Antibodies against ev-d68

Abstract

This disclosure provides antibodies that bind enteroviruses. In some aspects, the disclosed antibodies bind and neutralize viruses from two or more clades of enterovirus. The disclosure also provides methods of using the disclosed antibodies to prevent infection of a cell with enterovirus, to protect an individual from enterovirus infection, and to treat an individual for an enterovirus infection.

Description

Atty Docket No.40574-131 ANTIBODIES AGAINST EV-D68

[0000] FIELD OF THE DISCLOSURE

[0001] The field of the disclosure relates generally to antibodies that bind enteroviruses,including those that bind Enterovirus D68 (EV-D68).

[0002] REFERENCE TO SEQUENCE LISTING

[0003] This application includes a Sequence Listing filed electronically as an XML file named40574131SEQ, created on April 30, 2025, with a size of 611.5 KB. The Sequence Listing is incorporated herein by reference.

[0004] BACKGROUND OF THE DISCLOSURE

[0005] Enterovirus D68 (EV-D68) is a re-emerging respiratory enterovirus within the diversePicornaviridae family. EV-D68 is a nonenveloped virus with an icosahedral capsid comprised of four structural proteins (VP1-VP4) that possess five-, three-, and two-fold symmetry. Infection with EV-D68 is associated with severe respiratory disease. Infection can be also be associated with a paralytic syndrome known as acute flaccid myelitis (AFM) that is similar to poliomyelitis. EV- D68 caused outbreaks in the United States and Europe in 2014, 2016 and 2018. Interestingly, a large outbreak of EV-D68 respiratory disease was reported in 2022 but was not associated with an increase in AFM. Since its discovery in 1962, EV-D68 has diversified into genetically distinct clades and subclades: A1 and A2 (also known as clade D), B1, B2, B3, and clade C. The B3 and A2 / D subclades are the currently circulating viruses. There are currently no approved vaccines or anti-viral treatments for EV-D68 while treatment for AFM can be limited to rehabilitation and supportive care. The re-emergence and continued circulation of EV-D68 highlights a long-felt but unsolved need to develop preventative interventions. Ideally, a vaccine would mitigate respiratory disease burden and prevent the progression of EV-D68 infection to AFM in children.

[0006] Antibody responses have been demonstrated as the main correlate of protection inmouse models of EV-D68 respiratory disease and AFM. Inactivated and virus-like particle (VLP) EV-D68 vaccines have been shown to be protective in mice. In this regard, a recently-reported dEV-D68 B3 subclade VLP vaccine candidate showed immunogenicity in nonhuman primates (NHPs). In a mouse model of respiratory infection, VLP-elicited antibodies reduce viral replication in the lung as well as dissemination to the blood and spleen. Monoclonal antibody (mAb) treatment after infection and the onset of paralysis in a mouse model has been shown to reduce disease severity. One study reported that a two-mAb cocktail can protect mice from lethal EV-D68 - 1 - 116104230Atty Docket No.40574-131 infection when administered prophylactically or therapeutically. In another report, potent neutralizing mAbs isolated from naturally-infected human subjects targeted the five- and three- fold axes of symmetry. Indeed, the most potent mAb, EV68-228, protected mice against respiratory disease when administered prophylactically. However, so far, the epitope specificity and protective potential of mAbs derived from NHP immunization with a VLP-based vaccine has not been demonstrated. Thus, there is a long-felt but unsolved need for additional protective antibodies, and a description of the epitopes to which such antibodies bind. The present disclosure addresses this need and provides other benefits as well. Accordingly, there is a long-felt but unsolved need for new therapeutics that may be used to prevent and treat infections by not only individual enteroviruses but also by enteroviruses from multiple clades. The present disclosure provides, inter alia, such novel therapeutics and provides other benefits as well.

[0007] SUMMARY OF THE DISCLOSURE

[0008] The present disclosure relates to antibodies that bind to and neutralize enteroviruses,such as EV-D68. In some embodiments, the antibodies are isolated.

[0009] One embodiment of the disclosure is an isolatedantibody that neutralizes viruses fromat least two different clades of enterovirus. In certain aspects, the isolatedantibody may neutralize viruses from at least three different or at least four different clades of enterovirus. In certainHXVLJYX& YOL <6 / * UM YOL HTYPIUK^ PX RLXX YOHT / hN)S>& RLXX YOHT . hN)S>& RLXX YOHT - hN)S>& RLXXYOHT , hN)S>& UW RLXX YOHT + hN)S>( <T JLWYHPT HXVLJYX& YOL HTYPIUK^ PTOPIPYX IPTKPTN UM HTYPIUK^EV-D68-228.

[0010] One embodiment of the disclosure is an antibody in which the specificity determiningresidues of the antibody interact with at least 8 contact residues in enterovirus D68 (EV-D68) selected from the group consisting of T30 of the EV-D68 VP1 protein, F31 of the EV-D68 VP1 protein, Y32 of the EV-D68 VP1 protein, Y33 of the EV-D68 VP1 protein, K71 of the EV-D68 VP1 protein, R72 of the EV-D68 VP1 protein, S73 of the EV-D68 VP1 protein, F74 of the EV- D68 VP1 protein, E75 of the EV-D68 VP1 protein, A84 of the EV-D68 VP1 protein, Q85 of the EV-D68 VP1 protein, T86 of the EV-D68 VP1 protein, D87 of the EV-D68 VP1 protein, T95 of the EV-D68 VP1 protein, S99 of the EV-D68 VP1 protein, F100 of the EV-D68 VP1 protein, N128 of the EV-D68 VP1 protein, G129 of the EV-D68 VP1 protein, T234 of the EV-D68 VP1 protein, Y259 of the EV-D68 VP1 protein, M260 of the EV-D68 VP1 protein, K268 of the EV- D68 VP1 protein, E52 of the EV-D68 VP2 protein, A106 of the EV-D68 VP2 protein, Y107, of - 2 - 116104230Atty Docket No.40574-131 the EV-D68 VP2 protein, Y33 of the EV-D68 VP3 protein, and Y93 of the EV-D68 VP3 protein, I236 of the EV-D68 VP3 protein, D237 of the EV-D68 VP3 protein, H238 of the EV-D68 VP3 protein, L239 of the EV-D68 VP3 protein, H240 of the EV-D68 VP3 protein, A242 of the EV- D68 VP3 protein, E243 of the EV-D68 VP3 protein, and Y246 of the EV-D68 VP3 protein. In certain aspects, the specificity determining residues of the antibody interact with at least 10 contact residues in EV-D68 selected from the group consisting of R72 of the EV-D68 VP1 protein, K268 of the EV-D68 VP1 protein, G269 of the EV-D68 VP1 protein, K270 of the EV-D68 VP1 protein, E271 of the EV-D68 VP1 protein, R272 of the EV-D68 VP1 protein, A273 of the EV-D68 VP1 protein, P274 of the EV-D68 VP1 protein, A276 of the EV-D68 VP1 protein, L277 of the EV-D68 VP1 protein, N278 of the EV-D68 VP1 protein, A279 of the EV-D68 VP1 protein, H135 of the EV-D68 VP2 protein, N136 of the EV-D68 VP2 protein, T138 of the EV-D68 VP2 protein, H157 of the EV-D68 VP2 protein, E59 of the EV-D68 VP3 protein, S60 of the EV-D68 VP3 protein, A61 of the EV-D68 VP3 protein, V62 of the EV-D68 VP3 protein, R104 of the EV-D68 VP3 protein, P231 of the EV-D68 VP3 protein, D232 of the EV-D68 VP3 protein, I233 of the EV-D68 VP3 protein, G234 of the EV-D68 VP3 protein, Q235 of the EV-D68 VP3 protein, I236 of the EV-D68 VP3 protein, D237 of the EV-D68 VP3 protein, H238 of the EV-D68 VP3 protein, L239 of the EV-D68 VP3 protein, H240 of the EV-D68 VP3 protein, G241 of the EV-D68 VP3 protein, and E243 of the EV-D68 VP3 protein.

[0011] One embodiment of the disclosure is an antibody in which the specificity determiningresidues of the heavy chain interact with at least 20, optionally at least 22, optionally at least 24, optionally at least 26, or optionally all, contact residues in enterovirus D-68 selected from the group consisting of K71 of the EV-D68 VP1 protein, R72 of the EV-D68 VP1 protein, S73 of the EV-D68 VP1 protein, F74 of the EV-D68 VP1 protein, E75 of the EV-D68 VP1 protein, A84 of the EV-D68 VP1 protein, Q85 of the EV-D68 VP1 protein, T86 of the EV-D68 VP1 protein, D87 of the EV-D68 VP1 protein, S99 of the EV-D68 VP1 protein, F100 of the EV-D68 VP1 protein, N128 of the EV-D68 VP1 protein, G129 of the EV-D68 VP1 protein, T234 of the EV-D68 VP1 protein, Y259 of the EV-D68 VP1 protein, M260 of the EV-D68 VP1 protein, K268 of the EV- D68 VP1 protein, A106 of the EV-D68 VP2 protein, Y107, of the EV-D68 VP2 protein, I236 of the EV-D68 VP3 protein, D237 of the EV-D68 VP3 protein, H238 of the EV-D68 VP3 protein, L239 of the EV-D68 VP3 protein, H240 of the EV-D68 VP3 protein, A242 of the EV-D68 VP3 protein, E243 of the EV-D68 VP3 protein, and Y246 of the EV-D68 VP3 protein. In certain - 3 - 116104230Atty Docket No.40574-131 aspects, the specificity determining residues of the light chain interact with at least 5, optionally at least 6, optionally at least 7, or optionally all, contact residues in enterovirus D-68 selected from the group consisting of T30 of the EV-D68 VP1 protein, F31 of the EV-D68 VP1 protein, Y32 of the EV-D68 VP1 protein, Y33 of the EV-D68 VP1 protein, T95 of the EV-D68 VP1 protein, E52 of the EV-D68 VP2 protein, Y33 of the EV-D68 VP3 protein, and Y93 of the EV-D68 VP3 protein In certain aspects, the specificity determining residues of the heavy chain interact with at least 18, optionally at least 20, optionally at least 21, optionally at least 22, optionally at least 23, optionally at least 24, or optionally all, contact residues in enterovirus D-68 selected from the group consisting of K268 of the EV-D68 VP1 protein, G269 of the EV-D68 VP1 protein, K270 of the EV-D68 VP1 protein, E271 of the EV-D68 VP1 protein, R272 of the EV-D68 VP1 protein, A273 of the EV-D68 VP1 protein, P274 of the EV-D68 VP1 protein, A276 of the EV-D68 VP1 protein, L277 of the EV-D68 VP1 protein, N278 of the EV-D68 VP1 protein, A279 of the EV-D68 VP1 protein, H135 of the EV-D68 VP2 protein, N136 of the EV-D68 VP2 protein, H157 of the EV- D68 VP2 protein, E59 of the EV-D68 VP3 protein, S60 of the EV-D68 VP3 protein, A61 of the EV-D68 VP3 protein, V62 of the EV-D68 VP3 protein, R104 of the EV-D68 VP3 protein, P231 of the EV-D68 VP3 protein, D232 of the EV-D68 VP3 protein, I233 of the EV-D68 VP3 protein, G234 of the EV-D68 VP3 protein, Q235 of the EV-D68 VP3 protein, and I236 of the EV-D68 VP3 protein. In certain aspects, the specificity determining residues of the light chain interact with at least 6, optionally at least 7, optionally at least 8, optionally at least 8, or optionally all, contact residues in enterovirus D-68 selected from the group consisting of R72 of the EV-D68 VP1 protein, K268 of the EV-D68 VP1 protein, T138 of the EV-D68 VP2 protein I236, D237 of the EV-D68 VP3 protein, H238 of the EV-D68 VP3 protein, L239 of the EV-D68 VP3 protein, H240 of the EV-D68 VP3 protein, G241 of the EV-D68 VP3 protein, and E243 of the EV-D68 VP3 protein.

[0012] One embodiment of the disclosure is an antibody comprising a heavy chain variableregion and a light chain variable region, wherein the specificity determining residues of the heavy chain variable region interact with at least 20, optionally at least 22, optionally at least 24, optionally at least 26, or all, contact residues selected from the group consisting of K71 of the EV- D68 VP1 protein, R72 of the EV-D68 VP1 protein, S73 of the EV-D68 VP1 protein, F74 of the EV-D68 VP1 protein, E75 of the EV-D68 VP1 protein, A84 of the EV-D68 VP1 protein, Q85 of the EV-D68 VP1 protein, T86 of the EV-D68 VP1 protein, D87 of the EV-D68 VP1 protein, S99 of the EV-D68 VP1 protein, F100 of the EV-D68 VP1 protein, N128 of the EV-D68 VP1 protein, - 4 - 116104230Atty Docket No.40574-131 G129 of the EV-D68 VP1 protein, T234 of the EV-D68 VP1 protein, Y259 of the EV-D68 VP1 protein, M260 of the EV-D68 VP1 protein, K268 of the EV-D68 VP1 protein, A106 of the EV- D68 VP2 protein, Y107, of the EV-D68 VP2 protein, I236 of the EV-D68 VP3 protein, D237 of the EV-D68 VP3 protein, H238 of the EV-D68 VP3 protein, L239 of the EV-D68 VP3 protein, H240 of the EV-D68 VP3 protein, A242 of the EV-D68 VP3 protein, E243 of the EV-D68 VP3 protein, and Y246 of the EV-D68 VP3 protein, and the specificity determining residues of the light chain variable region interact with at least 5, optionally at least 6, optionally at least 7, or all, contact residues selected from the group consisting of T30 of the EV-D68 VP1 protein, F31 of the EV-D68 VP1 protein, Y32 of the EV-D68 VP1 protein, Y33 of the EV-D68 VP1 protein, T95 of the EV-D68 VP1 protein, E52 of the EV-D68 VP2 protein, Y33 of the EV-D68 VP3 protein, and Y93 of the EV-D68 VP3 protein.

[0013] One embodiment of the disclosure is an antibody comprising a heavy chain variableregion and a light chain variable region (e.g., EVD2303), wherein the specificity determining residues of the heavy chain variable region interact with at least 18, optionally at least 20, optionally at least 21, optionally at least 22, optionally at least 23, optionally at least 24, or all, contact residues selected from the group consisting of K268 of the EV-D68 VP1 protein, G269 of the EV-D68 VP1 protein, K270 of the EV-D68 VP1 protein, E271 of the EV-D68 VP1 protein, R272 of the EV-D68 VP1 protein, A273 of the EV-D68 VP1 protein, P274 of the EV-D68 VP1 protein, A276 of the EV-D68 VP1 protein, L277 of the EV-D68 VP1 protein, N278 of the EV- D68 VP1 protein, A279 of the EV-D68 VP1 protein, H135 of the EV-D68 VP2 protein, N136 of the EV-D68 VP2 protein, H157 of the EV-D68 VP2 protein, E59 of the EV-D68 VP3 protein, S60 of the EV-D68 VP3 protein, A61 of the EV-D68 VP3 protein, V62 of the EV-D68 VP3 protein, R104 of the EV-D68 VP3 protein, P231 of the EV-D68 VP3 protein, D232 of the EV-D68 VP3 protein, I233 of the EV-D68 VP3 protein, G234 of the EV-D68 VP3 protein, Q235 of the EV-D68 VP3 protein, and I236 of the EV-D68 VP3 protein, and the specificity determining residues of the light chain variable region interact with at least 6, optionally at least 7, optionally at least 8, optionally at least 8, or all, contact residues selected from the group consisting of R72 of the EV- D68 VP1 protein, K268 of the EV-D68 VP1 protein, T138 of the EV-D68 VP2 protein I236, D237 of the EV-D68 VP3 protein, H238 of the EV-D68 VP3 protein, L239 of the EV-D68 VP3 protein, H240 of the EV-D68 VP3 protein, G241 of the EV-D68 VP3 protein, and E243 of the EV-D68 VP3 protein. - 5 - 116104230Atty Docket No.40574-131

[0014] One embodiment of the disclosure is an antibody that comprises one or more heavychain CDRs and / or one or more light chain CDRs from Table 1. In certain aspects, the antibody may comprise one or more antibody-matched sequences from Table 1. In certain aspects, the antibody comprises one or more antibody-matched heavy chain CDRs and light chain CDRs from Table 1. In certain aspects, the antibody comprises a heavy chain variable region comprising an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, or at least 99% identical, to a heavy chain variable region from Table 1, wherein the heavy chain variable region comprises antibody-matched VHCDR1, VHCDR2, and VHCDR3 sequences from Table 1 and / or an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, or at least 99% identical, to a light chain variable region from Table 1, wherein the light chain variable region comprises antibody-matched VLCDR1, VLCDR2, and VLCDR3 sequences from Table 1. In certain aspects, the antibody comprises a heavy chain variable region and an antibody- matched light chain variable region, the antibody-matched, heavy and light chain variable regions comprising amino acid sequences at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, or at least 99% identical, to a heavy chain variable region and a light chain variable region, respectively, from Table 1, wherein the heavy chain variable region comprises antibody-matched VHCDR1, VHCDR2, and VHCDR3 sequences from Table 1 and the light chain variable region comprises antibody-matched VLCDR1, VLCDR2, and VLCDR3 sequences from Table 1. In certain aspects, the antibody may comprise a heavy chain comprising an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, or at least 99% identical, to a heavy chain from Table 1, wherein the heavy chain comprises antibody-matched VHCDR1, VHCDR2, and VHCDR3 sequences from Table 1. In certain aspects, the antibody may comprise a light chain comprising an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, or at least 99% identical, to a light chain from Table 1, wherein the light chain comprises antibody-matched VLCDR1, VLCDR2, and VLCDR3 sequences from Table 1. In certain aspects, the antibody may comprise a heavy chain variable region and an antibody-matched light chain variable region, the antibody-matched, heavy and light chain variable regions comprising amino acid sequences at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, or at least 99% - 6 - 116104230Atty Docket No.40574-131 identical, to a heavy chain variable region and a light chain variable region, respectively, from Table 1, wherein the heavy chain variable region comprises antibody-matched VHCDR1, VHCDR2, and VHCDR3 sequences from Table 1 and the light chain variable region comprises antibody-matched VLCDR1, VLCDR2, and VLCDR3 sequences from Table 1. In certain aspects, the antibody may comprise a heavy chain and an antibody-matched light chain, the antibody- matched, heavy chain and the light chain comprising amino acid sequences at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, or at least 99% identical, to a heavy chain and a light chain, respectively, from Table 1, wherein the heavy chain comprises antibody-matched VHCDR1, VHCDR2, and VHCDR3 sequences from Table 1 and the light chain comprises antibody-matched VLCDR1, VLCDR2, and VLCDR3 sequences from Table 1.

[0015] On embodiment of the disclosure is an antibody comprising a heavy chain variableregion (VH) complementarity determining region 3 (CDR3) comprising or consisting of SEQ ID NO:3, SEQ ID NO:13, SEQ ID NO:23, SEQ ID NO:33, SEQ ID NO:43, SEQ ID NO:53, SEQ ID NO:63, SEQ ID NO:73, SEQ ID NO:83, SEQ ID NO:93, SEQ ID NO:103, or SEQ ID NO:113. In certain aspects, the antibody may comprise a light chain variable region (VL) CDR3 comprising or consisting of SEQ ID NO:8, SEQ ID NO:18, SEQ ID NO:28, SEQ ID NO:38, SEQ ID NO:48, SEQ ID NO:58, SEQ ID NO:68, SEQ ID NO:78, SEQ ID NO:88, SEQ ID NO:98, SEQ ID NO:108, or SEQ ID NO:118. In certain aspects, the antibody may comprise a VH CDR2 comprising or consisting of SEQ ID NO:2, SEQ ID NO:12, SEQ ID NO:22, SEQ ID NO:32, SEQ ID NO:42, SEQ ID NO:52, SEQ ID NO:62, SEQ ID NO:72, SEQ ID NO:82, SEQ ID NO:92, SEQ ID NO:102, or SEQ ID NO:112. In certain aspects, the antibody may comprise a VLCDR2 comprising or consisting of SEQ ID NO:7, SEQ ID NO:17, SEQ ID NO:27, SEQ ID NO:37, SEQ ID NO:47, SEQ ID NO:57, SEQ ID NO:67, SEQ ID NO:77, SEQ ID NO:87, SEQ ID NO:97, SEQ ID NO:107, or SEQ ID NO:117. In certain aspects, the antibody may comprise a VH CDR1 comprising or consisting of SEQ ID NO:1, SEQ ID NO:11, SEQ ID NO:21, SEQ ID NO:31, SEQ ID NO:41, SEQ ID NO:51, SEQ ID NO:61, SEQ ID NO:71, SEQ ID NO:81, SEQ ID NO:91,SEQ ID NO:101, or SEQ ID NO:111. In certain aspects, the antibody may comprise a VLCDR1 comprising or consisting of SEQ ID NO:6, a VLCDR1 comprising or consisting of SEQ ID NO:16, SEQ ID NO:26, SEQ ID NO:36, SEQ ID NO:46, SEQ ID NO:56, SEQ ID NO:66, SEQ ID NO:76, SEQ ID NO:86, SEQ ID NO:96, SEQ ID NO:106, or SEQ ID NO:116. - 7 - 116104230Atty Docket No.40574-131

[0016] One embodiment of the disclosure is an antibody comprising a VH CDR3 and a VLCDR3. In certain aspects, the VH CDR3 may comprise or consist of SEQ ID NO:3 and the VL CDR3 may comprise or consist of SEQ ID NO:8. In certain aspects, the VH CDR3 may comprise or consist of SEQ ID NO:13 and the VL CDR3 may comprise or consist of SEQ ID NO:18. In certain aspects, the VHCDR3 may comprise or consist of SEQ ID NO:23 and the VLCDR3 may comprise or consist of SEQ ID NO:28. In certain aspects, the VHCDR3 may comprise or consist of SEQ ID NO:33 and the VLCDR3 may comprise or consist of SEQ ID NO:38. In certain aspects, the VHCDR3 comprising or consisting of SEQ ID NO:43 and the VLCDR3 may comprise or consist of SEQ ID NO:48. In certain aspects, the VH CDR3 may comprise or consist of SEQ ID NO:53 and the VL CDR3 may comprise or consist of SEQ ID NO:58. In certain aspects, the VH CDR3 may comprise or consist of SEQ ID NO:63 and the VL CDR3 may comprise or consist of SEQ ID NO:68. In certain aspects, the VH CDR3 may comprise or consist of SEQ ID NO:73 and the VLCDR3 may comprise or consist of SEQ ID NO:78. In certain aspects, the VHCDR3 may comprise or consist of SEQ ID NO:83 and the VLCDR3 may comprise or consist of SEQ ID NO:88. In certain aspects, the VHCDR3 may comprise or consist of SEQ ID NO:93 and the VLCDR3 may comprise or consist of SEQ ID NO:98. In certain aspects, the VH CDR3 may comprise or consist of SEQ ID NO:103 and the VL CDR3 may comprise or consist of SEQ ID NO:108. In certain aspects, the VH CDR3 may comprise or consist of SEQ ID NO:113 and the VL CDR3 may comprise or consist of SEQ ID NO:118. In certain aspects, the antibody may comprise a VH CDR1 comprising or consisting of SEQ ID NO:1, a VHCDR2 comprising or consisting of SEQ ID NO:2, and a VHCDR3 comprising or consisting of SEQ ID NO:3. In certain aspects, the antibody may comprise a VHCDR1 comprising or consisting of SEQ ID NO:11, a VHCDR2 comprising or consisting of SEQ ID NO:12, and a VH CDR3 comprising or consisting of SEQ ID NO:13. In certain aspects, the antibody may comprise a VH CDR1 comprising or consisting of SEQ ID NO:21, a VH CDR2 comprising or consisting of SEQ ID NO:22, and a VH CDR3 comprising or consisting of SEQ ID NO:23. In certain aspects, the antibody may comprise a VH CDR1 comprising or consisting of SEQ ID NO:31, a VHCDR2 comprising or consisting of SEQ ID NO:32, and a VHCDR3 comprising or consisting of SEQ ID NO:33. In certain aspects, the antibody may comprise a VHCDR1 comprising or consisting of SEQ ID NO:41, a VHCDR2 comprising or consisting of SEQ ID NO:42, and a VHCDR3 comprising or consisting of SEQ ID NO:43. In certain aspects, the antibody may comprise a VH CDR1 comprising or consisting of - 8 - 116104230Atty Docket No.40574-131 SEQ ID NO:51, a VH CDR2 comprising or consisting of SEQ ID NO:52, and a VH CDR3 comprising or consisting of SEQ ID NO:53. In certain aspects, the antibody may comprise a VH CDR1 comprising or consisting of SEQ ID NO:61, a VH CDR2 comprising or consisting of SEQ ID NO:62, and a VH CDR3 comprising or consisting of SEQ ID NO:63. In certain aspects, the antibody may comprise a VHCDR1 comprising or consisting of SEQ ID NO:71, a VHCDR2 comprising or consisting of SEQ ID NO:72, and a VHCDR3 comprising or consisting of SEQ ID NO:73. In certain aspects, the antibody may comprise a VHCDR1 comprising or consisting of SEQ ID NO:81, a VHCDR2 comprising or consisting of SEQ ID NO:82, and a VHCDR3 comprising or consisting of SEQ ID NO:83. In certain aspects, the antibody may comprise a VH CDR1 comprising or consisting of SEQ ID NO:91, a VH CDR2 comprising or consisting of SEQ ID NO:92, and a VH CDR3 comprising or consisting of SEQ ID NO:93. In certain aspects, the antibody may comprise a VH CDR1 comprising or consisting of SEQ ID NO:101, a VH CDR2 comprising or consisting of SEQ ID NO:102, and a VHCDR3 comprising or consisting of SEQ ID NO:103. In certain aspects, the antibody may comprise a VHCDR1 comprising or consisting of SEQ ID NO:111, a VHCDR2 comprising or consisting of SEQ ID NO:112, and a VHCDR3 comprising or consisting of SEQ ID NO:113. In certain aspects, the antibody may comprise a VL CDR1 comprising or consisting of SEQ ID NO:6, a VL CDR2 comprising or consisting of SEQ ID NO:7, and a VL CDR3 comprising or consisting of SEQ ID NO:8. In certain aspects, the antibody may comprise a VL CDR1 comprising or consisting of SEQ ID NO:16, a VL CDR2 comprising or consisting of SEQ ID NO:17, and a VLCDR3 comprising or consisting of SEQ ID NO:18.In certain aspects, the antibody may comprise a VLCDR1 comprising or consisting of SEQ ID NO:26, a VLCDR2 comprising or consisting of SEQ ID NO:27, and a VLCDR3 comprising or consisting of SEQ ID NO:28. In certain aspects, the antibody may comprise a VL CDR1 comprising or consisting of SEQ ID NO:36, a VL CDR2 comprising or consisting of SEQ ID NO:37, and a VL CDR3 comprising or consisting of SEQ ID NO:38. In certain aspects, the antibody may comprise a VL CDR1 comprising or consisting of SEQ ID NO:46, a VL CDR2 comprising or consisting of SEQ ID NO:47, and a VLCDR3 comprising or consisting of SEQ ID NO:48. In certain aspects, the antibody may comprise a VLCDR1 comprising or consisting of SEQ ID NO:56, a VLCDR2 comprising or consisting of SEQ ID NO:57, and a VLCDR3 comprising or consisting of SEQ ID NO:58. In certain aspects, the antibody may comprise a VLCDR1 comprising or consisting of SEQ ID NO:66, a VL CDR2 comprising or consisting of SEQ - 9 - 116104230Atty Docket No.40574-131 ID NO:67, and a VL CDR3 comprising or consisting of SEQ ID NO:68. In certain aspects, the antibody may comprise a VL CDR1 comprising or consisting of SEQ ID NO:76, a VL CDR2 comprising or consisting of SEQ ID NO:77, and a VL CDR3 comprising or consisting of SEQ ID NO:78. In certain aspects, the antibody may comprise a VL CDR1 comprising or consisting of SEQ ID NO:86, a VLCDR2 comprising or consisting of SEQ ID NO:87, and a VLCDR3 comprising or consisting of SEQ ID NO:88. In certain aspects, the antibody may comprise a VLCDR1 comprising or consisting of SEQ ID NO:96, a VLCDR2 comprising or consisting of SEQ ID NO:97, and a VLCDR3 comprising or consisting of SEQ ID NO:98. In certain aspects, the antibody may comprise a VL CDR1 comprising or consisting of SEQ ID NO:106, a VL CDR2 comprising or consisting of SEQ ID NO:107, and a VL CDR3 comprising or consisting of SEQ ID NO:108. In certain aspects, the antibody may comprise a VL CDR1 comprising or consisting of SEQ ID NO:116, a VL CDR2 comprising or consisting of SEQ ID NO:117, or a VL CDR3 comprising or consisting of SEQ ID NO:118. In certain aspects, the antibody may comprise a VHCDR1 comprising or consisting of SEQ ID NO:1, a VHCDR2 comprising or consisting of SEQ ID NO:2, a VHCDR3 comprising or consisting of SEQ ID NO:3, a VLCDR1 comprising or consisting of SEQ ID NO:6, a VL CDR2 comprising or consisting of SEQ ID NO:7, and a VL CDR3 comprising or consisting of SEQ ID NO:8. In certain aspects, the antibody may comprise a VH CDR1 comprising or consisting of SEQ ID NO:11, a VH CDR2 comprising or consisting of SEQ ID NO:12, a VH CDR3 comprising or consisting of SEQ ID NO:13; a VL CDR1 comprising or consisting of SEQ ID NO:16, a VLCDR2 comprising or consisting of SEQ ID NO:17, and a VLCDR3 comprising or consisting of SEQ ID NO:18. In certain aspects, the antibody may comprise a VHCDR1 comprising or consisting of SEQ ID NO:21, a VHCDR2 comprising or consisting of SEQ ID NO:22, a VH CDR3 comprising or consisting of SEQ ID NO:23; a VL CDR1 comprising or consisting of SEQ ID NO:26, a VL CDR2 comprising or consisting of SEQ ID NO:27, and a VL CDR3 comprising or consisting of SEQ ID NO:28. In certain aspects, the antibody may comprise a VH CDR1 comprising or consisting of SEQ ID NO:31, a VH CDR2 comprising or consisting of SEQ ID NO:32, a VHCDR3 comprising or consisting of SEQ ID NO:33; a VLCDR1 comprising or consisting of SEQ ID NO:36, a VLCDR2 comprising or consisting of SEQ ID NO:37, and a VLCDR3 comprising or consisting of SEQ ID NO:38. In certain aspects, the antibody may comprise a VHCDR1 comprising or consisting of SEQ ID NO:41, a VHCDR2 comprising or consisting of SEQ ID NO:42, a VH CDR3 comprising or consisting of SEQ ID NO:43; a VL CDR1 comprising - 10 - 116104230Atty Docket No.40574-131 or consisting of SEQ ID NO:46, a VL CDR2 comprising or consisting of SEQ ID NO:47, and a VL CDR3 comprising or consisting of SEQ ID NO:48. In certain aspects, the antibody may comprise a VH CDR1 comprising or consisting of SEQ ID NO:51, a VH CDR2 comprising or consisting of SEQ ID NO:52, a VH CDR3 comprising or consisting of SEQ ID NO:53; a VL CDR1 comprising or consisting of SEQ ID NO:56, a VLCDR2 comprising or consisting of SEQ ID NO:57, and a VLCDR3 comprising or consisting of SEQ ID NO:58. In certain aspects, the antibody may comprise a VHCDR1 comprising or consisting of SEQ ID NO:61, a VHCDR2 comprising or consisting of SEQ ID NO:62, a VHCDR3 comprising or consisting of SEQ ID NO:63; a VLCDR1 comprising or consisting of SEQ ID NO:66, a VL CDR2 comprising or consisting of SEQ ID NO:67, and a VL CDR3 comprising or consisting of SEQ ID NO:68. In certain aspects, the antibody may comprise a VH CDR1 comprising or consisting of SEQ ID NO:71, a VH CDR2 comprising or consisting of SEQ ID NO:72, a VH CDR3 comprising or consisting of SEQ ID NO:73; a VL CDR1 comprising or consisting of SEQ ID NO:76, a VLCDR2 comprising or consisting of SEQ ID NO:77, and a VLCDR3 comprising or consisting of SEQ ID NO:78. In certain aspects, the antibody may comprise a VHCDR1 comprising or consisting of SEQ ID NO:81, a VHCDR2 comprising or consisting of SEQ ID NO:82, a VH CDR3 comprising or consisting of SEQ ID NO:83; a VL CDR1 comprising or consisting of SEQ ID NO:86, a VL CDR2 comprising or consisting of SEQ ID NO:87, and a VL CDR3 comprising or consisting of SEQ ID NO:88. In certain aspects, the antibody may comprise a VH CDR1 comprising or consisting of SEQ ID NO:91, a VH CDR2 comprising or consisting of SEQ ID NO:92, a VHCDR3 comprising or consisting of SEQ ID NO:93; a VLCDR1 comprising or consisting of SEQ ID NO:96, a VLCDR2 comprising or consisting of SEQ ID NO:97, and a VLCDR3 comprising or consisting of SEQ ID NO:98. In certain aspects, the antibody may comprise a VH CDR1 comprising or consisting of SEQ ID NO:101, a VH CDR2 comprising or consisting of SEQ ID NO:102, a VH CDR3 comprising or consisting of SEQ ID NO:103; a VL CDR1 comprising or consisting of SEQ ID NO:106, a VL CDR2 comprising or consisting of SEQ ID NO:107, and a VL CDR3 comprising or consisting of SEQ ID NO:108. In certain aspects, the antibody may comprise a VHCDR1 comprising or consisting of SEQ ID NO:111, a VHCDR2 comprising or consisting of SEQ ID NO:112, a VHCDR3 comprising or consisting of SEQ ID NO:113, a VLCDR1 comprising or consisting of SEQ ID NO:116, a VLCDR2 comprising or consisting of SEQ ID NO:117, or a VLCDR3 comprising or consisting of SEQ ID NO:118. - 11 - 116104230Atty Docket No.40574-131

[0017] One embodiment of the disclosure is an antibody comprising heavy chain variableregion. In certain aspects, the heavy chain variable region may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:4, wherein the variable region comprises VHCDR1 comprising or consisting of SEQ ID NO:1, VHCDR2 comprising or consisting of SEQ ID NO:2, and VHCDR3 comprising or consisting of SEQ ID NO3. In certain aspects, the heavy chain variable region may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:14, wherein the variable region comprises VH CDR1 comprising or consisting of SEQ ID NO:11, VH CDR2 comprising or consisting of SEQ ID NO:12, and VH CDR3 comprising or consisting of SEQ ID NO:13. In certain aspects, the heavy chain variable region may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:24, wherein the variable region comprises VHCDR1 comprising or consisting of SEQ ID NO:21, VHCDR2 comprising or consisting of SEQ ID NO:22, and VH CDR3 comprising or consisting of SEQ ID NO:23. In certain aspects, the heavy chain variable region may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:34, wherein the variable region comprises VHCDR1 comprising or consisting of SEQ ID NO:31, VHCDR2 comprising or consisting of SEQ ID NO:32, and VHCDR3 comprising or consisting of SEQ ID NO:33. In certain aspects, the heavy chain variable region may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:44, wherein the variable region comprises VH CDR1 comprising or consisting of SEQ ID NO:41, VH CDR2 comprising or consisting of SEQ ID NO:42, and VH CDR3 comprising or consisting of SEQ ID NO:43. In certain aspects, the heavy chain variable region may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:54, wherein the variable region comprises VHCDR1 comprising or consisting of SEQ ID NO:51, VHCDR2 comprising or consisting of SEQ ID NO:52, and VH CDR3 comprising or consisting of SEQ ID NO:53. In certain - 12 - 116104230Atty Docket No.40574-131 aspects, the heavy chain variable region may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:64, wherein the variable region comprises VH CDR1 comprising or consisting of SEQ ID NO:61, VH CDR2 comprising or consisting of SEQ ID NO:62, and VHCDR3 comprising or consisting of SEQ ID NO:63. an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:74, wherein the variable region comprises VHCDR1 comprising or consisting of SEQ ID NO:71, VHCDR2 comprising or consisting of SEQ ID NO:72, and VHCDR3 comprising or consisting of SEQ ID NO:73. In certain aspects, the heavy chain variable region may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:84, wherein the variable region comprises VHCDR1 comprising or consisting of SEQ ID NO:81, VHCDR2 comprising or consisting of SEQ ID NO:82, and VHCDR3 comprising or consisting of SEQ ID NO:83. In certain aspects, the heavy chain variable region may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:94, wherein the variable region comprises VH CDR1 comprising or consisting of SEQ ID NO:91, VH CDR2 comprising or consisting of SEQ ID NO:92, and VH CDR3 comprising or consisting of SEQ ID NO:93. In certain aspects, the heavy chain variable region may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:104, wherein the variable region comprises VH CDR1 comprising or consisting of SEQ ID NO:101, VH CDR2 comprising or consisting of SEQ ID NO:102, and VH CDR3 comprising or consisting of SEQ ID NO:103. In certain aspects, the heavy chain variable region may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:114, wherein the variable region comprises VHCDR1 comprising or consisting of SEQ ID NO:111, VHCDR2 comprising or consisting of SEQ ID NO:112, and VHCDR3 comprising or consisting of SEQ ID NO:113. In certain aspects, the antibody may comprise a light chain variable region comprising an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, - 13 - 116104230Atty Docket No.40574-131 at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:9, wherein the variable region comprises VL CDR1 comprising or consisting of SEQ ID NO:6, VL CDR2 comprising or consisting of SEQ ID NO:7, and VL CDR3 comprising or consisting of SEQ ID NO:8. In certain aspects, the light chain variable region may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:19, wherein the variable region comprises VLCDR1 comprising or consisting of SEQ ID NO:16, VLCDR2 comprising or consisting of SEQ ID NO:17, and VLCDR3 comprising or consisting of SEQ ID NO:18. In certain aspects, the light chain variable region may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:29, wherein the variable region comprises VL CDR1 comprising or consisting of SEQ ID NO:26, VL CDR2 comprising or consisting of SEQ ID NO:27, and VLCDR3 comprising or consisting of SEQ ID NO:28. In certain aspects, the light chain variable region may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:39, wherein the variable region comprises VL CDR1 comprising or consisting of SEQ ID NO:36, VL CDR2 comprising or consisting of SEQ ID NO:37, and VL CDR3 comprising or consisting of SEQ ID NO:38. In certain aspects, the light chain variable region may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:49, wherein the variable region comprises VLCDR1 comprising or consisting of SEQ ID NO:46, VLCDR2 comprising or consisting of SEQ ID NO:47, and VL CDR3 comprising or consisting of SEQ ID NO:48. In certain aspects, the light chain variable region may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:59, wherein the variable region comprises VLCDR1 comprising or consisting of SEQ ID NO:56, VLCDR2 comprising or consisting of SEQ ID NO:57, and VLCDR3 comprising or consisting of SEQ ID NO:58. In certain aspects, the light chain variable region may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:69, wherein the variable region - 14 - 116104230Atty Docket No.40574-131 comprises VL CDR1 comprising or consisting of SEQ ID NO:66, VL CDR2 comprising or consisting of SEQ ID NO:67, and VL CDR3 comprising or consisting of SEQ ID NO:68. In certain aspects, the light chain variable region may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:79, wherein the variable region comprises VLCDR1 comprising or consisting of SEQ ID NO:76, VLCDR2 comprising or consisting of SEQ ID NO:77, and VLCDR3 comprising or consisting of SEQ ID NO:78. In certain aspects, the light chain variable region may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:89, wherein the variable region comprises VL CDR1 comprising or consisting of SEQ ID NO:86, VL CDR2 comprising or consisting of SEQ ID NO:87, and VL CDR3 comprising or consisting of SEQ ID NO:88. In certain aspects, the light chain variable region may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:99, wherein the variable region comprises VL CDR1 comprising or consisting of SEQ ID NO:96, VL CDR2 comprising or consisting of SEQ ID NO:97, and VL CDR3 comprising or consisting of SEQ ID NO:98. In certain aspects, the light chain variable region may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:109, wherein the variable region comprises VLCDR1 comprising or consisting of SEQ ID NO:106, VLCDR2 comprising or consisting of SEQ ID NO:107, and VLCDR3 comprising or consisting of SEQ ID NO:108. In certain aspects, the light chain variable region may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:119, wherein the variable region comprises VL CDR1 comprising or consisting of SEQ ID NO:116, VL CDR2 comprising or consisting of SEQ ID NO:117, and VLCDR3 comprising or consisting of SEQ ID NO:118. In certain aspects, the antibody may comprise a heavy chain. In certain aspects, the heavy chain may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:5, wherein the heavy chain comprises VH CDR1 comprising or consisting of SEQ - 15 - 116104230Atty Docket No.40574-131 ID NO:1, VH CDR2 comprising or consisting of SEQ ID NO:2, and VH CDR3 comprising or consisting of SEQ ID NO3. In certain aspects, the heavy chain may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:15, wherein the heavy chain comprises VHCDR1 comprising or consisting of SEQ ID NO:11, VHCDR2 comprising or consisting of SEQ ID NO:12, and VHCDR3 comprising or consisting of SEQ ID NO:13. In certain aspects, the heavy chain may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:25, wherein the heavy chain comprises VH CDR1 comprising or consisting of SEQ ID NO:21, VH CDR2 comprising or consisting of SEQ ID NO:22, and VH CDR3 comprising or consisting of SEQ ID NO:23. In certain aspects, the heavy chain may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:35, wherein the heavy chain comprises VHCDR1 comprising or consisting of SEQ ID NO:31, VHCDR2 comprising or consisting of SEQ ID NO:32, and VH CDR3 comprising or consisting of SEQ ID NO:33. In certain aspects, the heavy chain may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:45, wherein the heavy chain comprises VH CDR1 comprising or consisting of SEQ ID NO:41, VHCDR2 comprising or consisting of SEQ ID NO:42, and VHCDR3 comprising or consisting of SEQ ID NO:43. In certain aspects, the heavy chain may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:55, wherein the heavy chain comprises VH CDR1 comprising or consisting of SEQ ID NO:51, VH CDR2 comprising or consisting of SEQ ID NO:52, and VH CDR3 comprising or consisting of SEQ ID NO:53. In certain aspects, the heavy chain may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:65, wherein the heavy chain comprises VHCDR1 comprising or consisting of SEQ ID NO:61, VHCDR2 comprising or consisting of SEQ ID NO:62, and VHCDR3 comprising or consisting of SEQ ID NO:63. In certain aspects, the heavy chain may comprise an amino acid sequence at least 80% identical, at least 85% - 16 - 116104230Atty Docket No.40574-131 identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:75, wherein the heavy chain comprises VH CDR1 comprising or consisting of SEQ ID NO:71, VH CDR2 comprising or consisting of SEQ ID NO:72, and VHCDR3 comprising or consisting of SEQ ID NO:73. In certain aspects, the heavy chain may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:85, wherein the heavy chain comprises VHCDR1 comprising or consisting of SEQ ID NO:81, VHCDR2 comprising or consisting of SEQ ID NO:82, and VHCDR3 comprising or consisting of SEQ ID NO:83. In certain aspects, the heavy chain may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:95, wherein the heavy chain comprises VH CDR1 comprising or consisting of SEQ ID NO:91, VH CDR2 comprising or consisting of SEQ ID NO:92, and VHCDR3 comprising or consisting of SEQ ID NO:93. In certain aspects, the heavy chain may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:105, wherein the heavy chain comprises VH CDR1 comprising or consisting of SEQ ID NO:101, VH CDR2 comprising or consisting of SEQ ID NO:102, and VH CDR3 comprising or consisting of SEQ ID NO:103. In certain aspects, the heavy chain may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:115, wherein the heavy chain comprises VHCDR1 comprising or consisting of SEQ ID NO:111, VHCDR2 comprising or consisting of SEQ ID NO:112, and VH CDR3 comprising or consisting of SEQ ID NO:113. In certain aspects, the antibody may comprise a light chain. In certain aspects, the light chain may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:10, wherein the light chain comprises VLCDR1 comprising or consisting of SEQ ID NO:6, VLCDR2 comprising or consisting of SEQ ID NO:7, and VLCDR3 comprising or consisting of SEQ ID NO:8. In certain aspects, the light chain may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:20, wherein the light chain - 17 - 116104230Atty Docket No.40574-131 comprises VL CDR1 comprising or consisting of SEQ ID NO:16, VL CDR2 comprising or consisting of SEQ ID NO:17, and VL CDR3 comprising or consisting of SEQ ID NO:18. In certain aspects, the light chain may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:30, wherein the light chain comprises VLCDR1 comprising or consisting of SEQ ID NO:26, VLCDR2 comprising or consisting of SEQ ID NO:27, and VLCDR3 comprising or consisting of SEQ ID NO:28. In certain aspects, the light chain may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:40, wherein the light chain comprises VL CDR1 comprising or consisting of SEQ ID NO:36, VL CDR2 comprising or consisting of SEQ ID NO:37, and VL CDR3 comprising or consisting of SEQ ID NO:38. In certain aspects, the light chain may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:50, wherein the light chain comprises VLCDR1 comprising or consisting of SEQ ID NO:46, VLCDR2 comprising or consisting of SEQ ID NO:47, and VL CDR3 comprising or consisting of SEQ ID NO:48. In certain aspects, the light chain may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:60, wherein the light chain comprises VL CDR1 comprising or consisting of SEQ ID NO:56, VLCDR2 comprising or consisting of SEQ ID NO:57, and VLCDR3 comprising or consisting of SEQ ID NO:58. In certain aspects, the light chain may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:70, wherein the light chain comprises VL CDR1 comprising or consisting of SEQ ID NO:66, VL CDR2 comprising or consisting of SEQ ID NO:67, and VL CDR3 comprising or consisting of SEQ ID NO:68. In certain aspects, the light chain may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:80, wherein the light chain comprises VLCDR1 comprising or consisting of SEQ ID NO:76, VLCDR2 comprising or consisting of SEQ ID NO:77, and VLCDR3 comprising or consisting of SEQ ID NO:78. In certain aspects, the light chain may comprise an amino acid sequence at least 80% identical, at - 18 - 116104230Atty Docket No.40574-131 least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:90, wherein the light chain comprises VL CDR1 comprising or consisting of SEQ ID NO:86, VL CDR2 comprising or consisting of SEQ ID NO:87, and VL CDR3 comprising or consisting of SEQ ID NO:88. In certain aspects, the light chain may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:100, wherein the light chain comprises VLCDR1 comprising or consisting of SEQ ID NO:96, VLCDR2 comprising or consisting of SEQ ID NO:97, and VLCDR3 comprising or consisting of SEQ ID NO:98. In certain aspects, the light chain may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:110, wherein the light chain comprises VL CDR1 comprising or consisting of SEQ ID NO:106, VL CDR2 comprising or consisting of SEQ ID NO:107, and VLCDR3 comprising or consisting of SEQ ID NO:108. In certain aspects, the light chain may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:120, wherein the light chain comprises VL CDR1 comprising or consisting of SEQ ID NO:116, VL CDR2 comprising or consisting of SEQ ID NO:117, and VL CDR3 comprising or consisting of SEQ ID NO:118. In certain aspects, the antibody may comprise a heavy chain and a light chain. In certain aspects, the heavy chain may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:5, wherein the heavy chain comprises VHCDR1 comprising or consisting of SEQ ID NO:1, VH CDR2 comprising or consisting of SEQ ID NO:2, and VH CDR3 comprising or consisting of SEQ ID NO3, and the light chain may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:10, wherein the light chain comprises VLCDR1 comprising or consisting of SEQ ID NO:6, VLCDR2 comprising or consisting of SEQ ID NO:7, and VLCDR3 comprising or consisting of SEQ ID NO:8. In certain aspects, the heavy chain may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:15, wherein the heavy chain comprises VH CDR1 - 19 - 116104230Atty Docket No.40574-131 comprising or consisting of SEQ ID NO:11, VH CDR2 comprising or consisting of SEQ ID NO:12, and VH CDR3 comprising or consisting of SEQ ID NO:13, and the light chain may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:20, wherein the light chain comprises VLCDR1 comprising or consisting of SEQ ID NO:16, VLCDR2 comprising or consisting of SEQ ID NO:17, and VLCDR3 comprising or consisting of SEQ ID NO:18. In certain aspects, the heavy chain may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:25, wherein the heavy chain comprises VH CDR1 comprising or consisting of SEQ ID NO:21, VH CDR2 comprising or consisting of SEQ ID NO:22, and VH CDR3 comprising or consisting of SEQ ID NO:23, and the light chain may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:30, wherein the light chain comprises VLCDR1 comprising or consisting of SEQ ID NO:26, VLCDR2 comprising or consisting of SEQ ID NO:27, and VLCDR3 comprising or consisting of SEQ ID NO:28. In certain aspects, the heavy chain may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:35, wherein the heavy chain comprises VH CDR1 comprising or consisting of SEQ ID NO:31, VH CDR2 comprising or consisting of SEQ ID NO:32, and VHCDR3 comprising or consisting of SEQ ID NO:33, and the light chain may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:40, wherein the light chain comprises VL CDR1 comprising or consisting of SEQ ID NO:36, VL CDR2 comprising or consisting of SEQ ID NO:37, and VL CDR3 comprising or consisting of SEQ ID NO:38. In certain aspects, the heavy chain may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:45, wherein the heavy chain comprises VHCDR1 comprising or consisting of SEQ ID NO:41, VHCDR2 comprising or consisting of SEQ ID NO:42, and VHCDR3 comprising or consisting of SEQ ID NO:43, and the light chain may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% - 20 - 116104230Atty Docket No.40574-131 identical, at least 99% identical, or 100% identical, to SEQ ID NO:50, wherein the light chain comprises VL CDR1 comprising or consisting of SEQ ID NO:46, VL CDR2 comprising or consisting of SEQ ID NO:47, and VL CDR3 comprising or consisting of SEQ ID NO:48. In certain aspects, the heavy chain may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:55, wherein the heavy chain comprises VHCDR1 comprising or consisting of SEQ ID NO:51, VHCDR2 comprising or consisting of SEQ ID NO:52, and VHCDR3 comprising or consisting of SEQ ID NO:53, and the light chain may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:60, wherein the light chain comprises VL CDR1 comprising or consisting of SEQ ID NO:56, VL CDR2 comprising or consisting of SEQ ID NO:57, and VL CDR3 comprising or consisting of SEQ ID NO:58. In certain aspects, the heavy chain may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:65, wherein the heavy chain comprises VH CDR1 comprising or consisting of SEQ ID NO:61, VH CDR2 comprising or consisting of SEQ ID NO:62, and VH CDR3 comprising or consisting of SEQ ID NO:63, and the light chain may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:70, wherein the light chain comprises VLCDR1 comprising or consisting of SEQ ID NO:66, VLCDR2 comprising or consisting of SEQ ID NO:67, and VLCDR3 comprising or consisting of SEQ ID NO:68. In certain aspects, the heavy chain may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:75, wherein the heavy chain comprises VH CDR1 comprising or consisting of SEQ ID NO:71, VH CDR2 comprising or consisting of SEQ ID NO:72, and VHCDR3 comprising or consisting of SEQ ID NO:73, and the light chain may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:80, wherein the light chain comprises VLCDR1 comprising or consisting of SEQ ID NO:76, VLCDR2 comprising or consisting of SEQ ID NO:77, and VL CDR3 comprising or consisting of SEQ ID NO:78. In certain aspects, the heavy chain may - 21 - 116104230Atty Docket No.40574-131 comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:85, wherein the heavy chain comprises VH CDR1 comprising or consisting of SEQ ID NO:81, VH CDR2 comprising or consisting of SEQ ID NO:82, and VH CDR3 comprising or consisting of SEQ ID NO:83, and the light chain may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:90, wherein the light chain comprises VLCDR1 comprising or consisting of SEQ ID NO:86, VLCDR2 comprising or consisting of SEQ ID NO:87, and VL CDR3 comprising or consisting of SEQ ID NO:88. In certain aspects, the heavy chain may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:95, wherein the heavy chain comprises VH CDR1 comprising or consisting of SEQ ID NO:91, VHCDR2 comprising or consisting of SEQ ID NO:92, and VHCDR3 comprising or consisting of SEQ ID NO:93, and the light chain may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:100, wherein the light chain comprises VL CDR1 comprising or consisting of SEQ ID NO:96, VL CDR2 comprising or consisting of SEQ ID NO:97, and VL CDR3 comprising or consisting of SEQ ID NO:98. In certain aspects, the heavy chain may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:105, wherein the heavy chain comprises VHCDR1 comprising or consisting of SEQ ID NO:101, VHCDR2 comprising or consisting of SEQ ID NO:102, and VH CDR3 comprising or consisting of SEQ ID NO:103, and the light chain may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:110, wherein the light chain comprises VL CDR1 comprising or consisting of SEQ ID NO:106, VLCDR2 comprising or consisting of SEQ ID NO:107, and VLCDR3 comprising or consisting of SEQ ID NO:108. In certain aspects, the heavy chain may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:115, wherein the heavy chain comprises VH CDR1 comprising or consisting of - 22 - 116104230Atty Docket No.40574-131 SEQ ID NO:111, VH CDR2 comprising or consisting of SEQ ID NO:112, and VH CDR3 comprising or consisting of SEQ ID NO:113, and the light chain may comprise an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:120, wherein the light chain comprises VLCDR1 comprising or consisting of SEQ ID NO:116, VLCDR2 comprising or consisting of SEQ ID NO:117, and VLCDR3 comprising or consisting of SEQ ID NO:118. In certain aspects, the antibody may be selected from the group consisting of EVD2301 (aka 1E11), 2302 (aka 2A09), 2303 (aka 5H03), 2304 (aka 5C10), 2305 (aka 1A09), 2306 (1B04), 2307 (aka 4B03), 2308 (aka 3C10), 2309 (aka 3B05), 2310 (aka 1C01), 2311 (aka 11E03), and 2312 (aka 15A03). In certain aspects, the antibody or antigen-binding fragment is a humanized antibody. In certain aspects of the disclosure, the antibody comprises a light chain comprising a light chain variable region of the disclosure joined to a human light chain constant region. In certain aspects of the disclosure, the antibody comprises a heavy chain comprising a heavy chain variable region of the disclosure joined to a human heavy chain constant region.

