. In some embodiments, the mucoadhesive peptide fragment is a polylysine peptide having at least about 5 (e.g., about 5-30, e.g., 12) lysines (e.g., comprising at least about 5 (e.g., about 5-30, e.g., 12) consecutive lysines). In some embodiments, the positively charged amino acid residue is histidine. In some embodiments, the mucoadhesive peptide fragment is a polyhistidine peptide having at least about 5 (e.g., about 5-30, e.g., 12) histidines (e.g., comprising at least about 5 (e.g., about 5-30, e.g., 12) consecutive histidines). In some embodiments, the positively charged amino acid residue is arginine. In some embodiments, the mucoadhesive peptide fragment is a polyarginine peptide having at least about 5 (e.g., about 5-30, e.g., 12) arginines (e.g., comprising at least about 5 (e.g., about 5-30, e.g., 12) consecutive arginines). In some embodiments, the positively charged amino acid residue is ornithine. In some embodiments, the mucoadhesive peptide fragment is a polyornithine peptide having at least about 5 (e.g., about 5-30, e.g., 12) ornithines (e.g., comprising at least about 5 (e.g., about 5-30, e.g., 12) consecutive ornithines). In some embodiments, the positively charged amino acid residues are contiguous to one another. In some embodiments, the positively charged amino acid residues are interspersed with non-positively charged amino acid residues. In some embodiments, the influenza virus is an influenza A virus (IAV), an influenza B virus (IBV), an influenza C virus (ICV), an influenza D virus (IDV), or a variant, subtype, or reassortant thereof.In some embodiments, the influenza virus comprises an HA antigen, e.g., an HA selected from the group consisting of H1, H2, H3, H5, H6, H7, H9, and H10, or a variant or reassortant thereof. In some embodiments, the influenza virus comprises an NA antigen, e.g., an NA selected from the group consisting of N1, 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 an 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 variants thereof cause a respiratory infection, hi some embodiments, the mucosa is selected from the group consisting of nasal mucosa, laryngeal mucosa, tracheal mucosa, bronchial mucosa, pulmonary mucosa, ocular mucosa, and combinations thereof.

[0100]

[0109] In some embodiments, provided are chimeric proteins (e.g., fusion proteins) comprising: (a) a first scFv and a second scFv that specifically bind to a component of an influenza virus or a variant thereof, respectively; and (b) a first and a second mucoadhesive peptide fragment, each of the mucoadhesive peptide fragments comprising at least about five positively charged amino acid residues (e.g., about 5 to about 30 positively charged amino acid residues), and the mucoadhesive peptide fragments promote adhesion of the chimeric protein to a mucosa, the chimeric protein comprising: (1) a first polypeptide comprising, from N-terminus to C-terminus, the first scFv, an optional linker, a CH2 domain, a CH3 domain, an optional linker, and the first mucoadhesive peptide fragment; and (2) a second polypeptide comprising, from N-terminus to C-terminus, the second scFv, an optional linker, a CH2 domain, a CH3 domain, an optional linker, and the second mucoadhesive peptide fragment. In some embodiments, the first mucoadhesive peptide fragment is identical to the second mucoadhesive peptide fragment. In some embodiments, the first mucoadhesive peptide fragment is different from the second mucoadhesive peptide fragment. In some embodiments, the first scFv and the second scFv specifically bind to the same component of an influenza virus or variant thereof. In some embodiments, the first scFv and the second scFv specifically bind to different variants of the same component, different components of the same influenza virus, or components of different influenza viruses. In some embodiments, the positively charged amino acid residue is selected from the group consisting of lysine, arginine, histidine, ornithine, and combinations thereof. In some embodiments, the positively charged amino acid residue is lysine. In some embodiments, the mucoadhesive peptide fragment is a polylysine peptide having at least about 5 (e.g., about 5-30, e.g., 12) consecutive lysines (e.g., comprising at least about 5 (e.g., about 5-30, e.g., 12) consecutive lysines). In some embodiments, the positively charged amino acid residue is histidine.In some embodiments, the mucoadhesive peptide fragment is a polyhistidine peptide having at least about five (e.g., about 5-30, e.g., 12) histidines (e.g., comprising at least about five (e.g., about 5-30, e.g., 12) consecutive histidines). In some embodiments, the positively charged amino acid residue is arginine. In some embodiments, the mucoadhesive peptide fragment is a polyarginine peptide having at least about five (e.g., about 5-30, e.g., 12) arginines (e.g., comprising at least about five (e.g., about 5-30, e.g., 12) consecutive arginines). In some embodiments, the positively charged amino acid residue is ornithine. In some embodiments, the mucoadhesive peptide fragment is a polyornithine peptide having at least about 5 (e.g., about 5-30, e.g., 12) ornithines (e.g., comprising at least about 5 (e.g., about 5-30, e.g., 12) consecutive ornithines). In some embodiments, the positively charged amino acid residues are contiguous with one another. In some embodiments, the positively charged amino acid residues are interspersed with non-positively charged amino acid residues. In some embodiments, the influenza virus is an influenza A virus (IAV), an influenza B virus (IBV), an influenza C virus (ICV), an influenza D virus (IDV), or a variant, subtype, or reassortant thereof. In some embodiments, the influenza virus comprises an HA antigen, e.g., an HA antigen selected from the group consisting of H1, H2, H3, H5, H6, H7, H9, and H10, or a variant or reassortant thereof. In some embodiments, the influenza virus comprises an NA antigen, e.g., an NA selected from the group consisting of N1, 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 variants 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 variants thereof causes a respiratory infection. In some embodiments, the mucosa is selected from the group consisting of nasal mucosa, laryngeal mucosa, tracheal mucosa, bronchial mucosa, pulmonary mucosa, ocular mucosa, and combinations thereof.

[0101]

[0110] In some embodiments, the half-life of the chimeric protein on the mucosa is at least about n hours, where n hours is selected from 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 30, 36, and 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.

[0102]

[0111] The half-life of a chimeric protein on mucosal membranes can be determined using in vitro assays known in the art. Given the size and polarity of the chimeric protein, mucosal (e.g., nasal) absorption of the chimeric protein is minimal due to its low membrane permeability. However, mucociliary clearance of the chimeric protein may affect its half-life. Mucoadhesive peptide fragments can improve the retention time of the chimeric protein on mucosal membranes. For example, using an in vitro model cell system such as mucosal epithelial cells, the amount of chimeric protein remaining on the cell / mucin surface can be determined by FACS or immunofluorescence. As another example, a mucosal-associated component, such as mucin, can be used to incubate the chimeric protein, and the amount of chimeric protein bound to the mucin can be determined by ELISA. In either method, for chimeric proteins containing IgG, an anti-IgG secondary antibody can be used as a detection probe.

[0103]

[0112] Exemplary chimeric proteins are provided herein that include an antibody portion that specifically binds to a component of an influenza virus or variant thereof and a mucoadhesive peptide fragment that includes at least about five positively charged amino acids (e.g., about 5 to about 30 positively charged amino acid residues). Table 1 provides sequences of several exemplary chimeric proteins that include an antibody light chain ("LC") polypeptide and an antibody heavy chain ("HC") polypeptide fused to a mucoadhesive peptide fragment. TIFF2025512515000003.tif250170TIFF2025512515000004.tif250170TIFF2025512515000005.tif250170TIFF2025512515000006.tif241170TIFF2025512515000007.tif250170TIFF2025512515000008.tif229170TIFF2025512515000009.tif250170TIFF2025512515000010.tif250170TIFF2025512515000011.tif229170TIFF2025512515000012.tif250170TIFF2025512515000013.tif245170TIFF2025512515000014.tif237170TIFF2025512515000015.tif250170TIFF2025512515000016.tif251170TIFF2025512515000017.tif242170TIFF2025512515000018.tif246170TIFF2025512515000019.tif227170TIFF2025512515000020.tif250170TIFF2025512515000021.tif250170TIFF2025512515000022.tif241170TIFF2025512515000023.tif250170TIFF2025512515000024.tif237170TIFF2025512515000025.tif250170TIFF2025512515000026.tif250170TIFF2025512515000027.tif251170TIFF2025512515000028.tif242170TIFF2025512515000029.tif250170TIFF2025512515000030.tif250170

[0104]

[0113] Additional chimeric proteins comprising any of the anti-influenza virus (e.g., anti-HA or anti-NA) antibody portions or variants thereof, mucoadhesive fragments, and / or linkers provided herein are also contemplated. It should be understood that various other chimeric proteins comprising anti-influenza virus antibody portions or variants known in the art fused to any of the mucoadhesive peptide fragments and / or linkers provided herein may also be encompassed within the scope of the present invention.

