Broadly neutralizing antibodies against RSV and MPV paramyxoviruses

Abstract

The present disclosure provides antibodies and antigen-binding fragments that are capable of binding to RSV and / or MPV fusion glycoproteins and that are capable of neutralizing RSV and / or MPV infection. Also provided are polynucleotides encoding the antibodies, vectors comprising such polynucleotides, host cells capable of expressing these antibodies, related compositions, and methods of using the compositions disclosed herein, for example, to treat or prevent RSV and / or MPV infection.

Description

[0001] Reference to an electronic sequence listing

[0002] The contents of the electronic sequence listing (430WO_SeqListing.xml; size: 1030 kilobytes; and creation date: July 26, 2023) are incorporated herein by reference in their entirety. Background Art

[0003] Respiratory syncytial virus (RSV) and metapneumovirus (MPV) are common cold viruses belonging to the paramyxovirus family that share a common target population and represent a major health problem in neonates and immunocompromised patients.

[0004] RSV is the leading cause of acute respiratory illness in infants and adults worldwide. Between 0.5% and 3.2% of children with RSV infection require hospitalization (Thompson et al., JAMA: The Journal of the American Medical Association 289:179-186 (2003)), and 5% to 10% of children have prolonged severe infection, a factor believed to predispose to wheezing and asthma-like symptoms later in childhood. Immunity to RSV appears to be short-lived, so reinfection often occurs (Ogra, Pediatric Respiratory Reviews 5 Suppl A:S119-126 (2003)).

[0005] Human MPV was first isolated in 2001 and is now considered the second leading cause of acute respiratory illness in infants and adults. It is estimated that it infects more than 50% of two-year-old infants and almost all five-year-old children. MPV accounts for about 5% to 15% of respiratory diseases in hospitalized children (Alto, The Journal of the American Board of Family Practice / American Board of Family Practice 17:466-469 (2004); Williams et al., N Engl J Med 350:443-450 (2004)). MPV infection is a major burden on dangerous premature infants, premature chronic lung disease, congestive heart disease and immunodeficiency (Martino et al., Biology of Blood and Marrow Transplantation: Journal of the American Society for Blood and Marrow Transplantation 11:781-796 (2005)).

[0006] Co-infection with MPV and RSV may be common due to their prevalence and overlapping winter epidemics. Although it is unclear whether synergistic pathology can occur between the two viruses, exacerbations resulting in particularly severe respiratory illness have been observed in some children co-infected with MPV and RSV (Greensill, Emerging Infectious Diseases 9:372 (2003)).

[0007] RSV, belonging to the genus Pneumovirus within the subfamily Pneumovirinae, and MPV, belonging to the genus Metapneumovirus within the subfamily Pneumovirinae, share some similarities in their genetic structure, although MPV lacks the nonstructural genes NS1 and NS2 found in RSV. The RSV and MPV envelopes contain three virally encoded transmembrane surface glycoproteins: the major attachment glycoprotein G, the fusion glycoprotein F, and the small hydrophobic SH protein. Although the RSV and MPV envelopes contain functionally similar proteins, it is important to note that the RSV and MPV F proteins share only 33% amino acid sequence identity.

[0008] RSV and MPV F glycoprotein instructs virus penetration by the fusion between virion envelope and host cell plasma membrane.After infection, the F protein expressed on cell surface can mediate the fusion with neighboring cells to form syncytium (Collins et al., PNAS81:7683-7687 (1984)). In both cases, the N-terminal (called fusogenic peptide) of the F subunit produced and containing amino acid whose hydrophobic fragment is directly inserted into the target membrane to initiate fusion by proteolytic cleavage. After being combined with target cell and subsequently activated, a series of structural rearrangements are experienced by F protein before metastable fusion, causing fusogenic peptide to be inserted into the target cell membrane, subsequently forming a stable helical bundle, which is formed when virus and cell membrane are relative. These structural changes result in the formation of F protein after stable fusion.

[0009] Only one vaccine for RSV has been approved in the United States and is only available for older patients, and there is no vaccine available for MPV. As RSV cases become clear, even if more vaccines are developed, they will not be readily available for all age groups.

[0010] The evidence of the effect of serum antibodies in the protection for RSV virus has appeared from epidemiology and animal studies. In infants, the titer of the antibody transmitted by the mother is relevant to the resistance to serious diseases (Glezen et al., Journal of Pediatrics (The Journal of Pediatrics) 98:708-715 (1981)), and in adults, in the presence of high-level serum RSV neutralizing antibodies, the morbidity and severity of lower respiratory tract involvement are reduced (Mcintosh et al., Journal of Infectious Diseases (The Journal of Infectious Diseases) 138:24-32 (1978)). Monoclonal antibody palivizumab (palivizumab) (Synagis) is registered for the RSV infection of preventing premature newborns. However, palivizumab is not always effective in preventing RSV infection and is not effective therapeutically. In addition, resistant strains of the virus have emerged after prolonged lung replication of RSV in animals in the presence of palivizumab (Zhao and Sullender, Journal of Virology 79:3962-3968 (2005)). Another monoclonal antibody, nirsevimab (Astra Zeneca / Sanofi), was recently approved in Europe and is still in the process of being approved for RSV infection in infants and very young children, and clesrovimab (Merck) is in clinical studies. Long-term studies of this antibody are not available. There are currently no monoclonal antibodies for the treatment or prevention of MPV infection.

[0011] The lack of a good working animal model for the most severe forms of RSV infection is related to the fact that RSV and MPV are host-restricted pneumovirus pathogens. The development of new drugs for RSV and MPV infection therapy has been hampered by the lack of animal models that can recapitulate all the symptoms and severity of the human disease. In fact, RSV and MPV are not natural mouse pathogens and only induce limited, mild symptoms and rapidly terminated primary infections in response to large, non-physiological viral inocula. Pneumovirus of mice (PVM) is a natural rodent pneumovirus pathogen that belongs to the same family, subfamily and genus (Pneumovirus) as human and bovine RSV.

[0012] The PVM F protein shares only 40% amino acid identity with the huma RSV F protein, but has the same genetic organization, except for the M2-L overlap, which is present in RSV but not in PVM. Infection with the natural mouse pathogen PVM replicates many of the signs and symptoms of the most severe form of RSV, as seen in human infants. PVM infection is characterized by rapid viral replication, accompanied by a large inflammatory response leading to respiratory failure and death (Rosemberg and Domachowske, Immunology Letters 118: 6-12 (2008)). It is therefore believed that PVM infection in mice is the most relevant animal model for severe infection with human RSV and MPV. The lack of preventive treatment for MPV infection and widely available vaccines for RSV and MPV infection, as well as the ineffectiveness of palivizumab treatment and the lack of long-term data for nisavir and clesovir monoclonal antibodies, highlight the need for new preventive and therapeutic agents for these prominent human pathogens. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Figure 1 As described in Example 1, the results of a neutralization assay against RSV infection in HEp-2 cells are shown.

[0014] Figure 2 The results of a neutralization assay against MPV infection in HEp-2 cells are shown (IC50 reported in μg / ml) as described in Example 3. Antibody MPH12 was also tested as well as antibodies MPE33, MPE8, MPF5 and RSD5.

[0015] Figures 3A to 3U As described in Example 6, antibody binding to RSV-F, MPV-F D280 ("MPV-F" in the figure), and MPV-F N280 proteins (also referred to as "MPV-F D280N") is shown, as measured by surface plasmon resonance (SPR). Figures 3A to 3RThe sample ID at the top of each graph in the table (see also FIG3V ) is associated with the MPK antibody name (e.g., sample 9 is MPK9, sample 44 is MPK44); Figures 3S to 3U Data are shown for antibodies MPH12, MPE8, or RSD5, as indicated by the sample ID at the top of each graph.

[0016] Figures 4A to 4I As described in Example 6, individual SPR data plots are shown for each antibody pair tested in the competitive binding assay.

[0017] Figure 5A As described in Example 6, the results of a post-fusion RSV F protein binding assay using MPE8 are shown.

[0018] Figure 5B As described in Example 6, the results of a post-fusion RSV F protein binding assay using MPH12 are shown.

[0019] Figure 6A and Figure 6B As described in Example 7, neutralization of RSV A and RSV B strains, and MPV A and MPV B strains by MPE8 and MPH12 antibodies is shown (reported in ng / ml). Figure 6A Neutralization of RSV strains is shown. Figure 6B Neutralization of MPV A and MPV B strains is shown.

[0020] Figure 7 The binding of MPH12-v1, MPH12-v2, MPH12-v3, and MPH12-v4 to DS-Cav1 (reported in ng / ml) as measured by ELISA is shown as described in Example 8. MPH12 was tested as a reference.

[0021] Figure 8A and Figure 8B As described in Example 8, RSV A / A2 / 61 ( Figure 8A ) and MPV A1 / 6621( Figure 8B ), as measured by ELISA by antibodies MPH12v1, MPH12v2, MPH12v3, and MPH12v4 (reported in ng / ml). MPH12 without mutations ("MPH12-rIgG1") was tested as a reference.

[0022] Figure 9A and Figure 9B Shown are two rotated views of the MPH12 H-CDR3 model generated using homology modeling, as described in Example 9. The five homology models are shown in different shades of green, while the crystal structure of MPH12 is shown in grey.

[0023] 10A to 10D As described in Example 9, four rotated views of the Fab structure of MPH12 are shown. Figure 10C In FIG, a groove corresponding to the space occupied by H-CDR3 is shown between L-CDR1 and L-CDR3; H-CDR3 is shown occupying the groove.

[0024] Figure 11A and Figure 11B As described in Example 9, two rotated views of the MPH12H-CDR3 conformation at 100 K are shown ( Figure 11A ) and two rotation views of the MPH12H-CDR3 conformation at 293K (room temperature- Figure 11B ).

[0025] Figure 12A and Figure 12B As described in Example 9, the affinity of MPH12 to purified RSV-F ( Figure 12A ) and purified MPV-F D280 (labeled as "MPV-F" in the figure) ( Figure 12B ) combination.

[0026] Figure 13 As described in Example 10, the Fab structure of MPH12 obtained using the 2.5A room temperature X-ray structure with the broadest CDR definition (all CDR definitions combined) is shown.

[0027] Figure 14 As described in Example 11, the production titers of six variant antibodies (MPH12-v16, MPH12-v17, MPH12-v28, MPH12-v29, MPH12-v34, and MPH12-v35, as shown in Tables 2 and 20, with reference to Table 1 and the Sequence Listing) selected for further characterization are shown. MPH 12* (parent MPH12-wt) was included as a comparator.

[0028] Figures 15A to 15C As described in Example 11, MPH12 and MPH12 variant antibodies (MPH12-v16, MPH12-v17, MPH12-v28, MPH12-v29, MPH12-v34, and MPH12-v35) were shown to bind to RSV-F ( Figure 15A )、MPV-F D280 (marked as "MPV-F" in the figure) ( Figure 15B ) and MPV-F N280( Figure 15C ) as measured using bio-layer interferometry (BLI).

[0029] Figure 16A and Figure 16B As described in Example 11, six MPH12 variant antibodies were shown to be effective against RSV ( Figure 16A ) and MPV( Figure 16B ), as measured using a GFP-based in vitro neutralization assay.

[0030] Figure 17 The thermal stability of six MPH12 variant antibodies measured using the ProteinShift assay is shown, as described in Example 11. The MPH12 parent antibody and rituximab were included as comparators.

[0031] Figure 18 Six MPH12 variant antibodies were shown to lack polyreactivity when tested in the Eurimmune 293 slide assay, as described in Example 11. The MPH12 parent antibody ("WT") was included as a comparator.

[0032] 19A to 19C As described in Example 11, antibody activation of FcγRIIIa (F158 allele) and FcγRIIa (H131 allele) was shown. MPH12-v16 and MPH12-v34 were tested, as well as comparator antibodies MPE8-v3 (pl1), MPE8-v3 (pl2), palivizumab, and MEDI8897-YTE. Activation of Jurkat-FcγRIIIa (F158 allele) using RSV-F transfected Expi293 target cells was tested ( Figure 19A ), activation of Jurkat-FcγRIIIa (F158 allele) in Expi293 target cells transfected with MPV-F D280 ( Figure 19B ) and activation of Jurkat-FcγRIIa (H131 allele) in Expi293 target cells transfected with RSV-F ( Figure 19C ).

[0033] Figure 20 As described in Example 12, the results of competition / binning assays of MPK73, MPK65, MPK 44, MPK36, MPK15, and MPH12 with comparator antibodies MPE8, D25, and RSD5 (as shown in Tables 2, 3, and 4, with reference to Table 1 and the Sequence Listing) are shown.

[0034] Figure 21 As described in Example 13, the results of the RSV ADCC assay for MPK44 and MPK65-v2 (shown in Table 2, with reference to Table 1 and the Sequence Listing) are presented.

[0035] Figure 22As described in Example 13, the results of the MPV ADCC assay for MPK15 are shown (as shown in Table 2, with reference to Table 1 and the Sequence Listing).

[0036] Figure 23A As described in Example 13, the results of RSV ADCC assays for various monoclonal antibodies (mAbs) are shown.

[0037] Figure 23B As described in Example 13, the results of the MPV ADCC assay for various mAbs are shown.

[0038] Figure 24 As described in Example 14, the results of the RSV-based ADCP assay for MPK44 and MPK65-v2 are shown.

[0039] Figure 25 As described in Example 14, the results of the MPV-based ADCP assay for MPK15 and comparator antibodies MPE33 and MPF5 are shown.

[0040] 26A to 26D As described in Example 14, the results of i) RSV-based ADCP assays for various antibodies are shown ( Figure 26A and Figure 26B ), and ii) the results of the MPV-based ADCP assay ( Figure 26C and Figure 26D ).

[0041] Figure 27 As described in Example 15, the results of the RSV escape mutant assay for various mAbs are shown.

[0042] Figure 28 As described in Example 16, the results of the MPV escape mutant assay for various mAbs are shown.

[0043] Figure 29 As described in Example 17, the results of MPK190 and MPK77 and the comparator antibody Nesevirab on body weight loss in RSV-infected mice are shown.

[0044] Figure 30 As described in Example 17, the results of MPK190 and MPK77 and the comparator antibody nevacorumab on the survival of RSV-infected mice are shown.

[0045] Figure 31 As described in Example 17, the results of MPK51 and MPK190 and the comparator antibody nevacorumab on weight loss and survival of RSV-infected mice are shown.

[0046] Figure 32As described in Example 17, the results of low doses of MPK190 and the comparator antibody nevacorumab on weight loss and survival of RSV-infected mice are shown.

[0047] Figure 33 As described in Example 18, heat maps of variant antibody binding to RSV A and RSV B strains as assessed by fluorescence activated cell sorting (FACS) are shown.

[0048] Figure 34 As described in Example 19, a heat map of binding of variant antibodies to MPV strains as assessed by FACS is shown.

[0049] Figure 35 As described in Example 21, the results of incubation of MPK190 with RSV A-GFP added to HEp-2 and LLC-MK2 cells after 8 cycles of reinfection are shown.

[0050] Figure 36 As described in Example 21, the results of incubation of MPK104 with RSV A-GFP added to HEp-2 and LLC-MK2 cells after 8 cycles of reinfection are shown.

[0051] Figure 37 As described in Example 21, the results of incubation of MPK51 with RSV A-GFP added to HEp-2 and LLC-MK2 cells after 8 cycles of reinfection are shown.

[0052] Figure 38 As described in Example 21, the results of incubation of MPK77 with RSV A-GFP added to HEp-2 and LLC-MK2 cells after 8 cycles of reinfection are shown.

[0053] Figure 39 As described in Example 21, the results of incubation of palivizumab with RSV A-GFP added to HEp-2 and LLC-MK2 cells after 8 cycles of reinfection are shown.

[0054] Figure 40 As described in Example 21, the results of incubation of MPK190 with MPV A2-GFP added to HEp-2 and LLC-MK2 cells after 8 cycles of reinfection are shown.

[0055] Figure 41 As described in Example 21, the results of incubation of MPK104 with MPV A2-GFP added to HEp-2 and LLC-MK2 cells after 8 cycles of reinfection are shown.

[0056] Figure 42As described in Example 21, the results of incubation of MPK51 with MPV A2-GFP added to HEp-2 and LLC-MK2 cells after 8 cycles of reinfection are shown.

[0057] Figure 43 As described in Example 21, the results of incubation of MPK77 with MPV A2-GFP added to HEp-2 and LLC-MK2 cells after 8 cycles of reinfection are shown.

[0058] Figure 44 As described in Example 21, the results of incubation of MPE8 with MPV A2-GFP added to HEp-2 and LLC-MK2 cells after 8 cycles of reinfection are shown.

[0059] Figure 45 As described in Example 22, a plot of mAb concentration versus day for MPK190, MPK51, MPK104, and MPK77 in the in vivo PK study is shown.

[0060] Figure 46 As described in Example 17, IC50 graphs are shown for neutralization of mouse-adapted RSV clones by MPK190, MPK104, MPK51, MPK77, and MEDI8897 in RSV-infected mice.

[0061] Figure 47 As described in Example 17, the results of MPK104 and MPK51 and the comparator antibody nevacorumab on body weight loss in RSV-infected mice are shown.

[0062] Figure 48 As described in Example 17, the results of MPK104 and MPK51 and the comparator antibody nevacorumab on the survival of RSV-infected mice are shown.

[0063] Figure 49 The lack of polyreactivity of selected MPK variant antibodies when tested in the Euroimmun 1522-2010 slide assay was demonstrated as described in Example 23. An MPK wild-type antibody ("WT") was included as a comparator.

[0064] Figures 50A to 50C As described in Example 23, MPK104 variant antibodies (MPK104-v1.1, MPK104-v1.2, MPK104-v1.3, MPK104-v4.1, MPK104-v4.2, and MPK104-v4.3) were shown to bind to RSV-F ( Figure 50A )、MPV-F( Figure 50B ) and MPV-F D280N( Figure 50C) as measured using BLI.

[0065] Figures 51A to 51C As described in Example 23, MPK190 variant antibodies (MPK190-v1.1, MPK190-v1.3, MPK190-v3.1, MPK190-v3.3, MPK190-v4.1, and MPK190-v4.3) were shown to bind to RSV-F ( Figure 51A )、MPV-F( Figure 51B ) and MPV-F D280N( Figure 51C ) as measured using BLI.

[0066] Figures 52A to 52C As described in Example 23, MPK51 variant antibodies (MPK51-v1.1, MPK51-v3.1, and MPK51-v4.1) were shown to bind to RSV-F ( Figure 52A )、MPV-F( Figure 52B ) and MPV-F D280N( Figure 52C ) as measured using BLI.

[0067] Figures 53A to 53C As described in Example 23, MPK77 variant antibodies (MPK77-v3.1 and MPK-v1.1) were shown to bind to RSV-F ( Figure 53A )、MPV-F( Figure 53B ) and MPV-F D280N( Figure 53C ) as measured using BLI.

[0068] Figures 54A to 54C As described in Example 24, MPK190 variants were shown to be compatible with RSV-F ( Figure 54A )、MPV-F( Figure 54B ) and MPV-F D280N( Figure 54C ) as measured using BLI.

[0069] Figure 55 As described in Example 24, binding of MPK190 variants to MPV-FD280N following forced deamidation of MPK-190 was shown, as measured using BLI.

[0070] Figure 56 As described in Example 26, it was shown that selected MPK variant antibodies lacked polyreactivity when tested in the Euroimmun 1522-2010 slide assay.

[0071] Figures 57A to 57D As described in Example 28, the MPK antibody variants were shown to be cleaved from RSV F™ WT ( Figure 57A )、MPVF D280N( Figure 57B )、MPV F( Figure 57C ) binding (FACS) and mock binding ( Figure 57D ) results.

[0072] Figures 58A to 58C As described in Example 28, the results of a PK study of MPK190-v1.1 were shown, testing its activity against RSV F ( Figure 58A )、MPV F( Figure 58B ) and D280N F( Figure 58C ) combination.

[0073] Figure 59A and Figure 59B As described in Example 29, it was shown that compared with Nissavir, the anti-tumor effect of Nissavir on RSV A-infected Hep2 cells ( Figure 59A ) and MPV A 1-infected Hep2 cells ( Figure 57B ), MPK190-v1.3 (MPK190 variant with NG motif) activates FcγRIIa (ADCP) and FcRγIIIa (ADCC), and induces NK cell killing (ADCC) (NK-mediated cell killing is not shown in Figure 59B middle).

[0074] Figure 60A and Figure 60B As described in Example 30, it was shown that 2 mg / kg ( Figure 60A ) and 0.5mg / kg( Figure 60B )'s MPK190-v1.3, MEDI18897, MPE8-v3, and the comparator antibody palivizumab on body weight loss in RSV-infected mice.

[0075] Figure 61A and Figure 61B As described in Example 30, it was shown that 2 mg / kg ( Figure 61A ) and 0.5mg / kg( Figure 61B )'s MPK190-v1.3, MEDI18897, MPE8-v3, and the comparator antibody palivizumab on the survival of RSV-infected mice.

[0076] Figure 62A and Figure 62B As described in Examples 31 and 32, the results of neutralization screening of MPV / RSV antibodies against MPV strain A and MPV strain B, including MPK190-v1.3 (designated MPK 190 in the figures), are shown.

[0077] Figure 63 As described in Example 31, a heat map of RSV antibodies and their binding to a panel of F proteins of recently circulating RSV B strains is shown.

[0078] Figure 64A (IC50) and Figure 64B (IC90) As described in Examples 31 and 32, the results of neutralization screening of MPV / RSV antibodies, including MPK190-v1.3, and RSV-only antibodies, including MPK102 and MPK176, against various laboratory-adapted and circulating strains of RSV A and RSV B are shown.

[0079] Figure 65 As described in Example 32, the results of neutralization testing of MPK190-v1.3 and various comparator antibodies against representatives of all four MPV subtypes are shown.

[0080] Figure 66 As described in Example 32, the results of MPK190-v1.3 neutralization of a representative MPV B1 strain virus (NL / 1 / 99) are shown.

[0081] Figure 67 As described in Example 32, the results of ADCC assay using Hep-2 cells infected with RSV A2 strain (MOI 2.5, NK 10:1) and MPK190 are shown.

[0082] Figures 68A to 68E As described in Examples 31 and 32, the use of RSV-FA transfected Expi293 target cells ( Figure 68A ), RSV-FB transfected Expi293 target cells ( Figure 68B ), MPV-FA transfected Expi293 target cells ( Figure 68D ) or MPV-FB transfected Expi293 target cells ( Figure 68E ) FcγRIIIa (F158 allele), and antibody-dependent killing of RSV-A2-transfected Hep-2 cells ( Figure 68C . Figures 68A to 68C The legend is shown in Figure 68C In, Figures 68D to 68E The legend is shown in Figure 68E middle.

[0083] Figure 69A and Figure 69B As described in Example 30, the effects of different doses of MPK190-v1.3 and comparator antibodies on exposure to RSV A ( Figure 69A ) or RSV B( Figure 69B ) in cotton rats.

[0084] Figures 70A to 70F As described in Example 32, the comparison between MPK190 and selected RSV-only antibodies for neutralization of RSV A ( Figures 70A to 70C ) or RSV F( Figures 70D to 70F ) synergistic effect.

[0085] Figure 71A and Figure 71B As described in Example 30, it was shown that 2 mg / kg ( Figure 71A and Figure 71C ) and 0.5mg / kg( Figure 71B and Figure 71D Effects of MPK176, MPK201, and MPK65-v2 and comparator antibodies on body weight changes and survival of RSV-infected mice.

[0086] Figure 72 As described in Example 32, MPK190-v1.3 was shown to neutralize various MPV subtypes.

[0087] Figure 73A and Figure 73B As described in Example 30, the effects of different doses of MPK190-v1.3 and comparator antibodies on viral titers in cotton rats exposed to MPV are shown.

[0088] Figure 74 As described in Example 32, predicted RSV F binding of MPK190-v1.3 to RSV F was shown compared to the binding of comparator antibodies MPE8 and MPH12.

[0089] Figures 75A to 75E As described in Example 33, luminescence of FcγRIIIa (V158 allele) of Expi293 target cells transfected with RSV-FB was shown for various combinations of MPK190-v1.2 and RSV antibodies alone.

[0090] Figure 76 As described in Example 33, it is shown that Figures 75A to 75E The AUC results of the data.

[0091] Figure 77 As described in Example 33, single antibodies and RSV antibodies alone were shown to be Figures 75A to 75E Summary of RSV A2 neutralization data for MPK190-v1.3 combinations.

[0092] Figure 78 As described in Example 33, a summary of RSV A2 neutralization data for RSV antibodies alone in combination with MPK190-v1.3 is shown.

[0093] Figure 79A and Figure 79B Neutralization data for RSV A (upper panel) and MPV (lower panel) by RSV antibodies and Fab fragments of MPK190-v1.3 are shown as described in Examples 31 and 32. Figure 79A ) and summary diagram ( Figure 79B ).

[0094] Figure 80 As described in Examples 31 and 32, a summary of the effector functions of MPK190-v1.3 and RSV antibodies alone is presented. DETAILED DESCRIPTION

[0095] Provided herein are antibodies and antigen-binding fragments that can bind to and, in some embodiments, effectively neutralize the infection caused by RSV and / or MPV. Also provided are polynucleotides, vectors, host cells, and related compositions encoding antibodies and antigen-binding fragments, as well as methods for treating (e.g., reducing, delaying, eliminating, or preventing) RSV and / or MPV infections in subjects and / or manufacturing drugs for treating RSV and / or MPV infections in subjects using antibodies, nucleic acids, vectors, host cells, and related compositions.

[0096] In some embodiments, the antibodies or antigen-binding fragments thereof of the present disclosure are capable of treating infections caused by MPV with the D280N mutation, as well as other variants of MPV. The D280N mutation found in the B2 subtype of the virus has proven difficult to treat with other potential therapeutic agents.

[0097] In some embodiments, the antibodies or antigen-binding fragments thereof of the present disclosure can bind to and / or neutralize multiple RSV and / or MPV strains (sometimes also referred to as RSV and / or MPV types or subtypes), and treat and / or prevent infection caused by these strains.

[0098] In other embodiments, the antibodies or antigen-binding fragments thereof of the present disclosure can promote survival and reduce weight loss in RSV-infected patients at least as well as nevacor, an anti-RSV antibody with favorable clinical trial results.

[0099] In some embodiments, the antibodies or antigen-binding fragments thereof of the present disclosure can provide unique broad treatment and protection to patients without the need for complex diagnostics to determine whether the infection is RSV, MPV, or which MPV, because the antibodies or antigen-binding fragments can effectively bind to the F proteins of both RSV and MPV, even in the presence of the D280N mutation in MPV.

[0100] Before describing the present disclosure in more detail, it may be helpful to understand the present disclosure by providing definitions of certain terms used herein. Additional definitions are set forth throughout the present disclosure.

[0101] In this specification, any concentration range, percentage range, ratio range or integer range should be understood to include the value of any integer in the stated range, and its fraction (such as one tenth and one hundredth of an integer) when appropriate, unless otherwise specified. In addition, any quantitative range related to any physical characteristics such as polymer subunits, size or thickness stated herein should be understood to include any integer in the stated range, unless otherwise specified. As used herein, the term "about" means ± 20% of the indicated range, value or structure, unless otherwise specified. It should be understood that, as used herein, the term "one / a kind of" refers to "one or more / one or more" components in the listed components. The use of alternatives (e.g., "or") should be understood to mean one, two or any combination thereof in the alternatives. As used herein, the terms "include," "have," and "comprise" are used synonymously, and these terms and their variants are intended to be interpreted as non-restrictive.

[0102] “Optional” or “optionally” means that the subsequently described element, component, event or circumstance may or may not occur, and that the description includes instances where the element, component, event or circumstance occurs and instances where it does not.

[0103] In addition, it should be understood that this application discloses individual constructs or groups of constructs derived from various combinations of structures and subunits described herein to the same extent as if each construct or group of constructs were individually set forth. Therefore, the selection of a particular structure or a particular subunit is within the scope of this disclosure.

[0104] The term "consisting essentially of" is not equivalent to "comprising" and refers to specified materials or steps of a claim, or to materials or steps that do not materially affect the basic characteristics of the claimed subject matter. For example, a protein domain, region, module (e.g., a binding domain) or protein "consists essentially of" a particular amino acid sequence when the amino acid sequence of the domain, region, module or protein includes extensions, deletions, mutations, or combinations thereof (e.g., amino acids at the amino or carboxyl termini or between domains) that, in total, account for up to 20% (e.g., up to 15%, 10%, 8%, 6%, 5%, 4%, 3%, 2%, or 1%) of the length of the domain, region, module or protein and do not substantially affect (i.e., do not reduce the activity by more than 50%, such as by no more than 40%, 30%, 25%, 20%, 15%, 10%, 5%, or 1%) the activity of the domain, region, module or protein (e.g., the target binding affinity of the binding protein).

[0105] As used herein, "amino acid" refers to naturally occurring or synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, as well as those that are later modified, for example, hydroxyproline, γ-carboxyglutamate, and O-phosphoserine. Amino acid analogs refer to compounds that have the same basic chemical structure as naturally occurring amino acids (i.e., an α-carbon bound to a hydrogen, carboxyl, amino, and R group), for example, homoserine, norleucine, methionine sulfoxide, methionine methylsulfonium. Such analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as naturally occurring amino acids. Amino acid mimetics refer to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but function in a manner similar to naturally occurring amino acids.

[0106] As used herein, "mutation" refers to a change in the sequence of a nucleic acid molecule or polypeptide molecule compared to a reference or wild-type nucleic acid molecule or polypeptide molecule, respectively. A mutation can cause several different types of changes in the sequence, including substitutions, insertions, or deletions of nucleotides or amino acids.

[0107] "Conservative substitutions" refer to amino acid substitutions that do not significantly affect or change the binding properties of a particular protein. Generally speaking, conservative substitutions are substitutions in which the substituted amino acid residue is replaced with an amino acid residue with a similar side chain. Conservative substitutions include substitutions found in one of the following groups: Group 1: Alanine (Ala or A), Glycine (Gly or G), Serine (Ser or S), Threonine (Thr or T); Group 2: Aspartic acid (Asp or D), Glutamic acid (Glu or Z); Group 3: Asparagine (Asn or N), Glutamine (Gln or Q); Group 4: Arginine (Arg or R), Lysine (Lys or K), Histidine (His or H); Group 5: Isoleucine (Ile or I), Leucine (Leu or L), Methionine (Met or M), Valine (Val or V); and Group 6: Phenylalanine (Phe or F), Tyrosine (Tyr or Y), Tryptophan (Trp or W). Additionally or alternatively, amino acids can be grouped into conservative substitution groups based on similar function, chemical structure, or composition (e.g., acidic, basic, aliphatic, aromatic, or sulfur-containing). For example, for substitution purposes, an aliphatic grouping may include Gly, Ala, Val, Leu, and Ile. Other conservative substitution groups include: sulfur-containing: Met and cysteine ​​(Cys or C); acidic: Asp, Glu, Asn, and Gln; small aliphatic, nonpolar, or slightly polar residues: Ala, Ser, Thr, Pro, and Gly; polar, negatively charged residues and their amides: Asp, Asn, Glu, and Gln; polar, positively charged residues: His, Arg, and Lys; large aliphatic, nonpolar residues: Met, Leu, Ile, Val, and Cys; and large aromatic residues: Phe, Tyr, and Trp. Additional information can be found in Creighton (1984) Proteins, WH Freeman and Company.

[0108] As used herein, "protein" or "polypeptide" refers to a polymer of amino acid residues. Protein applies to naturally occurring amino acid polymers, as well as amino acid polymers in which one or more amino acid residues are artificial chemical mimetics of the corresponding naturally occurring amino acids, and non-naturally occurring amino acid polymers. Variants of the proteins, peptides, and polypeptides of the present disclosure are also contemplated. In certain embodiments, the variant proteins, peptides, and polypeptides comprise or consist of an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identical to an amino acid sequence as defined or referenced herein.

[0109] "Nucleic acid molecule" or "polynucleotide" or "polynucleic acid" refers to a polymer compound comprising covalently linked nucleotides, which may be composed of natural subunits (e.g., purine or pyrimidine bases) or non-natural subunits (e.g., morpholine rings). Purine bases include adenine, guanine, hypoxanthine, and xanthine, and pyrimidine bases include uracil, thymine, and cytosine. Nucleic acid molecules include: polyribonucleic acid (RNA), which includes mRNA, microRNA, siRNA, viral genomic RNA, and synthetic RNA; and polydeoxyribonucleic acid (DNA), which includes cDNA, genomic DNA, and synthetic DNA, any of which may be single-stranded or double-stranded. If single-stranded, the nucleic acid molecule may be a coding strand or a non-coding (antisense) strand. Nucleic acid molecules encoding an amino acid sequence include all nucleotide sequences encoding the same amino acid sequence. Some versions of the nucleotide sequence may also contain introns to the extent that the introns will be removed by co-transcriptional or post-transcriptional mechanisms. In other words, due to redundancy or degeneracy of the genetic code, or by splicing, different nucleotide sequences can encode the same amino acid sequence.

[0110] Variants of the nucleic acid molecules disclosed herein are also contemplated. Variant nucleic acid molecules are at least 70%, 75%, 80%, 85%, 90%, and preferably 95%, 96%, 97%, 98%, 99%, or 99.9% identical to a nucleic acid molecule defined as a reference polynucleotide as described herein, with percent sequence identity defined as set forth below. Variants of nucleic acid molecules retain the ability to encode a binding domain having a function as described herein, such as binding to a target molecule.

[0111] "Percentage of sequence identity" refers to the relationship between two or more sequences as determined by comparing sequences. The preferred method for determining sequence identity is designed to achieve the best match between the compared sequences. For example, for the best comparison purpose, the sequences are aligned (for example, a gap can be introduced in one or both of the first amino acid or nucleic acid sequence and the second amino acid or nucleic acid sequence for optimal comparison). In addition, for the purpose of comparison, non-homologous sequences can be ignored. Unless otherwise specified, the percentages of sequence identity mentioned herein are calculated over the length of the reference sequence. Methods for determining sequence identity and similarity can be found in publicly available computer programs. BLAST programs (for example, BLAST2.0, BLASTP, BLASTN or BLASTX) can be used for sequence alignment and identity percentage calculation. The mathematical algorithm used in the BLAST program can be found in Altschul et al., Nucleic Acids Res. 25: 3389-3402, 1997. In the context of the present disclosure, it should be understood that when using sequence analysis software for analysis, the results of the analysis are based on the "default values" of the cited program. "Default values" means any set of values ​​or parameters initially loaded when the software is first initialized. Other examples include Clustal W, MAFFT, Clustal Omega, AlignMe, Praline, GAP, BESTFIT, Needle (EMBOSS), Stretcher (EMBOSS), GGEARCH2SEQ, Water (EMBOSS), Matcher (EMBOSS), LALIGN, and SSEARCH2SEQ. Global alignment algorithms (such as the Needleman and Wunsch algorithms) can be used to align two sequences over their entire length, maximizing the number of matches and minimizing the number of gaps. Default values ​​can be used.

[0112] To generate a similarity score for two amino acid sequences, a scoring matrix can be used that assigns positive scores to some non-identical amino acids (e.g., conservative amino acid substitutions, amino acids with similar physicochemical properties, and / or amino acids that exhibit frequent substitutions in orthologs, homologs, or paralogs). Non-limiting examples of scoring matrices include PAM30, PAM70, PAM250, BLOSUM45, BLOSUM50, BLOUM62, BLOSUM80, and BLOSUM90.

[0113] The term "isolated" means that the material is removed from its original environment (e.g., the natural environment if the material occurs in nature). For example, a naturally occurring nucleic acid or polypeptide present in a living animal is not isolated, but the same nucleic acid or polypeptide separated from some or all coexisting materials in the natural system is isolated. Such a nucleic acid can be part of a vector, and / or such a nucleic acid or polypeptide can be part of a composition (e.g., a cell lysate) and still be isolated because such a vector or composition is not part of the natural environment of the nucleic acid or polypeptide.

[0114] The term "gene" means a segment of DNA or RNA involved in producing a polypeptide chain; in certain contexts, a gene includes regions preceding and following the coding region (e.g., 5' untranslated region (UTR) and 3' UTR) as well as intervening sequences (introns) between individual coding segments (exons).

[0115] A "functional variant" refers to a polypeptide or polynucleotide that is structurally similar or substantially structurally similar to a parent or reference compound of the present disclosure but slightly different in composition (e.g., one base, atom, or functional group is different, added, or removed), such that the polypeptide or encoded polypeptide performs one or more functions of the parent polypeptide with at least 50% efficiency, preferably at least 55%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.9% or 100% of the activity level of the parent polypeptide. In other words, when a functional variant of a polypeptide or encoded polypeptide of the present disclosure performs in a selected assay (such as an assay for measuring binding affinity (e.g., measuring association (Ka) or dissociation (K)) D ) constant A functional variant has “similar binding,” “similar affinity,” or “similar activity” when it exhibits no more than a 50% decrease in performance compared to the parent or reference polypeptide in a monoclonal antibody assay (e.g., immunoblotting, immunohistochemistry, or tetramer staining).

[0116] As used herein, "functional portion" or "functional fragment" refers to a polypeptide or polynucleotide that contains only a domain, part or fragment of a parent or reference compound, and the polypeptide or encoded polypeptide retains at least 50% of the activity associated with the domain, part or fragment of the parent or reference compound, preferably at least 55%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.9% or 100% of the activity level of the parent polypeptide, or provides a biological benefit (e.g., effector function). When a "functional portion" or "functional fragment" of a polypeptide or encoded polypeptide of the present invention shows no more than 50% reduction in performance (preferably no more than 20% or 10%, or no more than a logarithmic difference in affinity compared to the parent or reference) in a selected assay, the functional portion or fragment has "similar binding" or "similar activity".