[0018] One embodiment of the disclosure is a vector comprising a nucleic acid molecule thatcomprises a polynucleotide sequence encoding an antibody of the disclosure, or a light chain or heavy chain CDR, a light chain or heavy chain variable region, a light chain, or a heavy chain thereof. In certain aspects the vector may be an expression vector, in which the polynucleotide sequence may be operatively joined to a promoter that drives expression of the polynucleotide sequence. The vector may comprise a plasmid or a viral vector, which may be a poxvirus vector, an adenovirus vector, a herpesvirus vector, an adeno-associated virus vector, a lentivirus vector, a plant virus vector, or an insect virus vector.

[0019] One embodiment of the disclosure is an engineered cell comprising an antibody or avector of the disclosure.

[0020] One embodiment of the disclosure is a composition comprising at least one antibody,a vector, or an engineered cell of the disclosure. In some embodiments, the composition comprises a plurality of antibodies, a plurality of vectors, or a plurality of engineered cells of the disclosure. The composition may comprise one or more therapeutic compounds in addition to the antibody, the vector, or the engineered cell. The therapeutic one or more compounds may target symptoms resulting from infection with an enterovirus. In certain aspects, the one or more compounds may comprise an antiviral compound, an antibiotic, a steroid, rupintrivir–vemurafenib, vemurafenib– - 23 - 116104230Atty Docket No.40574-131 pleconaril, rupintrivir–pleconaril or rupintrivir–cycloheximide. The composition may be formulated for administration in an individual.

[0021] One embodiment of the disclosure is a kit comprising an antibody, a vector, anengineered cell, or a composition of the disclosure.

[0022] One embodiment of the disclosure is a method of detecting an enterovirus, or anassociated antigen thereof, comprising: a) contacting an antibody of the disclosure with a test sample under conditions suitable for forming a complex between the enterovirus, if present, of the associated antigen thereof, if present; and b) detecting the presence of an antibody:enterovirus complex of an antibody:enterovirus-associated antigen complex; thereby detecting the presence of the enterovirus.

[0023] One embodiment of the disclosure is a method of identifying the enterovirus infectionstatus of an individual, comprising testing a sample from the individual for the presence of enterovirus or an associated antigen thereof using the antibody of the disclosure, or a composition of the disclosure, wherein if the presence of enterovirus, or an associated antigen thereof, is detected, identifying the individual as having an enterovirus infection, or if the presence of enterovirus or an associated antigen thereof is not detected, identifying the individual as not having an enterovirus infection. The step of testing may comprise i) contacting the sample with the antibody of the disclosure under conditions suitable for forming a complex between an antibody and the enterovirus or the associated antigen thereof, if present; and ii) detecting the presence of an antibody:enterovirus complex, or an antibody:enterovirus-associated antigen complex; wherein if an antibody:enterovirus complex, or an antibody:enterovirus-associated antigen complex, is detected, identifying the individual as having an enterovirus infection, or if an antibody:enterovirus complex, or an antibody:enterovirus-associated antigen complex is not detected, identifying the individual as not having an enterovirus infection.

[0024] On e embodiment of the disclosure is a method of purifying an enterovirus, or anassociated antigen thereof, comprising contacting a sample comprising the enterovirus or associated antigen thereof with an antibody of the disclosure to form an antibody:enterovirus, or antibody:enterovirus-associated antigen complex, such that the enterovirus or associated antigen thereof is removed from majority of components in the sample, thereby purifying the enterovirus or an associated antigen thereof. In certain aspects, once the antibody:enterovirus, or antibody:enterovirus-associated antigen, complex is formed, washing the antibody:enterovirus, or - 24 - 116104230Atty Docket No.40574-131 antibody:enterovirus-associated antigen, complex to remove non-desirable components present in the sample. In certain asepcts, the method may comprise treating the antibody:enterovirus or antibody:enterovirus-associated antigen complex to remove the enterovirus or associated antigen thereof.

[0025] One embodiment of the disclosure is a method of preventing infection of a cell by anenterovirus, comprising contacting the enterovirus with an antibody, or a composition, of the disclosure prior to, or concurrent with, contact of the enterovirus with the cell.

[0026] One embodiment of the disclosure is a method of protecting an individual againstinfection with an enterovirus, comprising administering to the individual an antibody, a vector, an engineered cell, or a composition of the disclosure. The individual may be known to be free of enterovirus, or the individual may be at risk for infection with enterovirus.

[0027] One embodiment of the disclosure is a method of treating an individual having anenterovirus infection, comprising administering to the individual an antibody or antigen-binding fragment thereof, a vector, an engineered cell, or a composition of the disclosure.

[0028] One embodiment of the disclosure is a method of reducing disease symptoms in anindividual infected with enterovirus, comprising administering to the individual an antibody or antigen-binding fragment thereof, a vector, an engineered cell, or a composition of the disclosure.

[0029] One embodiment of the disclosure is method protecting an individual against infectionwith an enterovirus, treating an individual having an enterovirus infection, or reducing disease symptoms in an individual infected with enterovirus, comprising administering to the individual an antibody or antigen-binding fragment thereof. In some embodiments, the subject is administered a composition comprising the antibody or antigen-binding fragment thereof. In some embodiments, the composition further comprises at least one therapeutic agent. In some embodiments, the at least one therapeutic agent comprises an antiviral compound, an antibiotic, a steroid, rupintrivir–vemurafenib, vemurafenib–pleconaril, rupintrivir–pleconaril or rupintrivir– cycloheximide. In some embodiments, the individual is administered the antibody or antigen- binding fragment thereof by one route of administration and the at least one therapeutic agent by another route of administration.

[0030] One embodiment of the discourse is use of an antibody or antigen-binding fragmentthereof, a vector, an engineered cell, a composition, or a kit of the disclosure, in the preparation of a medicament for protecting an individual against infection with an enterovirus. - 25 - 116104230Atty Docket No.40574-131

[0031] One embodiment of the disclosure is use of use of an antibody, a vector, an engineeredcell, a composition, or a kit of the disclosure, in the preparation of a medicament for treating an individual infected with an enterovirus.

[0032] One embodiment of the disclosure is use of use of an antibody, a vector, an engineeredcell, a composition, or a kit of the disclosure, in the preparation of a medicament for reducing symptoms in an individual infected with enterovirus.

[0033] In these embodiments, the enterovirus may be any enterovirus disclosed herein, whichincludes EV-68, EV-68 B3, EV-68 A2 / D, or EV-A71.

[0034] BRIEF DESCRIPTION OF THE DRAWINGS

[0035] The embodiments described herein may be better understood by referring to thefollowing description in conjunction with the accompanying drawings.

[0036] FIGS. 1A & 1B – generation of enterovirus neutralizing antibody. FIG. 1A illustratesthe procedure used to immunize macaques with EV-D68 B3 VLP. FIG. 1B shows neutralization titers for sera from two rhesus macaques immunized with EV-D68 B3 VLP for EV-D68 B1, EV- D68 D1 and EV-D68 A1.

[0037] FIGS. 2A-2C – binding characteristics of monoclonal antibodies from rhesus macaquesimmunized with EV-D68 B3 and A2 VLPs. FIG.2A shows enzyme-linked immunosorbent assay (“ELISA”) results demonstrating that monoclonal antibodies from rhesus macaques immunized with EV-D68 B3 VLP bind both B3 VLP and A2 VLP. FIG. 2B shows the B3 / A2 ELISA ratio. FIG. 2C shows the normalized ELISA binding activity for monoclonal antibodies against B3 and A2 VLPs. Antibodies that exhibited neutralization activity are colored red.

[0038] FIGS. 3A-3D – binding characteristics of cloned antibodies. FIG. 3A shows the abilityof cloned and purified antibodies from B-cells obtained from the vaccinated macaques to bind B3 VLP or A2 VLP by ELISA. FIG.3B shows the ability of cloned antibodies from B-cells obtained from the vaccinated macaques to neutralize B3 VLP or A2 VLP. FIG. 3C shows the ability of specific cloned antibodies to neutralize VLP matched B3 and A2 EV-D68 isolates, as well as an older B1 virus that is no longer circulating. FIG. 3D shows IC50 values for several of the cloned antibodies against EV-D68 B1, EV-D68 B3, and EV-D68 A2.

[0039] FIGS. 4A-4E -determination of binding kinetics for antigen-binding fragments (Fabs)of top five neutralizing antibodies. FIG. 4A shows the result of Bio-layer interferometry. FIGS. - 26 - 116104230Atty Docket No.40574-131 4B & 4C show association and dissociation rates, respectively, for the five antibodies. FIG. 4D shows the dissociation constant for the five antibodies. FIG 4E shows the results of binning.

[0040] FIGS. 5A-5D – fab fragment neutralization assays. FIGS. 5A & 5B shows the resultsof neutralization assays against B3 and A2 viruses using monoclonal fab fragments, respectively. FIGS. 5C & 5D shows a comparison of the ability of intact IgG and their respective Fabs to neutralize B3 and A2 virus, respectively.

[0041] FIGS. 6A-6F - protective potential of VLP-induced EV-D68 NHP mAbs in a mousemodel of EV-D68 respiratory infection. FIG. 6A illustrates the protocol used to test mice for protection. FIG.6B shows the results of neutralization assays performed using sera obtained from the mice 24 hours after passive immunization. FIGS.6C & 6D shows the viral load detected in the lung and spleen, respectively, following viral challenge. FIG.6E shows B3 Mp20 viral load in the blood of animals treated with non-neutralizing antibody A9 (negative control). FIG. 6F shows a comparison of lung viral titers and post-mAb transfer neutralization titers.

[0042] FIGS. 7A-7E - viral load in the lung following passive immunization of mice. FIG. 7Ashows the viral load in the lung detected after passive immunization and viral challenge. FIG. 7B shows prechallenge neutralization titers in sera from mice sampled 24 hours after passive immunization. FIG. 7C shows Pearson correlation of prechallenge neutralization titer and lung viral load illustrating a strong negative correlation between neutralization titer in the blood and viral replication in the lung. FIGS.7D and 7E show the viral load in the spleen (D) and blood (E) detected after passive immunization and viral challenge.

[0043] FIG. 8 - Immunization of Rhesus macaques with EV-D68 B3 or A2 VLPs generatesrobust neutralizing antibody responses. The upper panel shows the study design timeline with the immunizations indicated on top of the timeline while the study week and blood collection are indicated below the timeline. Blood was collected from immunized NHPs at the indicated time points. The lower charts show endpoint neutralization titers against the indicated EV-D68 virus isolate for both animals used in the study.

[0044] FIGS. 9A-9E - Isolation and screening of monoclonal antibodies from immunizedRhesus macaques using RATPIg. EV-D68 specific B cells were sorted using B3 and A2 subclade VLPs as B cell probes while monoclonal antibodies were isolated using RATPIg. Panel A shows flow cytometry plots showing A2 or B3 probe binding B cell populations from the week 26 sample. The right-hand panel shows the proportion of A2 VLP reactive B cells within the B3 reactive B - 27 - 116104230Atty Docket No.40574-131 cell population. Panel B shows flow cytometry plots showing A2 or B3 probe binding B cell populations from the week 30 sample. The right-hand panel shows the proportion of A2 VLP reactive B cells within the B3 reactive B cell population. Panel C shows charts showing the measured optical density at 450 nm from ELISAs used to screen for RATPIg cell culture supernatants that bound the B3 VLP (upper chart) or A2 VLP (lower chart). For each chart, the dashed line indicates a cutoff value of 3 times the background signal. Panel D shows ELISA data from panel C represented as a ratio of B3 VLP binding over A2 VLP binding and displayed as a histogram. Bins of 1.00 or greater indicate a binding preference for the B3 VLP over the A2 VLP. Panel E shows normalized ELISA binding values for monoclonal antibodies against both the B3 and A2 VLPs. Antibodies that exhibited neutralization in a two-point screening assay are colored red. Empty circles indicate antibodies that did not exhibit any neutralization activity against either B3 or A2 virus.

[0045] Figure 10 - Characterization of selected EV-D68 mAbs. Antibodies that were cloned,expressed, and purified were characterized using ELISA binding, virus neutralization, binding kinetics and epitope binning. Panel A shows ELISA binding for purified mAbs against the B3 (top row) or A2 (bottom row) VLP expressed at the log10 molar EC50 value determined by nonlinear regression. Panel B shows antibody neutralization potency against the B3 (top row) or A2 (bottom row) viruses expressed as the log10 molar IC50 value determined by nonlinear regression. Panel C shows charts showing neutralization curves for selected potent EV-D68 mAbs against the indicated EV-D68 virus isolate. Antibody 5E01 binds but does not neutralize the EV-68 virus isolate and serves as a negative control. The error bars indicate standard deviation. Panel D showscomparisons of IC50 [HRZLX L]VWLXXLK HX hN)S> MUW YOL PTKPJHYLK S4I HNHPTXY YOL YOWLL 8F'702virus isolates used in this study. Panel E shows dissociation constants for the indicated mAb measured using the EV-D68 B3 VLP. Error bars indicate standard error. Panel F shows epitope binning competition results shown as percent inhibition of the second Fab after association of the first Fab.

[0046] Figure 11: Cryo-electron microscopic (cryo-EM) structures of B3 VLP complexed with1E11 Fabs. Panel A shows a surface-rendered representation showing the overall structure of 1E11 Fabs in complex with a EV-D68 B3 VLP. The VP0, the VP1, the VP3, the 1E11 heavy chains, and the 1E11 light chains are colored red, forest green, blue, dark orange, and tan, respectively. Panel B shows a 1E11 Fab binding position comparison on an asymmetric unit. B3 VLP capsid proteins - 28 - 116104230Atty Docket No.40574-131 are colored in green (VP1), red (VP0), and blue (VP3). 1E11 heavy chains are colored in orange while 1E11 light chains are colored in tan. Panel C shows 1E11-B3 VLP density maps that are colored by radius to particle center. The color key shows the radius range from 116 Å to 193 Å. Panel D shows a binding interface between a 1E11 Fab and an EV-D68 B3 VLP protomer. The canyon, north rim, and south rim are indicated by black arrows. The fivefold axis and twofold axis are shown as pentagonal and elliptical symbols. Panel E shows detailed interactions among 1E11 a Fab heavy chain, a VP1 beta-chain loop, and a VP3 C-terminus. The VP1, VP3 and paratope residues in the 1E11 Fab heavy chain are shown in cartoon representation. Hydrogen bonds and salt bridges are indicated with black dashed lines. Panel F shows detailed interactions among a 1E11 Fab light chain, a VP1 C-terminus and a VP0 EF loop. The VP1 residues, the VP2 residues, and the paratope residues in the 1E11 Fab light chain are shown as a cartoon representation. Hydrogen bonds and salt bridges are indicated with black dashed lines.

[0047] Figure 12– Cryo-EM structures of EV-D68 B3 VLP in complex with a 5H03 Fab. PanelA shows a surface-rendered representation showing the overall structure of 5H03 Fabs in complex with an EV-D68 B3 VLP. The VP0, the VP1, the VP3, the 5H03 heavy chains, and the 5H03 light chains are colored red, forest green, blue, medium purple, and pink, respectively. Panel B shows a 5H03 Fab binding position comparison on an asymmetric unit. B3 VLP capsid proteins are colored in green (VP1), red (VP0), and blue (VP3).5H03 heavy chains are colored in medium purple while 5H03 light chains are colored in pink. Panel C shows 5H03-B3 VLP density maps colored by radius to particle center. The color key shows the radius range from 116 Å to 193 Å. Panel E shows the detailed interactions among a 5H03 Fab heavy chain, a VP1 C-terminus, and a VP0 EF loop. The VP1 residues, the VP0 residues and the paratope residues in the 5H03 Fab heavy chain are shown in cartoon representation. Hydrogen bonds and salt bridges are indicated with black dashed lines. Panel F shows detailed interactions among a 5H03 Fab light chain and an VP3 C-terminus. The VP3 and paratope residues in 5H03 Fab light chain are shown in cartoon representation. Hydrogen bonds and salt bridges are indicated with black dashed lines.

[0048] Figure 13 - A comparison of the epitopes recognized by the Fabs EV68-228, 1E11, and5H03. Panel A shows that the epitope of EV68-228 Fab has a surface area of 1087 Å2; such epitope is shown on the surface. The heavy chain epitope surface and the light chain epitope surface are colored in light blue and cyan, respectively. Panel B shows that the epitope of the 1E11 Fab has a surface area of 1221 Å2; such epitope is shown on the surface. The heavy chain epitope surfaces - 29 - 116104230Atty Docket No.40574-131 and the light chain epitope surfaces are colored in dark orange and tan, respectively. Panel C shows that the epitope of 5H03 Fab has a surface area of 1090.2 Å2; such epitope is shown on the surface. The heavy chain epitope surfaces and the light chain epitope surfaces are colored by medium purple and pink, respectively. Panel D shows an overlay of the 1E11 epitope, the 5H03 epitope, and the EV68-228 epitope on the B3 VLP capsid; the sialic acid binding site from the Fermon isolate is highlighted (Protein Data Bank (“PDB”) accession no. 6CVB) and the MFSD6 binding site is also highlighted (PDB accession no. 9MXC). Panel E shows a hemagglutination inhibition assay of EV-D68 B3 virus with serial dilution of the mAbs 1E11, 5H03, and EV68-228.

[0049] Figure 14 - Selection of antibody escape substitutions using an EV-D68 B3 virus. PanelA shows a molecular model of an inactivated EV-D68 B3 virion pentamer colored to indicate the different capsid subunits and locations of distinct monoclonal antibody escape substitutions. VP2 is in grey, VP1 is in black and VP3 is in white. The locations and identities of various escape substitutions and the mAb with which they were generated are indicated. Panel B shows the results of neutralization assays demonstrating that selected escape mutants are insensitive to the monoclonal antibody against which they were generated against but are still sensitive to an unrelated antibody. This indicates that the selected variants are specific for a single monoclonal antibody. Panel C shows details of the molecular interaction between residue H236 on the VP3 C- terminus and the heavy chain of the mAb 1E11. This illustrates that disruption of this interaction by the H236R substitution could disrupt neutralization by the mAb 1E11. Panel D shows details of the molecular interaction between residue D237 on the VP3 C-terminus and the light chain of the mAb 5H03. This illustrates that disruption of this interaction by the D237N substitution could disrupt neutralization by the 5H03 mAbs.

[0050] Figure 15: VLP-Elicited NHP mAb are protective in a mouse model of EV-D68respiratory infection. Panel A shows serum neutralization titers for animals that were passively immunized with the indicated mAb at a dose of 3.0 mg / kg before EV-D68 Mp20 viral challenge. The red circles indicate animals with poor antibody titers resulting from inefficient passive immunization; these animals were excluded from subsequent analysis. The dashed line indicates a lower limit of detection. Panel B shows the amount of EV-68 Mp20 virus recovered from the lungs of passively immunized and challenged animals. The dashed lines indicate lower and upper limits of detection. Panel C shows serum neutralization titers for animals that were passively immunized with the indicated mAb at a dose of 0.2 mg / kg before EV-D68 Mp20 viral challenge. The red - 30 - 116104230Atty Docket No.40574-131 circles indicate animals with poor antibody titers resulting from inefficient passive immunization; these animals were excluded from subsequent analysis. The dashed line indicates the lower limit of detection. Panel D shows the amount of EV-68 Mp20 virus recovered from the lungs of passively immunized and challenged animals. The dashed lines indicate lower and upper limits of detection.

[0051] Figure 16: Kinetic analysis original data and plotted association and dissociation ratesfor the indicated monoclonal antibodies. Panel A shows sensorgrams indicating the response values for each antibody at the indicated concentration for binding to the EV-D68 B3 VLP except for antibody 5C10 for which steady-state kinetics were used to estimate the dissociation constant. Panel B shows log transformed computed association rates for the indicated antibody. N.D. indicates that the association rate constant could not be calculated. Panel C shows log transformed computed dissociation rates for the indicated antibody. N.D. indicates that the rate constant could not be calculated. - 31 - 116104230Atty Docket No.40574-131

[0052] DETAILED DESCRIPTION OF THE DISCLOSURE

[0053] The present disclosure relates to therapeutic agents capable of binding to andneutralizing one or more clades and or subtypes of enterovirus (EV). Preferably, an antibody of the disclosure neutralizes EVs from at least two, and preferably, at least three, clades or serotypes of EV. In certain aspects, antibodies of the disclosure neutralize EV-D68. Thus, the teachings of the disclosure may generally be practiced by producing an antibody that neutralizes EVs from at least two, and preferably, at least three, clades or serotypes of EV, and preferably EV-D68.

[0054] Before the present invention is further described, it is to be understood that thisinvention is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the invention will be limited only by the claims.

[0055] It must be noted that as used herein and in the appended claims, the singular forms "a,""an," and "the" include plural referents unless the context clearly dictates otherwise. For example, a nucleic acid molecule refers to one or more nucleic acid molecules. As such, the terms "a", "an", "one or more" and "at least one" can be used interchangeably.

[0056] Similarly, the terms "comprising", "including" and "having" can be usedinterchangeably. As used herein, the term “comprising” may be replaced with “consisting of” or with “consisting essentially of” in particular aspects, as desired.

[0057] It is further noted that the claims may be drafted to exclude any optional element. Assuch, this statement is intended to serve as antecedent basis for use of such exclusive terminology as "solely," "only" and the like in connection with the recitation of claim elements or use of a "negative" limitation.

[0058] Unless otherwise expressly stated, it is in no way intended that any method or aspectset forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is in no way intended that an order be inferred, in any respect. This holds for any possible non-expressed basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification. - 32 - 116104230Atty Docket No.40574-131

[0059] It is appreciated that certain features of the invention, which are, for clarity, describedin the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub- combination. All combinations of the embodiments are specifically embraced by the present invention and are disclosed herein just as if each and every combination was individually and explicitly disclosed. In addition, all sub-combinations are also specifically embraced by the present invention and are disclosed herein just as if each and every such sub-combination was individually and explicitly disclosed herein.

[0060] Publications discussed herein are provided solely for their disclosure prior to the filingdate of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates, which may need to be independently confirmed. Any patents or patent publications mentioned herein are incorporated herein in their entirety.

[0061] In some embodiments, numbers expressing quantities of ingredients, properties such asmolecular weight, reaction conditions, and so forth, used to describe and claim certain embodiments of the present disclosure are to be understood as being modified in some instances by the term “about.” In some embodiments, the term “about” is used to indicate that a value includes the standard deviation of the mean for the device or method being employed to determine the value. In some embodiments, the numerical parameters set forth in the written description and attached claims are approximations that vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters are to be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the present disclosure are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable. The numerical values presented in some embodiments of the present disclosure may contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements. The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually - 33 - 116104230Atty Docket No.40574-131 to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein.

[0062] All compositions and / or methods disclosed and claimed herein may be made and / orexecuted without undue experimentation in light of the present disclosure. While the compositions and methods of this disclosure have been described in terms of the embodiments included herein, it will be apparent to those of ordinary skill in the art that variations may be applied to the compositions and / or methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit, and scope of the disclosure. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope, and concept of the disclosure as defined by the appended claims.

[0063] All numerical designations, e.g., pH, temperature, time, concentration and molecular\LPNOY& PTJRZKPTN WHTNLX& HWL HVVWU]PSHYPUTX \OPJO HWL [HWPLK #%$ UW #c$ I^ PTJWLSLTYX UM +(* UW*(+& HX HVVWUVWPHYL& UW HRYLWTHYP[LR^ I^ H [HWPHYPUT UM %)c+ / "& UW HRYLWTHYP[LR^ +*"& UW HRYLWTHYP[LR^5% or alternatively 2%. It is to be understood, although not always explicitly stated, that all numerical designations are preceded by the term “about”. It also is to be understood, although not always explicitly stated, that the reagents described herein are merely exemplary and that equivalents of such are known in the art.

[0064] Various terms relating to aspects of the present disclosure are used throughout thespecification and claims. Such terms are to be given their ordinary meaning in the art, unless otherwise indicated. Other specifically defined terms are to be construed in a manner consistent with the definitions provided herein. Definitions and methods described herein are provided to better define the present disclosure and to guide those of ordinary skill in the art in the practice of the present disclosure. Unless otherwise noted, terms are to be understood according to conventional usage by those of ordinary skill in the relevant art.

[0065] One embodiment of the disclosure is an antibody that binds to EV-D86. In someaspects, the antibody neutralizes EV-D86. As used herein, the term “antibody” refers to a polypeptide ligand comprising at least a light chain or heavy chain complementarity determining region (CDR) that, either alone or in combination with other CDRs, specifically recognizes and binds an epitope of an antigen. The term “antibody” may refer to immunoglobulins or immunoglobulin-like molecules including by way of example and without limitation, IgA, IgD, IgE, IgG and IgM, combinations thereof, portions thereof, and similar molecules produced during - 34 - 116104230Atty Docket No.40574-131 an immune response in an individual. The term “antibody” includes whole immunoglobulins / whole antibodies and fragments thereof (a.k.a., “antibody fragments” or “antigen binding fragments”) that specifically bind to an antigen of interest or to a group of highly similar antigens of interest. As such, the term “antibody” encompasses whole immunoglobulins, digestion fragments of whole immunoglobulins, specified portions of immunoglobulins, derivatives and variants thereof, including antibody mimetics or portions of antibodies that mimic the structure and / or function of an antibody or specified fragment or portion thereof, including single chain antibodies and fragments thereof. Examples of antibodies useful for practicing theVWLXLTY KPXJRUXZWL PTJRZKL& IZY HWL TUY RPSPYLK YU& 9HI MWHNSLTYX& 9#HId$2 MWHNSLTYX& 9HId MWHNSLTYX&9HId'C; MWHNSLTYX& H K45 MWHNSLTY& X9v fragments, dsFv fragments, bispecific scFv fragments,bispecific dsFv fragments, single chain Fv proteins (“scFv”), sc(Fv)2 fragments, disulfide stabilized Fv proteins (“dsFv”), minibodies, diabodies, triabodies (as are known in the art), DART antibodies, BiKE antibodies, TriKE antibodies, camelid antibodies (see, for example, U.S. Pat. No. 6,015,695), shark antibodies, VnH domain antibodies, V-NAR domain antibodies and variationsthereon. The term “antibody” also includes genetically engineered forms of antibodies such aschimeric antibodies (e.g., humanized murine antibodies) and heteroconjugate antibodies, such as, bispecific antibodies.

[0066] As is known in the art, whole antibodies comprise a heavy and a light chain, each ofwhich has a variable region, termed the variable heavy (VH) region, and a variable light (VL) region, respectively. In whole antibodies, the CDRs are found within the variable region and the VHregion and the VLregion are responsible for binding the antigen recognized by the antibody. Certain antibodies of the disclosure may contain only a VHregion and / or a VLregion.

[0067] Typically, in a whole immunoglobulin the heavy (H) chains and light (L) chains arePTYLWJUTTLJYLK I^ KPXZRMPKL IUTKX( DOLWL HWL Y\U Y^VLX UM RPNOY JOHPT& RHSIKH #g$ HTK QHVVH #f$(There are five main heavy chain classes (or isotypes) which determine the functional activity of an antibody molecule: IgM, IgD, IgG, IgA, and IgE. Each heavy and light chain contains a constant region and a variable region, (the regions are also known as “domains”). The light and heavy chain variable regions contain a “framework” region interrupted by three hypervariable regions, also called “complementarity-determining regions” or “CDRs”. The extent of the framework region and CDRs have been defined (see, Kabat et al., Sequences of Proteins of Immunological Interest, U.S. Department of Health and Human Services, 1991). The Kabat database is now maintained - 35 - 116104230Atty Docket No.40574-131 online. The amino acid sequences set forth in SEQ ID NOs:1-124 are numbered in accordance with Kabat while the amino acid sequences set forth in SEQ ID NOs:125-700 are numbered in accordance with IMGT (available at www.imgt.org / IMGTScientificChart / Numbering / IMGTnumbering.html). The sequences of the framework regions of different light or heavy chains are relatively conserved within a species. The framework region of an antibody, that is theJUSIPTLK MWHSL\UWQ WLNPUTX UM YOL JUTXYPYZLTY RPNOY HTK OLH[^ JOHPTX& RHWNLR^ HKUVY e'XOLLYJUTMUWSHYPUT HTK YOL 67BX MUWS RUUVX \OPJO JUTTLJY& HTK PT XUSL JHXLX MUWS VHWY UM& YOL e'XOLLYstructure. Thus, framework regions act to form a scaffold that provides for positioning the CDRs in correct orientation by inter-chain, non-covalent interactions.

[0068] The CDRs are primarily responsible for binding to an epitope of an antigen. The CDRsof each chain are typically referred to as CDR1, CDR2, and CDR3, numbered sequentially starting from the N-terminus, and are also typically identified by the chain in which the particular CDR is located. Thus, a VHCDR3 is located in the variable domain of the heavy chain of the antibody in which it is found, whereas a VLCDR1 is the CDR1 from the variable domain of the light chain of the antibody in which it is found. Although it is the CDRs that vary from antibody to antibody, only a limited number of amino acid positions within the CDRs are directly involved in antigen binding. These positions within the CDRs are called specificity determining residues (SDRs). SDRs interact with amino acid residues (called contact residues) in an antigen, resulting in binding of the antibody to the antigen.

[0069] As used herein, an “epitope” or “antigenic determinant” refers to particular chemicalgroups or contiguous or non-contiguous peptide sequences on a molecule that are antigenic, i.e., that elicit a specific immune response. An antibody binds a particular antigenic epitope. Epitopes usually consist of chemically active surface groupings of molecules such as amino acids or sugar side chains and may, but need not, have specific three-dimensional structural characteristics, as well as specific charge characteristics. Conformational and non-conformational epitopes may be distinguished in that the binding to the former but not the latter is lost in the presence of denaturing solvents.

[0070] As used herein, the term “antibody derivative” is intended to encompass molecules thatbind an epitope as defined herein and which are modifications or derivatives of an antibody of this disclosure. Derivatives include, but are not limited to, for example, bispecific, heterospecific, trispecific, tetraspecific, multispecific antibodies, diabodies, chimeric, recombinant antibodies, - 36 - 116104230Atty Docket No.40574-131 and humanized antibodies. As used herein, the term “bispecific molecule” refers to an antibody that has two different binding specificities. As used herein, the term “multispecific molecule” or “heterospecific molecule” is intended to include any antibody that has more than two different binding specificities. Derivatives also include antibodies of the disclosure comprising mutations and / or modifications intended to, for example, increase thermal stability, proteolytic stability, half- life, solubility, integrate different Fc -effector functions, and / or increase therapeutic efficacy. Examples of such modifications include, but are not limited to, LALA (L234A / L235A), modification (introduction or removal) of glycosylation sites (e.g., N297), GASD / ALIE mutations, YTE mutations, DHS mutations, LS mutations, and enzymatic or chemical addition or removal of glycans. As used herein, a humanized antibody refers to an engineered (i.e., made by human hands) antibody in which at least a portion of an antibody of the disclosure is “inserted” (i.e., by genetic engineering) into an antibody comprising sequences obtained from a human immunoglobulin molecule. For example, an antibody comprising one or more CDRs from an antibody of the present disclosure in a framework region having at least 70%, at least 80%, at least 85%, at least 90%, at least 94%, at least 95%, at least 97%, at least 98%, or at least 99%, sequence identity with a framework region from a human immunoglobulin molecule, would be considered humanized. Similarly, an antibody comprising a variable region of the instant disclosure joined to a constant region having at least 70%, at least 80%, at least 85%, at least 90%, at least 94%, at least 95%, at least 97%, at least 98%, or at least 99%, sequence identity with a corresponding constant region from a human immunoglobulin molecule, would be considered humanized. Techniques for producing humanized antibodies are known to those skilled in the relevant art.

[0071] As used herein, the term “antigen” refers to a compound or complex (e.g., proteincomplex) that elicits an immune response and is specifically bound by the products of the immune response, such as an antibody molecule or a T-cell receptor. Antigens can comprise any type of molecule including, for example, haptens, sugars (e.g., oligosaccharides), lipids, as well as macromolecules such as complex carbohydrates (e.g., polysaccharides), phospholipids, and proteins.

[0072] As used herein, “specifically binds”, “specific binding”, and the like, means that anantibody binds an antigen of interest to the substantial exclusion of binding to other molecules (for example, antibodies and antibody fragments that have a binding constant for the molecule of interest that is at least 103Mc+greater, at least 104Mc+greater, at least 105Mc+, or at least - 37 - 116104230Atty Docket No.40574-131 106Mc+greater than their binding constant for other molecules in a biological sample). As used herein, “binding affinity” refers to the strength of binding (typically non-covalent) between one molecule and a second molecule, such as the strength of binding between an antibody and an antigen. A binding affinity can be measured as a binding constant, which binding affinity for a specific binding pair (such as an antibody / antigen pair) may be at leastat least 1×10c0M, at least 1×10c1M, at least 1×10c2M, at least 1×10c3M, at least 1×10c+*M, at least or at least 1×10c+,M. Methods of determining binding affinity are known to those skilled in the art and include, but are not limited to, the Scatchard method described by Frankel et al., Mol. Immunol., 16:101-106, 1979, determining antigen / antibody dissociation rate, and competition radioimmunoassay.

[0073] As used herein, the term “enterovirus” is used as commonly understood by those in theart and refers to a genus of viruses of the Picornaviridae family. As used herein, “enterovirus” includes both polio and non-polio enteroviruses. Examples of enteroviruses that may be bound, and neutralized, by antibodies of the disclosure include, but are not limited to coxsackievirus A2, A3, A4, A5, A6, A7, A8, A10, A12, A14, A16, enterovirus A71, A76, A89, A90, A91, A92, A144, A119, A120, A121, A122 (simian virus 19), A123 (simian virus 43), A124 (simian virus 46), A125 (baboon enterovirus A13), coxsackievirus B1,2,3,4,5,6; coxsackievirus A9; echovirus 1–33 and enterovirus B69–113; coxsackieviruses A1, A11, A13, A18, A17, 20, A21, A22, A24 and enterovirus C95, C96, C99, C102, C104, C105, C109, C113, C118, enterovirus D68.

[0074] One embodiment of the disclosure is an antibody that specifically binds at least onevirus from the genus enterovirus. In certain aspects, the antibody specifically binds enteroviruses from at least two clades of enterovirus. In certain aspects, the antibody specifically binds enteroviruses from at least three clades of enterovirus. In certain aspects, the antibody specifically binds enteroviruses from at least four clades of enterovirus. In certain aspects, the antibody neutralizes at least one virus from the genus enterovirus. In certain aspects, the antibody neutralizes viruses from at least two clades of enterovirus. In certain aspects, the antibody neutralizes viruses from at least three clades of enterovirus. In certain aspects, the antibody neutralizes one or more enterovirus selected from the group consisting of EV-B1, EV-B3, EV-D68 and EV-A71.

[0075] As used herein, the term “neutralizes” means the antibody blocks or reduces theinfectivity of a virus. “Infectivity” refers to the ability of a virus to enter a host cell, replicate and spread to another host cell. Thus, an antibody of the disclosure may neutralize a virus by interfering - 38 - 116104230Atty Docket No.40574-131 with any step of the replicative cycle. For example, a neutralizing antibody may inhibit binding of the virus to the cell, entry of the virus into the cell, uncoating of the virus, escape of the virus from an endocytic vesicle, replication of the viral genome, formation of new virus particles, and / or release of the virus from the infected cell. In certain aspects, neutralization of infectivity reduces the amount of viral replication by at least 25%, at least 50%, at least 75% or at least 100%. In certain aspects, neutralization of infectivity reduces the amount of viral replication by at least 0.5 x 10-1, at least 10-2, at least 10-3, at least 10-4, at least 10-5, or at least 10-6. In certain aspects, the antibody may neutralize EV-D68, EV-B1, EV-B3, or EV-A2. In certain aspects, the antibody may neutralize EV-D68.

[0076] One embodiment of the disclosure is an antibody that neutralizes EV-D68. In certainaspects, the antibody may be selected from the group consisting of:

[0077] a. an antibody (e.g., EVD2301) in which the specificity determining residues of theantibody interact with at least 8, optionally at least 22, optionally at least 24, optionally at least 26 optionally at least 28, optionally at least 30, optionally at least 31, optionally at least 32, or all, contact residues selected from the group consisting of T30 of the EV-D68 VP1 protein, F31 of the EV-D68 VP1 protein, Y32 of the EV-D68 VP1 protein, Y33 of the EV-D68 VP1 protein, K71 of the EV-D68 VP1 protein, R72 of the EV-D68 VP1 protein, S73 of the EV-D68 VP1 protein, F74 of the EV-D68 VP1 protein, E75 of the EV-D68 VP1 protein, A84 of the EV-D68 VP1 protein, Q85 of the EV-D68 VP1 protein, T86 of the EV-D68 VP1 protein, D87 of the EV-D68 VP1 protein, T95 of the EV-D68 VP1 protein, S99 of the EV-D68 VP1 protein, F100 of the EV-D68 VP1 protein, N128 of the EV-D68 VP1 protein, G129 of the EV-D68 VP1 protein, T234 of the EV-D68 VP1 protein, Y259 of the EV-D68 VP1 protein, M260 of the EV-D68 VP1 protein, K268of the EV-D68 VP1 protein, E52 of the EV-D68 VP2 protein, A106 of the EV-D68 VP2 protein,Y107, of the EV-D68 VP2 protein, Y33 of the EV-D68 VP3 protein, and Y93 of the EV-D68 VP3 protein, I236 of the EV-D68 VP3 protein, D237 of the EV-D68 VP3 protein, H238 of the EV-D68 VP3 protein, L239 of the EV-D68 VP3 protein, H240 of the EV-D68 VP3 protein, A242 of the EV-D68 VP3 protein, E243 of the EV-D68 VP3 protein, and Y246 of the EV-D68 VP3 protein; and

[0078] b. an antibody (e.g., EVD2303) in which the specificity determining residues of theantibody interact with at least 10, optionally at least 25, optionally at least 27, optionally at least 30 optionally at least 31, optionally at least 32, optionally at least 33, optionally at least 34, or all, - 39 - 116104230Atty Docket No.40574-131 contact residues selected from the group consisting of R72 of the EV-D68 Vp1 protein, K268 of the EV-D68 VP1 protein, G269 of the EV-D68 VP1 protein, K270 of the EV-D68 VP1 protein, E271 of the EV-D68 VP1 protein, R272 of the EV-D68 VP1 protein, A273 of the EV-D68 VP1 protein, P274 of the EV-D68 VP1 protein, A276 of the EV-D68 VP1 protein, L277 of the EV-D68 VP1 protein, N278 of the EV-D68 VP1 protein, A279 of the EV-D68 VP1 protein, H135 of theEV-D68 VP2 protein, N136 of the EV-D68 VP2 protein, T138 of the EV-D68 VP2 protein, H157of the EV-D68 VP2 protein, E59 of the EV-D68 VP3 protein, S60 of the EV-D68 VP3 protein, A61 of the EV-D68 VP3 protein, V62 of the EV-D68 VP3 protein, R104 of the EV-D68 VP3 protein, P231 of the EV-D68 VP3 protein, D232 of the EV-D68 VP3 protein, I233 of the EV-D68 VP3 protein, G234 of the EV-D68 VP3 protein, Q235 of the EV-D68 VP3 protein, I236 of the EV-D68 VP3 protein, D237 of the EV-D68 VP3 protein, H238 of the EV-D68 VP3 protein, L239 of the EV-D68 VP3 protein, H240 of the EV-D68 VP3 protein, G241 of the EV-D68 VP3 protein, and E243 of the EV-D68 VP3 protein.