[0105]

[0114] In some embodiments, the chimeric protein comprises an anti-HA antibody portion and one or more mucoadhesive peptide fragments described herein. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently comprising a heavy chain of a full-length anti-HA antibody, and third and fourth polypeptide chains, each independently comprising a light chain of a full-length anti-HA antibody, such as the chimeric proteins provided in Table 1 above, e.g., HA1-hIgG-6H; HA1-hIgG-12H; HA1-hIgG-30H; HA1-hIgG-4H; HA1-hIgG-5H; ...5H; HA1-hIgG-5H; HA1-hIgG-5H; HA1-hIgG-5H; HA1-hIgG-5H; HA1-hIgG-5H; HA1-hIgG-5H; HA1-hIgG-5H; HA1-hIgG-5H; HA1-hIgG-5H; HA1-hIgG-5H; HA1-hIgG-5H; HA1-hIgG-5H; HA1-hIgG-5H; HA1-hIgG-5H; HA1-hIgG-5H; HA1-hIgG-5H; HA1-hIgG-5H; HA1-hIgG-5H; HA1-hIgG-5H -6K;HA1-hIgG-12K;HA1-hIgG-30K;HA1-hIgG-6R;HA1-hIgG-12R;HA1-hIgG-30R;HA1-hIgG-6O;HA1-hIgG-12O;HA1-hIgG-30O;HA1-hIgG-6 X-1;HA1-hIgG-6X-2;HA1-hIgG-6X-3;HA1-hIgG-6X-4;HA1-hIgG-12X-1;HA1-hIgG-30X-1;HA1-hIgG-6X-2;HA1-hIgG-12X-2;HA1-hIgG-30X -2;HA1-hIgG-6X-3;HA1-hIgG-12X-3;HA1-hIgG-30X-3;HA1-hIgG-12X-4;HA1-hIgG-30X-4;HA2-hIgG-6H;HA2-hIgG-12H;HA2-hIgG-30H;H A2-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-hIgG-30X-1;HA1-hIgG-5H;HA1-hIgG-7X-1;HA1-hIgG-12X-7;HA1-hIgG-12X-8;HA2-hIgG-5H;HA2-hIgG -7X-1;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-30O;HA15-hIgG-6X-1;HA15-hIgG-6X-2;HA 15-hIgG-6X-3;HA15-hIgG-6X-4;HA15-hIgG-6X-5;HA15-hIgG-6X-6;HA15-hIgG-6X-7;HA15-hIgG-7X-1;HA15-hIgG-12X-1;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-1; HA15-hIgG-30X-2; HA15-hIgG-30X-3; HA15-hIgG-30X-4; HA15-hIgG-35X-1; HA15-hIgG-40X-2; HA15-hIgG-42X-1; HA15-hIgG-45X-1; HA15-hIgG-50X-1; and HA15-hIgG-50X-2.

[0106]

[0115] In some embodiments, the chimeric protein comprises a heavy chain (HC) polypeptide comprising the amino acid sequence of any one of SEQ ID NOs: 414, 420, and 446, or a variant thereof comprising at least about 90% sequence identity (e.g., 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: 414, 420, and 446, and a light chain (LC) polypeptide comprising the amino acid sequence of any one of SEQ ID NOs: 217, 244, and 447, or a variant thereof comprising at least about 90% sequence identity (e.g., 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: 217, 244, and 447.

[0107]

[0116] In some embodiments, the chimeric protein comprises an HC polypeptide comprising the amino acid sequence of SEQ ID NO: 414, or a variant thereof comprising at least about 90% sequence identity (e.g., 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: 414, and an LC polypeptide comprising the amino acid sequence of SEQ ID NO: 217, or a variant thereof comprising at least about 90% sequence identity (e.g., 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: 217.

[0108]

[0117] In some embodiments, the chimeric protein comprises an HC polypeptide comprising the amino acid sequence of SEQ ID NO: 420, or a variant thereof comprising at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 420 (e.g., at least about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%), and an LC polypeptide comprising the amino acid sequence of SEQ ID NO: 244, or a variant thereof comprising at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 244 (e.g., at least about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%).

[0109]

[0118] In some embodiments, the chimeric protein comprises an HC polypeptide comprising the amino acid sequence of SEQ ID NO: 446, or a variant thereof comprising at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 446 (e.g., at least about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%), and an LC polypeptide comprising the amino acid sequence of SEQ ID NO: 447, or a variant thereof comprising at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 447 (e.g., at least about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%).

[0110]

[0119] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 216, 218-234, 236, 237, 239-242, and 416-419, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 217. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of any one of SEQ ID NOs: 216, 218-234, 236, 237, 239-242, and 416-419, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 217.

[0111]

[0120] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 216, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 217. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 216, and third and fourth polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein is HA1-hIgG-6H, as described in Table 1.

[0112]

[0121] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 218, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 217. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 218, and third and fourth polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein is HA1-hIgG-12H, as described in Table 1.

[0113]

[0122] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 219, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 217. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 219, and third and fourth polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein is HA1-hIgG-30H, as described in Table 1.

[0114]

[0123] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 220, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 217. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 220, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein is HA1-hIgG-6K, as described in Table 1.

[0115]

[0124] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 221, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 217. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 221, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein is HA1-hIgG-12K, as described in Table 1.

[0116]

[0125] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 222, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 217. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 222, and third and fourth polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein is HA1-hIgG-30K, as described in Table 1.

[0117]

[0126] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 223, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 217. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 223, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein is HA1-hIgG-6R, as described in Table 1.

[0118]

[0127] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 224, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 217. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 224, and third and fourth polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein is HA1-hIgG-12R, as described in Table 1.

[0119]

[0128] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 225, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 217. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 225, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein is HA1-hIgG-30R, as described in Table 1.

[0120]

[0129] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 226, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 217. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 226, and third and fourth polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein is HA1-hIgG-6O, as described in Table 1.

[0121]

[0130] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 227, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 217. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 227, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein is HA1-hIgG-12O, as described in Table 1.

[0122]

[0131] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 228, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 217. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 228, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein is HA1-hIgG-30O, as described in Table 1.

[0123]

[0132] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 229, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 217. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 229, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein is HA1-hIgG-6X-1, as described in Table 1.

[0124]

[0133] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 230, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 217. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 230, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein is HA1-hIgG-6X-2, as described in Table 1.

[0125]

[0134] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 231, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 217. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 231, and third and fourth polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein is HA1-hIgG-6X-3, as described in Table 1.

[0126]

[0135] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 232, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 217. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 232, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein is HA1-hIgG-6X-4, as described in Table 1.

[0127]

[0136] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 233, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 217. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 233, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein is HA1-hIgG-12X-1, as described in Table 1.

[0128]

[0137] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 234, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 217. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 234, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein is HA1-hIgG-30X-1, as described in Table 1.

[0129]

[0138] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 236, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 217. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 236, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein is HA1-hIgG-12X-2, as described in Table 1.

[0130]

[0139] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 237, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 217. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 237, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein is HA1-hIgG-30X-2, as described in Table 1.

[0131]

[0140] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 239, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 217. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 239, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein is HA1-hIgG-12X-3, as described in Table 1.

[0132]

[0141] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 240, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 217. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 240, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein is HA1-hIgG-30X-3, as described in Table 1.

[0133]

[0142] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 241, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 217. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 241, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein is HA1-hIgG-12X-4, as described in Table 1.

[0134]

[0143] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 242, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 217. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 242, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein is HA1-hIgG-30X-4, as described in Table 1.

[0135]

[0144] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 416, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 217. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 416, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein is HA1-hIgG-5H, as described in Table 1.

[0136]

[0145] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 417, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 217. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 417, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein is HA1-hIgG-7X-1, as described in Table 1.

[0137]

[0146] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 418, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 217. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 418, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein is HA1-hIgG-12X-7, as described in Table 1.

[0138]

[0147] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 419, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 217. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 419, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein is HA1-hIgG-12X-8, as described in Table 1.

[0139]

[0148] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 243, 245-258, and 422-425, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 244. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of any one of SEQ ID NOs: 243, 245-258, and 422-425, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 244.

[0140]

[0149] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 243, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 244. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 243, and third and fourth polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 244. In some embodiments, the chimeric protein is HA2-hIgG-6H, as described in Table 1.

[0141]

[0150] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 245, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 244. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 245, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 244. In some embodiments, the chimeric protein is HA2-hIgG-12H, as described in Table 1.

[0142]

[0151] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 246, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 244. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 246, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 244. In some embodiments, the chimeric protein is HA2-hIgG-30H, as described in Table 1.

[0143]

[0152] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 247, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 244. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 247, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 244. In some embodiments, the chimeric protein is HA2-hIgG-6K, as described in Table 1.

[0144]

[0153] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 248, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 244. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 248, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 244. In some embodiments, the chimeric protein is HA2-hIgG-12K, as described in Table 1.

[0145]

[0154] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 249, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 244. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 249, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 244. In some embodiments, the chimeric protein is HA2-hIgG-30K, as described in Table 1.

[0146]

[0155] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 250, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 244. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 250, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 244. In some embodiments, the chimeric protein is HA2-hIgG-6R, as described in Table 1.

[0147]

[0156] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 251, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 244. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 251, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 244. In some embodiments, the chimeric protein is HA2-hIgG-12R, as described in Table 1.

[0148]

[0157] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 252, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 244. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 252, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 244. In some embodiments, the chimeric protein is HA2-hIgG-30R, as described in Table 1.

[0149]

[0158] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 253, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 244. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 253, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 244. In some embodiments, the chimeric protein is HA2-hIgG-6O, as described in Table 1.

[0150]

[0159] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 254, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 244. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 254, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 244. In some embodiments, the chimeric protein is HA2-hIgG-12O, as described in Table 1.

[0151]

[0160] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 255, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 244. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 255, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 244. In some embodiments, the chimeric protein is HA2-hIgG-30O, as described in Table 1.

[0152]

[0161] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 256, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 244. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 256, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 244. In some embodiments, the chimeric protein is HA2-hIgG-6X-7, as described in Table 1.

[0153]

[0162] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 257, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 244. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 257, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 244. In some embodiments, the chimeric protein is HA2-hIgG-12X-5, as described in Table 1.

[0154]

[0163] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 258, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 244. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 258, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 244. In some embodiments, the chimeric protein is HA2-hIgG-30X-1, as described in Table 1.