[0117] As used herein, the terms "engineered," "recombinant," or "non-natural" refer to organisms, microorganisms, cells, nucleic acid molecules, or vectors that contain one or more genetic alterations or have been modified by the introduction of exogenous or heterologous nucleic acid molecules, wherein such alterations or modifications are introduced by genetic engineering (i.e., human intervention). Genetic alterations include, for example, modifications that introduce expressible nucleic acid molecules encoding functional RNA, proteins, fusion proteins, or enzymes, or other functional disruptions of the genetic material of cells by additions, deletions, substitutions, or other nucleic acid molecules. Additional modifications include, for example, non-coding regulatory regions where modifications alter the expression of polynucleotides, genes, or operons.

[0118] As used herein, "heterologous" or "non-endogenous" or "exogenous" refers to any gene, protein, compound, nucleic acid molecule, or activity that is not native to the host cell or subject, or any gene, protein, compound, nucleic acid molecule, or activity that is native to the host cell or subject but has been altered. Heterologous, non-endogenous, or exogenous includes genes, proteins, compounds, or nucleic acid molecules that have been mutated or otherwise altered such that the structure, activity, or both differ between the native and altered genes, proteins, compounds, or nucleic acid molecules. In certain embodiments, heterologous, non-endogenous, or exogenous genes, proteins, or nucleic acid molecules (e.g., receptors, ligands, etc.) may not be endogenous to the host cell or subject, and nucleic acids encoding such genes, proteins, or nucleic acid molecules may have been added to the host cell by conjugation, transformation, transfection, electroporation, or the like, where the added nucleic acid molecules may be integrated into the host cell genome or may be present as extrachromosomal genetic material (e.g., as a plasmid or other self-replicating vector). The term "homolog" or "homolog" refers to a gene, protein, compound, nucleic acid molecule, or activity found in or derived from a host cell, species, or strain. For example, a heterologous or exogenous polynucleotide or gene encoding a polypeptide can be homologous to a native polynucleotide or gene and encode a homologous polypeptide or activity, but the polynucleotide or polypeptide can have an altered structure, sequence, expression level, or any combination thereof. The non-endogenous polynucleotide or gene and the encoded polypeptide or activity can be from the same species, a different species, or a combination thereof.

[0119] In certain embodiments, a nucleic acid molecule native to the host cell is considered heterologous to the host cell if it has been altered or mutated, or a nucleic acid molecule native to the host cell is considered heterologous if it has been altered with a heterologous expression control sequence or has been altered with an endogenous expression control sequence not normally associated with the nucleic acid molecule native to the host cell. Additionally, the term "heterologous" can refer to a biological activity that is different, altered, or not endogenous to the host cell. As described herein, more than one heterologous nucleic acid molecule can be introduced into the host cell as separate nucleic acid molecules, as multiple individually controlled genes, as polycistronic nucleic acid molecules, as a single nucleic acid molecule encoding a fusion protein, or any combination thereof.

[0120] As used herein, the term "endogenous" or "native" refers to a polynucleotide, gene, protein, compound, molecule or activity that is normally present in a host cell or subject.

[0121] As used herein, the term "expression" refers to the process by which a polypeptide is produced based on the coding sequence of a nucleic acid molecule (such as a gene). The process may include transcription, post-transcriptional control, post-transcriptional modification, translation, post-translational control, post-translational modification, or any combination thereof. The expressed nucleic acid molecule is typically operably linked to an expression control sequence (e.g., a promoter).

[0122] The term "operably linked" refers to the association of two or more nucleic acid molecules on a single nucleic acid fragment so that the function of one is affected by the other. For example, a promoter is operably linked to a coding sequence when it affects the expression of the coding sequence (i.e., the coding sequence is under the transcriptional control of the promoter). "Not linked" means that the related genetic elements are not closely associated with each other and the function of one does not affect the other.

[0123] As described herein, more than one heterologous nucleic acid molecule can be introduced into a host cell as a single nucleic acid molecule, as multiple individually controlled genes, as a polycistronic nucleic acid molecule, as a single nucleic acid molecule encoding a protein (e.g., a heavy chain of an antibody), or any combination thereof. When two or more heterologous nucleic acid molecules are introduced into a host cell, it should be understood that the two or more heterologous nucleic acid molecules can be introduced as a single nucleic acid molecule (e.g., on a single vector), introduced on separate vectors, integrated into the host chromosome at a single site or multiple sites, or any combination thereof. The number of heterologous nucleic acid molecules or protein activities cited refers to the number of encoding nucleic acid molecules or protein activities, not the number of individual nucleic acid molecules introduced into the host cell.

[0124] The term "construct" refers to any polynucleotide comprising a recombinant nucleic acid molecule (or, when the context clearly indicates, a fusion protein of the present disclosure). The (polynucleotide) construct may be present in a vector (e.g., a bacterial vector, a viral vector) or may be integrated into a genome. A "vector" is a nucleic acid molecule that transports another nucleic acid molecule. A vector may be, for example, a plasmid, a cosmid, a virus, an RNA vector, or a linear or circular DNA or RNA molecule that may include a chromosomal, non-chromosomal, semisynthetic or synthetic nucleic acid molecule. The vectors of the present disclosure also include transposon systems (e.g., Sleeping Beauty, see, for example, Geurts et al., Mol. Ther. 8: 108, 2003; Mátés et al., Nat. Genet. 41: 753, 2009). Exemplary vectors are autonomously replicating vectors (episomal vectors), vectors that deliver polynucleotides to the cell genome (e.g., viral vectors), or vectors that express the nucleic acid molecule to which they are attached (expression vectors).

[0125] As used herein, "expression vector" or "vector" refers to a DNA construct comprising a nucleic acid molecule that is operably linked to a suitable control sequence for expressing the nucleic acid molecule in a suitable host. Such control sequences include a promoter for transcription, an optional operator sequence for controlling such transcription, a sequence encoding a suitable mRNA ribosome binding site, and a sequence for controlling the termination of transcription and translation. The vector can be a plasmid, a phage particle, a virus, or simply a potential genome insert. Once transformed into a suitable host, the vector can replicate and function independently of the host genome, or in some cases, can be integrated into the genome itself or the polynucleotide contained in the vector can be delivered to the genome in the absence of a vector sequence. In this manual, "plasmid," "expression plasmid," "virus," and "vector" are generally used interchangeably.

[0126] The term "introduced," in the context of inserting a nucleic acid molecule into a cell, means "transfection," "transformation," or "transduction" and includes reference to the incorporation of a nucleic acid molecule into a eukaryotic or prokaryotic cell, where the nucleic acid molecule may be incorporated into the genome of the cell (e.g., chromosome, plasmid, plastid, or mitochondrial DNA), converted into an autonomous replicon, or transiently expressed (e.g., transfected mRNA).

[0127] In certain embodiments, the polynucleotides of the present disclosure are operably linked to certain elements of the vector. For example, the polynucleotide sequences required to achieve expression and processing of the coding sequence to which the polynucleotide sequence is linked are operably linked. Expression control sequences may include appropriate transcription initiation, termination, promoter, and enhancer sequences; efficient RNA processing signals, such as splicing and polyadenylation signals; sequences that stabilize cytoplasmic mRNA; sequences that enhance translation efficiency (i.e., Kozak consensus sequences); sequences that enhance protein stability; and sequences that may enhance protein secretion. An expression control sequence is operably linked if it is adjacent to a gene of interest and an expression control sequence that acts in trans or at a distance to control the gene of interest.

[0128] In certain embodiments, the vector comprises a plasmid vector or a viral vector (e.g., a lentiviral vector or a gamma-retroviral vector). Viral vectors include retroviruses; adenoviruses; parvoviruses (e.g., adeno-associated viruses); coronaviruses; negative-strand RNA viruses such as orthomyxoviruses (e.g., influenza viruses), rhabdoviruses (e.g., rabies and vesicular stomatitis viruses), paramyxoviruses (e.g., measles and Sendai viruses); positive-strand RNA viruses such as picornaviruses and alphaviruses; and double-stranded DNA viruses including adenoviruses, herpes viruses (e.g., herpes simplex virus type 1 and type 2, Epstein-Barr virus, cytomegalovirus), and pox viruses (e.g., cowpox, fowlpox, and canarypox). Other viruses include, for example, Norwalk virus, togavirus, flavivirus, reovirus, papovavirus, hepadnavirus, and hepatitis virus. Examples of retroviruses include avian leukosis-sarcoma, mammalian C virus, B virus, D virus, HTLV-BLV groups, lentivirus, foamy virus (Coffin, JM, Retroviridae: The viruses and their replication, in Fundamental Virology, 3rd edition, BN Fields et al., eds., Lippincott-Raven Publishers, Philadelphia, 1996).

[0129] A "retrovirus" is a virus with an RNA genome that is reverse-transcribed into DNA using the enzyme reverse transcriptase, which is then incorporated into the host cell genome. A "gammaretrovirus" refers to a genus of the family Retroviridae. Examples of gammaretroviruses include mouse stem cell virus, murine leukemia virus, feline leukemia virus, feline sarcoma virus, and avian reticuloendotheliosis virus.

[0130] "Lentiviral vectors" include HIV-based lentiviral vectors for gene delivery, which can be integrated or non-integrated, have a relatively large packaging capacity, and can transduce a range of different cell types. Lentiviral vectors are typically generated after transient transfection of three (packaging, envelope, and transfer) or more plasmids into production cells. Similar to HIV, lentiviral vectors enter target cells through the interaction of viral surface glycoproteins with receptors on the cell surface. Upon entry, viral RNA undergoes reverse transcription, which is mediated by the viral reverse transcriptase complex. The product of reverse transcription is double-stranded linear viral DNA, which is a substrate for viral integration into infected cell DNA.

[0131] In certain embodiments, the viral vector can be a gammaretrovirus, e.g., a Moloney murine leukemia virus (MLV)-derived vector. In other embodiments, the viral vector can be a more complex retrovirus-derived vector, e.g., a lentivirus-derived vector. HIV-1-derived vectors fall into this category. Other examples include lentiviral vectors derived from HIV-2, FIV, equine infectious anemia virus, SIV, and Maedi-Visna virus (ovine lentivirus). Methods for using retroviral and lentiviral vectors and packaging cells to transduce mammalian host cells with viral particles containing a transgene are known in the art and have been previously described, for example, in U.S. Patent No. 8,119,772; Walchli et al., PLoS One 6:327930, 2011; Zhao et al., J. Immunol. 174:4415, 2005; Engels et al., Hum. Gene Ther. 14:1155, 2003; Frecha et al., Mol. Ther. 18:1748, 2010; and Verhoeyen et al., Methods Mol. Biol. 506:97, 2009. Retroviral and lentiviral vector constructs and expression systems are also commercially available. Other viral vectors can also be used for polynucleotide delivery, including DNA viral vectors, including, for example, adenovirus-based vectors and adeno-associated virus (AAV)-based vectors; vectors derived from herpes simplex virus (HSV), including amplicon vectors, replication-defective HSV, and attenuated HSV (Krisky et al., Gene Ther. 5:1517, 1998).

[0132] Other vectors that can be used with the compositions and methods of the present disclosure include vectors derived from baculovirus and alphavirus (Jolly, DJ. 1999. Emerging Viral Vectors. pp. 209-40, in Friedmann T. ed., The Development of Human Gene Therapy. New York: Cold Spring Harbor Lab), or plasmid vectors (such as Sleeping Beauty or other transposon vectors).

[0133] When the viral vector genome comprises multiple polynucleotides to be expressed as separate transcripts in a host cell, the viral vector may further comprise additional sequences between the two (or more) transcripts, thereby allowing bicistronic or polycistronic expression. Examples of such sequences for viral vectors include an internal ribosome entry site (IRES), a furin cleavage site, a viral 2A peptide, or any combination thereof.

[0134] Further described herein are plasmid vectors, including DNA-based antibody- or antigen-binding fragment-encoding plasmid vectors for direct administration to a subject.

[0135] As used herein, the term "host" refers to a target cell or microorganism that is genetically modified with a heterologous nucleic acid molecule to produce a polypeptide of interest (eg, an antibody of the present disclosure).

[0136] The host cell may include any single cell or cell culture that can accept a vector or incorporate nucleic acid or express protein. The term also encompasses offspring of the host cell, whether identical or different in heredity or phenotype. Suitable host cells may depend on the vector and may include mammalian cells, animal cells, human cells, monkey cells, insect cells, yeast cells, and bacterial cells. These cells may be induced to incorporate vectors or other materials by using viral vectors, conversion via calcium phosphate precipitation, DEAE-dextran, electroporation, microinjection, or other methods. See, for example, Sambrook et al., Molecular Cloning: A Laboratory Manual, 2nd edition (Cold Spring Harbor Laboratory, 1989).

[0137] In the context of RSV or MPV infection, "host" refers to a cell or subject infected with RSV and / or MPV.

[0138] As used herein, "antigen" or "Ag" refers to an immunogenic molecule that causes an immune response. This immune response may involve antibody production, activation of specific immunocompetent cells, activation of complement, antibody-dependent cellular toxicity, or any combination thereof. Antigens (immunogenic molecules) can be, for example, peptides, glycopeptides, polypeptides, glycopolypeptides, polynucleotides, polysaccharides, lipids, and the like. It is apparent that antigens can be synthesized, recombinantly produced, or derived from biological samples. Exemplary biological samples that may contain one or more antigens include tissue samples, fecal samples, cells, biological fluids, or a combination thereof. Antigens can be produced by cells that have been modified or genetically engineered to express antigens. Antigens may also be present in RSV and / or MPV fusion glycoprotein antigens, such as being present in virions, or expressed or presented on the surface of cells infected by RSV and / or MPV.

[0139] The term "epitope" or "antigenic epitope" includes any molecule, structure, amino acid sequence, or protein determinant that is recognized and specifically bound by a cognate binding molecule (such as an immunoglobulin) or other binding molecule, domain, or protein. Epitope determinants typically comprise chemically active surface groupings of molecules such as amino acids or sugar side chains, and may have specific three-dimensional structural characteristics as well as specific charge characteristics. Where the antigen is or comprises a peptide or protein, the epitope may be composed of contiguous amino acids (e.g., a linear epitope), or may be composed of amino acids from different parts or regions of a protein that are brought close together by protein folding (e.g., a discontinuous or conformational epitope), or may be composed of non-contiguous amino acids that are in close proximity regardless of protein folding.

[0140] Antibodies, antigen-binding fragments and compositions

[0141] In one aspect, the present disclosure provides isolated antibodies or antigen-binding fragments that bind to and / or neutralize the fusion glycoprotein of RSV and / or MPV from a human subject. When referring to an antibody or antigen-binding fragment of the present disclosure, "binding" to RSV or MPV means binding to the fusion glycoprotein of such virus. In addition, any antibody or antigen-binding fragment of the present disclosure that "binds" to RSV or MPV (or any otherwise specified antigen, epitope, or binding site thereof) is also "capable of binding to" or "capable of binding to" such RSV or MPV.

[0142] In certain embodiments, the antibodies or antigen-binding fragments of the present disclosure associate or associate with the fusion glycoprotein of RSV or MPV, or the fusion glycoproteins of both RSV and MPV, without significantly associating or associating with any other molecule or component in the sample.

[0143] In certain embodiments, antibodies or antigen-binding fragments of the present disclosure specifically bind to RSV fusion glycoprotein (also referred to herein as "RSV-F") and / or MPV fusion glycoprotein (also referred to herein as "MPV-F"). In certain embodiments, antibodies or antigen-binding fragments bind to RSV-F in a pre-fusion conformation, and in some embodiments, also bind to RSV-F in a post-fusion conformation. Unless otherwise indicated herein, binding to RSV-F refers to binding to the pre-fusion conformation. In some embodiments, MPV-F is a wild-type protein or a wild-type protein at D280 but containing other mutations (also referred to herein as "MPV-F D280"). However, in other embodiments, MPV-F contains a D280N mutation (also referred to herein as "MPV-F N280" or "D280N"). In some embodiments, MPV-F is an otherwise wild-type protein with a mutation at D280 other than N (for purposes of this disclosure, if it behaves more like MPV-F without the mutation at D280, it can be considered MPV-F D280, or if it behaves more like MPV-F with the D280N mutation, it can be considered MPV-F D280N).

[0144] In some embodiments, the RSV / MPV cross-binding and / or neutralizing antibodies or antigen-binding fragments of the present disclosure specifically bind to: i) both RSV-F and MPV-F D280, ii) both RSV-F and MPV-F N280, iii) and / or iii) RSV-F, MPV-F D280, or MPV-F N280. In some embodiments, the RSV binding and / or neutralizing antibodies or antigen-binding fragments of the present disclosure specifically bind to RSV-F. In some embodiments, the MPV binding and / or neutralizing antibodies or antigen-binding fragments of the present disclosure specifically bind to: i) MPV-F N280, ii) MPV-F D280, or iii) both MPV-F N280 and MPV-F D280.

[0145] As used herein, "specific binding" refers to the association or binding of an antibody or antigen-binding fragment to an antigen where the affinity or K a (i.e., the equilibrium association constant for a specific binding interaction, expressed in 1 / M) equal to or greater than 10 5 M -1 (It is equal to the association rate of the association reaction [K on ] and dissociation rate [K off ] ratio) without significantly associating or uniting with any other molecule or component in the sample. Alternatively, affinity can be defined as the equilibrium dissociation constant (K) for a specific binding interaction. d ), the unit is M (for example, 10-5 M to 10 -13 M). Antibodies can be classified as "high affinity" antibodies or "low affinity" antibodies. "High affinity" antibodies are those that a For at least 10 9 M -1 , at least 10 10 M -1 , at least 10 11 M -1 , at least 10 12 M -1 or at least 10 13 M -1 "Low affinity" antibodies are those with K a Up to 10 8 M -1 , up to 10 7 M -1 , up to 10 6 M -1 , up to 10 5 M -1 Alternatively, affinity can be defined as the equilibrium dissociation constant (K d ), the unit is M (for example, 10 -5 M to 10 - 13 M).

[0146] A variety of assays are known for identifying antibodies of the disclosure that bind to a particular target, and for determining binding domain or binding protein affinity, such as Western blot, ELISA (e.g., direct, indirect, or sandwich), analytical ultracentrifugation, spectroscopy, and surface plasmon resonance. Assays for assessing affinity or apparent affinity or relative affinity are also known.

[0147] In certain examples, RSV-F and / or MPV-F antigens can be expressed recombinantly in host cells (e.g., by transfection) and immunostained (e.g., fixed or fixed and permeabilized) host cells with antibodies and analyzed by flow cytometry (e.g., using a ZE5 cell analyzer). Binding is determined by analyzing the binding using FlowJo software (TreeStar). In some embodiments, positive binding can be defined by differential antibody staining of cells expressing RSV-F and / or MPV-F and control (e.g., mock) cells.

[0148] In some embodiments, the antibodies or antigen-binding fragments of the disclosure bind to RSV-F and / or MPV-F as measured using bio-layer interferometry or by surface plasmon resonance.

[0149] In some embodiments, surface plasmon resonance can be used to assess competitive binding of an antibody or antigen-binding fragment of the disclosure against another antibody or antigen-binding fragment.

[0150] IC50 or EC50 values ​​can be used to describe certain properties of the currently disclosed antibodies or antigen-binding fragments. In certain embodiments, IC50 is the concentration of a composition (e.g., an antibody) that causes half-maximal inhibition of an indicated biological or biochemical function, activity, or response. In certain embodiments, EC50 is the concentration of a composition that provides half-maximal response in an assay. In some embodiments, for example, to describe the ability of a currently disclosed antibody or antigen-binding fragment to neutralize infection caused by RSV and / or MPV, IC50 and EC50 are used interchangeably.

[0151] In certain embodiments, the antibodies or antigen-binding fragments of the present disclosure neutralize infections caused by RSV and / or MPV. As used herein, a "neutralizing antibody" is an antibody that "neutralizes," i.e., prevents, inhibits, reduces, hinders, or interferes with the ability of a pathogen to cause and / or perpetuate an infection in a host. The terms "neutralizing antibody" or "neutralizing antibody" are used interchangeably herein. In any of the embodiments currently disclosed, the neutralizing antibody or antigen-binding fragment prevents and / or neutralizes RSV and / or MPV infection in an in vitro infection model, an in vivo infection animal model, and / or a human. A "neutralizing antibody" is also "capable of" or "capable of" performing any activity attributed to the neutralizing antibody in this paragraph, and a "neutralizing" antibody or antigen-binding fragment thereof is also "capable of neutralizing" or "capable of neutralizing."

[0152] In certain embodiments, the antibody or antigen-binding fragment is a RSV-binding and / or neutralizing antibody or antigen-binding fragment as shown in Table 2, with reference to the sequence definitions in Table 1 and the Sequence Listing.

[0153] In certain embodiments, the antibody or antigen-binding fragment is an MPV-binding and / or neutralizing antibody or antigen-binding fragment as shown in Table 2, with reference to the sequence definitions in Table 1 and the Sequence Listing.

[0154] In certain embodiments, the antibody or antigen-binding fragment is an RSV / MPV cross-binding and / or neutralizing antibody or antigen-binding fragment as shown in Table 2, with reference to the sequence definitions in Table 1, Table 20 and the Sequence Listing.

[0155] A similar naming convention is used for antibodies herein according to the following principles, which applies to antibody and variant nomenclature.

[0156] As used herein, "MPH12" (e.g., MPH12-v2), not further identified as a variant, refers to an antibody having MPH12 VH and MPH-12VL as shown in Tables 1 and 2 and the Sequence Listing, or a CRD associated with MPH12 VH and MPH-12VL as shown in Tables 1 and 2 and the Sequence Listing, and an rIgG1 constant region. "MPH-v[#]" refers to variants of MPH12 as shown in Tables 2 and 20, which are collectively referred to as MPH12 "variants" with reference to Table 1 and the Sequence Listing. The first or only number in the variant refers to the VH variant, while the two-digit "xy" variant refers to the VH.VL variant. Typically, unless otherwise indicated in the sequence herein, VH.1 refers to the parent VH and VL.1 refers to the parent VL.

[0157] As used herein, MPK[#] refers to antibodies whose names begin with "MPK" in Table 2, with reference to Table 1 and the Sequence Listing. These antibodies may be collectively referred to as "MPK antibodies."

[0158] As used herein, other MP[letter][#] combinations are each referred to in a manner similar to the MPK antibodies, whose names begin with "MP[letter][#]" in Table 2, with reference to Table 1 and the Sequence Listing. Antibodies with the same MP[letter][#] combination may be collectively referred to as specific "MP[letter][#] antibodies."

[0159] "MP[letter][#]-v[#].[#]" refers to variants of MP[letter][#] as shown in Table 2 and Table 20, which are collectively referred to as MP[letter][#] "variants" with reference to Table 1 and the Sequence Listing. The first number in the variant refers to the VH variant, while the second number refers to the VL variant. For example, MPK190-v1.3 refers to an MPK190 antibody with VH.1 and VL.3 variants of the parent MPK190. MPK176-v1.3 refers to an antibody with VH.1 and VL.3 variants of the parent MPK176. MPK176-v4.3 refers to an antibody with VH.4 and VL.3 variants of the parent MPK176. MPK201-v1.2 refers to an antibody with VH.1 and VL.2 variants of the parent MPK201. MPK201-v4.1 refers to an antibody with VH.4 and VL.2 variants of the parent MPK201.

[0160] Certain antibodies are designated as variants of a parent antibody without reference to the specific VH and VL variants. These antibodies are designated MP[letter][#]-v[#], where v[#] is a single digit, and can be considered the parent antibody and can be referred to without the "v[#]" designation. MPK65-v2 is an example of such an antibody. The VH and VL variants of this type of antibody are designated the same as other MP[letter][#] antibodies. For example, MPK65-v2-v1.2 refers to an antibody with the VH.1 and VL.2 variants of the parent MPK65-v2. MPK65-v2-v3.1 refers to an antibody with the VH.3 and VL.1 variants of the parent MPK65-v2. MPK65-v2 is sometimes referred to simply as "MPK65."

[0161] Certain comparator antibodies or antibodies that can be used in various combinations with MPH, MPK, MPM, MPO, MPP, MPR or other MP[letter][#] antibodies (including HMB[#]) and RSD5 are described in Tables 3 and 4, with reference to Table 1 and the sequence listing. MPE33 and MPE8 are described in Corti et al. Nature. 2013 Sep 19;501(7467):439-43. doi:10.1038 / nature12442. Epub 2013 Aug 18. MPF5 and RSD5 are described in Jones et al. PLoS Patho. 15(7):e1007944(2019); doi:10.1371 / journal.ppat.1007944. Antibodies with the same VH and VL as these reference antibodies but with variations in the Fc region can also be used in place of them, as similar binding properties are expected.

[0162] In certain embodiments, the antibodies or antigen-binding fragments are human, humanized, or chimeric.

[0163] In certain embodiments, the antibody or antigen-binding fragment comprises one or more of the VH and / or VL depicted in SEQ ID NOs: 1-530, 811-862, and 891-903, and / or two or more of CDRH1, CDRH2, CDRH3, CDRL1, CRL2, and / or CDRL3, and binds to RSV-F in a prefusion conformation with a PCR reaction rate of 1.0E-12 or less, 1.0E-11 or less, 4.5E-11 or less, 1.0E-10 or less, or 1.0E-11 or less. In some embodiments, the binding is any of the foregoing values ​​or ranges of 1.0E-9 or less, which is high affinity binding according to the present disclosure.

[0164] In certain embodiments, the antibody or antigen-binding fragment comprises one or more of the VH and / or VL as described in SEQ ID NOs: 531-556, and / or two or more of CDRH1, CDRH2, CDRH3, CDRL1, CRL2, and / or CDRL3, and binds to RSV-F in a prefusion conformation with a KD (in M) of 1.0E-10 or less, 7.5E-10 or less, 1.0E-9 or less, or 1.5E-9 or less, or in the range of 1.0E-10 to 1.5E-9, 1.0E-10 to 1.0E-9, 1.0E-10 to 7.5E-10, or 7.5E-10 to 1.5E-9, wherein binding is optionally assessed by surface plasmon resonance (SPR). In some embodiments, binding is any of the foregoing values ​​or ranges of 1.0E-9 or less, which is high-affinity binding according to the present disclosure.

[0165] In certain embodiments, the antibody or antigen-binding fragment comprises one or more of the VH and / or VL as set forth in SEQ ID NOs: 1-530, 811-862, and 891-903, and / or two or more of CDRH1, CDRH2, CDRH3, CDRL1, CRL2, and / or CDRL3, and is expressed in an amount of 1.0E-12M or less, 1.0E-11 or less, 4.5E-11 or less, 1.0E-10 or less, 1.0E-9 or less. In some embodiments, the binding is any of the foregoing values ​​or ranges of 1.0E-9 or less, which is high affinity binding according to the present disclosure.

[0166] In certain embodiments, the antibody or antigen-binding fragment comprises one or more of the VH and / or VL depicted in SEQ ID NOs: 531-556, and / or two or more of CDRH1, CDRH2, CDRH3, CDRL1, CRL2, and / or CDRL3, and binds to MPV-F D280 with a K (in M) of 1.0E-12 or less, 1.0E-11 or less, 4.5E-11 or less, or 1.0E-10 or less, or in the range of 1.0E-12 to 1.0E-11, 1.0E-12 to 4.5E-11, or 1.0E-12 to 1.0E-10, wherein binding is optionally assessed by surface plasmon resonance (SPR).

[0167] In certain embodiments, the antibody or antigen-binding fragment comprises one or more of the VH and / or VL as set forth in SEQ ID NOs: 1-530, 811-862, and 891-903, and / or two or more of CDRH1, CDRH2, CDRH3, CDRL1, CRL2, and / or CDRL3, and is present in an amount of 1.0E-12 or less, 1.0E-11 or less, 5.8E-11 or less, 1.0E-10 or less, 1.0E-9 or less, 8.0E-11 or less, or 1.0E-12 or less. In some embodiments, the binding is any of the foregoing values ​​or ranges of 1.0E-9 or less, which is designated as high affinity binding in accordance with the present disclosure.

[0168] In certain embodiments, the antibody or antigen-binding fragment comprises one or more of the VH and / or VL as set forth in SEQ ID NOs: 531-556, and / or two or more of CDRH1, CDRH2, CDRH3, CDRL1, CRL2, and / or CDRL3, and binds to MPV-F N280 with a KD (in M) of 1.0E-10 or less, 1.0E-9 or less, 2.5E-9 or less, or 1.0E-8 or less, or in the range of 1.0E-10 to 1.0E-8, 1.0E-10 to 1.0E-9, or 1.0E-10 to 2.5E-9, wherein binding is optionally assessed by surface plasmon resonance (SPR). In some embodiments, binding is any of the foregoing values ​​or ranges of 1.0E-9 or less, which is high affinity binding according to the present disclosure.

[0169] In certain embodiments, the antibody or antigen-binding fragment comprises one or more of the VH and / or VL depicted in SEQ ID NOs: 1-530, 811-862, and 891-903, and / or two or more of CDRH1, CDRH2, CDRH3, CDRL1, CRL2, and / or CDRL3, and neutralizes RSV with an IC50 of 30 ng / ml or less, 15 ng / ml or less, 10 ng / ml or less, 2.0 ng / ml or less, 1.0 ng / ml or less, or 0.2 ng / ml or less, or in the range of 0.2 ng / ml to 30 ng / ml, 0.2 ng / ml to 15 ng / ml, 0.2 ng / ml to 2.0 ng / ml, 1.0 ng / ml to 30 ng / ml, or 2.0 ng / ml to 15 ng / ml as measured in vitro.

[0170] In certain embodiments, the antibody or antigen-binding fragment comprises one or more of the VH and / or VL depicted in SEQ ID NOs: 1-530, 811-862, and 891-903, and / or two or more of CDRH1, CDRH2, CDRH3, CDRL1, CRL2, and / or CDRL3, and has an expression level of 30 ng / ml or less, 15 ng / ml or less, 10 ng / ml or less, 7.0 ng / ml or less, 6.0 ng / ml or less, 5 ng / ml or less, or 1.5 ng / ml as measured in vitro. l or less, or neutralizes MPV with an IC50 in the range of 1.0 ng / ml to 30 ng / ml, 1.0 ng / ml to 15 ng / ml, 1.0 ng / ml to 10 ng / ml, 1.0 ng / ml to 7.0 ng / ml, 1.0 ng / ml to 5.0 ng / ml, 5.0 ng / ml to 30 ng / ml, 5.0 ng / ml to 15 ng / ml, 7.0 ng / ml to 30 ng / ml, or 7.0 ng / ml to 15 ng / ml.

[0171] In certain embodiments, the antibody or antigen-binding fragment comprises one or more of the VH and / or VL depicted in SEQ ID NOs: 531-556, and / or two or more of CDRH1, CDRH2, CDRH3, CDRL1, CRL2, and / or CDRL3, and neutralizes RSV with an IC50 in the range of 30 ng / ml or less, 15 ng / ml or less, 10 ng / ml or less, 8.0 ng / ml or less, 5.0 ng / ml or less, or 3.5 ng / ml or less, or in the range of 3.0 ng / ml to 30 ng / ml, 3.0 ng / ml to 15 ng / ml, 3.0 ng / ml to 10 ng / ml, 3.0 ng / ml to 8 ng / ml, 3.0 ng / ml to 5.0 ng / ml, 5.0 ng / ml to 30 ng / ml, or 5.0 ng / ml to 15 ng / ml as measured in vitro.

[0172] In certain embodiments, the antibody or antigen-binding fragment comprises one or more of the VH and / or VL depicted in SEQ ID NOs: 531-556, and / or two or more of CDRH1, CDRH2, CDRH3, CDRL1, CRL2, and / or CDRL3, and neutralizes MPV as measured in vitro with an IC50 of 30 ng / ml or less, 15 ng / ml or less, 10 ng / ml or less, 5.0 ng / ml or less, or 3.8 ng / ml or less, or in the range of 3.5 ng / ml to 30 ng / ml, 3.5 ng / ml to 15 ng / ml, 3.5 ng / ml to 10 ng / ml, 3.5 ng / ml to 5.0 ng / ml, 5.0 ng / ml to 30 ng / ml, or 5.0 ng / ml to 15 ng / ml.

[0173] In certain embodiments, the in vitro measurement comprises an ELISA.

[0174] In certain embodiments, the antibody or antigen-binding fragment binds to or neutralizes two or more of RSV-F, MPV-F D280, and MPV-FN280 with a KD or IC50 for each protein as indicated above.

[0175] In certain embodiments, the antibody or antigen-binding fragment binds to or neutralizes DS-Cav1, or two or more of DS-Cav1, RSV-F, MPV-F D280, and MPV-F N280, with a KD or IC50 for each protein as indicated above.

[0176] In certain embodiments, RSV-F comprises DS-Cav1, a stable trimer of the prefusion conformation of RSV-F protein, comprising the amino acid mutations: S155C, S190F, V207L, and S290C, wherein optionally the RSV comprises strain B18537 (NCBI: txid11251).

[0177] In certain embodiments, the antibody or antigen binding fragment activates human FcγRIIIa (or "can" or "can" activate human FcγRIIIa). In other embodiments, activation is determined using a host cell (optionally, Jurkat cells) after the antibody or antigen binding fragment is incubated with target cells infected with IAV (e.g., A549 cells) (e.g., 23 hours), the host cell comprising: (i) human FcγRIIIa (optionally, F158 allele); and (ii) NFAT expression control sequence, which is incubated (e.g., 23 hours) with target cells transiently transfected with RSV-F and / or MPV-F (e.g., Expi293 cells), operably linked to a sequence encoding a reporter gene such as a luciferase reporter gene. In other embodiments, activation is determined after the antibody or antigen binding fragment is incubated with target cells transiently transfected with RSV-F and / or MPV-F (optionally, for about 23 hours).

[0178] In certain embodiments, the antibodies or antigen-binding fragments neutralize infection caused by RSV and / or MPV. In certain embodiments, RSV and / or MPV are antiviral resistant (e.g., ribavirin resistant). In certain embodiments, MPV does not contain the D280N mutation in its fusion glycoprotein. In certain embodiments, MPV contains the D280N mutation in its fusion glycoprotein.

[0179] In certain embodiments, the antibody or antigen-binding fragment treats and / or prevents (or is "capable of treating and / or preventing" or "capable of treating and / or preventing") (i) RSV infection and / or (ii) MPV infection in a subject.

[0180] In certain embodiments, the antibody or antigen-binding fragment prolongs survival (or is "capable of prolonging survival" or "capable of prolonging survival") of a subject having RSV infection and / or MPV infection.

[0181] In certain embodiments, the antibody or antigen-binding fragment reduces (or is "capable of reducing" or "capable of reducing") viral load in nasal tissue, nasal homogenate, bronchoalveolar fluid (BALF) and / or lung homogenate of a subject with RSV infection and / or MPV infection.

[0182] In certain embodiments, the antibody or antigen-binding fragment reduces (or is "capable of reducing" or "capable of reducing") infection-associated lung pathology in a subject having RSV infection and / or MPV infection.

[0183] In any of the above embodiments, the antibody or antigen-binding fragment can treat and / or attenuate (or "can treat and / or attenuate" or "can treat and / or attenuate") an infection caused by an MPV virus expressing MPV-F D280 (such as MPV-F wt) and / or an MPV virus expressing MPV-F N280. Such antibodies can be therapeutically administered to a human subject without the need to determine whether the MPV virus infecting the subject contains an MPV-F N280 mutation.

[0184] Similarly, if the antibody or antigen-binding fragment can treat and / or attenuate (or is "capable of treating and / or attenuating" or "capable of treating and / or attenuating") infection caused by both RSV and MPV (optionally MPV with or without the D280N mutation), then the antibody or antigen-binding fragment can be therapeutically administered to a human subject in whom it is desired to determine whether the virus infecting the subject has RSV infection or MPV infection, or optionally whether the virus contains the MPV-F N280 mutation.

[0185] In some embodiments, the antibodies or antigen-binding fragments thereof of the present disclosure can bind to, neutralize, neutralize infection caused by, prevent infection caused by, treat infection caused by, reduce viral load, reduce infection-associated lung pathology, or any combination thereof, of various RSV and / or MPV strains (sometimes also referred to as RSV and / or MPV types or subtypes).

[0186] In some embodiments, the present invention relates to an antibody or antigen-binding fragment of the present invention. For example, RSV binding antibodies or its antigen-binding fragment can be combined with RSV A and RSV B strains, neutralize it, neutralize the infection caused by it, prevent the infection caused by it, treat the infection caused by it, reduce its viral load, reduce the relevant pulmonary pathology or any combination thereof. RSV binding antibodies can be combined with the multiple hypotypes of RSV A strain, neutralize it, neutralize the infection caused by it, prevent the infection caused by it, treat the infection caused by it, reduce its viral load, reduce the relevant pulmonary pathology or any combination thereof. RSV binding antibodies or its antigen-binding fragment can be combined with the multiple hypotypes of RSV B strain, neutralize it, neutralize the infection caused by it, prevent the infection caused by it, treat the infection caused by it, reduce its viral load, reduce the relevant pulmonary pathology or any combination thereof.