[0079] One embodiment of the disclosure is an antibody selected from the group consistingof:

[0080] a. an antibody (e.g., EVD2301) in which the specificity determining residues of theheavy chain interact with at least 20, optionally at least 22, optionally at least 24, optionally at least 26, or optionally all, contact residues selected from the group consisting of K71 of the EV-D68 VP1 protein, R72 of the EV-D68 VP1 protein, S73 of the EV-D68 VP1 protein, F74 of the EV- D68 VP1 protein, E75 of the EV-D68 VP1 protein, A84 of the EV-D68 VP1 protein, Q85 of the EV-D68 VP1 protein, T86 of the EV-D68 VP1 protein, D87 of the EV-D68 VP1 protein, S99 of the EV-D68 VP1 protein, F100 of the EV-D68 VP1 protein, N128 of the EV-D68 VP1 protein, G129 of the EV-D68 VP1 protein, T234 of the EV-D68 VP1 protein, Y259 of the EV-D68 VP1 protein, M260 of the EV-D68 VP1 protein, K268 of the EV-D68 VP1 protein, A106 of the EV- D68 VP2 protein, Y107, of the EV-D68 VP2 protein, I236 of the EV-D68 VP3 protein, D237 of the EV-D68 VP3 protein, H238 of the EV-D68 VP3 protein, L239 of the EV-D68 VP3 protein, H240 of the EV-D68 VP3 protein, A242 of the EV-D68 VP3 protein, E243 of the EV-D68 VP3 protein, and Y246 of the EV-D68 VP3 protein;

[0081] b. an antibody (e.g., EVD2301) in which the specificity determining residues of thelight chain interact with at least 5, optionally at least 6, optionally at least 7, or optionally all, contact residues selected from the group consisting of T30 of the EV-D68 VP1 protein, F31 of the - 40 - 116104230Atty Docket No.40574-131 EV-D68 VP1 protein, Y32 of the EV-D68 VP1 protein, Y33 of the EV-D68 VP1 protein, T95 of the EV-D68 VP1 protein, E52 of the EV-D68 VP2 protein, Y33 of the EV-D68 VP3 protein, and Y93 of the EV-D68 VP3 protein;

[0082] c. an antibody (e.g., EVD2303) in which the specificity determining residues of theheavy chain interact with at least 18, optionally at least 20, optionally at least 21, optionally at least 22, optionally at least 23, optionally at least 24, or optionally all, contact residues selected from the group consisting of K268 of the EV-D68 VP1 protein, G269 of the EV-D68 VP1 protein, K270 of the EV-D68 VP1 protein, E271 of the EV-D68 VP1 protein, R272 of the EV-D68 VP1 protein, A273 of the EV-D68 VP1 protein, P274 of the EV-D68 VP1 protein, A276 of the EV-D68 VP1 protein, L277 of the EV-D68 VP1 protein, N278 of the EV-D68 VP1 protein, A279 of the EV- D68 VP1 protein, H135 of the EV-D68 VP2 protein, N136 of the EV-D68 VP2 protein, H157 of the EV-D68 VP2 protein, E59 of the EV-D68 VP3 protein, S60 of the EV-D68 VP3 protein, A61 of the EV-D68 VP3 protein, V62 of the EV-D68 VP3 protein, R104 of the EV-D68 VP3 protein, P231 of the EV-D68 VP3 protein, D232 of the EV-D68 VP3 protein, I233 of the EV-D68 VP3 protein, G234 of the EV-D68 VP3 protein, Q235 of the EV-D68 VP3 protein, and I236 of the EV- D68 VP3 protein; and

[0083] d. an antibody (e.g., EVD2303) in which the specificity determining residues of thelight chain interact with at least 6, optionally at least 7, optionally at least 8, optionally at least 8, or optionally all, contact residues selected from the group consisting of R72 of the EV-D68 VP1 protein, K268 of the EV-D68 VP1 protein, T138 of the EV-D68 VP2 protein I236, D237 of the EV-D68 VP3 protein, H238 of the EV-D68 VP3 protein, L239 of the EV-D68 VP3 protein, H240 of the EV-D68 VP3 protein, G241 of the EV-D68 VP3 protein, and E243 of the EV-D68 VP3 protein.

[0084] One embodiment of the disclosure is an antibody selected from the group consistingof:

[0085] a. an antibody comprising a heavy chain variable region and a light chain variableregion (e.g., EVD2301), wherein the specificity determining residues of the heavy chain interact with at least 20, optionally at least 22, optionally at least 24, optionally at least 26, or all, contact residues selected from the group consisting of K71 of the EV-D68 VP1 protein, R72 of the EV- D68 VP1 protein, S73 of the EV-D68 VP1 protein, F74 of the EV-D68 VP1 protein, E75 of the EV-D68 VP1 protein, A84 of the EV-D68 VP1 protein, Q85 of the EV-D68 VP1 protein, T86 of - 41 - 116104230Atty Docket No.40574-131 the EV-D68 VP1 protein, D87 of the EV-D68 VP1 protein, S99 of the EV-D68 VP1 protein, F100 of the EV-D68 VP1 protein, N128 of the EV-D68 VP1 protein, G129 of the EV-D68 VP1 protein, T234 of the EV-D68 VP1 protein, Y259 of the EV-D68 VP1 protein, M260 of the EV-D68 VP1 protein, K268 of the EV-D68 VP1 protein, A106 of the EV-D68 VP2 protein, Y107, of the EV- D68 VP2 protein, I236 of the EV-D68 VP3 protein, D237 of the EV-D68 VP3 protein, H238 of the EV-D68 VP3 protein, L239 of the EV-D68 VP3 protein, H240 of the EV-D68 VP3 protein, A242 of the EV-D68 VP3 protein, E243 of the EV-D68 VP3 protein, and Y246 of the EV-D68 VP3 protein; and

[0086] wherein the specificity determining residues of the light chain interact with at least 5,optionally at least 6, optionally at least 7, or all, contact residues selected from the group consisting of T30 of the EV-D68 VP1 protein, F31 of the EV-D68 VP1 protein, Y32 of the EV-D68 VP1 protein, Y33 of the EV-D68 VP1 protein, T95 of the EV-D68 VP1 protein, E52 of the EV-D68 VP2 protein, Y33 of the EV-D68 VP3 protein, and Y93 of the EV-D68 VP3 protein; and

[0087] b. an antibody comprising a heavy chain variable region and a light chain variableregion (e.g., EVD2303), wherein the specificity determining residues of the heavy chain variable region interact with at least 18, optionally at least 20, optionally at least 21, optionally at least 22, optionally at least 23, optionally at least 24, or all, contact residues selected from the group consisting of K268 of the EV-D68 VP1 protein, G269 of the EV-D68 VP1 protein, K270 of the EV-D68 VP1 protein, E271 of the EV-D68 VP1 protein, R272 of the EV-D68 VP1 protein, A273 of the EV-D68 VP1 protein, P274 of the EV-D68 VP1 protein, A276 of the EV-D68 VP1 protein, L277 of the EV-D68 VP1 protein, N278 of the EV-D68 VP1 protein, A279 of the EV-D68 VP1 protein, H135 of the EV-D68 VP2 protein, N136 of the EV-D68 VP2 protein, H157 of the EV- D68 VP2 protein, E59 of the EV-D68 VP3 protein, S60 of the EV-D68 VP3 protein, A61 of the EV-D68 VP3 protein, V62 of the EV-D68 VP3 protein, R104 of the EV-D68 VP3 protein, P231 of the EV-D68 VP3 protein, D232 of the EV-D68 VP3 protein, I233 of the EV-D68 VP3 protein, G234 of the EV-D68 VP3 protein, Q235 of the EV-D68 VP3 protein, and I236 of the EV-D68 VP3 protein; and

[0088] wherein the specificity determining residues of the light chain variable region interactwith at least 6, optionally at least 7, optionally at least 8, optionally at least 8, or all, contact residues selected from the group consisting of R72 of the EV-D68 VP1 protein, K268 of the EV-D68 VP1 protein, T138 of the EV-D68 VP2 protein I236, D237 of the EV-D68 VP3 protein, H238 of the - 42 - 116104230Atty Docket No.40574-131 EV-D68 VP3 protein, L239 of the EV-D68 VP3 protein, H240 of the EV-D68 VP3 protein, G241 of the EV-D68 VP3 protein, and E243 of the EV-D68 VP3 protein.

[0089] In certain aspects, the antibody interacts with the recited contact residues in the VP1(SEQ ID NO:121), VP2 (SEQ ID NO:122) and / or VP3 (SEQ ID NO:123) protein when the VP1, VP2 and / or the VP3 proteins are present in an enterovirus particle or an enterovirus-like particle.

[0090] One embodiment of the disclosure is an antibody comprising antibody-matchedsequences from Table 1.

[0091] Table 1. Sequences of antibodies disclosed herein- 43 - 116104230Atty Docket No.40574-131- 44 - 116104230Atty Docket No.40574-131- 45 - 116104230Atty Docket No.40574-131- 46 - 116104230Atty Docket No.40574-131- 47 - 116104230Atty Docket No.40574-131- 48 - 116104230Atty Docket No.40574-131- 49 - 116104230Atty Docket No.40574-131- 50 - 116104230Atty Docket No.40574-131- 51 - 116104230Atty Docket No.40574-131- 52 - 116104230Atty Docket No.40574-131- 53 - 116104230Atty Docket No.40574-131- 54 - 116104230Atty Docket No.40574-131- 55 - 116104230Atty Docket No.40574-131- 56 - 116104230Atty Docket No.40574-131

[0092] Table 2. Sequences of additional antibodies disclosed herein- 57 - 116104230Atty Docket No.40574-131- 58 - 116104230Atty Docket No.40574-131- 59 - 116104230Atty Docket No.40574-131- 60 - 116104230Atty Docket No.40574-131- 61 - 116104230Atty Docket No.40574-131- 62 - 116104230Atty Docket No.40574-131- 63 - 116104230Atty Docket No.40574-131- 64 - 116104230Atty Docket No.40574-131- 65 - 116104230Atty Docket No.40574-131- 66 - 116104230Atty Docket No.40574-131- 67 - 116104230Atty Docket No.40574-131- 68 - 116104230Atty Docket No.40574-131- 69 - 116104230Atty Docket No.40574-131- 70 - 116104230Atty Docket No.40574-131- 71 - 116104230Atty Docket No.40574-131- 72 - 116104230Atty Docket No.40574-131- 73 - 116104230Atty Docket No.40574-131- 74 - 116104230Atty Docket No.40574-131- 75 - 116104230Atty Docket No.40574-131- 76 - 116104230Atty Docket No.40574-131- 77 - 116104230Atty Docket No.40574-131- 78 - 116104230Atty Docket No.40574-131- 79 - 116104230Atty Docket No.40574-131- 80 - 116104230Atty Docket No.40574-131- 81 - 116104230Atty Docket No.40574-131- 82 - 116104230Atty Docket No.40574-131- 83 - 116104230Atty Docket No.40574-131

[0093] As used herein, “antibody-matched”’ means that sequences that are from the sameantibody. For example, in Table 1 above, SEQ ID NOs:1-10 represent sequences of various - 84 - 116104230Atty Docket No.40574-131 portions of antibody EV2301. Any such sequences, e.g., SEQ ID NO:1 and SEQ ID NO:6, would be considered antibody-matches, as would SEQ ID NOS: 1-3, 3 and 4, etc.

[0094] One embodiment of the disclosure is an antibody, or an antigen-binding fragmentthereof, comprising one or more heavy chain CDRs, and / or one or more light chain CDRs, from Table 1. In certain aspects, the antibody, or antigen-binding fragment thereof, comprises one or more heavy chain CDRs, and one or more antibody-matched light chain CDRs, from Table 1. In certain aspects, the antibody, or antigen-binding fragment thereof, comprises heavy and light chains comprising amino acid sequences at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to antibody-matched, heavy and light chain variable region sequences from Table 1. In certain aspects, the antibody, or antigen-binding fragment thereof, comprises heavy and light chains comprising amino acid sequences at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to antibody-matched, heavy and light chain sequences from Table 1. In certain aspects, the antibody, or antigen-binding fragment thereof, comprises heavy and light chains comprising amino acid sequences at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to antibody-matched, heavy and light chain sequences from Table 1, wherein the heavy chain comprises antibody- matched VHCDR1, VHCDR2, and VHCDR3 sequences from Table 1 and wherein the light chain comprise antibody-matched VLCDR1, VLCDR2, and VLCDR3 sequences from Table 1. In certain aspects, the antibody is selected from the group of antibodies consisting of EVD2301 (aka, 1E11), 2302, 2303 (aka, 5H03), 2304, 2305, 2306, 2307, 2308, 2309, 2310, 2311, and 2312, comprising the sequences defined in Table 1.

[0095] In certain aspects, the antibody may comprise a VH CDR3 selected from the groupconsisting of: a VH CDR3 comprising or consisting of SEQ ID NO:3, a VH CDR3 comprising or consisting of SEQ ID NO:13, a VH CDR3 comprising or consisting of SEQ ID NO:23, a VH CDR3 comprising or consisting of SEQ ID NO:33, a VHCDR3 comprising or consisting of SEQ ID NO:43, a VHCDR3 comprising or consisting of SEQ ID NO:53, a VHCDR3 comprising or consisting of SEQ ID NO:63, a VHCDR3 comprising or consisting of SEQ ID NO:73, a VHCDR3 comprising or consisting of SEQ ID NO:83, a VHCDR3 comprising or consisting of SEQ ID - 85 - 116104230Atty Docket No.40574-131 NO:93, a VH CDR3 comprising or consisting of SEQ ID NO:103, and a VH CDR3 comprising or consisting of SEQ ID NO:113.

[0096] In certain aspects, the antibody may comprise a VL CDR3 selected from the groupconsisting of: a VL CDR3 comprising or consisting of SEQ ID NO:8, a VL CDR3 comprising or consisting of SEQ ID NO:18, a VLCDR3 comprising or consisting of SEQ ID NO:28, a VLCDR3 comprising or consisting of SEQ ID NO:38, a VLCDR3 comprising or consisting of SEQ ID NO:48, a VLCDR3 comprising or consisting of SEQ ID NO:58, a VLCDR3 comprising or consisting of SEQ ID NO:68, a VLCDR3 comprising or consisting of SEQ ID NO:78, a VLCDR3 comprising or consisting of SEQ ID NO:88, a VL CDR3 comprising or consisting of SEQ ID NO:98, a VL CDR3 comprising or consisting of SEQ ID NO:108, and a VL CDR3 comprising or consisting of SEQ ID NO:118.

[0097] In certain aspects, the antibody may comprise a VH CDR3 and a VL CDR3. In certainaspects, the VHCDR3 may comprise or consist of SEQ ID NO:3 and the VLCDR3 may comprise or consist of SEQ ID NO:8. In certain aspects, the VHCDR3 may comprise or consist of SEQ ID NO:13 and the VLCDR3 may comprise or consist of SEQ ID NO:18. In certain aspects, the VH CDR3 may comprise or consist of SEQ ID NO:23 and the VL CDR3 may comprise or consist of SEQ ID NO:28. In certain aspects, the VH CDR3 may comprise or consist of SEQ ID NO:33 and the VL CDR3 may comprise or consist of SEQ ID NO:38. In certain aspects, the VH CDR3 may comprise or consist of SEQ ID NO:43 and the VL CDR3 may comprise or consist of SEQ ID NO:48. In certain aspects, the VHCDR3 may comprise or consist of SEQ ID NO:53 and the VLCDR3 may comprise or consist of SEQ ID NO:58. In certain aspects, the VHCDR3 may comprise or consist of SEQ ID NO:63 and the VLCDR3 may comprise or consist of SEQ ID NO:68. In certain aspects, the VH CDR3 may comprise or consist of SEQ ID NO:73 and the VL CDR3 may comprise or consist of SEQ ID NO:78. In certain aspects, the VH CDR3 may comprise or consist of SEQ ID NO:83 and the VL CDR3 may comprise or consist of SEQ ID NO:88. In certain aspects, the VH CDR3 may comprise or consist of SEQ ID NO:93 and the VLCDR3 may comprise or consist of SEQ ID NO:98. In certain aspects, the VHCDR3 may comprise or consist of SEQ ID NO:103 and the VLCDR3 may comprise or consist of SEQ ID NO:108. In certain aspects, the VHCDR3 may comprise or consist of SEQ ID NO:113 and the VLCDR3 may comprise or consist of SEQ ID NO:118. - 86 - 116104230Atty Docket No.40574-131

[0098] In certain aspects, the antibody may comprise a VH CDR3 and a VH CDR2. In certainaspects, the VH CDR3 may comprise or consist of SEQ ID NO:3 and the VH CDR2 may comprise or consist of SEQ ID NO:2. In certain aspects, the VH CDR3 may comprise or consist of SEQ ID NO:13 and the VH CDR2 may comprise or consist of SEQ ID NO:12. In certain aspects, the VHCDR3 may comprise or consist of SEQ ID NO:23 and the VHCDR2 may comprise or consist of SEQ ID NO:22. In certain aspects, the VHCDR3 may comprise or consist of SEQ ID NO:33 and the VHCDR2 may comprise or consist of SEQ ID NO:32. In certain aspects, the VHCDR3 may comprise or consist of SEQ ID NO:43 and the VHCDR2 may comprise or consist of SEQ ID NO:42. In certain aspects, the VH CDR3 may comprise or consist of SEQ ID NO:53 and the VH CDR2 may comprise or consist of SEQ ID NO:52. In certain aspects, the VH CDR3 may comprise or consist of SEQ ID NO:63 and the VH CDR2 may comprise or consist of SEQ ID NO:62. In certain aspects, the VH CDR3 may comprise or consist of SEQ ID NO:73 and the VHCDR2 may comprise or consist of SEQ ID NO:72. In certain aspects, the VHCDR3 may comprise or consist of SEQ ID NO:83 and the VHCDR2 may comprise or consist of SEQ ID NO:82. In certain aspects, the VHCDR3 may comprise or consist of SEQ ID NO:93 and the VH CDR2 may comprise or consist of SEQ ID NO:92. In certain aspects, the VH CDR3 may comprise or consist of SEQ ID NO:103 and the VH CDR2 may comprise or consist of SEQ ID NO:102. In certain aspects, the VH CDR3 may comprise or consist of SEQ ID NO:113 and the VH CDR2 may comprise or consist of SEQ ID NO:112.

[0099] In certain aspects, the antibody may comprise a VL CDR3 and a VL CDR2. In certainaspects, the VLCDR3 may comprise or consist of SEQ ID NO:8 and the VLCDR2 may comprise or consist of SEQ ID NO:7. In certain aspects, the VLCDR3 may comprise or consist of SEQ ID NO:18 and the VL CDR2 may comprise or consist of SEQ ID NO:17. In certain aspects, the VL CDR3 may comprise or consist of SEQ ID NO:28 and the VL CDR2 may comprise or consist of SEQ ID NO:27. In certain aspects, the VL CDR3 may comprise or consist of SEQ ID NO:38 and the VL CDR2 may comprise or consist of SEQ ID NO:37. In certain aspects, the VL CDR3 may comprise or consist of SEQ ID NO:48 and the VLCDR2 may comprise or consist of SEQ ID NO:47. In certain aspects, the VLCDR3 may comprise or consist of SEQ ID NO:58 and the VLCDR2 may comprise or consist of SEQ ID NO:57. In certain aspects, the VLCDR3 may comprise or consist of SEQ ID NO:68 and the VLCDR2 may comprise or consist of SEQ ID NO:67. In certain aspects, the VL CDR3 may comprise or consist of SEQ ID NO:78 and the - 87 - 116104230Atty Docket No.40574-131 VL CDR2 may comprise or consist of SEQ ID NO:77. In certain aspects, the VL CDR3 may comprise or consist of SEQ ID NO:88 and the VL CDR2 may comprise or consist of SEQ ID NO:87. In certain aspects, the VL CDR3 may comprise or consist of SEQ ID NO:98 and the VL CDR2 may comprise or consist of SEQ ID NO:97. In certain aspects, the VL CDR3 may comprise or consist of SEQ ID NO:108 and the VLCDR2 may comprise or consist of SEQ ID NO:107. In certain aspects, the VLCDR3 may comprise or consist of SEQ ID NO:118 and the VLCDR2 may comprise or consist of SEQ ID NO:117.

[0100] In certain aspects, the antibody may comprise a VH CDR1, a VH CDR2, and a VH CDR3.In certain aspects, the VH CDR1 may comprise or consist of SEQ ID NO:1, the VH CDR2 may comprise or consist of SEQ ID NO:2, and the VH CDR3 may comprise or consist of SEQ ID NO:3. In certain aspects, the VH CDR1 may comprise or consist of SEQ ID NO:11, the VH CDR2 may comprise or consist of SEQ ID NO:12, and the VH CDR3 may comprise or consist of SEQ ID NO1:3. In certain aspects, the VHCDR1 may comprise or consist of SEQ ID NO:21, the VHCDR2 may comprise or consist of SEQ ID NO:22, and the VHCDR3 may comprise or consist of SEQ ID NO:23. In certain aspects, the VHCDR1 may comprise or consist of SEQ ID NO:31, the VHCDR2 may comprise or consist of SEQ ID NO:32, and the VH CDR3 may comprise or consist of SEQ ID NO:33. In certain aspects, the VH CDR1 may comprise or consist of SEQ ID NO:41, the VH CDR2 may comprise or consist of SEQ ID NO:42, and the VH CDR3 may comprise or consist of SEQ ID NO:43. In certain aspects, the VH CDR1 may comprise or consist of SEQ ID NO:51, the VH CDR2 may comprise or consist of SEQ ID NO:52, and the VHCDR3 may comprise or consist of SEQ ID NO:53. In certain aspects, the VHCDR1 may comprise or consist of SEQ ID NO:61, the VHCDR2 may comprise or consist of SEQ ID NO:62, and the VHCDR3 may comprise or consist of SEQ ID NO:63. In certain aspects, the VH CDR1 may comprise or consist of SEQ ID NO:71, the VH CDR2 may comprise or consist of SEQ ID NO:72, and the VH CDR3 may comprise or consist of SEQ ID NO:73. In certain aspects, the VH CDR1 may comprise or consist of SEQ ID NO:81, the VH CDR2 may comprise or consist of SEQ ID NO:82, and the VH CDR3 may comprise or consist of SEQ ID NO:83. In certain aspects, the VHCDR1 may comprise or consist of SEQ ID NO:91, the VHCDR2 may comprise or consist of SEQ ID NO:92, and the VHCDR3 may comprise or consist of SEQ ID NO:93. In certain aspects, the VHCDR1 may comprise or consist of SEQ ID NO:101, the VHCDR2 may comprise or consist of SEQ ID NO:102, and the VHCDR3 may comprise or consist of SEQ ID NO:103. In certain aspects, the VH CDR1 may comprise or consist of SEQ ID NO:111, - 88 - 116104230Atty Docket No.40574-131 the VH CDR2 may comprise or consist of SEQ ID NO:112, and the VH CDR3 may comprise or consist of SEQ ID NO:113.

[0101] In certain aspects, the antibody may comprise a VL CDR1, a VL CDR2, and aVL CDR3. In certain aspects, the VL CDR1 may comprise or consist of SEQ ID NO:6, the VLCDR2 may comprise or consist of SEQ ID NO:7, and the VLCDR3 may comprise or consist of SEQ ID NO:8. In certain aspects, the VLCDR1 may comprise or consist of SEQ ID NO:16, the VLCDR2 may comprise or consist of SEQ ID NO:17, and the VLCDR3 may comprise or consist of SEQ ID NO:18. In certain aspects, the VLCDR1 may comprise or consist of SEQ ID NO:26, the VLCDR2 may comprise or consist of SEQ ID NO:27, and the VL CDR3 may comprise or consist of SEQ ID NO:28. In certain aspects, the VL CDR1 may comprise or consist of SEQ ID NO:36, the VLCDR2 may comprise or consist of SEQ ID NO:37, and the VL CDR3 may comprise or consist of SEQ ID NO:38. In certain aspects, the VL CDR1 may comprise or consist of SEQ ID NO:46, the VLCDR2 may comprise or consist of SEQ ID NO:47, and the VLCDR3 may comprise or consist of SEQ ID NO:48. In certain aspects, the VLCDR1 may comprise or consist of SEQ ID NO:56, the VLCDR2 may comprise or consist of SEQ ID NO:57, and the VLCDR3 may comprise or consist of SEQ ID NO:58. In certain aspects, the VL CDR1 may comprise or consist of SEQ ID NO:66, the VLCDR2 may comprise or consist of SEQ ID NO:67, and the VL CDR3 may comprise or consist of SEQ ID NO:68. In certain aspects, the VL CDR1 may comprise or consist of SEQ ID NO:76, the VLCDR2 may comprise or consist of SEQ ID NO:77, and the VL CDR3 may comprise or consist of SEQ ID NO:78. In certain aspects, the VLCDR1 may comprise or consist of SEQ ID NO:86, the VLCDR2 may comprise or consist of SEQ ID NO:87, and the VLCDR3 may comprise or consist of SEQ ID NO:88. In certain aspects, the VLCDR1 may comprise or consist of SEQ ID NO:96, the VLCDR2 may comprise or consist of SEQ ID NO:97, and the VL CDR3 may comprise or consist of SEQ ID NO:98. In certain aspects, the VL CDR1 may comprise or consist of SEQ ID NO:106, the VLCDR2 may comprise or consist of SEQ ID NO:107, and the VL CDR3 may comprise or consist of SEQ ID NO:108. In certain aspects, the VL CDR1 may comprise or consist of SEQ ID NO:116, the VLCDR2 may comprise or consist of SEQ ID NO:117, and the VLCDR3 may comprise or consist of SEQ ID NO:118.

[0102] In certain aspects, the antibody may comprise a VH CDR1, a VH CDR2, VH CDR3, aVLCDR1, a VLCDR2, and a VLCDR3. In certain aspects, the VHCDR1 may comprise or consist of SEQ ID NO:1, the VHCDR2 may comprise or consist of SEQ ID NO:2, the VH CDR3 may - 89 - 116104230Atty Docket No.40574-131 comprise or consist of SEQ ID NO:3, the VL CDR1 may comprise or consist of SEQ ID NO:6, the VL CDR2 may comprise or consist of SEQ ID NO:7, and the VL CDR3 may comprise or consist of SEQ ID NO:8. In certain aspects, the VH CDR1 may comprise or consist of SEQ ID NO:11, the VHCDR2 may comprise or consist of SEQ ID NO:12, the VH CDR3 may comprise or consist of SEQ ID NO:13, the VLCDR1 may comprise or consist of SEQ ID NO:16, the VLCDR2 may comprise or consist of SEQ ID NO:17, and the VLCDR3 may comprise or consist of SEQ ID NO:18. In certain aspects, the VHCDR1 may comprise or consist of SEQ ID NO:21, the VHCDR2 may comprise or consist of SEQ ID NO:22, the VHCDR3 may comprise or consist of SEQ ID NO:23, the VL CDR1 may comprise or consist of SEQ ID NO:26, the VL CDR2 may comprise or consist of SEQ ID NO:27, and the VL CDR3 may comprise or consist of SEQ ID NO:28. In certain aspects, the VH CDR1 may comprise or consist of SEQ ID NO:31, the VHCDR2 may comprise or consist of SEQ ID NO:32, the VH CDR3 may comprise or consist of SEQ ID NO:33, the VL CDR1 may comprise or consist of SEQ ID NO:36, the VLCDR2 may comprise or consist of SEQ ID NO:37, and the VLCDR3 may comprise or consist of SEQ ID NO:38. In certain aspects, the VHCDR1 may comprise or consist of SEQ ID NO:41, the VHCDR2 may comprise or consist of SEQ ID NO:42, the VH CDR3 may comprise or consist of SEQ ID NO:43, the VL CDR1 may comprise or consist of SEQ ID NO:46, the VL CDR2 may comprise or consist of SEQ ID NO:47, and the VL CDR3 may comprise or consist of SEQ ID NO:48. In certain aspects, the VH CDR1 may comprise or consist of SEQ ID NO:51, the VHCDR2 may comprise or consist of SEQ ID NO:52, the VHCDR3 may comprise or consist of SEQ ID NO:53, the VLCDR1 may comprise or consist of SEQ ID NO:56, the VLCDR2 may comprise or consist of SEQ ID NO:57, and the VLCDR3 may comprise or consist of SEQ ID NO:58. In certain aspects, the VHCDR1 may comprise or consist of SEQ ID NO:61, the VHCDR2 may comprise or consist of SEQ ID NO:62, the VH CDR3 may comprise or consist of SEQ ID NO:63, the VL CDR1 may comprise or consist of SEQ ID NO:66, the VL CDR2 may comprise or consist of SEQ ID NO:67, and the VL CDR3 may comprise or consist of SEQ ID NO:68. In certain aspects, the VH CDR1 may comprise or consist of SEQ ID NO:71, the VHCDR2 may comprise or consist of SEQ ID NO:72, the VHCDR3 may comprise or consist of SEQ ID NO:73, the VLCDR1 may comprise or consist of SEQ ID NO:76, the VLCDR2 may comprise or consist of SEQ ID NO:77, and the VLCDR3 may comprise or consist of SEQ ID NO:78. In certain aspects, the VHCDR1 may comprise or consist of SEQ ID NO:81, the VHCDR2 may comprise or consist of SEQ ID NO:82, the VH CDR3 may comprise or - 90 - 116104230Atty Docket No.40574-131 consist of SEQ ID NO:83, the VL CDR1 may comprise or consist of SEQ ID NO:86, the VL CDR2 may comprise or consist of SEQ ID NO:87, and the VL CDR3 may comprise or consist of SEQ ID NO:88. In certain aspects, the VH CDR1 may comprise or consist of SEQ ID NO:91, the VHCDR2 may comprise or consist of SEQ ID NO:92, the VH CDR3 may comprise or consist of SEQ ID NO:93, the VLCDR1 may comprise or consist of SEQ ID NO:96, the VLCDR2 may comprise or consist of SEQ ID NO:97, and the VLCDR3 may comprise or consist of SEQ ID NO:98. In certain aspects, the VHCDR1 may comprise or consist of SEQ ID NO:101, the VHCDR2 may comprise or consist of SEQ ID NO:102, the VHCDR3 may comprise or consist of SEQ ID NO:103, the VL CDR1 may comprise or consist of SEQ ID NO:106, the VL CDR2 may comprise or consist of SEQ ID NO:107, and the VL CDR3 may comprise or consist of SEQ ID NO:108. In certain aspects, the VH CDR1 may comprise or consist of SEQ ID NO:111, the VHCDR2 may comprise or consist of SEQ ID NO:112, the VH CDR3 may comprise or consist of SEQ ID NO:113, the VL CDR1 may comprise or consist of SEQ ID NO:116, the VLCDR2 may comprise or consist of SEQ ID NO:117, and the VLCDR3 may comprise or consist of SEQ ID NO:118.

[0103] In certain aspects, the antibody may comprise a heavy chain variable region thatcomprises an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical to SEQ ID NO:4, 14, 24, 34, 44, 54, 64, 74, 84, 94, 104, and 114, wherein the antibody may comprise one or more antibody-matched heavy chain CDRs from Table 1.

[0104] In certain aspects, the antibody may comprise a heavy chain variable region selectedfrom the group consisting of:

[0105] a heavy chain variable region comprising or consisting of an amino acid sequence atleast 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:4, wherein the heavy chain variable region comprises VH CDR1 comprising or consisting of SEQ ID NO:1, VH CDR2 comprising or consisting of SEQ ID NO:2, and VH CDR3 comprising or consisting of SEQ ID NO:3;

[0106] a heavy chain variable region comprising or consisting of an amino acid sequence atleast 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:14, wherein the heavy chain variable region comprises VH CDR1 comprising or consisting of SEQ ID NO:11, VH CDR2 - 91 - 116104230Atty Docket No.40574-131 comprising or consisting of SEQ ID NO:12, and VH CDR3 comprising or consisting of SEQ ID NO:13;

[0107] a heavy chain variable region comprising or consisting of an amino acid sequence atleast 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:24, wherein the heavy chain variable region comprises VHCDR1 comprising or consisting of SEQ ID NO:21, VHCDR2 comprising or consisting of SEQ ID NO:22, and VHCDR3 comprising or consisting of SEQ ID NO:23;

[0108] a heavy chain variable region comprising or consisting of an amino acid sequence atleast 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:34, wherein the heavy chain variable region comprises VH CDR1 comprising or consisting of SEQ ID NO:31, VH CDR2 comprising or consisting of SEQ ID NO:32, and VHCDR3 comprising or consisting of SEQ ID NO:33;

[0109] a heavy chain variable region comprising or consisting of an amino acid sequence atleast 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:44, wherein the heavy chain variable region comprises VH CDR1 comprising or consisting of SEQ ID NO:41, VH CDR2 comprising or consisting of SEQ ID NO:42, and VH CDR3 comprising or consisting of SEQ ID NO:43;

[0110] a heavy chain variable region comprising or consisting of an amino acid sequence atleast 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:54, wherein the heavy chain variable region comprises VH CDR1 comprising or consisting of SEQ ID NO:51, VH CDR2 comprising or consisting of SEQ ID NO:52, and VH CDR3 comprising or consisting of SEQ ID NO:53;

[0111] a heavy chain variable region comprising or consisting of an amino acid sequence atleast 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:64, wherein the heavy chain variable region comprises VHCDR1 comprising or consisting of SEQ ID NO:61, VHCDR2 - 92 - 116104230Atty Docket No.40574-131 comprising or consisting of SEQ ID NO:62, and VH CDR3 comprising or consisting of SEQ ID NO:63;

[0112] a heavy chain variable region comprising or consisting of an amino acid sequence atleast 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:74, wherein the heavy chain variable region comprises VHCDR1 comprising or consisting of SEQ ID NO:71, VHCDR2 comprising or consisting of SEQ ID NO:72, and VHCDR3 comprising or consisting of SEQ ID NO:73;

[0113] a heavy chain variable region comprising or consisting of an amino acid sequence atleast 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:84, wherein the heavy chain variable region comprises VH CDR1 comprising or consisting of SEQ ID NO:81, VH CDR2 comprising or consisting of SEQ ID NO:82, and VHCDR3 comprising or consisting of SEQ ID NO:83;

[0114] a heavy chain variable region comprising or consisting of an amino acid sequence atleast 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:94, wherein the heavy chain variable region comprises VH CDR1 comprising or consisting of SEQ ID NO:91, VH CDR2 comprising or consisting of SEQ ID NO:92, and VH CDR3 comprising or consisting of SEQ ID NO:93;

[0115] a heavy chain variable region comprising or consisting of an amino acid sequence atleast 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:104, wherein the heavy chain variable region comprises VH CDR1 comprising or consisting of SEQ ID NO:101, VH CDR2 comprising or consisting of SEQ ID NO:102, and VH CDR3 comprising or consisting of SEQ ID NO:103; and

[0116] a heavy chain variable region comprising or consisting of an amino acid sequence atleast 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:114, wherein the heavy chain variable region comprises VHCDR1 comprising or consisting of SEQ ID NO:111, VHCDR2 - 93 - 116104230Atty Docket No.40574-131 comprising or consisting of SEQ ID NO:112, and VH CDR3 comprising or consisting of SEQ ID NO:113.

[0117] In certain aspects, the antibody may comprise a light chain variable region comprisingan amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical to SEQ ID NO: 9, 19, 29, 39, 49, 59, 69, 79, 89, 99, 109, or 119.

[0118] In certain aspects, the antibody may comprise a light chain variable region selectedfrom the group consisting of:

[0119] a light chain variable region comprising an amino acid sequence at least 80% identical,at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:9, wherein the light chain variable region comprises VLCDR1 comprising or consisting of SEQ ID NO:6, VLCDR2 comprising or consisting of SEQ ID NO:7, and VLCDR3 comprising or consisting of SEQ ID NO:8;

[0120] a light chain variable region comprising an amino acid sequence at least 80% identical,at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:19, wherein light chain variable region comprises VL CDR1 comprising or consisting of SEQ ID NO:16, VL CDR2 comprising or consisting of SEQ ID NO:17, and VL CDR3 comprising or consisting of SEQ ID NO:18;

[0121] a light chain variable region comprising an amino acid sequence at least 80% identical,at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:29, wherein the light chain variable region comprises VLCDR1 comprising or consisting of SEQ ID NO:26, VLCDR2 comprising or consisting of SEQ ID NO:27, and VL CDR3 comprising or consisting of SEQ ID NO:28;

[0122] a light chain variable region comprising an amino acid sequence at least 80% identical,at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:39, wherein the light chain variable region comprises VLCDR1 comprising or consisting of SEQ ID NO:36, VLCDR2 comprising or consisting of SEQ ID NO:37, and VLCDR3 comprising or consisting of SEQ ID NO:38;

[0123] a light chain variable region comprising an amino acid sequence at least 80% identical,at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:49, wherein the light chain variable region - 94 - 116104230Atty Docket No.40574-131 comprises VL CDR1 comprising or consisting of SEQ ID NO:46, VL CDR2 comprising or consisting of SEQ ID NO:47, and VL CDR3 comprising or consisting of SEQ ID NO:48;

[0124] a light chain variable region comprising an amino acid sequence at least 80% identical,at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:59, wherein the light chain variable region comprises VLCDR1 comprising or consisting of SEQ ID NO:56, VLCDR2 comprising or consisting of SEQ ID NO:57, and VLCDR3 comprising or consisting of SEQ ID NO:58;

[0125] a light chain variable region comprising an amino acid sequence at least 80% identical,at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:69, wherein the light chain variable region comprises VL CDR1 comprising or consisting of SEQ ID NO:66, VL CDR2 comprising or consisting of SEQ ID NO:67, and VL CDR3 comprising or consisting of SEQ ID NO:68;

[0126] a light chain variable region comprising an amino acid sequence at least 80% identical,at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:79, wherein the light chain variable region comprises VL CDR1 comprising or consisting of SEQ ID NO:76, VL CDR2 comprising or consisting of SEQ ID NO:77, and VL CDR3 comprising or consisting of SEQ ID NO:78;

[0127] a light chain variable region comprising an amino acid sequence at least 80% identical,at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:89, wherein the light chain variable region comprises VLCDR1 comprising or consisting of SEQ ID NO:86, VLCDR2 comprising or consisting of SEQ ID NO:87, and VLCDR3 comprising or consisting of SEQ ID NO:88;

[0128] a light chain variable region comprising an amino acid sequence at least 80% identical,at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:99, wherein the light chain variable region comprises VL CDR1 comprising or consisting of SEQ ID NO:96, VL CDR2 comprising or consisting of SEQ ID NO:97, and VLCDR3 comprising or consisting of SEQ ID NO:98;

[0129] a light chain variable region comprising an amino acid sequence at least 80% identical,at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:109, wherein the light chain variable region - 95 - 116104230Atty Docket No.40574-131 comprises VL CDR1 comprising or consisting of SEQ ID NO:106, VL CDR2 comprising or consisting of SEQ ID NO:107, and VL CDR3 comprising or consisting of SEQ ID NO:108; and

[0130] a light chain variable region comprising an amino acid sequence at least 80% identical,at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:119, wherein the light chain variable region comprises VLCDR1 comprising or consisting of SEQ ID NO:116, VLCDR2 comprising or consisting of SEQ ID NO:117, and VLCDR3 comprising or consisting of SEQ ID NO:118;

[0131] In certain aspects, the antibody (e.g., EVD2301) may comprise a heavy chain variableregion and a light chain variable region, wherein the heavy chain variable region comprises an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:4, and the light chain variable region comprises an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical to SEQ ID NO:9. In certain aspects, the heavy chain may comprise a VHCDR1 comprising or consisting of SEQ ID NO:1, a VHCDR2 comprising or consisting of SEQ ID NO:2, and a VH CDR3 comprising or consisting of SEQ ID NO:3. In certain aspects, the light chain may comprise a VL CDR1 comprising or consisting of SEQ ID NO:6, a VL CDR2 comprising or consisting of SEQ ID NO:7, and a VL CDR3 comprising or consisting of SEQ ID NO:8. In certain aspects, the heavy chain variable region may comprise SEQ ID NO:4 and the light chain variable may comprise SEQ ID NO:9.

[0132] In certain aspects, the antibody (e.g., EVD2302) may comprise a heavy chain variableregion and a light chain variable, wherein the heavy chain variable region comprises an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:14, and the light chain variable region comprises an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical to SEQ ID NO:19. In certain aspects, the heavy chain may comprise a VHCDR1 comprising or consisting of SEQ ID NO:11, a VHCDR2 comprising or consisting of SEQ ID NO:12, and a VHCDR3 comprising or consisting of SEQ ID NO:13. In certain aspects, the light chain may comprise a VLCDR1 comprising or consisting of SEQ ID NO:16, a VLCDR2 comprising or consisting of SEQ ID NO:17, and a VL CDR3 comprising or consisting of SEQ ID - 96 - 116104230Atty Docket No.40574-131 NO:18. In certain aspects, the heavy chain variable region may comprise SEQ ID NO:14 and the light chain variable may comprise SEQ ID NO:19.

[0133] In certain aspects, the antibody (e.g., EVD2303) may comprise a heavy chain variableregion and a light chain variable, wherein the heavy chain variable region comprises an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:24, and the light chain variable region comprises an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical to SEQ ID NO:29. In certain aspects, the heavy chain may comprise a VH CDR1 comprising or consisting of SEQ ID NO:21, a VH CDR2 comprising or consisting of SEQ ID NO:22, and a VH CDR3 comprising or consisting of SEQ ID NO:23. In certain aspects, the light chain may comprise a VL CDR1 comprising or consisting of SEQ ID NO:26, a VL CDR2 comprising or consisting of SEQ ID NO:27, and a VLCDR3 comprising or consisting of SEQ ID NO:28. In certain aspects, the heavy chain variable region may comprise SEQ ID NO:24 and the light chain variable may comprise SEQ ID NO:29.

[0134] In certain aspects, the antibody (e.g., EVD2304) may comprise a heavy chain variableregion and a light chain variable, wherein the heavy chain variable region comprises an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:34, and the light chain variable region comprises an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical to SEQ ID NO:39. In certain aspects, the heavy chain may comprise a VH CDR1 comprising or consisting of SEQ ID NO:31, a VH CDR2 comprising or consisting of SEQ ID NO:32, and a VH CDR3 comprising or consisting of SEQ ID NO:33. In certain aspects, the light chain may comprise a VL CDR1 comprising or consisting of SEQ ID NO:36, a VL CDR2 comprising or consisting of SEQ ID NO:37, and a VL CDR3 comprising or consisting of SEQ ID NO:38. In certain aspects, the heavy chain variable region may comprise SEQ ID NO:34 and the light chain variable may comprise SEQ ID NO:39.

[0135] In certain aspects, the antibody (e.g., EVD2305) may comprise a heavy chain variableregion and a light chain variable, wherein the heavy chain variable region comprises an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, - 97 - 116104230Atty Docket No.40574-131 at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:44, and the light chain variable region comprises an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical to SEQ ID NO:49. In certain aspects, the heavy chain may comprise a VHCDR1 comprising or consisting of SEQ ID NO:41, a VHCDR2 comprising or consisting of SEQ ID NO:42, and a VHCDR3 comprising or consisting of SEQ ID NO:43. In certain aspects, the light chain may comprise a VLCDR1 comprising or consisting of SEQ ID NO:46, a VLCDR2 comprising or consisting of SEQ ID NO:47, and a VLCDR3 comprising or consisting of SEQ ID NO:48. In certain aspects, the heavy chain variable region may comprise SEQ ID NO:44 and the light chain variable may comprise SEQ ID NO:49.

[0136] In certain aspects, the antibody (e.g., EVD2306) may comprise a heavy chain variableregion and a light chain variable, wherein the heavy chain variable region comprises an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:54, and the light chain variable region comprises an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical to SEQ ID NO:59. In certain aspects, the heavy chain may comprise a VH CDR1 comprising or consisting of SEQ ID NO:51, a VH CDR2 comprising or consisting of SEQ ID NO:52, and a VH CDR3 comprising or consisting of SEQ ID NO:53. In certain aspects, the light chain may comprise a VLCDR1 comprising or consisting of SEQ ID NO:56, a VLCDR2 comprising or consisting of SEQ ID NO:57, and a VLCDR3 comprising or consisting of SEQ ID NO:58. In certain aspects, the heavy chain variable region may comprise SEQ ID NO:54 and the light chain variable may comprise SEQ ID NO:59.

[0137] In certain aspects, the antibody (e.g., EVD2307) may comprise a heavy chain variableregion and a light chain variable, wherein the heavy chain variable region comprises an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:64, and the light chain variable region comprises an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical to SEQ ID NO:69. In certain aspects, the heavy chain may comprise a VH CDR1 comprising or consisting of SEQ ID NO:61, a VH CDR2 comprising or consisting of - 98 - 116104230Atty Docket No.40574-131 SEQ ID NO:62, and a VH CDR3 comprising or consisting of SEQ ID NO:63. In certain aspects, the light chain may comprise a VL CDR1 comprising or consisting of SEQ ID NO:66, a VL CDR2 comprising or consisting of SEQ ID NO:67, and a VL CDR3 comprising or consisting of SEQ ID NO:68. In certain aspects, the heavy chain variable region may comprise SEQ ID NO:64 and the light chain variable may comprise SEQ ID NO:69.

[0138] In certain aspects, the antibody (e.g., EVD2308) may comprise a heavy chain variableregion and a light chain variable, wherein the heavy chain variable region comprises an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:74, and the light chain variable region comprises an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical to SEQ ID NO:79. In certain aspects, the heavy chain may comprise a VHCDR1 comprising or consisting of SEQ ID NO:71, a VHCDR2 comprising or consisting of SEQ ID NO:72, and a VHCDR3 comprising or consisting of SEQ ID NO:73. In certain aspects, the light chain may comprise a VLCDR1 comprising or consisting of SEQ ID NO:76, a VLCDR2 comprising or consisting of SEQ ID NO:77, and a VL CDR3 comprising or consisting of SEQ ID NO:78. In certain aspects, the heavy chain variable region may comprise SEQ ID NO:74 and the light chain variable may comprise SEQ ID NO:79.

[0139] In certain aspects, the antibody (e.g., EVD2309) may comprise a heavy chain variableregion and a light chain variable, wherein the heavy chain variable region comprises an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:84, and the light chain variable region comprises an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical to SEQ ID NO:89. In certain aspects, the heavy chain may comprise a VH CDR1 comprising or consisting of SEQ ID NO:81, a VH CDR2 comprising or consisting of SEQ ID NO:82, and a VHCDR3 comprising or consisting of SEQ ID NO:83. In certain aspects, the light chain may comprise a VLCDR1 comprising or consisting of SEQ ID NO:86, a VLCDR2 comprising or consisting of SEQ ID NO:87, and a VLCDR3 comprising or consisting of SEQ ID NO:88. In certain aspects, the heavy chain variable region may comprise SEQ ID NO:84 and the light chain variable may comprise SEQ ID NO:89. - 99 - 116104230Atty Docket No.40574-131

[0140] In certain aspects, the antibody (e.g., EVD2310) may comprise a heavy chain variableregion and a light chain variable, wherein the heavy chain variable region comprises an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:94, and the light chain variable region comprises an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical to SEQ ID NO:99. In certain aspects, the heavy chain may comprise a VHCDR1 comprising or consisting of SEQ ID NO:91, a VHCDR2 comprising or consisting of SEQ ID NO:92, and a VH CDR3 comprising or consisting of SEQ ID NO:93. In certain aspects, the light chain may comprise a VL CDR1 comprising or consisting of SEQ ID NO:96, a VL CDR2 comprising or consisting of SEQ ID NO:97, and a VL CDR3 comprising or consisting of SEQ ID NO:98. In certain aspects, the heavy chain variable region may comprise SEQ ID NO:94 and the light chain variable may comprise SEQ ID NO:99.

[0141] In certain aspects, the antibody (e.g., EVD23011) may comprise a heavy chain variableregion and a light chain variable, wherein the heavy chain variable region comprises an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:104, and the light chain variable region comprises an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical to SEQ ID NO:109. In certain aspects, the heavy chain may comprise a VHCDR1 comprising or consisting of SEQ ID NO:101, a VHCDR2 comprising or consisting of SEQ ID NO:102, and a VHCDR3 comprising or consisting of SEQ ID NO:103. In certain aspects, the light chain may comprise a VL CDR1 comprising or consisting of SEQ ID NO:106, a VL CDR2 comprising or consisting of SEQ ID NO:107, and a VL CDR3 comprising or consisting of SEQ ID NO:108. In certain aspects, the heavy chain variable region may comprise SEQ ID NO:104 and the light chain variable may comprise SEQ ID NO:109.

[0142] In certain aspects, the antibody (e.g., EVD23012) may comprise a heavy chain variableregion and a light chain variable, wherein the heavy chain variable region comprises an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:114, and the light chain variable region comprises an amino acid sequence at least 80% identical, at least 85% - 100 - 116104230Atty Docket No.40574-131 identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical to SEQ ID NO:119. In certain aspects, the heavy chain may comprise a VH CDR1 comprising or consisting of SEQ ID NO:111, a VH CDR2 comprising or consisting of SEQ ID NO:112, and a VH CDR3 comprising or consisting of SEQ ID NO:113. In certain aspects, the light chain may comprise a VLCDR1 comprising or consisting of SEQ ID NO:116, a VLCDR2 comprising or consisting of SEQ ID NO:117, and a VLCDR3 comprising or consisting of SEQ ID NO:118. In certain aspects, the heavy chain variable region may comprise SEQ ID NO:114 and the light chain variable may comprise SEQ ID NO:119.