[0155]

[0164] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 422, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 244. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 422, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 244. In some embodiments, the chimeric protein is HA2-hIgG-5H, as described in Table 1.

[0156]

[0165] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 423, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 244. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 423, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 244. In some embodiments, the chimeric protein is HA2-hIgG-7X-1, as described in Table 1.

[0157]

[0166] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 424, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 244. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 424, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 244. In some embodiments, the chimeric protein is HA2-hIgG-12X-7, as described in Table 1.

[0158]

[0167] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 425, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 244. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 425, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 244. In some embodiments, the chimeric protein is HA2-hIgG-12X-8, as described in Table 1.

[0159]

[0168] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 448-486, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 447. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of any one of SEQ ID NOs: 448-486, and third and fourth polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 447.

[0160]

[0169] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 448, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 447. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 448, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-5H, as described in Table 1.

[0161]

[0170] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 449, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 447. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 449, and third and fourth polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-6H, as described in Table 1.

[0162]

[0171] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 450, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 447. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 450, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-12H, as described in Table 1.

[0163]

[0172] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 451, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 447. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 451, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-30H, as described in Table 1.

[0164]

[0173] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 452, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 447. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 452, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-6K, as described in Table 1.

[0165]

[0174] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 453, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 447. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 453, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-12K, as described in Table 1.

[0166]

[0175] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 454, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 447. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 454, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-30K, as described in Table 1.

[0167]

[0176] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 455, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 447. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 455, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-6R, as described in Table 1.

[0168]

[0177] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 456, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 447. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 456, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-12R, as described in Table 1.

[0169]

[0178] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 457, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 447. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 457, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-30R, as described in Table 1.

[0170]

[0179] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 458, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 447. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 458, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-6O, as described in Table 1.

[0171]

[0180] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 459, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 447. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 459, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-12O, as described in Table 1.

[0172]

[0181] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 460, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 447. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 460, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-30O, as described in Table 1.

[0173]

[0182] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 461, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 447. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 461, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-6X-1, as described in Table 1.

[0174]

[0183] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 462, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 447. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 462, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-6X-2, as described in Table 1.

[0175]

[0184] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 463, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 447. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 463, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-6X-3, as described in Table 1.

[0176]

[0185] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 464, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 447. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 464, and third and fourth polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-6X-4, as described in Table 1.

[0177]

[0186] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 465, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 447. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 465, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-6X-5, as described in Table 1.

[0178]

[0187] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 466, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 447. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 466, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-6X-6, as described in Table 1.

[0179]

[0188] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 467, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 447. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 467, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-6X-7, as described in Table 1.

[0180]

[0189] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 468, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 447. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 468, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-7X-1, as described in Table 1.

[0181]

[0190] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 469, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 447. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 469, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-12X-1, as described in Table 1.

[0182]

[0191] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 470, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 447. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 470, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-12X-2, as described in Table 1.

[0183]

[0192] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 471, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 447. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 471, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-12X-3, as described in Table 1.

[0184]

[0193] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 472, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 447. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 472, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-12X-4, as described in Table 1.

[0185]

[0194] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 473, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 447. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 473, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-12X-5, as described in Table 1.

[0186]

[0195] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 474, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 447. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 474, and third and fourth polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-12X-6, as described in Table 1.

[0187]

[0196] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 475, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 447. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 475, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-12X-7, as described in Table 1.

[0188]

[0197] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 476, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 447. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 476, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-12X-8, as described in Table 1.

[0189]

[0198] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 477, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 447. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 477, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-30X-1, as described in Table 1.

[0190]

[0199] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 478, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 447. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 478, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-30X-2, as described in Table 1.

[0191]

[0200] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 479, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 447. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 479, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-30X-3, as described in Table 1.

[0192]

[0201] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 480, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 447. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 480, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-30X-4, as described in Table 1.

[0193]

[0202] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 481, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 447. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 481, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-35X-1, as described in Table 1.

[0194]

[0203] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 482, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 447. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 482, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-40X-2, as described in Table 1.

[0195]

[0204] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 483, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 447. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 483, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-42X-1, as described in Table 1.

[0196]

[0205] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 484, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 447. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 484, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-45X-1, as described in Table 1.

[0197]

[0206] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 485, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 447. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 485, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-50X-1, as described in Table 1.

[0198]

[0207] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 486, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 447. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 486, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-50X-2, as described in Table 1.

[0199]

[0208] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently comprising a V of a full-length anti-NA antibody. H and a third and fourth polypeptide chains each independently comprising a V of a full-length anti-NA antibody. Land a third and fourth polypeptide chain comprising, for example, the chimeric proteins provided in Table 1 above, e.g., NA1-hIgG-6H; NA1-hIgG-12H; NA1-hIgG-30H; NA1-hIgG-6K; NA1-hIgG-12K; NA1-hIgG-30K; NA1-hIgG-6R; NA1-hIgG-12R; NA1-hIgG-30R; NA1-hIgG-6O; NA1-hIgG-12O; NA1-hIgG-30O; NA1-hIgG-6X-5; NA1-hIgG-12X-5; NA1-hIgG-30X-1; NA2-hIgG-6H; NA2-hIgG-12H; NA2-hIgG-30 H; 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-1; NA1-hIgG-5H; NA1-hIgG-7X-1; NA1-hIgG-12X-7; NA1-hIgG-12X-8; NA2-hIgG-5H; NA2-hIgG-7X-1; NA2-hIgG-12X-7; and NA2-hIgG-12X-8.

[0200]

[0209] In some embodiments, the chimeric protein comprises an HC polypeptide comprising the amino acid sequence of SEQ ID NO: 426 or 432, or a variant thereof comprising at least about 90% sequence identity (e.g., 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: 426 or 432, and an LC polypeptide comprising the amino acid sequence of SEQ ID NO: 260 or 276, or a variant thereof comprising at least about 90% sequence identity (e.g., 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: 260 or 276.

[0201]

[0210] In some embodiments, the chimeric protein comprises an HC polypeptide comprising the amino acid sequence of SEQ ID NO: 426, or a variant thereof comprising at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 426 (e.g., at least about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%), and an LC polypeptide comprising the amino acid sequence of SEQ ID NO: 260, or a variant thereof comprising at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 260 (e.g., at least about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%).

[0202]

[0211] In some embodiments, the chimeric protein comprises an HC polypeptide comprising the amino acid sequence of SEQ ID NO: 432, or a variant thereof comprising at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 432 (e.g., at least about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%), and an LC polypeptide comprising the amino acid sequence of SEQ ID NO: 276, or a variant thereof comprising at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 276 (e.g., at least about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%).

[0203]

[0212] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 259, 261-274, and 428-431, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 260. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of any one of SEQ ID NOs: 259, 261-274, and 428-431, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 260.

[0204]

[0213] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 259, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 260. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 259, and third and fourth polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 260. In some embodiments, the chimeric protein is NA1-hIgG-6H, as described in Table 1.

[0205]

[0214] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 261, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 260. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 261, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 260. In some embodiments, the chimeric protein is NA1-hIgG-12H, as described in Table 1.

[0206]

[0215] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 262, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 260. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 262, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 260. In some embodiments, the chimeric protein is NA1-hIgG-30H, as described in Table 1.

[0207]

[0216] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 263, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 260. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 263, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 260. In some embodiments, the chimeric protein is NA1-hIgG-6K, as described in Table 1.

[0208]

[0217] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 264, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 260. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 264, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 260. In some embodiments, the chimeric protein is NA1-hIgG-12K, as described in Table 1.

[0209]

[0218] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 265, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 260. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 265, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 260. In some embodiments, the chimeric protein is NA1-hIgG-30K, as described in Table 1.

[0210]

[0219] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 266, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 260. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 266, and third and fourth polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 260. In some embodiments, the chimeric protein is NA1-hIgG-6R, as described in Table 1.

[0211]

[0220] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 267, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 260. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 267, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 260. In some embodiments, the chimeric protein is NA1-hIgG-12R, as described in Table 1.

[0212]

[0221] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 268, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 260. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 268, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 260. In some embodiments, the chimeric protein is NA1-hIgG-30R, as described in Table 1.

[0213]

[0222] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 269, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 260. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 269, and third and fourth polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 260. In some embodiments, the chimeric protein is NA1-hIgG-6O, as described in Table 1.

[0214]

[0223] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 270, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 260. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 270, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 260. In some embodiments, the chimeric protein is NA1-hIgG-12O, as described in Table 1.

[0215]

[0224] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 271, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 260. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 271, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 260. In some embodiments, the chimeric protein is NA1-hIgG-30O, as described in Table 1.

[0216]

[0225] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 272, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 260. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 272, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 260. In some embodiments, the chimeric protein is NA1-hIgG-6X-5, as described in Table 1.

[0217]

[0226] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 273, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 260. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 273, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 260. In some embodiments, the chimeric protein is NA1-hIgG-12X-5, as described in Table 1.

[0218]

[0227] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 274, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 260. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 274, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 260. In some embodiments, the chimeric protein is NA1-hIgG-30X-1, as described in Table 1.

[0219]

[0228] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 428, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 260. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 428, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 260. In some embodiments, the chimeric protein is NA1-hIgG-5H, as described in Table 1.

[0220]

[0229] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 429, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 260. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 429, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 260. In some embodiments, the chimeric protein is NA1-hIgG-7X-1, as described in Table 1.

[0221]

[0230] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 430, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 260. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 430, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 260. In some embodiments, the chimeric protein is NA1-hIgG-12X-7, as described in Table 1.

[0222]

[0231] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 431, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 260. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 431, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 260. In some embodiments, the chimeric protein is NA1-hIgG-12X-8, as described in Table 1.