[0187] For another example, the MPV-binding antibodies or antigen-binding fragments thereof can bind to, neutralize, neutralize infection caused by, prevent infection caused by, treat infection caused by, reduce viral load, reduce infection-related lung pathology, or any combination thereof, both MPV A and MPV B strains. The MPV-binding antibodies can bind to, neutralize, neutralize infection caused by, prevent infection caused by, treat infection caused by, reduce viral load, reduce infection-related lung pathology, or any combination thereof, multiple subtypes of MPV A strains, such as MPV A1 strains, MPV A2 strains (including A2a, A2b, or both subtypes), or a combination thereof. The MPV-binding antibodies or antigen-binding fragments thereof can bind to, neutralize, neutralize infection caused by, prevent infection caused by, treat infection caused by, reduce viral load, reduce infection-related lung pathology, or any combination thereof, multiple subtypes of MPV B strains, such as MPV B1 strains, MPV B2 strains, or a combination thereof.

[0188] In one embodiment, the antibodies or antigen-binding fragments thereof of the present disclosure can bind to, neutralize, neutralize infection caused by, prevent infection caused by, treat infection caused by, reduce viral load, reduce infection-associated lung pathology, or any combination thereof, RSV A strain, RSV B strain, and MPVA strain.

[0189] In another embodiment, the antibodies or antigen-binding fragments thereof of the present disclosure can bind to, neutralize, neutralize infection caused by, prevent infection caused by, treat infection caused by, reduce viral load, reduce infection-associated lung pathology, or any combination thereof, RSV A strain, RSV B strain, and MPVB strain.

[0190] In another embodiment, the antibodies or antigen-binding fragments thereof of the present disclosure can bind to, neutralize, neutralize infection caused by, prevent infection caused by, treat infection caused by, reduce viral load, reduce infection-associated lung pathology, or any combination thereof, RSV A strain, MPV A strain, and MPV B strain.

[0191] In another embodiment, the antibodies or antigen-binding fragments thereof of the present disclosure can bind to, neutralize, neutralize infection caused by, prevent infection caused by, treat infection caused by, reduce viral load, reduce infection-associated lung pathology, or any combination thereof, RSV A strain, MPV A strain, and MPV B strain.

[0192] In another embodiment, the antibody or antigen-binding fragment thereof can bind to, neutralize, neutralize infection caused by, prevent infection caused by, treat infection caused by, reduce viral load, reduce infection-associated lung pathology, or any combination thereof, RSV B strain, MPV A strain, and MPV B strain.

[0193] In one embodiment, the antibodies or antigen-binding fragments thereof of the present disclosure can bind to any combination of the following subcombinations of virus strains: RSV A, RSV B, MPV A1, MPV A2 (MPV A2a, MPV A2b, or both), MPV B1, and MPV B2, neutralize them, neutralize infection caused by them, prevent infection caused by them, treat infection caused by them, reduce viral loads thereof, reduce infection-associated lung pathology, or any combination thereof.

[0194] In a specific embodiment, the antigens or antigen-binding fragments thereof of the present disclosure can bind to, neutralize, neutralize infection caused by, prevent infection caused by, treat infection caused by, reduce viral load, reduce infection-associated lung pathology, or any combination thereof, RSV A, RSV B, MPV A1, MPV A2, MPV B1, and MPV B2.

[0195] In any of the above embodiments, antibodies or antigen-binding fragments that can treat and / or attenuate (or "capable of treating and / or attenuating" or "capable of treating and / or attenuating") infection caused by both RSV strain A and RSV strain B can be therapeutically administered to a human subject without the need to determine the viral subtype of the RSV virus infecting the subject.

[0196] Similarly, antibodies or antigen-binding fragments that can treat and / or attenuate (or "are capable of treating and / or attenuating" or "are capable of treating and / or attenuating") infection caused by both MPV strain A and MPV strain B can be therapeutically administered to a human subject without the need to determine the viral subtype of the MPV virus that infects the subject.

[0197] In addition, antibodies or antigen-binding fragments that can treat and / or attenuate (or "capable of treating and / or attenuating" or "capable of treating and / or attenuating") infection caused by both RSV A and RSV B strains, and both MPV A and MPV B strains, can be therapeutically administered to a human subject without the need to determine whether RSV or MPV is infecting the subject.

[0198] In one embodiment, the antibodies or antigen-binding fragments thereof of the present disclosure bind to site III of the RSV F protein. In a more specific embodiment, such antibodies or antigen-binding fragments thereof can bind to both RSV and MPV and treat infections caused by both RSV and MPV.

[0199] In one embodiment, an antibody or antigen-binding fragment thereof of the present disclosure binds to a site of the RSV F protein. In a more specific embodiment, the antibody or antigen-binding fragment thereof can bind to RSV and treat infection caused by RSV.

[0200] In one embodiment, the antibodies or antigen-binding fragments thereof of the present disclosure bind to site IV of the RSV F protein. In a more specific embodiment, such antibodies or antigen-binding fragments thereof can bind to RSV and treat infection caused by RSV.

[0201] For each of the above embodiments of antibodies, antigen-binding fragments, and compositions, in parallel embodiments, a combination of two or more antibodies or antigen-binding fragments thereof disclosed herein (as separate antibodies in a single composition, or as bispecific antibodies) can have the same RSV and MPV binding, neutralization, infection prevention and / or treatment, and other listed properties.

[0202] In certain embodiments, the antibodies or antigen-binding fragments (e.g., comprising an IgG1 isotype) have a lifespan in mice (e.g., tg32 mice) of about 10 days to about 17 days, about 10 days to about 16 days, about 10 days to about 15 days, about 10 days to about 14 days, about 10 days to about 13 days, about 10 days to about 12 days, about 11 days to about 17 days, about 11 days to about 16 days, about 11 days to about 15 days, about 11 days to about 14 days, about 11 days to about 11 days, days to about 13 days, about 11 days to about 12 days, about 12 days to about 17 days, about 12 days to about 16 days, about 12 days to about 15 days, about 12 days to about 14 days, about 12 days to about 13 days, about 12.5 days to about 16 days, about 12.5 days to about 15.5 days, about 12.5 days to about 15 days, about 12.5 days to about 14.5 days, about 12.5 days to about 14 days, about 12.5 days to about 13.5 days, about 12.5 days to about 13 days, about 13 days to about 16 days, about 13 days to about 15.5 days, about 13 days to about 15 days, about 13 days to about 14.5 days, about 13 days to about 14 days, about 13 days to about 13.5 days, about 13.5 days to about 16 days, about 13.5 days to about 15.5 days, about 13.5 days to about 15 days, about 13.5 days to about 14.5 days, about 13.5 days to about 14 days, about 14 days to about 16 days, about 14 days to about 15. In some embodiments, the present invention may have an in vivo half-life in the range of about 15 days, about 14 days to about 15 days, about 14 days to about 14.5 days, about 14.5 days to about 16 days, about 14.5 days to about 15.5 days, about 14.5 days to about 15 days, about 15 days to about 16 days, about 15 days to about 15.5 days, about 15.5 days to about 16 days, or about 10, 11, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, or 17 days.

[0203] In some embodiments, the antibodies or antigen-binding fragments of the present disclosure can reduce weight loss in RSV-infected mice at least as well as nevacorumab when administered in a similar manner to similar mice at a similar stage of RSV infection.

[0204] In some embodiments, the antibodies or antigen-binding fragments of the present disclosure can increase the survival of RSV-infected mice at least as well as necirimab, or an antibody having the same VH and VL as necirimab, when administered in a similar manner to similar mice at a similar stage of RSV infection.

[0205] Unless explicitly defined in different ways herein, the terms understood by those skilled in the art of antibody technology are each given the existing meaning in this area.For example, the term "antibody" refers to a complete antibody comprising two or more heavy (H) chains and two light (L) chains interconnected by a disulfide bond, and any antigen-binding portion thereof or fragment thereof, which has or retains the ability to be combined with the antigen target molecule identified by the complete antibody, such as scFv, Fab or Fab'2 fragment. Therefore, the term "antibody" is used in the broadest sense herein and includes polyclonal and monoclonal antibodies, including complete antibodies and functional (antigen binding) antibody fragments, including fragment antigen binding (Fab) fragments, F (ab') 2 fragments, Fab' fragments, Fv fragments, recombinant IgG (rIgG) fragments, single-chain antibody fragments, including single-chain variable fragments (scFv) and single-domain antibodies (for example, sdAb, sdFv, nanobody) fragments. The term encompasses genetically engineered and / or otherwise modified immunoglobulin forms, such as intrabodies, peptibodies, chimeric antibodies, fully human antibodies, humanized antibodies and heteroconjugated antibodies, multispecific (e.g., bispecific) antibodies, diabodies, triabodies, tetrabodies, tandem double scFvs and tandem three scFvs. Unless otherwise indicated, the term "antibody" should be understood to encompass functional antibody fragments. The term also encompasses complete or full-length antibodies, including antibodies of any class or subclass, including IgG and its subclasses (IgG1, IgG2, IgG3, IgG4), IgM, IgE, IgA and IgD.

[0206] The antibody or antigen-binding fragment can be any allotype or combination of allotypes. "Allotype" refers to the allelic variation found in the IgG subclass. For example, allotypes can include G1m1 (or G1m(a)), G1m2 (or G1m(x)), G1m3 (or G1m(f)), G1m17 (or Gm(z))m), G1m27 and / or G1m28 (G1m27 and G1m28 have been described as "alloallotypes").

[0207] The G1m3 and G1m17 allotypes are located at the same position in the CH1 domain (position 214 according to EU numbering). G1m3 contains R214 (EU), while G1m17 contains K214 (EU). The G1m1 allotype is located in the CH3 domain (at positions 356 and 358 (EU)) and refers to the substitutions E356D and M358L. The G1m2 allotype refers to the substitution of alanine at position 431 (EU) with glycine. G1m allotypes, heteromorphic allotypes, and their characteristics are known in the art and described, for example, in<www.imgt.org / IMGTrepertoire / Proteins / allotypes / human / IGH / IGHC / G1m_allotypes.html> and Lefranc, M.-P. and Lefranc, G. Human Gm, Km and Am allotypes and their molecular characterization: a remarkable demonstration of polymorphism, In: B. Tait, F. Christiansen (eds.), Immunogenetics, Chapter 34, Humana Press, Springer, New York, USA. Methods Mol. Biol. 2012;882, 635-680. PMID: 22665258, LIGM: 406, the contents of which and allotype and allotype information are incorporated herein by reference.

[0208] The G1m1 allotype can be combined, for example, with the G1m3, G1m17, G1m27, G1m2, and / or G1m28 allotypes. In some embodiments, the allotype is G1m3 without G1m1 (G1m3,-1). In some embodiments, the allotype is the G1m17,1 allotype. In some embodiments, the allotype is G1m3,1. In some embodiments, the allotype is G1m17 without G1m1 (G1m17,-1). Optionally, these allotypes can be combined (or not combined) with the G1m2, G1m27, or G1m28 allotypes. For example, the allotype can be G1m17,1,2.

[0209] In some embodiments, the antibodies or antigen-binding fragments of the present disclosure comprise a G1m3 allotype or a G1m3,1 allotype. In some embodiments, the antibodies or antigen-binding fragments of the present disclosure comprise a G1m3 allotype and comprise M428L and N434S or M428L and N434A mutations or any other mutations that enhance binding to human FcRn, such as those described herein. In some embodiments, the antibodies or antigen-binding fragments of the present disclosure comprise a G1m3,1 allotype and comprise M428L and N434S or M428L and N434A mutations or any other mutations that enhance binding to human FcRn, such as those described herein. In some embodiments, the antibodies or antigen-binding fragments of the present disclosure comprise a G1m17,1 allotype. In some embodiments, the antibodies or antigen-binding fragments of the present disclosure comprise the G1m17,1 allotype and comprise M428L and N434S or M428L and N434A mutations, or any other mutations that enhance binding to human FcRn, as further described herein.

[0210] The term "V L ” or “VL” and “V H " or "VH" refer to the variable binding region from the antibody light chain and antibody heavy chain, respectively. In certain embodiments, the VL is of the kappa (κ) class (also referred to herein as "VK"). In certain embodiments, the VL is of the lambda (λ) class. The variable binding region includes discrete, well-defined subregions called "complementarity determining regions" (CDRs) and "framework regions" (FRs). The terms "complementarity determining regions" and "CDRs" are synonymous with "hypervariable regions" or "HVRs" and refer to amino acid sequences within the variable region of an antibody that, in general, collectively confer antigen specificity and / or binding affinity to the antibody, wherein consecutive CDRs (i.e., CDR1 and CDR2, CDR2 and CDR3) are separated from each other in the primary structure by framework regions. Each Each variable region has three CDRs (HCDR1, HCDR2, HCDR3; LCDR1, LCDR2, LCDR3; also referred to as CDRH and CDRL, respectively). In certain embodiments, the antibody VH comprises the following four FRs and three CDRs: FR1-HCDR1-FR2-HCDR2-FR3-HCDR3-FR4; and the antibody VL comprises the following four FRs and three CDRs: FR1-LCDR1-FR2-LCDR2-FR3-LCDR3-FR4. Generally speaking, the VH and VL form an antigen binding site together through their corresponding CDRs. In certain embodiments, one or more CDRs do not contact the antigen and / or do not contribute energetically to antigen binding.

[0211] As used herein, a "variant" of a CDR refers to a functional variant of a CDR sequence having up to 1 to 3 amino acid substitutions (eg, conservative or non-conservative substitutions), deletions, or a combination thereof.

[0212] The numbering of the CDRs and framework regions may be according to any known method or scheme, such as the Kabat, Chothia, EU, Martin (enhanced Chothia), Contact, AbM, CCG, EU, or AHo numbering schemes, or a combination of two or more of these IMGT, North, and AHo numbering schemes (see, e.g., Kabat et al., "Sequences of Proteins of Immunological Interest," U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health). Health), 1991, 5th edition; Chothia and Lesk, J. Mol. Biol. 196: 901-917 (1987); Lefranc et al., Dev. Comp. Immunol. 27: 55, 2003; Honegger and Plückthun, J. Mol. Bio. 309: 657-670 (2001). Equivalent residue positions can be annotated using the Antigen Receptor Numbering and Receptor Classification (ANARCI) software tool (2016, Bioinformatics 15: 298-300) and compared for equivalent residue positions of different molecules. Thus, identifying the CDRs of the variable domain (VH or VL) sequences as provided herein according to one numbering scheme does not exclude antibodies comprising CDRs of the same variable domain as determined using a different numbering scheme.

[0213] In certain embodiments, an antibody or antigen-binding fragment that binds RSV-F is provided, comprising an antibody or antigen-binding fragment according to SEQ ID NO: 2, 136, 146, 159, 169, 175, 181, 189, 196, 202, 210, 215, 225, 233, 243, 250, 254, 261, 271, 277, 284, 293, 300, 309, 316, 321, 327, 332, 342, 347, 352, 357, 362, 369, 727, 737, 746, 755, 765, 775, 784, 794, 804, 813, 817, 820, 823, 826, 828, 831, 834, 837, 840, 843, 883, 886 , 470, 475, 480, 485, 491, 497, 532, 537, 539, 542, 545, 547, 550, 504, 513, 524, 527, 702, 707, 712, and 716, and / or the VH sequence of any one of SEQ ID NO: NO:77, 141, 150, 155, 164, 172, 178, 185, 192, 199, 205, 212, 220, 229, 238, 247, 252, 257, 266, 274, 282, 288, 296, 305, 312, 319, 324, 330 ,337,345,349,355,360,367,374,732,742,751,760,770,780,789,799,808,847,851,855,858,860,862,865,868,870,873,875,877,8 553, 558, 560, 563, 567, 570, 572, 574, 704, and 710, as determined using any known CDR numbering method,These methods include Kabat, Chothia, EU, Martin (Enhanced Chothia), Contact, AbM, CCG, EU or AHo numbering methods, or a combination of two or more of these IMGT, Martin (Enhanced Chothia), Contact, North and AHo numbering methods, including as determined by a combination of any two or more of these numbering methods. In certain embodiments, the CDRs are according to the IMGT numbering method. In certain embodiments, the CDRs are according to the antibody numbering method developed by the Chemical Computing Group (CCG); for example, using the Molecular Operating Environment (MOE) software. ,

[0214] In certain embodiments, an antibody or antigen-binding fragment that binds to RSV-F is provided, comprising an antibody or antigen-binding fragment according to SEQ ID NO: 2, 136, 146, 159, 169, 175, 181, 189, 196, 202, 210, 215, 225, 233, 243, 250, 254, 261, 271, 277, 284, 293, 300, 309, 316, 321, 327, 332, 342, 347, 352, 357, 362 , 369, 727, 737, 746, 755, 765, 775, 784, 794, 804, 813, 817, 820, 823, 826, 828, 831, 834, 837, 840, 843, 883, 886, 889, 893, 896, 899, 901 and 903, and / or the VH sequence of any one of SEQ ID NO:7, 141, 150, 155, 164, 172, 178, 185, 192, 199, 205, 212, 220, 229, 238, 247, 252, 257, 266, 274, 282, 288, 296, 305, 312, 319, 324, 330, 337, 345, 349, 355, 360, 367, 374, 732, 742, 751, 760, 770, 780, 789, 799, 808, 847, 851, 855, 858, 860, 862, 865, 868, 87 In some embodiments, the CDRs of the VL sequences of any one of 870, 873, 875, 877, 879, and 881 are numbered as defined using any known CDR numbering method, including Kabat, Chothia, EU, Martin (enhanced Chothia), Contact, AbM, CCG, EU, or AHo numbering methods, or a combination of two or more of these IMGT, Martin (enhanced Chothia), Contact, North, and AHo numbering methods, including as defined by a combination of any two or more of these numbering methods. In certain embodiments, the CDRs are numbered according to the IMGT numbering method. In certain embodiments, the CDRs are numbered according to the antibody numbering method developed by the Chemical Computing Group (CCG); e.g., using the Molecular Operating Environment (MOE) software).

[0215] In some embodiments that bind only MPK, the CDRs comprise or consist of CDRs of MPK15.

[0216] More specifically, the VH and VL of the antibody or antigen-binding fragment that binds to RSV-F may comprise or consist of the VH and VL amino acid sequences of the anti-RSV MPK antibody or MPH antibody in Table 2, respectively, and have the corresponding amino acid sequences shown in Table 1 and the sequence listing. Specifically, the CDRs comprise or consist of the following CDRs: MPK44, MPK65-v2, MPK161-v2, MPK163, MPK165, MPK167, MPK168, MPK169-v2, MPK170, MPK171-v1, MPK171-v2, MPK173, MPK175, MPK176, MPK177, MPK178, MPK179-v4, MPK180, MPK181, MPK182, MPK185, MPK186, MPK187, MPK188, MPK189, MPK191, MPK193, MPK194-v2, MPK195, MPK197, MPK198, MPK201, MPK202, MPK203, and MPK204. PM2, MPM8, MPO1, MPO7, MPP1, MPP2, MPR16, MPR19-v2, MPM10, MPM2, MPM8, MPO1, MPO7, MPP1, MPP2, MPR16, MPR19-v2, MPK65-v (any of 1-7) (any of 1-2), MPK201-v (any of 1-6) (any of 1-2), MPK176-v (any of 1-6) (any of 5) or MPM2-v (any of 1, 2, 4, 5) (any of 1-9), for example, MPK176-v1.3, MPK176-v4.3, MPK201-v1.2, MPK201-v4.1, MPK65v2-v1.2 or MPK65v2-v3.1. It will be understood that, for example, MPK201-v1.2 comprises the VH of MPK201 VH.1 (SEQ ID NO: 357) and the VL of MPK201 VL.2 (SEQ ID NO: 847).

[0217] In some embodiments, the antibody or antigen-binding fragment comprises the six CDRs of MPK176-v1.3, MPK176-v4.3, MPK201-v1.2, MPK201-v4.1, MPK65v2-v1.2, or MPK65v2-v3.1.

[0218] More specifically, the VH and VL of the antibody or antigen-binding fragment that binds RSV-F comprise or consist of a VH and VL having the following sequences, respectively: 1) SEQ ID NOs: 2 and 6; 2) SEQ ID NOs: 136 and 141; 3) SEQ ID NOs: 146 and 150; 4) SEQ ID NOs: 146 and 155; 5) SEQ ID NOs: 159 and 164; 6) SEQ ID NOs: 169 and 172; 7) SEQ ID NOs: 175 and 178; 8) SEQ ID NOs: 181 and 185; 9) SEQ ID NOs: 189 and 192; 10) SEQ ID NOs: 196 and 199; 11) SEQ ID NOs: 202 and 205; 12) SEQ ID NOs: 210 and 212; 13) SEQ ID NOs: 215 and 220; 14) SEQ ID NOs: 225 and 229; 15) SEQ ID NOs: SEQ ID NOs: 233 and 238; 16) SEQ ID NOs: 243 and 247; 17) SEQ ID NOs: 250 and 252; 18) SEQ ID NOs: 254 and 257; 19) SEQ ID NOs: 261 and 266; 20) SEQ ID NOs: 271 and 274; 21) SEQ ID NOs: 277 and 282; 22) SEQ ID NOs: 284 and 288; 23) SEQ ID NOs: 293 and 296; 24) SEQ ID NOs: 300 and 305; 25) SEQ ID NOs: 309 and 312; 26) SEQ ID NOs: 316 and 319; 27) SEQ ID NOs: 321 and 324; 28) SEQ ID NOs: 327 and 330; 29) SEQ ID NOs: 332 and 337; 30) SEQ ID NOs: 342 and 345; 31) SEQ ID NOs: NO:347 and 349; 32) SEQ ID NO:352 and 355; 33) SEQ ID NO:357 and 360; 34) SEQ ID NO:362 and 367; 35) SEQ ID NO:369 and 374, 36) SEQ ID NO:883 and 742; 37) SEQ ID NO:737 and 742; 38) SEQ ID NO:727 and 732; 39) SEQ ID NO:746 and 751; 40) SEQ ID NO:755 and 760; 41) SEQ ID NO:765 and 770; 42) SEQ ID NO:775 and 770; 43) SEQ ID NO:784 and 789; 44) SEQ ID NO:794 and 799; 45) SEQ ID NO:804 and 808; 46) SEQ ID NO:233 and 858;47) SEQ ID NOs: 837 and 858; 48) SEQ ID NOs: 357 and 847; 49) SEQ ID NOs: 899 and 360; 50) SEQ ID NOs: 136 and 851; 51) SEQ ID NOs: 817 and 141; 52) SEQ ID NOs: 883 and 742; 53) SEQ ID NOs: 886 and 742; or 54) SEQ ID NOs: 883 and 875.

[0219] More specifically, the VH and VL of the antibody or antigen-binding fragment that binds MPV-F may comprise or consist of the VH and VL identified for anti-MPVMPK antibodies or MPH antibodies in Table 2, and have the corresponding amino acid sequences shown in Table 1 and the Sequence Listing.

[0220] In some embodiments, an antibody or antigen-binding fragment that binds MPV-F is provided, which may comprise a VH sequence according to any one of SEQ ID NOs: 101, 129, 12, 38, 46, 53, 59, 69, 120, 73, 79, 86, 95, 22, 111, 30, 378, 386, 395, 404, 412, 416, 422, 426, 431, 440, 451, 458, 463, 470, 475, 480, 485, 491, 497, 532, 537, 539, 542, 545, 547, 550, 504, 513, 524, 527, 702, 707, 712, and 716, and / or a VH sequence according to any one of SEQ ID NOs: NO:106, 133, 17, 42, 50, 56, 64, 71, 125, 76, 83, 91, 98, 27, 116, 35, 382, ​​391, 400, 408, 414, 419, 424, 429, 434, 436, 4 44, 449, 455, 461, 466, 473, 478, 483, 487, 495, 501, 509, 518, 522, 530, 553, 558, 560, 563, 567, 570, 572, 574, 704 and 71 0, respectively, as determined using any known CDR numbering method, including Kabat, Chothia, EU, Martin (enhanced Chothia), Contact, AbM, CCG, EU or AHo numbering method, or a combination of two or more of these IMGT, Martin (enhanced Chothia), Contact, North and AHo numbering methods, including as determined by any combination of two or more of these numbering methods. In certain embodiments, the CDR is according to the IMGT numbering method, including as determined by any combination of two or more of these numbering methods. In certain embodiments, the CDR is according to the antibody numbering method developed by the Chemical Computing Group (CCG); for example, using the Molecular Operating Environment (MOE) software.

[0221] More specifically, the VH and VL of the antibody or antigen-binding fragment that binds MPV-F may comprise or consist of VH and VL having the sequences of SEQ ID NOs: 101 and 106, respectively.

[0222] In certain embodiments, antibodies or antigen-binding fragments that bind RSV-F and / or MPV-F are provided that can comprise a VH sequence according to any one of SEQ ID NOs: 129, 12, 38, 46, 53, 59, 69, 120, 73, 79, 86, 95, 22, 111, 30, 378, 386, 395, 404, 412, 416, 422, 426, 431, 440, 451, 458, 463, 470, 475, 480, 485, 491, 497, 532, 537, 539, 542, 545, 547, 550, 504, 513, 524, 527, and 702, 707, 712, and 716, and / or a VH sequence according to any one of SEQ ID NOs: NO:133, 17, 42, 50, 56, 64, 71, 125, 76, 83, 91, 98, 27, 116, 35, 382, ​​391, 400, 408, 414, 419, 424, 429, 434, 436, 444, 449, 455, 461, 466, 473, 478, 483, 487, 495, 501, 509, 518, 522, 530, 553, 558, 560, 563, 567, 570, 572, 574, 704 and 710 In some embodiments, the CDRs of the VL sequences of any one of the antibodies of the present invention are numbered as defined by any known CDR numbering method, including Kabat, Chothia, EU, Martin (enhanced Chothia), Contact, AbM, CCG, EU, or AHo numbering methods, or a combination of two or more of these IMGT, Martin (enhanced Chothia), Contact, North, and AHo numbering methods, including as defined by a combination of any two or more of these numbering methods. In certain embodiments, the CDRs are numbered according to the IMGT numbering method. In certain embodiments, the CDRs are numbered according to the antibody numbering method developed by the Chemical Computing Group (CCG); for example, using the Molecular Operating Environment (MOE) software.

[0223] In certain embodiments, antibodies or antigen-binding fragments that bind to RSV-F and / or MPV-F are provided that may comprise a VH sequence according to any one of SEQ ID NOs: 532, 537, 539, 542, 545, 547, and 550, and / or a VL sequence according to any one of SEQ ID NOs: 553, 558, 560, 563, 567, 570, 572, and 574, as determined using any known CDR numbering method, including Kabat, Chothia, EU, Martin (enhanced Chothia), Contact, AbM, CCG, EU, or AHo numbering methods, or a combination of two or more of these IMGT, Martin (enhanced Chothia), Contact, North, and AHo numbering methods, including as determined by a combination of any two or more of these numbering methods. In certain embodiments, the CDRs are according to the IMGT numbering method. In certain embodiments, the CDRs are numbered according to the antibody numbering method developed by the Chemical Computing Group (CCG); e.g., using the Molecular Operating Environment (MOE) software.

[0224] More specifically, the VH and VL of the antibody or antigen-binding fragment that binds to RSV-F and / or MPV-F comprise or consist of any VH and any VL identified for anti-RSV / MPV MPK antibodies or MPH antibodies in Tables 2 and 20, and have the corresponding amino acid sequences shown in Table 1 and the sequence listing. In some embodiments, both VH and VL are from the same antibody identified in Tables 2 and 20. However, in other embodiments, VH may be from the first antibody identified in Table 2 or Table 20, while VL may be from a different second antibody identified in Table 2 or Table 20. In some such cases, both the first and second antibodies may be MPK antibodies, or both the first and second antibodies may be MPH antibodies. However, VH from an MPK antibody and VL from an MPH antibody may also be used, or vice versa, particularly if V(D)J usage is the same between the MPH antibody and the MPK antibody.

[0225] In a specific embodiment, the CDRs of an antibody or antigen-binding fragment that binds to RSV-F and / or MPV-F comprise or consist of the CDRs of MPK190-v1.3, MPK9, MPK10, MPK18, MPK30-v1, MPK36-v3, MPK51, MPK51-v1.1, MPK67, MPK73, MPK77, MPK77-v1.1, MPK86, MPK92, MPK99, MPK102, MPK104, MPK104-v1.1, MPK104, v1.3, MPK108, MPK109, MPK200, MPK201, MPK202, MPK203, MPK204-v1.1, MPK204, MPK206, MPK208, MPK209, MPK209, MPK201, MPK202, MPK203, MPK204-v1.1, MPK206, MPK208, MPK209, MPK209, MPK201, MPK202, MPK203, MPK204, MPK206-v1.1, MPK208, MPK209, MPK208, MPK209, MPK209, MPK201 126. MPK127, MPK129, MPK130, MPK132-v2, MPK133, MPK136, MPK141, MPK142-v1, MPK142-v2, MPK144, MPK145, MPK146, MPK149, MPK150 -v2, MPK151, MPK152, MPK153, MPK155, MPK157, MPK158, MPK162, MPK174-v2, MPK190, MPK190-v1.1, MPK196, MPK204, MPH12 or MPH12 variant. In some embodiments, the CDRs are all from the same antibody identified in Table 2 and Table 20, such as all from MPK190-v1.3, MPK190-v1.1, MPK51-v1.1, MPK77-v1.1, MPK104-v1.1, or MPK104-v1.3. However, in other embodiments, CDRH1, CDRH2, and CDRH3 may be from a first antibody identified in Table 2 or Table 20, while CDRL1, CDRL2, and CDRL3 may be from a different second antibody identified in Table 2 or Table 20. In some such cases, the first and second antibodies may both be MPK antibodies, or the first and second antibodies may both be MPH antibodies. However, CDRH1, CDRH2, and CDRH3 from an MPK antibody and CDRL1, CDRL2, and CDRL3 from an MPH antibody may also be used, or vice versa, particularly if V(D)J usage is the same between the MPH antibody and the MPK antibody. In some embodiments, one or more of the first and second antibodies is MPK190-v1.3. In some embodiments, one or more of the first and second antibodies is MPK190-v1.1. In some embodiments, one or more of the first and second antibodies is MPK51-v1.1. In some embodiments, one or more of the first and second antibodies is MPK77-v1.1. In some embodiments, one or more of the first and second antibodies is MPK104-v1.1.In some embodiments, one or more of the first antibody and the second antibody is MPK 104-v1.3.

[0226] The cross-binding and / or cross-neutralizing antibodies and antigen-binding fragments of the present disclosure can also be used to bind RSV-F alone, or to bind MPV-F alone; their utility is not limited to situations in which binding and / or neutralization of both RSV and MPV targets occurs.

[0227] More specifically, the VH and VL of the antibody or antigen-binding fragment that binds to RSV-F and / or MPV-F and / or neutralizes RSV and / or MPV comprises or consists of a VH and VL having the following sequences, respectively: 1) SEQ ID NOs: 129 and 133; 2) SEQ ID NOs: 12 and 17; 3) SEQ ID NOs: 38 and 42; 4) SEQ ID NOs: 46 and 50; 5) SEQ ID NOs: 53 and 56; 6) SEQ ID NOs: 59 and 64; 7) SEQ ID NOs: 69 and 71; 8) SEQ ID NOs: 120 and 125; 9) SEQ ID NOs: 73 and 76; 10) SEQ ID NOs: 79 and 83; 11) SEQ ID NOs: 86 and 91; 12) SEQ ID NOs: 95 and 98; 13) SEQ ID NOs: 22 and 27; 14) SEQ ID NOs: 111 and 116; 15) SEQ ID NOs: SEQ ID NOs: 30 and 35; 16) SEQ ID NOs: 378 and 382; 17) SEQ ID NOs: 386 and 391; 18) SEQ ID NOs: 395 and 400; 19) SEQ ID NOs: 404 and 408; 20) SEQ ID NOs: 412 and 414; 21) SEQ ID NOs: 416 and 419; 22) SEQ ID NOs: 422 and 424; 23) SEQ ID NOs: 426 and 429; 24) SEQ ID NOs: 431 and 434; 25) SEQ ID NOs: 431 and 436; 26) SEQ ID NOs: 440 and 444; 27) SEQ ID NOs: 431 and 449; 28) SEQ ID NOs: 451 and 455; 29) SEQ ID NOs: 458 and 461; 30) SEQ ID NOs: 463 and 466; 31) SEQ ID NOs: 464 and 467; NO:470 and 473; 32) SEQ ID NO:475 and 478; 33) SEQ ID NO:480 and 483; 34) SEQ ID NO:485 and 487; 35) SEQ ID NO:491 and 495; 36) SEQ ID NO:497 and 501; 37) SEQ ID NO:504 and 509; 38) SEQ ID NO:513 and 518; 39) SEQ ID NO:120 and 522; 40) SEQ ID NO:524 and 518; 41) SEQ ID NO:527 and 530; 42) SEQ ID NO:532 and 553; 43) SEQ ID NO:532 and 558; 44) SEQ ID NO:532 and 577; 45) SEQ ID NO:532 and 563; 46) SEQ ID NO:532 and 567;47) SEQ ID NOs: 532 and 570; 48) SEQ ID NOs: 532 and 572; 49) SEQ ID NOs: 532 and 574; 50) SEQ ID NOs: 537 and 553; 51) SEQ ID NOs: 537 and 558; 52) SEQ ID NOs: 537 and 577; 53) SEQ ID NOs: 537 and 563; 54) SEQ ID NOs: 537 and 567; 55) SEQ ID NOs: 537 and 570; 56) SEQ ID NOs: 537 and 572; 57) SEQ ID NOs: 537 and 574; 58) SEQ ID NOs: 539 and 553; 59) SEQ ID NOs: 539 and 558; 60) SEQ ID NOs: 539 and 577; 61) SEQ ID NOs: 539 and 563; 62) SEQ ID NOs: 539 and 567; 63) SEQ ID NOs: NO:539 and 570; 64) SEQ ID NO:539 and 572; 65) SEQ ID NO:539 and 574; 66) SEQ ID NO:542 and 553; 67) SEQ ID NO:542 and 558; 68) SEQ ID NO:542 and 577; 69) SEQ ID NO:542 and 563; 70) SEQ ID NO:542 and 567; 71) SEQ ID NO:542 and 570; 72) SEQ ID NO:542 and 572; 73) SEQ ID NO:542 and 574; 74) SEQ ID NO:545 and 553; 75) SEQ ID NO:545 and 558; 76) SEQ ID NO:545 and 577; 77) SEQ ID NO:545 and 563; 78) SEQ ID NO:545 and 567; 79) SEQ ID NO:545 NO:545 and 570; 80) SEQ ID NO:545 and 572; 81) SEQ ID NO:545 and 574; 82) SEQ ID NO:547 and 553; 83) SEQ ID NO:547 and 558; 84) SEQ ID NO:547 and 577; 85) SEQ ID NO:547 and 563; 86) SEQ ID NO:547 and 567; 87) SEQ ID NO:547 and 570; 88) SEQ ID NO:547 and 572; 89) SEQ ID NO:547 and 574; 90) SEQ ID NO:550 and 553, 91) SEQ ID NO:702 and 704; 92) SEQ ID NO:707 and 708; 93) SEQ ID NO:707 and 709; 94) SEQ ID NO:712 and 76;95) SEQ ID NOs: 716 and 64; or 96) SEQ ID NOs: 717 and 116. ;

[0228] In certain embodiments, the present disclosure provides antibodies or antigen-binding fragments that bind RSV-F, comprising a heavy chain variable domain (VH) comprising complementarity determining regions (CDRs) H1, CDRH2, and CDRH3, and a light chain variable domain (VL) comprising CDRL1, CDRL2, and CDRL3, wherein the CDRs are identified according to the IMGT numbering system, and wherein: (i) optionally, CDRH1 comprises or consists of: SEQ ID NO: NO:3, 137, 147, 160, 170, 182, 216, 234, 244, 262, 278, 285, 301, 333, 363, 370, 13, 23, 31, 39, 54, 60, 74, 80, 87, 112, 121, 130, 380, 387, 396, 728, 738, 747, 756, 766, 776, 785, 795, 805, 81 4, 887, 890, 417, 441, 452, 459, 471, 481, 492, 498, 505, 514, 528 and 533, or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline-encoded amino acids; (ii) optionally, CDRH2 comprises or consists of: SEQ 42, 453, 464, 506, 515, 534, 540, 543, and 548, or a functional variant thereof comprising one, two, or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline-encoded amino acids;(iii) Optionally, the CDRH3 comprises or consists of SEQ ID NO: 5, 139, 148, 162, 176, 183, 190, 197, 203, 218, 227, 236, 245, 255, 264, 272, 280, 286, 294, 303, 310, 317, 322, 328, 335, 343, 353, 358, 365, 372, 730, 740, 749, 758, 768, 778, 787, 797, 806, 821, 824, 832, 835, 841, 842 4, 15, 25, 33, 48, 62, 89, 114, 123, 131, 389, 398, 406, 427, 432, 476, 493, 499, 507, 516, 535 and 551, or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline-encoded amino acids; (iv) optionally, CDRL1 comprises or consists of: SEQ 445, 456, 488, 554, 561, 564, and 568, or a functional variant thereof comprising one, two, or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline-encoded amino acids; (v) optionally, CDRL2 comprises or consists of: The amino acid sequence of any one of NOs: 9, 143, 152, 156, 166, 200, 207, 222, 240, 268, 290, 314, 339, 734, 752, 762, 772, 791, 801, 856, 871, 19, 43, 66, 117, 392, 409, 467, 489, 510, 519, 555 and 705, or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline-encoded amino acids;and / or (vi) optionally, CDRL3 comprises or consists of SEQ ID NO: 10, 144, 153, 157, 167, 179, 187, 194, 208, 213, 223, 231, 241, 248, 259, 269, 275, 291, 298, 307, 325, 340, 376, 735, 744, 753, 763, 773, 782, 792, 802, 810, 848, 852, 866, 20, 28, 36, 44 , 51, 57, 67, 77, 84, 93, 118, 127, 134, 384, 393, 402, 410, 420, 438, 446, 468, 502, 511, 556 and 520, or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline-encoded amino acids. ;

[0229] In certain embodiments, the present disclosure provides antibodies or antigen-binding fragments that bind RSV-F, comprising a heavy chain variable domain (VH) comprising complementarity determining regions (CDRs) H1, CDRH2, and CDRH3, and a light chain variable domain (VL) comprising CDRL1, CDRL2, and CDRL3, wherein the CDRs are identified according to the IMGT numbering system, and wherein: (i) optionally, CDRH1 comprises or consists of: SEQ ID NO: NO:3, 137, 147, 160, 170, 182, 216, 234, 244, 262, 278, 285, 301, 333, 363, 370, 728, 738, 747, 756, 766, 776, 785, 795, 805, 814, 887 and 890, or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline-encoded amino acids; (ii) optionally, CDRH2 comprises or consists of: SEQ ID NO:3, 137, 147, 160, 170, 182, 216, 234, 244, 262, 278, 285, 301, 333, 363, 370, 728, 738, 747, 756, 766, 776, 785, 795, 805, 814, 887 and 890, NO:4, 138, 161, 217, 226, 235, 263, 279, 302, 334, 364, 371, 729, 739, 748, 757, 767, 777, 786, 796, 815, 818, 838, 884, 894 and 897, or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline-encoded amino acids; (iii) optionally, the CDRH3 comprises or consists of: SEQ ID NO:4, 138, 161, 217, 226, 235, 263, 279, 302, 334, 364, 371, 729, 739, 748, 757, 767, 777, 786, 796, 815, 818, 838, 884, 894 and 897, or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline-encoded amino acids; 821, 824, 832, 835, 841, and 844, or a functional variant thereof comprising one, two, or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline-encoded amino acids;(iv) Optionally, CDRL1 comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 8, 142, 151, 165, 173, 186, 193, 206, 221, 230, 239, 258, 267, 289, 297, 306, 313, 338, 350, 375, 733, 743, 761, 771, 781, 790, 800 and 809, or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline-encoded amino acids; (v) Optionally, CDRL2 comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 8, 142, 151, 165, 173, 186, 193, 206, 221, 230, 239, 258, 267, 289, 297, 306, 313, 338, 350, 375, 733, 743, 761, 771, 781, 790, 800 and 809; NO:9, 143, 152, 156, 166, 200, 207, 222, 240, 268, 290, 314, 339, 734, 752, 762, 772, 791, 801, 856 and 871, or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline-encoded amino acids; and / or (vi) optionally, CDRL3 comprises or consists of: SEQ ID NO:9, 143, 152, 156, 166, 200, 207, 222, 240, 268, 290, 314, 339, 734, 752, 762, 772, 791, 801, 856 and 871, or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline-encoded amino acids; and / or The amino acid sequence of any one of NO: 10, 144, 153, 157, 167, 179, 187, 194, 208, 213, 223, 231, 241, 248, 259, 269, 275, 291, 298, 307, 325, 340, 376, 735, 744, 753, 763, 773, 782, 792, 802, 810, 848, 852 and 852, or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline-encoded amino acids.