[0143] In certain aspects, the antibody may comprise an immunoglobulin heavy chaincomprising an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:5, 15, 25, 35, 45, 55, 65, 75, 85, 95, 105, or 115.

[0144] In certain aspects, the antibody may comprise a heavy chain selected from the groupconsisting of:

[0145] a heavy chain comprising or consisting of an amino acid sequence at least 80%identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:5, wherein the heavy chain comprises VH CDR1 comprising or consisting of SEQ ID NO:1, VH CDR2 comprising or consisting of SEQ ID NO:2, and VH CDR3 comprising or consisting of SEQ ID NO:3;

[0146] a heavy chain comprising or consisting of an amino acid sequence at least 80%identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:15, wherein the heavy chain comprises VH CDR1 comprising or consisting of SEQ ID NO:11, VH CDR2 comprising or consisting of SEQ ID NO:12, and VH CDR3 comprising or consisting of SEQ ID NO:13;

[0147] a heavy chain comprising or consisting of an amino acid sequence at least 80%identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:25, wherein the heavy chain comprises VHCDR1 comprising or consisting of SEQ ID NO:21, VHCDR2 comprising or consisting of SEQ ID NO:22, and VHCDR3 comprising or consisting of SEQ ID NO:23;

[0148] a heavy chain comprising or consisting of an amino acid sequence at least 80%identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, - 101 - 116104230Atty Docket No.40574-131 at least 99% identical, or 100% identical, to SEQ ID NO:35, wherein the heavy chain comprises VH CDR1 comprising or consisting of SEQ ID NO:31, VH CDR2 comprising or consisting of SEQ ID NO:32, and VH CDR3 comprising or consisting of SEQ ID NO:33;

[0149] a heavy chain comprising or consisting of an amino acid sequence at least 80%identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:45, wherein the heavy chain comprises VHCDR1 comprising or consisting of SEQ ID NO:41, VHCDR2 comprising or consisting of SEQ ID NO:42, and VHCDR3 comprising or consisting of SEQ ID NO:43;

[0150] a heavy chain comprising or consisting of an amino acid sequence at least 80%identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:55, wherein the heavy chain comprises VH CDR1 comprising or consisting of SEQ ID NO:51, VH CDR2 comprising or consisting of SEQ ID NO:52, and VHCDR3 comprising or consisting of SEQ ID NO:53;

[0151] a heavy chain comprising or consisting of an amino acid sequence at least 80%identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:65, wherein the heavy chain comprises VH CDR1 comprising or consisting of SEQ ID NO:61, VH CDR2 comprising or consisting of SEQ ID NO:62, and VH CDR3 comprising or consisting of SEQ ID NO:63;

[0152] a heavy chain comprising or consisting of an amino acid sequence at least 80%identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:75, wherein the heavy chain comprises VHCDR1 comprising or consisting of SEQ ID NO:71, VHCDR2 comprising or consisting of SEQ ID NO:72, and VH CDR3 comprising or consisting of SEQ ID NO:73;

[0153] a heavy chain comprising or consisting of an amino acid sequence at least 80%identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:85, wherein the heavy chain comprises VHCDR1 comprising or consisting of SEQ ID NO:81, VHCDR2 comprising or consisting of SEQ ID NO:82, and VHCDR3 comprising or consisting of SEQ ID NO:83;

[0154] a heavy chain comprising or consisting of an amino acid sequence at least 80%identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:95, wherein the heavy chain comprises - 102 - 116104230Atty Docket No.40574-131 VH CDR1 comprising or consisting of SEQ ID NO:91, VH CDR2 comprising or consisting of SEQ ID NO:92, and VH CDR3 comprising or consisting of SEQ ID NO:93;

[0155] a heavy chain comprising or consisting of an amino acid sequence at least 80%identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:105, wherein the heavy chain comprises VHCDR1 comprising or consisting of SEQ ID NO:101, VHCDR2 comprising or consisting of SEQ ID NO:102, and VHCDR3 comprising or consisting of SEQ ID NO:103; and

[0156] a heavy chain comprising or consisting of an amino acid sequence at least 80%identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:115, wherein the heavy chain comprises VH CDR1 comprising or consisting of SEQ ID NO:111, VH CDR2 comprising or consisting of SEQ ID NO:112, and VH CDR3 comprising or consisting of SEQ ID NO:113.

[0157] In certain aspects, the antibody may comprise an immunoglobulin light chaincomprising an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical to SEQ ID NO: 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, or 120.

[0158] In certain aspects, the antibody may comprise a light chain selected from the groupconsisting of:

[0159] a light chain comprising an amino acid sequence at least 80% identical, at least 85%identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:10, wherein the light chain comprises VLCDR1 comprising or consisting of SEQ ID NO:6, VLCDR2 comprising or consisting of SEQ ID NO:7, and VLCDR3 comprising or consisting of SEQ ID NO:8;

[0160] a light chain comprising an amino acid sequence at least 80% identical, at least 85%identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:20, wherein light chain comprises VL CDR1 comprising or consisting of SEQ ID NO:16, VLCDR2 comprising or consisting of SEQ ID NO:17, and VLCDR3 comprising or consisting of SEQ ID NO:18;

[0161] a light chain comprising an amino acid sequence at least 80% identical, at least 85%identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:30, wherein the light chain comprises VL CDR1 comprising or - 103 - 116104230Atty Docket No.40574-131 consisting of SEQ ID NO:26, VL CDR2 comprising or consisting of SEQ ID NO:27, and VL CDR3 comprising or consisting of SEQ ID NO:28;

[0162] a light chain comprising an amino acid sequence at least 80% identical, at least 85%identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:40, wherein the light chain comprises VLCDR1 comprising or consisting of SEQ ID NO:36, VLCDR2 comprising or consisting of SEQ ID NO:37, and VLCDR3 comprising or consisting of SEQ ID NO:38;

[0163] a light chain comprising an amino acid sequence at least 80% identical, at least 85%identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:50, wherein the light chain comprises VL CDR1 comprising or consisting of SEQ ID NO:46, VL CDR2 comprising or consisting of SEQ ID NO:47, and VL CDR3 comprising or consisting of SEQ ID NO:48;

[0164] a light chain comprising an amino acid sequence at least 80% identical, at least 85%identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:60, wherein the light chain comprises VLCDR1 comprising or consisting of SEQ ID NO:56, VL CDR2 comprising or consisting of SEQ ID NO:57, and VL CDR3 comprising or consisting of SEQ ID NO:58;

[0165] a light chain comprising an amino acid sequence at least 80% identical, at least 85%identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:70, wherein the light chain comprises VLCDR1 comprising or consisting of SEQ ID NO:66, VLCDR2 comprising or consisting of SEQ ID NO:67, and VLCDR3 comprising or consisting of SEQ ID NO:68;

[0166] a light chain comprising an amino acid sequence at least 80% identical, at least 85%identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:80, wherein the light chain comprises VL CDR1 comprising or consisting of SEQ ID NO:76, VL CDR2 comprising or consisting of SEQ ID NO:77, and VL CDR3 comprising or consisting of SEQ ID NO:78;

[0167] a light chain comprising an amino acid sequence at least 80% identical, at least 85%identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:90, wherein the light chain comprises VLCDR1 comprising or - 104 - 116104230Atty Docket No.40574-131 consisting of SEQ ID NO:86, VL CDR2 comprising or consisting of SEQ ID NO:87, and VL CDR3 comprising or consisting of SEQ ID NO:88;

[0168] a light chain comprising an amino acid sequence at least 80% identical, at least 85%identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:100, wherein the light chain comprises VLCDR1 comprising or consisting of SEQ ID NO:96, VLCDR2 comprising or consisting of SEQ ID NO:97, and VLCDR3 comprising or consisting of SEQ ID NO:98;

[0169] a light chain comprising an amino acid sequence at least 80% identical, at least 85%identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:110, wherein the light chain comprises VL CDR1 comprising or consisting of SEQ ID NO:106, VL CDR2 comprising or consisting of SEQ ID NO:107, and VL CDR3 comprising or consisting of SEQ ID NO:108; and

[0170] a light chain comprising an amino acid sequence at least 80% identical, at least 85%identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:120, wherein the light chain comprises VLCDR1 comprising or consisting of SEQ ID NO:116, VL CDR2 comprising or consisting of SEQ ID NO:117, and VL CDR3 comprising or consisting of SEQ ID NO:118;

[0171] In certain aspects, the antibody (e.g., EVD2301) may comprise a heavy chain and alight chain, wherein the heavy chain comprises an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:5, and the light chain comprises an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical to SEQ ID NO:10. In certain aspects, the heavy chain may comprise a VH CDR1 comprising or consisting of SEQ ID NO:1, a VH CDR2 comprising or consisting of SEQ ID NO:2, and a VH CDR3 comprising or consisting of SEQ ID NO:3. In certain aspects, the light chain may comprise a VL CDR1 comprising or consisting of SEQ ID NO:6, a VLCDR2 comprising or consisting of SEQ ID NO:7, and a VLCDR3 comprising or consisting of SEQ ID NO:8. In certain aspects, the heavy chain may comprise SEQ ID NO:5 and the light chain may comprise SEQ ID NO:10.

[0172] In certain aspects, the antibody (e.g., EVD2302) may comprise a heavy chain and alight chain, wherein the heavy chain comprises an amino acid sequence at least 80% identical, at - 105 - 116104230Atty Docket No.40574-131 least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:15, and the light chain comprises an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical to SEQ ID NO:20. In certain aspects, the heavy chain may comprise a VHCDR1 comprising or consisting of SEQ ID NO:11, a VHCDR2 comprising or consisting of SEQ ID NO:12, and a VHCDR3 comprising or consisting of SEQ ID NO:13. In certain aspects, the light chain may comprise a VLCDR1 comprising or consisting of SEQ ID NO:16, a VLCDR2 comprising or consisting of SEQ ID NO:17, and a VL CDR3 comprising or consisting of SEQ ID NO:18. In certain aspects, the heavy chain may comprise SEQ ID NO:15 and the light chain may comprise SEQ ID NO:20.

[0173] In certain aspects, the antibody (e.g., EVD2303) may comprise a heavy chain and alight chain, wherein the heavy chain comprises an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:25, and the light chain comprises an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical to SEQ ID NO:30. In certain aspects, the heavy chain may comprise a VH CDR1 comprising or consisting of SEQ ID NO:21, a VH CDR2 comprising or consisting of SEQ ID NO:22, and a VH CDR3 comprising or consisting of SEQ ID NO:23. In certain aspects, the light chain may comprise a VL CDR1 comprising or consisting of SEQ ID NO:26, a VLCDR2 comprising or consisting of SEQ ID NO:27, and a VLCDR3 comprising or consisting of SEQ ID NO:28. In certain aspects, the heavy chain may comprise SEQ ID NO:25 and the light chain may comprise SEQ ID NO:30.

[0174] In certain aspects, the antibody (e.g., EVD2304) may comprise a heavy chain and alight chain, wherein the heavy chain comprises an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:35, and the light chain comprises an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical to SEQ ID NO:40. In certain aspects, the heavy chain may comprise a VHCDR1 comprising or consisting of SEQ ID NO:31, a VHCDR2 comprising or consisting of SEQ ID NO:32, and a VHCDR3 comprising or consisting of SEQ ID NO:33. In certain aspects, the light chain may comprise a VL CDR1 comprising or - 106 - 116104230Atty Docket No.40574-131 consisting of SEQ ID NO:36, a VL CDR2 comprising or consisting of SEQ ID NO:37, and a VL CDR3 comprising or consisting of SEQ ID NO:38. In certain aspects, the heavy chain may comprise SEQ ID NO:35 and the light chain may comprise SEQ ID NO:40.

[0175] In certain aspects, the antibody (e.g., EVD2305) may comprise a heavy chain and alight chain, wherein the heavy chain comprises an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:45, and the light chain comprises an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical to SEQ ID NO:50. In certain aspects, the heavy chain may comprise a VH CDR1 comprising or consisting of SEQ ID NO:41, a VH CDR2 comprising or consisting of SEQ ID NO:42, and a VH CDR3 comprising or consisting of SEQ ID NO:43. In certain aspects, the light chain may comprise a VL CDR1 comprising or consisting of SEQ ID NO:46, a VLCDR2 comprising or consisting of SEQ ID NO:47, and a VLCDR3 comprising or consisting of SEQ ID NO:48. In certain aspects, the heavy chain may comprise SEQ ID NO:45 and the light chain may comprise SEQ ID NO:50.

[0176] In certain aspects, the antibody (e.g., EVD2306) may comprise a heavy chain and alight chain, wherein the heavy chain comprises an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:55, and the light chain comprises an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical to SEQ ID NO:60. In certain aspects, the heavy chain may comprise a VHCDR1 comprising or consisting of SEQ ID NO:51, a VH CDR2 comprising or consisting of SEQ ID NO:52, and a VH CDR3 comprising or consisting of SEQ ID NO:53. In certain aspects, the light chain may comprise a VL CDR1 comprising or consisting of SEQ ID NO:56, a VL CDR2 comprising or consisting of SEQ ID NO:57, and a VL CDR3 comprising or consisting of SEQ ID NO:58. In certain aspects, the heavy chain may comprise SEQ ID NO:55 and the light chain may comprise SEQ ID NO:60.

[0177] In certain aspects, the antibody (e.g., EVD2307) may comprise a heavy chain and alight chain, wherein the heavy chain comprises an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:65, and the light chain comprises an amino acid - 107 - 116104230Atty Docket No.40574-131 sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical to SEQ ID NO:70. In certain aspects, the heavy chain may comprise a VH CDR1 comprising or consisting of SEQ ID NO:61, a VH CDR2 comprising or consisting of SEQ ID NO:62, and a VH CDR3 comprising or consisting of SEQ ID NO:63. In certain aspects, the light chain may comprise a VLCDR1 comprising or consisting of SEQ ID NO:66, a VLCDR2 comprising or consisting of SEQ ID NO:67, and a VLCDR3 comprising or consisting of SEQ ID NO:68. In certain aspects, the heavy chain may comprise SEQ ID NO:65 and the light chain may comprise SEQ ID NO:70.

[0178] In certain aspects, the antibody (e.g., EVD2308) may comprise a heavy chain and alight chain, wherein the heavy chain comprises an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:75, and the light chain comprises an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical to SEQ ID NO:80. In certain aspects, the heavy chain may comprise a VHCDR1 comprising or consisting of SEQ ID NO:71, a VH CDR2 comprising or consisting of SEQ ID NO:72, and a VH CDR3 comprising or consisting of SEQ ID NO:73. In certain aspects, the light chain may comprise a VL CDR1 comprising or consisting of SEQ ID NO:76, a VL CDR2 comprising or consisting of SEQ ID NO:77, and a VL CDR3 comprising or consisting of SEQ ID NO:78. In certain aspects, the heavy chain may comprise SEQ ID NO:75 and the light chain may comprise SEQ ID NO:80.

[0179] In certain aspects, the antibody (e.g., EVD2309) may comprise a heavy chain and alight chain, wherein the heavy chain comprises an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:85, and the light chain comprises an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical to SEQ ID NO:90. In certain aspects, the heavy chain may comprise a VHCDR1 comprising or consisting of SEQ ID NO:81, a VHCDR2 comprising or consisting of SEQ ID NO:82, and a VHCDR3 comprising or consisting of SEQ ID NO:83. In certain aspects, the light chain may comprise a VLCDR1 comprising or consisting of SEQ ID NO:86, a VLCDR2 comprising or consisting of SEQ ID NO:87, and a - 108 - 116104230Atty Docket No.40574-131 VL CDR3 comprising or consisting of SEQ ID NO:88. In certain aspects, the heavy chain may comprise SEQ ID NO:85 and the light chain may comprise SEQ ID NO:90.

[0180] In certain aspects, the antibody (e.g., EVD2310) may comprise a heavy chain and alight chain, wherein the heavy chain comprises an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:95, and the light chain comprises an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical to SEQ ID NO:100. In certain aspects, the heavy chain may comprise a VH CDR1 comprising or consisting of SEQ ID NO:91, a VH CDR2 comprising or consisting of SEQ ID NO:92, and a VH CDR3 comprising or consisting of SEQ ID NO:93. In certain aspects, the light chain may comprise a VL CDR1 comprising or consisting of SEQ ID NO:96, a VL CDR2 comprising or consisting of SEQ ID NO:97, and a VLCDR3 comprising or consisting of SEQ ID NO:98. In certain aspects, the heavy chain may comprise SEQ ID NO:95 and the light chain may comprise SEQ ID NO:100.

[0181] In certain aspects, the antibody (e.g., EVD23011) may comprise a heavy chain and alight chain, wherein the heavy chain comprises an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:105, and the light chain comprises an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical to SEQ ID NO:110. In certain aspects, the heavy chain may comprise a VHCDR1 comprising or consisting of SEQ ID NO:101, a VHCDR2 comprising or consisting of SEQ ID NO:102, and a VHCDR3 comprising or consisting of SEQ ID NO:103. In certain aspects, the light chain may comprise a VL CDR1 comprising or consisting of SEQ ID NO:106, a VL CDR2 comprising or consisting of SEQ ID NO:107, and a VL CDR3 comprising or consisting of SEQ ID NO:108. In certain aspects, the heavy chain may comprise SEQ ID NO:105 and the light chain may comprise SEQ ID NO:110.

[0182] In certain aspects, the antibody (e.g., EVD23012) may comprise a heavy chain and alight chain, wherein the heavy chain comprises an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:115, and the light chain comprises an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, - 109 - 116104230Atty Docket No.40574-131 at least 97% identical, at least 99% identical, or 100% identical to SEQ ID NO:120. In certain aspects, the heavy chain may comprise a VH CDR1 comprising or consisting of SEQ ID NO:111, a VH CDR2 comprising or consisting of SEQ ID NO:112, and a VH CDR3 comprising or consisting of SEQ ID NO:113. In certain aspects, the light chain may comprise a VL CDR1 comprising or consisting of SEQ ID NO:116, a VLCDR2 comprising or consisting of SEQ ID NO:117, and a VLCDR3 comprising or consisting of SEQ ID NO:118. In certain aspects, the heavy chain may comprise SEQ ID NO:115 and the light chain may comprise SEQ ID NO:120.

[0183] One embodiment of the disclosure is a vector, which may be an expression vector,comprising a nucleic acid molecule that encodes at least a portion of an antibody of the disclosure, wherein the portion comprises the amino acid sequence of at least one CDR of the disclosure. In certain aspects, the nucleic acid molecule encodes a VH CDR1, a VH CDR2, a VH CDR3, a VL CDR1, a VL CDR2, a VL CDR3, a heavy chain variable region, a light chain variable region, a heavy chain, and / or a light chain of the disclosure, or antibody-matched combinations thereof. In certain aspects, the nucleic acid molecule encodes a VH CDR1, a VH CDR2, a VH CDR3, a VL CDR1, a VL CDR2, a VL CDR3, a heavy chain variable region, a light chain variable region, a heavy chain, and / or a light chain disclosed in Table 1, or antibody-matched combinations thereof. Suitable expression vectors include, but are not limited to, plasmids and virus-based expression vectors, such as poxviruses, adenoviruses, herpesviruses, adeno-associated viruses, lentiviruses, plant viruses and insect viruses.

[0184] One embodiment of the disclosure is an engineered cell comprising a nucleic acidmolecule comprising a polynucleotide sequence encoding at least a portion of an antibody of the disclosure, wherein the portion comprises the amino acid sequence of at least one CDR of the disclosure. In certain aspects, the nucleic acid molecule encodes a VH CDR1, a VH CDR2, a VH CDR3, a VL CDR1, a VL CDR2, a VL CDR3, a heavy chain variable region, a light chain variable region, a heavy chain, and / or a light chain of the disclosure, or antibody-matched combinations thereof. In certain aspects, the nucleic acid molecule encodes a VH CDR1, a VH CDR2, a VH CDR3, a VL CDR1, a VL CDR2, a VL CDR3, a heavy chain variable region, a light chain variable region, a heavy chain, and / or a light chain disclosed in Table 1, or antibody- matched combinations thereof. In certain aspects, the engineered call may comprise a vector of the disclosure. In certain aspects, the nucleic acid molecule comprising the polynucleotide sequence encoding the at least a portion of an antibody of the disclosure may be integrated into the genome - 110 - 116104230Atty Docket No.40574-131 of the cell. In certain aspects, the polynucleotide sequence encoding the at least a portion of an antibody of the disclosure is under the control of a promoter, thereby allowing expression of polynucleotide sequence such that an antibody of the disclosure is produced.

[0185] One embodiment of the disclosure is a composition comprising an antibody of thedisclosure, a vector of the disclosure, or an engineered cell of the disclosure. In certain aspects, the composition may be a liquid composition. In certain aspects, the composition may comprise a solid composition. Compositions of the disclosure may comprise excipients, such as buffers, stabilizers, solubilizers, antioxidants, emulsifiers, and carriers. Examples of buffers include, but are not limited to, phosphate, citrate, succinate, acetate and other organic acids, histidine, arginine, Hanks' solution, Ringer's solution, or physiological saline buffer. Stabilizers help maintain the integrity of the composition and / or the structure of the antibody. They can also help reduce degradation of the antibody, thereby increasing the life of the antibody beyond the life of an antibody in the body. Examples of stabilizers include, but are not limited to, polyols, sugars, amino acids, amines, salts, cyclodextrins, and chelating agents, such as ethylenediaminetetraacetic acid (EDTA). Solubilizers may increase the solubility of ingredients, such as antibodies, in the composition. Examples of solubilizers include, but are not limited to, water-soluble organic solvents (polyethylene glycol 300, polyethylene glycol 400, ethanol, propylene glycol, glycerin, N-methyl-2-pyrrolidone, dimethylacetamide, and dimethylsulfoxide), non-ionic surfactants (Cremophor EL, Cremophor RH 40, Cremophor RH 60, d-alpha-tocopherol polyethylene glycol 1000 succinate, polysorbate 20, polysorbate 80, Solutol HS 15, sorbitan monooleate, poloxamer 407, Labrafil M-1944CS, Labrafil M-2125CS, Labrasol, Gellucire 44 / 14, Softigen 767, and mono- and di-fatty acid esters of PEG 300, 400, or 1750), water-insoluble lipids (castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chain triglycerides of coconut oil and palm seed oil), organic liquids / semi-solids (beeswax, d-alpha-tocopherol, oleic acid, medium-chain mono- and diglycerides), various cyclodextrins (alpha-cyclodextrin, beta-cyclodextrin, hydroxypropyl-beta- cyclodextrin, and sulfobutylether-beta-cyclodextrin), and phospholipids (hydrogenated soy phosphatidylcholine, distearoylphosphatidylglycerol, L-alpha-dimyristoylphosphatidylcholine, L- alpha-dimyristoylphosphatidylglycerol). Antioxidants protect ingredients in the composition from degradation and extend the life of the composition and particularly the antibody. Examples of - 111 - 116104230Atty Docket No.40574-131 antioxidants include, but are not limited to, ascorbic acid, tocopherols, cysteine, ascorbyl palmitate, monothioglycerol, sodium bisulfite, and butylaed hydroxytoluene.

[0186] Compositions of the disclosure may be formulated in any suitable form, and, in largepart, the form may be determined by the intended mode of administration. Compositions can be in the form of a solid, semi-solid or liquid. Examples of forms useful for administering antibodies of the disclosure include, but are not limited to, liquid compositions, emulsions, suspensions, tablets, capsules, powders, troches, lozenges, suspensions, gels, pastes, slurries, soft-gel capsules, and syrups. Preferably the compositions are produced in a unit dosage form suitable for administration of a precise dose. Injectables may be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions.

[0187] Compositions for parenteral administration of an antibody include sterile solutionsready for injection, sterile dry soluble products, such as lyophilized powders, ready to be combined with a solvent just prior to use, including hypodermic tablets, sterile suspensions ready for injection, sterile dry insoluble products ready to be combined with a vehicle just prior to use and sterile emulsions. The solutions may be either aqueous or nonaqueous.

[0188] Compounds and compositions of the disclosure may be administered by any suitableroute. Such routes of administration include, but are not limited to, injection, including intravenous, intraperitoneal, intramuscular, and subcutaneous injection, oral administration, transmucosal administration, transdermal administration, topical administration, nasal administration, ocular administration, or via suppository.

[0189] One embodiment of the disclosure is a method of detecting an enterovirus or anassociated antigen thereof, comprising contacting an antibody of the disclosure with a test sample to form a mixture, and testing the mixture for the presence of an antibody:enterovirus antigen complex, wherein the presence of such complex indicates the sample contained enterovirus or an associated antigen thereof, and wherein the absence of such complex indicates the sample did not contain enterovirus. As used herein, the term “contacting” refers to mixing of the test sample, which may or may not contain an enterovirus or an associated antigen, with an antibody, or antibody-containing composition, of the disclosure under conditions suitable for forming antibody:antigen complexes. When an enterovirus, or an associated antigen, is present in the sample, an enterovirus:antibody, or an associated antigen:antibody, complex is then formed. Such - 112 - 116104230Atty Docket No.40574-131 complex formation refers to the ability of the antibody to selectively bind to the enterovirus or an associated antigen, to form a stable complex that can be detected. Detection may be qualitative, quantitative, or semi-quantitative. Binding may be measured using a variety of methods standard in the art including, but not limited to, enzyme linked immunosorbent assay (ELISA), radioimmunoassay (RIA), immunoradiometric assay, fluoroimmunoassay, chemiluminescent assay, bioluminescent assay, bead-based assays, lateral-flow assays, flow-through assays, immunoblot assays, Western blots, and the like. In certain aspects, the antibody may comprise a detectable label, which includes, but is not limited to, a fluorescent label, a chemiluminescent label, a luminescent label, a radiolabel, a dye, an enzyme, an antigenic label, and the like.

[0190] One embodiment of the disclosure is a method of identifying an individual having anenterovirus infection, comprising testing a sample from the individual for the presence of enterovirus or an associated antigen thereof, wherein detection of enterovirus, or an associated antigen thereof, indicates the individual has an enterovirus infection. In certain aspects, testing comprises contacting the sample from the individual with an antibody of the disclosure to form a mixture under conditions suitable for formation of antibody:enterovirus or antibody:enterovirus- associated antigen complexes, and assaying the mixture for the presence or absence of antibody: enterovirus antigen complexes. In certain aspects, if antibody:enterovirus, or antibody:enterovirus- associated antigen, complexes are detected in the mixture, the individual is identified as having an enterovirus infection. In certain aspects, if no antibody:enterovirus, or antibody:enterovirus- associated antigen, complexes are detected in the mixture, the individual is identified as not having an enterovirus infection. Methods of detecting antibody:enterovirus and antibody:enterovirus- associated antigen complexes, have been disclosed elsewhere herein. In certain aspects, the sample may comprise a biological fluid, such as blood, serum, cerebrospinal fluid, saliva, urine, and lacrimal fluid. In certain aspects, the sample comprises a tissue sample.

[0191] One embodiment of the disclosure is a method of purifying an enterovirus or anassociated antigen therefrom, comprising contacting a sample comprising the enterovirus or associated antigen therefrom with an antibody of the disclosure to form antibody:enterovirus, or antibody:enterovirus-associated antigen complexes, such that the enterovirus or associated antigen therefrom is removed from majority of components in the sample, thereby purifying the enterovirus or an associated antigen thereof. In certain aspects, the antibody is linked to a solid support, such as a column matrix or resin (e.g., polystyrene, methacrylate polymer, heparin. etc.), - 113 - 116104230Atty Docket No.40574-131 a bead, or a plate. Once antibody:enterovirus, or antibody:enterovirus-associated antigen complexes have been formed, such complexes may then be washed with a solution suitable for removing unwanted and / or non-enterovirus, or enterovirus associated antigen, materials, after which, the enterovirus, or associated antigen, may, but need not, be released from the antibody of the disclosure, thereby purifying the enterovirus or associated antigen therefrom. In certain aspects, the method may comprise separation methods, such as, liquid chromatography, FPLC, HPLC, affinity chromatography, ion-exchange chromatography, flow cytometry, bead-based (including magnetic beads) separation, centrifugation, immunoprecipitation, flow cytometry, and the like.

[0192] One embodiment of the disclosure is a method of preventing infection of a cell by anenterovirus, comprising contacting the enterovirus with an antibody of the disclosure prior to, or concurrent with, contacting the enterovirus with the cell.

[0193] One embodiment of the disclosure is a method of protecting an individual againstinfection with an enterovirus, comprising administering to the individual an antibody of the disclosure, a vector of the disclosure, or a composition of the disclosure. The terms individual, subject, and patient are well-recognized in the art, and are herein used interchangeably to refer to any human or other animal susceptible to infection by an enterovirus. Examples include, but are not limited to, humans and other primates, including non-human primates such as macaques, chimpanzees and other apes and monkey species; farm animals such as cattle, sheep, pigs, seals, goats and horses; domestic mammals such as dogs and cats; laboratory animals including rodents such as mice, rats and guinea pigs; birds, including domestic, wild and game birds such as chickens, turkeys and other gallinaceous birds, ducks, geese, and the like; and fish, such as salmon. The terms individual, subject, and patient by themselves, do not denote a particular age, sex, race, and the like. Thus, individuals of any age, whether male or female, are covered by the present disclosure and include, but are not limited to the elderly, adults, children, babies, infants, and toddlers. Likewise, the methods of the present invention can be applied to any race, including, for example, Caucasian (white), African-American (black), Native American, Native Hawaiian, Hispanic, Latino, Asian, and European.

[0194] In certain aspects, administration of the antibody, vector, or composition, of thedisclosure protects the individual against a single clade of enterovirus. In certain aspects, administration of the antibody, or composition, of the disclosure may protect the individual against infection with enteroviruses from at least two clades of enterovirus. In certain aspects, - 114 - 116104230Atty Docket No.40574-131 administration of the antibody, vector, or composition, of the disclosure may protect the individual against infection with enteroviruses from at least three clades of enterovirus. In certain aspects, administration of the antibody, vector, or composition, of the disclosure may protect the individual against infection with enterovirus A71, enterovirus B3, enterovirus D, or enterovirus D68.

[0195] One embodiment of the disclosure is a method of treating an individual for anenterovirus infection, comprising administering to the individual an antibody, vector, or composition, of the disclosure. In certain aspects, administration of the antibody, or composition, of the disclosure may treat the individual for infection with enteroviruses from at least two clades of enterovirus. In certain aspects, administration of the antibody, or composition, of the disclosure may treat the individual for infection with enteroviruses from at least three clades of enterovirus. In certain aspects, administration of the antibody, or composition, of the disclosure may treat the individual for infection with enteroviruses with enterovirus A71, enterovirus B3, enterovirus D, or enterovirus D68.

[0196] One embodiment of the disclosure is a method of treating an individual for anenterovirus infection, comprising identifying the individual as having an enterovirus infection using a method comprising:

[0197] contacting a sample from the individual with an antibody of the disclosure to form amixture, the step of contacting being performed under conditions suitable for formation of antibody:enterovirus or antibody:enterovirus-associated antigen complexes; and

[0198] assaying the mixture for the presence or absence of antibody: enterovirus antigencomplexes, wherein if antibody:enterovirus, or antibody:enterovirus-associated antigen, complexes are detected in the mixture, administering to the individual an antibody, vector, or composition, of the disclosure.

[0199] In these aspects, the antibody or composition of the disclosure may be administered byany suitable means including, but not limited to, traditional syringes, needleless injection devices, pills, and solutions. Suitable routes of administration include, but are not limited to, parenteral delivery, such as intramuscular, intradermal, subcutaneous, intramedullary injections, as well as, intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections, just to name a few. For injection, the compounds of one embodiment of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiological saline buffer. - 115 - 116104230Atty Docket No.40574-131

[0200] One embodiment of the disclosure is a kit comprising an antibody of the disclosure, avector of the disclosure, and / or a composition of the disclosure. Such kit may also contain associated components, such as, but not limited to, buffers, labels, containers, inserts, tubing, vials, syringes and the like.

[0201] One aspect of the disclosure is an antibody of the disclosure, a vector of the disclosure,and / or a composition of the disclosure, for use in preparation of a medicament for preventing infection of an individual by a virus from at least one clade of enterovirus. In certain aspects, the antibody may prevent infection of the individual by viruses from at least two clades of enteroviruses. In certain aspects, the antibody may prevent infection of the individual by viruses from at least three clades of enteroviruses.

[0202] One aspect of the disclosure is an antibody of the disclosure, a vector of the disclosure,and / or a composition of the disclosure, for use in preparation of a medicament for treating individual that has been infected by an enterovirus. In certain aspects, the antibody may treat an individual infected by viruses from at least two clades of enteroviruses. In certain aspects, the antibody may treat an individual infected by viruses from at least three clades of enteroviruses.

[0203] This written description uses examples to disclose the disclosure, including the bestmode, and to enable any person skilled in the art to practice the disclosure, including making and using any devices or systems and performing any incorporated methods. The patentable scope of the disclosure is defined by the claims, and may include other examples that occur to those skilled in the art. Such other examples are intended to be within the scope of the claims if they have structural elements that do not differ from the literal language of the claims, or if they include equivalent structural elements with insubstantial differences from the literal language of the claims.

[0204] In some embodiments, the antibody or antigen-binding fragment thereof comprises oneor more heavy chain CDRs from Table 2.

[0205] In some embodiments, the antibody or antigen-binding fragment thereof comprises oneor more light chain CDRs from Table 2.

[0206] In some embodiments, the antibody or antigen-binding fragment thereof comprises oneor more antibody-matched heavy chain CDRs and light chain CDRs from Table 2.

[0207] In some embodiments, the antibody or antigen-binding fragment thereof comprises aheavy chain variable region comprising an amino acid sequence at least 80% identical, at least - 116 - 116104230Atty Docket No.40574-131 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, or at least 99% identical, to a heavy chain variable region from Table 2, wherein the heavy chain variable region comprises antibody-matched VHCDR1, VHCDR2, and VHCDR3 sequences from Table 2.

[0208] In some embodiments, the antibody or antigen-binding fragment thereof comprises alight chain variable region comprising an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, or at least 99% identical, to a light chain variable region from Table 2, wherein the light chain variable region comprises antibody-matched VLCDR1, VLCDR2, and VLCDR3 sequences from Table 2.

[0209] In some embodiments, the antibody or antigen-binding fragment thereof comprises aheavy chain variable region and an antibody-matched light chain variable region, the antibody- matched, heavy and light chain variable regions comprising amino acid sequences at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, or at least 99% identical, to a heavy chain variable region and a light chain variable region, respectively, from Table 2, wherein the heavy chain variable region comprises antibody- matched VHCDR1, VHCDR2, and VHCDR3 sequences from Table 2 and the light chain variable region comprises antibody-matched VLCDR1, VLCDR2, and VLCDR3 sequences from Table 2.

[0210] In some embodiments, the antibody or antigen-binding fragment thereof comprises aheavy chain comprising an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, or at least 99% identical, to a heavy chain from Table 2, wherein the heavy chain comprises antibody-matched VHCDR1, VHCDR2, and VHCDR3 sequences from Table 2.

[0211] In some embodiments, the antibody or antigen-binding fragment thereof comprises alight chain comprising an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, or at least 99% identical, to a light chain from Table 2, wherein the light chain comprises antibody-matched VLCDR1, VLCDR2, and VLCDR3 sequences from Table 2.

[0212] In some embodiments, the antibody or antigen-binding fragment thereof comprises aheavy chain variable region and an antibody-matched light chain variable region, the antibody- matched, heavy and light chain variable regions comprising amino acid sequences at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, or at least 99% identical, to a heavy chain variable region and a light chain variable - 117 - 116104230Atty Docket No.40574-131 region, respectively, from Table 2, wherein the heavy chain variable region comprises antibody- matched VHCDR1, VHCDR2, and VHCDR3 sequences from Table 2 and the light chain variable region comprises antibody-matched VLCDR1, VLCDR2, and VLCDR3 sequences from Table 2.

[0213] In some embodiments, the antibody or antigen-binding fragment thereof comprises aheavy chain and an antibody-matched light chain, the antibody-matched, heavy chain and the light chain comprising amino acid sequences at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, or at least 99% identical, to a heavy chain and a light chain, respectively, from Table 2, wherein the heavy chain comprises antibody-matched VHCDR1, VHCDR2, and VHCDR3 sequences from Table 2 and the light chain comprises antibody- matched VLCDR1, VLCDR2, and VLCDR3 sequences from Table 2.

[0214] In some embodiments, the antibody or antigen-binding fragment thereof comprisesantibody-matched sequences from Table 2.

[0215] In some embodiments, the antibody or antigen-binding fragment thereof comprises aheavy chain variable region (VH) complementarity determining region 3 (CDR3) selected from the group consisting of a VHCDR3 comprising or consisting of SEQ ID NO:130, a VHCDR3 comprising or consisting of SEQ ID NO:144, a VH CDR3 comprising or consisting of SEQ ID NO:148, a VH CDR3 comprising or consisting of SEQ ID NO:172, a VH CDR3 comprising or consisting of SEQ ID NO:186, a VH CDR3 comprising or consisting of SEQ ID NO:200, a VH CDR3 comprising or consisting of SEQ ID NO:214, a VH CDR3 comprising or consisting of SEQ ID NO:228, a VHCDR3 comprising or consisting of SEQ ID NO:242, a VHCDR3 comprising or consisting of SEQ ID NO:256, a VHCDR3 comprising or consisting of SEQ ID NO:270, a VHCDR3 comprising or consisting of SEQ ID NO:284, a VHCDR3 comprising or consisting of SEQ ID NO:298, a VH CDR3 comprising or consisting of SEQ ID NO:312, a VH CDR3 comprising or consisting of SEQ ID NO:326, a VH CDR3 comprising or consisting of SEQ ID NO:340, a VH CDR3 comprising or consisting of SEQ ID NO:354, a VH CDR3 comprising or consisting of SEQ ID NO:368, a VH CDR3 comprising or consisting of SEQ ID NO:382, 396, a VH CDR3 comprising or consisting of SEQ ID NO:410, a VHCDR3 comprising or consisting of SEQ ID NO:424, a VHCDR3 comprising or consisting of SEQ ID NO:438, a VHCDR3 comprising or consisting of SEQ ID NO:452, a VHCDR3 comprising or consisting of SEQ ID NO:466, a VHCDR3 comprising or consisting of SEQ ID NO:480, a VHCDR3 comprising or consisting of SEQ ID NO:494, a VHCDR3 comprising or consisting of SEQ ID NO:508, a VH CDR3 comprising or consisting of SEQ - 118 - 116104230Atty Docket No.40574-131 ID NO:522,, a VH CDR3 comprising or consisting of SEQ ID NO:536, a VH CDR3 comprising or consisting of SEQ ID NO:550, a VH CDR3 comprising or consisting of SEQ ID NO:564, a VH CDR3 comprising or consisting of SEQ ID NO:578, a VH CDR3 comprising or consisting of SEQ ID NO:592, a VH CDR3 comprising or consisting of SEQ ID NO:606, and a VH CDR3 comprising or consisting of SEQ ID NO:620.

[0216] In some embodiments, the antibody or antigen-binding fragment thereof comprises alight chain variable region (VL) CDR3 selected from the group consisting of a VLCDR3 comprising or consisting of SEQ ID NO:137, a VLCDR3 comprising or consisting of SEQ ID NO:151, a VLCDR3 comprising or consisting of SEQ ID NO:165, a VL CDR3 comprising or consisting of SEQ ID NO:179, a VL CDR3 comprising or consisting of SEQ ID NO:193, a VL CDR3 comprising or consisting of SEQ ID NO:207, a VL CDR3 comprising or consisting of SEQ ID NO:221, a VL CDR3 comprising or consisting of SEQ ID NO:235, a VL CDR3 comprising or consisting of SEQ ID NO:249, a VLCDR3 comprising or consisting of SEQ ID NO:263, a VLCDR3 comprising or consisting of SEQ ID NO:277, a VLCDR3 comprising or consisting of SEQ ID NO:291, a VLCDR3 comprising or consisting of SEQ ID NO:305, a VLCDR3 comprising or consisting of SEQ ID NO:319, a VL CDR3 comprising or consisting of SEQ ID NO:333, a VL CDR3 comprising or consisting of SEQ ID NO:347, a VL CDR3 comprising or consisting of SEQ ID NO:361, a VL CDR3 comprising or consisting of SEQ ID NO:375, a VL CDR3 comprising or consisting of SEQ ID NO:389, a VL CDR3 comprising or consisting of SEQ ID NO:403, a VL CDR3 comprising or consisting of SEQ ID NO:417, a VLCDR3 comprising or consisting of SEQ ID NO:431, a VLCDR3 comprising or consisting of SEQ ID NO:445, a VLCDR3 comprising or consisting of SEQ ID NO:459, a VLCDR3 comprising or consisting of SEQ ID NO:473, a VLCDR3 comprising or consisting of SEQ ID NO:487, a VL CDR3 comprising or consisting of SEQ ID NO:501, a VL CDR3 comprising or consisting of SEQ ID NO:515, a VL CDR3 comprising or consisting of SEQ ID NO:529, a VL CDR3 comprising or consisting of SEQ ID NO:543, a VL CDR3 comprising or consisting of SEQ ID NO:557, a VL CDR3 comprising or consisting of SEQ ID NO:571, a VLCDR3 comprising or consisting of SEQ ID NO:585, a VLCDR3 comprising or consisting of SEQ ID NO:599, a VLCDR3 comprising or consisting of SEQ ID NO:612, or a VLCDR3 comprising or consisting of SEQ ID NO:627.

[0217] In some embodiments, the antibody or antigen-binding fragment thereof comprises aVH CDR2 selected from the group consisting of a VH CDR2 comprising or consisting of SEQ ID - 119 - 116104230Atty Docket No.40574-131 NO:128, a VH CDR2 comprising or consisting of SEQ ID NO:142, a VH CDR2 comprising or consisting of SEQ ID NO:156, a VH CDR2 comprising or consisting of SEQ ID NO:170, a VH CDR2 comprising or consisting of SEQ ID NO:184, a VH CDR2 comprising or consisting of SEQ ID NO:198, a VH CDR2 comprising or consisting of SEQ ID NO:226, a VH CDR2 comprising or consisting of SEQ ID NO:240, a VHCDR2 comprising or consisting of SEQ ID NO:254, a VHCDR2 comprising or consisting of SEQ ID NO:268, a VHCDR2 comprising or consisting of SEQ ID NO:282, a VHCDR2 comprising or consisting of SEQ ID NO:296, a VHCDR2 comprising or consisting of SEQ ID NO:296, a VHCDR2 comprising or consisting of SEQ ID NO:310, a VHCDR2 comprising or consisting of SEQ ID NO:324, a VH CDR2 comprising or consisting of SEQ ID NO:338, a VH CDR2 comprising or consisting of SEQ ID NO:352, a VH CDR2 comprising or consisting of SEQ ID NO:366, a VH CDR2 comprising or consisting of SEQ ID NO:380, a VH CDR2 comprising or consisting of SEQ ID NO:394, a VH CDR2 comprising or consisting of SEQ ID NO:408, a VHCDR2 comprising or consisting of SEQ ID NO:422, a VHCDR2 comprising or consisting of SEQ ID NO:436, a VHCDR2 comprising or consisting of SEQ ID NO:450, a VHCDR2 comprising or consisting of SEQ ID NO:464, a VHCDR2 comprising or consisting of SEQ ID NO:478, a VH CDR2 comprising or consisting of SEQ ID NO:492, a VH CDR2 comprising or consisting of SEQ ID NO:506, a VH CDR2 comprising or consisting of SEQ ID NO:520, a VH CDR2 comprising or consisting of SEQ ID NO:534, a VH CDR2 comprising or consisting of SEQ ID NO:548, a VH CDR2 comprising or consisting of SEQ ID NO:562, a VH CDR2 comprising or consisting of SEQ ID NO:576, a VHCDR2 comprising or consisting of SEQ ID NO:590, a VHCDR2 comprising or consisting of SEQ ID NO:604, or a VHCDR2 comprising or consisting of SEQ ID NO:618.

[0218] In some embodiments, the antibody or antigen-binding fragment thereof comprises aVL CDR2 selected from the group consisting of a VL CDR2 comprising or consisting of SEQ ID NO:7, a VL CDR2 comprising or consisting of SEQ ID NO:17, a VL CDR2 comprising or consisting of SEQ ID NO:27, a VL CDR2 comprising or consisting of SEQ ID NO:37, a VL CDR2 comprising or consisting of SEQ ID NO:47, a VLCDR2 comprising or consisting of SEQ ID NO:57, a VLCDR2 comprising or consisting of SEQ ID NO:67, a VLCDR2 comprising or consisting of SEQ ID NO:77, a VLCDR2 comprising or consisting of SEQ ID NO:87, a VLCDR2 comprising or consisting of SEQ ID NO:97, a VLCDR2 comprising or consisting of SEQ ID NO:107, and a VL CDR2 comprising or consisting of SEQ ID NO:117. - 120 - 116104230Atty Docket No.40574-131

[0219] In some embodiments, the antibody or antigen-binding fragment thereof comprises aVH CDR1 selected from the group consisting of a VH CDR1 comprising or consisting of SEQ ID NO:126, a VH CDR1 comprising or consisting of SEQ ID NO:140, a VH CDR1 comprising or consisting of SEQ ID NO:154, a VH CDR1 comprising or consisting of SEQ ID NO:168, a VH CDR1 comprising or consisting of SEQ ID NO:182, a VHCDR1 comprising or consisting of SEQ ID NO:196, a VHCDR1 comprising or consisting of SEQ ID NO:210, a VHCDR1 comprising or consisting of SEQ ID NO:224, a VHCDR1 comprising or consisting of SEQ ID NO:238, a VHCDR1 comprising or consisting of SEQ ID NO:252, a VHCDR1 comprising or consisting of SEQ ID NO:266, a VH CDR1 comprising or consisting of SEQ ID NO:280, a VH CDR1 comprising or consisting of SEQ ID NO:294, a VH CDR1 comprising or consisting of SEQ ID NO:308, a VH CDR1 comprising or consisting of SEQ ID NO:322, a VH CDR1 comprising or consisting of SEQ ID NO:336, a VH CDR1 comprising or consisting of SEQ ID NO:350, a VH CDR1 comprising or consisting of SEQ ID NO:364, a VHCDR1 comprising or consisting of SEQ ID NO:378, a VHCDR1 comprising or consisting of SEQ ID NO:392, a VHCDR1 comprising or consisting of SEQ ID NO:406, a VHCDR1 comprising or consisting of SEQ ID NO:420, a VHCDR1 comprising or consisting of SEQ ID NO:434, a VH CDR1 comprising or consisting of SEQ ID NO:448, a VH CDR1 comprising or consisting of SEQ ID NO:462, a VH CDR1 comprising or consisting of SEQ ID NO:476, a VH CDR1 comprising or consisting of SEQ ID NO:490, a VH CDR1 comprising or consisting of SEQ ID NO:504, a VH CDR1 comprising or consisting of SEQ ID NO:518, a VH CDR1 comprising or consisting of SEQ ID NO:532, a VHCDR1 comprising or consisting of SEQ ID NO:546, a VHCDR1 comprising or consisting of SEQ ID NO:560, a VHCDR1 comprising or consisting of SEQ ID NO:574, a VHCDR1 comprising or consisting of SEQ ID NO:588, a VHCDR1 comprising or consisting of SEQ ID NO:602, or a VH CDR1 comprising or consisting of SEQ ID NO:616.