[0223]

[0232] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 275, 277-290, and 434-437, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 276. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of any one of SEQ ID NOs: 275, 277-290, and 434-437, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 276.

[0224]

[0233] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 275, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 276. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 275, and third and fourth polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 276. In some embodiments, the chimeric protein is NA2-hIgG-6H, as described in Table 1.

[0225]

[0234] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 277, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 276. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 277, and third and fourth polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 276. In some embodiments, the chimeric protein is NA2-hIgG-12H, as described in Table 1.

[0226]

[0235] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 278, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 276. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 278, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 276. In some embodiments, the chimeric protein is NA2-hIgG-30H, as described in Table 1.

[0227]

[0236] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 279, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 276. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 279, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 276. In some embodiments, the chimeric protein is NA2-hIgG-6K, as described in Table 1.

[0228]

[0237] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 280, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 276. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 280, and third and fourth polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 276. In some embodiments, the chimeric protein is NA2-hIgG-12K, as described in Table 1.

[0229]

[0238] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 281, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 276. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 281, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 276. In some embodiments, the chimeric protein is NA2-hIgG-30K, as described in Table 1.

[0230]

[0239] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 282, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 276. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 282, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 276. In some embodiments, the chimeric protein is NA2-hIgG-6R, as described in Table 1.

[0231]

[0240] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 283, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 276. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 283, and third and fourth polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 276. In some embodiments, the chimeric protein is NA2-hIgG-12R, as described in Table 1.

[0232]

[0241] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 284, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 276. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 284, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 276. In some embodiments, the chimeric protein is NA2-hIgG-30R, as described in Table 1.

[0233]

[0242] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 285, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 276. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 285, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 276. In some embodiments, the chimeric protein is NA2-hIgG-6O, as described in Table 1.

[0234]

[0243] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 286, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 276. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 286, and third and fourth polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 276. In some embodiments, the chimeric protein is NA2-hIgG-12O, as described in Table 1.

[0235]

[0244] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 287, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 276. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 287, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 276. In some embodiments, the chimeric protein is NA2-hIgG-30O, as described in Table 1.

[0236]

[0245] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 288, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 276. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 288, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 276. In some embodiments, the chimeric protein is NA2-hIgG-6X-6, as described in Table 1.

[0237]

[0246] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 289, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 276. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 289, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 276. In some embodiments, the chimeric protein is NA2-hIgG-12X-6, as described in Table 1.

[0238]

[0247] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 290, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 276. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 290, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 276. In some embodiments, the chimeric protein is NA2-hIgG-30X-1, as described in Table 1.

[0239]

[0248] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 434, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 276. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 434, and third and fourth polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 276. In some embodiments, the chimeric protein is NA2-hIgG-5H, as described in Table 1.

[0240]

[0249] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 435, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 276. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 435, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 276. In some embodiments, the chimeric protein is NA2-hIgG-7X-1, as described in Table 1.

[0241]

[0250] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 436, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 276. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 436, and third and fourth polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 276. In some embodiments, the chimeric protein is NA2-hIgG-12X-7, as described in Table 1.

[0242]

[0251] In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having at least about 90% sequence identity (e.g., 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: 437, and third and fourth polypeptide chains, each having at least about 90% sequence identity (e.g., 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: 276. In some embodiments, the chimeric protein comprises first and second polypeptide chains, each independently having the amino acid sequence of SEQ ID NO: 437, and third and fourth polypeptide chains, each having the amino acid sequence of SEQ ID NO: 276. In some embodiments, the chimeric protein is NA2-hIgG-12X-8, as described in Table 1.

[0243]

[0252] Without being bound by any theory or hypothesis, influenza virus infection occurs primarily via respiratory droplets, with the possibility of airborne transmission. The upper respiratory tract surface is the primary and initial site of influenza virus infection. The nasal epithelium creates a physical glycoprotein barrier against inhaled particles, including allergens and pathogens, preventing their penetration through the epithelial surface of mucosal tissue. One of the major components of the mucosal layer of the nose and respiratory tract is mucin, a family of large glycoproteins that coat the surface of the respiratory epithelium. Mucin, the major non-aqueous component of mucus, has a complex, heterogeneous structure and carries a strong negative charge. In some embodiments, the inventors of the present invention have designed a tail containing at least five positively charged amino acids (e.g., lysine, histidine, arginine, ornithine, or a combination thereof), which, when covalently attached to an antibody or antibody moiety, confers a positive charge to the conjugate (i.e., chimeric protein). Antibodies with positively charged tails can coat the nose / respiratory tract and form a layer of influenza-binding antibodies that can prevent the virus from binding to viral receptor-expressing epithelial cells. Positively charged antibodies can also bind to the similarly negatively charged phospholipid bilayer of cell membranes. This "sticky" property of the positively charged polymer amino acid chains increases the half-life of the antibody in the respiratory mucosal epithelium, extending the period of protection. Therefore, the designed antibody-mucoadhesive polymer conjugates can function as neutralizing antibodies, blocking the entry of influenza viruses into cells in the respiratory cavity, even if the virus can cross the mucosal barrier and reach virus receptor-positive epithelial cells. In other embodiments, positively charged mucoadhesive amino acids can be interspersed with non-positively charged amino acids without destroying the mucoadhesive properties of the chimeric protein. Furthermore, the chimeric protein can be expressed as a fusion protein, or mucoadhesive peptide fragments can be chemically conjugated to the antibody.

[0244]

[0253] Different aspects and embodiments are described in further detail in various sections below.

[0245] A. Anti-influenza antibody moiety

[0254] The chimeric proteins described herein comprise an antibody portion that specifically binds to a component of an influenza virus (including influenza virus variants), such as the HA or NA influenza virus surface protein. Contemplated antibody portions include, for example, scFv, Fab, Fc fusion proteins (e.g., scFv-Fc), full-length antibodies, and multispecific antibodies.

[0246]

[0255] In some embodiments, an antibody portion comprises one or more (e.g., two, three, four, or more) polypeptide chains, which can be linked together, for example, via disulfide bonds (i.e., S-S bonds) or multimerization domains.

[0247]

[0256] In some embodiments, the antibody portion is a full-length antibody or any suitable antigen-binding fragment thereof. In some embodiments, the antibody portion is a full-length antibody. In some embodiments, the antibody portion is selected from the group consisting of IgG, IgA, IgM, and IgD. In some embodiments, the antibody portion is selected from the group consisting of Fab, Fab', (Fab')2, Fv, single-chain Fv (scFv), scFv-Fc, disulfide-stabilized Fv fragment (dsFv), (dsFv)2, scFv dimer, domain antibody, camelid single domain antibody, bivalent domain antibody, minibody, and V H H. In some embodiments, the antibody portion is an animal, human, humanized, camelid, or chimeric antibody, or antigen-binding fragment thereof.

[0248]

[0257] In some embodiments, the antibody portion comprises an scFv. In some embodiments, the antibody portion is an scFv. In some embodiments, the antibody portion is an scFv-Fc fusion protein. In some embodiments, the antibody portion is an scFv-CH3 fusion protein. In some embodiments, the scFv is (GGGS) n or via a flexible peptide linker such as the similar peptides disclosed in Table 9, SEQ ID NOs: 343-348L V fused with H In some embodiments, the scFv comprises V H V fused with L Includes.

[0249]

[0258] In humans, IgA is the predominant antibody isotype secreted in the upper respiratory tract, and its presence correlates with resistance to infection by some respiratory viruses, such as influenza virus or its variants. Delivery of antibodies to the upper respiratory mucosal surface that mimic naturally secreted antibodies could block viruses from reaching their targets or directly neutralize infectious viruses, potentially representing a highly useful strategy for prevention. Indeed, antibodies have been shown to confer airway protection from viral infection when administered prophylactically. IgA antibodies have a unique structure and glycosylation pattern that allows them to bind to mucin molecules in the respiratory epithelium, resulting in an extended half-life at the mucosa. While secretory IgA antibodies are more efficient at providing effective viral protection than IgG antibodies, IgG antibodies have established methods for large-scale production and characterization, both of which are essential for providing an inexpensive and scalable antibody source for prophylactic approaches.

[0250]

[0259] In some embodiments, the antibody portion comprises a purification tag, for example, a His tag, such as DYKDDDDKHHHHHH (Flag-His(6), SEQ ID NO: 342).

[0251]

[0260] In some embodiments, the influenza virus or variants thereof cause a respiratory infection.

[0252]

[0261] The component of an influenza virus or variant thereof may be a protein-based molecule or a non-protein-based molecule (e.g., an oligosaccharide). In some embodiments, the component is a glycoprotein.

[0253]

[0262] The component of an influenza virus or variant thereof may be a surface molecule of the influenza virus. For example, the component may be a glycoprotein on the surface of the influenza virus. In some embodiments, the component is a capsid protein, an envelope protein, or a viral membrane fusion protein. In some embodiments, the component is lipopolysaccharide (LPS). In some embodiments, the component is a viral surface protein or a fragment thereof. In some embodiments, the viral surface protein is HA. In some embodiments, the viral surface protein is NA.

[0254]

[0263] Exemplary influenza viruses and antibody moieties are further described below.

[0255] influenza

[0264] The chimeric proteins of the invention comprise an antibody portion that specifically binds to a component of an influenza virus or variant thereof.