[0230] In additional embodiments, the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 of the antibody or antigen-binding fragment that binds RSV-F comprise or consist of the CDRs identified in Table 2 for anti-RSV MPK antibodies and have the corresponding amino acid sequences shown in Table 1 and the Sequence Listing. Specifically, the CDRs may comprise or consist of the following CDRs: MPK44, MPK65-v2, MPK161-v2, MPK163, MPK165, MPK167, MPK168, MPK169-v2, MPK170, MPK171-v1, MPK171-v2, MPK173, MPK175, MPK176, MPK177, MPK178, MPK179-v4, MPK180, MPK181, MPK182, MPK185, MPK186, MPK187, MPK188, MPK189, MPK191, MPK193, MPK194-v2, MPK195, MPK197, MPK198, MPK201, MPK202, MPK203, MPK204, MPK205, MPK206, MPK207, MPK208, MPK209, MPK210, MPK211, MPK212, MPK213, MPK214, MPK215, MPK216, MPK217, MPK218 K202, MPK203, MPM10, MPM2, MPM8, MPO1, MPO7, MPP1, MPP2, MPR16 or MPR19-v2, MPK65-v (any of 1-7) (any of 1-2), MPK201-v (any of 1-6) (any of 1-2), MPK176-v (any of 1-6) (any of 5) or MPM2-v (any of 1, 2, 4, 5) (any of 1-9), in particular MPK176-v1.3, MPK176-v4.3, MPK201-v1.1, MPK201-v1.2, MPK201-v4.1, MPK65v2-v1.2 or MPK65v2-v3.1.

[0231] More specifically, the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 of the antibody or antigen-binding fragment that binds RSV-F comprise or consist of CDRs having the following sequences, respectively: 1) SEQ ID NOs: 3-5 and 8-10; 2) SEQ ID NOs: 137-139 and 142-144; 3) SEQ ID NOs: 147, 138, 148, and 151-153; 4) SEQ ID NOs: 147, 138, 148, 142, 156, and 157; 5) SEQ ID NOs: 160-162 and 165-167; 6) SEQ ID NOs: 170, 138, 148, 173, 156, and 157; 7) SEQ ID NOs: 137, 138, 176, 142, 143, and 179; 8) SEQ ID NOs: NO:182, 138, 183, 186, 143 and 187; 9) SEQ ID NO:137, 138, 190, 193, 143, 194; 10) SEQ ID NO:137, 138, 197, 142, 200 and 157; 11) SEQ ID NO:137, 138, 203 and 206-208; 12) SEQ ID NO:137, 138, 203, 142, 143 and 213; 13) SEQ ID NO:216-218 and 221-223; 14) SEQ ID NO:137, 226, 227, 230, 143 and 231; 15) SEQ ID NO:234-236 and 239-241; 16) SEQ ID NO: NO: 244, 138, 245, 173, 143 and 248; 17) SEQ ID NO: 182, 138, 148, 142, 156 and 157; 18) SEQ ID NO: 137, 138, 255, 258, 156 and 259; 19) SEQ ID NO: 262-264 and 267-269; 20) SEQ ID NO: 137, 138, 272, 173, 143 and 275; 21) SEQ ID NO: 278-280 and 206-208; 22) SEQ ID NO: 285, 138, 286 and 289-291; 23) SEQ ID NO: 137, 226, 294, 297, 143 and 298; 24) SEQ ID NO: NO: 301-303, 306, 268 and 307; 25) SEQ ID NO: 137, 138, 310, 313, 314 and 157; 26) 137, 138, 317, 142, 143 and 213; 27) SEQ ID NO: 137, 138, 322, 142, 143 and 325;28) SEQ ID NOs: 137, 138, 322, 142, 143, and 325; 29) SEQ ID NOs: 170, 138, 328, 142, 143, and 157; 30) SEQ ID NOs: 333-335 and 338-340; 31) SEQ ID NOs: 137, 138, 343, 173, 143, and 213; 32) SEQ ID NOs: 301-303, 350, 268, and 307; 33) SEQ ID NOs: 137, 138, 353, 142, 143, and 213; 34) SEQ ID NOs: 137, 226, 358, 142, 143, and 231; 35) SEQ ID NOs: 363-365, 368-370; 36) SEQ ID NOs: 371-372 NO:370-372, 375, 143 and 376; 37) SEQ ID NO:738, 884, 740, 743, 240 and 744; 38) SEQ ID NO:738-740, 743, 240 and 744; 39) SEQ ID NO:728-730 and 733-735; 40) SEQ ID NO:747-749, 221 and 752-753; 41) SEQ ID NO:756-758 and 761-763; 42) SEQ ID NO:766-768 and 771-773; 43) SEQ ID NO:776-778, 781, 268 and 782; 44) SEQ ID NO:785-787 and 790-792; 45) SEQ ID NO: NO:795-797 and 800-802; 46) SEQ ID NO:805, 796, 806, 809, 801 and 810; 47) SEQ ID NO:234, 838, 236 and 239-241; 48) SEQ ID NO:137, 226, 358, 142, 143 and 848; 49) SEQ ID NO:814, 226, 358, 142, 143 and 231; 50) SEQ ID NO:137-139, 142, 143 and 852; 51) SEQ ID NO:814, 818, 139 and 142-144; 52) 738, 884, 740, 743, 240 and 744; 53) SEQ ID NO: NO:887, 884, 740, 743, 240 and 744; or 54) SEQ ID NO:738, 884, 740, 743, 240 and 744. ;

[0232] In another embodiment, the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 of the antibody or antigen-binding fragment that binds MPV-F comprise or consist of the CDRs identified for the anti-MPV MPK antibodies in Table 2 and have the corresponding amino acid sequences shown in Table 1 and the Sequence Listing. Specifically, the CDRs comprise or consist of the CDRs of MPK15 disclosed herein.

[0233] In certain embodiments, the present disclosure provides antibodies or antigen-binding fragments that bind MPV-F, comprising a heavy chain variable domain (VH) comprising complementarity determining regions (CDRs) H1, CDRH2, and CDRH3, and a light chain variable domain (VL) comprising CDRL1, CDRL2, and CDRL3, wherein the CDRs are identified according to the IMGT numbering system, and wherein: (i) optionally, CDRH1 comprises or consists of: SEQ ID NO: NO:102, 13, 23, 31, 39, 54, 60, 74, 80, 87, 112, 121, 130, 380, 387, 396, 417, 441, 452, 459, 471, 481, 492, 498, 505, 514, 528 and 533, or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline-encoded amino acids; (ii) optionally, CDRH2 comprises or consists of: SEQ ID NO:102, 13, 23, 31, 39, 54, 60, 74, 80, 87, 112, 121, 130, 380, 387, 396, 417, 441, 452, 459, 471, 481, 492, 498, 505, 514, 528 and 533, NO: 103, 14, 24, 32, 40, 47, 61, 81, 88, 96, 113, 122, 388, 397, 405, 442, 453, 464, 506, 515, 534, 540, 543 and 548, or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline-encoded amino acids; (iii) optionally, the CDRH3 comprises or consists of: SEQ ID NO: 103, 14, 24, 32, 40, 47, 61, 81, 88, 96, 113, 122, 388, 397, 405, 442, 453, 464, 506, 515, 534, 540, 543 and 548, or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline-encoded amino acids; 476, 493, 499, 507, 516, 535, and 551, or a functional variant thereof comprising one, two, or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline-encoded amino acids; (iv) optionally, CDRL1 comprises or consists of the amino acid sequence set forth in any one of SEQ ID NOs: 107, 18, 65, 92, 99, 126, 383, 401, 437, 445, 456, 488, 554, 561, 564, and 568, or a functional variant thereof comprising one, two, or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline-encoded amino acids;(v) optionally, CDRL2 comprises or consists of the amino acid sequence set forth in any one of SEQ ID NOs: 108, 19, 43, 66, 117, 392, 409, 467, 489, 510, 519, 555 and 705, or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline-encoded amino acids; and / or (vi) optionally, CDRL3 comprises or consists of the amino acid sequence set forth in any one of SEQ ID NOs: 108, 19, 43, 66, 117, 392, 409, 467, 489, 510, 519, 555 and 705, or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline-encoded amino acids; The amino acid sequence shown in any one of NOs: 109, 20, 28, 36, 44, 51, 57, 67, 77, 84, 93, 118, 127, 134, 384, 393, 402, 410, 420, 438, 446, 468, 502, 511, 556 and 520, or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline-encoded amino acids.

[0234] In certain embodiments, the present disclosure provides antibodies or antigen-binding fragments that bind MPV-F, comprising a heavy chain variable domain (VH) comprising complementarity determining regions (CDRs) H1, CDRH2, and CDRH3, and a light chain variable domain (VL) comprising CDRL1, CDRL2, and CDRL3, wherein the CDRs are identified according to the IMGT numbering system, and wherein: (i) optionally, CDRH1 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 102, or a functional variant thereof comprising one, two, or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline-encoded amino acids; (ii) optionally, CDRH2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 103, or a functional variant thereof comprising one, two, or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline-encoded amino acids; (iii) optionally, CDRH3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: or (iv) optionally, CDRL1 comprises or consists of the amino acid sequence shown in SEQ ID NO: 107 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions for a germline-encoded amino acid; (v) optionally, CDRL2 comprises or consists of the amino acid sequence shown in SEQ ID NO: 108 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions for a germline-encoded amino acid; and / or (vi) optionally, CDRL3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 109 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions for a germline-encoded amino acid.

[0235] In certain embodiments, the present disclosure provides antibodies or antigen-binding fragments that bind to RSV-F and / or MPV-F, comprising a heavy chain variable domain (VH) comprising complementarity determining regions (CDRs) H1, CDRH2, and CDRH3, and a light chain variable domain (VL) comprising CDRL1, CDRL2, and CDRL3, wherein the CDRs are identified according to the IMGT numbering system, and wherein: (i) optionally, CDRH1 comprises or consists of: SEQ ID NO: NO: 13, 23, 31, 39, 54, 60, 74, 80, 87, 112, 121, 130, 380, 387, 396, 417, 441, 452, 459, 471, 481, 492, 498, 505, 514, 528 and 533, or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline-encoded amino acids; (ii) optionally, CDRH2 comprises or consists of: SEQ ID NO: 13, 23, 31, 39, 54, 60, 74, 80, 87, 112, 121, 130, 380, 387, 396, 417, 441, 452, 459, 471, 481, 492, 498, 505, 514, 528 and 533, NO: 14, 24, 32, 40, 47, 61, 81, 88, 96, 113, 122, 388, 397, 405, 442, 453, 464, 506, 515, 534, 540, 543 and 548, or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline-encoded amino acids; (iii) optionally, the CDRH3 comprises or consists of: SEQ ID NO: 14, 24, 32, 40, 47, 61, 81, 88, 96, 113, 122, 388, 397, 405, 442, 453, 464, 506, 515, 534, 540, 543 and 548, or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline-encoded amino acids; 561, 564, and 568, or a functional variant thereof comprising one, two, or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline-encoded amino acids; (iv) optionally, CDRL1 comprises or consists of the amino acid sequence set forth in any one of SEQ ID NOs: 18, 65, 92, 99, 126, 383, 401, 437, 445, 456, 488, 554, 561, 564, and 568, or a functional variant thereof comprising one, two, or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline-encoded amino acids;(v) optionally, CDRL2 comprises or consists of the amino acid sequence set forth in any one of SEQ ID NOs: 19, 43, 66, 117, 392, 409, 467, 489, 510, 519, 555 and 705, or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline-encoded amino acids; and / or (vi) optionally, CDRL3 comprises or consists of the amino acid sequence set forth in any one of SEQ ID NOs: 19, 43, 66, 117, 392, 409, 467, 489, 510, 519, 555 and 705, or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline-encoded amino acids; The amino acid sequence shown in any one of NOs: 20, 28, 36, 44, 51, 57, 67, 77, 84, 93, 118, 127, 134, 384, 393, 402, 410, 420, 438, 446, 468, 502, 511, 556 and 520, or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline-encoded amino acids.

[0236] In additional embodiments, the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 of the antibody or antigen-binding fragment that binds RSV-F and / or MPV-F comprise or consist of the CDRs identified in Tables 2 and 20 for anti-RSV / MPV MPK antibodies or MPH antibodies, and have the corresponding amino acid sequences shown in Table 1 and the Sequence Listing. Specifically, the CDRs comprise or consist of the following CDRs: MPK190-v1.3, MPK9, MPK10, MPK18, MPK30-v1, MPK36-v3, MPK51, MPK51-v1.1, MPK67, MPK73, MPK77, MPK77-v1.1, MPK86, MPK92, MPK99, MPK102, MPK104, MPK104-v.1.1, MPK104-v1.3, MPK108, MPK126, MPK127, MPK129 disclosed herein. , MPK130, MPK132-v2, MPK133, MPK136, MPK141, MPK142-v1, MPK142-v2, MPK144, MPK145, MPK146, MPK149, MPK150-v2, MPK151, MPK152, MPK153, MPK155, MPK157, MPK158, MPK162, MPK174-v2, MPK190, MPK190-v1.1, MPK196, MPK204, MPH12, and variants of MPH12. These cross-binding or cross-neutralizing antibodies can also be used to bind RSV-F alone, or to bind MPV-F alone; they do not need to be used in situations where binding and / or neutralization of both RSV and MPV targets occurs.

[0237] The term "CL" refers to "immunoglobulin light chain constant region" or "light chain constant region", i.e., the constant region from the antibody light chain. The term "CH" refers to "immunoglobulin heavy chain constant region" or "heavy chain constant region", which can be further divided into CH1, CH2 and CH3 (IgA, IgD, IgG) or CH1, CH2, CH3 and CH4 domains (IgE, IgM) according to the antibody isotype. The Fc region of the antibody heavy chain is further described herein. In any of the embodiments currently disclosed, the antibodies or antigen-binding fragments of the present disclosure comprise any one or more of CL, CH1, CH2 and CH3. In any of the embodiments currently disclosed, the antibodies or antigen-binding fragments of the present disclosure may comprise any one or more of CL, CH1, CH2 and CH3. In certain embodiments, CL comprises an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 905. In certain embodiments, CL comprises an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to a human lambda light chain constant domain.

[0238] In certain embodiments, CH1-CH3 comprises an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 664-668.

[0239] It will be appreciated that, for example, production in mammalian cell lines can remove one or more C-terminal lysines of an antibody heavy chain (see, e.g., Liu et al., mAbs 6(5): 1145-1154 (2014)). Thus, the antibodies or antigen-binding fragments of the present disclosure may comprise a heavy chain, CH1-CH3, CH3, or Fc polypeptide in which a C-terminal lysine residue or a C-terminal glycine-lysine is present or absent; in other words, embodiments in which the C-terminal residue of the heavy chain, CH1-CH3, or Fc polypeptide is not lysine, as well as embodiments in which lysine is the C-terminal residue, are encompassed. In certain embodiments, a composition comprises a plurality of antibodies and / or antigen-binding fragments of the present disclosure, wherein one or more antibodies or antigen-binding fragments do not comprise a lysine residue or a C-terminal glycine-lysine at the C-terminus of a heavy chain, CH1-CH3, or Fc polypeptide, and wherein one or more antibodies or antigen-binding fragments comprise a lysine residue at the C-terminus of a heavy chain, CH1-CH3, or Fc polypeptide.

[0240] "Fab" (fragment antigen binding) is the part of an antibody that binds to an antigen and comprises the variable region of the heavy chain and CH1 connected to a light chain by an interchain disulfide bond. Each Fab fragment is monovalent with respect to antigen binding, i.e., it has a single antigen binding site. Pepsin treatment of an antibody produces a single large F(ab')2 fragment, which roughly corresponds to two disulfide-linked Fab fragments with divalent antigen binding activity and still cross-links antigen. Fab and F(ab')2 are both examples of "antigen binding fragments." Fab' fragments differ from Fab fragments in having several additional residues at the carboxyl terminus of the CH1 domain, including one or more cysteines from the antibody hinge region. Fab'-SH is herein the designation for Fab' in which the cysteine ​​residues of the constant domains bear a free sulfhydryl group. F(ab')2 antibody fragments were originally produced as pairs of Fab' fragments with hinge cysteines between them. Other chemical couplings of antibody fragments are also known.

[0241] Fab fragments can be connected, for example, by peptide linkers to form single-chain Fab, also referred to herein as "scFab". In these embodiments, the interchain disulfide bonds present in natural Fab may not be present, and the linker is used in whole or in part to link or connect the Fab fragments in a single polypeptide chain. The heavy chain-derived Fab fragment (e.g., comprising, consisting of, or essentially consisting of VH+CH1 or "Fd") and the light chain-derived Fab fragment (e.g., comprising, consisting of, or essentially consisting of VL+CL) can be connected in any arrangement to form scFab. For example, scFab can be arranged in the N-terminal to C-terminal direction according to (heavy chain Fab fragment-linker-light chain Fab fragment) or (light chain Fab fragment-linker-heavy chain Fab fragment). Peptide linkers and exemplary linker sequences for scFab are discussed in further detail herein.

[0242] "Fv" is a small antibody fragment that contains a complete antigen recognition and antigen binding site. The fragment generally consists of a dimer of one heavy-chain variable region domain and one light-chain variable region domain in tight, non-covalent association. 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, but generally with lower affinity than the entire binding site.

[0243] "Single-chain Fv" is also abbreviated as "sFv" or "scFv" and is a fragment comprising V sequences linked into a single polypeptide chain. H and V L In some embodiments, the scFv polypeptide comprises an antibody fragment comprising an antibody domain. H With V LA polypeptide linker between the domains and connecting these domains enables scFv to retain or form the desired structure for antigen binding. Such peptide linkers can be incorporated into fusion polypeptides using standard techniques well known in the art. For a review of scFv, see Pluckthun, The Pharmacology of Monoclonal Antibodies, Vol. 113, Rosenburg and Moore, eds., Springer-Verlag, New York, pp. 269-315 (1994); Borrebaeck 1995, see below. In certain embodiments, an antibody or antigen-binding fragment includes an scFv comprising a VH domain, a VL domain, and a peptide linker connecting the VH domain to the VL domain. In a specific embodiment, an scFv comprises a VH domain connected to a VL domain via a peptide linker, which may be in a VH-linker-VL orientation or in a VL-linker-VH orientation. Any scFv disclosed herein can be engineered such that the C-terminus of the VL domain is linked to the N-terminus of the VH domain via a short peptide sequence, or vice versa (i.e., (N)VL(C)-linker-(N)VH(C) or (N)VH(C)-linker-(N)VL(C). Alternatively, in some embodiments, the linker can be attached to the N-terminal portion or N-terminus of the VH domain, the VL domain, or both.

[0244] The peptide linker sequence can be selected, for example, based on: (1) its ability to adopt a flexible, extended conformation; (2) its inability or inability to adopt a secondary structure that can interact with a functional epitope on the first and second polypeptides and / or on the target molecule; and / or (3) the lack or relative lack of hydrophobic residues or charged residues that may react with the polypeptides and / or target molecules. Other considerations for linker design (e.g., length) may include the conformation or range of conformations in which VH and VL can form a functional antigen binding site. In certain embodiments, the peptide linker sequence contains, for example, Gly, Asn, and Ser residues. Other nearly neutral amino acids (such as Thr and Ala) may also be included in the linker sequence. Other amino acid sequences that can be used effectively as linkers include those disclosed in Maratea et al., Gene 40:39-46 (1985); Murphy et al., Proc. Natl. Acad. Sci. USA 83:8258-8262 (1986); U.S. Pat. No. 4,935,233 and U.S. Pat. No. 4,751,180. Other illustrative and non-limiting examples of linkers, when present in a single iteration or repeated 1 to 5 times or more, can include, for example, Glu-Gly-Lys-Ser-Ser-Gly-Ser-Gly-Ser-Glu-Ser-Lys-Val-Asp (Chaudhary et al., Proc. Natl. Acad. Sci. USA 87: 1066-1070 (1990)) and Lys-Glu-Ser-Gly-Ser-Val-Ser-Ser-Glu-Gln-Leu-Ala-Gln-Phe-Arg-Ser-Leu-Asp (Bird et al., Science 242: 423-426 (1988)), as well as the pentamer Gly-Gly-Gly-Gly-Ser. Any suitable linker can be used, and generally, will be about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 15 23, 24, 25, 26, 27, 28, 29, 30, 40, 50, 60, 70, 80, 90, 100 amino acids in length, or less than about 200 amino acids in length, and will preferably have a flexible structure (which can provide flexibility and space for conformational movement between the two regions, domains, motifs, fragments or modules connected by the linker), and will preferably be biologically inert and / or have a low risk of immunogenicity in humans.

[0245] scFvs can be constructed using any combination of VH and VL sequences disclosed herein, or any combination of CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences.

[0246] In some embodiments, a linker sequence is not required; for example, when the first and second polypeptides have non-essential N-terminal amino acid regions that can be used to separate the functional domains and prevent steric interference.

[0247] During antibody development, the DNA in germline variable region (V), connecting region (J) and diversity region (D) locus can be rearranged and insertion and / or deletion of nucleotides in the coding sequence can occur. Somatic mutations can be encoded by the resulting sequence and can be identified by reference to corresponding known germline sequences. In some contexts, somatic mutations that are not important to the desired properties of the antibody (for example, binding to RSV and / or MPV fusion glycoprotein antigens) or somatic mutations that give undesirable properties to the antibody (for example, the risk of immunogenicity in a subject to which the antibody has been administered increases) or both can be replaced by corresponding germline encoded amino acids or different amino acids so that the desired properties of the antibody are improved or maintained and the undesirable properties of the antibody are reduced or eliminated. Therefore, in some embodiments, compared to a parent antibody or antigen-binding fragment, an antibody or antigen-binding fragment of the present disclosure includes one or more above germline encoded amino acids in the variable region, provided that the parent antibody or antigen-binding fragment includes one or more somatic mutations. Variable region and CDR amino acid sequences of exemplary anti-RSV-F, anti-MPV-F, and anti-RSV-F and / or MPV-F antibodies of the present disclosure are provided in Table 1, Table 2, and the Sequence Listing.

[0248] In certain embodiments, the antibodies or antigen-binding fragments contain amino acid modifications (eg, substitution mutations) to remove the risk of undesirable oxidation, deamidation, and / or isomerization.

[0249] Also provided herein are variant antibodies comprising one or more amino acid changes in the variable region (e.g., VH, VL, framework, or CDR) compared to the presently disclosed ("parent") antibodies, wherein the variant antibodies bind to RSV and / or MPV fusion glycoproteins.

[0250] In certain embodiments, the antibody binds to RSV-F and

[0251] (i) VH comprises the same polypeptide as SEQ ID NO: 2, 136, 146, 159, 169, 175, 181, 189, 196, 202, 210, 215, 225, 233, 243, 250, 254, 261, 271, 277, 284, 293, 300, 309, 316, 321, 327, 332, 342, 347, 352, 357, 362, 369, 727, 73 7, 746, 755, 765, 775, 784, 794, 804, 813, 817, 820, 823, 826, 828, 831, 834, 837, 840, 843, 883, 886, 889, 893, 896, 899, 901, 903, 129, 12, 38, 46, 53, 59, 69, 120, 73, 79, 86, 95, 22, 111, 30, 378, 386, 395, 404, 412, 416, 422, 426, 431, 440, 451, 458, 463, 470, 475, 480, 485, 491, 497, 532, 537, 539, 542, 545, 547, 550, 504, 513, 524, 527, 702, 707, 712, and 71 6, wherein the sequence variation is optionally limited to one or more framework regions and / or the sequence variation comprises one or more substitutions to the germline-encoded amino acid; and / or

[0252] (ii) VL comprises the same peptide as SEQ ID NO: 7, 141, 150, 155, 164, 172, 178, 185, 192, 199, 205, 212, 220, 229, 238, 247, 252, 257, 266, 274, 282, 288, 296, 305, 312, 319, 324, 330, 337, 345, 349, 355, 360, 367, 37 4, 732, 742, 751, 760, 770, 780, 789, 799, 808, 847, 851, 855, 858, 860, 862, 865, 868, 870, 873, 875, 877, 879, 881, 133, 17, 42, 50, 56, 64, 71, 125, 76, 83, 91, 98, 27, 116, 3 , 482, 483, 487, 495, 501, 509, 518, 522, 530, 553, 558, 560, 563, 567, 570, 572, 574, 704, and 710, wherein the sequence variation is optionally limited to one or more framework regions and / or the sequence variation comprises one or more substitutions to germline-encoded amino acids.

[0253] In certain embodiments, the antibody binds to RSV-F and

[0254] (i) a VH comprising the sequence of SEQ ID NO: 2, 136, 146, 159, 169, 175, 181, 189, 196, 202, 210, 215, 225, 233, 243, 250, 254, 261, 271, 277, 284, 293, 300, 309, 316, 321, 327, 332, 342, 347, 352, 357, 362, 369, 727, 737, 746, 755, 765, 775, 784, 794, 804, 813, 817, 820, 823, 826, 8, 831, 834, 837, 840, 843, 883, 886, 889, 893, 896, 899, 901, and 903, wherein the sequence variation is optionally limited to one or more framework regions and / or the sequence variation comprises one or more substitutions to germline-encoded amino acids; and / or

[0255] (ii) a VL comprising the same sequence as SEQ ID NO: 7, 141, 150, 155, 164, 172, 178, 185, 192, 199, 205, 212, 220, 229, 238, 247, 252, 257, 266, 274, 282, 288, 296, 305, 312, 319, 324, 330, 337, 345, 349, 355, 360, 367, 374, 732, 742, 751, 760, 770, 780, 789, 799, 808, 847, 851, 855, 858, 860, 862, 865, 868, 870, 873, 875, 877, 879, and 881, wherein the sequence variation is optionally limited to one or more framework regions and / or the sequence variation comprises one or more substitutions to the germline-encoded amino acid.

[0256] In certain embodiments, the antibody binds to MVP-F and

[0257] (i) a VH comprising the sequence of SEQ ID NO: 101, 132, 16, 41, 49, 55, 63, 70, 124, 75, 82, 90, 97, 26, 115, 34, 381, 390, 399, 407, 413, 418, 423, 428, 433, 435, 443, 448, 454, 460, 465, 472, 477, 482, 486, 494, 500, 508, 517, 521, 525, 529 , 703, 707, 712, and 716, wherein the sequence variation is optionally limited to one or more framework regions and / or the sequence variation comprises one or more substitutions to the germline-encoded amino acid; and / or

[0258] (ii) a VL comprising the same sequence as SEQ ID NO: 106, 133, 17, 42, 50, 56, 64, 71, 125, 76, 83, 91, 98, 27, 116, 35, 382, ​​391, 400, 408, 414, 419, 424, 429, 434, 436, 444, 449, 455, 461, 466, 473, 478, 483, 487, 495, 501, 509, 518, 522, 530, 553, 558, 560 , 563, 567, 570, 572, 574, 704 and 710 have at least 80% (e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identity to the amino acid sequence set forth in any one of , 563, 567, 570, 572, 574, 704 and 710, or consist of an amino acid sequence having at least 80% (e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identity, wherein the sequence variation is optionally limited to one or more framework regions and / or the sequence variation comprises one or more substitutions to germline-encoded amino acids.

[0259] In certain embodiments, the antibody binds to MVP-F and

[0260] (i) the VH comprises or consists of an amino acid sequence that is at least 80% (e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identical to the amino acid sequence set forth in SEQ ID NO: 101, wherein the sequence variation is optionally limited to one or more framework regions and / or the sequence variation comprises one or more substitutions to germline-encoded amino acids; and / or

[0261] (ii) the VL comprises or consists of an amino acid sequence that is at least 80% (e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identical to the amino acid sequence set forth in SEQ ID NO: 106, wherein the sequence variation is optionally limited to one or more framework regions and / or the sequence variation comprises one or more substitutions to germline-encoded amino acids.

[0262] In certain embodiments, the antibody binds to RSV-F and / or MPV-F and

[0263] (i) VH comprises the same polypeptide as SEQ ID NO: 129, 12, 38, 46, 53, 59, 69, 120, 73, 79, 86, 95, 22, 111, 30, 378, 386, 395, 404, 412, 416, 422, 426, 431, 440, 451, 458, 463, 470, 475, 480, 485, 491, 497, 532, 537, 539, 542, 545, 547, 550, 504, 513, 5 24, 527, 702, 707, 712, and 716, wherein the sequence variation is optionally limited to one or more framework regions and / or the sequence variation comprises one or more substitutions to germline-encoded amino acids; and / or

[0264] (ii) VL comprises the same peptide as SEQ ID NO: 133, 17, 42, 50, 56, 64, 71, 125, 76, 83, 91, 98, 27, 116, 35, 382, ​​391, 400, 408, 414, 419, 424, 429, 434, 436, 444, 449, 455, 461, 466, 473, 478, 483, 487, 495, 501, 509, 518, 522, 530, 553, 558, 560, 570 63, 567, 570, 572, 574, 704, and 710, wherein the sequence variation is optionally limited to one or more framework regions and / or the sequence variation comprises one or more substitutions to germline-encoded amino acids.

[0265] In certain embodiments, the antibody binds to RSV-F and / or MPV-F and

[0266] (i) the VH comprises, or consists of, an amino acid sequence that is at least 80% (e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identical to the amino acid sequence set forth in any one of SEQ ID NOs: 532, 537, 539, 542, 545, 547 or 550, wherein the sequence variation is optionally limited to one or more framework regions and / or the sequence variation comprises one or more substitutions to germline-encoded amino acids; and / or

[0267] (ii) the VL comprises or consists of an amino acid sequence that is at least 80% (e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identical to the amino acid sequence set forth in any one of SEQ ID NOs: 553, 558, 560, 563, 567, 570, 572 or 574, wherein the sequence variation is optionally limited to one or more framework regions and / or the sequence variation comprises one or more substitutions to germline-encoded amino acids.

[0268] In certain embodiments, the antibodies or antigen-binding fragments of the present disclosure are monospecific (e.g., bind to a single epitope) or multispecific (e.g., bind to multiple epitopes and / or target molecules). Antibodies and antigen-binding fragments can be constructed in a variety of formats. Exemplary antibody formats are disclosed in Spiess et al., Mol. Immunol. 67(2):95 (2015) and in Brinkmann and Kontermann, mAbs 9(2):282-212 (2017), which formats and methods for their preparation are incorporated herein by reference and include, for example, bispecific T cell engagers (BiTEs), DARTs, Knobs-Into-Holes (KIH) assemblies, scFv-CH3-KIH assemblies, KIH common light chain antibodies, TandAbs, triabodies, TriBi minibodies, Fab-scFv, scFv-CH-CL-scFv, F(ab')2-scFv2, tetravalent HCabs, intrabodies, CrossMabs, dual-acting Fabs (DAFs) (two-in-one or four-in-one), DutaMabs, DT-IgGs, charge pairs, Fab arm exchange, and Fab-arm Exchange), SEEDbodies, Triomabs, LUZ-Y assemblies, Fcabs, kappa bodies, orthogonal Fabs, DVD-Igs (e.g., U.S. Pat. No. 8,258,268, the entirety of which is incorporated herein by reference), IgG(H)-scFv, scFv-(H)IgG, IgG(L)-scFv, scFv-(L)IgG, IgG(L,H)-Fv, IgG(H)-V, V(H)-IgG, IgG(L)-V, V(L)-IgG, KIH IgG-scFab, 2scFv-IgG, IgG-2scFv, scFv4-Ig, Zybodies, and DVI-IgG (four-in-one), as well as so-called FIT-Igs (e.g., PCT Publication No. WO 2015 / 103072, the entirety of which is incorporated herein by reference), the so-called WuxiBody format (e.g., PCT Publication No. WO 2015 / 103074, the entirety of which is incorporated herein by reference), 2019 / 057122, which formats are incorporated herein by reference in their entirety) and the so-called In-Elbow-Insert Ig format (IEI-Ig; for example, PCT Publication Nos. WO 2019 / 024979 and WO 2019 / 025391, which formats are incorporated herein by reference in their entirety).

[0269] In certain embodiments, the antibody or antigen-binding fragment comprises two or more VH domains, two or more VL domains, or both (i.e., two or more VH domains and two or more VL domains). In a specific embodiment, the antigen-binding fragment has the format (N-terminal to C-terminal direction) VH-linker Vl-linker Vh-linker VL, wherein the two VH sequences may be the same or different and the two VL sequences may be the same or different. Such linked scFvs may comprise any combination of VH and VL domains arranged to bind to a given target, and in a format comprising two or more VH and / or two or more VL, may bind to one, two or more different epitopes or antigens. It should be understood that the format incorporating multiple antigen-binding domains may comprise VH and / or VL sequences in any combination or orientation. For example, the antigen-binding fragment may have the format VL-linker Vh-linker Vl-linker VH, VH-linker Vl-linker Vl-linker VH, or VL-linker Vh-linker Vh-linker VL.

[0270] In embodiments comprising two VH domains and / or two VL domains, one or more VH domains or VL domains or one or more or two or more CDRs thereof are according to the sequences shown in Table 1 and SEQ ID NOs: 1-574 and 701-903 of the Sequence Listing, and optionally according to the combinations shown for specific antibodies in Table 2 and Table 20. In such embodiments, one or more VH or VL or one or more or two or more CDRs may also be according to the sequences shown in Table 1 and SEQ ID NOs: 575-655 of the Sequence Listing, and optionally, for anti-RSV antibodies, according to the combinations shown for specific antibodies in Table 3, or for anti-RSV / MPV antibodies, according to the combinations shown for specific antibodies in Table 4.

[0271] More specifically, one or more VH can bind to RSV-F and can include a CDR according to a VH sequence of any one of SEQ ID NO: 576, 586, 591, 600, 604, 613, and 617, and one or more VL can bind to RSV-F and can include a VL sequence according to any one of SEQ ID NO: 581, 588, 596, 602, 609, 615, and 622, as determined using any known CDR numbering method, including Kabat, Chothia, EU, Martin (enhanced Chothia), Contact, AbM, CCG, EU, or AHo numbering methods, or a combination of two or more of these IMGT, Martin (enhanced Chothia), Contact, North, and AHo numbering methods. In certain embodiments, the CDRs are according to the IMGT numbering method. In certain embodiments, the CDRs are according to the antibody numbering method developed by the Chemical Computing Group (CCG); for example, using the Molecular Operating Environment (MOE) software.