[0220] In some embodiments, the antibody or antigen-binding fragment thereof comprises aVL CDR1 selected from the group consisting of a VL CDR1 comprising or consisting of SEQ ID NO:133, a VLCDR1 comprising or consisting of SEQ ID NO:147, a VLCDR1 comprising or consisting of SEQ ID NO:161, a VLCDR1 comprising or consisting of SEQ ID NO:175, a VLCDR1 comprising or consisting of SEQ ID NO:189, a VLCDR1 comprising or consisting of SEQ ID NO:203, a VLCDR1 comprising or consisting of SEQ ID NO:217, a VLCDR1 comprising or consisting of SEQ ID NO:231, a VL CDR1 comprising or consisting of SEQ ID NO:245, a VL - 121 - 116104230Atty Docket No.40574-131 CDR1 comprising or consisting of SEQ ID NO:259, a VL CDR1 comprising or consisting of SEQ ID NO:273, a VL CDR1 comprising or consisting of SEQ ID NO:287, a VL CDR1 comprising or consisting of SEQ ID NO:301, a VL CDR1 comprising or consisting of SEQ ID NO:315, a VL CDR1 comprising or consisting of SEQ ID NO:329, a VL CDR1 comprising or consisting of SEQ ID NO:343, a VLCDR1 comprising or consisting of SEQ ID NO:357, a VLCDR1 comprising or consisting of SEQ ID NO:371, a VLCDR1 comprising or consisting of SEQ ID NO:385, a VLCDR1 comprising or consisting of SEQ ID NO:399, a VLCDR1 comprising or consisting of SEQ ID NO:413, a VLCDR1 comprising or consisting of SEQ ID NO:427, a VLCDR1 comprising or consisting of SEQ ID NO:441, a VL CDR1 comprising or consisting of SEQ ID NO:455, a VL CDR1 comprising or consisting of SEQ ID NO:469, a VL CDR1 comprising or consisting of SEQ ID NO:483, a VL CDR1 comprising or consisting of SEQ ID NO:497, a VL CDR1 comprising or consisting of SEQ ID NO:511, a VL CDR1 comprising or consisting of SEQ ID NO:525, a VL CDR1 comprising or consisting of SEQ ID NO:539, a VLCDR1 comprising or consisting of SEQ ID NO:553, a VLCDR1 comprising or consisting of SEQ ID NO:567, a VLCDR1 comprising or consisting of SEQ ID NO:581, a VLCDR1 comprising or consisting of SEQ ID NO:595, a VLCDR1 comprising or consisting of SEQ ID NO:609, or a VL CDR1 comprising or consisting of SEQ ID NO:623.

[0221] In some embodiments, the antibody or antigen-binding fragment thereof comprises: i)a VH CDR3 comprising or consisting of SEQ ID NO:130 and a VL CDR3 comprising or consisting of SEQ ID NO:137; ii) a VHCDR3 comprising or consisting of SEQ ID NO:144 and a VLCDR3 comprising or consisting of SEQ ID NO:151; iii) a VHCDR3 comprising or consisting of SEQ ID NO:158 and a VLCDR3 comprising or consisting of SEQ ID NO:165; iv) a VHCDR3 comprising or consisting of SEQ ID NO:172 and a VL CDR3 comprising or consisting of SEQ ID NO:179; v) a VH CDR3 comprising or consisting of SEQ ID NO:186 and a VL CDR3 comprising or consisting of SEQ ID NO:193; vi) a VH CDR3 comprising or consisting of SEQ ID NO:200 and a VL CDR3 comprising or consisting of SEQ ID NO:207; vii) a VH CDR3 comprising or consisting of SEQ ID NO:214 and a VLCDR3 comprising or consisting of SEQ ID NO:221; viii) a VHCDR3 comprising or consisting of SEQ ID NO:228 and a VLCDR3 comprising or consisting of SEQ ID NO:235; ix) a VHCDR3 comprising or consisting of SEQ ID NO:242 and a VLCDR3 comprising or consisting of SEQ ID NO:249; x) a VHCDR3 comprising or consisting of SEQ ID NO:256 and a VL CDR3 comprising or consisting of SEQ ID NO:263; xi) a VH CDR3 comprising or consisting - 122 - 116104230Atty Docket No.40574-131 of SEQ ID NO:270 and a VL CDR3 comprising or consisting of SEQ ID NO:277; xii) a VH CDR3 comprising or consisting of SEQ ID NO:284 and a VL CDR3 comprising or consisting of SEQ ID NO:291; xiii) a VH CDR3 comprising or consisting of SEQ ID NO:298 and a VL CDR3 comprising or consisting of SEQ ID NO:305; xiv) a VH CDR3 comprising or consisting of SEQ ID NO:312 and a VLCDR3 comprising or consisting of SEQ ID NO:319; xv) a VHCDR3 comprising or consisting of SEQ ID NO:326 and a VLCDR3 comprising or consisting of SEQ ID NO:333; xvi) a VHCDR3 comprising or consisting of SEQ ID NO:340 and a VLCDR3 comprising or consisting of SEQ ID NO:347; xvii) a VHCDR3 comprising or consisting of SEQ ID NO:354 and a VLCDR3 comprising or consisting of SEQ ID NO:361; xviii) a VH CDR3 comprising or consisting of SEQ ID NO:368 and a VL CDR3 comprising or consisting of SEQ ID NO:375; xix) a VH CDR3 comprising or consisting of SEQ ID NO:382 and a VL CDR3 comprising or consisting of SEQ ID NO:389; xx) a VH CDR3 comprising or consisting of SEQ ID NO:396 and a VL CDR3 comprising or consisting of SEQ ID NO:403; xxi) a VHCDR3 comprising or consisting of SEQ ID NO:410 and a VLCDR3 comprising or consisting of SEQ ID NO:417; xxii) a VHCDR3 comprising or consisting of SEQ ID NO:424 and a VLCDR3 comprising or consisting of SEQ ID NO:431; xxiii) a VH CDR3 comprising or consisting of SEQ ID NO:438 and a VL CDR3 comprising or consisting of SEQ ID NO:445; xxiv) a VH CDR3 comprising or consisting of SEQ ID NO:452 and a VL CDR3 comprising or consisting of SEQ ID NO:459; xxv) a VH CDR3 comprising or consisting of SEQ ID NO:466 and a VL CDR3 comprising or consisting of SEQ ID NO:473; xxvi) a VH CDR3 comprising or consisting of SEQ ID NO:480 and a VLCDR3 comprising or consisting of SEQ ID NO:487; xxvii) a VHCDR3 comprising or consisting of SEQ ID NO:494 and a VLCDR3 comprising or consisting of SEQ ID NO:501; xxviii) a VHCDR3 comprising or consisting of SEQ ID NO:508 and a VL CDR3 comprising or consisting of SEQ ID NO:515; xxix) a VH CDR3 comprising or consisting of SEQ ID NO:522 and a VL CDR3 comprising or consisting of SEQ ID NO:529; xxx) a VH CDR3 comprising or consisting of SEQ ID NO:536 and a VL CDR3 comprising or consisting of SEQ ID NO:543; xxxi) a VH CDR3 comprising or consisting of SEQ ID NO:550 and a VLCDR3 comprising or consisting of SEQ ID NO:557; xxxii) a VHCDR3 comprising or consisting of SEQ ID NO:564 and a VLCDR3 comprising or consisting of SEQ ID NO:571; xxxiii) a VHCDR3 comprising or consisting of SEQ ID NO:578 and a VLCDR3 comprising or consisting of SEQ ID NO:585; xxxiv) a VHCDR3 comprising or consisting of SEQ ID NO:592 and a VLCDR3 comprising or consisting of SEQ ID NO:599; xxxv) a VH CDR3 comprising or consisting - 123 - 116104230Atty Docket No.40574-131 of SEQ ID NO:606 and a VL CDR3 comprising or consisting of SEQ ID NO:613; or xxxvi) a VH CDR3 comprising or consisting of SEQ ID NO:620 and a VL CDR3 comprising or consisting of SEQ ID NO:627.

[0222] In some embodiments, the antibody or antigen-binding fragment thereof comprises: i)a VHCDR1 comprising or consisting of SEQ ID NO:126, a VHCDR2 comprising or consisting of SEQ ID NO:128, and a VHCDR3 comprising or consisting of SEQ ID NO:130; ii) a VHCDR1 comprising or consisting of SEQ ID NO:140, a VHCDR2 comprising or consisting of SEQ ID NO:142, and a VHCDR3 comprising or consisting of SEQ ID NO:144; iii) a VHCDR1 comprising or consisting of SEQ ID NO:154, a VH CDR2 comprising or consisting of SEQ ID NO:156, and a VH CDR3 comprising or consisting of SEQ ID NO:158; iv) a VH CDR1 comprising or consisting of SEQ ID NO:168, a VH CDR2 comprising or consisting of SEQ ID NO:170, and a VH CDR3 comprising or consisting of SEQ ID NO:172; v) a VH CDR1 comprising or consisting of SEQ ID NO:182, a VHCDR2 comprising or consisting of SEQ ID NO:184, and a VHCDR3 comprising or consisting of SEQ ID NO:186; vi) a VHCDR1 comprising or consisting of SEQ ID NO:196, a VHCDR2 comprising or consisting of SEQ ID NO:198, and a VHCDR3 comprising or consisting of SEQ ID NO:200; vii) a VH CDR1 comprising or consisting of SEQ ID NO:210, a VH CDR2 comprising or consisting of SEQ ID NO:212, and a VH CDR3 comprising or consisting of SEQ ID NO:214; viii) a VH CDR1 comprising or consisting of SEQ ID NO:224, a VH CDR2 comprising or consisting of SEQ ID NO:226, and a VH CDR3 comprising or consisting of SEQ ID NO:228; ix) a VHCDR1 comprising or consisting of SEQ ID NO:238, a VHCDR2 comprising or consisting of SEQ ID NO:240, and a VHCDR3 comprising or consisting of SEQ ID NO:242; x) a VHCDR1 comprising or consisting of SEQ ID NO:252, a VHCDR2 comprising or consisting of SEQ ID NO:254, and a VH CDR3 comprising or consisting of SEQ ID NO:256; xi) a VH CDR1 comprising or consisting of SEQ ID NO:266, a VH CDR2 comprising or consisting of SEQ ID NO:268, and a VH CDR3 comprising or consisting of SEQ ID NO:270; xii) a VH CDR1 comprising or consisting of SEQ ID NO:280, a VH CDR2 comprising or consisting of SEQ ID NO:282, and a VH CDR3 comprising or consisting of SEQ ID NO:284; xiii) a VHCDR1 comprising or consisting of SEQ ID NO:294, a VHCDR2 comprising or consisting of SEQ ID NO:296, and a VHCDR3 comprising or consisting of SEQ ID NO:298; xiv) a VHCDR1 comprising or consisting of SEQ ID NO:308, a VHCDR2 comprising or consisting of SEQ ID NO:310, and a VHCDR3 comprising or consisting of SEQ ID NO:312; xv) a VH CDR1 comprising or consisting of SEQ ID NO:322, a VH CDR2 - 124 - 116104230Atty Docket No.40574-131 comprising or consisting of SEQ ID NO:324, and a VH CDR3 comprising or consisting of SEQ ID NO:326; xvi) a VH CDR1 comprising or consisting of SEQ ID NO:336, a VH CDR2 comprising or consisting of SEQ ID NO:338, and a VH CDR3 comprising or consisting of SEQ ID NO:340; xvii) a VH CDR1 comprising or consisting of SEQ ID NO:350, a VH CDR2 comprising or consisting of SEQ ID NO:352, and a VHCDR3 comprising or consisting of SEQ ID NO:354; xviii) a VHCDR1 comprising or consisting of SEQ ID NO:364, a VHCDR2 comprising or consisting of SEQ ID NO:366, and a VHCDR3 comprising or consisting of SEQ ID NO:368; xix) a VHCDR1 comprising or consisting of SEQ ID NO:378, a VHCDR2 comprising or consisting of SEQ ID NO:380, and a VH CDR3 comprising or consisting of SEQ ID NO:382; xx) a VH CDR1 comprising or consisting of SEQ ID NO:392, a VH CDR2 comprising or consisting of SEQ ID NO:394, and a VH CDR3 comprising or consisting of SEQ ID NO:396; xxi) a VH CDR1 comprising or consisting of SEQ ID NO:406, a VH CDR2 comprising or consisting of SEQ ID NO:408, and a VH CDR3 comprising or consisting of SEQ ID NO:410; xxii) a VHCDR1 comprising or consisting of SEQ ID NO:420, a VHCDR2 comprising or consisting of SEQ ID NO:422, and a VHCDR3 comprising or consisting of SEQ ID NO:424; xxiii) a VHCDR1 comprising or consisting of SEQ ID NO:434, a VH CDR2 comprising or consisting of SEQ ID NO:436, and a VH CDR3 comprising or consisting of SEQ ID NO:438; xxiv) a VH CDR1 comprising or consisting of SEQ ID NO:448, a VH CDR2 comprising or consisting of SEQ ID NO:450, and a VH CDR3 comprising or consisting of SEQ ID NO:452; xxv) a VH CDR1 comprising or consisting of SEQ ID NO:462, a VH CDR2 comprising or consisting of SEQ ID NO:464, and a VHCDR3 comprising or consisting of SEQ ID NO:466; xxvi) a VHCDR1 comprising or consisting of SEQ ID NO:476, a VHCDR2 comprising or consisting of SEQ ID NO:478, and a VHCDR3 comprising or consisting of SEQ ID NO:480; xxvii) a VH CDR1 comprising or consisting of SEQ ID NO:490, a VH CDR2 comprising or consisting of SEQ ID NO:492, and a VH CDR3 comprising or consisting of SEQ ID NO:494; xviii) a VH CDR1 comprising or consisting of SEQ ID NO:504, a VH CDR2 comprising or consisting of SEQ ID NO:506, and a VH CDR3 comprising or consisting of SEQ ID NO:508; xxix) a VH CDR1 comprising or consisting of SEQ ID NO:518, a VHCDR2 comprising or consisting of SEQ ID NO:520, and a VHCDR3 comprising or consisting of SEQ ID NO:522; xxx) a VHCDR1 comprising or consisting of SEQ ID NO:532, a VHCDR2 comprising or consisting of SEQ ID NO:534, and a VHCDR3 comprising or consisting of SEQ ID NO:536; xxxi) a VHCDR1 comprising or consisting of SEQ ID NO:546, a VH CDR2 comprising or consisting of SEQ ID - 125 - 116104230Atty Docket No.40574-131 NO:548, and a VH CDR3 comprising or consisting of SEQ ID NO:550; xxxii) a VH CDR1 comprising or consisting of SEQ ID NO:560, a VH CDR2 comprising or consisting of SEQ ID NO:562, and a VH CDR3 comprising or consisting of SEQ ID NO:564; xxxiii) a VH CDR1 comprising or consisting of SEQ ID NO:574, a VH CDR2 comprising or consisting of SEQ ID NO:576, and a VHCDR3 comprising or consisting of SEQ ID NO:578; xxxiv) a VHCDR1 comprising or consisting of SEQ ID NO:588, a VHCDR2 comprising or consisting of SEQ ID NO:590, and a VHCDR3 comprising or consisting of SEQ ID NO:592; xxxv) a VHCDR1 comprising or consisting of SEQ ID NO:602, a VHCDR2 comprising or consisting of SEQ ID NO:604, and a VH CDR3 comprising or consisting of SEQ ID NO:606; or xxxvi) a VH CDR1 comprising or consisting of SEQ ID NO:616, a VH CDR2 comprising or consisting of SEQ ID NO:618, and a VH CDR3 comprising or consisting of SEQ ID NO:620.

[0223] In some embodiments, the antibody or antigen-binding fragment thereof comprises: i)a VLCDR1 comprising or consisting of SEQ ID NO:133, a VLCDR2 comprising or consisting of SEQ ID NO:135, and a VLCDR3 comprising or consisting of SEQ ID NO:137; ii) a VLCDR1 comprising or consisting of SEQ ID NO:147, a VLCDR2 comprising or consisting of SEQ ID NO:149, and a VL CDR3 comprising or consisting of SEQ ID NO:151; iii) a VL CDR1 comprising or consisting of SEQ ID NO:161, a VL CDR2 comprising or consisting of SEQ ID NO:163, and a VL CDR3 comprising or consisting of SEQ ID NO:165; iv) a VL CDR1 comprising or consisting of SEQ ID NO:175, a VL CDR2 comprising or consisting of SEQ ID NO:177, and a VL CDR3 comprising or consisting of SEQ ID NO:179; v) a VLCDR1 comprising or consisting of SEQ ID NO:189, a VLCDR2 comprising or consisting of SEQ ID NO:191, and a VLCDR3 comprising or consisting of SEQ ID NO:193; vi) a VLCDR1 comprising or consisting of SEQ ID NO:203, a VLCDR2 comprising or consisting of SEQ ID NO:205, and a VL CDR3 comprising or consisting of SEQ ID NO:207; vii) a VL CDR1 comprising or consisting of SEQ ID NO:217, a VL CDR2 comprising or consisting of SEQ ID NO:219, and a VL CDR3 comprising or consisting of SEQ ID NO:221; viii) a VL CDR1 comprising or consisting of SEQ ID NO:231, a VL CDR2 comprising or consisting of SEQ ID NO:233, and a VLCDR3 comprising or consisting of SEQ ID NO:235; ix) a VLCDR1 comprising or consisting of SEQ ID NO:245, a VLCDR2 comprising or consisting of SEQ ID NO:247, and a VLCDR3 comprising or consisting of SEQ ID NO:249; x) a VLCDR1 comprising or consisting of SEQ ID NO:259, a VLCDR2 comprising or consisting of SEQ ID NO:261, and a VL CDR3 comprising or consisting of SEQ ID NO:263; xi) a VL CDR1 comprising - 126 - 116104230Atty Docket No.40574-131 or consisting of SEQ ID NO:273, a VL CDR2 comprising or consisting of SEQ ID NO:275, and a VL CDR3 comprising or consisting of SEQ ID NO:277; xii) a VL CDR1 comprising or consisting of SEQ ID NO:287, a VL CDR2 comprising or consisting of SEQ ID NO:289, and a VL CDR3 comprising or consisting of SEQ ID NO:291; xiii) a VL CDR1 comprising or consisting of SEQ ID NO:301, a VLCDR2 comprising or consisting of SEQ ID NO:303, or a VLCDR3 comprising or consisting of SEQ ID NO:305; xiv) a VLCDR1 comprising or consisting of SEQ ID NO:315, a VLCDR2 comprising or consisting of SEQ ID NO:317, or a VLCDR3 comprising or consisting of SEQ ID NO:319; xv) a VLCDR1 comprising or consisting of SEQ ID NO:329, a VLCDR2 comprising or consisting of SEQ ID NO:331, or a VL CDR3 comprising or consisting of SEQ ID NO:333; xvi) a VL CDR1 comprising or consisting of SEQ ID NO:343, a VL CDR2 comprising or consisting of SEQ ID NO:345, or a VL CDR3 comprising or consisting of SEQ ID NO:347; xvii) a VL CDR1 comprising or consisting of SEQ ID NO:357, a VL CDR2 comprising or consisting of SEQ ID NO:359, or a VLCDR3 comprising or consisting of SEQ ID NO:361; xviii) a VLCDR1 comprising or consisting of SEQ ID NO:371, a VLCDR2 comprising or consisting of SEQ ID NO:373, or a VLCDR3 comprising or consisting of SEQ ID NO:375; xix) a VLCDR1 comprising or consisting of SEQ ID NO:385, a VL CDR2 comprising or consisting of SEQ ID NO:387, or a VL CDR3 comprising or consisting of SEQ ID NO:389; xx) a VL CDR1 comprising or consisting of SEQ ID NO:399, a VL CDR2 comprising or consisting of SEQ ID NO:401, or a VL CDR3 comprising or consisting of SEQ ID NO:403; xxi) a VL CDR1 comprising or consisting of SEQ ID NO:413, a VLCDR2 comprising or consisting of SEQ ID NO:415, or a VLCDR3 comprising or consisting of SEQ ID NO:417; xxii) a VLCDR1 comprising or consisting of SEQ ID NO:427, a VLCDR2 comprising or consisting of SEQ ID NO:429, or a VLCDR3 comprising or consisting of SEQ ID NO:431; xxiii) a VL CDR1 comprising or consisting of SEQ ID NO:441, a VL CDR2 comprising or consisting of SEQ ID NO:443, or a VL CDR3 comprising or consisting of SEQ ID NO:445; xxiv) a VL CDR1 comprising or consisting of SEQ ID NO:455, a VL CDR2 comprising or consisting of SEQ ID NO:457, or a VL CDR3 comprising or consisting of SEQ ID NO:459; xxv) a VLCDR1 comprising or consisting of SEQ ID NO:469, a VLCDR2 comprising or consisting of SEQ ID NO:471, or a VLCDR3 comprising or consisting of SEQ ID NO:473; xxvi) a VLCDR1 comprising or consisting of SEQ ID NO:483, a VLCDR2 comprising or consisting of SEQ ID NO:485, or a VLCDR3 comprising or consisting of SEQ ID NO:487; xxvii) a VLCDR1 comprising or consisting of SEQ ID NO:497, a VL CDR2 comprising or consisting of SEQ ID - 127 - 116104230Atty Docket No.40574-131 NO:499, or a VL CDR3 comprising or consisting of SEQ ID NO:501; xxviii) a VL CDR1 comprising or consisting of SEQ ID NO:511, a VL CDR2 comprising or consisting of SEQ ID NO:513, or a VL CDR3 comprising or consisting of SEQ ID NO:515; xxix) a VL CDR1 comprising or consisting of SEQ ID NO:525, a VL CDR2 comprising or consisting of SEQ ID NO:527, or a VLCDR3 comprising or consisting of SEQ ID NO:529; xxx) a VLCDR1 comprising or consisting of SEQ ID NO:539, a VLCDR2 comprising or consisting of SEQ ID NO:541, or a VLCDR3 comprising or consisting of SEQ ID NO:543; xxxi) a VLCDR1 comprising or consisting of SEQ ID NO:553, a VLCDR2 comprising or consisting of SEQ ID NO:555, or a VLCDR3 comprising or consisting of SEQ ID NO:557; xxxii) a VL CDR1 comprising or consisting of SEQ ID NO:567, a VL CDR2 comprising or consisting of SEQ ID NO:569, or a VL CDR3 comprising or consisting of SEQ ID NO:571; xxxiii) a VL CDR1 comprising or consisting of SEQ ID NO:581, a VL CDR2 comprising or consisting of SEQ ID NO:583, or a VL CDR3 comprising or consisting of SEQ ID NO:585; xxxiv) a VLCDR1 comprising or consisting of SEQ ID NO:595, a VLCDR2 comprising or consisting of SEQ ID NO:597, or a VLCDR3 comprising or consisting of SEQ ID NO:599; xxxv) a VLCDR1 comprising or consisting of SEQ ID NO:609, a VLCDR2 comprising or consisting of SEQ ID NO:611, or a VL CDR3 comprising or consisting of SEQ ID NO:613; or xxxvi) a VL CDR1 comprising or consisting of SEQ ID NO:623, a VL CDR2 comprising or consisting of SEQ ID NO:625, or a VL CDR3 comprising or consisting of SEQ ID NO:627.

[0224] In some embodiments, the antibody or antigen-binding fragment thereof comprises: i)a VHCDR1 comprising or consisting of SEQ ID NO:126, a VHCDR2 comprising or consisting of SEQ ID NO:128, a VHCDR3 comprising or consisting of SEQ ID NO:130, a VLCDR1 comprising or consisting of SEQ ID NO:133, a VLCDR2 comprising or consisting of SEQ ID NO:135, and a VL CDR3 comprising or consisting of SEQ ID NO:137; ii) a VH CDR1 comprising or consisting of SEQ ID NO:140, a VH CDR2 comprising or consisting of SEQ ID NO:142, a VH CDR3 comprising or consisting of SEQ ID NO:144; a VL CDR1 comprising or consisting of SEQ ID NO:147, a VL CDR2 comprising or consisting of SEQ ID NO:149, and a VL CDR3 comprising or consisting of SEQ ID NO:151; iii) a VHCDR1 comprising or consisting of SEQ ID NO:154, a VHCDR2 comprising or consisting of SEQ ID NO:156, a VHCDR3 comprising or consisting of SEQ ID NO:158; a VLCDR1 comprising or consisting of SEQ ID NO:161, a VLCDR2 comprising or consisting of SEQ ID NO:163, and a VLCDR3 comprising or consisting of SEQ ID NO:165; iv) a VH CDR1 comprising or consisting of SEQ ID NO:168, a VH CDR2 comprising or consisting of - 128 - 116104230Atty Docket No.40574-131 SEQ ID NO:170, a VH CDR3 comprising or consisting of SEQ ID NO:172; a VL CDR1 comprising or consisting of SEQ ID NO:175, a VL CDR2 comprising or consisting of SEQ ID NO:177, and a VL CDR3 comprising or consisting of SEQ ID NO:179; v) a VH CDR1 comprising or consisting of SEQ ID NO:182, a VH CDR2 comprising or consisting of SEQ ID NO:184, a VH CDR3 comprising or consisting of SEQ ID NO:186; a VLCDR1 comprising or consisting of SEQ ID NO:189, a VLCDR2 comprising or consisting of SEQ ID NO:191, and a VLCDR3 comprising or consisting of SEQ ID NO:193; vi) a VHCDR1 comprising or consisting of SEQ ID NO:196, a VHCDR2 comprising or consisting of SEQ ID NO:198, a VHCDR3 comprising or consisting of SEQ ID NO:200; a VL CDR1 comprising or consisting of SEQ ID NO:203, a VL CDR2 comprising or consisting of SEQ ID NO:205, and a VL CDR3 comprising or consisting of SEQ ID NO:207; vii) a VH CDR1 comprising or consisting of SEQ ID NO:210, a VH CDR2 comprising or consisting of SEQ ID NO:212, a VH CDR3 comprising or consisting of SEQ ID NO:214; a VL CDR1 comprising or consisting of SEQ ID NO:217, a VLCDR2 comprising or consisting of SEQ ID NO:219, and a VLCDR3 comprising or consisting of SEQ ID NO:221; viii) a VHCDR1 comprising or consisting of SEQ ID NO:224, a VHCDR2 comprising or consisting of SEQ ID NO:226, a VHCDR3 comprising or consisting of SEQ ID NO:228; a VL CDR1 comprising or consisting of SEQ ID NO:231, a VL CDR2 comprising or consisting of SEQ ID NO:233, and a VL CDR3 comprising or consisting of SEQ ID NO:235; ix) a VH CDR1 comprising or consisting of SEQ ID NO:238, a VH CDR2 comprising or consisting of SEQ ID NO:240, a VH CDR3 comprising or consisting of SEQ ID NO:242; a VLCDR1 comprising or consisting of SEQ ID NO:245, a VLCDR2 comprising or consisting of SEQ ID NO:247, and a VLCDR3 comprising or consisting of SEQ ID NO:249; x) a VHCDR1 comprising or consisting of SEQ ID NO:252, a VHCDR2 comprising or consisting of SEQ ID NO:254, a VH CDR3 comprising or consisting of SEQ ID NO:256; a VL CDR1 comprising or consisting of SEQ ID NO:259, a VL CDR2 comprising or consisting of SEQ ID NO:261, and a VL CDR3 comprising or consisting of SEQ ID NO:263; xi) a VH CDR1 comprising or consisting of SEQ ID NO:266, a VH CDR2 comprising or consisting of SEQ ID NO:268, a VH CDR3 comprising or consisting of SEQ ID NO:270; a VLCDR1 comprising or consisting of SEQ ID NO:273, a VLCDR2 comprising or consisting of SEQ ID NO:275, and a VLCDR3 comprising or consisting of SEQ ID NO:277; xii) a VHCDR1 comprising or consisting of SEQ ID NO:280, a VHCDR2 comprising or consisting of SEQ ID NO:282, a VHCDR3 comprising or consisting of SEQ ID NO:284, a VL CDR1 comprising or consisting of SEQ ID NO:287, a VL CDR2 comprising or - 129 - 116104230Atty Docket No.40574-131 consisting of SEQ ID NO:289, or a VL CDR3 comprising or consisting of SEQ ID NO:291; xiii) a VH CDR1 comprising or consisting of SEQ ID NO:294, a VH CDR2 comprising or consisting of SEQ ID NO:296, a VH CDR3 comprising or consisting of SEQ ID NO:298, a VL CDR1 comprising or consisting of SEQ ID NO:301, a VL CDR2 comprising or consisting of SEQ ID NO:303, or a VLCDR3 comprising or consisting of SEQ ID NO:305; xiv) a VHCDR1 comprising or consisting of SEQ ID NO:308, a VHCDR2 comprising or consisting of SEQ ID NO:310, a VHCDR3 comprising or consisting of SEQ ID NO:312, a VLCDR1 comprising or consisting of SEQ ID NO:315, a VLCDR2 comprising or consisting of SEQ ID NO:317, or a VLCDR3 comprising or consisting of SEQ ID NO:319; xv) a VH CDR1 comprising or consisting of SEQ ID NO:322, a VH CDR2 comprising or consisting of SEQ ID NO:324, a VH CDR3 comprising or consisting of SEQ ID NO:326, a VL CDR1 comprising or consisting of SEQ ID NO:329, a VL CDR2 comprising or consisting of SEQ ID NO:331, or a VL CDR3 comprising or consisting of SEQ ID NO:333; xvi) a VHCDR1 comprising or consisting of SEQ ID NO:336, a VHCDR2 comprising or consisting of SEQ ID NO:338, a VHCDR3 comprising or consisting of SEQ ID NO:340, a VLCDR1 comprising or consisting of SEQ ID NO:343, a VLCDR2 comprising or consisting of SEQ ID NO:345, or a VL CDR3 comprising or consisting of SEQ ID NO:347; xvii) a VH CDR1 comprising or consisting of SEQ ID NO:350, a VH CDR2 comprising or consisting of SEQ ID NO:352, a VH CDR3 comprising or consisting of SEQ ID NO:354, a VL CDR1 comprising or consisting of SEQ ID NO:357, a VL CDR2 comprising or consisting of SEQ ID NO:359, or a VL CDR3 comprising or consisting of SEQ ID NO:361; xviii) a VHCDR1 comprising or consisting of SEQ ID NO:364, a VHCDR2 comprising or consisting of SEQ ID NO:366, a VHCDR3 comprising or consisting of SEQ ID NO:368, a VLCDR1 comprising or consisting of SEQ ID NO:371, a VLCDR2 comprising or consisting of SEQ ID NO:373, or a VL CDR3 comprising or consisting of SEQ ID NO:375; xix) a VH CDR1 comprising or consisting of SEQ ID NO:378, a VH CDR2 comprising or consisting of SEQ ID NO:380, a VH CDR3 comprising or consisting of SEQ ID NO:382, a VL CDR1 comprising or consisting of SEQ ID NO:385, a VL CDR2 comprising or consisting of SEQ ID NO:387, or a VLCDR3 comprising or consisting of SEQ ID NO:389; xx) a VHCDR1 comprising or consisting of SEQ ID NO:392, a VHCDR2 comprising or consisting of SEQ ID NO:394, a VHCDR3 comprising or consisting of SEQ ID NO:396, a VLCDR1 comprising or consisting of SEQ ID NO:399, a VLCDR2 comprising or consisting of SEQ ID NO:401, or a VLCDR3 comprising or consisting of SEQ ID NO:403; xxi) a VH CDR1 comprising or consisting of SEQ ID NO:406, a - 130 - 116104230Atty Docket No.40574-131 VH CDR2 comprising or consisting of SEQ ID NO:408, a VH CDR3 comprising or consisting of SEQ ID NO:410, a VL CDR1 comprising or consisting of SEQ ID NO:413, a VL CDR2 comprising or consisting of SEQ ID NO:415, or a VL CDR3 comprising or consisting of SEQ ID NO:417; xxii) a VH CDR1 comprising or consisting of SEQ ID NO:420, a VH CDR2 comprising or consisting of SEQ ID NO:422, a VHCDR3 comprising or consisting of SEQ ID NO:424, a VLCDR1 comprising or consisting of SEQ ID NO:427, a VLCDR2 comprising or consisting of SEQ ID NO:429, or a VLCDR3 comprising or consisting of SEQ ID NO:431; xxiii) a VHCDR1 comprising or consisting of SEQ ID NO:434, a VHCDR2 comprising or consisting of SEQ ID NO:436, a VH CDR3 comprising or consisting of SEQ ID NO:438, a VL CDR1 comprising or consisting of SEQ ID NO:441, a VL CDR2 comprising or consisting of SEQ ID NO:443, or a VL CDR3 comprising or consisting of SEQ ID NO:445; xxiv) a VH CDR1 comprising or consisting of SEQ ID NO:448, a VH CDR2 comprising or consisting of SEQ ID NO:450, a VH CDR3 comprising or consisting of SEQ ID NO:452, a VLCDR1 comprising or consisting of SEQ ID NO:455, a VLCDR2 comprising or consisting of SEQ ID NO:457, or a VLCDR3 comprising or consisting of SEQ ID NO:459; xxv) a VHCDR1 comprising or consisting of SEQ ID NO:462, a VH CDR2 comprising or consisting of SEQ ID NO:464, a VH CDR3 comprising or consisting of SEQ ID NO:466, a VL CDR1 comprising or consisting of SEQ ID NO:469, a VL CDR2 comprising or consisting of SEQ ID NO:471, or a VL CDR3 comprising or consisting of SEQ ID NO:473; xxvi) a VH CDR1 comprising or consisting of SEQ ID NO:476, a VH CDR2 comprising or consisting of SEQ ID NO:478, a VHCDR3 comprising or consisting of SEQ ID NO:480, a VLCDR1 comprising or consisting of SEQ ID NO:483, a VLCDR2 comprising or consisting of SEQ ID NO:485, or a VLCDR3 comprising or consisting of SEQ ID NO:487; xxvii) a VHCDR1 comprising or consisting of SEQ ID NO:490, a VH CDR2 comprising or consisting of SEQ ID NO:492, a VH CDR3 comprising or consisting of SEQ ID NO:494, a VL CDR1 comprising or consisting of SEQ ID NO:497, a VL CDR2 comprising or consisting of SEQ ID NO:499, or a VL CDR3 comprising or consisting of SEQ ID NO:501; xxviii) a VH CDR1 comprising or consisting of SEQ ID NO:504, a VHCDR2 comprising or consisting of SEQ ID NO:506, a VHCDR3 comprising or consisting of SEQ ID NO:508, a VLCDR1 comprising or consisting of SEQ ID NO:511, a VLCDR2 comprising or consisting of SEQ ID NO:513, or a VLCDR3 comprising or consisting of SEQ ID NO:515; xxix) a VHCDR1 comprising or consisting of SEQ ID NO:518, a VH CDR2 comprising or consisting of SEQ ID NO:520, a VH CDR3 comprising or consisting of - 131 - 116104230Atty Docket No.40574-131 SEQ ID NO:522, a VL CDR1 comprising or consisting of SEQ ID NO:525, a VL CDR2 comprising or consisting of SEQ ID NO:527, or a VL CDR3 comprising or consisting of SEQ ID NO:529; xxx) a VH CDR1 comprising or consisting of SEQ ID NO:532, a VH CDR2 comprising or consisting of SEQ ID NO:534, a VH CDR3 comprising or consisting of SEQ ID NO:536, a VL CDR1 comprising or consisting of SEQ ID NO:539, a VLCDR2 comprising or consisting of SEQ ID NO:541, or a VLCDR3 comprising or consisting of SEQ ID NO:543; xxxi) a VHCDR1 comprising or consisting of SEQ ID NO:546, a VHCDR2 comprising or consisting of SEQ ID NO:548, a VHCDR3 comprising or consisting of SEQ ID NO:550, a VLCDR1 comprising or consisting of SEQ ID NO:553, a VL CDR2 comprising or consisting of SEQ ID NO:555, or a VL CDR3 comprising or consisting of SEQ ID NO:557; xxxii) a VH CDR1 comprising or consisting of SEQ ID NO:560, a VH CDR2 comprising or consisting of SEQ ID NO:562, a VH CDR3 comprising or consisting of SEQ ID NO:564, a VL CDR1 comprising or consisting of SEQ ID NO:567, a VLCDR2 comprising or consisting of SEQ ID NO:569, or a VLCDR3 comprising or consisting of SEQ ID NO:571; xxxiii) a VHCDR1 comprising or consisting of SEQ ID NO:574, a VHCDR2 comprising or consisting of SEQ ID NO:576, a VHCDR3 comprising or consisting of SEQ ID NO:578, a VL CDR1 comprising or consisting of SEQ ID NO:581, a VL CDR2 comprising or consisting of SEQ ID NO:583, or a VL CDR3 comprising or consisting of SEQ ID NO:585; xxxiv) a VH CDR1 comprising or consisting of SEQ ID NO:588, a VH CDR2 comprising or consisting of SEQ ID NO:590, a VH CDR3 comprising or consisting of SEQ ID NO:592, a VL CDR1 comprising or consisting of SEQ ID NO:595, a VLCDR2 comprising or consisting of SEQ ID NO:597, or a VLCDR3 comprising or consisting of SEQ ID NO:599; xxxv) a VHCDR1 comprising or consisting of SEQ ID NO:602, a VHCDR2 comprising or consisting of SEQ ID NO:604, a VH CDR3 comprising or consisting of SEQ ID NO:606, a VL CDR1 comprising or consisting of SEQ ID NO:609, a VL CDR2 comprising or consisting of SEQ ID NO:611, or a VL CDR3 comprising or consisting of SEQ ID NO:613; or xxxvi) a VH CDR1 comprising or consisting of SEQ ID NO:616, a VH CDR2 comprising or consisting of SEQ ID NO:618, a VH CDR3 comprising or consisting of SEQ ID NO:620, a VLCDR1 comprising or consisting of SEQ ID NO:623, a VLCDR2 comprising or consisting of SEQ ID NO:625, or a VLCDR3 comprising or consisting of SEQ ID NO:627.

[0225] In some embodiments, the antibody or antigen-binding fragment thereof is selectedfrom the group consisting of 1E11, 2A09, 5H03, 5C10, and 1A09-H. - 132 - 116104230Atty Docket No.40574-131

[0226] In some embodiments, the antibody or antigen-binding fragment thereof is a humanizedantibody.

[0227] In some embodiments, the antibody or antigen-binding fragment thereof is isolated.

[0228] In some embodiments, the antibody or antigen-binding fragment thereof is complexedwith an EV-D68 virion.

[0229] In some embodiments, the antibody or antigen-binding fragment thereof inhibitsbinding of an EV-D68-228 antibody to an EV-D68 virion.

[0230] Disclosed are compositions comprising at least one antibody or antigen-bindingfragment thereof, wherein the composition comprises a plurality of antibodies or antigen-binding fragments thereof.

[0231] In some embodiments, the composition further comprises at least one therapeuticcompound.

[0232] In some embodiments, the at least one therapeutic compound comprises an antiviralcompound, an antibiotic, a steroid, rupintrivir–vemurafenib, vemurafenib–pleconaril, rupintrivir– pleconaril, or rupintrivir–cycloheximide.

[0233] Disclosed are methods of protecting an individual against infection with an enterovirus,treating an individual having an enterovirus infection, or reducing disease symptoms in an individual infected with an enterovirus, comprising administering to the individual an antibody or antigen-binding fragment thereof or a composition.

[0234] In some embodiments, the individual is administered a composition comprising anantibody or antigen-binding fragment thereof.

[0235] In some embodiments, the composition further comprises at least one therapeutic agent.

[0236] In some embodiments, the at least one therapeutic agent comprises an antiviralcompound, an antibiotic, a steroid, rupintrivir–vemurafenib, vemurafenib–pleconaril, rupintrivir– pleconaril or rupintrivir–cycloheximide.

[0237] In some embodiments, the individual is administered the antibody or antigen-bindingfragment thereof by one route of administration and at least one therapeutic agent by another route of administration.

[0238] In some embodiments, the at least one therapeutic agent comprises an antiviralcompound, an antibiotic, a steroid, rupintrivir–vemurafenib, vemurafenib–pleconaril, rupintrivir– pleconaril or rupintrivir–cycloheximide. - 133 - 116104230Atty Docket No.40574-131

[0239] Examples

[0240] Example 1. Vaccination of rhesus macaques with an EV-D68 VLP generates robustneutralizing antibody responses against multiple EV-D68 subclades.

[0241] Previous work has shown that an EV-D68 B3 subclade VLP vaccine induces cross-clade neutralizing antibody responses in mice and NHP. Sera from mice immunized with an EV- D68 B3 VLP exhibited reduced neutralization capacity for both the B1 and A2 subclade viruses. However, sera from two rhesus macaques immunized with EV-D68 B3 VLP exhibited similar neutralizing activity against a B3 subclade isolate and its B1 ancestor, as well as an A2 subclade isolate (FIGS.1A & 1B). The NHP study was extended to two additional vaccinations with an EV- D68 A2 subclade VLP to test the effect of a boost 20 weeks after a previous immunization and to expand the breadth of EV-D68 reactive antibodies. We observed a robust boost in EV-D68 serum neutralizing antibodies against B1, B3, and A2 EV-D68 subclades demonstrating that vaccination of NHP with a EV-D68 VLP vaccine induces broadly reactive antibodies.

[0242] Example 2. Identification and screening of NHP EV-D68 monoclonal antibodies

[0243] VLP-elicited antibodies were evaluated by isolating individual EV-D68 reactive B cellsand generating monoclonal antibodies. EV-D68 B3 and A2 subclade VLPs were used as B-cell capture probes in a multiparameter flow cytometry panel to stain and single-cell sort EV-D68 specific B cells binding one or both VLPs from peripheral blood mononuclear cells (PMBCs) collected two weeks after the third and fourth doses from immunized NHPs. Within the IgG+ B cell population, distinct populations of EV-D68 reactive B cells that either bound both VLPs or were specific for only the B3 VLP were observed. Cell culture supernatants containing mAbs along with heavy and light chain gene sequences were generated using the RATP-Ig pipeline. See Lima et al., Nat. Commun. 13:7733 (2022). Cell culture supernatants were screened for by ELISA for antibodies binding to either the B3 or A2 VLP. It was found that most of the antibodies bound both VLPs (FIG. 2A). When the binding of the B3 to the A2 VLP was compared, it was observed that most antibodies exhibited no preference for either VLP with a ratio at or close to one (FIG. 2B). Because antibody concentration in the cell culture supernatants were not normalized before ELISA screening, differences in binding and the magnitude of ELISA signal could not be distinguished from differences in affinity or expression levels of the recombinant antibody.

[0244] Antibodies that bound either B3 or both VLPs for which sequence data were obtainedwere then screened for neutralizing activity in a two-point neutralization assay against both B3 - 134 - 116104230Atty Docket No.40574-131 and A2 virus isolates at a 1:10 and 1:500 dilution. Antibodies that neutralized either the B3 or A2 viruses exhibited a broad range of ELISA binding activity with a binding preference for either the B3 VLP or both the B3 and A2 VLPs (FIG.2C). Most of the antibodies we screened for which we also had sequence data did not neutralize EV-D68. We identified 36 unique antibodies that exhibited neutralization activity against either (or both) B3 and A2 isolates of EV-D68 for further characterization. Antibody sequence data for these clones are shown in Table 1.

[0245] Example 3. VLP-vaccine elicited EV-D68 antibodies exhibit a broad range of bindingand neutralization activity

[0246] The heavy and light chains for the 36 down selected antibodies were cloned andexpressed to determine their binding and neutralization properties and potency. Binding against the B3 and A2 VLPs was evaluated by indirect ELISA and EC50 values to both VLPs (FIG3A) were calculated. Nearly all antibodies tested exhibited a binding EC50 at or below 5 µg / mL for both VLPs while a few antibodies exhibited lower affinity for the A2 VLP than the B3 VLP. Two antibodies, 1C12 and 2H09, demonstrated a strong preference for the B3 VLP compared to the A2 VLP. As anticipated based on down-selection criteria, all antibodies tested exhibited neutralizingHJYP[PY^ HNHPTXY 5- 8F'702 HTK SUXY TLZYWHRP_LK HY HT <6 / * ILRU\ / hN)S> #9<:-5$( 8RL[LTantibodies exhibited greatly reduced or undetectable neutralizing activity against an A2 isolate despite exhibiting similar binding activity by ELISA. Five antibodies were selected for further characterization because they exhibited higher neutralization potency against both the B3 and A2 isolates compared to antibody EV68-228, a known potent, EV-neutralizing human mAb (see, for example, U.S. Patent Publication No.2022 / 0289828, which is incorporated herein by reference in its entirety) or exhibited equal potency against both isolates.

[0247] The selected antibodies were tested for neutralization against the VLP matched B3 andA2 EV-D68 isolates as well as an older B1 virus that is no longer circulating (FIG. 3C). All antibodies neutralized the B3 and A2 viruses more potently than EV68-228 except for antibody 5C10 which was chosen for further characterization because it neutralized both A2 and B3 viruses with equal potency (FIG. 3D). Only one antibody, 2A09, neutralized an EV-D68 B1 virus as potently as EV68-228 while all other antibodies neutralized B1 with reduced potency compared to EV68-228. These data demonstrate that EV-D68 VLP vaccine candidates elicit neutralizing antibodies with comparable potency to one generated by natural infection in humans. - 135 - 116104230Atty Docket No.40574-131

[0248] The binding kinetics of potent antibodies for the EV-D68 B3 VLP was characterizedusing Bio-layer interferometry (BLI). Fab fragments from the top five neutralizing antibodies and EV68-228 were generated and a kinetic analysis performed (FIG. 4A). Kinetic analysis software was used to determine the association and dissociation rates and dissociation constants for each fab. More potent antibodies in general exhibited a higher association rate (FIG. 4B) and a lower dissociation rate (FIG.4C) and a lower dissociation constant (FIG.4D). Antibody 5H03 exhibited inferior association and dissociation rates compared to other antibodies such as 1E11 and 1A09, but this did not translate into significant differences in neutralization IC50. Antibody 5C10 required higher concentrations to generate reproducible sensorgrams and exhibited high association and dissociation rates that were difficult to reliably measure. Antibody EV68-228 exhibited the highest dissociation rate for the EV-D68 B3 VLP but maintained a high association rate which may account for its retained neutralization potency against the B3 and A2 viruses. Potent EV-D68 antibodies isolated from immunized NHPs exhibited a range of binding kinetic characteristics that do not necessarily predict neutralization potency.

[0249] To test if differences in fab binding kinetics translated into differences in fabneutralization potency, with a higher dissociation rate predicting reduced neutralization potency of the corresponding fab, neutralization assays against B3 and A2 viruses were performed using antibody fabs (FIGS.5A and 5B). Decreased neutralization potency for all fabs compared to their corresponding IgGs (FIGS. 5C and 5D) was observed. In particular Fabs from mAbs 1E11, 5C10 and EV68-228 exhibited the greatest change in neutralization potency against the B3 virus while against the A2 virus fabs 1E11, 2A09 and EV68-228 performed the most poorly. These data suggest that fab dissociation rate in BLI kinetic assays is a poor predictor of fab potency and other factors in a neutralization assay may be more important such as epitope specificity and association rate.

[0250] The fabs generated for kinetic analysis were used to perform an epitope binningexperiment using BLI and the EV-D68 B3 VLP. To identify binding sites, two antibodies with known binding sites were included: EV68-228, which binds at the five-fold axis of symmetry, and 15C5, a mouse antibody that binds at the three-fold axis of symmetry. Fabs for all five of the selected NHP antibodies blocked binding of EV68-228 fab and not 15C5 fab suggesting that they bind at or near the five-fold axis of symmetry (Fig.4E). Fab 5C10 blocked 15C5 only when it was bound to the VLP first, suggesting indirect blocking by steric hinderance rather than a shared - 136 - 116104230Atty Docket No.40574-131 epitope. Blocking when fab EV68-228 was loaded first was complicated by its high dissociation rate (Fig. 4C). These data suggest that screening for potent neutralizing antibodies in EV-D68- immunized NHP enriches for antibodies that target the five-fold axis of symmetry.