[0256]

[0265] In some embodiments, the influenza virus is an influenza A virus (IAV), an influenza B virus (IBV), an influenza C virus (ICV), an influenza D virus (IDV), or a variant, subtype, or reassortant thereof. In some embodiments, the influenza virus comprises an HA antigen, e.g., an HA antigen selected from the group consisting of H1, H2, H3, H5, H6, H7, H9, and H10, or a variant or reassortant thereof. In some embodiments, the influenza virus comprises an NA antigen, e.g., an NA antigen selected from the group consisting of N1, 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 variants or reassortant thereof.

[0257]

[0266] In some embodiments, the antibody portion specifically binds to a component on the surface of an influenza virus or variant thereof, such as the HA protein or the NA protein, hi some embodiments, the antibody portion is derived from a sub-neutralizing or non-neutralizing antibody to a pathogenic influenza virus or variant thereof.

[0258]

[0267] Influenza viruses are a group of related, yet antigenically and genetically diverse, viruses that cause disease in mammals and birds. In humans, influenza viruses cause respiratory tract infections ranging from mild to fatal. The most common symptoms include sudden onset of fever, cough (usually dry), headache, muscle and joint pain, severe fatigue (feeling unwell), sore throat, and runny nose. The incubation period for influenza is 1-4 days, with symptoms appearing approximately 2 days after exposure to the influenza virus. Complications of influenza virus infection can include pneumonia (direct viral pneumonia or secondary bacterial pneumonia) and bronchitis (direct viral bronchitis or secondary bacterial bronchitis).

[0259]

[0268] There are four types of influenza viruses: type A (IAV), type B (IBV), type C (ICV), and type D (IDV). Of the four types of influenza viruses, three types (A, B, and C) infect humans. Influenza type A viruses (also referred to herein as "influenza A") are the most virulent human pathogens and cause the most severe disease. Influenza A viruses can be classified based on the different subtypes of the major viral surface proteins, HA and NA, present. Currently, there are 18 different HAs and 11 different NAs among various influenza A virus strains, resulting in various subtypes or strain combinations of viral surface proteins (e.g., H1N1, H5N1). Influenza type B viruses typically cause less severe disease than influenza A viruses and are more commonly found in children, long-term care facilities, university campuses, and military camps. Influenza C viruses generally cause mild respiratory illness.

[0260]

[0269] Influenza A and B viruses continually evolve, generating new variants, a phenomenon known as antigenic drift. As a result, antibodies produced in response to past viruses may be insufficiently protective or non-protective against newly drifted viruses. Therefore, new vaccines may need to be manufactured each year against viruses predicted to emerge. Tables 2A and 2B show exemplary influenza A (Table 2A) and influenza B (Table 2B) antigens for the 2019 influenza season. Table 3 shows examples of influenza antigens from various influenza seasons. TIFF2025512515000031.tif247170TIFF2025512515000032.tif130170TIFF20255125150 00033.tif247170TIFF2025512515000034.tif147170TIFF2025512515000035.tif119170

[0261]

[0270] Exemplary antibodies against influenza virus HA antigens (e.g., human and animal HA antigens) are known in the art and include, for example, FI6V3, F045-092, mAb35490, KPF1, H1H14611N2, FluA-20, H5.28, H5.31, H7-200, 12mab, mAb14303, VIS410, FluAB_MLNS, D7, AT10_004, CR8001, and CR9114, which are disclosed in U.S. Patent Nos. 10,815,294, 9,605,053, 11,114, 12,126, 12,142, 12,146 ... Nos. 68,129, 11,230,593, 9,611,317, 9,718,874, U.S. Patent Application Publication No. 2021 / 0171612, 2021 / 0371505, 2021 / 0252150, PCT / US2020 / 017889, PCT / CN2020 / 071524, PCT / EP2020 / 062160, CN111704665, and PCT / EP2012 / 063637, which are incorporated by reference in their entireties. Exemplary antibodies against the NA protein of influenza viruses (e.g., human and animal) are also known in the art, including, for example, 1G05, 2E01, IF2, 1F4, 1092A9, 1092B6, 3C05, SEQ42-43, SEQ40-41, SEQ44-45, 2D04, 1D05, 1G03, and 2B04 reported in U.S. Patent No. 10,079,518, U.S. Patent Application Publication No. 2021 / 0047389, U.S. Patent Application Publication No. 2021 / 0002354, PCT / US2021 / 016879, and PCT / US2020 / 035323, which are incorporated by reference in their entireties. Exemplary human antibody sequences against the HA and NA of various influenza viruses or variants thereof are listed in Tables 4A-4B, respectively. Exemplary animal anti-HA antibody sequences are listed in Table 6. Exemplary animal anti-NA antibodies targeting the NA protein of the zoonotic IAV strain H7N9 have been published in the literature (D3 and 7H2, Xiong, et al., Emerging Microbes & Infections 9(1):78-87(2020)). Additionally, another zoonotic strain, IAV H5N1 (N1-V)H H, Cardoso, et al. Journal of Virology, 88(15):8278-96(2014)) have been described.

[0262]

[0271] New antibodies against components of influenza viruses or variants thereof (e.g., antibodies against HA and NA antigens, such as human or animal HA and NA antigens) can be developed using techniques known in the art, and the variable region sequences of such antibodies, or fragments thereof, can be used as the antibody portion of the chimeric proteins of the present disclosure. In some embodiments, the influenza virus is a known influenza virus. In some embodiments, the influenza virus is a variant of a known influenza virus. In some embodiments, the influenza virus is a future influenza virus. In some embodiments, the influenza virus is a variant of a future influenza virus.

[0263]

[0272] In some embodiments, the antibody portion is a derivative of any one of the antibodies to the HA or NA protein of an influenza virus or variants thereof described herein. In some embodiments, an antibody that competes with any of these art-recognized antibodies for binding to the HA or NA protein of an influenza virus or variants thereof can be used.

[0264]

[0273] HA is the primary target of neutralizing antibodies induced by infection of an individual with influenza virus or its variants or vaccination against influenza virus or its variants. HA induces influenza virus binding to cells with sialic acid on their membranes, such as cells of the upper respiratory tract, e.g., cells of the nasal cavity, larynx, trachea, bronchi, or lungs. In addition, HA is responsible for the fusion of the influenza virus envelope with the endosomal membrane, allowing the capsid and viral genome to enter and infect the host.

[0265]

[0274] HA is a homotrimeric integral membrane glycoprotein composed of three identical monomers, each consisting of an intact single polypeptide chain containing the HA1 and HA2 domains linked by two disulfide bridges. Each HA2 domain adopts an α-helical coiled-coil structure and primarily forms the HA "stem" region, while the HA1 domain is a small globular domain (the HA "head" region) composed of a combination of α / β structures. The globular HA head region promotes binding to viral receptors expressed on host cells (usually sialic acid-containing glycoproteins, gangliosides, or glycolipids ("sialic acid receptors")), while the HA stem region mediates subsequent fusion between the viral and cellular membranes. While the highly variable and immunodominant HA globular head domain undergoes constant antigenic drift, the HA stem region is highly conserved across influenza subtypes. Current influenza vaccines generally target immune responses to the HA head region. (See, e.g., Kirkpatrick et al., Nat Sci Rep, 8:10432 (2018)). Therefore, protection from a particular influenza vaccine typically lasts for only a few years, necessitating annual redevelopment of influenza vaccines.

[0266]

[0275] Recently, a new class of influenza-neutralizing antibodies targeting conserved regions of the HA stem have been developed as therapeutic agents for influenza viruses. These antibodies targeting the HA stem region typically exhibit broader neutralizing activity than antibodies targeting the HA head region. A summary of broadly neutralizing influenza A antibodies is provided in Corti and Lanzavecchia, Annu Rev Immunol, 31:705-742 (2013).

[0267]

[0276] The other major surface glycoprotein of influenza A and B viruses is NA, which is absent from influenza C viruses. NA is a receptor-destroying enzyme responsible for cleaving terminal sialic acid residues from N-linked glycans present on cell surfaces and progeny virions. This activity is important for the release of invading influenza viruses trapped on the glycans of host innate defense proteins at mucosal surfaces and for the release of nascent influenza viruses budding from infected host cells. Anti-NA antibodies can block this cleavage activity by directly binding to the enzymatic active site of NA or by sterically interfering with the interaction between NA and its substrates.

[0268]

[0277] NA is a homotetrameric transmembrane glycoprotein composed of four identical subunits. The NA protein consists of four major regions: a cytoplasmic tail domain, a hydrophobic transmembrane domain, a stalk region, and a globular head domain containing the enzymatic active site. The structure of each individual NA subunit is composed of six topologically identical four-stranded antiparallel β-sheets. The enzymatic active site (19 amino acids) is located at the center of each subunit. The active site is a deep pocket composed of amino acids that are highly conserved across all influenza virus strains. The antibody binding site is located on a surface loop surrounding the enzymatic active site. Additional information on NA is provided, for example, in Jagadesh et al., Arch Virol, 161:2087-2094 (2016). As explained above, influenza viruses can mutate antigenic sites in HA (especially the HA stem region) at a high rate, but NA has been shown to exhibit slower antigenic drift, resulting in broader cross-reactivity of anti-NA antibodies compared to anti-HA antibodies.