[0272] In certain embodiments, CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 may comprise or consist of SEQ ID NO: 577, 592, 605, or 618; SEQ ID NO: 578, 593, 606, or 619; SEQ ID NO: 579, 594, 607, or 620; SEQ ID NO: 582, 597, 610, or 623; SEQ ID NO: 583, 143, 268, or 624, or SEQ ID NO: 584, 597, 610, or 625, respectively. NO:584, 598, 611 or 625, or in each case, a functional variant comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or are substitutions of germline-encoded amino acids, or an amino acid sequence that is at least 80% (e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identical to an amino acid sequence.

[0273] The monospecific or multispecific antibodies or antigen-binding fragments of the present disclosure are constructed to comprise any combination of VH and VL sequences disclosed herein in SEQ ID NOs: 1-574 and 701-903 of Table 1 and the Sequence Listing and / or any combination of CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences, and optionally, according to the combinations set forth for specific antibodies in Table 2 and Table 20. In some embodiments, the bispecific or multispecific antibodies or antigen-binding fragments may comprise one, two, or more antigen-binding domains (e.g., VH and VL) of the present disclosure, and one or more VH or VL, or one or more or two or more CDRs thereof, may also be according to the sequences set forth in SEQ ID NOs: 575-655 of Table 1 and the Sequence Listing, and optionally, for anti-RSV antibodies, according to the combinations set forth for specific antibodies in Table 3 and the Sequence Listing, or, for anti-RSV / MPV antibodies, according to the combinations set forth for specific antibodies in Table 4 and the Sequence Listing. There may be two or more binding domains that bind to the same or different RSV-F and / or MPV-F epitopes, and in some embodiments, the bispecific or multispecific antibodies or antigen-binding fragments as provided herein contain additional RSV-F and / or MPV-F specific binding domains and / or may contain binding domains that bind to different antigens or pathogens entirely.

[0274] In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain, and can be, for example, an IgG1m3 comprising M428L and N434S mutations in the heavy chain. In some embodiments, the antibody or antigen-binding fragment comprises a light chain, and can be, for example, a kappa light chain or a lambda light chain.

[0275] In any of the presently disclosed embodiments, the antibody or antigen-binding fragment can be multispecific; eg, bispecific, trispecific, etc.

[0276] In certain embodiments, the antibody or antigen-binding fragment is at least bispecific and comprises at least a VH and a VL, or three CDRs of the VH and three CDRs of the VL of at least one of the following: i) MPK65-v2-v1.2, MPK65-v2-v3.1, MPK176-v1.3, MPK76-v43., MPK201-v1.2, and MPK 201-v1.4; or ii) the VH and VL amino acid sequences set forth in any one of the following: SEQ ID NOs: 136 and 851; 814 and 141; 233 and 858; 837 and 858; 357 and 847; or 899 and 360, respectively.

[0277] In certain embodiments, the antibody or antigen-binding fragment is at least bispecific and comprises at least the VH and VL of MPK190-v1.3, or the three CDRs of VH and the three CDRs of VL, or the VH and VL amino acid sequences shown in SEQ ID NOs: 702 and 704, respectively.

[0278] In certain embodiments, the antibody or antigen-binding fragment is at least bispecific and comprises at least (A) a first VH and VL, or a first set of six CDRs of at least one of the following, wherein the first set of six CDRs are three HCDRs and three LCDRs of VH and VL: i) MPK65-v2-v1.2, MPK65-v2-v3.1, MPK176-v1.3, MPK76-v43, MPK201-v1.2, and MPK 201-v1.4; or ii) a VH and VL set forth in any one of the following: SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17 NO:136 and 851; 814 and 141; 233 and 858; 837 and 858; 357 and 847; and 899 and 360; and (B) at least a second VH and VL, or a second set of six CDRs, wherein the second set of six CDRs are the three HCDRs and three LCDRs of the VH and VL of MPK190-v1.3, or the VH and VL shown in SEQ ID NO:702 and 704.

[0279] In some embodiments, the antibody or antigen-binding fragment may further comprise an Fc polypeptide or fragment thereof, which Fc polypeptide or fragment thereof comprises or consists of an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical to the amino acid sequence shown in any one of SEQ ID NOs: 664-700, more specifically any one of SEQ ID NOs: 670-700.

[0280] It will be appreciated that, for example, production in a mammalian cell line can remove one or more C-terminal lysines of an antibody heavy chain (see, e.g., Liu et al. mAbs 6(5): 1145-1154 (2014)). Production can also remove one or more C-terminal glycines of an antibody heavy chain. Thus, the antibodies or antigen-binding fragments of the present disclosure may comprise a heavy chain, CH1-CH3, CH3, or Fc polypeptide, wherein a C-terminal lysine and / or glycine residue is present or absent; in other words, embodiments in which the C-terminal residue of a heavy chain, CH1-CH3, or Fc polypeptide is not lysine or glycine, as well as embodiments in which lysine or glycine is the C-terminal residue are encompassed. In certain embodiments, a composition comprises a plurality of antibodies and / or antigen-binding fragments of the present disclosure, wherein one or more antibodies or antigen-binding fragments do not comprise a lysine and / or glycine residue at the C-terminus of a heavy chain, CH1-CH3, or Fc polypeptide, and wherein one or more antibodies or antigen-binding fragments comprise a lysine or glycine residue at the C-terminus of a heavy chain, CH1-CH3, or Fc polypeptide.

[0281] In certain embodiments, an antibody or antigen-binding fragment comprises an Fc polypeptide or fragment thereof. An "Fc" fragment or Fc polypeptide comprises the carboxyl-terminal portions of two antibody H chains (i.e., the CH2 and CH3 domains of an IgG) held together by disulfide bonds. An Fc polypeptide may comprise a dimer composed of two Fc polypeptides (i.e., two CH2-CH3 polypeptides). Antibody "effector functions" refer to biological activities attributable to the Fc region (a native sequence Fc region or an amino acid sequence variant Fc region) of an antibody and vary with the antibody isotype. Examples of antibody effector functions include: C1q binding and complement-dependent cytotoxicity; Fc receptor binding; antibody-dependent cellular cytotoxicity (ADCC); phagocytosis; downregulation of cell surface receptors (e.g., B cell receptors); and B cell activation. As discussed herein, the Fc domain may be modified (e.g., by amino acid substitution) to modify (e.g., improve, reduce, or eliminate) one or more functions of an Fc-containing polypeptide (e.g., an antibody of the present disclosure). Such functions include, for example, Fc receptor (FcR) binding, antibody half-life modulation (e.g., by binding to FcRn), ADCC function, protein A binding, protein G binding, and complement binding. Amino acid modifications that modify (e.g., improve, reduce, or eliminate) Fc function include, for example, T250Q / M428L, M252Y / S254T / T256E, H433K / N434F, M428L / N434S, M428L / N434A, E233P / L234V / L235A / G236+A327G / A330S / P331S, E333A, S239D / A330L / I332E, P257I / Q311, K326W / E333S, S239D / I332E / G236A, N297Q, K322A, S228P, L235E+E318A / K320A / K322A, L234A / L235A (also referred to herein as "LALA"), and L234A / L235A / P329G mutations, which are summarized and annotated in "Engineered Fc Regions" published by InvivoGen (2011), and are incorporated herein by reference.

[0282] For example, to activate the complement cascade, when an immunoglobulin molecule is attached to an antigenic target, the C1q protein complex can bind to two or more IgG1 molecules or one IgM molecule (Ward, ES and Ghetie, V., Ther. Immunol. 2 (1995) 77-94). Burton, DR (Mol. Immunol. 22 (1985) 161-206) described the involvement of the heavy chain region comprising amino acid residues 318 to 337 in complement fixation. Duncan, AR and Winter, G. (Nature 332 (1988) 738-740) used site-directed mutagenesis to report that Glu318, Lys320, and Lys322 form a binding site for C1q. The role of Glu318, Lys320, and Lys322 residues in C1q binding was confirmed by the ability of short synthetic peptides containing these residues to inhibit complement-mediated lysis.

[0283] For example, FcR binding can be mediated by the interaction of the Fc portion (of an antibody) with an Fc receptor (FcR), which is a specialized cell surface receptor on cells including hematopoietic cells. Fc receptors belong to the immunoglobulin superfamily and have been shown to mediate both the clearance of antibody-coated pathogens by phagocytosis of immune complexes and antibody-dependent cellular cytotoxicity (ADCC; Van de Winkel, JG and Anderson, CL, J. Leukoc. Biol. 49 (1991) 511-524). FcRs are defined by their specificity for an immunoglobulin class; the Fc receptor for IgG antibodies is known as FcγR, the Fc receptor for IgE antibodies is known as FcεR, the Fc receptor for IgA antibodies is known as FcαR, etc., and the neonatal Fc receptor is known as FcRn. Fc receptor binding is described, for example, in Ravetch, JV and Kinet, JP, Annu. Rev. Immunol. 9 (1991) 457-492; Capel, PJ et al., Immunomethods 4 (1994) 25-34; de Haas, M. et al., J Lab. Clin. Med. 126 (1995) 330-341; and Gessner, JE et al., Ann. Hematol. 76 (1998) 231-248.

[0284] Cross-linking of the Fc domain of native IgG antibodies to receptors (FcγRs) triggers a variety of effector functions, including phagocytosis, antibody-dependent cellular cytotoxicity, and release of inflammatory mediators, as well as immune complex clearance and regulation of antibody production. This article considers the Fc portion that provides cross-linking of receptors (e.g., FcγRs). In humans, the following three classes of FcγRs have been characterized to date: (i) FcγRI (CD64), which binds monomeric IgG with high affinity and is expressed on macrophages, monocytes, neutrophils, and eosinophils; (ii) FcγRII (CD32), which binds complexed IgG with moderate to low affinity, is widely expressed (especially on leukocytes), is considered a core player in antibody-mediated immunity, and can be divided into FcγRIIA, FcγRIIB, and FcγRIIC, which are expressed in immune (iii) FcγRIII (CD16), which binds IgG with intermediate to low affinity and is found in two forms: FcγRIIIA, which is found on NK cells, macrophages, eosinophils, and some monocytes and T cells and is thought to mediate ADCC; and FcγRIIIB, which is highly expressed on neutrophils.

[0285] FcγRIIA is found on many cells (for example, macrophages, monocytes, neutrophils) involved in killing and seems to be able to activate the killing process. FcγRIIB seems to play a role in the suppression process and is found on B cells, macrophages and mast cells and eosinophils. Importantly, it has been shown that 75% of all FcγRIIB are found in the liver (Ganesan, LP et al., 2012: " FcγRIIb on liver sinusoidal endothelium clearssmall immune complexes, " Journal of Immunology 189: 4981-4988). FcγRIIB is expressed in large quantities in Kupffer cells on liver sinusoidal endothelium (referred to as LSEC) and in the liver, and LSEC is the main site of clearing small immune complexes (Ganesan, LP et al., 2012: FcγRIIb on liver sinusoidal endothelium clearssmall immune complexes. Journal of Immunology 189: 4981-4988).

[0286] In some embodiments, the antibodies and antigen-binding fragments thereof disclosed herein comprise an Fc polypeptide or fragment thereof for binding to FcγRIIb, particularly an Fc region, such as, for example, an IgG-type antibody. In addition, the Fc portion can be engineered to enhance FcγRIIb binding by introducing mutations S267E and L328F, as described in Chu, SY et al., 2008: Inhibition of Bcell receptor-mediated activation of primary human B cells by coengagement of CD19 and FcgammaRIIb with Fc-engineered antibodies. Molecular Immunology 45, 3926-3933. Thus, the clearance of immune complexes can be enhanced (Chu, S. et al., 2014: Accelerated Clearance of IgE In Chimpanzees Is Mediated By Xmab7195, An Fc-Engineered Antibody With Enhanced Affinity For Inhibitory Receptor FcγRIIb. Am J Respir Crit, American Thoracic Society International Conference Abstracts). In some embodiments, the antibodies or antigen-binding fragments thereof of the present disclosure comprise an engineered Fc portion having mutations S267E and L328F, specifically as described in Chu, SY et al., 2008: Inhibition of B cell receptor-mediated activation of primary human B cells by coengagement of CD19 and FcgammaRIIb with Fc-engineered antibodies. Molecular Immunology 45, 3926-3933.

[0287] On B cells, FcγRIIB may function to inhibit further immunoglobulin production and isotype switching to, for example, the IgE class. On macrophages, FcγRIIB is thought to inhibit phagocytosis mediated by FcγRIIA. On eosinophils and mast cells, the B form may help inhibit activation of these cells by binding of IgE to its individual receptors.

[0288] Regarding FcγRI binding, modifications of one or more of E233-G236, P238, D265, N297, A327, and P329 in native IgG reduce binding to FcγRI. Substitution of IgG2 residues at positions 233-236 in IgG1 and IgG4 to the corresponding positions reduces IgG1 and IgG4 binding to FcγRI by 103-fold and eliminates the response of human monocytes to antibody-sensitized erythrocytes (Armour, KL et al., Eur. J. Immunol. 29 (1999) 2613-2624).

[0289] With respect to FcyRII binding, reduced binding to FcyRIIA was found, for example, for IgG mutations of one or more of E233-G236, P238, D265, N297, A327, P329, D270, Q295, A327, R292, and K414.

[0290] The two allelic forms of human FcγRIIA are the "H131" variant, which binds to IgG1 Fc with higher affinity, and the "R131" variant, which binds to IgG1 Fc with lower affinity. See, e.g., Bruhns et al., Blood 113:3716-3725 (2009).

[0291] Regarding FcγRIII binding, reduced binding to FcγRIIIA was found, for example, for mutations in one or more of E233-G236, P238, D265, N297, A327, P329, D270, Q295, A327, S239, E269, E293, Y296, V303, A327, K338, and D376. Mapping of the binding site for the Fc receptor on human IgG1, the mutation sites described above, and methods for measuring binding to FcγRI and FcγRIIA are described in Shields, RL et al., J. Biol. Chem. 276 (2001) 6591-6604.

[0292] The two allelic forms of human FcγRIIIA are the "F158" variant, which binds to IgG1 Fc with lower affinity, and the "V158" variant, which binds to IgG1 Fc with higher affinity. See, e.g., Bruhns et al., Blood 113:3716-3725 (2009).

[0293] Regarding binding to FcγRII, two regions of native IgG Fc appear to be involved in the interaction between FcγRII and IgG, namely (i) the lower hinge site of IgG Fc, specifically amino acid residues L, L, G, G (234-237, EU numbering), and (ii) the adjacent region of the CH2 domain of IgG Fc, specifically the loops and chains in the upper CH2 domain adjacent to the lower hinge region, for example, in the region of P331 (Wines, BD et al., J. Immunol. 2000; 164: 5313-5318). In addition, FcγRI appears to bind to the same site on IgG Fc, while FcRn and protein A bind to different sites on IgG Fc, which appear to be located at the CH2-CH3 interface (Wines, BD et al., J. Immunol. 2000; 164: 5313-5318).

[0294] Mutations that increase the binding affinity of the Fc polypeptides or fragments thereof of the present disclosure to (i.e., one or more) Fcγ receptors (e.g., compared to a reference Fc polypeptide or fragment thereof or a reference Fc polypeptide or fragment thereof that does not contain the mutation) are also contemplated. See, e.g., Delillo and Ravetch, Cell 161(5):1035-1045 (2015) and Ahmed et al., J. Struc. Biol. 194(1):78 (2016), which Fc mutations and techniques are incorporated herein by reference.

[0295] In any of the embodiments disclosed herein, the antibody or antigen-binding fragment may include an Fc polypeptide or fragment thereof comprising a mutation selected from the group consisting of G236A, S239D, A330L, and I332E, or a combination of any two or more thereof; for example, S239D / I332E, S239D / A330L / I332E, G236A / S239D / I332E, G236A / A330L / I332E (also referred to herein as "GAALIE"), or G236A / S239D / A330L / I332E. In some embodiments, the Fc polypeptide or fragment thereof does not comprise S239D. In some embodiments, the Fc polypeptide or fragment thereof comprises an S at position 239 (EU numbering). In some embodiments, the Fc polypeptide or fragment thereof comprises the amino acid sequence set forth in SEQ ID NOs: 672-678.

[0296] In certain embodiments, the Fc polypeptide or fragment thereof may comprise or consist of at least a portion of an Fc polypeptide or fragment thereof that participates in FcRn binding. In certain embodiments, the Fc polypeptide or fragment thereof comprises one or more amino acid modifications that increase binding affinity to FcRn (e.g., enhance binding to FcRn) (e.g., at a pH of about 6.0), and in some embodiments, thereby extending the in vivo half-life of the molecule comprising the Fc polypeptide or fragment thereof (e.g., compared to a reference Fc polypeptide or fragment thereof or antibody that is otherwise identical but does not comprise the modification). In certain embodiments, the Fc polypeptide or fragment thereof comprises or is derived from IgG Fc and the half-life extending mutations comprise any one or more of the following: M428L; N434S; N434H; N434A; N434S; M252Y; S254T; T256E; T250Q; P257I; Q311I; D376V; T307A; E380A (EU numbering). In certain embodiments, the half-life extension mutation comprises M428L / N434S (also referred to herein as "MLNS," "LS," "-LS," and "-LS"). In certain embodiments, the half-life extension mutation is in an Fc polypeptide or fragment thereof comprising or consisting of the amino acid sequence set forth in SEQ ID NOs: 679-684. In certain embodiments, the half-life extension mutation comprises M252Y / S254T / T256E. In certain embodiments, the half-life extension mutation comprises T250Q / M428L. In certain embodiments, the half-life extension mutation comprises P257I / Q311I. In certain embodiments, the half-life extension mutation comprises P257I / N434H. In certain embodiments, the half-life extension mutation comprises D376V / N434H. In certain embodiments, the half-life extension mutation comprises T307A / E380A / N434A. In certain embodiments, the half-life extension mutation comprises M428L / N434A (also referred to herein as "MLNA," "LA," "-LA," and "-LA"). In certain embodiments, the half-life extension mutation is in an Fc polypeptide or fragment thereof comprising or consisting of the amino acid sequence set forth in SEQ ID NOs: 685-690.

[0297] In some embodiments, the antibody or antigen-binding fragment comprises an Fc portion comprising a substitution mutation M428L / N434S or M428L / N434A. In some embodiments, the antibody or antigen-binding fragment comprises an Fc polypeptide or fragment thereof comprising a substitution mutation G236A / A330L / I332E. In certain embodiments, the antibody or antigen-binding fragment comprises an (e.g., IgG) Fc portion comprising a G236A mutation, an A330L mutation, and an I332E mutation (GAALIE), and does not comprise an S239D mutation (e.g., comprising a native S at position 239). In specific embodiments, the antibody or antigen-binding fragment comprises an Fc polypeptide or fragment thereof comprising the substitution mutations: M428L / N434S and G236A / A330L / I332E (and may comprise or consist of the amino acid sequence set forth in SEQ ID NOs: 691-695), and optionally does not comprise S239D (e.g., comprises S at 239). In specific embodiments, the antibody or antigen-binding fragment comprises an Fc polypeptide or fragment thereof comprising the substitution mutations: M428L / N434A and G236A / A330L / I332E (and may comprise or consist of the amino acid sequence set forth in SEQ ID NOs: 696-700), and optionally does not comprise S239D (e.g., comprises S at 239). In certain embodiments, the antibody or antigen-binding fragment comprises an Fc polypeptide or fragment thereof comprising the substitution mutations: M428L / N434S (or M428L / N434A) and G236A / S239D / A330L / I332E.

[0298] In some embodiments, an antibody or antigen-binding fragment (further described herein) is provided, which comprises in a (e.g., human) IgG1 heavy chain the amino acid mutations listed in any one of (i) to (xviii): (i) G236A, L328V and Q295E; (ii) G236A, P230A and Q295E; (iii) G236A, R292P and I377N; (iv) G236A, K334A and Q295E; (v) G236S, R292P and Y300L; (vi) G236A and Y300L; (vii) G236A, R292P and Y300L; (viii) G236S, (xvi) G236W; (xvii) F243L, G446E, P396L and S267E; (xviii) G236A, S239D and H268E, wherein the numbering of amino acid residues is according to the EU index as set forth in Kabat. In certain embodiments, the antibody or antigen-binding fragment is afucosylated. In some embodiments, the antibody or antigen-binding fragment further comprises one or more mutations that enhance binding to human FcRn, such as M428L and N434S mutations or M428L and N434A mutations (EU numbering) or any other mutation that enhances binding to human FcRn, such as those described herein. In certain embodiments, the antibody or antigen-binding fragment is afucosylated.

[0299] In specific embodiments, the antibody or antigen-binding fragment comprises i) a VH and VL, respectively, as set forth anywhere herein; or (iii) CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, as set forth anywhere herein or as determined by any CDR determination scheme disclosed herein, and (A) an Fc portion comprising the following substitution mutations: (i) G236A, L328V, and Q295E; (ii) G236A, P23 0A and Q295E; (iii) G236A, R292P and I377N; (iv) G236A, K334A and Q295E; (v) G236S, R292P and Y300L; (vi) G236A and Y300L; (vii) G236A, R292P and Y300L; (viii) G236S, G420V, G446E and L309T; (ix) G236A and R292P; (x) R292P and Y 300L; (xi) G236A and R292P; (xii) Y300L; (xiii) E345K, G236S, L235Y and S267E; (xiv) E272R, L309T, S219Y and S267E; (xv) G236Y; (xvi) G236W; (xvii) F243L, G446E, P396L and S267E; (xviii) G236A, S239D and H268E; (xi x) M428L / N434S; (xx) M428L / N434A; (xxi) G236A / A330L / I332E / M428L / N434S; (xxii) G236A / A330L / I332E / M428L / N434A; or (xxiii) any two or more of (i)-(xxii); or (B) an Fc portion comprising or consisting of an Fc polypeptide or fragment thereof comprising the sequence of SEQ any one of SEQ ID NOs: 664-700 having, or consisting of, an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical, optionally to naturally occurring variants thereof, or comprises, or consists of, an amino acid sequence as set forth in any one of SEQ ID NOs: 672-700.

[0300] In certain embodiments, the antibody or antigen-binding fragment comprises a mutation that alters glycosylation, wherein the mutation that alters glycosylation comprises N297A, N297Q, or N297G, and / or the antibody or antigen-binding fragment is partially or completely deglycosylated and / or partially or completely defucosylated. Host cell lines and methods for preparing partially or completely deglycosylated or partially or completely defucosylated antibodies and antigen-binding fragments are known (see, e.g., PCT Publication No. WO2016 / 181357; Suzuki et al. Clin. Cancer Res. 13(6): 1875-82 (2007); North et al. MAbs 6: 1-12 (2018)).

[0301] The antibodies or antigen-binding fragments of the present disclosure can be fucosylated (e.g., comprising one or more fucosyl moieties, and typically comprising a native (wild-type) fucosylation pattern or a fucosylation pattern having one or more additional or fewer fucosyl moieties compared to native), or can be defucosylated. Specifically, native IgG1 antibodies carry a glycan site at N297, and this is typically the only site where a core fucosyl moiety can be found in an antibody, but some glycan sites can be generated by mutation (e.g., in the variable domain) during antibody development. Fucosylation of Fc polypeptides or fragments thereof, or fucosylation of antibodies can be affected by introducing amino acid mutations to introduce or disrupt fucosylation sites (e.g., mutations at N297, such as N297Q or N297A, to disrupt the formation of glycans that can contain a core fucose moiety), but it is generally preferred to maintain N297 and its glycans, such as by expressing the polypeptide in a host cell that has been genetically engineered to lack the ability to fucosylate the polypeptide (or to have inhibited or impaired ability); by expressing the polypeptide under conditions in which the host cell's ability to fucosylate the polypeptide is impaired (e.g., in the presence of 2-fluoro-L-fucose (2FF)); and the like. A defucosylated polypeptide may contain no, or substantially no, fucose moieties, and / or may be expressed by a host cell that has been genetically engineered to lack the ability (or have an inhibited or impaired ability) to fucosylate the polypeptide, and / or may be expressed under conditions where the host cell's ability to fucosylate the polypeptide is impaired (e.g., in the presence of 2-fluoro-L-fucose (2FF)). In some embodiments, the polypeptide does not contain a core fucose moiety at Asn297. In some embodiments, the defucosylated polypeptide has increased binding to FcγRIIIA. In some contexts, adding 2FF to a culture medium containing host cells expressing an antibody results in about 85% or more of the antibodies being free of fucose moieties. Thus, when a plurality of antibodies are produced in the presence of 2FF or a similar agent, the plurality of antibodies or antigen-binding fragments may be described as "defucosylated." In some contexts, a plurality of polypeptides or antibodies may be described as, for example, defucosylated, meaning that about 85% or more of the individual polypeptide or antibody molecules in the plurality of antibodies or antigen-binding fragments do not contain a fucose moiety. In certain preferred embodiments, the defucosylated antibody or polypeptide, or a population or plurality of defucosylated antibodies or antigen-binding fragments thereof, comprises asparagine (N) at EU position 297. Fucosylation or the lack thereof can be assessed using, for example, mass spectrometry (e.g., electrospray mass spectrometry (ESI-MS)). In some embodiments, a plurality of compositions comprising any one or more of the presently disclosed polypeptides are provided, wherein the composition comprises a defucosylated polypeptide.

[0302] In certain embodiments, the antibody or antigen-binding fragment elicits sustained protection in the subject, even when no detectable levels of the antibody or antigen-binding fragment are found in the subject (i.e., when the antibody or antigen-binding fragment has been cleared from the subject after administration). This protection is referred to herein as a vaccine effect. Without wishing to be bound by theory, it is believed that dendritic cells can internalize the complex of the antibody and antigen and then induce or contribute to an endogenous immune response to the antigen. In certain embodiments, the antibody or antigen-binding fragment comprises one or more modifications, such as, for example, mutations comprising G236A, A330L, and I332E in Fc, which activate dendritic cells that can induce, for example, T cell immunity to the antigen.

[0303] In certain embodiments, the antibodies or antigen-binding fragments of the present disclosure comprise an Fc variant selected from the Fc variants summarized in Table A (see also PCT Publication No. WO 2022 / 251119). In certain embodiments, the Fc variant, or antibody or antigen-binding fragment is fucosylated. In other embodiments, the Fc variant, or antibody or antigen-binding fragment is afucosylated.

[0304] Table A. Certain Fc variants (fucosylated unless otherwise indicated) and their properties

[0305]

[0306] In some embodiments, an anti-parvovirus antibody or antigen-binding fragment is provided, which comprises in the (e.g., human) IgG1 heavy chain the amino acid mutations listed in any one of (i) to (xviii): (i) G236A, L328V and Q295E; (ii) G236A, P230A and Q295E; (iii) G236A, R292P and I377N; (iv) G236A, K334A and Q295E; (v) G236S, R292P and Y300L; (vi) G236A and Y300L; (vii) G236A, R292P and Y300L; (viii) G236S, G42 (xvi) G236W; (xvii) F243L, G446E, P396L and S267E; (xviii) G236A, S239D and H268E, wherein the numbering of amino acid residues is according to the EU index as set forth in Kabat. In certain embodiments, the antibody or antigen-binding fragment is afucosylated. In some embodiments, the antibody or antigen-binding fragment further comprises one or more mutations that enhance binding to human FcRn, such as M428L and N434S mutations or M428L and N434A mutations (EU numbering) or any other mutation that enhances binding to human FcRn, such as those described herein. In certain embodiments, the antibody or antigen-binding fragment is afucosylated.

[0307] In any of the presently disclosed embodiments, the antibody or antigen-binding fragment comprises an Fc polypeptide or fragment thereof, including CH2 (or a fragment thereof), CH3 (or a fragment thereof), or CH2 and CH3, wherein CH2, CH3, or both can be of any isotype and can contain amino acid substitutions or other modifications compared to the corresponding wild-type CH2 or CH3, respectively. In certain embodiments, the Fc of the present disclosure comprises two CH2-CH3 polypeptides that associate to form a dimer.

[0308] In any embodiment of the presently disclosed embodiment, antibody or Fab can be monoclonal.As used herein, the term "monoclonal antibody" (mAb) refers to the antibody obtained from a substantially homogeneous antibody population, that is, except for the possible naturally occurring mutation that may exist (in some cases, a small amount of existence), the individual antibodies constituting the population are identical. Monoclonal antibodies are highly specific and are directed to a single antigenic site. In addition, in contrast to the polyclonal antibody preparations comprising different antibodies directed to different epitopes, each monoclonal antibody is directed to a single epitope of the antigen. In addition to their specificity, the advantage of monoclonal antibodies is that they can be synthesized when not contaminated by other antibodies. The term "monoclonal" should not be interpreted as needing to produce antibodies by any ad hoc method. For example, monoclonal antibodies that can be used for the present invention can be prepared by the hybridoma method described by Kohler et al., Nature 256:495 (1975), or recombinant DNA methods can be used to prepare in bacteria, eukaryotic animals or plant cells (see, for example, U.S. Patent number 4,816,567). Monoclonal antibodies can also be isolated from phage antibody libraries using techniques such as those described in Clackson et al., Nature, 352:624-628 (1991) and Marks et al., J. Mol. Biol., 222:581-597 (1991). Monoclonal antibodies can also be obtained using the methods disclosed in PCT Publication No. WO 2004 / 076677A2.

[0309] The antibodies and antigen-binding fragments of the present disclosure include "chimeric antibodies," in which a portion of the heavy and / or light chain is identical or homologous to a corresponding sequence in an antibody derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain is identical or homologous to a corresponding sequence in an antibody derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, as long as they exhibit the desired biological activity (see, U.S. Patent Nos. 4,816,567; 5,530,101 and 7,498,415; and Morrison et al., Proc. Natl. Acad. Sci. USA, 81: 6851-6855 (1984)). For example, a chimeric antibody may contain both human and non-human residues. In addition, a chimeric antibody may contain residues that are not found in the recipient antibody or the donor antibody. These modifications are made to further improve antibody performance. For more 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). Chimeric antibodies also include primatized and humanized antibodies.

[0310] "Humanized antibodies" are generally considered to be human antibodies with one or more amino acid residues introduced therein from a non-human source. These non-human amino acid residues are generally taken from the variable domains. Humanization can be performed according to the method of Winter and colleagues (Jones et al., Nature, 321:522-525 (1986); Reichmann et al., Nature, 332:323-327 (1988); Verhoeyen et al., Science, 239:1534-1536 (1988)), specifically by replacing the corresponding sequences of human antibodies with non-human variable sequences. Therefore, such "humanized" antibodies are chimeric antibodies (U.S. Patent Nos. 4,816,567; 5,530,101 and 7,498,415), in which substantially less than a complete human variable domain has been replaced by a corresponding sequence from a non-human species. In some cases, "humanized" antibodies are produced by non-human cells or animals and contain human sequences (e.g., H C domain) antibodies.

[0311] "Human antibodies" are antibodies that contain only sequences present in antibodies produced by humans (i.e., sequences encoded by human antibody encoding genes). However, as used herein, human antibodies may contain residues or modifications not found in naturally occurring human antibodies (e.g., antibodies isolated from humans), including those modifications and variant sequences described herein. These are usually made to further improve or enhance antibody performance. In some cases, human antibodies are produced by transgenic animals. For example, see U.S. Patent Nos. 5,770,429; 6,596,541 and 7,049,426.

[0312] In certain embodiments, the antibodies or antigen-binding fragments of the disclosure are chimeric, humanized, or human.

[0313] In some embodiments, various pharmacokinetic ("PK") parameters are used to describe or characterize the antibodies or antigen-binding fragments provided herein. Details regarding collecting antibody serum concentrations for the purpose of assessing PK parameters are described in conjunction with the Examples herein. The term "t 1 / 2 " or "half-life" refers to the elimination half-life of an antibody contained in a pharmaceutical composition administered to a subject. The term "C 最后 ” generally refers to the last measurable plasma concentration (i.e., after which the substance is no longer present in plasma in measurable concentrations).

[0314] MPK190-v1.3 antibody

[0315] In some embodiments, the antibodies or antigen-binding fragments of the present disclosure are MPK190-v1.3 antibodies or antigen-binding fragments thereof. Such antibodies or antigen-binding fragments thereof can bind to and / or neutralize both RSV and MPV.

[0316] In some embodiments, the MPK190-v1.3 antibody may have a VH, VL, HC, LC, CDRH1-H3, and / or CDRL1-L3 comprising or consisting of the amino acid sequence, or encoded by a polynucleotide having the following sequence:

[0317]

[0318] In some embodiments, the VH and VL of the MPK190-v1.3 antibody or antigen-binding fragment that binds RSV-F and MPV-F and / or neutralizes RSV and / or MPV comprises or consists of a VH and VL having the sequence of SEQ ID NO: 702 and 704, respectively.

[0319] In certain embodiments, the antibodies or antigen-binding fragments of the present disclosure bind to RSV-F and MPV-F and / or neutralize RSV and MPV and:

[0320] (i) the VH comprises, or consists of, an amino acid sequence that is at least 80% (e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identical to the amino acid sequence set forth in SEQ ID NO: 702, wherein the sequence variation is optionally limited to one or more framework regions and / or the sequence variation comprises one or more substitutions to germline-encoded amino acids; and / or

[0321] (ii) the VL comprises or consists of an amino acid sequence that is at least 80% (e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identical to the amino acid sequence set forth in SEQ ID NO: 704, wherein the sequence variation is optionally limited to one or more framework regions and / or the sequence variation comprises one or more substitutions to germline-encoded amino acids.

[0322] In some embodiments, the variation compared to SEQ ID NO: 702 or SEQ ID NO: 704 is limited to one or more framework regions. In some embodiments, the variation comprises or consists of one, two, three, four, five, six, seven, eight, nine, or ten amino acid substitutions (any or all of which may be conservative substitutions), insertions, or deletions in VH, VL, or both. In some embodiments, the variation comprises one or more amino acid substitutions, insertions, and / or deletions of amino acids at two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, or more amino acid positions from the N-terminal and / or C-terminal amino acids of the CDRs.

[0323] Framework regions can be identified according to a numbering scheme (e.g., IMGT, Kabat, Chothia, North, EU, Martin (enhanced Chothia), Contact, AbM, CCG, EU, or AHo, or a combination of two or more of these. CDRs can be identified within a variable domain or within a heavy or light chain according to a numbering scheme or a combination of numbering schemes, and preferably, FRs can be identified using the same numbering scheme or combination of numbering schemes.

[0324] For example, in some embodiments, the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 of MPK190-v1.3, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 are according to IMGT (optionally IMGT-linked for CDRH3 and CDRL3), and the antibody or antigen-binding fragment further comprises one or more framework sequences from MPK190-v1.3 and / or one or more framework sequences that are variants of MPK190-v1.3 framework sequences, wherein one or more framework sequences of MPK190-v1.3 are according to IMGT (and if IMGT-linked for CDRH3 and CDRL3, this is indicated).

[0325] In other embodiments, the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 of MPK190-v1.3, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 are according to Kabat, and the antibody or antigen-binding fragment further comprises one or more framework sequences from [MPK190-v1.3 and / or one or more framework sequences that are variants of the MPK190-v1.3 framework sequences, wherein the one or more framework sequences of MPK190-v1.3 are according to Kabat.

[0326] In other embodiments, the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 of MPK190-v1.3, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 are according to Chothia, and the antibody or antigen-binding fragment further comprises one or more framework sequences from MPK190-v1.3 and / or one or more framework sequences that are variants of the MPK190-v1.3 framework sequences, wherein the one or more framework sequences of MPK190-v1.3 are according to Chothia.

[0327] In other embodiments, the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 of MPK190-v1.3, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 are according to Martin (Enhanced Chothia), and the antibody or antigen-binding fragment further comprises one or more framework sequences from MPK190-v1.3 and / or one or more framework sequences that are variants of the MPK190-v1.3 framework sequences, wherein the one or more framework sequences of MPK190-v1.3 are according to Martin (Enhanced Chothia).

[0328] In other embodiments, the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 of MPK190-v1.3, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 are according to AbM, and the antibody or antigen-binding fragment further comprises one or more framework sequences from MPK190-v1.3 and / or one or more framework sequences that are variants of the MPK190-v1.3 framework sequences, wherein the one or more framework sequences of MPK190-v1.3 are according to AbM.

[0329] In other embodiments, the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 of MPK190-v1.3, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 are according to North, and the antibody or antigen-binding fragment further comprises one or more framework sequences from MPK190-v1.3 and / or one or more framework sequences that are variants of the MPK190-v1.3 framework sequences, wherein the one or more framework sequences of MPK190-v1.3 are according to North.

[0330] In other embodiments, the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 are according to Contact, and the antibody or antigen-binding fragment further comprises one or more framework sequences from MPK190-v1.3 and / or one or more framework sequences that are variants of the MPK190-v1.3 framework sequences, wherein the one or more framework sequences of MPK190-v1.3 are according to Contact.

[0331] In other embodiments, the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 of MPK190-v1.3, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 are according to CCG, and the antibody or antigen-binding fragment further comprises one or more framework sequences from MPK190-v1.3 and / or one or more framework sequences that are variants of the MPK190-v1.3 framework sequences, wherein the one or more framework sequences of MPK190-v1.3 are according to CCG.

[0332] In other embodiments, the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 of MPK190-v1.3, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 are according to EU, and the antibody or antigen-binding fragment further comprises one or more framework sequences from MPK190-v1.3 and / or one or more framework sequences that are variants of the MPK190-v1.3 framework sequences, wherein the one or more framework sequences of MPK190-v1.3 are according to EU.