[0251] Example 4. Structural analysis of EV-D68 antibodies

[0252] Epitope binning demonstrated that potent VLP-elicited NHP mAbs bind at or near thefive-fold axis of symmetry and compete with EV68-228, suggesting that these mAbs share a common or similar epitope. To confirm these observations, cryo-electron microscopy (Cryo-EM) structures of EV-D68 B3 VLP in complex with fabs generated from mAbs 1E11 and 5H03 were produced. E11 was chosen due to its potency and favorable binding kinetics and 5H03 because BLI binning data suggested it may be targeting a distinct epitope. Analysis of the Cryo-EM B3 VLP and 1E11 fab model revealed that this antibody does indeed target the five-fold axis. Close inspection of the molecular interface showed that the 1E11 heavy chain contacts the VP1 BC loop and VP3 C-terminus and regions of the VLP that form the canyon while the light chain contacts the VP1 C-terminus and VP0 EF loop. 1E11 therefore neutralizes EV-D68 by binding to the canyon and blocking receptor binding.

[0253] Examination of the B3 VLP and 5H03 fab constructure showed that 5H03 also targetsthe five-fold axis. However, the heavy and light chain positions are flipped 180 degrees relative to how mAb 1E11 binds the VLP. Examination of the molecular interface reveals that the 5H03 heavy chain contacts the VP1 C-terminus and VP0 EF loop while the light chain contacts the VP3 C-terminus and the canyon. Interestingly, mAb 5H03 does not contact the VP1 BC loop which contains residues that vary between different isolates of the B3 strain as well as between the B3 and A2 / D subclades.

[0254] The epitopes of mAbs 1E11 and 5H03 were compared with that of EV68-228 that hasbeen previously reported. It was observed that mAb 1E11 and EV68-228 recognize nearly identical epitopes on the EV-D68 B3 VLP or EV-D68 B1 inactivated virus respectively.5H03 on the other hand recognizes an overlapping but unique epitope compared to 1E11 and EV68-228. Both antibodies, 1E11 and 5H03, contact the VLP with more of their light chain compared to EV68- 228 which mostly contacts the virus with its heavy chain. Structural determination of the 1E11 and 5H03 mAbs confirmed that these high potency VLP-elicited neutralizing antibodies target the five- fold axis of symmetry.

[0255] Example 5. Protective efficacy of EV-D68 in a mouse model of respiratory infection- 137 - 116104230Atty Docket No.40574-131

[0256] The protective potential of VLP-induced EV-D68 NHP mAbs in a mouse model of EV-D68 respiratory infection was tested. In this model, interferon receptor knockout mice AG129 are passively immunized with purified serum IgG or mAb, infected intranasally with mouse-adapted EV-D68 (B3 Mp20) then virus titer is assessed in tissues two days post infection (FIG. 6A). The B3 Mp20 virus contains capsid mutations resulting from mouse adaptation that in preliminary experiments rendered the virus insensitive to neutralization by antibodies 1A09 and 5C10 so these mAbs were not tested for protection in this study. In previous studies, it was observed that antibody EV68-228 transferred at doses of 3.0 and 0.3 mg / kg is capable of completely blocking EV-D68 replication in the lung (FIG. 7A). To compare the protective potential of the instant EV-D68 antibodies to EV68-228, a transfer dose of 0.2 mg / kg was used to capture potential differences between the potency of these antibodies in a mouse model. To confirm antibody transfer, serum was taken twenty hours after passive immunization to detect neutralizing antibodies against our B3 Mp20 virus (FIG. 6B). Passive immunization does not always result in consistent serum neutralizing antibody titers in each animal and animals with inefficient transfer (FIG. 6B red circles) were excluded from the rest of the analyses. Following viral challenge, no difference in B3 Mp20 lung titer (FIG.6C) or viral load in the spleen (FIG.6D) was observed among the treated groups. B3 Mp20 virus was only detected in the blood of animals treated with the non-neutralizing mouse antibody A9 as a negative control (FIG. 6E). Lung viral titers were negatively correlated with post-mAb transfer neutralization titers (Pearson r = -0.642; FIG. 6F). To observe complete protection against viral replication in the lung and dissemination to the spleen, an additional passive immunization experiment was performed using a dose of 3.0 mg / kg of mAb. Inefficient transfers were observed in all groups that received protective antibody (FIG. 7A). However, no virus in the lungs of animals with the highest pre-infection neutralization titers was detected (FIG. 7B) and a strong correlation between pre-infection neutralization titer and virus recovery from the lung was observed (FIG. 7C). No virus was recovered from the spleen or blood of animals that received protective mAb demonstrating that a higher dose of mAb can completely protect against viral dissemination to these sites (FIG. 7D and 7E). Overall, these data demonstrate that at a dose of 0.2 mg / kg and 3.0 mg / kg the EV-D68 antibodies tested here were equally protective in a mouse model of EV-D68 respiratory infection.

[0257] Discussion- 138 - 116104230Atty Docket No.40574-131

[0258] The data demonstrates that an EV-D68 VLP vaccine candidate displays similarepitopes to the native virus and can generate potent neutralizing antibodies in NHPs like those observed in humans elicited by infection with EV-D68. While previous work has shown that EV- D68 VLPs are immunogenic and can generate protective antibodies, detailed characterization of VLP-elicited monoclonal antibodies from nonhuman primates has not been reported until this present study. The results demonstrate that VLP immunization generates protective antibodies that target epitopes at the five-fold axis of symmetry suggesting that these epitopes are similar between the EV-D68 VLP and mature virion. These findings further support the development of EV-D68 VLPs as vaccine candidates to mitigate EV-D68 respiratory disease and AFM outcomes.

[0259] The continued circulation of EV-D68 has caused biennial outbreaks of severerespiratory disease and hospitalization of children prompting the centers for disease control and prevention in the United States to issue a health alert in 2022. Vaccines for other picornaviruses such as poliovirus and enterovirus A71 has proven highly effective at reducing disease burden in children or, in the case of poliovirus, near complete eradication of the wild-type virus. Therefore, vaccination to mitigate the burdens of EV-D68 infection, respiratory disease and associated AFM is an attractive and viable strategy. VLP based vaccines have advantages over those based on inactivated virus and have been shown to be immunogenic in mice and NHPs as well as protective in a mouse model of respiratory infection.

[0260] Example 5. Vaccination of Rhesus macaques with an EV-D68 VLP generated robustneutralizing antibody responses against multiple EV-D68 subclades.

[0261] It has been shown that an EV-D68 B3 subclade VLP vaccine induces cross-cladeneutralizing antibody responses in mice and NHPs. See Krug et al., Sci. Adv.9: eadg6076 (2023), While sera from mice immunized with an EV-D68 B3 VLP exhibited reduced neutralization against heterologous B1 and A2 subclade viruses, sera from two Rhesus macaques immunized with an EV-D68 B3 VLP exhibited similar neutralizing activity across EV-D68 isolates from the B3, B1 and A2(D) subclades (Fig.8). To augment B cell responses and expand the breadth of EV- D68 reactive antibodies, macaques were twice boosted with an EV-D68 A2 subclade VLP. Following the EV-D68 A2 VLP vaccinations, serum endpoint neutralizing antibody titers increased against EV-D68 subclades B1, B3, and A2 without skewing the response to the A2 subclade, and established set points by week 56 that were 2-16 times higher than week 24, when the first A2 VLP vaccination was given (Fig. 8). - 139 - 116104230Atty Docket No.40574-131

[0262] Example 6: Identification and screening of EV-D68 VLP-elicited mAbs from NHP.VLP-elicited antibodies were next evaluated by isolating individual EV-D68 reactive B cells and generating mAbs encoded by those B cells. Using EV-D68 B3 and A2 subclade VLPs as capture probes for B cells using multiparameter flow cytometry, EV-D68-specific B cells from NHP peripheral blood mononuclear cells (PMBCs) collected two weeks after each A2 subclade VLP immunization were single-cell sorted (Fig. 9A and 9B). A high proportion (up to 7%) of IgG+B cells bound the VLP probes with distinct populations binding only the B3 VLP or both the B3 and A2 VLPs. (Fig. 9A and 9B). Using the Rapid Assembly Transfection and Production of Immunoglobulins (RATP-Ig) method (see Lima et al., Nat. Commun. 13:7733 (2022)) immunoglobulin heavy sequencing, immunoglobulin light chain sequencing, and corresponding recombinant mAb generation for the sorted B cells were simultaneously performed. Cell culture supernatants containing mAbs were screened by ELISA for binding to the B3 and A2 VLP with most of the mAbs binding both VLPs (Fig. 9C). When comparing the ELISA reactivity of mAbs against the B3 and A2 VLPs, the largest bin of mAbs exhibited no preference for binding to either VLP with a ratio at or close to one while many other mAbs preferred the B3 VLP over the A2 VLP (Fig. 9D). Overall, more than 75% of the over 600 mAbs tested bound EV-D68 VLPs and moved on to the next phase of the screen.

[0263] Antibodies that bound either B3 or A2 VLP for which sequence data were obtained andscreened for neutralizing activity in a two-point neutralization assay against both B3 and A2 virus isolates at a 1:10 and 1:500 dilution. Neutralizing antibodies exhibited a broad range of ELISA binding activity with a binding preference for either the B3 VLP or both the B3 and A2 VLPs (Fig. 9E). After screening, thirty-six unique mAbs with neutralizing activity against B3 and / or A2 isolates of EV-D68 were selected for further evaluation.

[0264] Example 7: VLP vaccine-elicited EV-D68 mAbs exhibit a broad range of binding andneutralizing activity. The thirty-six selected mAbs were expressed and purified to determine their binding and neutralizing properties. Indirect ELISA was used to measure binding strength for each mAb against the B3 and A2 VLPs (Fig.10A). Nearly all mAbs tested exhibited a binding EC50 at or below 5 µg / mL for both VLPs while a few exhibited an inferior binding EC50for the A2 VLP compared to the B3 VLP. Two mAbs, 1C12 and 2H09, demonstrated a particularly strong preference for the B3 VLP. Indeed, all the mAbs tested exhibited neutralizing activity against B3EV-D68 and most neutralized at an IC50 ILRU\ / hN)S> #9PN( +*5$& \OPRL LRL[LT HTYPIUKPLX- 140 - 116104230Atty Docket No.40574-131 exhibited reduced or undetectable neutralizing activity against an A2 isolate despite having similar binding activity by ELISA. Antibodies 1A09, 1E11, 2A09 and 5H03 were selected for further evaluation because they neutralized the B3 and A2 isolates more potently than the benchmark human mAb EV68-228 (see Vogt et al., Sci. Immunol. doi:10.1126 / sciimmunol.aba4902 (2023)), while 5C10 was selected because it neutralized A2 and B3 viruses with equal potency. When tested against a 2014-era B1 subclade virus, 2A09 neutralized B1 as potently as EV68-228, while the other mAbs neutralized B1 less potently than EV68-228 (Fig. 10C and 10D). These data demonstrate inter alia that B3-subclade based VLP vaccine candidates elicit neutralizing antibodies with high potency against contemporary B3 and A2 subclades. These properties were comparable to a potent antibody elicited by natural infection in humans.

[0265] To determine binding kinetics of Fabs of potent mAbs to the EV-D68 B3 VLP, bio-layer interferometry (BLI) was used (Fig. 16A). For Fab 5C10 that exhibited association and dissociation rates that were too fast to be reliably measured, steady-state kinetics were evaluated. In general, the Fabs of more potent mAbs exhibited a higher association rate (Fig. 16B) and a lower dissociation rate and dissociation constant when compared to EV68-228. Antibody 5H03 exhibited inferior association and dissociation rates compared to other antibodies such as 1E11 and 1A09, but this did not translate into significant differences in neutralization potency (Fig 10D). EV68-228 had the highest measured dissociation rate for the EV-D68 B3 VLP but maintained a high association rate which may account for its sustained neutralization potency against the B3 and A2 viruses.

[0266] BLI was used to identify NHP mAb epitopes along with two mAbs with defined epitopespecificity. EV68-228 was found to bind near the five-fold axis of symmetry and 15C5, a mouse antibody, binds at the three-fold axis of symmetry. See Zheng et al., Nat. Microbiol. 4:124-33 (2019); see Vogt et al., Sci. Immunol. doi:10.1126 / sciimmunol.aba4902 (2020). Fabs for all five of the selected NHP antibodies blocked binding of the EV68-228 Fab but not the 15C5 Fab, thereby suggesting that such Fabs bind an epitope at or near the five-fold axis of symmetry (Fig. 10F). Fab 5C10 blocked 15C5 only when it was bound to the VLP first, thereby suggesting indirect blocking by steric hinderance rather than a shared epitope. Overall, epitope binning indicated that potent VLP-elicited NHP mAbs bind at or near the five-fold axis of symmetry and compete with EV68-228, thereby suggesting that these mAbs may share a common or similar epitope.1E11 and - 141 - 116104230Atty Docket No.40574-131 5H03 were selected for structural analyses as highly potent mAbs with distinct competition profiles.

[0267] Example 7: Structural definition of epitope specificities for two potent VLP-elicitedmAbs. To gain molecular insights into EV-D68 neutralization and better define the epitopes targeted by the highly potent neutralizing mAbs, cryo-EM was used to determine the structures of the EV-D68 B3 VLP in complex with either the 1E11 or the 5H03 Fabs. Data processing yielded structures at resolutions of 2.59 Å and 2.83 Å, respectively. In each structure, 60 copies of Fab bound to the VLP. Strong electron densities for the Fab variable domains enabled precise atomic modeling of the antibody residues and determination of the critical features at the Fab-VLP binding interface.

[0268] Structural analysis of the B3 VLP-1E11 Fab complex confirmed binding around thefive-fold axis (Fig. 11A and 11B), consistent with the epitope binning results showing that 1E11 completely inhibited EV68-228 binding and did not compete with 15C5 in either direction (Fig.10F). The radius to particle center in 1E11 Fab – B3 VLP complex ranged from 116 Å to 193 Å(Fig. 11C). In each asymmetric unit, EV-D68 VLP promoter engaged with one 1E11 Fab, which bound to the north rim and south rim of the canyon (Fig. 11D). To define the 1E11 epitope, the interactions between 1E11 and EV-D68 B3 VLP were analyzed. Detailed analysis of the 1E11 molecular interface revealed that the 1E11 heavy chain uses its framework 1 region (FR1) and heavy-chain complementarity determining region 1 (CDRH1), heavy-chain complementarity determining region 2 (CDRH2), and heavy-chain complementarity determining region 3 (CDRH3) to contact the VP1 BC loop, the VP3 C-terminus, and the regions of the VLP that form the canyon24(Fig.11D-11F). See Lima et al., Nat. Commun.13:7733 (2022). S28 and H30 from the 1E11 heavy chain FR1 form a hydrogen bond and salt bridge with D87 and E75 in the VP1 BC loop, respectively. Three residues (D237, H238 and E243) from the VP3 C-terminus form hydrogen bonds with the Y32 and Y34 from CDRH1, the Y53 from CDRH2, and the G102 from CDRH3 (Fig. 11E). The light chain of 1E11 uses the light-chain complementarity determining region 1 (CDRL1), heavy-chain complementarity determining region 2 (CDRL2), and light-chain complementarity determining region 3 (CDRL3) to contact the VP1 C-terminus and VP0 EF loop of the VLP (Fig. 11F). See Hodcroft et al., PLOS Pathog. 18, e1010515 (2022). Side chains of G269 and E271 from the VP1 C-terminus form hydrogen bonds with Y32 from CDRL1 and T95 from CDRL3, respectively. K268 in the VP1 C-terminus formed hydrogen bonds with the main - 142 - 116104230Atty Docket No.40574-131 chain residues of Y32 from CDRL1, as well as N105 and A106 from CDRH3. The side chain of Y107 from CDRH3 and E52 from CDRL2 formed hydrogen bonds with N136 and T138 of the VP0 EF loop, respectively (Fig. 11F). Therefore, 1E11 bound to the B3 VLP around the fivefold axes and recognized the VP1 BC loop, the VP1 C-terminus, the VP0 EF loop, and the VP3 C- terminus.

[0269] Structural determination revealed that 5H03 targeted the five-fold axis, adopting anorientation in which the heavy and light chain positions are flipped 180 degrees relative to that of 1E11 bound to VLP (Fig.12A and 12B). Indeed, a similarly flipped heavy and light chain binding orientation has been previously reported for two mAbs isolated from EV-D68 VLP immunized mice. See Zhang et al., Nat. Commun.12:2904 (2021). Similar to 1E11, the radius to particle centerin the 5H03 Fab-B3 VLP complex ranged from 116 Å to 193 Å (Fig. 12C). In each asymmetricunit, the EV-D68 VLP protomer interacted with a single 5H03 Fab, which bound exclusively to the south rim of the canyon, with its heavy chain spatially covering the canyon (Fig. 12D). As 5H03 adopted the flipped heavy and light chains compared to JC228 and 1E11, all the crucial loops on the B3 VLP surface were contacted reversely by heavy and light chains (Fig. 12E and 12F).

[0270] Examination of the Fab-VLP molecular interface demonstrated that the 5H03 heavychain contacts the VP1 C-terminus and the VP0 EF loop at the south rim of the canyon. This examination further demonstrated the quasi three-fold axis of symmetry using CDRH1 and CDRH2 (Fig. 12D-F). Residue D31 in the CDRH1 forms a salt bridge with the VP1 C-terminal residue R272. Moreover, multiple CDRH2 residues form salt bridges and hydrogen bond interactions with the VP1 C-terminus (Fig.12E). The 5H03 CDRH3 contacts the VP3 C-terminus with residue Y111 forming a hydrogen bond with the main chain of the VP3 C-terminus (Fig. 12F). The 5H03 Fab light chain contacted the VP3 C-terminus. Additionally, the canyon utilizing CDRL1 with residues V30 and S31 formed a hydrogen bond with VP3 C-terminus residue D237 and the carboxyl backbone of residue I236 (Fig. 12E and 12F). Overall, 5H03 bound the B3 VLP around the five-fold axis, thereby recognizing the VP0 EF loop, the VP1 C-terminus, and the VP3 C-terminus.

[0271] A comparison of the epitopes of mAbs 1E11 and 5H03 with the available structure ofEV68-228 revealed that the mAb 1E11 and the EV68-228 virus shared a nearly identical footprint on the B3 VLP or B1 virus, respectively. The binding area measured 1221 Å2for the 1E11 Fab - 143 - 116104230Atty Docket No.40574-131 and 1087 Å2for the EV68-228 Fab (Fig. 13A and 13B). 5H03, on the other hand, recognized a partly overlapping epitope with that of the 1E11 Fab and the EV68-228 virus with a binding area of 1090 Å2(Fig. 13C). The heavy chains of these three mAbs primarily contributed to the interaction surface. Further analysis indicated that epitopes of the 1E11 Fab, the 5H03 Fab, and the EV68-228 virus occupied a shared epitope at the center of the viral capsid. This covered key antigenic loops including the VP0 EF loop and the VP3 C-terminus. These neutralizing antibody epitopes also overlapped with the reported binding site for the putative EV-D68 receptor major facilitator superfamily domain-containing protein 6 (MFSD6) as well as the sialic acid binding site of the Fermon strain of EV-D68 (Fig. 13D). See Liu et al., Nat. Commun. 6, 8865 (2015); Liu et al., Cell Host Microbe S1931-3128(24)00482–7 (2024) doi:10.1016 / j.chom.2024.12.015; Liu, X. et al. MFSD6 is an entry receptor for respiratory enterovirus D68. Cell Host Microbe S1931- 3128(24)00482–7 (2024) doi:10.1016 / j.chom.2024.12.015; Varanese, L. et al. MFSD6 is an entry receptor for enterovirus D68. Nature 1–3 (2025) doi:10.1038 / s41586-025-08908-0. In a hemagglutination inhibition assay using purified EV-D68 B3 subclade virus, neutralizing mAbs 1E11, 5H03, and EV68-228 successfully blocked virus-mediated hemagglutination, whereas the non-neutralizing mouse antibody A9 did not (Fig. 13E). These results demonstrated that VLP- elicited mAbs 1E11 and 5H03 bind to the viral capsid, prevent sialic acid binding, and block binding of the viral receptor MFSD6 to neutralize EV-D68.

[0272] A surface-rendered representation indicated 1E11 Fab did not overlap with 15C5 Fab,whereas 5H03 Fab exhibited potential steric hinderance with 15C5 Fab. Structural analysis of the 1E11 and 5H03 mAbs confirmed that both potent VLP-elicited neutralizing antibodies target the five-fold axis of symmetry, with some overlap in the recognition of subclade-distinguishing antigenic loops.

[0273] Example 8: Single capsid substitutions allow for escape from neutralizing VLP-elicitedmAbs.

[0274] To determine critical virus capsid residues for antibody interactions, B3 EV-D68 viruswas serially passaged in the presence of either 1E11 or 5H03 to generate antibody escape mutants. Sequencing the resistant virus populations revealed that single amino acid substitutions in the P1 coding region enabled escape from both 1E11 and 5H03 (Fig. 14A). These adjacent substitutions were located on the rim of the canyon of the capsid, D237N for 5H03 and H238R for 1E11. Despite their proximity, these substitutions resulted in a selective loss of neutralizing activity for either - 144 - 116104230Atty Docket No.40574-131 1E11 or 5H03 without affecting neutralization by the other antibody (Fig. 14B). D237 and H238 are located at the C-terminus of VP3, with the side chain of D237 forming a hydrogen bond with that of Y34 in the 1E11 Fab CDRH1. Moreover, H238 forms hydrogen bonds with CDRH2 residue Y53 and CDRH3 residue G102 of the 1E11 Fab (Fig.14C).

[0275] The side chain of D237 in the VP3 C-terminus formed a hydrogen bond with the mainchain N atom of V30 in CDRL1 of 1E11 but H238 does not interact with the 5H03 Fab (Figs.12F and 14D).

[0276] B3 virus escape mutants were also generated to mAbs 1A09 and 5C10. Sequencing ofthe resistant virus populations revealed nonsynonymous mutations in the P1 coding region resulting in one or two amino acid changes for each the mAb-selected virus population (Fig.14A). A single amino acid substitution conferring resistance to 1A09 was in VP2 and consisted of a T139I substitution. 5C10 escape occurred following two amino acid substitutions in VP2, T137N and D144G. These changes to the viral capsid resulted in a complete loss of neutralizing activity for 1A09 or 5C10 against their corresponding escape virus. While 5C10 was still able to neutralize virus resistant to 1A09 a reduction in potency of 1A09 against the 5C10 escaped virus was observed, suggesting they share an overlapping epitope, changes in the local structural resulting from the 5C10 escape substitution, or the occurrence of some epistatic change in the 1A09 epitope induced by the 5C10 escape mutation (Fig. 14E). While molecular structures of 1A09 and 5C10 bound to the B3 VLP were not obtained, mAb escape experiments provide information on the location of their respective epitopes on the viral capsid indicating they also target the five-fold axis of symmetry. These data further support the epitope binning data using Fab fragments (Fig. 10F) and confirm that EV-D68 VLP vaccination readily elicits potent antibodies targeting this site of vulnerability.

[0277] Example 9: Protective efficacy of mAbs in a mouse model of EV-D68 respiratoryinfection.

[0278] The next question addresses whether the potently neutralizing EV-D68 VLP-elicitedNHP mAbs 1E11, 2A09, and 5H03 could protect against EV-D68 in a mouse model of respiratory infection. The B3 Mp20 virus contains three capsid substitutions (VP1 Q86R, VP1 G208C, and VP2 G142E) that render it insensitive to neutralization by antibodies 1A09 and 5C10. Notably, these substitutions are different than those obtained in our mAb escape studies for 1A09 and 5C10. However, the substitutions G208C and G142E are near those escape mutations (Fig. 14A). This - 145 - 116104230Atty Docket No.40574-131 suggests that the VP1 Q86R, VP1 G208C, and VP2 G142E are all contained in the same or similar epitope.

[0279] Interferon receptor knockout mice (AG129) received an intraperitoneal injection with1E11, 2A09, 5H03, or control mAbs one day before intranasal infection with mouse-adapted EV- D68 (B3 Mp20). See Krug et al., Sci. Adv.9:eadg6076 (2023). Virus in the lung, blood, and spleen was measured two days post-infection. A dose of 3 mg / kg was first evaluated, which was a protective dose for EV68-228 in this model. See Krug et al., Sci. Adv.9:eadg6076 (2023). Twenty- four hours after passive immunization, EV-D68 B3 Mp20 neutralizing activity in the serum was measured (Fig. 15A), and two animals with ineffective transfers (Fig. 15A red circles) were excluded from the subsequent analyses. Following viral challenge, complete abrogation of lung virus replication was observed for all NHP mAbs and the EV68-228 treated groups while robust lung virus replication was observed in the negative control group treated with a non-neutralizing EV-D68-specific mouse mAb A9 (Fig. 15B). Viral dissemination to the spleen and blood was prevented in all groups except the control A9 treated group, where virus could be detected in both the blood and spleen. As protection was complete at a high dose, the detection of differences between mAbs at a threshold dose of 0.2 mg / kg was sought. Serum samples taken prior to infection revealed some animals with inefficient transfer which were excluded from the subsequent analysis of viral titer in tissues (Fig.15C, red circles). After challenge, there were no significant differences in B3 Mp20 lung titer (Fig.15D) or viral load in the spleen or blood among the treated groups. In contrast, the control animals had a high viral burden, thereby demonstrating that NHP-derived mAbs 1E11, 2A09, and 5H03 were equally protective as mAb EV68-228 in a mouse model of EV- D68 respiratory infection even at the lower dose.

[0280] Discussion of Examples 5-9An EV-D68 vaccine is sought to ameliorate biennialoutbreaks of respiratory disease in young children that can progress to severe complications, including acute flaccid myelitis. It has been shown here that an EV-D68 VLP vaccine candidate elicits neutralizing antibodies in NHPs with similar potency to those elicited following EV-D68 infection in humans. The in-depth assessment of B cell responses to EV-D68 VLP in NHP demonstrated that, as in infected humans, the five-fold axis of symmetry is the target of the most potently neutralizing and protective antibodies. While potent five-fold axis-targeting antibodies represent a small fraction of the overall response, VLP immunization readily elicits antibodies targeting this major viral site of vulnerability in NHPs despite some structural differences between - 146 - 116104230Atty Docket No.40574-131 VLP and mature infectious EV-D68 virions. Most of the neutralizing antibodies identified exhibited variable cross-reactivity against circulating virus subclades with the most potent ones recognizing antigenic loops where single amino acid changes confer resistance to neutralization. These disclosures suggest that viral evolution may necessitate updates to mAb-based countermeasures and support further development of multivalent mAb therapeutic approaches and vaccines such as VLP, which elicit a polyclonal response to broaden specificity and impede viral escape.

[0281] The most potent NHP mAbs competed with EV68-228 for binding at or near the five-fold axis of symmetry of the EV-D68 B3 VLP, but not with the three-fold axis-binding mouse antibody 15C5. High-resolution cryo-EM structures confirmed that mAbs 1E11 and 5H03 both bound the EV-D68 B3 VLP at the five-fold axis and provided molecular insights into antibody- mediated neutralization. Also observed was a distinct 5H03 epitope on EV-D68 capsid, which binds further towards the threefold axes than other structurally characterized potent five-fold axis targeting EV-D68 neutralizing antibodies. See Zheng et al., Nat. Microbiol. 4:124-33 (2019); Zhang et al., Nat. Commun. 12:2904 (2021); and Vogt et al., Sci. Immunol. doi:10.1126 / sciimmunol.aba4902 (2020). Structural analyses of 1E11 and 5H03 epitopes revealed that both mAbs recognized distinct but overlapping epitopes.

[0282] In summary, an EV-D68 VLP displayed antigenically intact epitopes like the maturevirus, generates broad polyclonal antibody responses in NHPs, and is a viable candidate for a human vaccine against EV-D68.

[0283] Materials and Methods for Examples 5-9

[0284] Virus and Cells. Rhabdomyosarcoma (RD) cells (ATCC Accession No. CCL-136)were cultured in Dulbecco’s modified Eagle’s medium (DMEM) (Invitrogen) supplemented with 10% fetal bovine serum (Gemini Bioproducts) and penicillin / streptomycin (Invitrogen) in a humidified cell culture incubator at 37°C and 5% CO2. EV-D68 isolates (B3 USA / 2018-23087, B1 US / MO / 2014-18947, A2 US / KY / 2014-18953) were obtained from BEI resources. To culture virus for neutralization assays, confluent monolayers of RD cells were infected at a MOI of 0.1 TCID50per cell and incubated at 33°C in a cell culture incubator. Virus-containing media was harvested when cells exhibited 95% cytopathic effect. Flask contents were frozen and thawed, clarified by centrifugation and virus-containing supernatant was aliquoted and stored at -80°C. Virus stocks were titered by infecting RD cells with quadruplicate serial dilutions of virus stocks - 147 - 116104230Atty Docket No.40574-131 in 96-well plates. After 5 days, the cells were fixed and stained with ExCellPlus fixative (StatLab) containing crystal violet to visualize cytopathic effect. Virus quantification was determined by TCID50 end point titration using the Spearman-Karber method. See Hierholzer & Killington, 2 - Virus isolation and quantitation. in Virology Methods Manual (eds. Mahy, B. W. & Kangro, H. O.) 25–46 (Academic Press, London, 1996).

[0285] Production of EV-D68 VLPs and Probes. EV-D68 VLPs were prepared as previouslydescribed. See Krug et al., Sci. Adv.9:eadg6076 (2023). Briefly, capsid and 3CD protease protein sequences from EV-D68 B3 (USA / 2018-23209) and A2 (US / KY / 2014-18953) isolates were codon optimized for human cell expression, synthesized and cloned into expression vectors. Plasmid DNA was used to transfect Expi293 cells following the manufacturer’s instructions. Five days after transfection cell cultures were harvested and frozen at -80°C. For purification, VLP containing cell culture supernatants were clarified by centrifugation at 2700 x g for 20 minutes to pellet cell debris and filtered through at 0.45 µm vacuum filter. VLPs were concentrated by centrifugation over a 20% sucrose cushion in Tris-NaCl-EDTA (TNE) buffer at 20,000 rpm and 4°C for 2.5 hours using a Beckman SW-32Ti rotor. Pellets were resuspended in TNE buffer and loaded onto a 15-45% sucrose gradient and centrifuged for 18 hours at 17,000 rpm at 4°C using a Beckman SW-41Ti rotor. Gradients were fractionated and VLPs were detected by Pierce BCA assay and SDS-polyacrylamide gel electrophoresis (SDS-PAGE) under reducing conditions. Fractions containing VLP were pooled and exchanged into sterile phosphate buffered saline (PBS) using a 100kDa cutoff centrifugal concentrator (Millipore). VLP concentration was determined by BCA assay and purity was determined by SDS-PAGE. VLPs were aliquoted and stored at -80°C. To make B cell probes, purified VLPs were biotinylated using the EZ-Link Sulfo-NHS- Biotinylation Kit (ThermoFisher Scientific) following the manufacturer’s instructions. Biotinylation and antigenicity were confirmed using BLI before mixing with streptavidin conjugated fluorophores in 10 mM HEPES buffer.

[0286] Vaccination of nonhuman primates. Animal work using rhesus macaques was approvedby the Vaccine Research Center Animal Care and Use Committee, protocol VRC-21-0933. All animal work disclosed herein followed the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. Two Rhesus macaques, one male and one female, were immunized intramuscularly (IM) with 50 µg of EV-D68 B3 VLP mixed with 20% adjuplex adjuvant with each animal receiving a half dose in each leg muscle. Animals were boosted 4 weeks - 148 - 116104230Atty Docket No.40574-131 after their first EV-D68 B3 VLP dose with the same formulation.20 weeks after their second EV- D68 B3 VLP dose animals were boosted again with the same formulation of an EV-D68 A2 VLP followed by another boost with the same A2 VLP formulation 4 weeks later. Two weeks after each A2 immunization, blood was collected from both animals and used to isolate serum for neutralization assays, peripheral blood mononuclear cells (PBMCs) for cell sorting, and antibody discovery. When possible, blood collections were performed on a non-anesthesia table using facility SOPs. When this was not possible animals were sedated with ketamine 5 mg / kg to 10 mg / kg IM or a combination of ketamine 4 mg / kg to 10 mg / kg + dexmedetomidine 0.015 mg / kg to 0.03 mg / kg IM. If dexmedetomidine was used, atipamezole would be given IM as a reversal in equal volume.

[0287] Isolation of EV-D68 specific monoclonal antibodies. PBMCs from one of the twoimmunized macaques were stained using a multiparameter B cell flow cytometry panel along with EV-D68 B3 and A2 VLP probes. Fluorescently labeled antibodies against human proteins IgD, IgM, IgA, CD20, CD27, CD14, CD8, CD16, CD19, IgG, CD3, CD38, CD21 and CXCR5 were used. CD19 and CD20 positive B cells were gated on IgG expression and then for binding to EV- D68 B3 or A2 VLP probes. B cells positive for B3 or A2 VLPs were sorted using a BD FACSymphony S6 cell sorter into 96-well plates. Immunoglobin genes were isolated and used to generate expression cassettes using the rapid assembly transfection and production of immunoglobins (RATP-Ig) pipeline4. Lima et al., Nat. Commun.13:7733 (2022). Linear cassettes encoding the heavy and light chains from each individually isolated VLP reactive B cell were used to transfect Expi293 cells to generate antibody-containing cell culture supernatant in 96 well plates. These supernatants were used to screen antibodies for VLP reactivity by ELISA and neutralization activity by EV-D68 neutralization assay. Cassettes were also sequenced to identify immunoglobulin amino acid sequences, which were cloned for expression and purification of monoclonal antibodies. Antibody heavy and light chain sequences of interest were cloned into expression vectors containing human IgG1 constant regions and plasmid DNA was purified by Genscript. Plasmid DNA was used to transfect Expi293 cells following the manufacturer’s instructions and antibodies were purified from the cell culture supernatant using Protein G agarose B beads following the manufacturer’s instructions. Antibodies were concentrated using amicon 10 kDa centrifugal concentrators (Millipore) and stored in phosphate buffered saline in aliquots at - 80°C. - 149 - 116104230Atty Docket No.40574-131

[0288] ELISA. EV-D68 VLP ELISA was performed as described previously. See Moss et al.,PLOS Pathog. 20:e1012159 (2024). Briefly, MaxiSorp 384-well plates (ThermoFisher Scientific)\LWL JUHYLK \PYO , / h> VLW \LRR UM + hN)S> UM 8F'702 5- UW 4, F>A U[LWTPNOY HY .`6( ARHYLX\LWL YOLT \HXOLK \PYO +** h> VLW \LRR UM \HXO IZMMLW #A5CD& A5C JUTYHPTPTN *(*+" Y\LLT',*$and blocked with blocking buffer (PBST containing 5% non-fat dry milk) for 1 hour at room temperature. Plates were washed and incubated with 1:6 serially diluted antibodies starting at 25hN)S> UW / aN)S> MUW + OUZW HY WUUS YLSVLWHYZWL( ARHYLX \LWL \HXOLK HTK PTJZIHYLK \PYO , / h>per well of peroxidase conjugated goat-anti-human IgG at a 1:6000 dilution in blocking buffer for+ OUZW HY WUUS YLSVLWHYZWL( ARHYLX \LWL \HXOLK HTK KL[LRUVLK \PYO / * h> VLW \LRR UM =A>SureBlue 1-component TMB peroxidase substrate for 10 minutes at room temperature. TheWLHJYPUT \HX XYUVVLK I^ YOL HKKPYPUT UM / * h> VLW \LRR UM +'@ XZRMZWPJ HJPK HTK HIXUWIHTJL HY . / *nm was measured using a Bio-Tek plate reader. Antibody dilutions were log-transformed and plotted using GraphPad Prism 9.3 software. Data were fit using a non-linear regression model to calculate the EC50.

[0289] Neutralization Assays. Monoclonal antibody neutralization assays were performedusing RD cells seeded on white-walled black 96-well plates. Antibodies were diluted serially 1:3 in DMEM containing 1% penicillin / streptomycin in untreated U-bottom 96 well plates. An equal volume of virus neutralization stock containing 200 TCID50 of the indicated virus was added and mixtures were incubated for 1 hour at 33°C in a cell culture incubator. After incubation antibody- virus mixtures were added to plates containing 95% confluent RD cells and incubated for 5 days at 33°C. Assays were developed using the CellTiter-Glo 2.0 viability assay reagent (Promega) and luminescence was read on a Bio-Tek plate reader. Background luminescence was determined using wells that only received virus and no antibody, luminescence values for these wells was subtracted from the wells that received antibody-virus mixtures. Percent viability was determined using wells that did not receive virus or antibody which served as 100% viability wells. Viability data was fit using nonlinear-regression and GraphPad Prism 9.3 software to calculate IC50 values.

[0290] Hemagglutination Inhibition Assays. EV-D68 hemagglutination inhibition assay wasperformed using EV-D68 B3 isolate 23087 and purified mAbs. Virus was diluted to 6.7 x107TCID50 / mL in phosphate buffered saline and mixed with an equal volume of diluted mAb in a v- bottom 96 well polystyrene plate. An equal volume of washed 0.75% guinea pig red blood cells in - 150 - 116104230Atty Docket No.40574-131 phosphate buffered saline were added to the mAb-virus mixture and incubated at room temperate for 1 hour before imaging. Wells were assessed for hemagglutination visually.

[0291] For epitope binning, Fab fragments were generated from purified antibodies byovernight digestion with LysC. Fabs were then purified using Protein G7 agarose beads and Ultrafree centrifugal filters (Millipore). Concentration of Fab fragments was determined by ultraviolet spectrometry. Epitope binning was performed using a ForteBio Octet bio-layer interferometry instrument and streptavidin-conjugated tips. Biotinylated EV-D68 B3 VLP at 3.13hN)S> \HX ZXLK YU RUHK YOL YPVX ILMUWL KPVVPTN PTYU \LRRX JUTYHPTPTN PTKP[PKZHR 9HIX( 4RR WLHNLTYXwere diluted in Octet buffer (PBS + 1% BSA) and Fabs were diluted to a concentration of 500 nM. Binn...

Claims

Atty Docket No.40574-131 WHAT IS CLAIMED IS:

1. An antibody or antigen-binding fragment thereof that neutralizes viruses from at least twodifferent clades of enterovirus.

2. The antibody or antigen-binding fragment thereof of claim 1, wherein the antibody orantigen-binding fragment thereof neutralizes viruses from at least three different clades of enterovirus.

3. The antibody or antigen-binding fragment thereof of claim 1 or 2, wherein the IC50 of theHTYPIUK^ PX RLXX YOHT / hN)S>(4. The antibody or antigen-binding fragment thereof of any one of claims 1-3, wherein theantibody or antigen-binding fragment thereof inhibits binding of antibody EV-D68-228.

5. The antibody or antigen-binding fragment thereof of any one of claims 1-4, wherein theantibody or antigen-binding fragment thereof is selected from the group consisting of: a. an antibody or antigen-binding fragment thereof in which the specificitydetermining residues of the antibody or antigen-binding fragment thereof interact with at least 8 contact residues in enterovirus D-68 selected from the group consisting of T30 of the EV-D68 VP1 protein, F31 of the EV-D68 VP1 protein, Y32 of the EV-D68 VP1 protein, Y33 of the EV-D68 VP1 protein, K71 of the EV-D68 VP1 protein, R72 of the EV- D68 VP1 protein, S73 of the EV-D68 VP1 protein, F74 of the EV-D68 VP1 protein, E75 of the EV-D68 VP1 protein, A84 of the EV-D68 VP1 protein, Q85 of the EV-D68 VP1 protein, T86 of the EV-D68 VP1 protein, D87 of the EV-D68 VP1 protein, T95 of the EV- D68 VP1 protein, S99 of the EV-D68 VP1 protein, F100 of the EV-D68 VP1 protein, N128 of the EV-D68 VP1 protein, G129 of the EV-D68 VP1 protein, T234 of the EV-D68 VP1 protein, Y259 of the EV-D68 VP1 protein, M260 of the EV-D68 VP1 protein, K268 of the EV-D68 VP1 protein, E52 of the EV-D68 VP2 protein, A106 of the EV-D68 VP2 protein, Y107, of the EV-D68 VP2 protein, Y33 of the EV-D68 VP3 protein, and Y93 of the EV- D68 VP3 protein, I236 of the EV-D68 VP3 protein, D237 of the EV-D68 VP3 protein, H238 of the EV-D68 VP3 protein, L239 of the EV-D68 VP3 protein, H240 of the EV-D68 VP3 protein, A242 of the EV-D68 VP3 protein, E243 of the EV-D68 VP3 protein, and Y246 of the EV-D68 VP3 protein; and b. an antibody or antigen-binding fragment thereof in which the specificitydetermining residues of the antibody or antigen-binding fragment thereof interact with at - 158 - 116104230Atty Docket No.40574-131 least 10 contact residues in enterovirus D-68 selected from the group consisting of R72 of the EV-D68 Vp1 protein, K268 of the EV-D68 VP1 protein, G269 of the EV-D68 VP1 protein, K270 of the EV-D68 VP1 protein, E271 of the EV-D68 VP1 protein, R272 of the EV-D68 VP1 protein, A273 of the EV-D68 VP1 protein, P274 of the EV-D68 VP1 protein, A276 of the EV-D68 VP1 protein, L277 of the EV-D68 VP1 protein, N278 of the EV-D68 VP1 protein, A279 of the EV-D68 VP1 protein, H135 of the EV-D68 VP2 protein, N136 of the EV-D68 VP2 protein, T138 of the EV-D68 VP2 protein, H157 of the EV-D68 VP2 protein, E59 of the EV-D68 VP3 protein, S60 of the EV-D68 VP3 protein, A61 of the EV- D68 VP3 protein, V62 of the EV-D68 VP3 protein, R104 of the EV-D68 VP3 protein, P231 of the EV-D68 VP3 protein, D232 of the EV-D68 VP3 protein, I233 of the EV-D68 VP3 protein, G234 of the EV-D68 VP3 protein, Q235 of the EV-D68 VP3 protein, I236 of the EV-D68 VP3 protein, D237 of the EV-D68 VP3 protein, H238 of the EV-D68 VP3 protein, L239 of the EV-D68 VP3 protein, H240 of the EV-D68 VP3 protein, G241 of the EV-D68 VP3 protein, and E243 of the EV-D68 VP3 protein.

6. The antibody or antigen-binding fragment thereof of any one of claims 1-4, wherein theantibody or antigen-binding fragment thereof is selected from the group consisting of: a. an antibody or antigen-binding fragment thereof (e.g., EVD2301) in which thespecificity determining residues of the heavy chain interact with at least 20, optionally at least 22, optionally at least 24, optionally at least 26, or optionally all, contact residues in enterovirus D-68 selected from the group consisting of K71 of the EV-D68 VP1 protein, R72 of the EV-D68 VP1 protein, S73 of the EV-D68 VP1 protein, F74 of the EV-D68 VP1 protein, E75 of the EV-D68 VP1 protein, A84 of the EV-D68 VP1 protein, Q85 of the EV- D68 VP1 protein, T86 of the EV-D68 VP1 protein, D87 of the EV-D68 VP1 protein, S99 of the EV-D68 VP1 protein, F100 of the EV-D68 VP1 protein, N128 of the EV-D68 VP1 protein, G129 of the EV-D68 VP1 protein, T234 of the EV-D68 VP1 protein, Y259 of the EV-D68 VP1 protein, M260 of the EV-D68 VP1 protein, K268 of the EV-D68 VP1 protein, A106 of the EV-D68 VP2 protein, Y107, of the EV-D68 VP2 protein, I236 of the EV-D68 VP3 protein, D237 of the EV-D68 VP3 protein, H238 of the EV-D68 VP3 protein, L239 of the EV-D68 VP3 protein, H240 of the EV-D68 VP3 protein, A242 of the EV-D68 VP3 protein, E243 of the EV-D68 VP3 protein, and Y246 of the EV-D68 VP3 protein; - 159 - 116104230Atty Docket No.40574-131 b. an antibody or antigen-binding fragment thereof (e.g., EVD2301) in which thespecificity determining residues of the light chain interact with at least 5, optionally at least 6, optionally at least 7, or optionally all, contact residues in enterovirus D-68 selected from the group consisting of T30 of the EV-D68 VP1 protein, F31 of the EV-D68 VP1 protein, Y32 of the EV-D68 VP1 protein, Y33 of the EV-D68 VP1 protein, T95 of the EV-D68 VP1 protein, E52 of the EV-D68 VP2 protein, Y33 of the EV-D68 VP3 protein, and Y93 of the EV-D68 VP3 protein; c. an antibody or antigen-binding fragment thereof (e.g., EVD2303) in which thespecificity determining residues of the heavy chain interact with at least 18, optionally at least 20, optionally at least 21, optionally at least 22, optionally at least 23, optionally at least 24, or optionally all, contact residues in enterovirus D-68 selected from the group consisting of K268 of the EV-D68 VP1 protein, G269 of the EV-D68 VP1 protein, K270 of the EV-D68 VP1 protein, E271 of the EV-D68 VP1 protein, R272 of the EV-D68 VP1 protein, A273 of the EV-D68 VP1 protein, P274 of the EV-D68 VP1 protein, A276 of the EV-D68 VP1 protein, L277 of the EV-D68 VP1 protein, N278 of the EV-D68 VP1 protein, A279 of the EV-D68 VP1 protein, H135 of the EV-D68 VP2 protein, N136 of the EV-D68 VP2 protein, H157 of the EV-D68 VP2 protein, E59 of the EV-D68 VP3 protein, S60 of the EV-D68 VP3 protein, A61 of the EV-D68 VP3 protein, V62 of the EV-D68 VP3 protein, R104 of the EV-D68 VP3 protein, P231 of the EV-D68 VP3 protein, D232 of the EV-D68 VP3 protein, I233 of the EV-D68 VP3 protein, G234 of the EV-D68 VP3 protein, Q235 of the EV-D68 VP3 protein, and I236 of the EV-D68 VP3 protein; and d. an antibody or antigen-binding fragment thereof (e.g., EVD2303) in which thespecificity determining residues of the light chain interact with at least 6, optionally at least 7, optionally at least 8, optionally at least 8, or optionally all, contact residues in enterovirus D-68 selected from the group consisting of R72 of the EV-D68 VP1 protein, K268 of the EV-D68 VP1 protein, T138 of the EV-D68 VP2 protein I236, D237 of the EV-D68 VP3 protein, H238 of the EV-D68 VP3 protein, L239 of the EV-D68 VP3 protein, H240 of the EV-D68 VP3 protein, G241 of the EV-D68 VP3 protein, and E243 of the EV-D68 VP3 protein.