[0269]

[0278] In some embodiments, provided herein are chimeric proteins comprising an antibody or antigen-binding fragment thereof that binds to an epitope on HA or NA on the surface of an influenza virus or variants thereof. In some embodiments, the antibody or antigen-binding fragment thereof binds to an epitope on HA. In some embodiments, the HA epitope is from an HA antigen, such as an HA antigen of the HA1, HA2, HA3, HA4, HA5, HA6, HA7, HA8, HA9, HA10, HA11, HA12, HA13, HA14, HA15, HA16, HA17, or HA18 subtype, or a combination thereof. In some embodiments, the antibody or antigen-binding fragment thereof binds to an epitope on two or more HA subtypes (e.g., HA1, HA2, HA3, HA4, HA5, HA6, HA7, HA8, HA9, HA10, HA11, HA12, HA13, HA14, HA15, HA16, HA17, HA18). In some embodiments, the antibody or antigen-binding fragment thereof binds to an epitope on NA. In some embodiments, the NA epitope is from an NA antigen, such as an NA antigen of the N1, N2, N3, N4, N5, N6, N7, N8, N9, N10, or N11 subtype, or a combination thereof. In some embodiments, the antibody or antigen-binding fragment thereof binds to an epitope on two or more NA types (e.g., N1, N2, N3, N4, N5, N6, N7, N8, N9, N10, N11). In some embodiments, the chimeric protein treats or prevents infection with two or more types of influenza virus, e.g., H1N1, H1N2, H2N2, H3N2, H3N8, H5N1, H5N9, H6N1, H7N2, H7N3, H7N7, H7N9, H9N2, H10N7, or variants or reassortant thereof.

[0270] Anti-HA antibodies and anti-NA antibodies, and antigen-binding fragments thereof

[0279] The present application provides chimeric proteins (also referred to as "anti-HA antibodies or anti-NA antibodies") comprising an antibody or antigen-binding fragment thereof that specifically binds to the HA surface protein or NA surface protein of influenza virus (including influenza virus variants). The anti-HA and anti-NA antibodies described herein can be in any suitable full-length antibody or antigen-binding fragment format. Either the anti-HA antibody or anti-NA antibody, or an antigen-binding fragment thereof, can be used as the antibody portion in the chimeric proteins described herein or as the anti-HA antibody or anti-NA antibody portion in the anti-HA antibody or anti-NA antibody constructs described herein.

[0271]

[0280] In some embodiments, the anti-HA or anti-NA antibody is a full-length antibody or an immunoglobulin derivative. In some embodiments, the anti-HA or anti-NA antibody is IgG, IgA, IgD, IgE, or IgM. A full-length antibody is composed of two heavy chains and two light chains. The heavy chains of IgG, IgA, and IgD are each V H The heavy chains of IgM and IgE each contain an additional CH4, and a pair of CH2CH3 or CH2CH3CH4 fragments forms the Fc domain. The light chains each contain a V L and C L It consists of V H and V L are paired to form the variable region of an antibody, and CH1 and C L are paired as part of the antibody constant region. The complete constant region of a full-length antibody consists of two CH1-C L It is composed of one pair of CH2CH3 fragments and one pair of CH2CH3CH4 fragments.

[0272]

[0281] In some embodiments, the anti-HA or anti-NA antibody is an antigen-binding fragment, e.g., an antigen-binding fragment selected from the group consisting of Fab, Fab', F(ab')2, Fv fragment, disulfide-stabilized Fv fragment (dsFv), (dsFv)2, scFv dimer, domain antibody, bivalent domain antibody, single-chain Fv (scFv), scFv-Fc fusion protein, and minibody (i.e., scFv-CH3 fusion protein). In some embodiments, the anti-HA or anti-NA antibody is an scFv. In some embodiments, the anti-HA or anti-NA antibody is a fusion protein comprising an scFv fused to an Fc region. In some embodiments, the anti-HA or anti-NA antibody is a fusion protein comprising an scFv fused to a CH3 domain.

[0273]

[0282] In some embodiments, the anti-HA or anti-NA antibody is a chimeric antibody, an animal antibody, a human antibody, a partially humanized antibody, a fully humanized antibody, or a semi-synthetic antibody. In some embodiments, the anti-HA or anti-NA antibody is a semi-synthetic antibody comprising a fully human sequence and one or more synthetic regions. In some embodiments, the synthetic HC-CDR3 is about 5 to about 19 amino acids in length (e.g., about n, where n is selected from 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, and 19). In some embodiments, the anti-HA or anti-NA antibody is a semi-synthetic antibody comprising human CDRs and non-human framework sequences. In some embodiments, the non-human framework sequences include any sequences that can be used to generate synthetic heavy and / or light chain variable regions using one or more human CDR sequences described herein, including, for example, mammals such as mouse, rat, rabbit, pig, cattle (such as cows, bulls, and buffalo), deer, sheep, goat, chicken, cat, dog, ferret, primates (such as marmosets and rhesus monkeys), etc. In some embodiments, the anti-HA or anti-NA antibodies are generated by grafting one or more human CDR sequences described herein into non-human framework sequences (e.g., mouse or chicken framework sequences).

[0274]

[0283] In some embodiments, anti-HA or anti-NA antibodies comprise a particular sequence or a particular variant of such a sequence. In some embodiments, amino acid substitutions in the variant sequence do not substantially reduce the ability of the anti-HA or anti-NA antibody to specifically recognize the HA or NA protein, respectively, of an influenza virus or its variants. For example, modifications may be made that do not substantially reduce HA or NA binding affinity. Modifications that substantially improve HA or NA binding affinity or that affect other properties, such as specificity and / or cross-reactivity with related variants of the HA or NA protein, are also contemplated.

[0275]

[0284] Exemplary human antibody sequences are shown in Tables 4A-4B, and exemplary animal antibody sequences are shown in Table 6.

[0276]

[0285] Exemplary Human Anti-HA Antibodies

[0286] In some embodiments, chimeric proteins are provided that comprise an anti-HA antibody or antigen-binding fragment thereof (e.g., an anti-HA antibody portion) that specifically binds to a human HA antigen. In some embodiments, the anti-HA antibody or antigenic fragment thereof is a human anti-HA antibody or antigenic fragment thereof.

[0277]

[0287] Exemplary anti-HA antibodies are shown in Table 4A. TIFF2025512515000036.tif248170TIFF2025512515000037.tif250170TIFF2025512515000038.tif250170TIFF2025512515000039.tif246170

[0278]

[0288] In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises the HC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2, and LC-CDR3 of any one of antibodies HA1-HA16 in Table 4A. In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises the V of any one of antibodies HA1-HA16 in Table 4A. H and VL In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises the HC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2, and LC-CDR3 of antibody HA1 in Table 4A. In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises the V-CDR1, V-CDR2, V-CDR3, V-CDR1, V-CDR2, and V-CDR3 of antibody HA1 in Table 4A. H and V L In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises the HC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2, and LC-CDR3 of antibody HA2 in Table 4A. In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises the V H and V L In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises the HC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2, and LC-CDR3 of antibody HA15 in Table 4A. In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises the V-CDR1, V-CDR2, V-CDR3, V-CDR1, V-CDR2, and V-CDR3 of antibody HA15 in Table 4A. H and V L Includes.

[0279]

[0289] In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises: i) an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, or a variant thereof comprising up to about five (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions; an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 2, or a variant thereof comprising up to about five (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions; and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 3, or a variant thereof comprising up to about five (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions. Hand ii) V comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 4, or a variant thereof comprising up to about 5 (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an LC-CDR2 comprising the amino acid sequence of WAS, 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: 6, or a variant thereof comprising up to about 5 (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions. L In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises: i) a VHC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 3. H and ii) V comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 4, an LC-CDR2 comprising the amino acid sequence of WAS, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 6. L Includes.

[0280]

[0290] In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises a V comprising the amino acid sequence of SEQ ID NOs: 1, 2, and 3. H and V comprising WAS and the amino acid sequences of SEQ ID NOs: 4 and 6. L In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises a V domain comprising HC-CDR1, HC-CDR2, and HC-CDR3 of the amino acid sequence of SEQ ID NO: 76. H and V comprising LC-CDR1, LC-CDR2, and LC-CDR3 of the amino acid sequence of SEQ ID NO: 77. L In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises a V comprising the amino acid sequence of SEQ ID NO:76. H or variants thereof comprising at least about 90% sequence identity (e.g., 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: 76, and V comprising the amino acid sequence of SEQ ID NO: 77. Lor a variant thereof comprising at least about 90% sequence identity (e.g., 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: 77.

[0281]

[0291] In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises: i) an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 7, or a variant thereof comprising up to about five (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions; an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 8, or a variant thereof comprising up to about five (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions; and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 9, or a variant thereof comprising up to about five (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions. H and ii) a V comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 235, or a variant thereof comprising up to about five (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 238, or a variant thereof comprising up to about three (e.g., about any of 1, 2, or 3) amino acid substitutions, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 415, or a variant thereof comprising up to about five (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions. L In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises: i) a V CDR1 comprising the amino acid sequence of SEQ ID NO:7, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO:8, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO:9. H and ii) a V comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 235, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 238, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 415. L Includes.

[0282]

[0292] In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises a V comprising the amino acid sequence of SEQ ID NOs: 7, 8, and 9. H and V comprising the amino acid sequences of SEQ ID NOs: 235, 238, and 415. L In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises a V domain comprising HC-CDR1, HC-CDR2, and HC-CDR3 of the amino acid sequence of SEQ ID NO: 78. H and V comprising LC-CDR1, LC-CDR2, and LC-CDR3 of the amino acid sequence of SEQ ID NO: 79. L In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises a V comprising the amino acid sequence of SEQ ID NO:78. H or variants thereof comprising at least about 90% sequence identity (e.g., 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: 78, and V comprising the amino acid sequence of SEQ ID NO: 79. L or a variant thereof comprising at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 79 (e.g., at least about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%).