[0333] In other embodiments, the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 of MPK190-v1.3, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 are according to AHo, and the antibody or antigen-binding fragment further comprises one or more framework sequences from MPK190-v1.3 and / or one or more framework sequences that are variants of the MPK190-v1.3 framework sequences, wherein the one or more framework sequences of MPK190-v1.3 are according to AHo.

[0334] In certain embodiments, the antibody or antigen-binding fragment comprises a VH comprising FR1, FR2, FR3, and / or FR4 of the VH amino acid sequence set forth in SEQ ID NO: 702 (or a variant of FR1, FR2, FR3, and / or FR4 comprising one, two, three, four, or five amino acid substitutions (optionally comprising or consisting of one or more conservative substitutions), insertions, and / or deletions), and a VL comprising FR1, FR2, FR3, and / or FR4 of the VL amino acid sequence set forth in SEQ ID NO: 704 (or a variant of FR1, FR2, FR3, and / or FR4 comprising one, two, three, four, or five amino acid substitutions (optionally comprising or consisting of one or more conservative substitutions), insertions, and / or deletions). In some embodiments, FRs are defined according to the IMGT, Kabat, Chothia, North, EU, Martin (enhanced Chothia), Contact, AbM, CCG, or AHo numbering systems, or any combination thereof.

[0335] In certain embodiments, the antibodies or antigen-binding fragments comprise a VH and a VL, wherein the VH comprises, consists essentially of, or consists of a FR1, FR2, FR3, or FR4 that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the corresponding FR1, FR2, FR3, or FR4 of the VH amino acid sequence set forth in SEQ ID NO: 702, and the VL comprises, consists essentially of, or consists of the corresponding FR1, FR2, FR3, or FR4 of the VH amino acid sequence set forth in SEQ ID NO: 702. In some embodiments, the FR1, FR2, FR3, and / or FR4 are at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the corresponding FR1, FR2, FR3, or FR4 of the VL amino acid sequence set forth in SEQ ID NO: 704. In some embodiments, the FRs are defined according to the IMGT, Kabat, Chothia, North, EU, Martin (enhanced Chothia), Contact, AbM, CCG, or AHo numbering systems, or any combination thereof.

[0336] In certain embodiments, the antibodies or antigen-binding fragments comprise a VH and a VL, wherein the VH comprises, consists essentially of, or consists of a FR1, FR2, FR3, and FR4 that are at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the corresponding FR1, FR2, FR3, or FR4 of the VH amino acid sequence set forth in SEQ ID NO: 702, and the VL comprises, consists essentially of, or consists of a FR1, FR2, FR3, or FR4 that are at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the corresponding FR1, FR2, FR3, or FR4 of the VH amino acid sequence set forth in SEQ ID NO: 702. NO: 704, or a FR1, FR2, FR3, or FR4 that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to, or comprises, consists essentially of, or consists of, the corresponding FR1, FR2, FR3, or FR4 of SEQ ID NO: 704. In some embodiments, FRs are defined according to the IMGT, Kabat, Chothia, North, EU, Martin (enhanced Chothia), Contact, AbM, CCG, or AHo numbering systems, or according to any combination thereof.

[0337] In certain embodiments, the antibodies or antigen-binding fragments of the present disclosure bind to RSV-F and MPV-F and / or neutralize RSV and MPV, and may comprise one or more VHs that bind to RSV-F and MPV-F, and may further comprise CDRs according to the VH sequence of SEQ ID NO: 702, and may comprise one or more VLs that bind to RSV-F and MPV-F, and may further comprise CDRs according to the VL sequence of SEQ ID NO: 704, wherein the CDRs are as determined using any known CDR numbering method, including Kabat, Chothia, EU, Martin (enhanced Chothia), Contact, AbM, CCG, EU, or AHo numbering methods, or a combination of two or more of these IMGT, Martin (enhanced Chothia), Contact, North, and AHo numbering methods. In certain embodiments, the CDRs are according to the IMGT numbering method.

[0338] The antibodies or antigen-binding fragments of the present disclosure that bind to RSV-F and MPV-F and / or neutralize RSV and MPV may comprise a heavy chain variable domain (VH) comprising complementarity determining regions (CDRs) H1, CDRH2, and CDRH3, and a light chain variable domain (VL) comprising CDRL1, CDRL2, and CDRL3, wherein the CDRs are identified according to the IMGT numbering system, and wherein: (i) optionally, CDRH1 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 121, or a functional variant thereof comprising one, two, or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions for germline-encoded amino acids; (ii) optionally, CDRH2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 122, or a functional variant thereof comprising one, two, or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions for germline-encoded amino acids; (iii) optionally, CDRH3 comprises or consists of any of SEQ ID or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline-encoded amino acids; (iv) optionally, CDRL1 comprises or consists of the amino acid sequence shown in SEQ ID NO: 18 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline-encoded amino acids; (v) optionally, CDRL2 comprises or consists of the amino acid sequence shown in SEQ ID NO: 705 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline-encoded amino acids; and / or (vi) optionally, CDRL3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 127 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline-encoded amino acids.

[0339] In specific embodiments, the antibody or antigen-binding fragment comprises i) VH and VL; or CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3, as shown in this "MPK190-v1.3 Antibody" section or otherwise shown for the MPK190-v1.3 antibody or as determined by any CDR determination scheme disclosed herein, and ii) an Fc portion. In certain embodiments, such an antibody or antigen-binding fragment comprises a CH and / or CL (potentially including a kappa light chain constant region) or a fragment thereof associated with a VH or VL, respectively.

[0340] In specific embodiments, the antibody or antigen-binding fragment comprises a VH and a VL, or CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, as set forth in this "MPK190-v1.3 Antibody" section or otherwise set forth for the MPK190-v1.3 antibody or as determined by any of the CDR determination schemes disclosed herein, and (A) an Fc portion comprising the following substitution mutations: (i) G236A, L328V, and Q295E; (ii) G236A, P230A, and Q295E; (iii) G236A, R292P, and I377N; (iv) G236A, K334A, and Q295E; (v) G236S, R292P, and Y300L; (vi) G236A and Y300L; (vii) G236A, R292P, and Y300L; (viii) G236S, G420V, G446E, and L309T; (ix) G236A and R292P; (x) R 292P and Y300L; (xi) G236A and R292P; (xii) Y300L; (xiii) E345K, G236S, L235Y and S267E; (xiv) E272R, L309T, S219Y and S267E; (xv) G236Y; (xvi) G236W; (xvii) F243L, G446E, P396L and S267E; (xviii) G236A, S239D and H268E; (xix) M428L / N434S; (xx) M428L / N434A; (xxi) G236A / A330L / I332E / M428L / N434S; (xxii) G236A / A330L / I332E / M428L / N434A; or (xxiii) any two or more of (i)-(xxii); or (B) an Fc portion comprising or consisting of an Fc polypeptide or fragment thereof comprising the sequence of SEQ any one of SEQ ID NOs: 664-700 having, or consisting of, an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical, optionally to naturally occurring variants thereof, or comprises, or consists of, an amino acid sequence as set forth in any one of SEQ ID NOs: 672-700.

[0341] In certain embodiments, the antibody or antigen-binding fragment comprises i) a VH and a VL; or CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, as shown in this "MPK190-v1.3 Antibody" section or otherwise shown for the MPK190-v1.3 antibody or as determined by any of the CDR determination schemes disclosed herein, and ii) an Fc portion comprising or consisting of an Fc polypeptide or fragment thereof comprising or consisting of an amino acid sequence according to any of SEQ ID NOs: 679-684 and 688-690, or a fragment thereof having a sequence according to any of SEQ ID NOs: 679-684 and 688-690, or a fragment thereof having a sequence according to any of SEQ ID NOs: 679-684 and 688-690. The sequence of any one of NOs:679-684 and 688-690 has an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical.

[0342] In certain embodiments, the antibody or antigen-binding fragment comprises the MPK190-rIG1m3-LS antibody, wherein the HC has the amino acid sequence of SEQ ID NO:719 and can be encoded by a nucleic acid having a sequence of SEQ ID NO:718, and wherein the LC has the amino acid sequence of SEQ ID NO:721 and can be encoded by a nucleic acid having a sequence of SEQ ID NO:720.

[0343] In certain embodiments, the antibody or antigen-binding fragment comprises the MPK190-v1.3-rIG1m17,1-LS antibody, wherein the HC has an amino acid sequence of SEQ ID NO: 723 and can be encoded by a nucleic acid having a sequence of SEQ ID NO: 722, and wherein the LC has an amino acid sequence of SEQ ID NO: 725 and can be encoded by a nucleic acid having a sequence of SEQ ID NO: 724 or 904.

[0344] In certain embodiments, the antibody or antigen-binding fragment comprises a VH and a VL; or a CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, as shown in this "MPK190-v1.3 Antibody" section or otherwise shown for the MPK190-v1.3 antibody, or as determined by any CDR determination scheme disclosed herein, that exhibits a synergistic effect in neutralizing or treating and / or preventing infection caused by RSV when co-administered with at least one of MPK65-v2-v1.2, MPK65-v2-v.3.1, MPK176-v1.3, MPK176-v4.3, MPK201-v1.2, and MPK201-v4.1.

[0345] MPK65-v2-v1.2 Antibody

[0346] In some embodiments, the antibody or antigen-binding fragment of the present disclosure is an MPK65-v2-v1.2 antibody or antigen-binding fragment thereof. Such an antibody or antigen-binding fragment thereof can bind to and / or neutralize RSV.

[0347] In some embodiments, the MPK65-v2-v1.2 antibody may have a VH, VL, CDRH1-H3, and / or CDRL1-L3 comprising or consisting of the following amino acid sequence, or be encoded by a polynucleotide having the following sequence:

[0348]

[0349] In some embodiments, the VH and VL of the MPK65-v2-v1.2 antibody or antigen-binding fragment that binds RSV-F and / or neutralizes RSV comprise or consist of a VH and VL having the sequences of SEQ ID NOs: 136 and 851, respectively.

[0350] In certain embodiments, the antibodies or antigen-binding fragments of the present disclosure bind to RSV-F and / or neutralize RSV and:

[0351] (i) the VH comprises or consists of an amino acid sequence that is at least 80% (e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identical to the amino acid sequence set forth in SEQ ID NO: 136, wherein the sequence variation is optionally limited to one or more framework regions and / or the sequence variation comprises one or more substitutions to germline-encoded amino acids; and / or

[0352] (ii) the VL comprises or consists of an amino acid sequence that is at least 80% (e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identical to the amino acid sequence set forth in SEQ ID NO: 851, wherein the sequence variation is optionally limited to one or more framework regions and / or the sequence variation comprises one or more substitutions to germline-encoded amino acids.

[0353] In some embodiments, the variation compared to SEQ ID NO: 136 or SEQ ID NO: 851 is limited to one or more framework regions. In some embodiments, the variation comprises or consists of one, two, three, four, five, six, seven, eight, nine, or ten amino acid substitutions (any or all of which may be conservative substitutions), insertions, or deletions in VH, VL, or both. In some embodiments, the variation comprises one or more amino acid substitutions, insertions, and / or deletions of amino acids at two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, or more amino acid positions from the N-terminal and / or C-terminal amino acids of the CDRs.

[0354] Framework regions can be identified according to a numbering scheme (e.g., IMGT, Kabat, Chothia, North, EU, Martin (enhanced Chothia), Contact, AbM, CCG, EU, or AHo, or a combination of two or more of these. CDRs can be identified within a variable domain or within a heavy or light chain according to a numbering scheme or a combination of numbering schemes, and preferably, FRs can be identified using the same numbering scheme or combination of numbering schemes.

[0355] For example, in some embodiments, the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 of MPK65-v2-v1.2, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 are according to IMGT (optionally IMGT-linked for CDRH3 and CDRL3), and the antibody or antigen-binding fragment further comprises one or more framework sequences from MPK65-v2-v1.2 and / or one or more framework sequences that are variants of the MPK65-v2-v1.2 framework sequences, wherein one or more framework sequences of MPK65-v2-v1.2 are according to IMGT (and if IMGT-linked for CDRH3 and CDRL3, this is indicated).

[0356] In other embodiments, the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 of MPK65-v2-v1.2, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 are according to Kabat, and the antibody or antigen-binding fragment further comprises one or more framework sequences from MPK65-v2-v1.2 and / or one or more framework sequences that are variants of the MPK65-v2-v1.2 framework sequences, wherein the one or more framework sequences of MPK65-v2-v1.2 are according to Kabat.

[0357] In other embodiments, the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 of MPK65-v2-v1.2, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 are according to Chothia, and the antibody or antigen-binding fragment further comprises one or more framework sequences from MPK65-v2-v1.2 and / or one or more framework sequences that are variants of the MPK65-v2-v1.2 framework sequences, wherein the one or more framework sequences of MPK65-v2-v1.2 are according to Chothia.

[0358] In other embodiments, the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 of MPK65-v2-v1.2, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 are according to Martin (Enhanced Chothia), and the antibody or antigen-binding fragment further comprises one or more framework sequences from MPK65-v2-v1.2 and / or one or more framework sequences that are variants of the MPK65-v2-v1.2 framework sequences, wherein the one or more framework sequences of MPK65-v2-v1.2 are according to Martin (Enhanced Chothia).

[0359] In other embodiments, the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 of MPK65-v2-v1.2, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 are according to AbM, and the antibody or antigen-binding fragment further comprises one or more framework sequences from MPK65-v2-v1.2 and / or one or more framework sequences that are variants of the MPK65-v2-v1.2 framework sequences, wherein the one or more framework sequences of MPK65-v2-v1.2 are according to AbM.

[0360] In other embodiments, the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 of MPK65-v2-v1.2, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 are according to North, and the antibody or antigen-binding fragment further comprises one or more framework sequences from MPK65-v2-v1.2 and / or one or more framework sequences that are variants of the MPK65-v2-v1.2 framework sequences, wherein the one or more framework sequences of MPK65-v2-v1.2 are according to North.

[0361] In other embodiments, the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 are according to Contact, and the antibody or antigen-binding fragment further comprises one or more framework sequences from MPK65-v2-v1.2 and / or one or more framework sequences that are variants of the MPK65-v2-v1.2 framework sequences, wherein the one or more framework sequences of MPK65-v2-v1.2 are according to Contact.

[0362] In other embodiments, the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 of MPK65-v2-v1.2, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 are according to CCG, and the antibody or antigen-binding fragment further comprises one or more framework sequences from MPK65-v2-v1.2 and / or one or more framework sequences that are variants of the MPK65-v2-v1.2 framework sequences, wherein the one or more framework sequences of MPK65-v2-v1.2 are according to CCG.

[0363] In other embodiments, the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 of MPK65-v2-v1.2, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 are according to EU, and the antibody or antigen-binding fragment further comprises one or more framework sequences from MPK65-v2-v1.2 and / or one or more framework sequences that are variants of the MPK65-v2-v1.2 framework sequences, wherein the one or more framework sequences of MPK65-v2-v1.2 are according to EU.

[0364] In other embodiments, the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 of MPK65-v2-v1.2, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 are according to AHo, and the antibody or antigen-binding fragment further comprises one or more framework sequences from MPK65-v2-v1.2 and / or one or more framework sequences that are variants of the MPK65-v2-v1.2 framework sequences, wherein the one or more framework sequences of MPK65-v2-v1.2 are according to AHo.

[0365] In certain embodiments, the antibody or antigen-binding fragment comprises a VH comprising FR1, FR2, FR3, and / or FR4 of the VH amino acid sequence set forth in SEQ ID NO: 136 (or a variant of FR1, FR2, FR3, and / or FR4 comprising one, two, three, four, or five amino acid substitutions (optionally comprising or consisting of one or more conservative substitutions), insertions, and / or deletions), and a VL comprising FR1, FR2, FR3, and / or FR4 of the VL amino acid sequence set forth in SEQ ID NO: 851 (or a variant of FR1, FR2, FR3, and / or FR4 comprising one, two, three, four, or five amino acid substitutions (optionally comprising or consisting of one or more conservative substitutions), insertions, and / or deletions). In some embodiments, FRs are defined according to the IMGT, Kabat, Chothia, North, EU, Martin (enhanced Chothia), Contact, AbM, CCG, or AHo numbering systems, or any combination thereof.

[0366] In certain embodiments, the antibodies or antigen-binding fragments comprise a VH comprising, consisting essentially of, or consisting of a FR1, FR2, FR3, or FR4 that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the corresponding FR1, FR2, FR3, or FR4 of the VH amino acid sequence set forth in SEQ ID NO: 136, or comprises, consisting essentially of, or consisting of the corresponding FR1, FR2, FR3, or FR4 of the VH amino acid sequence set forth in SEQ ID NO: 702, and a VL comprising a VH comprising, consisting essentially of, or consisting of a FR1, FR2, FR3, or FR4 that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the corresponding FR1, FR2, FR3, or FR4 of the VH amino acid sequence set forth in SEQ ID NO: In some embodiments, the FR1, FR2, FR3, and / or FR4 are at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the corresponding FR1, FR2, FR3, or FR4 of the VL amino acid sequence set forth in SEQ ID NO: 851, or comprise, consist essentially of, or consist of the corresponding FR1, FR2, FR3, or FR4 of the VL amino acid sequence set forth in SEQ ID NO: 704. In some embodiments, the FRs are defined according to the IMGT, Kabat, Chothia, North, EU, Martin (enhanced Chothia), Contact, AbM, CCG, or AHo numbering systems, or according to any combination thereof.

[0367] In certain embodiments, the antibodies or antigen-binding fragments comprise a VH comprising, consisting essentially of, or consisting of the corresponding FR1, FR2, FR3, or FR4 of the VH amino acid sequence set forth in SEQ ID NO: 136, or a VL comprising, consisting essentially of, or consisting of the corresponding FR1, FR2, FR3, or FR4 of the VH amino acid sequence set forth in SEQ ID NO: 702, and the VL comprising, consisting essentially of, or consisting of the corresponding FR1, FR2, FR3, or FR4 of the VH amino acid sequence set forth in SEQ ID NO: 703. In some embodiments, the FR1, FR2, FR3, and FR4 are at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the corresponding FR1, FR2, FR3, or FR4 of SEQ ID NO: 851, or comprise, consist essentially of, or consist of the corresponding FR1, FR2, FR3, or FR4 of SEQ ID NO: 704. In some embodiments, the FRs are defined according to the IMGT, Kabat, Chothia, North, EU, Martin (enhanced Chothia), Contact, AbM, CCG, or AHo numbering systems, or according to any combination thereof.

[0368] In certain embodiments, antibodies or antigen-binding fragments of the present disclosure bind to RSV-F and / or neutralize RSV, and may include one or more VHs in conjunction with RSV-F, and may further include a CDR according to a VH sequence of SEQ ID NO: 136, and may include one or more VLs in conjunction with RSV-F, and may further include a CDR according to a VL sequence of SEQ ID NO: 851, wherein CDRs are as determined using any known CDR numbering method, including Kabat, Chothia, EU, Martin (enhanced Chothia), Contact, AbM, CCG, EU, or AHo numbering methods, or a combination of two or more of these IMGT, Martin (enhanced Chothia), Contact, North, and AHo numbering methods. In certain embodiments, CDRs are according to the IMGT numbering method. In certain embodiments, CDRs are according to the antibody numbering method developed by the Chemical Computing Group (CCG); For example, using the Molecular Operating Environment (MOE) software. In certain embodiments, CDRs are according to the Kabat numbering method. In certain embodiments, CDRs are according to the AHo numbering method. In certain embodiments, the CDRs are numbered according to the Northern numbering method.

[0369] The antibodies or antigen-binding fragments of the present disclosure that bind to RSV-F and / or neutralize RSV may comprise a heavy chain variable domain (VH) comprising complementarity determining regions (CDRs) H1, CDRH2, and CDRH3, and a light chain variable domain (VL) comprising CDRL1, CDRL2, and CDRL3, wherein the CDRs are determined according to the IMGT numbering system, and wherein: (i) optionally, CDRH1 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 137, or a functional variant thereof comprising one, two, or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions for germline-encoded amino acids; (ii) optionally, CDRH2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 138, or a functional variant thereof comprising one, two, or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions for germline-encoded amino acids; (iii) optionally, CDRH3 comprises or consists of any of SEQ ID or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of a germline-encoded amino acid; (iv) optionally, CDRL1 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 142 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of a germline-encoded amino acid; (v) optionally, CDRL2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 143 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of a germline-encoded amino acid; and / or (vi) optionally, CDRL3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 852 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of a germline-encoded amino acid.

[0370] In specific embodiments, the antibody or antigen-binding fragment comprises i) VH and VL; or CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3, as shown in the "MPK65-v2-v1.2 Antibody" section or otherwise shown for the MPK65-v2-v1.2 antibody or as determined by any of the CDR determination schemes disclosed herein, and ii) an Fc portion. In certain embodiments, such an antibody or antigen-binding fragment comprises a CH and / or CL (potentially including a kappa light chain constant region) or fragments thereof associated with the VH or VL, respectively.

[0371] In specific embodiments, the antibody or antigen-binding fragment comprises a VH and a VL; or a CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, as set forth in this "MPK65-v2-v1.2 Antibody" section or otherwise set forth for the MPK65-v2-v1.2 antibody or as determined by any of the CDR determination schemes disclosed herein, and (A) an Fc portion comprising the following substitution mutations: (i) G236A, L328V, and Q295E; (ii) G236A, L328V, and Q295E; ii) G236A, P230A and Q295E; (iii) G236A, R292P and I377N; (iv) G236A, K334A and Q295E; (v) G236S, R292P and Y300L; (vi) G236A and Y300L; (vii) G236A, R292P and Y300L; (viii) G236S, G420V, G446E and L309T; (ix) G236A and R292P; (x ) R292P and Y300L; (xi) G236A and R292P; (xii) Y300L; (xiii) E345K, G236S, L235Y and S267E; (xiv) E272R, L309T, S219Y and S267E; (xv) G236Y; (xvi) G236W; (xvii) F243L, G446E, P396L and S267E; (xviii) G236A, S239D and H268E (xix) M428L / N434S; (xx) M428L / N434A; (xxi) G236A / A330L / I332E / M428L / N434S; (xxii) G236A / A330L / I332E / M428L / N434A; or (xxiii) any two or more of (i)-(xxii); or (B) an Fc portion comprising or consisting of an Fc polypeptide or fragment thereof comprising the sequence of SEQ any one of SEQ ID NOs: 664-700 having, or consisting of, an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical, optionally to naturally occurring variants thereof, or comprises, or consists of, an amino acid sequence as set forth in any one of SEQ ID NOs: 672-700.

[0372] In certain embodiments, the antibody or antigen-binding fragment comprises i) a VH and a VL; or CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, as shown in this "MPK65-v2-v1.2 Antibody" section or otherwise shown for the MPK65-v2-v1.2 antibody or as determined by any of the CDR determination schemes disclosed herein, and ii) an Fc portion comprising or consisting of an Fc polypeptide or fragment thereof comprising or consisting of an amino acid sequence having a sequence according to any one of SEQ ID NOs: 679-684 and 688-690, or having a sequence according to any one of SEQ ID NOs: 679-684 and 688-690. The sequence of any one of NOs:679-684 and 688-690 has an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical.

[0373] In certain embodiments, the antibody or antigen-binding fragment comprises the MPK65-v2-v1.2-rIG1m3-LS antibody.

[0374] In certain embodiments, the antibody or antigen-binding fragment comprises the MPK65-v2-v1.2-rIG1m17,1-LS antibody.

[0375] MPK65-v2-v3.1 Antibody

[0376] In some embodiments, the antibodies or antigen-binding fragments of the present disclosure are MPK65-v2-v3.1 antibodies or antigen-binding fragments thereof. Such antibodies or antigen-binding fragments thereof can bind to and / or neutralize RSV.

[0377] In some embodiments, the MPK65-v2-v3.1 antibody may have a VH, VL, CDRH1-H3, and / or CDRL1-L3 comprising or consisting of the following amino acid sequence, or be encoded by a polynucleotide having the following sequence:

[0378]

[0379] In some embodiments, the VH and VL of the MPK65-v2-v3.1 antibody or antigen-binding fragment that binds RSV-F and / or neutralizes RSV comprise or consist of a VH and VL having the sequences of SEQ ID NOs: 817 and 141, respectively.

[0380] In certain embodiments, the antibodies or antigen-binding fragments of the present disclosure bind to RSV-F and / or neutralize RSV and:

[0381] (i) the VH comprises, or consists of, an amino acid sequence that is at least 80% (e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identical to the amino acid sequence set forth in SEQ ID NO: 817, wherein the sequence variation is optionally limited to one or more framework regions and / or the sequence variation comprises one or more substitutions to germline-encoded amino acids; and / or

[0382] (ii) the VL comprises or consists of an amino acid sequence that is at least 80% (e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identical to the amino acid sequence set forth in SEQ ID NO: 141, wherein the sequence variation is optionally limited to one or more framework regions and / or the sequence variation comprises one or more substitutions to germline-encoded amino acids.

[0383] In some embodiments, the variation compared to SEQ ID NO: 817 or SEQ ID NO: 141 is limited to one or more framework regions. In some embodiments, the variation comprises or consists of one, two, three, four, five, six, seven, eight, nine, or ten amino acid substitutions (any or all of which may be conservative substitutions), insertions, or deletions in VH, VL, or both. In some embodiments, the variation comprises one or more amino acid substitutions, insertions, and / or deletions of amino acids at two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, or more amino acid positions from the N-terminal and / or C-terminal amino acids of the CDRs.

[0384] Framework regions can be identified according to a numbering scheme (e.g., IMGT, Kabat, Chothia, North, EU, Martin (enhanced Chothia), Contact, AbM, CCG, EU, or AHo, or a combination of two or more of these. CDRs can be identified within a variable domain or within a heavy or light chain according to a numbering scheme or a combination of numbering schemes, and preferably, FRs can be identified using the same numbering scheme or combination of numbering schemes.

[0385] For example, in some embodiments, the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 of MPK65-v2-v3.1, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 are according to IMGT (optionally IMGT-linked for CDRH3 and CDRL3), and the antibody or antigen-binding fragment further comprises one or more framework sequences from MPK65-v2-v3.1 and / or one or more framework sequences that are variants of the MPK65-v2-v3.1 framework sequences, wherein the one or more framework sequences of MPK65-v2-v3.1 are according to IMGT (and if IMGT-linked for CDRH3 and CDRL3, this is indicated).

[0386] In other embodiments, the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 of MPK65-v2-v3.1, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 are according to Kabat, and the antibody or antigen-binding fragment further comprises one or more framework sequences from MPK65-v2-v3.1 and / or one or more framework sequences that are variants of the MPK65-v2-v3.1 framework sequences, wherein the one or more framework sequences of MPK65-v2-v3.1 are according to Kabat.

[0387] In other embodiments, the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 of MPK65-v2-v3.1, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 are according to Chothia, and the antibody or antigen-binding fragment further comprises one or more framework sequences from MPK65-v2-v3.1 and / or one or more framework sequences that are variants of the MPK65-v2-v3.1 framework sequences, wherein the one or more framework sequences of MPK65-v2-v3.1 are according to Chothia.

[0388] In other embodiments, the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 of MPK65-v2-v3.1, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 are according to Martin (Enhanced Chothia), and the antibody or antigen-binding fragment further comprises one or more framework sequences from MPK65-v2-v3.1 and / or one or more framework sequences that are variants of the MPK65-v2-v3.1 framework sequences, wherein the one or more framework sequences of MPK65-v2-v3.1 are according to Martin (Enhanced Chothia).

[0389] In other embodiments, the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 of MPK65-v2-v3.1, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 are according to AbM, and the antibody or antigen-binding fragment further comprises one or more framework sequences from MPK65-v2-v3.1 and / or one or more framework sequences that are variants of the MPK65-v2-v3.1 framework sequences, wherein the one or more framework sequences of MPK65-v2-v3.1 are according to AbM.

[0390] In other embodiments, the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 of MPK65-v2-v3.1, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 are according to North, and the antibody or antigen-binding fragment further comprises one or more framework sequences from MPK65-v2-v3.1 and / or one or more framework sequences that are variants of the MPK65-v2-v3.1 framework sequences, wherein the one or more framework sequences of MPK65-v2-v3.1 are according to North.

[0391] In other embodiments, the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 are according to Contact, and the antibody or antigen-binding fragment further comprises one or more framework sequences from MPK65-v2-v3.1 and / or one or more framework sequences that are variants of the MPK65-v2-v3.1 framework sequences, wherein the one or more framework sequences of MPK65-v2-v3.1 are according to Contact.

[0392] In other embodiments, the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 of MPK65-v2-v3.1, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 are according to CCG, and the antibody or antigen-binding fragment further comprises one or more framework sequences from MPK65-v2-v3.1 and / or one or more framework sequences that are variants of the MPK65-v2-v3.1 framework sequences, wherein the one or more framework sequences of MPK65-v2-v3.1 are according to CCG.

[0393] In other embodiments, the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 of MPK65-v2-v3.1, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 are according to EU, and the antibody or antigen-binding fragment further comprises one or more framework sequences from MPK65-v2-v3.1 and / or one or more framework sequences that are variants of the MPK65-v2-v3.1 framework sequences, wherein the one or more framework sequences of MPK65-v2-v3.1 are according to EU.

[0394] In other embodiments, the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 of MPK65-v2-v3.1, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 are according to AHo, and the antibody or antigen-binding fragment further comprises one or more framework sequences from MPK65-v2-v3.1 and / or one or more framework sequences that are variants of the MPK65-v2-v3.1 framework sequences, wherein the one or more framework sequences of MPK65-v2-v3.1 are according to AHo.

[0395] In certain embodiments, the antibody or antigen-binding fragment comprises a VH comprising FR1, FR2, FR3, and / or FR4 of the VH amino acid sequence set forth in SEQ ID NO: 817 (or a variant of FR1, FR2, FR3, and / or FR4 comprising one, two, three, four, or five amino acid substitutions (optionally comprising or consisting of one or more conservative substitutions), insertions, and / or deletions), and a VL comprising FR1, FR2, FR3, and / or FR4 of the VL amino acid sequence set forth in SEQ ID NO: 141 (or a variant of FR1, FR2, FR3, and / or FR4 comprising one, two, three, four, or five amino acid substitutions (optionally comprising or consisting of one or more conservative substitutions), insertions, and / or deletions). In some embodiments, FRs are defined according to the IMGT, Kabat, Chothia, North, EU, Martin (enhanced Chothia), Contact, AbM, CCG, or AHo numbering systems, or any combination thereof.

[0396] In certain embodiments, the antibodies or antigen-binding fragments comprise a VH comprising, consisting essentially of, or consisting of a FR1, FR2, FR3, or FR4 that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the corresponding FR1, FR2, FR3, or FR4 of the VH amino acid sequence set forth in SEQ ID NO: 817, or comprises, consists essentially of, or consists of the corresponding FR1, FR2, FR3, or FR4 of the VH amino acid sequence set forth in SEQ ID NO: 702, and a VL comprising a VH comprising, consisting essentially of, or consisting of a FR1, FR2, FR3, or FR4 that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the corresponding FR1, FR2, FR3, or FR4 of the VH amino acid sequence set forth in SEQ ID NO: In some embodiments, the FR1, FR2, FR3, and / or FR4 are at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the corresponding FR1, FR2, FR3, or FR4 of the VL amino acid sequence set forth in SEQ ID NO: 141, or comprise, consist essentially of, or consist of the corresponding FR1, FR2, FR3, or FR4 of the VL amino acid sequence set forth in SEQ ID NO: 704. In some embodiments, the FRs are defined according to the IMGT, Kabat, Chothia, North, EU, Martin (enhanced Chothia), Contact, AbM, CCG, or AHo numbering systems, or according to any combination thereof.

[0397] In certain embodiments, the antibodies or antigen-binding fragments comprise a VH comprising, consisting essentially of, or consisting of the corresponding FR1, FR2, FR3, or FR4 of the VH amino acid sequence set forth in SEQ ID NO: 817, or a VL comprising, consisting essentially of, or consisting of the corresponding FR1, FR2, FR3, or FR4 of the VH amino acid sequence set forth in SEQ ID NO: 702, and the VH comprising, consisting essentially of, or consisting of the corresponding FR1, FR2, FR3, or FR4 of the VH amino acid sequence set forth in SEQ ID NO: 703. In some embodiments, the FR1, FR2, FR3, and FR4 are at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the corresponding FR1, FR2, FR3, or FR4 of SEQ ID NO: 141, or comprise, consist essentially of, or consist of the corresponding FR1, FR2, FR3, or FR4 of SEQ ID NO: 704. In some embodiments, the FRs are defined according to the IMGT, Kabat, Chothia, North, EU, Martin (enhanced Chothia), Contact, AbM, CCG, or AHo numbering systems, or according to any combination thereof.

[0398] In certain embodiments, antibodies or antigen-binding fragments of the present disclosure bind to RSV-F and / or neutralize RSV, and may include one or more VHs in conjunction with RSV-F, and may further include a CDR according to a VH sequence of SEQ ID NO: 817, and may include one or more VLs in conjunction with RSV-F, and may further include a CDR according to a VL sequence of SEQ ID NO: 141, wherein CDRs are as determined using any known CDR numbering method, including Kabat, Chothia, EU, Martin (enhanced Chothia), Contact, AbM, CCG, EU, or AHo numbering methods, or a combination of two or more of these IMGT, Martin (enhanced Chothia), Contact, North, and AHo numbering methods. In certain embodiments, CDRs are according to the IMGT numbering method. In certain embodiments, CDRs are according to the antibody numbering method developed by the Chemical Computing Group (CCG); For example, using the Molecular Operating Environment (MOE) software. In certain embodiments, CDRs are according to the Kabat numbering method. In certain embodiments, CDRs are according to the AHo numbering method. In certain embodiments, the CDRs are numbered according to the Northern numbering method.

[0399] The antibodies or antigen-binding fragments of the present disclosure that bind to RSV-F and / or neutralize RSV may comprise a heavy chain variable domain (VH) comprising complementarity determining regions (CDRs) H1, CDRH2, and CDRH3, and a light chain variable domain (VL) comprising CDRL1, CDRL2, and CDRL3, wherein the CDRs are determined according to the IMGT numbering system, and wherein: (i) optionally, CDRH1 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 814, or a functional variant thereof comprising one, two, or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions for germline-encoded amino acids; (ii) optionally, CDRH2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 818, or a functional variant thereof comprising one, two, or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions for germline-encoded amino acids; (iii) optionally, CDRH3 comprises or consists of any of SEQ ID (iv) optionally, CDRL1 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 142 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions for germline-encoded amino acids; (v) optionally, CDRL2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 143 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions for germline-encoded amino acids; and / or (vi) optionally, CDRL3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 144 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions for germline-encoded amino acids.

[0400] In specific embodiments, the antibody or antigen-binding fragment comprises i) VH and VL; or CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3, as shown in the "MPK65-v2-v3.1 Antibody" section or otherwise shown for the MPK65-v2-v3.1 antibody or as determined by any CDR determination scheme disclosed herein, and ii) an Fc portion. In certain embodiments, such an antibody or antigen-binding fragment comprises a CH and / or CL (potentially including a kappa light chain constant region) or fragment thereof associated with a VH or VL, respectively.

[0401] In specific embodiments, the antibody or antigen-binding fragment comprises a VH and a VL; or a CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, as described in this "MPK65-v2-v3.1 Antibody" section or otherwise described for the MPK65-v2-v3.1 antibody or as determined by any of the CDR determination schemes disclosed herein, and (A) an Fc portion comprising the following substitution mutations: (i) G236A, L328V, and Q295E; (ii) G236A, L328V, and Q295E; ii) G236A, P230A and Q295E; (iii) G236A, R292P and I377N; (iv) G236A, K334A and Q295E; (v) G236S, R292P and Y300L; (vi) G236A and Y300L; (vii) G236A, R292P and Y300L; (viii) G236S, G420V, G446E and L309T; (ix) G236A and R292P; (x ) R292P and Y300L; (xi) G236A and R292P; (xii) Y300L; (xiii) E345K, G236S, L235Y and S267E; (xiv) E272R, L309T, S219Y and S267E; (xv) G236Y; (xvi) G236W; (xvii) F243L, G446E, P396L and S267E; (xviii) G236A, S239D and H268E (xix) M428L / N434S; (xx) M428L / N434A; (xxi) G236A / A330L / I332E / M428L / N434S; (xxii) G236A / A330L / I332E / M428L / N434A; or (xxiii) any two or more of (i)-(xxii); or (B) an Fc portion comprising or consisting of an Fc polypeptide or fragment thereof comprising the sequence of SEQ any one of SEQ ID NOs: 664-700 having, or consisting of, an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical, optionally to naturally occurring variants thereof, or comprises, or consists of, an amino acid sequence as set forth in any one of SEQ ID NOs: 672-700.

[0402] In certain embodiments, the antibody or antigen-binding fragment comprises i) a VH and a VL; or CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, as shown in this "MPK65-v2-v3.1 Antibody" section or otherwise shown for the MPK65-v2-v3.1 antibody or as determined by any of the CDR determination schemes disclosed herein, and ii) an Fc portion comprising or consisting of an Fc polypeptide or fragment thereof comprising or consisting of an amino acid sequence having a sequence according to any one of SEQ ID NOs: 679-684 and 688-690, or having a sequence according to any one of SEQ ID NOs: 689-701, 690-711, 691-723, 692-730, 693-744, 694-756, 695-767, 696-770, 697-781, 698-799, 700-711, 712-724, 699-735, 713-736, 691-737, 697-748, 698-759, 714-749, 699-750, 715-751, 699-761, 691-762, 691-763, 691-764, 692-765 The sequence of any one of NOs:679-684 and 688-690 has an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical.