7. The antibody or antigen-binding fragment thereof of any one of claims 1-6, wherein theantibody or antigen-binding fragment thereof is selected from the group consisting of: - 160 - 116104230Atty Docket No.40574-131a. an antibody or antigen-binding fragment thereof comprising a heavy chain variableregion and a light chain variable region (e.g., EVD2301), wherein the specificity determining residues of the heavy chain interact with at least 20, optionally at least 22, optionally at least 24, optionally at least 26, or all, contact residues selected from the group consisting of K71 of the EV-D68 VP1 protein, R72 of the EV-D68 VP1 protein, S73 of the EV-D68 VP1 protein, F74 of the EV-D68 VP1 protein, E75 of the EV-D68 VP1 protein, A84 of the EV-D68 VP1 protein, Q85 of the EV-D68 VP1 protein, T86 of the EV-D68 VP1 protein, D87 of the EV-D68 VP1 protein, S99 of the EV-D68 VP1 protein, F100 of the EV-D68 VP1 protein, N128 of the EV-D68 VP1 protein, G129 of the EV-D68 VP1 protein, T234 of the EV-D68 VP1 protein, Y259 of the EV-D68 VP1 protein, M260 of the EV-D68 VP1 protein, K268 of the EV-D68 VP1 protein, A106 of the EV-D68 VP2 protein, Y107, of the EV-D68 VP2 protein, I236 of the EV-D68 VP3 protein, D237 of the EV-D68 VP3 protein, H238 of the EV-D68 VP3 protein, L239 of the EV-D68 VP3 protein, H240 of the EV-D68 VP3 protein, A242 of the EV-D68 VP3 protein, E243 of the EV-D68 VP3 protein, and Y246 of the EV-D68 VP3 protein; and wherein the specificity determining residues of the light chain interact with at least 5, optionally at least 6, optionally at least 7, or all, contact residues selected from the group consisting of T30 of the EV-D68 VP1 protein, F31 of the EV-D68 VP1 protein, Y32 of the EV-D68 VP1 protein, Y33 of the EV- D68 VP1 protein, T95 of the EV-D68 VP1 protein, E52 of the EV-D68 VP2 protein, Y33 of the EV-D68 VP3 protein, and Y93 of the EV-D68 VP3 protein; andb. an antibody or antigen-binding fragment thereof comprising a heavy chain variableregion and a light chain variable region (e.g., EVD2303), wherein the specificity determining residues of the heavy chain variable region interact with at least 18, optionally at least 20, optionally at least 21, optionally at least 22, optionally at least 23, optionally at least 24, or all, contact residues selected from the group consisting of K268 of the EV-D68 VP1 protein, G269 of the EV-D68 VP1 protein, K270 of the EV-D68 VP1 protein, E271 of the EV-D68 VP1 protein, R272 of the EV-D68 VP1 protein, A273 of the EV-D68 VP1 protein, P274 of the EV-D68 VP1 protein, A276 of the EV-D68 VP1 protein, L277 of the EV-D68 VP1 protein, N278 of the EV-D68 VP1 protein, A279 of the EV-D68 VP1 protein, H135 of the EV-D68 VP2 protein, N136 of the EV-D68 VP2 protein, H157 of the EV-D68 VP2 protein, E59 of the EV-D68 VP3 protein, S60 of the EV-D68 VP3 protein, A61 of the - 161 - 116104230Atty Docket No.40574-131 EV-D68 VP3 protein, V62 of the EV-D68 VP3 protein, R104 of the EV-D68 VP3 protein, P231 of the EV-D68 VP3 protein, D232 of the EV-D68 VP3 protein, I233 of the EV-D68 VP3 protein, G234 of the EV-D68 VP3 protein, Q235 of the EV-D68 VP3 protein, and I236 of the EV-D68 VP3 protein; and wherein the specificity determining residues of the light chain variable region interact with at least 6, optionally at least 7, optionally at least 8, optionally at least 8, or all, contact residues selected from the group consisting of R72 of the EV-D68 VP1 protein, K268 of the EV-D68 VP1 protein, T138 of the EV-D68 VP2 protein I236, D237 of the EV-D68 VP3 protein, H238 of the EV-D68 VP3 protein, L239 of the EV-D68 VP3 protein, H240 of the EV-D68 VP3 protein, G241 of the EV-D68 VP3 protein, and E243 of the EV-D68 VP3 protein.

8. The antibody or antigen-binding fragment thereof of any one of claims 1-7, wherein theantibody comprises one or more heavy chain CDRs from Table 1 or Table 2.

9. The antibody or antigen-binding fragment thereof of any one of claims 1-8, wherein theantibody comprises one or more light chain CDRs from Table 1 or Table 2.

10. The antibody or antigen-binding fragment thereof of any one of claims 1-9, wherein theantibody comprises one or more antibody-matched heavy chain CDRs and light chain CDRs from Table 1 or Table 2.

11. The antibody or antigen-binding fragment thereof of any one of claims 1-10, wherein theantibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, or at least 99% identical, to a heavy chain variable region from Table 1, wherein the heavy chain variable region comprises antibody-matched VHCDR1, VHCDR2, and VHCDR3 sequences from Table 1 or Table 2.

12. The antibody or antigen-binding fragment thereof of any one of claims 1-11, wherein theantibody or antigen-binding fragment thereof comprises a light chain variable region comprising an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, or at least 99% identical, to a light chain variable region from Table 1, wherein the light chain variable region comprises antibody-matched VLCDR1, VLCDR2, and VLCDR3 sequences from Table 1 or Table 2.

13. The antibody or antigen-binding fragment thereof of any one of claims 1-12, wherein theantibody or antigen-binding fragment thereof comprises a heavy chain variable region and an - 162 - 116104230Atty Docket No.40574-131 antibody-matched light chain variable region, the antibody-matched, heavy and light chain variable regions comprising amino acid sequences at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, or at least 99% identical, to a heavy chain variable region and a light chain variable region, respectively, from Table 1 or Table 2, wherein the heavy chain variable region comprises antibody-matched VHCDR1, VHCDR2, and VHCDR3 sequences from Table 1 and the light chain variable region comprises antibody-matched VLCDR1, VLCDR2, and VLCDR3 sequences from Table 1 or Table 2.

14. The antibody or antigen-binding fragment thereof of any one of claims 1-13, wherein theantibody or antigen-binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, or at least 99% identical, to a heavy chain from Table 1 or Table 2, wherein the heavy chain comprises antibody-matched VHCDR1, VHCDR2, and VHCDR3 sequences from Table 1 or Table 2.

15. The antibody or antigen-binding fragment thereof of any one of claims 1-14, wherein theantibody comprises a light chain comprising an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, or at least 99% identical, to a light chain from Table 1, wherein the light chain comprises antibody-matched VLCDR1, VLCDR2, and VLCDR3 sequences from Table 1 or Table 2.

16. The antibody or antigen-binding fragment thereof of any one of claims 1-15, wherein theantibody or antigen-binding fragment thereof comprises a heavy chain variable region and an antibody-matched light chain variable region, the antibody-matched, heavy and light chain variable regions comprising amino acid sequences at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at last 97% identical, or at least 99% identical, to a heavy chain variable region and a light chain variable region, respectively, from Table 1 or Table 2, wherein the heavy chain variable region comprises antibody-matched VHCDR1, VHCDR2, and VHCDR3 sequences from Table 1 and the light chain variable region comprises antibody-matched VLCDR1, VLCDR2, and VLCDR3 sequences from Table 1 or Table 2.

17. The antibody or antigen-binding fragment thereof of any one of claims 1-16, wherein theantibody or antigen-binding fragment thereof comprises a heavy chain and an antibody-matched light chain, the antibody-matched, heavy chain and the light chain comprising amino acid sequences at least 80% identical, at least 85% identical, at least 90% identical, at least 95% - 163 - 116104230Atty Docket No.40574-131 identical, at last 97% identical, or at least 99% identical, to a heavy chain and a light chain, respectively, from Table 1 or Table 2, wherein the heavy chain comprises antibody-matched VHCDR1, VHCDR2, and VHCDR3 sequences from Table 1 or Table 2 and the light chain comprises antibody-matched VLCDR1, VLCDR2, and VLCDR3 sequences from Table 1 or Table 2.

18. The antibody of any one of claims 1-17, wherein the antibody or antigen-binding fragmentthereof comprises antibody-matched sequences from Table 1 or Table 2.

19. The antibody or antigen-binding fragment thereof of any one of claims 1-18, wherein theantibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) complementarity determining region 3 (CDR3) selected from the group consisting of a VH CDR3 comprising or consisting of SEQ ID NO:3, a VH CDR3 comprising or consisting of SEQ ID NO:13, a VH CDR3 comprising or consisting of SEQ ID NO:23, a VH CDR3 comprising or consisting of SEQ ID NO:33, a VHCDR3 comprising or consisting of SEQ ID NO:43, a VHCDR3 comprising or consisting of SEQ ID NO:53, a VHCDR3 comprising or consisting of SEQ ID NO:63, a VHCDR3 comprising or consisting of SEQ ID NO:73, a VHCDR3 comprising or consisting of SEQ ID NO:83, a VH CDR3 comprising or consisting of SEQ ID NO:93, a VH CDR3 comprising or consisting of SEQ ID NO:103, and a VH CDR3 comprising or consisting of SEQ ID NO:113.

20. The antibody or antigen-binding fragment thereof of any one of claims 1-19, wherein theantibody or antigen-binding fragment thereof comprises a light chain variable region (VL) CDR3 selected from the group consisting of a VLCDR3 comprising or consisting of SEQ ID NO:8, a VLCDR3 comprising or consisting of SEQ ID NO:18, a VLCDR3 comprising or consisting of SEQ ID NO:28, a VLCDR3 comprising or consisting of SEQ ID NO:38, a VLCDR3 comprising or consisting of SEQ ID NO:48, a VL CDR3 comprising or consisting of SEQ ID NO:58, a VL CDR3 comprising or consisting of SEQ ID NO:68, a VL CDR3 comprising or consisting of SEQ ID NO:78, a VL CDR3 comprising or consisting of SEQ ID NO:88, a VL CDR3 comprising or consisting of SEQ ID NO:98, a VL CDR3 comprising or consisting of SEQ ID NO:108, and a VL CDR3 comprising or consisting of SEQ ID NO:118.

21. The antibody or antigen-binding fragment thereof of any one of claims 1-20, wherein theantibody or antigen-binding fragment thereof comprises a VHCDR2 selected from the group consisting of a VHCDR2 comprising or consisting of SEQ ID NO:2, a VHCDR2 comprising or consisting of SEQ ID NO:12, a VH CDR2 comprising or consisting of SEQ ID NO:22, a VH CDR2 - 164 - 116104230Atty Docket No.40574-131 comprising or consisting of SEQ ID NO:32, a VH CDR2 comprising or consisting of SEQ ID NO:42, a VH CDR2 comprising or consisting of SEQ ID NO:52, a VH CDR2 comprising or consisting of SEQ ID NO:62, a VH CDR2 comprising or consisting of SEQ ID NO:72, a VH CDR2 comprising or consisting of SEQ ID NO:82, a VH CDR2 comprising or consisting of SEQ ID NO:92, a VHCDR2 comprising or consisting of SEQ ID NO:102, and a VHCDR2 comprising or consisting of SEQ ID NO:112.

22. The antibody or antigen-binding fragment thereof of any one of claims 1-21, wherein theantibody or antigen-binding fragment thereof comprises a VLCDR2 selected from the group consisting of a VL CDR2 comprising or consisting of SEQ ID NO:7, a VL CDR2 comprising or consisting of SEQ ID NO:17, a VL CDR2 comprising or consisting of SEQ ID NO:27, a VL CDR2 comprising or consisting of SEQ ID NO:37, a VL CDR2 comprising or consisting of SEQ ID NO:47, a VL CDR2 comprising or consisting of SEQ ID NO:57, a VL CDR2 comprising or consisting of SEQ ID NO:67, a VLCDR2 comprising or consisting of SEQ ID NO:77, a VLCDR2 comprising or consisting of SEQ ID NO:87, a VLCDR2 comprising or consisting of SEQ ID NO:97, a VLCDR2 comprising or consisting of SEQ ID NO:107, and a VLCDR2 comprising or consisting of SEQ ID NO:117.

23. The antibody or antigen-binding fragment thereof of any one of claims 1-22, wherein theantibody or antigen-binding fragment thereof comprises a VH CDR1 selected from the group consisting of a VH CDR1 comprising or consisting of SEQ ID NO:1, a VH CDR1 comprising or consisting of SEQ ID NO:11, a VHCDR1 comprising or consisting of SEQ ID NO:21, a VHCDR1 comprising or consisting of SEQ ID NO:31, a VHCDR1 comprising or consisting of SEQ ID NO:41, a VHCDR1 comprising or consisting of SEQ ID NO:51, a VHCDR1 comprising or consisting of SEQ ID NO:61, a VH CDR1 comprising or consisting of SEQ ID NO:71, a VH CDR1 comprising or consisting of SEQ ID NO:81, a VH CDR1 comprising or consisting of SEQ ID NO:91,a VH CDR1 comprising or consisting of SEQ ID NO:101, and a VH CDR1 comprising or consisting of SEQ ID NO:111.

24. The antibody or antigen-binding fragment thereof of any one of claims 1-23, wherein theantibody or antigen-binding fragment thereof comprises a VLCDR1 selected from the group consisting of a VLCDR1 comprising or consisting of SEQ ID NO:6, a VLCDR1 comprising or consisting of SEQ ID NO:16, a VLCDR1 comprising or consisting of SEQ ID NO:26, a VLCDR1 comprising or consisting of SEQ ID NO:36, a VL CDR1 comprising or consisting of SEQ ID - 165 - 116104230Atty Docket No.40574-131 NO:46, a VL CDR1 comprising or consisting of SEQ ID NO:56, a VL CDR1 comprising or consisting of SEQ ID NO:66, a VL CDR1 comprising or consisting of SEQ ID NO:76, a VL CDR1 comprising or consisting of SEQ ID NO:86, a VL CDR1 comprising or consisting of SEQ ID NO:96, a VL CDR1 comprising or consisting of SEQ ID NO:106, and a VL CDR1 comprising or consisting of SEQ ID NO:116.

25. The antibody or antigen-binding fragment thereof of any one of claims 1-24, wherein theantibody or antigen-binding fragment thereof comprises: i) a VH CDR3 comprising or consisting of SEQ ID NO:3 and a VL CDR3 comprisingor consisting of SEQ ID NO:8; ii) a VH CDR3 comprising or consisting of SEQ ID NO:13 and a VL CDR3 comprisingor consisting of SEQ ID NO:18; iii) a VH CDR3 comprising or consisting of SEQ ID NO:23 and a VL CDR3 comprisingor consisting of SEQ ID NO:28; iv) a VH CDR3 comprising or consisting of SEQ ID NO:33 and a VL CDR3 comprisingor consisting of SEQ ID NO:38; v) a VH CDR3 comprising or consisting of SEQ ID NO:43 and a VL CDR3 comprisingor consisting of SEQ ID NO:48; vi) a VH CDR3 comprising or consisting of SEQ ID NO:53 and a VL CDR3 comprisingor consisting of SEQ ID NO:58; vii) a VH CDR3 comprising or consisting of SEQ ID NO:63 and a VL CDR3 comprisingor consisting of SEQ ID NO:68; viii) a VH CDR3 comprising or consisting of SEQ ID NO:73 and a VL CDR3 comprisingor consisting of SEQ ID NO:78; ix) a VH CDR3 comprising or consisting of SEQ ID NO:83 and a VL CDR3 comprisingor consisting of SEQ ID NO:88; x) a VH CDR3 comprising or consisting of SEQ ID NO:93 and a VL CDR3 comprisingor consisting of SEQ ID NO:98; xi) a VH CDR3 comprising or consisting of SEQ ID NO:103 and a VL CDR3comprising or consisting of SEQ ID NO:108; and xii) a VH CDR3 comprising or consisting of SEQ ID NO:113 and a VL CDR3comprising or consisting of SEQ ID NO:

118. - 166 - 116104230Atty Docket No.40574-13126. The antibody or antigen-binding fragment thereof of any one of claims 1-25, wherein theantibody or antigen-binding fragment thereof comprises: i) a VH CDR1 comprising or consisting of SEQ ID NO:1, a VH CDR2 comprising orconsisting of SEQ ID NO:2, and a VH CDR3 comprising or consisting of SEQ ID NO:3; ii) a VH CDR1 comprising or consisting of SEQ ID NO:11, a VH CDR2 comprising orconsisting of SEQ ID NO:12, and a VHCDR3 comprising or consisting of SEQ ID NO:13; iii) a VH CDR1 comprising or consisting of SEQ ID NO:21, a VH CDR2 comprising orconsisting of SEQ ID NO:22, and a VHCDR3 comprising or consisting of SEQ ID NO:23; iv) a VH CDR1 comprising or consisting of SEQ ID NO:31, a VH CDR2 comprising orconsisting of SEQ ID NO:32, and a VH CDR3 comprising or consisting of SEQ ID NO:33; v) a VH CDR1 comprising or consisting of SEQ ID NO:41, a VH CDR2 comprising orconsisting of SEQ ID NO:42, and a VH CDR3 comprising or consisting of SEQ ID NO:43; vi) a VH CDR1 comprising or consisting of SEQ ID NO:51, a VH CDR2 comprising orconsisting of SEQ ID NO:52, and a VHCDR3 comprising or consisting of SEQ ID NO:53; vii) a VH CDR1 comprising or consisting of SEQ ID NO:61, a VH CDR2 comprising orconsisting of SEQ ID NO:62, and a VH CDR3 comprising or consisting of SEQ ID NO:63; viii) a VH CDR1 comprising or consisting of SEQ ID NO:71, a VH CDR2 comprising orconsisting of SEQ ID NO:72, and a VH CDR3 comprising or consisting of SEQ ID NO:73; ix) a VH CDR1 comprising or consisting of SEQ ID NO:81, a VH CDR2 comprising orconsisting of SEQ ID NO:82, and a VHCDR3 comprising or consisting of SEQ ID NO:83; x) a VH CDR1 comprising or consisting of SEQ ID NO:91, a VH CDR2 comprising orconsisting of SEQ ID NO:92, and a VHCDR3 comprising or consisting of SEQ ID NO:93; xi) a VH CDR1 comprising or consisting of SEQ ID NO:101, a VH CDR2 comprisingor consisting of SEQ ID NO:102, and a VH CDR3 comprising or consisting of SEQ ID NO:103; or xii) a VH CDR1 comprising or consisting of SEQ ID NO:111, a VH CDR2 comprisingor consisting of SEQ ID NO:112, and a VHCDR3 comprising or consisting of SEQ ID NO:113.

27. The antibody or antigen-binding fragment thereof of any one of claims 1-26, wherein theantibody or antigen-binding fragment thereof comprises: - 167 - 116104230Atty Docket No.40574-131 i) a VL CDR1 comprising or consisting of SEQ ID NO:6, a VL CDR2 comprising orconsisting of SEQ ID NO:7, and a VL CDR3 comprising or consisting of SEQ ID NO:8; ii) a VL CDR1 comprising or consisting of SEQ ID NO:16, a VL CDR2 comprising orconsisting of SEQ ID NO:17, and a VL CDR3 comprising or consisting of SEQ ID NO:18; iii) a VL CDR1 comprising or consisting of SEQ ID NO:26, a VL CDR2 comprising orconsisting of SEQ ID NO:27, and a VLCDR3 comprising or consisting of SEQ ID NO:28; iv) a VL CDR1 comprising or consisting of SEQ ID NO:36, a VL CDR2 comprising orconsisting of SEQ ID NO:37, and a VLCDR3 comprising or consisting of SEQ ID NO:38; v) a VL CDR1 comprising or consisting of SEQ ID NO:46, a VL CDR2 comprising orconsisting of SEQ ID NO:47, and a VL CDR3 comprising or consisting of SEQ ID NO:48; vi) a VL CDR1 comprising or consisting of SEQ ID NO:56, a VL CDR2 comprising orconsisting of SEQ ID NO:57, and a VL CDR3 comprising or consisting of SEQ ID NO:58; vii) a VL CDR1 comprising or consisting of SEQ ID NO:66, a VL CDR2 comprising orconsisting of SEQ ID NO:67, and a VLCDR3 comprising or consisting of SEQ ID NO:68; viii) a VL CDR1 comprising or consisting of SEQ ID NO:76, a VL CDR2 comprising orconsisting of SEQ ID NO:77, and a VL CDR3 comprising or consisting of SEQ ID NO:78; ix) a VL CDR1 comprising or consisting of SEQ ID NO:86, a VL CDR2 comprising orconsisting of SEQ ID NO:87, and a VL CDR3 comprising or consisting of SEQ ID NO:88; x) a VL CDR1 comprising or consisting of SEQ ID NO:96, a VL CDR2 comprising orconsisting of SEQ ID NO:97, and a VLCDR3 comprising or consisting of SEQ ID NO:98; xi) a VL CDR1 comprising or consisting of SEQ ID NO:106, a VL CDR2 comprisingor consisting of SEQ ID NO:107, and a VLCDR3 comprising or consisting of SEQ ID NO:108; or xii) a VL CDR1 comprising or consisting of SEQ ID NO:116, a VL CDR2 comprisingor consisting of SEQ ID NO:117, or a VL CDR3 comprising or consisting of SEQ ID NO:118.

28. The antibody or antigen-binding fragment thereof of any one of claims 1-27, wherein theantibody or antigen-binding fragment thereof comprises: i) a VH CDR1 comprising or consisting of SEQ ID NO:1, a VH CDR2 comprising orconsisting of SEQ ID NO:2, a VHCDR3 comprising or consisting of SEQ ID NO:3, a VL- 168 - 116104230Atty Docket No.40574-131 CDR1 comprising or consisting of SEQ ID NO:6, a VL CDR2 comprising or consisting of SEQ ID NO:7, and a VL CDR3 comprising or consisting of SEQ ID NO:8;ii) a VH CDR1 comprising or consisting of SEQ ID NO:11, a VH CDR2 comprising orconsisting of SEQ ID NO:12, a VH CDR3 comprising or consisting of SEQ ID NO:13; a VLCDR1 comprising or consisting of SEQ ID NO:16, a VLCDR2 comprising or consisting of SEQ ID NO:17, and a VLCDR3 comprising or consisting of SEQ ID NO:18;iii) a VH CDR1 comprising or consisting of SEQ ID NO:21, a VH CDR2 comprising orconsisting of SEQ ID NO:22, a VHCDR3 comprising or consisting of SEQ ID NO:23; a VL CDR1 comprising or consisting of SEQ ID NO:26, a VL CDR2 comprising or consisting of SEQ ID NO:27, and a VL CDR3 comprising or consisting of SEQ ID NO:28;iv) a VH CDR1 comprising or consisting of SEQ ID NO:31, a VH CDR2 comprising orconsisting of SEQ ID NO:32, a VH CDR3 comprising or consisting of SEQ ID NO:33; a VLCDR1 comprising or consisting of SEQ ID NO:36, a VLCDR2 comprising or consisting of SEQ ID NO:37, and a VLCDR3 comprising or consisting of SEQ ID NO:38;v) a VH CDR1 comprising or consisting of SEQ ID NO:41, a VH CDR2 comprising orconsisting of SEQ ID NO:42, a VH CDR3 comprising or consisting of SEQ ID NO:43; a VL CDR1 comprising or consisting of SEQ ID NO:46, a VL CDR2 comprising or consisting of SEQ ID NO:47, and a VL CDR3 comprising or consisting of SEQ ID NO:48;vi) a VH CDR1 comprising or consisting of SEQ ID NO:51, a VH CDR2 comprising orconsisting of SEQ ID NO:52, a VHCDR3 comprising or consisting of SEQ ID NO:53; a VLCDR1 comprising or consisting of SEQ ID NO:56, a VLCDR2 comprising or consisting of SEQ ID NO:57, and a VLCDR3 comprising or consisting of SEQ ID NO:58;vii) a VH CDR1 comprising or consisting of SEQ ID NO:61, a VH CDR2 comprising orconsisting of SEQ ID NO:62, a VH CDR3 comprising or consisting of SEQ ID NO:63; a VL CDR1 comprising or consisting of SEQ ID NO:66, a VL CDR2 comprising or consisting of SEQ ID NO:67, and a VL CDR3 comprising or consisting of SEQ ID NO:68;viii) a VH CDR1 comprising or consisting of SEQ ID NO:71, a VH CDR2 comprising orconsisting of SEQ ID NO:72, a VHCDR3 comprising or consisting of SEQ ID NO:73; a VLCDR1 comprising or consisting of SEQ ID NO:76, a VLCDR2 comprising or consisting of SEQ ID NO:77, and a VLCDR3 comprising or consisting of SEQ ID NO:78; - 169 - 116104230Atty Docket No.40574-131 ix) a VH CDR1 comprising or consisting of SEQ ID NO:81, a VH CDR2 comprising orconsisting of SEQ ID NO:82, a VH CDR3 comprising or consisting of SEQ ID NO:83; a VL CDR1 comprising or consisting of SEQ ID NO:86, a VL CDR2 comprising or consisting of SEQ ID NO:87, and a VL CDR3 comprising or consisting of SEQ ID NO:88; x) a VH CDR1 comprising or consisting of SEQ ID NO:91, a VH CDR2 comprising orconsisting of SEQ ID NO:92, a VHCDR3 comprising or consisting of SEQ ID NO:93; a VLCDR1 comprising or consisting of SEQ ID NO:96, a VLCDR2 comprising or consisting of SEQ ID NO:97, and a VLCDR3 comprising or consisting of SEQ ID NO:98; xi) a VH CDR1 comprising or consisting of SEQ ID NO:101, a VH CDR2 comprisingor consisting of SEQ ID NO:102, a VH CDR3 comprising or consisting of SEQ ID NO:103; a VL CDR1 comprising or consisting of SEQ ID NO:106, a VL CDR2 comprising or consisting of SEQ ID NO:107, and a VL CDR3 comprising or consisting of SEQ ID NO:108; or xii) a VH CDR1 comprising or consisting of SEQ ID NO:111, a VH CDR2 comprisingor consisting of SEQ ID NO:112, a VHCDR3 comprising or consisting of SEQ ID NO:113, a VL CDR1 comprising or consisting of SEQ ID NO:116, a VL CDR2 comprising or consisting of SEQ ID NO:117, or a VL CDR3 comprising or consisting of SEQ ID NO:118.

29. The antibody or antigen-binding fragment thereof of any one of claims 1-28, wherein theantibody or antigen-binding fragment thereof comprises a heavy chain variable region selected from the group consisting of: i) a heavy chain variable region comprising an amino acid sequence at least 80%identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:4, wherein the variable region comprises VH CDR1 comprising or consisting of SEQ ID NO:1, VH CDR2 comprising or consisting of SEQ ID NO:2, and VH CDR3 comprising or consisting of SEQ ID NO3; ii) a heavy chain variable region comprising an amino acid sequence at least 80%identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:14, wherein the variable region comprises VHCDR1 comprising or consisting of SEQ ID NO:11, VHCDR2 - 170 - 116104230Atty Docket No.40574-131 comprising or consisting of SEQ ID NO:12, and VH CDR3 comprising or consisting of SEQ ID NO:13;iii) a heavy chain variable region comprising an amino acid sequence at least 80%identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:24, wherein the variable region comprises VHCDR1 comprising or consisting of SEQ ID NO:21, VHCDR2 comprising or consisting of SEQ ID NO:22, and VHCDR3 comprising or consisting of SEQ ID NO:23;iv) a heavy chain variable region comprising an amino acid sequence at least 80%identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:34, wherein the variable region comprises VH CDR1 comprising or consisting of SEQ ID NO:31, VH CDR2 comprising or consisting of SEQ ID NO:32, and VHCDR3 comprising or consisting of SEQ ID NO:33;v) a heavy chain variable region comprising an amino acid sequence at least 80%identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:44, wherein the variable region comprises VH CDR1 comprising or consisting of SEQ ID NO:41, VH CDR2 comprising or consisting of SEQ ID NO:42, and VH CDR3 comprising or consisting of SEQ ID NO:43;vi) a heavy chain comprising variable region comprising an amino acid sequence atleast 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:54, wherein the variable region comprises VH CDR1 comprising or consisting of SEQ ID NO:51, VH CDR2 comprising or consisting of SEQ ID NO:52, and VH CDR3 comprising or consisting of SEQ ID NO:53;vii) a heavy chain variable region comprising an amino acid sequence at least 80%identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:64, wherein the variable region comprises VHCDR1 comprising or consisting of SEQ ID NO:61, VHCDR2 - 171 - 116104230Atty Docket No.40574-131 comprising or consisting of SEQ ID NO:62, and VH CDR3 comprising or consisting of SEQ ID NO:63;viii) a heavy chain variable region comprising an amino acid sequence at least 80%identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:74, wherein the variable region comprises VHCDR1 comprising or consisting of SEQ ID NO:71, VHCDR2 comprising or consisting of SEQ ID NO:72, and VHCDR3 comprising or consisting of SEQ ID NO:73;ix) a heavy chain variable region comprising an amino acid sequence at least 80%identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:84, wherein the variable region comprises VH CDR1 comprising or consisting of SEQ ID NO:81, VH CDR2 comprising or consisting of SEQ ID NO:82, and VHCDR3 comprising or consisting of SEQ ID NO:83;x) a heavy chain variable region comprising an amino acid sequence at least 80%identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:94, wherein the variable region comprises VH CDR1 comprising or consisting of SEQ ID NO:91, VH CDR2 comprising or consisting of SEQ ID NO:92, and VH CDR3 comprising or consisting of SEQ ID NO:93;xi) a heavy chain variable region comprising an amino acid sequence at least 80%identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:104, wherein the variable region comprises VH CDR1 comprising or consisting of SEQ ID NO:101, VH CDR2 comprising or consisting of SEQ ID NO:102, and VH CDR3 comprising or consisting of SEQ ID NO:103; andxii) a heavy chain variable region comprising an amino acid sequence at least 80%identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:114, wherein the variable region comprises VHCDR1 comprising or consisting of SEQ ID NO:111, VH- 172 - 116104230Atty Docket No.40574-131 CDR2 comprising or consisting of SEQ ID NO:112, and VH CDR3 comprising or consisting of SEQ ID NO:113.

30. The antibody or antigen-binding fragment thereof of any one of claims 1-29, wherein theantibody or antigen-binding fragment thereof comprises a light chain variable region: i) a light chain variable region comprising an amino acid sequence at least 80%identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:9, wherein the variable region comprises VLCDR1 comprising or consisting of SEQ ID NO:6, VLCDR2 comprising or consisting of SEQ ID NO:7, and VL CDR3 comprising or consisting of SEQ ID NO:

8. ii) a light chain variable region comprising an amino acid sequence at least 80%identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:19, wherein the variable region comprises VLCDR1 comprising or consisting of SEQ ID NO:16, VLCDR2 comprising or consisting of SEQ ID NO:17, and VLCDR3 comprising or consisting of SEQ ID NO:18; iii) a light chain variable region comprising an amino acid sequence at least 80%identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:29, wherein the variable region comprises VLCDR1 comprising or consisting of SEQ ID NO:26, VLCDR2 comprising or consisting of SEQ ID NO:27, and VLCDR3 comprising or consisting of SEQ ID NO:28; iv) a light chain variable region comprising an amino acid sequence at least 80%identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:39, wherein the variable region comprises VL CDR1 comprising or consisting of SEQ ID NO:36, VL CDR2 comprising or consisting of SEQ ID NO:37, and VLCDR3 comprising or consisting of SEQ ID NO:38; v) a light chain variable region comprising an amino acid sequence at least 80%identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:49, wherein the variable - 173 - 116104230Atty Docket No.40574-131 region comprises VL CDR1 comprising or consisting of SEQ ID NO:46, VL CDR2 comprising or consisting of SEQ ID NO:47, and VL CDR3 comprising or consisting of SEQ ID NO:48;vi) a light chain variable region comprising an amino acid sequence at least 80%identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:59, wherein the variable region comprises VLCDR1 comprising or consisting of SEQ ID NO:56, VLCDR2 comprising or consisting of SEQ ID NO:57, and VLCDR3 comprising or consisting of SEQ ID NO:58;vii) a light chain variable region comprising an amino acid sequence at least 80%identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:69, wherein the variable region comprises VLCDR1 comprising or consisting of SEQ ID NO:66, VLCDR2 comprising or consisting of SEQ ID NO:67, and VLCDR3 comprising or consisting of SEQ ID NO:68;viii) a light chain variable region comprising an amino acid sequence at least 80%identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:79, wherein the variable region comprises VL CDR1 comprising or consisting of SEQ ID NO:76, VL CDR2 comprising or consisting of SEQ ID NO:77, and VLCDR3 comprising or consisting of SEQ ID NO:78;ix) a light chain variable region comprising an amino acid sequence at least 80%identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:89, wherein the variable region comprises VL CDR1 comprising or consisting of SEQ ID NO:86, VL CDR2 comprising or consisting of SEQ ID NO:87, and VL CDR3 comprising or consisting of SEQ ID NO:88;x) a light chain variable region comprising an amino acid sequence at least 80%identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:99, wherein the variable region comprises VL CDR1 comprising or consisting of SEQ ID NO:96, VL CDR2 - 174 - 116104230Atty Docket No.40574-131 comprising or consisting of SEQ ID NO:97, and VL CDR3 comprising or consisting of SEQ ID NO:98; xi) a light chain variable region comprising an amino acid sequence at least 80%identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:109, wherein the variable region comprises VLCDR1 comprising or consisting of SEQ ID NO:106, VLCDR2 comprising or consisting of SEQ ID NO:107, and VLCDR3 comprising or consisting of SEQ ID NO:108; and xii) a light chain variable region comprising an amino acid sequence at least 80%identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:119, wherein the variable region comprises VL CDR1 comprising or consisting of SEQ ID NO:116, VL CDR2 comprising or consisting of SEQ ID NO:117, and VLCDR3 comprising or consisting of SEQ ID NO:118.

31. The antibody or antigen-binding fragment thereof of any one of claims 1-30, wherein theantibody or antigen-binding fragment thereof comprises a heavy chain selected from the group consisting of: i) a heavy chain comprising an amino acid sequence at least 80% identical, at least85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:5, wherein the heavy chain comprises VHCDR1 comprising or consisting of SEQ ID NO:1, VHCDR2 comprising or consisting of SEQ ID NO:2, and VHCDR3 comprising or consisting of SEQ ID NO3; ii) a heavy chain comprising an amino acid sequence at least 80% identical, at least85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:15, wherein the heavy chain comprises VH CDR1 comprising or consisting of SEQ ID NO:11, VH CDR2 comprising or consisting of SEQ ID NO:12, and VHCDR3 comprising or consisting of SEQ ID NO:13; iii) a heavy chain comprising an amino acid sequence at least 80% identical, at least85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:25, wherein the heavy chain comprises - 175 - 116104230Atty Docket No.40574-131 VH CDR1 comprising or consisting of SEQ ID NO:21, VH CDR2 comprising or consisting of SEQ ID NO:22, and VH CDR3 comprising or consisting of SEQ ID NO:23;iv) a heavy chain comprising an amino acid sequence at least 80% identical, at least85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:35, wherein the heavy chain comprises VHCDR1 comprising or consisting of SEQ ID NO:31, VHCDR2 comprising or consisting of SEQ ID NO:32, and VHCDR3 comprising or consisting of SEQ ID NO:33;v) a heavy chain comprising an amino acid sequence at least 80% identical, at least85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:45, wherein the heavy chain comprises VH CDR1 comprising or consisting of SEQ ID NO:41, VH CDR2 comprising or consisting of SEQ ID NO:42, and VH CDR3 comprising or consisting of SEQ ID NO:43;vi) a heavy chain comprising an amino acid sequence at least 80% identical, at least85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:55, wherein the heavy chain comprises VH CDR1 comprising or consisting of SEQ ID NO:51, VH CDR2 comprising or consisting of SEQ ID NO:52, and VH CDR3 comprising or consisting of SEQ ID NO:53;vii) a heavy chain comprising an amino acid sequence at least 80% identical, at least85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:65, wherein the heavy chain comprises VHCDR1 comprising or consisting of SEQ ID NO:61, VHCDR2 comprising or consisting of SEQ ID NO:62, and VHCDR3 comprising or consisting of SEQ ID NO:63;viii) a heavy chain comprising an amino acid sequence at least 80% identical, at least85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:75, wherein the heavy chain comprises VH CDR1 comprising or consisting of SEQ ID NO:71, VH CDR2 comprising or consisting of SEQ ID NO:72, and VHCDR3 comprising or consisting of SEQ ID NO:73;ix) a heavy chain comprising an amino acid sequence at least 80% identical, at least85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:85, wherein the heavy chain comprises - 176 - 116104230Atty Docket No.40574-131 VH CDR1 comprising or consisting of SEQ ID NO:81, VH CDR2 comprising or consisting of SEQ ID NO:82, and VH CDR3 comprising or consisting of SEQ ID NO:83; x) a heavy chain comprising an amino acid sequence at least 80% identical, at least85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:95, wherein the heavy chain comprises VHCDR1 comprising or consisting of SEQ ID NO:91, VHCDR2 comprising or consisting of SEQ ID NO:92, and VHCDR3 comprising or consisting of SEQ ID NO:93; xi) a heavy chain comprising an amino acid sequence at least 80% identical, at least85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:105, wherein the heavy chain comprises VH CDR1 comprising or consisting of SEQ ID NO:101, VH CDR2 comprising or consisting of SEQ ID NO:102, and VH CDR3 comprising or consisting of SEQ ID NO:103; and xii) a heavy chain comprising an amino acid sequence at least 80% identical, at least85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:115, wherein the heavy chain comprises VH CDR1 comprising or consisting of SEQ ID NO:111, VH CDR2 comprising or consisting of SEQ ID NO:112, and VH CDR3 comprising or consisting of SEQ ID NO:113.

32. The antibody or antigen-binding fragment thereof of any one of claims 1-31, wherein theantibody or antigen-binding fragment thereof comprises a light chain selected from the group consisting of: i) a light chain comprising an amino acid sequence at least 80% identical, at least 85%identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:10, wherein the light chain comprises VL CDR1 comprising or consisting of SEQ ID NO:6, VL CDR2 comprising or consisting of SEQ ID NO:7, and VL CDR3 comprising or consisting of SEQ ID NO:

8. ii) a light chain comprising an amino acid sequence at least 80% identical, at least 85%identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:20, wherein the light chain comprises VLCDR1 comprising or consisting of SEQ ID NO:16, VLCDR2 comprising or consisting of SEQ ID NO:17, and VLCDR3 comprising or consisting of SEQ ID NO:18; - 177 - 116104230Atty Docket No.40574-131iii) a light chain comprising an amino acid sequence at least 80% identical, at least 85%identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:30, wherein the light chain comprises VL CDR1 comprising or consisting of SEQ ID NO:26, VL CDR2 comprising or consisting of SEQ ID NO:27, and VLCDR3 comprising or consisting of SEQ ID NO:28;iv) a light chain comprising an amino acid sequence at least 80% identical, at least 85%identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:40, wherein the light chain comprises VLCDR1 comprising or consisting of SEQ ID NO:36, VL CDR2 comprising or consisting of SEQ ID NO:37, and VL CDR3 comprising or consisting of SEQ ID NO:38;v) a light chain comprising an amino acid sequence at least 80% identical, at least 85%identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:50, wherein the light chain comprises VLCDR1 comprising or consisting of SEQ ID NO:46, VLCDR2 comprising or consisting of SEQ ID NO:47, and VLCDR3 comprising or consisting of SEQ ID NO:48;vi) a light chain comprising an amino acid sequence at least 80% identical, at least 85%identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:60, wherein the light chain comprises VL CDR1 comprising or consisting of SEQ ID NO:56, VL CDR2 comprising or consisting of SEQ ID NO:57, and VLCDR3 comprising or consisting of SEQ ID NO:58;vii) a light chain comprising an amino acid sequence at least 80% identical, at least 85%identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:70, wherein the light chain comprises VL CDR1 comprising or consisting of SEQ ID NO:66, VL CDR2 comprising or consisting of SEQ ID NO:67, and VL CDR3 comprising or consisting of SEQ ID NO:68;viii) a light chain comprising an amino acid sequence at least 80% identical, at least 85%identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:80, wherein the light chain comprises VLCDR1 comprising or consisting of SEQ ID NO:76, VLCDR2 comprising or consisting of SEQ ID NO:77, and VLCDR3 comprising or consisting of SEQ ID NO:78; - 178 - 116104230Atty Docket No.40574-131 ix) a light chain comprising an amino acid sequence at least 80% identical, at least 85%identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:90, wherein the light chain comprises VL CDR1 comprising or consisting of SEQ ID NO:86, VL CDR2 comprising or consisting of SEQ ID NO:87, and VLCDR3 comprising or consisting of SEQ ID NO:88; x) a light chain comprising an amino acid sequence at least 80% identical, at least 85%identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:100, wherein the light chain comprises VLCDR1 comprising or consisting of SEQ ID NO:96, VL CDR2 comprising or consisting of SEQ ID NO:97, and VL CDR3 comprising or consisting of SEQ ID NO:98; xi) a light chain comprising an amino acid sequence at least 80% identical, at least 85%identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:110, wherein the light chain comprises VLCDR1 comprising or consisting of SEQ ID NO:106, VLCDR2 comprising or consisting of SEQ ID NO:107, and VLCDR3 comprising or consisting of SEQ ID NO:108; and xii) a light chain comprising an amino acid sequence at least 80% identical, at least 85%identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:120, wherein the light chain comprises VL CDR1 comprising or consisting of SEQ ID NO:116, VL CDR2 comprising or consisting of SEQ ID NO:117, and VLCDR3 comprising or consisting of SEQ ID NO:118.

33. The antibody or antigen-binding fragment thereof of any one of claims 1-32, wherein theantibody or antigen-binding fragment thereof is selected from the group consisting of: i) an antibody or antigen-binding fragment thereof comprising: a heavy chaincomprising an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:5, wherein the heavy chain comprises VH CDR1 comprising or consisting of SEQ ID NO:1, VHCDR2 comprising or consisting of SEQ ID NO:2, and VHCDR3 comprising or consisting of SEQ ID NO3; and a light chain comprising an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:10, wherein the light chain comprises VL CDR1 comprising or consisting of SEQ ID - 179 - 116104230Atty Docket No.40574-131 NO:6, VL CDR2 comprising or consisting of SEQ ID NO:7, and VL CDR3 comprising or consisting of SEQ ID NO:8;ii) an antibody or antigen-binding fragment thereof comprising: a heavy chaincomprising an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:15, wherein the heavy chain comprises VHCDR1 comprising or consisting of SEQ ID NO:11, VHCDR2 comprising or consisting of SEQ ID NO:12, and VHCDR3 comprising or consisting of SEQ ID NO:13; and a light chain comprising an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:20, wherein the light chain comprises VL CDR1 comprising or consisting of SEQ ID NO:16, VL CDR2 comprising or consisting of SEQ ID NO:17, and VL CDR3 comprising or consisting of SEQ ID NO:18;iii) an antibody or antigen-binding fragment thereof comprising: a heavy chaincomprising an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:25, wherein the heavy chain comprises VH CDR1 comprising or consisting of SEQ ID NO:21, VH CDR2 comprising or consisting of SEQ ID NO:22, and VH CDR3 comprising or consisting of SEQ ID NO:23; and a light chain comprising an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:30, wherein the light chain comprises VLCDR1 comprising or consisting of SEQ ID NO:26, VL CDR2 comprising or consisting of SEQ ID NO:27, and VL CDR3 comprising or consisting of SEQ ID NO:28;iv) an antibody or antigen-binding fragment thereof comprising: a heavy chaincomprising an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:35, wherein the heavy chain comprises VHCDR1 comprising or consisting of SEQ ID NO:31, VHCDR2 comprising or consisting of SEQ ID NO:32, and VHCDR3 comprising or consisting of SEQ ID NO:33; and a light chain comprising an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, - 180 - 116104230Atty Docket No.40574-131 at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:40, wherein the light chain comprises VL CDR1 comprising or consisting of SEQ ID NO:36, VL CDR2 comprising or consisting of SEQ ID NO:37, and VL CDR3 comprising or consisting of SEQ ID NO:38;v) an antibody or antigen-binding fragment thereof comprising: a heavy chaincomprising an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:45, wherein the heavy chain comprises VHCDR1 comprising or consisting of SEQ ID NO:41, VH CDR2 comprising or consisting of SEQ ID NO:42, and VH CDR3 comprising or consisting of SEQ ID NO:43; and a light chain comprising an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:50, wherein the light chain comprises VLCDR1 comprising or consisting of SEQ ID NO:46, VLCDR2 comprising or consisting of SEQ ID NO:47, and VLCDR3 comprising or consisting of SEQ ID NO:48;vi) an antibody or antigen-binding fragment thereof comprising: a heavy chaincomprising an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:55, wherein the heavy chain comprises VH CDR1 comprising or consisting of SEQ ID NO:51, VHCDR2 comprising or consisting of SEQ ID NO:52, and VHCDR3 comprising or consisting of SEQ ID NO:53; and a light chain comprising an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:60, wherein the light chain comprises VL CDR1 comprising or consisting of SEQ ID NO:56, VL CDR2 comprising or consisting of SEQ ID NO:57, and VL CDR3 comprising or consisting of SEQ ID NO:58;vii) an antibody or antigen-binding fragment thereof comprising: a heavy chaincomprising an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:65, wherein the heavy chain comprises VHCDR1 comprising or consisting of SEQ ID NO:61, VH CDR2 comprising or consisting of SEQ ID NO:62, and - 181 - 116104230Atty Docket No.40574-131 VH CDR3 comprising or consisting of SEQ ID NO:63; and a light chain comprising an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:70, wherein the light chain comprises VL CDR1 comprising or consisting of SEQ ID NO:66, VLCDR2 comprising or consisting of SEQ ID NO:67, and VLCDR3 comprising or consisting of SEQ ID NO:68;viii) an antibody or antigen-binding fragment thereof comprising: a heavy chaincomprising an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:75, wherein the heavy chain comprises VH CDR1 comprising or consisting of SEQ ID NO:71, VH CDR2 comprising or consisting of SEQ ID NO:72, and VHCDR3 comprising or consisting of SEQ ID NO:73; and a light chain comprising a variable region comprising an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:80, wherein the light chain comprises VLCDR1 comprising or consisting of SEQ ID NO:76, VL CDR2 comprising or consisting of SEQ ID NO:77, and VL CDR3 comprising or consisting of SEQ ID NO:78;ix) an antibody or antigen-binding fragment thereof comprising:a heavy chain comprising an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:85, wherein the heavy chain comprises VHCDR1 comprising or consisting of SEQ ID NO:81, VHCDR2 comprising or consisting of SEQ ID NO:82, and VH CDR3 comprising or consisting of SEQ ID NO:83; and a light chain comprising an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:90, wherein the light chain comprises VL CDR1 comprising or consisting of SEQ ID NO:86, VLCDR2 comprising or consisting of SEQ ID NO:87, and VLCDR3 comprising or consisting of SEQ ID NO:88;x) an antibody or antigen-binding fragment thereof comprising: a heavy chaincomprising an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% - 182 - 116104230Atty Docket No.40574-131 identical, to SEQ ID NO:95, wherein the heavy chain comprises VH CDR1 comprising or consisting of SEQ ID NO:91, VH CDR2 comprising or consisting of SEQ ID NO:92, and VH CDR3 comprising or consisting of SEQ ID NO:93; and a light chain comprising an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:100, wherein the light chain comprises VLCDR1 comprising or consisting of SEQ ID NO:96, VLCDR2 comprising or consisting of SEQ ID NO:97, and VLCDR3 comprising or consisting of SEQ ID NO:98;xi) an antibody or antigen-binding fragment thereof comprising: a heavy chaincomprising an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:105, wherein the heavy chain comprises VH CDR1 comprising or consisting of SEQ ID NO:101, VHCDR2 comprising or consisting of SEQ ID NO:102, and VHCDR3 comprising or consisting of SEQ ID NO:103; and a light chain comprising an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:110, wherein the light chain comprises VL CDR1 comprising or consisting of SEQ ID NO:106, VL CDR2 comprising or consisting of SEQ ID NO:107, and VL CDR3 comprising or consisting of SEQ ID NO:108; andxii) an antibody or antigen-binding fragment thereof comprising: a heavy chaincomprising an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:115, wherein the heavy chain comprises VH CDR1 comprising or consisting of SEQ ID NO:111, VH CDR2 comprising or consisting of SEQ ID NO:112, and VH CDR3 comprising or consisting of SEQ ID NO:113; and a light chain comprising an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical, or 100% identical, to SEQ ID NO:120, wherein the light chain comprises VLCDR1 comprising or consisting of SEQ ID NO:116, VLCDR2 comprising or consisting of SEQ ID NO:117, and VLCDR3 comprising or consisting of SEQ ID NO:

118. - 183 - 116104230Atty Docket No.40574-13134. The antibody or antigen-binding fragment thereof of any one of claims 1-33, wherein theantibody or antigen-binding fragment thereof is selected from the group consisting of EVD2301, 2302, 2303, 2304, 2305, 2306, 2307, 2308, 2309, 2310, 2311, and 2312.