[0283]

[0293] In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises: i) an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 10, or a variant thereof comprising up to about 5 (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions; an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 11, or a variant thereof comprising up to about 5 (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions; and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 12, or a variant thereof comprising up to about 5 (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions. Hand ii) a V comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 13, or a variant thereof comprising up to about 5 (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an LC-CDR2 comprising the amino acid sequence of AAS, 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: 15, or a variant thereof comprising up to about 5 (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions. L In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises: i) a VHC-CDR1 comprising the amino acid sequence of SEQ ID NO: 10, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 11, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 12. H and ii) V comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 13, an LC-CDR2 comprising the amino acid sequence of AAS, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 15. L Includes.

[0284]

[0294] In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises a V comprising the amino acid sequence of SEQ ID NOs: 10, 11, and 12. H and V comprising AAS and the amino acid sequences of SEQ ID NOs: 13 and 15. L In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises a V domain comprising HC-CDR1, HC-CDR2, and HC-CDR3 of the amino acid sequence of SEQ ID NO: 80. H and V comprising LC-CDR1, LC-CDR2, and LC-CDR3 of the amino acid sequence of SEQ ID NO: 81. L In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises a V comprising the amino acid sequence of SEQ ID NO: 80. H or variants thereof comprising at least about 90% sequence identity (e.g., 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: 80, and V comprising the amino acid sequence of SEQ ID NO: 81. Lor a variant thereof comprising at least about 90% sequence identity (e.g., 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: 81.

[0285]

[0295] In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises: i) an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 16, or a variant thereof comprising up to about five (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions; an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 17, or a variant thereof comprising up to about five (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions; and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 18, or a variant thereof comprising up to about five (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions. H and ii) a V comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 19, or a variant thereof comprising up to about 5 (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an LC-CDR2 comprising the amino acid sequence of DAS, 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: 21, or a variant thereof comprising up to about 5 (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions. L In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises: i) a VHC-CDR1 comprising the amino acid sequence of SEQ ID NO: 16, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 17, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 18. H and ii) V comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 19, an LC-CDR2 comprising the amino acid sequence of DAS, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 21. L Includes.

[0286]

[0296] In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises a V comprising the amino acid sequence of SEQ ID NOs: 16, 17, and 18. H and V comprising DAS and the amino acid sequences of SEQ ID NOs: 19 and 21. L In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises a V domain comprising HC-CDR1, HC-CDR2, and HC-CDR3 of the amino acid sequence of SEQ ID NO: 82. H and V comprising LC-CDR1, LC-CDR2, and LC-CDR3 of the amino acid sequence of SEQ ID NO: 83. L In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises a V comprising the amino acid sequence of SEQ ID NO: 82. H or variants thereof comprising at least about 90% sequence identity (e.g., 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: 82, and V comprising the amino acid sequence of SEQ ID NO: 83. L or a variant thereof comprising at least about 90% sequence identity (e.g., 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: 83.

[0287]

[0297] In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises: i) an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 22, or a variant thereof comprising up to about five (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions; an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 23, or a variant thereof comprising up to about five (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions; and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 24, or a variant thereof comprising up to about five (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions. Hand ii) a V comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 25, or a variant thereof comprising up to about 5 (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an LC-CDR2 comprising the amino acid sequence of GAS, 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: 27, or a variant thereof comprising up to about 5 (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions. L In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises: i) a VHC-CDR1 comprising the amino acid sequence of SEQ ID NO: 22, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 23, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 24. H and ii) a V comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 25, an LC-CDR2 comprising the amino acid sequence of GAS, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 27. L Includes.

[0288]

[0298] In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises a V comprising the amino acid sequence of SEQ ID NOs: 22, 23, and 24. H and GAS and V comprising the amino acid sequences of SEQ ID NOs: 25 and 27. L In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises a V domain comprising HC-CDR1, HC-CDR2, and HC-CDR3 of the amino acid sequence of SEQ ID NO: 84. H and V comprising LC-CDR1, LC-CDR2, and LC-CDR3 of the amino acid sequence of SEQ ID NO: 85. L In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises a V comprising the amino acid sequence of SEQ ID NO: 84. H or variants thereof comprising at least about 90% sequence identity (e.g., 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: 84, and V comprising the amino acid sequence of SEQ ID NO: 85. Lor a variant thereof comprising at least about 90% sequence identity (e.g., 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: 85.

[0289]

[0299] In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises: i) a VHC-CDR1 comprising the amino acid sequence of SEQ ID NO: 28, or a variant thereof comprising up to about five (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions; HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 29, or a variant thereof comprising up to about five (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions; and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 30, or a variant thereof comprising up to about five (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions. H and ii) a V comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 31, or a variant thereof comprising up to about 5 (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an LC-CDR2 comprising the amino acid sequence of AAS, 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: 33, or a variant thereof comprising up to about 5 (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions. L In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises: i) a VHC-CDR1 comprising the amino acid sequence of SEQ ID NO: 28, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 29, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 30. H and ii) a V comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 31, an LC-CDR2 comprising the amino acid sequence of AAS, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 33. L Includes.

[0290]

[0300] In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises a V comprising the amino acid sequence of SEQ ID NOs: 28, 29, and 30. H and V comprising AAS and the amino acid sequences of SEQ ID NOs: 31 and 33. L In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises a V domain comprising HC-CDR1, HC-CDR2, and HC-CDR3 of the amino acid sequence of SEQ ID NO: 86. H and V comprising LC-CDR1, LC-CDR2, and LC-CDR3 of the amino acid sequence of SEQ ID NO: 87. L In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises a V comprising the amino acid sequence of SEQ ID NO: 86. H or variants thereof comprising at least about 90% sequence identity (e.g., 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: 86, and V comprising the amino acid sequence of SEQ ID NO: 87. L or a variant thereof comprising at least about 90% sequence identity (e.g., 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: 87.

[0291]

[0301] In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises: i) a VHC-CDR1 comprising the amino acid sequence of SEQ ID NO: 34, or a variant thereof comprising up to about five (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions; HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 35, or a variant thereof comprising up to about five (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions; and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 36, or a variant thereof comprising up to about five (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions. Hand ii) a V comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 37, or a variant thereof comprising up to about 5 (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an LC-CDR2 comprising the amino acid sequence of AAS, 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: 39, or a variant thereof comprising up to about 5 (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions. L In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises: i) a VHC-CDR1 comprising the amino acid sequence of SEQ ID NO: 34, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 35, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 36. H and ii) a V comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 37, an LC-CDR2 comprising the amino acid sequence of AAS, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 39. L Includes.

[0292]

[0302] In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises a V comprising the amino acid sequence of SEQ ID NOs: 34, 35, and 36. H and V comprising AAS and the amino acid sequences of SEQ ID NOs: 37 and 39. L In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises a V domain comprising HC-CDR1, HC-CDR2, and HC-CDR3 of the amino acid sequence of SEQ ID NO: 88. H and V comprising LC-CDR1, LC-CDR2, and LC-CDR3 of the amino acid sequence of SEQ ID NO: 89. L In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises a V comprising the amino acid sequence of SEQ ID NO: 88. H or variants thereof comprising at least about 90% sequence identity (e.g., 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: 88, and V comprising the amino acid sequence of SEQ ID NO: 89. Lor a variant thereof comprising at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 89 (e.g., at least about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%).

[0293]

[0303] In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises: i) an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 40, or a variant thereof comprising up to about 5 (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions; an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 41, or a variant thereof comprising up to about 5 (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions; and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 42, or a variant thereof comprising up to about 5 (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions. H and ii) a V comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 43, or a variant thereof comprising up to about 5 (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an LC-CDR2 comprising the amino acid sequence of AAS, 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: 45, or a variant thereof comprising up to about 5 (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions. L In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises: i) a VHC-CDR1 comprising the amino acid sequence of SEQ ID NO: 40, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 41, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 42. H and ii) V comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 43, an LC-CDR2 comprising the amino acid sequence of AAS, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 45. L Includes.

[0294]

[0304] In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises a V comprising the amino acid sequence of SEQ ID NOs: 40, 41, and 42. H and V comprising AAS and the amino acid sequences of SEQ ID NOs: 43 and 45. L In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises a V domain comprising HC-CDR1, HC-CDR2, and HC-CDR3 of the amino acid sequence of SEQ ID NO: 90. H and V comprising LC-CDR1, LC-CDR2, and LC-CDR3 of the amino acid sequence of SEQ ID NO: 91. L In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises a V comprising the amino acid sequence of SEQ ID NO: 90. H or variants thereof comprising at least about 90% sequence identity (e.g., 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: 90, and V comprising the amino acid sequence of SEQ ID NO: 91. L or a variant thereof comprising at least about 90% sequence identity (e.g., 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: 91.

[0295]

[0305] In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises: i) an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 46, or a variant thereof comprising up to about five (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions; an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 47, or a variant thereof comprising up to about five (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions; and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 48, or a variant thereof comprising up to about five (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions. Hand ii) a V comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 49, or a variant thereof comprising up to about 5 (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an LC-CDR2 comprising the amino acid sequence of AAS, 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: 51, or a variant thereof comprising up to about 5 (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions. L In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises: i) a VHC-CDR1 comprising the amino acid sequence of SEQ ID NO: 46, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 47, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 48. H and ii) a V comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 49, an LC-CDR2 comprising the amino acid sequence of AAS, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 51. L Includes.