[0403] In certain embodiments, the antibody or antigen-binding fragment comprises the MPK65-v2-v3.1-rIG1m3-LS antibody.

[0404] In certain embodiments, the antibody or antigen-binding fragment comprises the MPK65-v2-v3.1-rIG1m17,1-LS antibody.

[0405] MPK176-v1.3 antibody

[0406] In some embodiments, the antibody or antigen-binding fragment of the present disclosure is an MPK176-v1.3 antibody or an antigen-binding fragment thereof. Such an antibody or antigen-binding fragment thereof can bind to RSV and / or neutralize RSV.

[0407] In some embodiments, the MPK176-v1.3 antibody may have a VH, VL, CDRH1-H3, and / or CDRL1-L3 comprising or consisting of the following amino acid sequence, or be encoded by a polynucleotide having the following sequence:

[0408]

[0409] In some embodiments, the VH and VL of the MPK176-v1.3 antibody or antigen-binding fragment that binds RSV-F and / or neutralizes RSV comprise or consist of a VH and VL having the sequences of SEQ ID NOs: 233 and 858, respectively.

[0410] In certain embodiments, the antibodies or antigen-binding fragments of the present disclosure bind to RSV-F and / or neutralize RSV and:

[0411] (i) the VH comprises, or consists of, an amino acid sequence that is at least 80% (e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identical to the amino acid sequence set forth in SEQ ID NO: 233, wherein the sequence variation is optionally limited to one or more framework regions and / or the sequence variation comprises one or more substitutions to germline-encoded amino acids; and / or

[0412] (ii) the VL comprises or consists of an amino acid sequence that is at least 80% (e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identical to the amino acid sequence set forth in SEQ ID NO: 858, wherein the sequence variation is optionally limited to one or more framework regions and / or the sequence variation comprises one or more substitutions to germline-encoded amino acids.

[0413] In some embodiments, the variation compared to SEQ ID NO: 233 or SEQ ID NO: 858 is limited to one or more framework regions. In some embodiments, the variation comprises or consists of one, two, three, four, five, six, seven, eight, nine, or ten amino acid substitutions (any or all of which may be conservative substitutions), insertions, or deletions in VH, VL, or both. In some embodiments, the variation comprises one or more amino acid substitutions, insertions, and / or deletions of amino acids at two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, or more amino acid positions from the N-terminal and / or C-terminal amino acids of the CDRs.

[0414] Framework regions can be identified according to a numbering scheme (e.g., IMGT, Kabat, Chothia, North, EU, Martin (enhanced Chothia), Contact, AbM, CCG, EU, or AHo, or a combination of two or more of these. CDRs can be identified within a variable domain or within a heavy or light chain according to a numbering scheme or a combination of numbering schemes, and preferably, FRs can be identified using the same numbering scheme or combination of numbering schemes.

[0415] For example, in some embodiments, the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 of MPK176-v1.3, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 are according to IMGT (optionally IMGT-linked for CDRH3 and CDRL3), and the antibody or antigen-binding fragment further comprises one or more framework sequences from MPK176-v1.3 and / or one or more framework sequences that are variants of MPK176-v1.3 framework sequences, wherein the one or more framework sequences of MPK176-v1.3 are according to IMGT (and if IMGT-linked for CDRH3 and CDRL3, this is indicated).

[0416] In other embodiments, the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 of MPK176-v1.3, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 are according to Kabat, and the antibody or antigen-binding fragment further comprises one or more framework sequences from MPK176-v1.3 and / or one or more framework sequences that are variants of the MPK176-v1.3 framework sequences, wherein the one or more framework sequences of MPK176-v1.3 are according to Kabat.

[0417] In other embodiments, the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 of MPK176-v1.3, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 are according to Chothia, and the antibody or antigen-binding fragment further comprises one or more framework sequences from MPK176-v1.3 and / or one or more framework sequences that are variants of the MPK176-v1.3 framework sequences, wherein the one or more framework sequences of MPK176-v1.3 are according to Chothia.

[0418] In other embodiments, the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 of MPK176-v1.3, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 are according to Martin (Enhanced Chothia), and the antibody or antigen-binding fragment further comprises one or more framework sequences from MPK176-v1.3 and / or one or more framework sequences that are variants of the MPK176-v1.3 framework sequences, wherein the one or more framework sequences of MPK176-v1.3 are according to Martin (Enhanced Chothia).

[0419] In other embodiments, the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 of MPK176-v1.3, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 are according to AbM, and the antibody or antigen-binding fragment further comprises one or more framework sequences from MPK176-v1.3 and / or one or more framework sequences that are variants of the MPK176-v1.3 framework sequences, wherein the one or more framework sequences of MPK176-v1.3 are according to AbM.

[0420] In other embodiments, the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 of MPK176-v1.3, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 are according to North, and the antibody or antigen-binding fragment further comprises one or more framework sequences from MPK176-v1.3 and / or one or more framework sequences that are variants of the MPK176-v1.3 framework sequences, wherein the one or more framework sequences of MPK176-v1.3 are according to North.

[0421] In other embodiments, the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 are according to Contact, and the antibody or antigen-binding fragment further comprises one or more framework sequences from MPK176-v1.3 and / or one or more framework sequences that are variants of the MPK176-v1.3 framework sequences, wherein the one or more framework sequences of MPK176-v1.3 are according to Contact.

[0422] In other embodiments, the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 of MPK176-v1.3, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 are according to CCG, and the antibody or antigen-binding fragment further comprises one or more framework sequences from MPK176-v1.3 and / or one or more framework sequences that are variants of the MPK176-v1.3 framework sequences, wherein the one or more framework sequences of MPK176-v1.3 are according to CCG.

[0423] In other embodiments, the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 of MPK176-v1.3, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 are according to EU, and the antibody or antigen-binding fragment further comprises one or more framework sequences from MPK176-v1.3 and / or one or more framework sequences that are variants of the MPK176-v1.3 framework sequences, wherein the one or more framework sequences of MPK176-v1.3 are according to EU.

[0424] In other embodiments, the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 of MPK176-v1.3, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 are according to AHo, and the antibody or antigen-binding fragment further comprises one or more framework sequences from MPK176-v1.3 and / or one or more framework sequences that are variants of the MPK176-v1.3 framework sequences, wherein the one or more framework sequences of MPK176-v1.3 are according to AHo.

[0425] In certain embodiments, the antibody or antigen-binding fragment comprises a VH comprising FR1, FR2, FR3, and / or FR4 of the VH amino acid sequence set forth in SEQ ID NO: 233 (or a variant of FR1, FR2, FR3, and / or FR4 comprising one, two, three, four, or five amino acid substitutions (optionally comprising or consisting of one or more conservative substitutions), insertions, and / or deletions), and a VL comprising FR1, FR2, FR3, and / or FR4 of the VL amino acid sequence set forth in SEQ ID NO: 858 (or a variant of FR1, FR2, FR3, and / or FR4 comprising one, two, three, four, or five amino acid substitutions (optionally comprising or consisting of one or more conservative substitutions), insertions, and / or deletions). In some embodiments, FRs are defined according to the IMGT, Kabat, Chothia, North, EU, Martin (enhanced Chothia), Contact, AbM, CCG, or AHo numbering systems, or any combination thereof.

[0426] In certain embodiments, the antibodies or antigen-binding fragments comprise a VH comprising, consisting essentially of, or consisting of a FR1, FR2, FR3, or FR4 that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the corresponding FR1, FR2, FR3, or FR4 of the VH amino acid sequence set forth in SEQ ID NO: 233, or comprises, consists essentially of, or consists of the corresponding FR1, FR2, FR3, or FR4 of the VH amino acid sequence set forth in SEQ ID NO: 702, and a VL comprising a VH comprising, consisting essentially of, or consisting of a FR1, FR2, FR3, or FR4 that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the corresponding FR1, FR2, FR3, or FR4 of the VH amino acid sequence set forth in SEQ ID NO: In some embodiments, the FR1, FR2, FR3, and / or FR4 are at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the corresponding FR1, FR2, FR3, or FR4 of the VL amino acid sequence set forth in SEQ ID NO: 858, or comprise, consist essentially of, or consist of the corresponding FR1, FR2, FR3, or FR4 of the VL amino acid sequence set forth in SEQ ID NO: 704. In some embodiments, the FRs are defined according to the IMGT, Kabat, Chothia, North, EU, Martin (enhanced Chothia), Contact, AbM, CCG, or AHo numbering systems, or according to any combination thereof.

[0427] In certain embodiments, the antibodies or antigen-binding fragments comprise a VH comprising, consisting essentially of, or consisting of the corresponding FR1, FR2, FR3, or FR4 of the VH amino acid sequence set forth in SEQ ID NO: 233, or a VL comprising, consisting essentially of, or consisting of the corresponding FR1, FR2, FR3, or FR4 of the VH amino acid sequence set forth in SEQ ID NO: 702, and the VL comprising, consisting essentially of, or consisting of the corresponding FR1, FR2, FR3, or FR4 of the VH amino acid sequence set forth in SEQ ID NO: 703. In some embodiments, the FR1, FR2, FR3, and FR4 are at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the corresponding FR1, FR2, FR3, or FR4 of SEQ ID NO: 858, or comprise, consist essentially of, or consist of the corresponding FR1, FR2, FR3, or FR4 of SEQ ID NO: 704. In some embodiments, the FRs are defined according to the IMGT, Kabat, Chothia, North, EU, Martin (enhanced Chothia), Contact, AbM, CCG, or AHo numbering systems, or according to any combination thereof.

[0428] In certain embodiments, antibodies or antigen-binding fragments of the present disclosure bind to RSV-F and / or neutralize RSV, and may include one or more VHs in conjunction with RSV-F, and may further include a CDR according to a VH sequence of SEQ ID NO: 233, and may include one or more VLs in conjunction with RSV-F, and may further include a CDR according to a VL sequence of SEQ ID NO: 858, wherein CDRs are as determined using any known CDR numbering method, including Kabat, Chothia, EU, Martin (enhanced Chothia), Contact, AbM, CCG, EU, or AHo numbering methods, or a combination of two or more of these IMGT, Martin (enhanced Chothia), Contact, North, and AHo numbering methods. In certain embodiments, CDRs are according to the IMGT numbering method. In certain embodiments, CDRs are according to the antibody numbering method developed by the Chemical Computing Group (CCG); For example, using Molecular Operating Environment (MOE) software. In certain embodiments, CDRs are according to the Kabat numbering method. In certain embodiments, CDRs are according to the AHo numbering method. In certain embodiments, the CDRs are numbered according to the Northern numbering method.

[0429] The antibodies or antigen-binding fragments of the present disclosure that bind to RSV-F and / or neutralize RSV may comprise a heavy chain variable domain (VH) comprising complementarity determining regions (CDRs) H1, CDRH2, and CDRH3, and a light chain variable domain (VL) comprising CDRL1, CDRL2, and CDRL3, wherein the CDRs are identified according to the IMGT numbering system, and wherein: (i) optionally, CDRH1 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 234, or a functional variant thereof comprising one, two, or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions for germline-encoded amino acids; (ii) optionally, CDRH2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 235, or a functional variant thereof comprising one, two, or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions for germline-encoded amino acids; (iii) optionally, CDRH3 comprises or consists of any of SEQ ID (iv) optionally, CDRL1 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 239 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions for germline-encoded amino acids; (v) optionally, CDRL2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 240 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions for germline-encoded amino acids; and / or (vi) optionally, CDRL3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 241 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions for germline-encoded amino acids.

[0430] In specific embodiments, the antibody or antigen-binding fragment comprises i) VH and VL; or CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3, as shown in the "MPK176-v1.3 Antibody" section or otherwise shown for the MPK176-v1.3 antibody or as determined by any CDR determination scheme disclosed herein, and ii) an Fc portion. In certain embodiments, such an antibody or antigen-binding fragment comprises a CH and / or CL (potentially including a kappa light chain constant region) or a fragment thereof associated with a VH or VL, respectively.

[0431] In a specific embodiment, the antibody or antigen-binding fragment comprises a VH and a VL; or a CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, as set forth in this "MPK176-v1.3 Antibody" section or otherwise set forth for the MPK176-v1.3 antibody or as determined by any of the CDR determination schemes disclosed herein, and (A) an Fc portion comprising the following substitution mutations: (i) G236A, L328V, and Q295E; (ii) G236A, P230A, and Q295E; (iii) G236A, R292P, and I377N; (iv) G236A, K334A, and Q295E; (v) G236S, R292P, and Y300L; (vi) G236A and Y300L; (vii) G236A, R292P, and Y300L; (viii) G236S, G420V, G446E, and L309T; (ix) G236A and R292P; (x) R 292P and Y300L; (xi) G236A and R292P; (xii) Y300L; (xiii) E345K, G236S, L235Y and S267E; (xiv) E272R, L309T, S219Y and S267E; (xv) G236Y; (xvi) G236W; (xvii) F243L, G446E, P396L and S267E; (xviii) G236A, S239D and H268E; (xix) M428L / N434S; (xx) M428L / N434A; (xxi) G236A / A330L / I332E / M428L / N434S; (xxii) G236A / A330L / I332E / M428L / N434A; or (xxiii) any two or more of (i)-(xxii); or (B) an Fc portion comprising or consisting of an Fc polypeptide or fragment thereof comprising the sequence of SEQ any one of SEQ ID NOs: 664-700 having, or consisting of, an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical, optionally to naturally occurring variants thereof, or comprises, or consists of, an amino acid sequence as set forth in any one of SEQ ID NOs: 672-700.

[0432] In certain embodiments, the antibody or antigen-binding fragment comprises i) a VH and a VL; or CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, as shown in this "MPK176-v1.3 Antibody" section or otherwise shown for the MPK176-v1.3 antibody or as determined by any of the CDR determination schemes disclosed herein, and ii) an Fc portion comprising or consisting of an Fc polypeptide or fragment thereof comprising or consisting of an amino acid sequence according to any of SEQ ID NOs: 679-684 and 688-690, or a fragment thereof having a sequence according to any of SEQ ID NOs: 679-684 and 688-690. The sequence of any one of NOs:679-684 and 688-690 has an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical.

[0433] In certain embodiments, the antibody or antigen-binding fragment comprises the MPK176-v1.3-rIG1m3-LS antibody.

[0434] In certain embodiments, the antibody or antigen-binding fragment comprises the MPK176-v1.3-rIG1m17,1-LS antibody.

[0435] MPK176-v4.3 antibody

[0436] In some embodiments, the antibody or antigen-binding fragment of the present disclosure is an MPK176-v4.3 antibody or an antigen-binding fragment thereof. Such an antibody or antigen-binding fragment thereof can bind to RSV and / or neutralize RSV.

[0437] In some embodiments, the MPK176-v4.3 antibody may have a VH, VL, CDRH1-H3 and / or CDRL1-L3 comprising or consisting of the following amino acid sequence, or be encoded by a polynucleotide having the following sequence:

[0438]

[0439] In some embodiments, the VH and VL of the MPK176-v4.3 antibody or antigen-binding fragment that binds RSV-F and / or neutralizes RSV comprise or consist of a VH and VL having the sequences of SEQ ID NOs: 837 and 858, respectively.

[0440] In certain embodiments, the antibodies or antigen-binding fragments of the present disclosure bind to RSV-F and / or neutralize RSV and:

[0441] (i) the VH comprises, or consists of, an amino acid sequence that is at least 80% (e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identical to the amino acid sequence set forth in SEQ ID NO: 837, wherein the sequence variation is optionally limited to one or more framework regions and / or the sequence variation comprises one or more substitutions to germline-encoded amino acids; and / or

[0442] (ii) the VL comprises or consists of an amino acid sequence that is at least 80% (e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identical to the amino acid sequence set forth in SEQ ID NO: 858, wherein the sequence variation is optionally limited to one or more framework regions and / or the sequence variation comprises one or more substitutions to germline-encoded amino acids.

[0443] In some embodiments, the variation compared to SEQ ID NO: 837 or SEQ ID NO: 858 is limited to one or more framework regions. In some embodiments, the variation comprises or consists of one, two, three, four, five, six, seven, eight, nine, or ten amino acid substitutions (any or all of which may be conservative substitutions), insertions, or deletions in VH, VL, or both. In some embodiments, the variation comprises one or more amino acid substitutions, insertions, and / or deletions of amino acids at two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, or more amino acid positions from the N-terminal and / or C-terminal amino acids of the CDRs.

[0444] Framework regions can be identified according to a numbering scheme (e.g., IMGT, Kabat, Chothia, North, EU, Martin (enhanced Chothia), Contact, AbM, CCG, EU, or AHo, or a combination of two or more of these. CDRs can be identified within a variable domain or within a heavy or light chain according to a numbering scheme or a combination of numbering schemes, and preferably, FRs can be identified using the same numbering scheme or combination of numbering schemes.

[0445] For example, in some embodiments, the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 of MPK176-v4.3, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 are according to IMGT (optionally IMGT-linked for CDRH3 and CDRL3), and the antibody or antigen-binding fragment further comprises one or more framework sequences from MPK176-v4.3 and / or one or more framework sequences that are variants of MPK176-v4.3 framework sequences, wherein one or more framework sequences of MPK176-v4.3 are according to IMGT (and if IMGT-linked for CDRH3 and CDRL3, this is indicated).

[0446] In other embodiments, the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 of MPK176-v4.3, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 are according to Kabat, and the antibody or antigen-binding fragment further comprises one or more framework sequences from MPK176-v4.3 and / or one or more framework sequences that are variants of the MPK176-v4.3 framework sequences, wherein the one or more framework sequences of MPK176-v4.3 are according to Kabat.

[0447] In other embodiments, the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 of MPK176-v4.3, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 are according to Chothia, and the antibody or antigen-binding fragment further comprises one or more framework sequences from MPK176-v4.3 and / or one or more framework sequences that are variants of the MPK176-v4.3 framework sequences, wherein the one or more framework sequences of MPK176-v4.3 are according to Chothia.

[0448] In other embodiments, the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 of MPK176-v4.3, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 are according to Martin (Enhanced Chothia), and the antibody or antigen-binding fragment further comprises one or more framework sequences from MPK176-v4.3 and / or one or more framework sequences that are variants of the MPK176-v4.3 framework sequences, wherein the one or more framework sequences of MPK176-v4.3 are according to Martin (Enhanced Chothia).

[0449] In other embodiments, the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 of MPK176-v4.3, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 are according to AbM, and the antibody or antigen-binding fragment further comprises one or more framework sequences from MPK176-v4.3 and / or one or more framework sequences that are variants of the MPK176-v4.3 framework sequences, wherein the one or more framework sequences of MPK176-v4.3 are according to AbM.

[0450] In other embodiments, the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 of MPK176-v4.3, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 are according to North, and the antibody or antigen-binding fragment further comprises one or more framework sequences from MPK176-v4.3 and / or one or more framework sequences that are variants of the MPK176-v4.3 framework sequences, wherein the one or more framework sequences of MPK176-v4.3 are according to North.

[0451] In other embodiments, the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 are according to Contact, and the antibody or antigen-binding fragment further comprises one or more framework sequences from MPK176-v4.3 and / or one or more framework sequences that are variants of the MPK176-v4.3 framework sequences, wherein the one or more framework sequences of MPK176-v4.3 are according to Contact.

[0452] In other embodiments, the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 of MPK176-v4.3, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 are according to CCG, and the antibody or antigen-binding fragment further comprises one or more framework sequences from MPK176-v4.3 and / or one or more framework sequences that are variants of the MPK176-v4.3 framework sequences, wherein the one or more framework sequences of MPK176-v4.3 are according to CCG.

[0453] In other embodiments, the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 of MPK176-v4.3, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 are according to EU, and the antibody or antigen-binding fragment further comprises one or more framework sequences from MPK176-v4.3 and / or one or more framework sequences that are variants of the MPK176-v4.3 framework sequences, wherein the one or more framework sequences of MPK176-v4.3 are according to EU.

[0454] In other embodiments, the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 of MPK176-v4.3, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 are according to AHo, and the antibody or antigen-binding fragment further comprises one or more framework sequences from MPK176-v4.3 and / or one or more framework sequences that are variants of the MPK176-v4.3 framework sequences, wherein the one or more framework sequences of MPK176-v4.3 are according to AHo.

[0455] In certain embodiments, the antibody or antigen-binding fragment comprises a VH comprising FR1, FR2, FR3, and / or FR4 of the VH amino acid sequence set forth in SEQ ID NO: 837 (or a variant of FR1, FR2, FR3, and / or FR4 comprising one, two, three, four, or five amino acid substitutions (optionally comprising or consisting of one or more conservative substitutions), insertions, and / or deletions), and a VL comprising FR1, FR2, FR3, and / or FR4 of the VL amino acid sequence set forth in SEQ ID NO: 858 (or a variant of FR1, FR2, FR3, and / or FR4 comprising one, two, three, four, or five amino acid substitutions (optionally comprising or consisting of one or more conservative substitutions), insertions, and / or deletions). In some embodiments, FRs are defined according to the IMGT, Kabat, Chothia, North, EU, Martin (enhanced Chothia), Contact, AbM, CCG, or AHo numbering systems, or any combination thereof.

[0456] In certain embodiments, the antibodies or antigen-binding fragments comprise a VH comprising, consisting essentially of, or consisting of a FR1, FR2, FR3, or FR4 that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the corresponding FR1, FR2, FR3, or FR4 of the VH amino acid sequence set forth in SEQ ID NO: 837, or comprises, consists essentially of, or consists of the corresponding FR1, FR2, FR3, or FR4 of the VH amino acid sequence set forth in SEQ ID NO: 702, and a VL comprising a VH comprising, consisting essentially of, or consisting of a FR1, FR2, FR3, or FR4 that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the corresponding FR1, FR2, FR3, or FR4 of the VH amino acid sequence set forth in SEQ ID NO: In some embodiments, the FR1, FR2, FR3, and / or FR4 are at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the corresponding FR1, FR2, FR3, or FR4 of the VL amino acid sequence set forth in SEQ ID NO: 858, or comprise, consist essentially of, or consist of the corresponding FR1, FR2, FR3, or FR4 of the VL amino acid sequence set forth in SEQ ID NO: 704. In some embodiments, the FRs are defined according to the IMGT, Kabat, Chothia, North, EU, Martin (enhanced Chothia), Contact, AbM, CCG, or AHo numbering systems, or according to any combination thereof.

[0457] In certain embodiments, the antibodies or antigen-binding fragments comprise a VH comprising, consisting essentially of, or consisting of the corresponding FR1, FR2, FR3, or FR4 of the VH amino acid sequence set forth in SEQ ID NO: 837, or a VL comprising, consisting essentially of, or consisting of the corresponding FR1, FR2, FR3, or FR4 of the VH amino acid sequence set forth in SEQ ID NO: 702, and the VL comprising a VH comprising, consisting essentially of, or consisting of the corresponding FR1, FR2, FR3, or FR4 of the VH amino acid sequence set forth in SEQ ID NO: 703. In some embodiments, the FR1, FR2, FR3, and FR4 are at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the corresponding FR1, FR2, FR3, or FR4 of SEQ ID NO: 858, or comprise, consist essentially of, or consist of the corresponding FR1, FR2, FR3, or FR4 of SEQ ID NO: 704. In some embodiments, the FRs are defined according to the IMGT, Kabat, Chothia, North, EU, Martin (enhanced Chothia), Contact, AbM, CCG, or AHo numbering systems, or according to any combination thereof.

[0458] In certain embodiments, antibodies or antigen-binding fragments of the present disclosure bind to RSV-F and / or neutralize RSV, and may include one or more VHs in conjunction with RSV-F, and may further include a CDR according to a VH sequence of SEQ ID NO: 837, and may include one or more VLs in conjunction with RSV-F, and may further include a CDR according to a VL sequence of SEQ ID NO: 858, wherein CDRs are as determined using any known CDR numbering method, including Kabat, Chothia, EU, Martin (enhanced Chothia), Contact, AbM, CCG, EU, or AHo numbering methods, or a combination of two or more of these IMGT, Martin (enhanced Chothia), Contact, North, and AHo numbering methods. In certain embodiments, CDRs are according to the IMGT numbering method. In certain embodiments, CDRs are according to the antibody numbering method developed by the Chemical Computing Group (CCG); For example, using Molecular Operating Environment (MOE) software. In certain embodiments, CDRs are according to the Kabat numbering method. In certain embodiments, CDRs are according to the AHo numbering method. In certain embodiments, the CDRs are numbered according to the Northern numbering method.

[0459] The antibodies or antigen-binding fragments of the present disclosure that bind to RSV-F and / or neutralize RSV may comprise a heavy chain variable domain (VH) comprising complementarity determining regions (CDRs) H1, CDRH2, and CDRH3, and a light chain variable domain (VL) comprising CDRL1, CDRL2, and CDRL3, wherein the CDRs are identified according to the IMGT numbering system, and wherein: (i) optionally, CDRH1 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 234, or a functional variant thereof comprising one, two, or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions for germline-encoded amino acids; (ii) optionally, CDRH2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 838, or a functional variant thereof comprising one, two, or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions for germline-encoded amino acids; (iii) optionally, CDRH3 comprises or consists of any of SEQ ID (iv) optionally, CDRL1 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 239 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions for a germline-encoded amino acid; (v) optionally, CDRL2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 240 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions for a germline-encoded amino acid; and / or (vi) optionally, CDRL3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 241 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions for a germline-encoded amino acid.

[0460] In specific embodiments, the antibody or antigen-binding fragment comprises i) VH and VL; or CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3, as shown in this "MPK176-v4.3 Antibody" section or otherwise shown for the MPK176-v4.3 antibody or as determined by any CDR determination scheme disclosed herein, and ii) an Fc portion. In certain embodiments, such an antibody or antigen-binding fragment comprises a CH and / or CL (potentially including a kappa light chain constant region) or a fragment thereof associated with a VH or VL, respectively.

[0461] In a specific embodiment, the antibody or antigen-binding fragment comprises a VH and a VL; or a CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, as set forth in this "MPK176-v4.3 Antibody" section or otherwise set forth for the MPK176-v4.3 antibody or as determined by any of the CDR determination schemes disclosed herein, and (A) an Fc portion comprising the following substitution mutations: (i) G236A, L328V, and Q295E; (ii) G236A, P230A, and Q295E; (iii) G236A, R292P, and I377N; (iv) G236A, K334A, and Q295E; (v) G236S, R292P, and Y300L; (vi) G236A and Y300L; (vii) G236A, R292P, and Y300L; (viii) G236S, G420V, G446E, and L309T; (ix) G236A and R292P; (x) R 292P and Y300L; (xi) G236A and R292P; (xii) Y300L; (xiii) E345K, G236S, L235Y and S267E; (xiv) E272R, L309T, S219Y and S267E; (xv) G236Y; (xvi) G236W; (xvii) F243L, G446E, P396L and S267E; (xviii) G236A, S239D and H268E; (xix) M428L / N434S; (xx) M428L / N434A; (xxi) G236A / A330L / I332E / M428L / N434S; (xxii) G236A / A330L / I332E / M428L / N434A; or (xxiii) any two or more of (i)-(xxii); or (B) an Fc portion comprising or consisting of an Fc polypeptide or fragment thereof comprising the sequence of SEQ any one of SEQ ID NOs: 664-700 having, or consisting of, an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical, optionally to naturally occurring variants thereof, or comprises, or consists of, an amino acid sequence as set forth in any one of SEQ ID NOs: 672-700.

[0462] In certain embodiments, the antibody or antigen-binding fragment comprises i) a VH and a VL; or CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, as shown in this "MPK176-v4.3 Antibody" section or otherwise shown for the MPK176-v4.3 antibody or as determined by any of the CDR determination schemes disclosed herein, and ii) an Fc portion comprising or consisting of an Fc polypeptide or fragment thereof comprising or consisting of an amino acid sequence having a sequence according to any one of SEQ ID NOs: 679-684 and 688-690, or having a sequence according to any one of SEQ ID NOs: 679-684 and 688-690. The sequence of any one of NOs:679-684 and 688-690 has an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical.

[0463] In certain embodiments, the antibody or antigen-binding fragment comprises the MPK176-v4.3-rIG1m3-LS antibody.

[0464] In certain embodiments, the antibody or antigen-binding fragment comprises the MPK176-v4.3-rIG1m17,1-LS antibody.

[0465] MPK201-v1.2 antibody

[0466] In some embodiments, the antibody or antigen-binding fragment of the present disclosure is the MPK201-v1.2 antibody or antigen-binding fragment thereof. Such an antibody or antigen-binding fragment thereof can bind to RSV and / or neutralize RSV.

[0467] In some embodiments, the MPK201-v1.2 antibody may have a VH, VL, CDRH1-H3, and / or CDRL1-L3 comprising or consisting of the following amino acid sequence, or be encoded by a polynucleotide having the following sequence:

[0468]

[0469] In some embodiments, the VH and VL of the MPK201-v1.2 antibody or antigen-binding fragment that binds RSV-F and / or neutralizes RSV comprise or consist of a VH and VL having the sequences of SEQ ID NOs: 357 and 847, respectively.

[0470] In certain embodiments, the antibodies or antigen-binding fragments of the present disclosure bind to RSV-F and / or neutralize RSV and:

[0471] (i) the VH comprises, or consists of, an amino acid sequence that is at least 80% (e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identical to the amino acid sequence set forth in SEQ ID NO: 357, wherein the sequence variation is optionally limited to one or more framework regions and / or the sequence variation comprises one or more substitutions to germline-encoded amino acids; and / or

[0472] (ii) the VL comprises or consists of an amino acid sequence that is at least 80% (e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identical to the amino acid sequence set forth in SEQ ID NO: 847, wherein the sequence variation is optionally limited to one or more framework regions and / or the sequence variation comprises one or more substitutions to germline-encoded amino acids.

[0473] In some embodiments, the variation compared to SEQ ID NO: 357 or SEQ ID NO: 847 is limited to one or more framework regions. In some embodiments, the variation comprises or consists of one, two, three, four, five, six, seven, eight, nine, or ten amino acid substitutions (any or all of which may be conservative substitutions), insertions, or deletions in VH, VL, or both. In some embodiments, the variation comprises one or more amino acid substitutions, insertions, and / or deletions of amino acids at two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, or more amino acid positions from the N-terminal and / or C-terminal amino acids of the CDRs.

[0474] Framework regions can be identified according to a numbering scheme (e.g., IMGT, Kabat, Chothia, North, EU, Martin (enhanced Chothia), Contact, AbM, CCG, EU, or AHo, or a combination of two or more of these. CDRs can be identified within a variable domain or within a heavy or light chain according to a numbering scheme or a combination of numbering schemes, and preferably, FRs can be identified using the same numbering scheme or combination of numbering schemes.

[0475] For example, in some embodiments, the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 of MPK201-v1.2, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 are according to IMGT (optionally IMGT-linked for CDRH3 and CDRL3), and the antibody or antigen-binding fragment further comprises one or more framework sequences from MPK201-v1.2 and / or one or more framework sequences that are variants of the MPK201-v1.2 framework sequences, wherein the one or more framework sequences of MPK201-v1.2 are according to IMGT (and if IMGT-linked for CDRH3 and CDRL3, this is indicated).

[0476] In other embodiments, the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 of MPK201-v1.2, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 are according to Kabat, and the antibody or antigen-binding fragment further comprises one or more framework sequences from MPK201-v1.2 and / or one or more framework sequences that are variants of the MPK201-v1.2 framework sequences, wherein the one or more framework sequences of MPK201-v1.2 are according to Kabat.

[0477] In other embodiments, the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 of MPK201-v1.2, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 are according to Chothia, and the antibody or antigen-binding fragment further comprises one or more framework sequences from MPK201-v1.2 and / or one or more framework sequences that are variants of the MPK201-v1.2 framework sequences, wherein the one or more framework sequences of MPK201-v1.2 are according to Chothia.

[0478] In other embodiments, the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 of MPK201-v1.2, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 are according to Martin (Enhanced Chothia), and the antibody or antigen-binding fragment further comprises one or more framework sequences from MPK201-v1.2 and / or one or more framework sequences that are variants of the MPK201-v1.2 framework sequences, wherein the one or more framework sequences of MPK201-v1.2 are according to Martin (Enhanced Chothia).

[0479] In other embodiments, the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 of MPK201-v1.2, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 are according to AbM, and the antibody or antigen-binding fragment further comprises one or more framework sequences from MPK201-v1.2 and / or one or more framework sequences that are variants of the MPK201-v1.2 framework sequences, wherein the one or more framework sequences of MPK201-v1.2 are according to AbM.

[0480] In other embodiments, the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 of MPK201-v1.2, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 are according to North, and the antibody or antigen-binding fragment further comprises one or more framework sequences from MPK201-v1.2 and / or one or more framework sequences that are variants of the MPK201-v1.2 framework sequences, wherein the one or more framework sequences of MPK201-v1.2 are according to North.

[0481] In other embodiments, the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 are according to Contact, and the antibody or antigen-binding fragment further comprises one or more framework sequences from MPK201-v1.2 and / or one or more framework sequences that are variants of the MPK201-v1.2 framework sequences, wherein the one or more framework sequences of MPK201-v1.2 are according to Contact.

[0482] In other embodiments, the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 of MPK201-v1.2, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 are according to CCG, and the antibody or antigen-binding fragment further comprises one or more framework sequences from MPK201-v1.2 and / or one or more framework sequences that are variants of the MPK201-v1.2 framework sequences, wherein the one or more framework sequences of MPK201-v1.2 are according to CCG.

[0483] In other embodiments, the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 of MPK201-v1.2, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 are according to EU, and the antibody or antigen-binding fragment further comprises one or more framework sequences from MPK201-v1.2 and / or one or more framework sequences that are variants of the MPK201-v1.2 framework sequences, wherein the one or more framework sequences of MPK201-v1.2 are according to EU.

[0484] In other embodiments, the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 of MPK201-v1.2, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 are according to AHo, and the antibody or antigen-binding fragment further comprises one or more framework sequences from MPK201-v1.2 and / or one or more framework sequences that are variants of the MPK201-v1.2 framework sequences, wherein the one or more framework sequences of MPK201-v1.2 are according to AHo.

[0485] In certain embodiments, the antibody or antigen-binding fragment comprises a VH comprising FR1, FR2, FR3, and / or FR4 of the VH amino acid sequence set forth in SEQ ID NO: 357 (or a variant of FR1, FR2, FR3, and / or FR4 comprising one, two, three, four, or five amino acid substitutions (optionally comprising or consisting of one or more conservative substitutions), insertions, and / or deletions), and a VL comprising FR1, FR2, FR3, and / or FR4 of the VL amino acid sequence set forth in SEQ ID NO: 847 (or a variant of FR1, FR2, FR3, and / or FR4 comprising one, two, three, four, or five amino acid substitutions (optionally comprising or consisting of one or more conservative substitutions), insertions, and / or deletions). In some embodiments, FRs are defined according to the IMGT, Kabat, Chothia, North, EU, Martin (enhanced Chothia), Contact, AbM, CCG, or AHo numbering systems, or any combination thereof.

[0486] In certain embodiments, the antibodies or antigen-binding fragments comprise a VH comprising, consisting essentially of, or consisting of a FR1, FR2, FR3, or FR4 that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the corresponding FR1, FR2, FR3, or FR4 of the VH amino acid sequence set forth in SEQ ID NO: 357, or comprises, consists essentially of, or consists of the corresponding FR1, FR2, FR3, or FR4 of the VH amino acid sequence set forth in SEQ ID NO: 702, and a VL comprising a VH comprising, consisting essentially of, or consisting of a FR1, FR2, FR3, or FR4 that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the corresponding FR1, FR2, FR3, or FR4 of the VH amino acid sequence set forth in SEQ ID NO: In some embodiments, the FR1, FR2, FR3, and / or FR4 are at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the corresponding FR1, FR2, FR3, or FR4 of the VL amino acid sequence set forth in SEQ ID NO: 847, or comprise, consist essentially of, or consist of the corresponding FR1, FR2, FR3, or FR4 of the VL amino acid sequence set forth in SEQ ID NO: 704. In some embodiments, the FRs are defined according to the IMGT, Kabat, Chothia, North, EU, Martin (enhanced Chothia), Contact, AbM, CCG, or AHo numbering systems, or according to any combination thereof.

[0487] In certain embodiments, the antibodies or antigen-binding fragments comprise a VH comprising, consisting essentially of, or consisting of the corresponding FR1, FR2, FR3, or FR4 of the VH amino acid sequence set forth in SEQ ID NO: 357, or a VL comprising, consisting essentially of, or consisting of the corresponding FR1, FR2, FR3, or FR4 of the VH amino acid sequence set forth in SEQ ID NO: 702, and the VL comprising, consisting essentially of, or consisting of the corresponding FR1, FR2, FR3, or FR4 of the VH amino acid sequence set forth in SEQ ID NO: 703. In some embodiments, the FR1, FR2, FR3, and FR4 are at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the corresponding FR1, FR2, FR3, or FR4 of SEQ ID NO: 847, or comprise, consist essentially of, or consist of the corresponding FR1, FR2, FR3, or FR4 of SEQ ID NO: 704. In some embodiments, the FRs are defined according to the IMGT, Kabat, Chothia, North, EU, Martin (enhanced Chothia), Contact, AbM, CCG, or AHo numbering systems, or according to any combination thereof.

[0488] In certain embodiments, antibodie...

Claims

1. An antibody or antigen-binding fragment comprising a heavy chain variable domain (VH) comprising complementarity determining regions (CDRs) H1, CDRH2 and CDRH3 and a light chain variable domain (VL) comprising CDRL1, CDRL2 and CDRL3, wherein the CDRs are numbered according to the IMGT numbering system, (A) wherein the antibody or antigen-binding fragment binds to respiratory syncytial virus (RSV) fusion glycoprotein (RSV-F), and wherein: (i) the CDRH1 comprises SEQ ID NO: 121, 3, 137, 147, 160, 170, 182, 216, 234, 244, 262, 278, 285, 301, 333, 363, 370, 728, 738, 747, 756, 766, 776, 785, 795, 805, 814, 887, 890, 13, 23, 31, 39, 54, 60, 74, 80, 87, 112, 1 30, 380, 387, 396, 417, 441, 452, 459, 471, 481, 492, 498, 505, 514, 528 and 533 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline-encoded amino acids; (ii) the CDRH2 comprises SEQ 42, 453, 464, 506, 515, 534, 540, 543 and 548, or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline encoded amino acids; (iii) the CDRH3 comprises the amino acid sequence of SEQ ID NO: 122, 4, 138, 161, 217, 226, 235, 263, 279, 302, 334, 364, 371, 729, 739, 748, 757, 767, 777, 786, 796, 815, 818, 838, 884, 894, 897, 14, 24, 32, 40, 47, 61, 81, 88, 96, 113, 388, 397, 405, 442, 453, 464, 506, 515, 534, 540, 543 and 548; NO:123, 5, 139, 148, 162, 176, 183, 190, 197, 203, 218, 227, 236, 245, 255, 264, 272, 280, 286, 294, 30 3. 310, 317, 322, 328, 335, 343, 353, 358, 365, 372, 730, 740, 749, 758, 768, 778, 787, 797, 806, 821, 8 24, 832, 835, 841, 844, 15, 25, 33, 48, 62, 89, 114, 131, 389, 398, 406, 427, 432, 476, 493, 499, 507, 516, 535 and 551, or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline-encoded amino acids;(iv) the CDRL1 comprises an amino acid sequence as shown in any one of SEQ ID NOs: 18, 8, 142, 151, 165, 173, 186, 193, 206, 221, 230, 239, 258, 267, 289, 297, 306, 313, 338, 350, 375, 733, 743, 761, 771, 781, 790, 800, 809, 65, 92, 99, 126, 383, 401, 437, 445, 456, 488, 554, 561, 564 and 568, or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline encoded amino acids; (v) the CDRL2 comprises an amino acid sequence as shown in any one of SEQ ID NOs: 18, 8, 142, 151, 165, 173, 186, 193, 206, 221, 230, 239, 258, 267, 289, 297, 306, 313, 338, 350, 375, 733, 743, 761, 771, 781, 790, 800, 809, 65, 92, 99, 126, 383, 401, 437, 445, 456, 488, 554, 561, 564 and 568, or a functional variant thereof comprising one NO:705, 9, 143, 152, 156, 166, 200, 207, 222, 240, 268, 290, 314, 339, 734, 752, 762, 772, 791, 801, 856, 871, 19, 43, 66, 117, 392, 409, 467, 489, 510, 519 and 555 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline encoded amino acids; and / or (vi) the CDRL3 comprises SEQ ID NO:127, 10, 144, 153, 157, 167, 179, 187, 194, 208, 213, 223, 231, 241, 248, 259, 269, 275, 29 1. 298, 307, 325, 340, 376, 735, 744, 753, 763, 773, 782, 792, 802, 810, 848, 852, 866, 20, 28, 3 6, 44, 51, 57, 67, 77, 84, 93, 118, 134, 384, 393, 402, 410, 420, 438, 446, 468, 502, 511, 556 and 520 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline-encoded amino acids; (B) wherein the antibody or antigen-binding fragment binds to the metapneumovirus (MPV) fusion glycoprotein (MPV-F), and wherein: (i) the CDRH1 comprises the amino acid sequence shown in any one of SEQ ID Nos: 102, 13, 23, 31, 39, 54, 60, 74, 80, 87, 112, 121, 130, 380, 387, 396, 417, 441, 452, 459, 471, 481, 492, 498, 505, 514, 528 and 533, or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline-encoded amino acids; (ii) the CDRH2 comprises the amino acid sequence shown in any one of SEQ ID Nos: 102, 13, 23, 31, 39, 54, 60, 74, 80, 87, 112, 121, 130, 380, 387, 396, 417, 441, 452, 459, 471, 481, 492, 498, 505, 514, 528 and 533; No: 103, 14, 24, 32, 40, 47, 61, 81, 88, 96, 113, 122, 388, 397, 405, 442, 453, 464, 506, 515, 534, 540, 543 and 548 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline-encoded amino acids; (iii) the CDRH3 comprises SEQ ID 445, 456, 488, 554, 561, 564 and 568 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline-encoded amino acids; (iv) the CDRL1 comprises an amino acid sequence as set forth in any one of SEQ ID Nos: 107, 18, 65, 92, 99, 126, 383, 401, 437, 445, 456, 488, 554, 561, 564 and 568 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline-encoded amino acids; (v) the CDRL2 comprises an amino acid sequence as set forth in any one of SEQ ID Nos: 107, 18, 65, 92, 99, 126, 383, 401, 437, 445, 456, 488 Nos: 108, 19, 43, 66, 117, 392, 409, 467, 489, 510, 519, 555 and 705, or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline-encoded amino acids;and / or (vi) the CDRL3 comprises an amino acid sequence as shown in any one of SEQ ID Nos: 109, 20, 28, 36, 44, 51, 57, 67, 77, 84, 93, 118, 127, 134, 384, 393, 402, 410, 420, 438, 446, 468, 502, 511, 556 and 520, or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline encoded amino acids; or; (C) wherein the antibody or antigen-binding fragment binds to respiratory syncytial virus (RSV) fusion glycoprotein (RSV-F) and metapneumovirus (MPV) fusion glycoprotein (MPV-F), and wherein: (i) the CDRH1 comprises an amino acid sequence as shown in any one of SEQ ID Nos: 13, 23, 31, 39, 54, 60, 74, 80, 87, 112, 121, 130, 380, 387, 396, 417, 441, 452, 459, 471, 481, 492, 498, 505, 514, 528 and 533, or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline-encoded amino acids; (ii) the CDRH2 comprises SEQ ID No: 14, 24, 32, 40, 47, 61, 81, 88, 96, 113, 122, 388, 397, 405, 442, 453, 464, 506, 515, 534, 540, 543 and 548 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline-encoded amino acids; (iii) the CDRH3 comprises SEQ ID 476, 493, 499, 507, 516, 535 and 551, or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline-encoded amino acids; (iv) the CDRL1 comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 18, 65, 92, 99, 126, 383, 401, 437, 445, 456, 488, 554, 561, 564 and 568, or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline-encoded amino acids; (v) the CDRL2 comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 18, 65, 92, 99, 126, 383, 401, 437, 445, 456, 488, Nos: 19, 43, 66, 117, 392, 409, 467, 489, 510, 519, 555 and 705, or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline-encoded amino acids;and / or (vi) the CDRL3 comprises an amino acid sequence as shown in any one of SEQ ID Nos: 20, 28, 36, 44, 51, 57, 67, 77, 84, 93, 118, 127, 134, 384, 393, 402, 410, 420, 438, 446, 468, 502, 511, 520 and 556 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline encoded amino acids.; 2. The antibody or antigen-binding fragment according to claim 1, wherein: (1) the VH and VL comprise amino acid sequences having at least 90% identity to the amino acid sequences set forth in: (i) SEQ ID NOs: 702 and 704, respectively; (ii) SEQ ID NOs: 136 and 851, respectively; (iii) SEQ ID NOs: 817 and 141, respectively; (iv) SEQ ID NOs: 899 and 360, respectively; (v) SEQ ID NOs: 136 and 851, respectively; (vi) SEQ ID NOs: 817 and 141, respectively; (vii) SEQ ID NOs: 233 and 858, respectively; (viii) SEQ ID NOs: 837 and 858, respectively; (ix) SEQ ID NOs: 357 and 847, respectively, wherein the sequence variation is optionally limited to one or more framework regions and / or the sequence variation comprises one or more substitutions for germline-encoded amino acids; (2) the antibody or antigen-binding fragment comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 amino acid sequences of the VH and VL amino acid sequences shown below: (i) SEQ ID NOs: 702 and 704, respectively; (ii) SEQ ID NOs: 136 and 851, respectively; (iii) SEQ ID NOs: 817 and 141, respectively; (iv) SEQ ID NOs: 899 and 360, respectively; (v) SEQ ID NOs: 136 and 851, respectively; (vi) SEQ ID NOs: 817 and 141, respectively; (vii) SEQ ID NOs: 233 and 858, respectively; (viii) SEQ ID NOs: 837 and 858, respectively; (ix) SEQ ID NOs: 357 and 847, respectively; or (3) (i) the CDRH1 comprises an amino acid sequence as shown in any one of SEQ ID NOs: 121, 137, 814, 234, 814 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline-encoded amino acids; (ii) the CDRH2 comprises an amino acid sequence as shown in any one of SEQ ID NOs: 122, 138, 818, 235, 838, 226 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline-encoded amino acids; (iii) the CDRH3 comprises an amino acid sequence as shown in any one of SEQ ID NOs: 123, 139, 236, 358 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline-encoded amino acids; (iv) the CDRL1 comprises SEQ ID NOs: NO:18, 142, 239 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline-encoded amino acids; (v) the CDRL2 comprises the amino acid sequence shown in any one of SEQ ID NO:705, 143, 240 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline-encoded amino acids; and / or (vi) the CDRL3 comprises the amino acid sequence shown in any one of SEQ ID NO:127, 852, 144, 241, 848, 231 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline-encoded amino acids.

3. The antibody or antigen-binding fragment according to claim 1 or claim 2, wherein: (A) the VH and the VL comprise an amino acid sequence that is at least 90% identical to the amino acid sequence set forth below: SEQ ID NOs: 136 and 851, respectively, wherein the sequence variation is optionally limited to one or more framework regions and / or the sequence variation comprises one or more substitutions to germline-encoded amino acids; (B) the antibody or antigen-binding fragment comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 amino acid sequences of the VH and VL amino acid sequences shown below: (i) SEQ ID NOs: 136 and 851, respectively; or (C) (i) the CDRH1 comprises the amino acid sequence of SEQ ID NO: 137 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline encoded amino acids; (ii) the CDRH2 comprises the amino acid sequence of SEQ ID NO: 138 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline encoded amino acids; (iii) the CDRH3 comprises the amino acid sequence of SEQ ID NO: 139 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline encoded amino acids; (iv) the CDRL1 comprises the amino acid sequence of SEQ ID NO: 142 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline encoded amino acids; (v) the CDRL2 comprises the amino acid sequence of SEQ ID NO: 143 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline encoded amino acids; NO:143 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions for germline-encoded amino acids; and / or (vi) the CDRL3 comprises the amino acid sequence shown in SEQ ID NO:852 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions for germline-encoded amino acids.

4. The antibody or antigen-binding fragment according to claim 1 or claim 2, wherein: (A) the VH and the VL comprise an amino acid sequence that is at least 90% identical to the amino acid sequence set forth below: SEQ ID NOs: 817 and 141, respectively, wherein the sequence variation is optionally limited to one or more framework regions and / or the sequence variation comprises one or more substitutions to germline-encoded amino acids; (B) the antibody or antigen-binding fragment comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 amino acid sequences of the VH and VL amino acid sequences shown below: (i) SEQ ID NOs: 817 and 141, respectively; or (C) (i) the CDRH1 comprises the amino acid sequence of SEQ ID NO: 814 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline encoded amino acids; (ii) the CDRH2 comprises the amino acid sequence of SEQ ID NO: 818 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline encoded amino acids; (iii) the CDRH3 comprises the amino acid sequence of SEQ ID NO: 139 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline encoded amino acids; (iv) the CDRL1 comprises the amino acid sequence of SEQ ID NO: 142 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline encoded amino acids; (v) the CDRL2 comprises the amino acid sequence of SEQ ID NO: 143 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline encoded amino acids; NO:143 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions for germline-encoded amino acids; and / or (vi) the CDRL3 comprises the amino acid sequence shown in SEQ ID NO:144 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions for germline-encoded amino acids.

5. The antibody or antigen-binding fragment according to claim 1 or claim 2, wherein: (A) the VH and the VL comprise an amino acid sequence that is at least 90% identical to the amino acid sequence set forth below: SEQ ID NOs: 233 and 858, respectively, wherein the sequence variation is optionally limited to one or more framework regions and / or the sequence variation comprises one or more substitutions to germline-encoded amino acids; (B) the antibody or antigen-binding fragment comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 amino acid sequences of the VH and VL amino acid sequences shown below: (i) SEQ ID NOs: 233 and 858, respectively; or (C) (i) the CDRH1 comprises the amino acid sequence of SEQ ID NO: 234 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline encoded amino acids; (ii) the CDRH2 comprises the amino acid sequence of SEQ ID NO: 235 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline encoded amino acids; (iii) the CDRH3 comprises the amino acid sequence of SEQ ID NO: 236 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline encoded amino acids; (iv) the CDRL1 comprises the amino acid sequence of SEQ ID NO: 239 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline encoded amino acids; (v) the CDRL2 comprises the amino acid sequence of SEQ ID NO: 235 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline encoded amino acids. NO:240 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions for germline-encoded amino acids; and / or (vi) the CDRL3 comprises the amino acid sequence shown in SEQ ID NO:241 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions for germline-encoded amino acids.

6. The antibody or antigen-binding fragment according to claim 1 or claim 2, wherein: (A) the VH and the VL comprise an amino acid sequence that is at least 90% identical to the amino acid sequence set forth below: SEQ ID NOs: 837 and 858, respectively, wherein the sequence variation is optionally limited to one or more framework regions and / or the sequence variation comprises one or more substitutions to germline-encoded amino acids; (B) the antibody or antigen-binding fragment comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 amino acid sequences of the VH and VL amino acid sequences shown below: (i) SEQ ID NOs: 837 and 858, respectively; (C) (i) the CDRH1 comprises the amino acid sequence of SEQ ID NO: 234 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline encoded amino acids; (ii) the CDRH2 comprises the amino acid sequence of SEQ ID NO: 838 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline encoded amino acids; (iii) the CDRH3 comprises the amino acid sequence of SEQ ID NO: 236 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline encoded amino acids; (iv) the CDRL1 comprises the amino acid sequence of SEQ ID NO: 239 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline encoded amino acids; (v) the CDRL2 comprises the amino acid sequence of SEQ ID NO: 838 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline encoded amino acids. NO:240 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions for germline-encoded amino acids; and / or (vi) the CDRL3 comprises the amino acid sequence shown in SEQ ID NO:241 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions for germline-encoded amino acids.

7. The antibody or antigen-binding fragment according to claim 1 or claim 2, wherein: (A) the VH and the VL comprise an amino acid sequence that is at least 90% identical to the amino acid sequence set forth below: SEQ ID NOs: 357 and 847, respectively, wherein the sequence variation is optionally limited to one or more framework regions and / or the sequence variation comprises one or more substitutions to germline-encoded amino acids; (B) the antibody or antigen-binding fragment comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 amino acid sequences of the VH and VL amino acid sequences shown below: (i) SEQ ID NOs: 357 and 847, respectively; (C) (i) the CDRH1 comprises the amino acid sequence of SEQ ID NO: 137 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline encoded amino acids; (ii) the CDRH2 comprises the amino acid sequence of SEQ ID NO: 226 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline encoded amino acids; (iii) the CDRH3 comprises the amino acid sequence of SEQ ID NO: 358 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline encoded amino acids; (iv) the CDRL1 comprises the amino acid sequence of SEQ ID NO: 142 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline encoded amino acids; (v) the CDRL2 comprises the amino acid sequence of SEQ ID NO: 234 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline encoded amino acids; NO:143 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions for germline-encoded amino acids; and / or (vi) the CDRL3 comprises the amino acid sequence shown in SEQ ID NO:848 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions for germline-encoded amino acids.

8. The antibody or antigen-binding fragment according to claim 1 or claim 2, wherein: (A) the VH and the VL comprise an amino acid sequence that is at least 90% identical to the amino acid sequence set forth below: SEQ ID NOs: 899 and 360, respectively, wherein the sequence variation is optionally limited to one or more framework regions and / or the sequence variation comprises one or more substitutions to germline-encoded amino acids; (B) the antibody or antigen-binding fragment comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 amino acid sequences of the VH and VL amino acid sequences shown below: (i) SEQ ID NOs: 899 and 360, respectively; or (C) (i) the CDRH1 comprises the amino acid sequence of SEQ ID NO: 814 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline encoded amino acids; (ii) the CDRH2 comprises the amino acid sequence of SEQ ID NO: 226 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline encoded amino acids; (iii) the CDRH3 comprises the amino acid sequence of SEQ ID NO: 358 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline encoded amino acids; (iv) the CDRL1 comprises the amino acid sequence of SEQ ID NO: 142 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline encoded amino acids; (v) the CDRL2 comprises the amino acid sequence of SEQ ID NO: 143 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline encoded amino acids; NO:143 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions for germline-encoded amino acids; and / or (vi) the CDRL3 comprises the amino acid sequence shown in SEQ ID NO:231 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions for germline-encoded amino acids.

9. The antibody or antigen-binding fragment according to claim 1 or claim 2, wherein: (A) the VH and the VL comprise an amino acid sequence that is at least 90% identical to the amino acid sequence set forth below: SEQ ID NOs: 702 and 704, respectively, wherein the sequence variation is optionally limited to one or more framework regions and / or the sequence variation comprises one or more substitutions to germline-encoded amino acids; (B) the antibody or antigen-binding fragment comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 amino acid sequences of the VH and VL amino acid sequences shown below: (i) SEQ ID NOs: 702 and 704, respectively; or (C) (i) the CDRH1 comprises the amino acid sequence of SEQ ID NO: 121 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline encoded amino acids; (ii) the CDRH2 comprises the amino acid sequence of SEQ ID NO: 122 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline encoded amino acids; (iii) the CDRH3 comprises the amino acid sequence of SEQ ID NO: 123 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline encoded amino acids; (iv) the CDRL1 comprises the amino acid sequence of SEQ ID NO: 18 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline encoded amino acids; (v) the CDRL2 comprises the amino acid sequence of SEQ ID NO: 124 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions of germline encoded amino acids. NO:705 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions for germline-encoded amino acids; and / or (vi) the CDRL3 comprises the amino acid sequence shown in SEQ ID NO:127 or a functional variant thereof comprising one, two or three amino acid substitutions, one or more of which are optionally conservative substitutions and / or substitutions for germline-encoded amino acids.

10. The antibody or antigen-binding fragment of any one of claims 1 to 9, wherein the antibody or antigen-binding fragment is of an IgG isotype selected from IgG1, IgG2, IgG3 and IgG4.

11. The antibody or antigen-binding fragment of any one of claims 1 to 10, wherein the antibody or the antigen-binding fragment comprises a human antibody, a monoclonal antibody, a purified antibody, a single-chain antibody, Fab, Fab', F(ab')2 or Fv.

12. The antibody or antigen-binding fragment of any one of claims 1 to 11, wherein the antibody or antigen-binding fragment is a multi-specific antibody or antigen-binding fragment, optionally a bispecific antibody or antigen-binding fragment, comprising (i) a first VH and a first VL; and (ii) a second VH and a second VL, wherein the first VH and the first VL together form a first antigen-binding site, and wherein the second VH and the second VL together form a second antigen-binding site; wherein the first VH and the first VL respectively comprise: i) a first antigen-binding site corresponding to SEQ ID NO:2, 136, 146, 159, 169, 175, 181, 189, 196, 202, 210, 215, 225, 233, 243, 250, 254, 261, 271, 277, 284, 293, 300, 309, 316, 321, 327, 332, 342, 347, 352, 357, 362 and 369 have an amino acid sequence that is at least 85% identical; and / or an amino acid sequence having at least 85% identity to the amino acid sequence set forth in any one of SEQ ID NO:7, 141, 150, 155, 164, 172, 178, 185, 192, 199, 205, 212, 220, 229, 238, 247, 252, 257, 266, 274, 282, 288, 296, 305, 312, 319, 324, 330, 337, 345, 349, 355, 360, 367 and 374; ii) an amino acid sequence that is at least 85% identical to the amino acid sequence of SEQ ID NO: 101; and / or an amino acid sequence that is at least 85% identical to the amino acid sequence of SEQ ID NO: 106; iii) an amino acid sequence that is at least 85% identical to the amino acid sequence of SEQ ID NO: an amino acid sequence having at least 85% identity to any one of NOS: 129, 12, 38, 46, 53, 59, 69, 120, 73, 79, 86, 95, 22, 111, 30, 378, 386, 395, 404, 412, 416, 422, 426, 431, 440, 451, 458, 463, 470, 475, 480, 485, 491, 497, 532, 537, 539, 542, 545, 547, 550, 504, 513, 524, 527, 702, 707, 712, and 716;iv) an amino acid sequence having at least 85% identity to the amino acid sequence set forth in any one of SEQ ID NOs: 133, 17, 42, 50, 56, 64, 71, 125, 76, 83, 91, 98, 27, 116, 35, 382, ​​391, 400, 408, 414, 419, 424, 429, 434, 436, 444, 449, 455, 461, 466, 473, 478, 483, 487, 495, 501, 509, 518, 522, 530, 553, 558, 560, 563, 567, 570, 572, 574, 704, and 710; iv) an amino acid sequence having at least 85% identity to the amino acid sequence set forth in any one of SEQ ID NOs: 133, 17, 42, 50, 56, NO:532, 537, 539, 542, 545, 547 and 550; and / or an amino acid sequence having at least 85% identity to the amino acid sequence shown in any one of SEQ ID NO:553, 558, 560, 563, 567, 570, 572 and 574; and / or v) an amino acid sequence having at least 85% identity to the amino acid sequence shown in any one of SEQ ID NO:532, 537, 539, 542, 545, 547 and 550; and / or an amino acid sequence having at least 85% identity to the amino acid sequence shown in any one of SEQ ID NO:553, 558, 560, 563, 567, 570, 572 and 574; and / or v) an amino acid sequence having at least 85 NO: 2, 136, 146, 159, 169, 175, 181, 189, 196, 202, 210, 215, 225, 233, 243, 250, 254, 261, 271, 277, 284, 293, 300, 309, 316, 321, 327, 332, 342, 347, 352, 357, 362, 369, 369, 727, 737, 746, 755, 765, 775, 784, 794, 804 ,813,817,820,823,826,828,831,834,837,840,843,883,886,889,89 3, an amino acid sequence that is at least 85% identical to any one of the amino acid sequences set forth in 4, 896, 899, 901, 903, 101, 129, 12, 38, 46, 53, 59, 69, 120, 73, 79, 86, 95, 22, 111, 30, 378, 386, 395, 404, 412, 416, 422, 426, 431, 440, 451, 458, 463, 470, 475, 480, 485, 491, 497, 504, 513, 524, 527, 702, 532, 537, 539, 542, 545, 547, 550, 707, 712, and 716;and / or SEQ ID NO:7, 141, 150, 155, 164, 172, 178, 185, 192, 199, 205, 212, 220, 229, 238, 247, 252, 257, 266, 274, 282, 288, 296, 305, 312, 319, 324, 330, 337, 345, 349 ,355,360,367,374,732,742,751,760,770,780,789,799,808,847,851,855,858,860,862,865,868,870,873,875,877,879,881,106,133,17,42,50 , 56, 64, 71, 125, 76, 83, 91, 98, 27, 116, 35, 382, ​​391, 400, 408, 414, 419, 424, 429, 434, 436, 444, 449, 455, 461, 466, 473, 478, 483, 487, 495, 501, 509, 518, 522, 530, 704, 553, 558, 560, 563, 567, 570, 572, 574 and 710, and wherein the second VH and the second VL are not identical to the first VH and the first VH, and respectively comprise: i) an amino acid sequence having at least 85% identity to the amino acid sequence of any one of SEQ ID NO:2, 136, 146, 159, 169, 175, 181, 189, 196, 202, 210, 215, 225, 233, 243, 250, 254, 261, 271, 277, 284, 293, 300, 309, 316, 321, 327, 332, 342, 347, 352, 357, 362, 369, 72 an amino acid sequence having at least 85% identity to any one of the amino acid sequences set forth in 7, 737, 746, 755, 765, 775, 784, 794, 804, 813, 817, 820, 823, 826, 828, 831, 834, 837, 840, 843, 883, 886, 889, 893, 896, 899, 901, and 903;and / or SEQ ID NO:7, 141, 150, 155, 164, 172, 178, 185, 192, 199, 205, 212, 220, 229, 238, 247, 252, 257, 266, 274, 282, 288, 296, 305, 312, 319, 324, 330, 337, 345, 349, 355, 360, 367, 374 732, 742, 751, 760, 770, 780, 789, 799, 808, 847, 851, 855, 858, 860, 862, 865, 868, 870, 873, 875, 877, 879 and 881; ii) an amino acid sequence that is at least 85% identical to the amino acid sequence of SEQ ID NO: 101; and / or an amino acid sequence that is at least 85% identical to the amino acid sequence of SEQ ID NO: 106; iii) an amino acid sequence that is at least 85% identical to the amino acid sequence of SEQ ID NO: 107; NO:129, 12, 38, 46, 53, 59, 69, 120, 73, 79, 86, 95, 22, 111, 30, 378, 386, 395, 404, 412, 416, 422, 426, 431, 440, 451, 458, 463, 470, 475, 480, 485, 491, 497, 532, 537, 539, 542, 545, 547, 550, 504, 513, 524, 527, 702, 707, 712, and 716; and / or an amino acid sequence having at least 85% identity to the amino acid sequence set forth in any one of SEQ ID iv) an amino acid sequence having at least 85% identity to any one of SEQ ID NOs:7, 133, 17, 42, 50, 56, 64, 71, 125, 76, 83, 91, 98, 27, 116, 35, 382, ​​391, 400, 408, 414, 419, 424, 429, 434, 436, 444, 449, 455, 461, 466, 473, 478, 483, 487, 495, 501, 509, 518, 522, 530, 553, 558, 560, 563, 567, 570, 572, 574, 704, and 710; iv) an amino acid sequence having at least 85% identity to any one of SEQ ID NOs:7, 133, 17, 42, 50, 56, 64, 71, 125, 76, 83, 91, 98, 27, 116, 35, 382, ​​391, 400, 408, 414, 419, 424, 429, 434, 436, 444, 449, An amino acid sequence that is at least 85% identical to the amino acid sequence set forth in any one of SEQ ID NOs: 532, 537, 539, 542, 545, 547, and 550; and / or an amino acid sequence that is at least 85% identical to the amino acid sequence set forth in any one of SEQ ID NOs: 553, 558, 560, 563, 567, 570, 572, and 574;v) an amino acid sequence having at least 85% identity to an amino acid sequence as shown in any one of SEQ ID NOs: 576, 586, 591, 600, 604, 613 and 617; and / or an amino acid sequence having at least 85% identity to an amino acid sequence as shown in any one of SEQ ID NOs: 581, 588, 596, 602, 609, 615 and 622; vi) an amino acid sequence having at least 85% identity to an amino acid sequence as shown in any one of SEQ ID NOs: 627, 636, 641, 648, 657 and 659; and / or an amino acid sequence having at least 85% identity to an amino acid sequence as shown in any one of SEQ ID NOs: 632, 638, 645, 653 and 662; and / or vii) an amino acid sequence having at least 85% identity to an amino acid sequence as shown in SEQ ID NOs: NO:2, 136, 146, 159, 169, 175, 181, 189, 196, 202, 210, 215, 225, 233, 243, 250 ,254,261,271,277,284,293,300,309,316,321,327,332,342,347,352,357, 362, 369, 727, 737, 746, 755, 765, 775, 784, 794, 804, 813, 817, 820, 823, 826, 828, 831, 834, 837, 840, 843, 883, 886, 889, 893, 896, 899, 901, 903, 101, 129, 12 ,38,46,53,59,69,120,73,79,86,95,22,111,30,378,386,395,404,412,416,422,426,431,440,451,458,463,470,475,480,485,491,497,504,513,524 , 527, 702, 532, 537, 539, 542, 545, 547, 550, 576, 586, 591, 600, 604, 613, 617, 627, 636, 641, 648, 657, 659, 707, 712, and 716;and / or with SEQ ID NO:7, 141, 150, 155, 164, 172, 178, 185, 192, 199, 205, 212, 220, 229, 238, 247, 252, 257, 266, 274, 282, 288, 296, 305, 312, 319, 324, 330, 337, 345, 349, 355, 360, 367, 374, 732, 742, 751, 760, 770, 780, 789, 799, 808, 847, 851, 855, 858, 860, 862, 865, 868, 870, 873, 875, 877, 879, 881, 106, 133, 17, 42, 50, 5 6, 64, 71, 125, 76, 83, 91, 98, 27, 116, 35, 382, ​​391, 400, 408, 414, 419, 424, 429, 434, 436, 444, 449, 455, 461, 466, 473, 478, 483, 487, 495, 501, 509, 518, 522, 530, 704, 553, 558, 560, 563, 567, 570, 572, 574, 581, 588, 596, 602, 609, 615, 622, 632, 638, 645, 653, 662, and 710. ; 13. The antibody or antigen-binding fragment according to claim 12, comprising: (A) (i) a first VH and a first VL; and (ii) a second VH and a second VL, wherein the first VH and the first VL together form a first antigen binding site, and wherein the second VH and the second VL together form a second antigen binding site; wherein the first VH and the first VL respectively comprise the VH and VL shown in: SEQ ID NOs: 136 and 851; 814 and 141; 233 and 858; 837 and 858; 357 and 847; and 899 and 360, respectively; (B) (i) a first VH and a first VL; and (ii) a second VH and a second VL, wherein the first VH and the first VL together form a first antigen-binding site, and wherein the second VH and the second VL together form a second antigen-binding site; wherein the first VH and the first VL comprise the VH and VL shown in SEQ ID NOs: 702 and 704, respectively; or (C) (i) a first VH and a first VL; and (ii) a second VH and a second VL, wherein the first VH and the first VL together form a first antigen binding site, and wherein the second VH and the second VL together form a second antigen binding site; wherein the first VH and VL comprise the VH and VL shown in the following: SEQ ID NOs: 136 and 851; 814 and 141; 233 and 858; 837 and 858; 357 and 847; and 899 and 360, respectively; and the second VH and VL comprise the VH and VL shown in SEQ ID NOs: 702 and 704.

14. The antibody or antigen-binding fragment of any one of claims 1 to 13, wherein the antibody or antigen-binding fragment comprises an Fc polypeptide or a fragment thereof.

15. The antibody or antigen-binding fragment of claim 14, wherein the Fc polypeptide comprises an Fc polypeptide or fragment thereof comprising an amino acid sequence having at least 85% identity to any one of SEQ ID NOs: 679-684 and 688-690, optionally differing from a naturally occurring variant thereof, or comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 679-684 and 688-690.

16. The antibody or antigen-binding fragment according to claim 15, wherein the antibody comprises a heavy chain (HC) and a light chain (LC), the heavy chain comprising a polypeptide or a fragment thereof, the polypeptide or a fragment thereof comprising the amino acid sequence shown in SEQ ID NO: 723, and the light chain comprising a polypeptide or a fragment thereof, the polypeptide or a fragment thereof comprising the amino acid sequence shown in SEQ ID NO:

725.

17. The antibody or antigen-binding fragment of any one of claims 1 to 16, wherein the antibody or antigen-binding fragment thereof binds to: a) both RSV A and RSV B strains; b) both MPV A and MPV B strains; c) any combination of RSV A, RSV B, MPV A, and MPV B strains.

18. The antibody or antigen-binding fragment of any one of claims 1 to 17, wherein the antibody or antigen-binding fragment thereof (A) activates human FcγRIIa or (B) activates human FcγRIIIa.

19. An antibody or antigen-binding fragment according to any one of claims 1 to 18, wherein (A) the antibody neutralizes infection caused by RSV and / or MPV; and / or (B) the antibody or antigen-binding fragment treats and / or prevents (i) RSV infection and / or (ii) MPV infection in a subject.

20. An isolated polynucleotide encoding the antibody or antigen-binding fragment according to any one of claims 1 to 19, or encoding the VH, heavy chain, VL, light chain and / or one or more CDRs of the antibody or antigen-binding fragment.

21. An isolated polynucleotide according to claim 20, wherein the polynucleotide comprises a polynucleotide having at least 50% identity with a VH encoding polynucleotide sequence shown in any one or more of SEQ ID NOs: 701, 135, 816, 232, 836, 356, 898 and / or a VL encoding polynucleotide sequence shown in any one or more of SEQ ID NOs: 703, 850, 140, 857, 846, 359.

22. A recombinant vector comprising the polynucleotide according to claim 20 or claim 21.

23. A host cell comprising a polynucleotide according to claim 20 or claim 21 and / or a vector according to claim 22, wherein the polynucleotide is heterologous to the host cell, and wherein the host cell expresses the encoded antibody or antigen-binding fragment.

24. An isolated human B cell comprising a polynucleotide according to claim 20 or claim 21 and / or a vector according to claim 22, wherein the polynucleotide is heterologous to the human B cell and / or wherein the human B cell is immortalized.

25. A composition comprising: (i) an antibody or antigen-binding fragment according to any one of claims 1 to 19; (ii) a polynucleotide according to claim 20 or claim 21; (iii) a recombinant vector according to claim 22; (iv) a host cell according to claim 23; and / or (v) a human B cell according to claim 24, and a pharmaceutically acceptable excipient, carrier or diluent.

26. A composition according to claim 25, comprising a first antibody or antigen-binding fragment and a second antibody or antigen-binding fragment, wherein the first antibody or antigen-binding fragment and the second antibody or antigen-binding fragment are each different and each complies with any one of claims 1 to 19, or at least one complies with any one of claims 1 to 19 and at least one is palivizumab, nicevir monoclonal antibody or clesovir monoclonal antibody, or an antibody having the VH and VL of any one of palivizumab, nicevir monoclonal antibody or clesovir monoclonal antibody.

27. The composition of claim 25 or claim 26, comprising a first antibody or antigen-binding fragment and a second antibody or antigen-binding fragment, wherein: (A) the first antibody or antigen-binding fragment comprises at least the VH and VL or the CDRs of the VH and VL as shown in any one of the following: SEQ ID NOs: 136 and 851; 814 and 141; 233 and 858; 837 and 858; 357 and 847; and 899 and 360, respectively; (B) the second antibody or antigen-binding fragment comprises at least VH and VL as shown in SEQ ID NOs: 702 and 704 or CDRs of said VH and VL; or (C) the first antibody or antigen-binding fragment comprises a VH and a VL as shown in any one of the following: SEQ ID NOs: 136 and 851; 814 and 141; 233 and 858; 837 and 858; 357 and 847; and 899 and 360, respectively; and the second antibody or antigen-binding fragment comprises a second VH and VL as shown in SEQ ID NOs: 702 and 704 or a second CDR of the VH and VL.

28. A composition comprising a polynucleotide according to claim 20 or claim 21 or a vector according to claim 22 encapsulated in a carrier molecule, wherein the carrier molecule optionally comprises a lipid, a lipid-derived delivery vehicle, such as a liposome, a solid lipid nanoparticle, an oily suspension, a submicron lipid emulsion, a lipid microbubble, a reverse lipid micelle, a cochlear liposome, a lipid microtubule, a lipid microcylinder, a lipid nanoparticle (LNP) or a nanoscale platform.

29. A method for preparing an antibody or antigen-binding fragment according to any one of claims 1 to 19, the method comprising culturing a host cell according to embodiment claim 23 or a human B cell according to claim 24 for a period of time under conditions sufficient for the host cell or human B cell to express the antibody or antigen-binding fragment, respectively.

30. A method for treating and / or preventing RSV infection and / or MPV infection in a subject, the method comprising administering to the subject an effective amount of: (i) an antibody or antigen-binding fragment according to any one of claims 1 to 19; (ii) a polynucleotide according to claim 20 or claim 21; (iii) a recombinant vector according to claim 22; (iv) a host cell according to claim 23; (v) a human B cell according to claim 24; and / or (vi) a composition according to any one of claims 25 to 28.

31. The antibody or antigen-binding fragment according to any one of claims 1 to 19, the polynucleotide according to claim 20 or claim 21, the recombinant vector according to claim 22, the host cell according to claim 23, the human B cell according to claim 24 and / or the composition according to any one of claims 25 to 28, for use in: (A) a method for treating or preventing RSV infection and / or MPV infection in a subject; or (B) preparing a medicament for treating or preventing RSV infection and / or MPV infection in a subject.

32. The method according to claim 30 or the antibody or antigen-binding fragment, polynucleotide, recombinant vector, host cell, human B cell and / or composition according to claim 31 used, wherein: a) the RSV comprises both RSV A and RSV B strains; b) the MPV comprises both MPV A and MPV B strains; c) the RSV and MPV comprise any combination of RSV A, RSV B, MPV A and MPV B strains.

33. A method for in vitro diagnosis of RSV infection and / or MPV infection, the method comprising: (i) contacting a sample from a subject with the antibody or antigen-binding fragment according to any one of claims 1 to 19; and (ii) detecting a complex comprising the antigen and the antibody, or comprising the antigen and the antigen-binding fragment.

34. A kit comprising a liquid composition, and instructions for use thereof for treating RSV and / or MPV infection in a subject, wherein the liquid composition comprises an antibody or antigen-binding fragment according to any one of claims 1 to 19, a polynucleotide according to claim 20 or claim 21, a recombinant vector according to claim 22, a host cell according to any one of claims 23 or 24, or a composition according to any one of claims 25 to 28.

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