[0296]

[0306] In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises a V comprising the amino acid sequence of SEQ ID NOs: 46, 47, and 48. H and V comprising AAS and the amino acid sequences of SEQ ID NOs: 49 and 51. L In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises a V domain comprising HC-CDR1, HC-CDR2, and HC-CDR3 of the amino acid sequence of SEQ ID NO: 92. H and V comprising LC-CDR1, LC-CDR2, and LC-CDR3 of the amino acid sequence of SEQ ID NO: 93. L In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises a V comprising the amino acid sequence of SEQ ID NO:92. H or variants thereof comprising at least about 90% sequence identity (e.g., 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: 92, and V comprising the amino acid sequence of SEQ ID NO: 93. Lor a variant thereof comprising at least about 90% sequence identity (e.g., 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: 93.

[0297]

[0307] In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises: i) an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 52, or a variant thereof comprising up to about five (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions; an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 53, or a variant thereof comprising up to about five (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions; and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 54, or a variant thereof comprising up to about five (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions. H and ii) a V comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 55, or a variant thereof comprising up to about 5 (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an LC-CDR2 comprising the amino acid sequence of GAT, 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: 57, or a variant thereof comprising up to about 5 (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions. L In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises: i) a VHC-CDR1 comprising the amino acid sequence of SEQ ID NO: 52, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 53, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 54. H and ii) a V comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 55, an LC-CDR2 comprising the amino acid sequence of GAT, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 57. L Includes.

[0298]

[0308] In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises a V comprising the amino acid sequence of SEQ ID NOs: 52, 53, and 54. H and GAT and V comprising the amino acid sequences of SEQ ID NOs: 55 and 57. L In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises a V domain comprising HC-CDR1, HC-CDR2, and HC-CDR3 of the amino acid sequence of SEQ ID NO:94. H and V comprising LC-CDR1, LC-CDR2, and LC-CDR3 of the amino acid sequence of SEQ ID NO: 95. L In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises a V comprising the amino acid sequence of SEQ ID NO:94. H or variants thereof comprising at least about 90% sequence identity (e.g., 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: 94, and V comprising the amino acid sequence of SEQ ID NO: 95. L or a variant thereof comprising at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 95 (e.g., at least about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%).

[0299]

[0309] In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises: i) an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 58, or a variant thereof comprising up to about five (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions; an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 59, or a variant thereof comprising up to about five (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions; and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 60, or a variant thereof comprising up to about five (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions. Hand ii) a V comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 61, or a variant thereof comprising up to about 5 (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an LC-CDR2 comprising the amino acid sequence of AAS, 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: 63, or a variant thereof comprising up to about 5 (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions. L In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises: i) a VHC-CDR1 comprising the amino acid sequence of SEQ ID NO: 58, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 59, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 60. H and ii) a V comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 61, an LC-CDR2 comprising the amino acid sequence of AAS, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 63. L Includes.

[0300]

[0310] In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises a V comprising the amino acid sequence of SEQ ID NOs: 58, 59, and 60. H and V comprising AAS and the amino acid sequences of SEQ ID NOs: 61 and 63. L In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises a V domain comprising HC-CDR1, HC-CDR2, and HC-CDR3 of the amino acid sequence of SEQ ID NO:96. H and V comprising LC-CDR1, LC-CDR2, and LC-CDR3 of the amino acid sequence of SEQ ID NO: 97. L In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises a V comprising the amino acid sequence of SEQ ID NO: 96. H or variants thereof comprising at least about 90% sequence identity (e.g., 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: 96, and V comprising the amino acid sequence of SEQ ID NO: 97. Lor a variant thereof comprising at least about 90% sequence identity (e.g., 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: 97.

[0301]

[0311] In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises: i) an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 64, or a variant thereof comprising up to about five (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions; an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 65, or a variant thereof comprising up to about five (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions; and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 66, or a variant thereof comprising up to about five (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions. H and ii) a V comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 67, or a variant thereof comprising up to about 5 (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 68, or a variant thereof comprising up to about 3 (e.g., about 1, 2, or 3) amino acid substitutions, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 69, or a variant thereof comprising up to about 5 (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions. L In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises: i) a VHC-CDR1 comprising the amino acid sequence of SEQ ID NO: 64, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 65, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 66. H and ii) a V comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 67, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 68, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 69. L Includes.

[0302]

[0312] In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises a V comprising the amino acid sequence of SEQ ID NOs: 64, 65, and 66. H and V comprising the amino acid sequences of SEQ ID NOs: 67, 68, and 69. L In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises a V domain comprising HC-CDR1, HC-CDR2, and HC-CDR3 of the amino acid sequence of SEQ ID NO:98. H and V comprising LC-CDR1, LC-CDR2, and LC-CDR3 of the amino acid sequence of SEQ ID NO: 99. L In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises a V comprising the amino acid sequence of SEQ ID NO:98. H or variants thereof comprising at least about 90% sequence identity (e.g., 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: 98, and V comprising the amino acid sequence of SEQ ID NO: 99. L or a variant thereof comprising at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 99 (e.g., at least about n% sequence identity, where n% is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%).

[0303]

[0313] In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises: i) a VHC-CDR1 comprising the amino acid sequence of SEQ ID NO: 70, or a variant thereof comprising up to about 5 (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions; HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 71, or a variant thereof comprising up to about 5 (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions; and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 72, or a variant thereof comprising up to about 5 (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions. Hand ii) a V comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 73, or a variant thereof comprising up to about 5 (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 74, or a variant thereof comprising up to about 3 (e.g., about any of 1, 2, or 3) amino acid substitutions, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 75, or a variant thereof comprising up to about 5 (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions. L In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises: i) a VHC-CDR1 comprising the amino acid sequence of SEQ ID NO: 70, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 71, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 72. H and ii) a V comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 73, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 74, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 75. L Includes.

[0304]

[0314] In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises a V comprising the amino acid sequence of SEQ ID NOs: 70, 71, and 72. H and V comprising the amino acid sequences of SEQ ID NOs: 73, 74, and 75. L In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises a V domain comprising HC-CDR1, HC-CDR2, and HC-CDR3 of the amino acid sequence of SEQ ID NO: 100. H and V comprising LC-CDR1, LC-CDR2, and LC-CDR3 of the amino acid sequence of SEQ ID NO: 101. L In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises a V comprising the amino acid sequence of SEQ ID NO: 100. H or variants thereof comprising at least about 90% sequence identity (e.g., 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: 100, and V comprising the amino acid sequence of SEQ ID NO: 101.L or a variant thereof comprising at least about 90% sequence identity (e.g., 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: 101.

[0305]

[0315] In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises a V domain comprising HC-CDR1, HC-CDR2, and HC-CDR3 of the amino acid sequence of SEQ ID NO: 102. H and V comprising LC-CDR1, LC-CDR2, and LC-CDR3 of the amino acid sequence of SEQ ID NO: 103. L In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises a V comprising the amino acid sequence of SEQ ID NO: 102. H or variants thereof comprising at least about 90% sequence identity (e.g., 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: 102, and V comprising the amino acid sequence of SEQ ID NO: 103. L or a variant thereof comprising at least about 90% sequence identity (e.g., 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: 103.

[0306]

[0316] In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises: i) an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 439, or a variant thereof comprising up to about five (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions; an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 440, or a variant thereof comprising up to about five (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions; and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 441, or a variant thereof comprising up to about five (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions.H and ii) a V comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 443, or a variant thereof comprising up to about 5 (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an LC-CDR2 comprising the amino acid sequence of SND, 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: 445, or a variant thereof comprising up to about 5 (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions. L In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises: i) a VHC-CDR1 comprising the amino acid sequence of SEQ ID NO: 439, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 440, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 441. H and ii) V comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 443, an LC-CDR2 comprising the amino acid sequence of SND, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 445. L Includes.

[0307]

[0317] In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises a V comprising the amino acid sequence of SEQ ID NOs: 439, 440, and 441. H and SND and V comprising the amino acid sequences of SEQ ID NOs: 443 and 445. L In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises a V domain comprising HC-CDR1, HC-CDR2, and HC-CDR3 of the amino acid sequence of SEQ ID NO: 438. H and V comprising LC-CDR1, LC-CDR2, and LC-CDR3 of the amino acid sequence of SEQ ID NO: 442. L In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises a V comprising the amino acid sequence of SEQ ID NO: 438. H or a variant thereof comprising at least about 90% sequence identity (e.g., 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: 438, and V comprising the amino acid sequence of SEQ ID NO: 442.L or a variant thereof comprising at least about 90% sequence identity (e.g., 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: 442.

[0308]

[0318] In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises: i) an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 488, or a variant thereof comprising up to about five (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions; an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 489, or a variant thereof comprising up to about five (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions; and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 490, or a variant thereof comprising up to about five (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions. H and ii) a V comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 492, or a variant thereof comprising up to about 5 (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 493, or a variant thereof comprising up to about 3 (e.g., about 1, 2, or 3) amino acid substitutions, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 493, or a variant thereof comprising up to about 5 (e.g., about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions. L In some embodiments, the anti-HA antibody or antigen-binding fragment thereof comprises: i) a VHC-CDR1 comprising the amino acid sequence of SEQ ID NO: 488, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 489, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 490. H and ii) a V comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 492, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 493, an...

Claims

[Claim 1] (a) an antibody moiety that specifically binds to components of the influenza virus or its variants; and (b) A mucosal-adhering peptide fragment containing at least about five positively charged amino acid residues, A chimeric protein containing, A chimeric protein in which the mucosal-adherent peptide fragment promotes the adhesion of the chimeric protein to the mucous membrane.

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