35. The antibody or antigen-binding fragment thereof of any one of claims1-33, wherein theantibody or antigen-binding fragment thereof is a humanized antibody or antigen-binding fragment thereof.

36. The antibody or antigen-binding fragment thereof according to any one of claims 1-35,wherein the antibody or antigen-binding fragment thereof is isolated.

37. A vector comprising a nucleic acid molecule that comprises a polynucleotide sequenceencoding an antibody or antigen-binding fragment thereof of any one of claims 1-36.

38. The vector of claim 37, wherein the vector is an expression vector.

39. The vector of claim 37 or claim 38, wherein the polynucleotide sequence is operativelyconnected to a promoter that drives expression of the polynucleotide sequence.

40. The vector of any one of claims 37-39, wherein the vector comprises a plasmid or a viralvector.

41. The vector of claim 40, wherein the viral vector is a poxvirus vector, an adenovirus vector,a herpesvirus vector, an adeno-associated virus vector, a lentivirus vector, a plant virus vector, or an insect virus vector.

42. An engineered cell comprising the antibody or antigen-binding fragment thereof of anyone of claims 1-36 or the vector of any one of claims 37-41.

43. A composition comprising the antibody or antigen-binding fragment thereof of any one ofclaims 1-36, the vector of any one of claims 37-41, or the engineered cell of claim 42.

44. The composition of claim 43, further comprising at least one therapeutic compound.

45. The composition of claim 44, wherein the at least one therapeutic compound is selectedfrom the group consisting of an antiviral compound, an antibiotic, a steroid, rupintrivir– vemurafenib, vemurafenib–pleconaril, rupintrivir–pleconaril, and rupintrivir–cycloheximide.

46. The composition of any one of claims 43-45, wherein the composition is formulated foradministration in an individual.

47. A kit comprising the antibody or antigen-binding fragment thereof of any one of claims 1-36, the vector of any one of claims 37-41, the engineered cell of claim 42 or the composition of any one of claims 43-46. - 184 - 116104230Atty Docket No.40574-13148. A method of detecting an enterovirus, or an associated antigen thereof, comprising:a. contacting the antibody or antigen-binding fragment thereof of any one of claims1-36 with a test sample under conditions suitable for forming a complex between the enterovirus, if present, of the associated antigen thereof, if present; and b. detecting the presence of an antibody or antigen-binding fragmentthereof:enterovirus complex of an antibody or antigen-binding fragment thereof: enterovirus-associated antigen complex; thereby detecting the presence of the enterovirus.

49. A method of identifying enterovirus infection status of an individual, comprising testing asample from the individual for the presence of enterovirus or an associated antigen thereof using the antibody or antigen-binding fragment thereof of any one of claims 1-36, wherein if the presence of enterovirus, or an associated antigen thereof, is detected, identifying the individual as having an enterovirus infection, or if the presence of enterovirus or an associated antigen thereof is not detected, identifying the individual as not having an enterovirus infection.

50. The method of claim 49, wherein the step of testing the sample from the individualcomprises: a. contacting the sample with the antibody or antigen-binding fragment thereof of anyone of claims 1-36 under conditions suitable for forming a complex between the enterovirus or the associated antigen thereof, if present; and b. detecting the presence of an antibody or antigen-binding fragmentthereof:enterovirus complex or an antibody or antigen-binding fragment thereof:enterovirus-associated antigen complex; wherein if an antibody or antigen-binding fragment thereof:enterovirus complex or an antibody or antigen-binding fragment thereof:enterovirus-associated antigen complex is detected, identifying the individual as having an enterovirus infection, or if an antibody or antigen-binding fragment thereof:enterovirus complex or an antibody or antigen-binding fragment thereof:enterovirus-associated antigen complex is not detected, identifying the individual as not having an enterovirus infection.

51. A method of purifying an enterovirus or an associated antigen thereof, comprisingcontacting a sample comprising the enterovirus or associated antigen thereof with an antibody or antigen-binding fragment thereof of any one of claims 1-36 to form antibody or antigen-binding - 185 - 116104230Atty Docket No.40574-131 fragment thereof: enterovirus, or antibody or antigen-binding fragment thereof: enterovirus- associated antigen complexes, such that the enterovirus or associated antigen thereof is removed from majority of components in the sample, thereby purifying the enterovirus or an associated antigen thereof.

52. The method of claim 51, wherein once the antibody or antigen-binding fragmentthereof:enterovirus or antibody or antigen-binding fragment thereof:enterovirus-associated antigen complex is formed, washing the antibody or antigen-binding fragment thereof:enterovirus or antibody or antigen-binding fragment thereof:enterovirus-associated antigen complex to remove non-desirable components present in the sample.

53. The method of claim 52, comprising treating the antibody or antigen-binding fragmentthereof:enterovirus or antibody or antigen-binding fragment thereof:enterovirus-associated antigen complex to remove the enterovirus or associated antigen thereof.

54. A method of preventing infection of a cell by an enterovirus, comprising contacting theenterovirus with the antibody of any one of claims 1-36 prior to, or concurrent with, contacting the enterovirus with the cell.

55. A method of protecting an individual against infection with an enterovirus, comprisingadministering to the individual the antibody or antigen-binding fragment thereof of any one of claims 1-36, the vector of any one of claims 37-41, the engineered cell of claim 42, or the composition of any one of claims 43-46.

56. The method of claim 55, wherein the individual is known to be free of enterovirus.

57. The method of claim 54 or claim 55, wherein the individual is at risk for infection withenterovirus.

58. A method of treating an individual having an enterovirus infection, comprisingadministering to the individual the antibody or antigen-binding fragment thereof of any one of claims 1-36, the vector of any one of claims 37-41, the engineered cell of claim 42, or the composition of any one of claims 43-46.

59. A method of reducing disease symptoms in an individual infected with enterovirus,comprising administering to the antibody or antigen-binding fragment thereof of any one of claims 1-36, the vector of any one of claims 37-41, the engineered cell of claim 42, or the composition of any one of claims 43-46. - 186 - 116104230Atty Docket No.40574-13160. Use of the antibody or antigen-binding fragment thereof of any one of claims 1-36, thevector of any one of claims 36-40, the engineered cell of claim 41, the composition of any one of claims 42-45, or the kit of claim 46, in the preparation of a medicament for protecting an individual against infection with an enterovirus.

61. Use of the antibody or antigen-binding fragment thereof of any one of claims 1-36, thevector of any one of claims 37-41, the engineered cell of claim 42, the composition of any one of claims 43-46, or the kit of claim 47, in the preparation of a medicament for treating an individual infected with an enterovirus.

62. Use of the antibody or antigen-binding fragment thereof of any one of claims 1-36, thevector of any one of claims 37-41, the engineered cell of claim 42, the composition of any one of claims 43-46, or the kit of claim 47, in the preparation of a medicament for reducing symptoms in an individual infected with enterovirus.

63. The method of any one of claims 48-59, or the use of any one of claims 60-62, wherein theenterovirus is selected from the group consisting of EV-68, EV-68 B3, EV-68 A2 / D, and EV-A71.

64. The antibody or antigen-binding fragment thereof of any one of claims 1-36, wherein theantibody or antigen-binding fragment thereof comprises one or more heavy chain CDRs from Table 2.

65. The antibody or antigen-binding fragment thereof of any one of claims 1-36 and 64,wherein the antibody or antigen-binding fragment thereof comprises one or more light chain CDRs from Table 2.

66. The antibody or antigen-binding fragment thereof of any one of claims 1-36, 64, or 65,wherein the antibody or antigen-binding fragment thereof comprises one or more antibody- matched heavy chain CDRs and light chain CDRs from Table 2.

67. The antibody or antigen-binding fragment thereof of any one of claims 1-36 or 64-66,wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, or at least 99% identical, to a heavy chain variable region from Table 2, wherein the heavy chain variable region comprises antibody- matched VHCDR1, VHCDR2, and VHCDR3 sequences from Table 2.

68. The antibody or antigen-binding fragment thereof of any one of claims 1-36 or 64-67,wherein the antibody or antigen-binding fragment thereof comprises a light chain variable region - 187 - 116104230Atty Docket No.40574-131 comprising an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, or at least 99% identical, to a light chain variable region from Table 2, wherein the light chain variable region comprises antibody-matched VLCDR1, VLCDR2, and VLCDR3 sequences from Table 2.

69. The antibody or antigen-binding fragment thereof of any one of claims 1-36 or 64-68,wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region and an antibody-matched light chain variable region, the antibody-matched, heavy and light chain variable regions comprising amino acid sequences at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, or at least 99% identical, to a heavy chain variable region and a light chain variable region, respectively, from Table 2, wherein the heavy chain variable region comprises antibody-matched VHCDR1, VHCDR2, and VHCDR3 sequences from Table 2 and the light chain variable region comprises antibody-matched VLCDR1, VLCDR2, and VLCDR3 sequences from Table 2.

70. The antibody or antigen-binding fragment thereof of any one of claims 1-36 or 64-69,wherein the antibody or antigen-binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, or at least 99% identical, to a heavy chain from Table 2, wherein the heavy chain comprises antibody-matched VHCDR1, VHCDR2, and VHCDR3 sequences from Table 2.

71. The antibody or antigen-binding fragment thereof of any one of claims 1-36 or 64-70,wherein the antibody or antigen-binding fragment thereof comprises a light chain comprising an amino acid sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, or at least 99% identical, to a light chain from Table 2, wherein the light chain comprises antibody-matched VLCDR1, VLCDR2, and VLCDR3 sequences from Table 2.

72. The antibody or antigen-binding fragment thereof of any one of claims 1-36 or 64-71,wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region and an antibody-matched light chain variable region, the antibody-matched, heavy and light chain variable regions comprising amino acid sequences at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, or at least 99% identical, to a heavy chain variable region and a light chain variable region, respectively, from Table 2, wherein - 188 - 116104230Atty Docket No.40574-131 the heavy chain variable region comprises antibody-matched VHCDR1, VHCDR2, and VHCDR3 sequences from Table 2 and the light chain variable region comprises antibody-matched VLCDR1, VLCDR2, and VLCDR3 sequences from Table 2.

73. The antibody or antigen-binding fragment thereof of any one of claims 1-36 or 64-72,wherein the antibody or antigen-binding fragment thereof comprises a heavy chain and an antibody-matched light chain, the antibody-matched, heavy chain and the light chain comprising amino acid sequences at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, or at least 99% identical, to a heavy chain and a light chain, respectively, from Table 2, wherein the heavy chain comprises antibody-matched VHCDR1, VHCDR2, and VHCDR3 sequences from Table 2 and the light chain comprises antibody-matched VLCDR1, VLCDR2, and VLCDR3 sequences from Table 2.

74. The antibody or antigen-binding fragment thereof of any one of claims 1-36 or 64-73,wherein the antibody or antigen-binding fragment thereof comprises antibody-matched sequences from Table 2.

75. The antibody or antigen-binding fragment thereof of any one of claims 1-36 or 64-74,wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) complementarity determining region 3 (CDR3) selected from the group consisting of a VH CDR3 comprising or consisting of SEQ ID NO:130, a VH CDR3 comprising or consisting of SEQ ID NO:144, a VH CDR3 comprising or consisting of SEQ ID NO:148, a VH CDR3 comprising or consisting of SEQ ID NO:172, a VHCDR3 comprising or consisting of SEQ ID NO:186, a VHCDR3 comprising or consisting of SEQ ID NO:200, a VHCDR3 comprising or consisting of SEQ ID NO:214, a VHCDR3 comprising or consisting of SEQ ID NO:228, a VHCDR3 comprising or consisting of SEQ ID NO:242, a VH CDR3 comprising or consisting of SEQ ID NO:256, a VH CDR3 comprising or consisting of SEQ ID NO:270, a VH CDR3 comprising or consisting of SEQ ID NO:284, a VH CDR3 comprising or consisting of SEQ ID NO:298, a VH CDR3 comprising or consisting of SEQ ID NO:312, a VH CDR3 comprising or consisting of SEQ ID NO:326, a VH CDR3 comprising or consisting of SEQ ID NO:340, a VHCDR3 comprising or consisting of SEQ ID NO:354, a VHCDR3 comprising or consisting of SEQ ID NO:368, a VHCDR3 comprising or consisting of SEQ ID NO:382, 396, a VHCDR3 comprising or consisting of SEQ ID NO:410, a VHCDR3 comprising or consisting of SEQ ID NO:424, a VHCDR3 comprising or consisting of SEQ ID NO:438, a VH CDR3 comprising or consisting of SEQ ID NO:452, a VH CDR3 comprising - 189 - 116104230Atty Docket No.40574-131 or consisting of SEQ ID NO:466, a VH CDR3 comprising or consisting of SEQ ID NO:480, a VH CDR3 comprising or consisting of SEQ ID NO:494, a VH CDR3 comprising or consisting of SEQ ID NO:508, a VH CDR3 comprising or consisting of SEQ ID NO:522,, a VH CDR3 comprising or consisting of SEQ ID NO:536, a VH CDR3 comprising or consisting of SEQ ID NO:550, a VH CDR3 comprising or consisting of SEQ ID NO:564, a VHCDR3 comprising or consisting of SEQ ID NO:578, a VHCDR3 comprising or consisting of SEQ ID NO:592, a VHCDR3 comprising or consisting of SEQ ID NO:606, and a VHCDR3 comprising or consisting of SEQ ID NO:620.

76. The antibody or antigen-binding fragment thereof of any one of claims 1-36 or 64-75,wherein the antibody or antigen-binding fragment thereof comprises a light chain variable region (VL) CDR3 selected from the group consisting of a VL CDR3 comprising or consisting of SEQ ID NO:137, a VL CDR3 comprising or consisting of SEQ ID NO:151, a VLCDR3 comprising or consisting of SEQ ID NO:165, a VL CDR3 comprising or consisting of SEQ ID NO:179, a VL CDR3 comprising or consisting of SEQ ID NO:193, a VLCDR3 comprising or consisting of SEQ ID NO:207, a VLCDR3 comprising or consisting of SEQ ID NO:221, a VLCDR3 comprising or consisting of SEQ ID NO:235, a VLCDR3 comprising or consisting of SEQ ID NO:249, a VLCDR3 comprising or consisting of SEQ ID NO:263, a VL CDR3 comprising or consisting of SEQ ID NO:277, a VL CDR3 comprising or consisting of SEQ ID NO:291, a VL CDR3 comprising or consisting of SEQ ID NO:305, a VL CDR3 comprising or consisting of SEQ ID NO:319, a VL CDR3 comprising or consisting of SEQ ID NO:333, a VL CDR3 comprising or consisting of SEQ ID NO:347, a VLCDR3 comprising or consisting of SEQ ID NO:361, a VLCDR3 comprising or consisting of SEQ ID NO:375, a VLCDR3 comprising or consisting of SEQ ID NO:389, a VLCDR3 comprising or consisting of SEQ ID NO:403, a VLCDR3 comprising or consisting of SEQ ID NO:417, a VL CDR3 comprising or consisting of SEQ ID NO:431, a VL CDR3 comprising or consisting of SEQ ID NO:445, a VL CDR3 comprising or consisting of SEQ ID NO:459, a VL CDR3 comprising or consisting of SEQ ID NO:473, a VL CDR3 comprising or consisting of SEQ ID NO:487, a VL CDR3 comprising or consisting of SEQ ID NO:501, a VL CDR3 comprising or consisting of SEQ ID NO:515, a VLCDR3 comprising or consisting of SEQ ID NO:529, a VLCDR3 comprising or consisting of SEQ ID NO:543, a VLCDR3 comprising or consisting of SEQ ID NO:557, a VLCDR3 comprising or consisting of SEQ ID NO:571, a VLCDR3 comprising or consisting of SEQ ID NO:585, a VLCDR3 comprising or consisting of SEQ ID NO:599, a VL- 190 - 116104230Atty Docket No.40574-131 CDR3 comprising or consisting of SEQ ID NO:612, or a VL CDR3 comprising or consisting of SEQ ID NO:627.

77. The antibody or antigen-binding fragment thereof of any one of claims 1-36 or 64-76,wherein the antibody or antigen-binding fragment thereof comprises a VH CDR2 selected from the group consisting of a VHCDR2 comprising or consisting of SEQ ID NO:128, a VHCDR2 comprising or consisting of SEQ ID NO:142, a VHCDR2 comprising or consisting of SEQ ID NO:156, a VHCDR2 comprising or consisting of SEQ ID NO:170, a VHCDR2 comprising or consisting of SEQ ID NO:184, a VHCDR2 comprising or consisting of SEQ ID NO:198, a VHCDR2 comprising or consisting of SEQ ID NO:226, a VH CDR2 comprising or consisting of SEQ ID NO:240, a VH CDR2 comprising or consisting of SEQ ID NO:254, a VH CDR2 comprising or consisting of SEQ ID NO:268, a VH CDR2 comprising or consisting of SEQ ID NO:282, a VH CDR2 comprising or consisting of SEQ ID NO:296, a VH CDR2 comprising or consisting of SEQ ID NO:296, a VHCDR2 comprising or consisting of SEQ ID NO:310, a VHCDR2 comprising or consisting of SEQ ID NO:324, a VHCDR2 comprising or consisting of SEQ ID NO:338, a VHCDR2 comprising or consisting of SEQ ID NO:352, a VHCDR2 comprising or consisting of SEQ ID NO:366, a VH CDR2 comprising or consisting of SEQ ID NO:380, a VH CDR2 comprising or consisting of SEQ ID NO:394, a VH CDR2 comprising or consisting of SEQ ID NO:408, a VH CDR2 comprising or consisting of SEQ ID NO:422, a VH CDR2 comprising or consisting of SEQ ID NO:436, a VH CDR2 comprising or consisting of SEQ ID NO:450, a VH CDR2 comprising or consisting of SEQ ID NO:464, a VHCDR2 comprising or consisting of SEQ ID NO:478, a VHCDR2 comprising or consisting of SEQ ID NO:492, a VHCDR2 comprising or consisting of SEQ ID NO:506, a VHCDR2 comprising or consisting of SEQ ID NO:520, a VHCDR2 comprising or consisting of SEQ ID NO:534, a VH CDR2 comprising or consisting of SEQ ID NO:548, a VH CDR2 comprising or consisting of SEQ ID NO:562, a VH CDR2 comprising or consisting of SEQ ID NO:576, a VH CDR2 comprising or consisting of SEQ ID NO:590, a VH CDR2 comprising or consisting of SEQ ID NO:604, or a VH CDR2 comprising or consisting of SEQ ID NO:618.

78. The antibody or antigen-binding fragment thereof of any one of claims 1-36 and 64-77,wherein the antibody or antigen-binding fragment thereof comprises a VLCDR2 selected from the group consisting of a VLCDR2 comprising or consisting of SEQ ID NO:7, a VLCDR2 comprising or consisting of SEQ ID NO:17, a VLCDR2 comprising or consisting of SEQ ID NO:27, a VLCDR2 comprising or consisting of SEQ ID NO:37, a VL CDR2 comprising or consisting of SEQ - 191 - 116104230Atty Docket No.40574-131 ID NO:47, a VL CDR2 comprising or consisting of SEQ ID NO:57, a VL CDR2 comprising or consisting of SEQ ID NO:67, a VL CDR2 comprising or consisting of SEQ ID NO:77, a VL CDR2 comprising or consisting of SEQ ID NO:87, a VL CDR2 comprising or consisting of SEQ ID NO:97, a VL CDR2 comprising or consisting of SEQ ID NO:107, and a VL CDR2 comprising or consisting of SEQ ID NO:117.

79. The antibody or antigen-binding fragment thereof of any one of claims 1-36 or 64-78,wherein the antibody or antigen-binding fragment thereof comprises a VHCDR1 selected from the group consisting of a VHCDR1 comprising or consisting of SEQ ID NO:126, a VHCDR1 comprising or consisting of SEQ ID NO:140, a VH CDR1 comprising or consisting of SEQ ID NO:154, a VH CDR1 comprising or consisting of SEQ ID NO:168, a VH CDR1 comprising or consisting of SEQ ID NO:182, a VH CDR1 comprising or consisting of SEQ ID NO:196, a VH CDR1 comprising or consisting of SEQ ID NO:210, a VH CDR1 comprising or consisting of SEQ ID NO:224, a VHCDR1 comprising or consisting of SEQ ID NO:238, a VHCDR1 comprising or consisting of SEQ ID NO:252, a VHCDR1 comprising or consisting of SEQ ID NO:266, a VHCDR1 comprising or consisting of SEQ ID NO:280, a VHCDR1 comprising or consisting of SEQ ID NO:294, a VH CDR1 comprising or consisting of SEQ ID NO:308, a VH CDR1 comprising or consisting of SEQ ID NO:322, a VH CDR1 comprising or consisting of SEQ ID NO:336, a VH CDR1 comprising or consisting of SEQ ID NO:350, a VH CDR1 comprising or consisting of SEQ ID NO:364, a VH CDR1 comprising or consisting of SEQ ID NO:378, a VH CDR1 comprising or consisting of SEQ ID NO:392, a VHCDR1 comprising or consisting of SEQ ID NO:406, a VHCDR1 comprising or consisting of SEQ ID NO:420, a VHCDR1 comprising or consisting of SEQ ID NO:434, a VHCDR1 comprising or consisting of SEQ ID NO:448, a VHCDR1 comprising or consisting of SEQ ID NO:462, a VH CDR1 comprising or consisting of SEQ ID NO:476, a VH CDR1 comprising or consisting of SEQ ID NO:490, a VH CDR1 comprising or consisting of SEQ ID NO:504, a VH CDR1 comprising or consisting of SEQ ID NO:518, a VH CDR1 comprising or consisting of SEQ ID NO:532, a VH CDR1 comprising or consisting of SEQ ID NO:546, a VH CDR1 comprising or consisting of SEQ ID NO:560, a VHCDR1 comprising or consisting of SEQ ID NO:574, a VHCDR1 comprising or consisting of SEQ ID NO:588, a VHCDR1 comprising or consisting of SEQ ID NO:602, or a VHCDR1 comprising or consisting of SEQ ID NO:616.

80. The antibody or antigen-binding fragment thereof of any one of claims 1-36 or 64-79,wherein the antibody or antigen-binding fragment thereof comprises a VL CDR1 selected from the - 192 - 116104230Atty Docket No.40574-131 group consisting of a VL CDR1 comprising or consisting of SEQ ID NO:133, a VL CDR1 comprising or consisting of SEQ ID NO:147, a VL CDR1 comprising or consisting of SEQ ID NO:161, a VL CDR1 comprising or consisting of SEQ ID NO:175, a VL CDR1 comprising or consisting of SEQ ID NO:189, a VL CDR1 comprising or consisting of SEQ ID NO:203, a VL CDR1 comprising or consisting of SEQ ID NO:217, a VLCDR1 comprising or consisting of SEQ ID NO:231, a VLCDR1 comprising or consisting of SEQ ID NO:245, a VLCDR1 comprising or consisting of SEQ ID NO:259, a VLCDR1 comprising or consisting of SEQ ID NO:273, a VLCDR1 comprising or consisting of SEQ ID NO:287, a VLCDR1 comprising or consisting of SEQ ID NO:301, a VL CDR1 comprising or consisting of SEQ ID NO:315, a VL CDR1 comprising or consisting of SEQ ID NO:329, a VL CDR1 comprising or consisting of SEQ ID NO:343, a VL CDR1 comprising or consisting of SEQ ID NO:357, a VL CDR1 comprising or consisting of SEQ ID NO:371, a VL CDR1 comprising or consisting of SEQ ID NO:385, a VL CDR1 comprising or consisting of SEQ ID NO:399, a VLCDR1 comprising or consisting of SEQ ID NO:413, a VLCDR1 comprising or consisting of SEQ ID NO:427, a VLCDR1 comprising or consisting of SEQ ID NO:441, a VLCDR1 comprising or consisting of SEQ ID NO:455, a VLCDR1 comprising or consisting of SEQ ID NO:469, a VL CDR1 comprising or consisting of SEQ ID NO:483, a VL CDR1 comprising or consisting of SEQ ID NO:497, a VL CDR1 comprising or consisting of SEQ ID NO:511, a VL CDR1 comprising or consisting of SEQ ID NO:525, a VL CDR1 comprising or consisting of SEQ ID NO:539, a VL CDR1 comprising or consisting of SEQ ID NO:553, a VL CDR1 comprising or consisting of SEQ ID NO:567, a VLCDR1 comprising or consisting of SEQ ID NO:581, a VLCDR1 comprising or consisting of SEQ ID NO:595, a VLCDR1 comprising or consisting of SEQ ID NO:609, or a VLCDR1 comprising or consisting of SEQ ID NO:623.

81. The antibody or antigen-binding fragment thereof of any one of claims 1-36 or 64-80,wherein the antibody or antigen-binding fragment thereof comprises: i) a VH CDR3 comprising or consisting of SEQ ID NO:130 and a VL CDR3comprising or consisting of SEQ ID NO:137; ii) a VH CDR3 comprising or consisting of SEQ ID NO:144 and a VL CDR3comprising or consisting of SEQ ID NO:151; iii) a VH CDR3 comprising or consisting of SEQ ID NO:158 and a VL CDR3comprising or consisting of SEQ ID NO:165; - 193 - 116104230Atty Docket No.40574-131iv) a VH CDR3 comprising or consisting of SEQ ID NO:172 and a VL CDR3comprising or consisting of SEQ ID NO:179;v) a VH CDR3 comprising or consisting of SEQ ID NO:186 and a VL CDR3comprising or consisting of SEQ ID NO:193;vi) a VH CDR3 comprising or consisting of SEQ ID NO:200 and a VL CDR3comprising or consisting of SEQ ID NO:207;vii) a VH CDR3 comprising or consisting of SEQ ID NO:214 and a VL CDR3comprising or consisting of SEQ ID NO:221;viii) a VH CDR3 comprising or consisting of SEQ ID NO:228 and a VL CDR3comprising or consisting of SEQ ID NO:235;ix) a VH CDR3 comprising or consisting of SEQ ID NO:242 and a VL CDR3comprising or consisting of SEQ ID NO:249;x) a VH CDR3 comprising or consisting of SEQ ID NO:256 and a VL CDR3comprising or consisting of SEQ ID NO:263;xi) a VH CDR3 comprising or consisting of SEQ ID NO:270 and a VL CDR3comprising or consisting of SEQ ID NO:277;xii) a VH CDR3 comprising or consisting of SEQ ID NO:284 and a VL CDR3comprising or consisting of SEQ ID NO:291;xiii) a VH CDR3 comprising or consisting of SEQ ID NO:298 and a VL CDR3comprising or consisting of SEQ ID NO:305;xiv) a VH CDR3 comprising or consisting of SEQ ID NO:312 and a VL CDR3comprising or consisting of SEQ ID NO:319;xv) a VH CDR3 comprising or consisting of SEQ ID NO:326 and a VL CDR3comprising or consisting of SEQ ID NO:333;xvi) a VH CDR3 comprising or consisting of SEQ ID NO:340 and a VL CDR3comprising or consisting of SEQ ID NO:347;xvii) a VH CDR3 comprising or consisting of SEQ ID NO:354 and a VL CDR3comprising or consisting of SEQ ID NO:361;xviii) a VH CDR3 comprising or consisting of SEQ ID NO:368 and a VL CDR3comprising or consisting of SEQ ID NO:375; - 194 - 116104230Atty Docket No.40574-131xix) a VH CDR3 comprising or consisting of SEQ ID NO:382 and a VL CDR3comprising or consisting of SEQ ID NO:389;xx) a VH CDR3 comprising or consisting of SEQ ID NO:396 and a VL CDR3comprising or consisting of SEQ ID NO:403;xxi) a VH CDR3 comprising or consisting of SEQ ID NO:410 and a VL CDR3comprising or consisting of SEQ ID NO:417;xxii) a VH CDR3 comprising or consisting of SEQ ID NO:424 and a VL CDR3comprising or consisting of SEQ ID NO:431;xxiii) a VH CDR3 comprising or consisting of SEQ ID NO:438 and a VL CDR3comprising or consisting of SEQ ID NO:445;xxiv) a VH CDR3 comprising or consisting of SEQ ID NO:452 and a VL CDR3comprising or consisting of SEQ ID NO:459;xxv) a VH CDR3 comprising or consisting of SEQ ID NO:466 and a VL CDR3comprising or consisting of SEQ ID NO:473;xxvi) a VH CDR3 comprising or consisting of SEQ ID NO:480 and a VL CDR3comprising or consisting of SEQ ID NO:487;xxvii) a VH CDR3 comprising or consisting of SEQ ID NO:494 and a VL CDR3comprising or consisting of SEQ ID NO:501;xxviii) a VH CDR3 comprising or consisting of SEQ ID NO:508 and a VL CDR3comprising or consisting of SEQ ID NO:515;xxix) a VH CDR3 comprising or consisting of SEQ ID NO:522 and a VL CDR3comprising or consisting of SEQ ID NO:529;xxx) a VH CDR3 comprising or consisting of SEQ ID NO:536 and a VL CDR3comprising or consisting of SEQ ID NO:543;xxxi) a VH CDR3 comprising or consisting of SEQ ID NO:550 and a VL CDR3comprising or consisting of SEQ ID NO:557;xxxii) a VH CDR3 comprising or consisting of SEQ ID NO:564 and a VL CDR3comprising or consisting of SEQ ID NO:571;xxxiii) a VH CDR3 comprising or consisting of SEQ ID NO:578 and a VL CDR3comprising or consisting of SEQ ID NO:585; - 195 - 116104230Atty Docket No.40574-131 xxxiv) a VH CDR3 comprising or consisting of SEQ ID NO:592 and a VL CDR3comprising or consisting of SEQ ID NO:599; xxxv) a VH CDR3 comprising or consisting of SEQ ID NO:606 and a VL CDR3comprising or consisting of SEQ ID NO:613; or xxxvi) a VH CDR3 comprising or consisting of SEQ ID NO:620 and a VL CDR3comprising or consisting of SEQ ID NO:627.

82. The antibody or antigen-binding fragment thereof of any one of claims 1-36 or 64-81,wherein the antibody or antigen-binding fragment thereof comprises: i) a VH CDR1 comprising or consisting of SEQ ID NO:126, a VH CDR2 comprisingor consisting of SEQ ID NO:128, and a VH CDR3 comprising or consisting of SEQ ID NO:130; ii) a VH CDR1 comprising or consisting of SEQ ID NO:140, a VH CDR2 comprisingor consisting of SEQ ID NO:142, and a VHCDR3 comprising or consisting of SEQ ID NO:144; iii) a VH CDR1 comprising or consisting of SEQ ID NO:154, a VH CDR2 comprisingor consisting of SEQ ID NO:156, and a VH CDR3 comprising or consisting of SEQ ID NO:158; iv) a VH CDR1 comprising or consisting of SEQ ID NO:168, a VH CDR2 comprisingor consisting of SEQ ID NO:170, and a VH CDR3 comprising or consisting of SEQ ID NO:172; v) a VH CDR1 comprising or consisting of SEQ ID NO:182, a VH CDR2 comprisingor consisting of SEQ ID NO:184, and a VHCDR3 comprising or consisting of SEQ ID NO:186; vi) a VH CDR1 comprising or consisting of SEQ ID NO:196, a VH CDR2 comprisingor consisting of SEQ ID NO:198, and a VH CDR3 comprising or consisting of SEQ ID NO:200; vii) a VH CDR1 comprising or consisting of SEQ ID NO:210, a VH CDR2 comprisingor consisting of SEQ ID NO:212, and a VHCDR3 comprising or consisting of SEQ ID NO:214; - 196 - 116104230Atty Docket No.40574-131viii) a VH CDR1 comprising or consisting of SEQ ID NO:224, a VH CDR2 comprisingor consisting of SEQ ID NO:226, and a VH CDR3 comprising or consisting of SEQ ID NO:228;ix) a VH CDR1 comprising or consisting of SEQ ID NO:238, a VH CDR2 comprisingor consisting of SEQ ID NO:240, and a VHCDR3 comprising or consisting of SEQ ID NO:242;x) a VH CDR1 comprising or consisting of SEQ ID NO:252, a VH CDR2 comprisingor consisting of SEQ ID NO:254, and a VHCDR3 comprising or consisting of SEQ ID NO:256;xi) a VH CDR1 comprising or consisting of SEQ ID NO:266, a VH CDR2 comprisingor consisting of SEQ ID NO:268, and a VH CDR3 comprising or consisting of SEQ ID NO:270; orxii) a VH CDR1 comprising or consisting of SEQ ID NO:280, a VH CDR2 comprisingor consisting of SEQ ID NO:282, and a VHCDR3 comprising or consisting of SEQ ID NO:284;xiii) a VH CDR1 comprising or consisting of SEQ ID NO:294, a VH CDR2 comprisingor consisting of SEQ ID NO:296, and a VH CDR3 comprising or consisting of SEQ ID NO:298;xiv) a VH CDR1 comprising or consisting of SEQ ID NO:308, a VH CDR2 comprisingor consisting of SEQ ID NO:310, and a VHCDR3 comprising or consisting of SEQ ID NO:312;xv) a VH CDR1 comprising or consisting of SEQ ID NO:322, a VH CDR2 comprisingor consisting of SEQ ID NO:324, and a VH CDR3 comprising or consisting of SEQ ID NO:326;xvi) a VH CDR1 comprising or consisting of SEQ ID NO:336, a VH CDR2 comprisingor consisting of SEQ ID NO:338, and a VH CDR3 comprising or consisting of SEQ ID NO:340;xvii) a VH CDR1 comprising or consisting of SEQ ID NO:350, a VH CDR2 comprisingor consisting of SEQ ID NO:352, and a VHCDR3 comprising or consisting of SEQ ID NO:354; - 197 - 116104230Atty Docket No.40574-131xviii) a VH CDR1 comprising or consisting of SEQ ID NO:364, a VH CDR2 comprisingor consisting of SEQ ID NO:366, and a VH CDR3 comprising or consisting of SEQ ID NO:368;xix) a VH CDR1 comprising or consisting of SEQ ID NO:378, a VH CDR2 comprisingor consisting of SEQ ID NO:380, and a VHCDR3 comprising or consisting of SEQ ID NO:382;xx) a VH CDR1 comprising or consisting of SEQ ID NO:392, a VH CDR2 comprisingor consisting of SEQ ID NO:394, and a VHCDR3 comprising or consisting of SEQ ID NO:396;xxi) a VH CDR1 comprising or consisting of SEQ ID NO:406, a VH CDR2 comprisingor consisting of SEQ ID NO:408, and a VH CDR3 comprising or consisting of SEQ ID NO:410;xxii) a VH CDR1 comprising or consisting of SEQ ID NO:420, a VH CDR2 comprisingor consisting of SEQ ID NO:422, and a VHCDR3 comprising or consisting of SEQ ID NO:424;xxiii) a VH CDR1 comprising or consisting of SEQ ID NO:434, a VH CDR2 comprisingor consisting of SEQ ID NO:436, and a VH CDR3 comprising or consisting of SEQ ID NO:438;xxiv) a VH CDR1 comprising or consisting of SEQ ID NO:448, a VH CDR2 comprisingor consisting of SEQ ID NO:450, and a VHCDR3 comprising or consisting of SEQ ID NO:452;xxv) a VH CDR1 comprising or consisting of SEQ ID NO:462, a VH CDR2 comprisingor consisting of SEQ ID NO:464, and a VH CDR3 comprising or consisting of SEQ ID NO:466;xxvi) a VH CDR1 comprising or consisting of SEQ ID NO:476, a VH CDR2 comprisingor consisting of SEQ ID NO:478, and a VH CDR3 comprising or consisting of SEQ ID NO:480;xxvii) a VH CDR1 comprising or consisting of SEQ ID NO:490, a VH CDR2 comprisingor consisting of SEQ ID NO:492, and a VHCDR3 comprising or consisting of SEQ ID NO:494; - 198 - 116104230Atty Docket No.40574-131 xxviii) a VH CDR1 comprising or consisting of SEQ ID NO:504, a VH CDR2 comprisingor consisting of SEQ ID NO:506, and a VH CDR3 comprising or consisting of SEQ ID NO:508; xxix) a VH CDR1 comprising or consisting of SEQ ID NO:518, a VH CDR2 comprisingor consisting of SEQ ID NO:520, and a VHCDR3 comprising or consisting of SEQ ID NO:522; xxx) a VH CDR1 comprising or consisting of SEQ ID NO:532, a VH CDR2 comprisingor consisting of SEQ ID NO:534, and a VHCDR3 comprising or consisting of SEQ ID NO:536; xxxi) a VH CDR1 comprising or consisting of SEQ ID NO:546, a VH CDR2 comprisingor consisting of SEQ ID NO:548, and a VH CDR3 comprising or consisting of SEQ ID NO:550; xxxii) a VH CDR1 comprising or consisting of SEQ ID NO:560, a VH CDR2 comprisingor consisting of SEQ ID NO:562, and a VHCDR3 comprising or consisting of SEQ ID NO:564; xxxiii) a VH CDR1 comprising or consisting of SEQ ID NO:574, a VH CDR2 comprisingor consisting of SEQ ID NO:576, and a VH CDR3 comprising or consisting of SEQ ID NO:578; xxxiv) a VH CDR1 comprising or consisting of SEQ ID NO:588, a VH CDR2 comprisingor consisting of SEQ ID NO:590, and a VHCDR3 comprising or consisting of SEQ ID NO:592; xxxv) a VH CDR1 comprising or consisting of SEQ ID NO:602, a VH CDR2 comprisingor consisting of SEQ ID NO:604, and a VH CDR3 comprising or consisting of SEQ ID NO:606; or xxxvi) a VH CDR1 comprising or consisting of SEQ ID NO:616, a VH CDR2 comprisingor consisting of SEQ ID NO:618, and a VH CDR3 comprising or consisting of SEQ ID NO:620.

83. The antibody or antigen-binding fragment thereof of any one of claims 1-36 or 64-82,wherein the antibody or antigen-binding fragment thereof comprises: - 199 - 116104230Atty Docket No.40574-131i) a VL CDR1 comprising or consisting of SEQ ID NO:133, a VL CDR2 comprisingor consisting of SEQ ID NO:135, and a VL CDR3 comprising or consisting of SEQ ID NO:137;ii) a VL CDR1 comprising or consisting of SEQ ID NO:147, a VL CDR2 comprisingor consisting of SEQ ID NO:149, and a VLCDR3 comprising or consisting of SEQ ID NO:151;iii) a VL CDR1 comprising or consisting of SEQ ID NO:161, a VL CDR2 comprisingor consisting of SEQ ID NO:163, and a VLCDR3 comprising or consisting of SEQ ID NO:165;iv) a VL CDR1 comprising or consisting of SEQ ID NO:175, a VL CDR2 comprisingor consisting of SEQ ID NO:177, and a VL CDR3 comprising or consisting of SEQ ID NO:179;v) a VL CDR1 comprising or consisting of SEQ ID NO:189, a VL CDR2 comprisingor consisting of SEQ ID NO:191, and a VLCDR3 comprising or consisting of SEQ ID NO:193;vi) a VL CDR1 comprising or consisting of SEQ ID NO:203, a VL CDR2 comprisingor consisting of SEQ ID NO:205, and a VL CDR3 comprising or consisting of SEQ ID NO:207;vii) a VL CDR1 comprising or consisting of SEQ ID NO:217, a VL CDR2 comprisingor consisting of SEQ ID NO:219, and a VLCDR3 comprising or consisting of SEQ ID NO:221;viii) a VL CDR1 comprising or consisting of SEQ ID NO:231, a VL CDR2 comprisingor consisting of SEQ ID NO:233, and a VL CDR3 comprising or consisting of SEQ ID NO:235;ix) a VL CDR1 comprising or consisting of SEQ ID NO:245, a VL CDR2 comprisingor consisting of SEQ ID NO:247, and a VL CDR3 comprising or consisting of SEQ ID NO:249;x) a VL CDR1 comprising or consisting of SEQ ID NO:259, a VL CDR2 comprisingor consisting of SEQ ID NO:261, and a VLCDR3 comprising or consisting of SEQ ID NO:263; - 200 - 116104230Atty Docket No.40574-131xi) a VL CDR1 comprising or consisting of SEQ ID NO:273, a VL CDR2 comprisingor consisting of SEQ ID NO:275, and a VL CDR3 comprising or consisting of SEQ ID NO:277;xii) a VL CDR1 comprising or consisting of SEQ ID NO:287, a VL CDR2 comprisingor consisting of SEQ ID NO:289, and a VLCDR3 comprising or consisting of SEQ ID NO:291;xiii) a VL CDR1 comprising or consisting of SEQ ID NO:301, a VL CDR2 comprisingor consisting of SEQ ID NO:303, or a VLCDR3 comprising or consisting of SEQ ID NO:305;xiv) a VL CDR1 comprising or consisting of SEQ ID NO:315, a VL CDR2 comprisingor consisting of SEQ ID NO:317, or a VL CDR3 comprising or consisting of SEQ ID NO:319;xv) a VL CDR1 comprising or consisting of SEQ ID NO:329, a VL CDR2 comprisingor consisting of SEQ ID NO:331, or a VLCDR3 comprising or consisting of SEQ ID NO:333;xvi) a VL CDR1 comprising or consisting of SEQ ID NO:343, a VL CDR2 comprisingor consisting of SEQ ID NO:345, or a VL CDR3 comprising or consisting of SEQ ID NO:347;xvii) a VL CDR1 comprising or consisting of SEQ ID NO:357, a VL CDR2 comprisingor consisting of SEQ ID NO:359, or a VLCDR3 comprising or consisting of SEQ ID NO:361;xviii) a VL CDR1 comprising or consisting of SEQ ID NO:371, a VL CDR2 comprisingor consisting of SEQ ID NO:373, or a VL CDR3 comprising or consisting of SEQ ID NO:375;xix) a VL CDR1 comprising or consisting of SEQ ID NO:385, a VL CDR2 comprisingor consisting of SEQ ID NO:387, or a VL CDR3 comprising or consisting of SEQ ID NO:389;xx) a VL CDR1 comprising or consisting of SEQ ID NO:399, a VL CDR2 comprisingor consisting of SEQ ID NO:401, or a VLCDR3 comprising or consisting of SEQ ID NO:403; - 201 - 116104230Atty Docket No.40574-131xxi) a VL CDR1 comprising or consisting of SEQ ID NO:413, a VL CDR2 comprisingor consisting of SEQ ID NO:415, or a VL CDR3 comprising or consisting of SEQ ID NO:417;xxii) a VL CDR1 comprising or consisting of SEQ ID NO:427, a VL CDR2 comprisingor consisting of SEQ ID NO:429, or a VLCDR3 comprising or consisting of SEQ ID NO:431;xxiii) a VL CDR1 comprising or consisting of SEQ ID NO:441, a VL CDR2 comprisingor consisting of SEQ ID NO:443, or a VLCDR3 comprising or consisting of SEQ ID NO:445;xxiv) a VL CDR1 comprising or consisting of SEQ ID NO:455, a VL CDR2 comprisingor consisting of SEQ ID NO:457, or a VL CDR3 comprising or consisting of SEQ ID NO:459;xxv) a VL CDR1 comprising or consisting of SEQ ID NO:469, a VL CDR2 comprisingor consisting of SEQ ID NO:471, or a VLCDR3 comprising or consisting of SEQ ID NO:473;xxvi) a VL CDR1 comprising or consisting of SEQ ID NO:483, a VL CDR2 comprisingor consisting of SEQ ID NO:485, or a VL CDR3 comprising or consisting of SEQ ID NO:487;xxvii) a VL CDR1 comprising or consisting of SEQ ID NO:497, a VL CDR2 comprisingor consisting of SEQ ID NO:499, or a VLCDR3 comprising or consisting of SEQ ID NO:501;xxviii) a VL CDR1 comprising or consisting of SEQ ID NO:511, a VL CDR2 comprisingor consisting of SEQ ID NO:513, or a VL CDR3 comprising or consisting of SEQ ID NO:515;xxix) a VL CDR1 comprising or consisting of SEQ ID NO:525, a VL CDR2 comprisingor consisting of SEQ ID NO:527, or a VL CDR3 comprising or consisting of SEQ ID NO:529;xxx) a VL CDR1 comprising or consisting of SEQ ID NO:539, a VL CDR2 comprisingor consisting of SEQ ID NO:541, or a VLCDR3 comprising or consisting of SEQ ID NO:543; - 202 - 116104230Atty Docket No.40574-131 xxxi) a VL CDR1 comprising or consisting of SEQ ID NO:553, a VL CDR2 comprisingor consisting of SEQ ID NO:555, or a VL CDR3 comprising or consisting of SEQ ID NO:557; xxxii) a VL CDR1 comprising or consisting of SEQ ID NO:567, a VL CDR2 comprisingor consisting of SEQ ID NO:569, or a VLCDR3 comprising or consisting of SEQ ID NO:571; xxxiii) a VL CDR1 comprising or consisting of SEQ ID NO:581, a VL CDR2 comprisingor consisting of SEQ ID NO:583, or a VLCDR3 comprising or consisting of SEQ ID NO:585; xxxiv) a VL CDR1 comprising or consisting of SEQ ID NO:595, a VL CDR2 comprisingor consisting of SEQ ID NO:597, or a VL CDR3 comprising or consisting of SEQ ID NO:599; xxxv) a VL CDR1 comprising or consisting of SEQ ID NO:609, a VL CDR2 comprisingor consisting of SEQ ID NO:611, or a VLCDR3 comprising or consisting of SEQ ID NO:613; or xxxvi) a VL CDR1 comprising or consisting of SEQ ID NO:623, a VL CDR2 comprisingor consisting of SEQ ID NO:625, or a VL CDR3 comprising or consisting of SEQ ID NO:627.

84. The antibody or antigen-binding fragment thereof of any one of claims 1-36 or 64-83,wherein the antibody or antigen-binding fragment thereof comprises: i) a VH CDR1 comprising or consisting of SEQ ID NO:126, a VH CDR2comprising or consisting of SEQ ID NO:128, a VHCDR3 comprising or consisting of SEQ ID NO:130, a VL CDR1 comprising or consisting of SEQ ID NO:133, a VL CDR2 comprising or consisting of SEQ ID NO:135, and a VL CDR3 comprising or consisting of SEQ ID NO:137; ii) a VH CDR1 comprising or consisting of SEQ ID NO:140, a VH CDR2comprising or consisting of SEQ ID NO:142, a VHCDR3 comprising or consisting of SEQ ID NO:144; a VLCDR1 comprising or consisting of SEQ ID NO:147, a VLCDR2 comprising or consisting of SEQ ID NO:149, and a VLCDR3 comprising or consisting of SEQ ID NO:151; - 203 - 116104230Atty Docket No.40574-131iii) a VH CDR1 comprising or consisting of SEQ ID NO:154, a VH CDR2comprising or consisting of SEQ ID NO:156, a VH CDR3 comprising or consisting of SEQ ID NO:158; a VL CDR1 comprising or consisting of SEQ ID NO:161, a VL CDR2 comprising or consisting of SEQ ID NO:163, and a VL CDR3 comprising or consisting of SEQ ID NO:165;iv) a VH CDR1 comprising or consisting of SEQ ID NO:168, a VH CDR2comprising or consisting of SEQ ID NO:170, a VHCDR3 comprising or consisting of SEQ ID NO:172; a VLCDR1 comprising or consisting of SEQ ID NO:175, a VLCDR2 comprising or consisting of SEQ ID NO:177, and a VL CDR3 comprising or consisting of SEQ ID NO:179;v) a VH CDR1 comprising or consisting of SEQ ID NO:182, a VH CDR2comprising or consisting of SEQ ID NO:184, a VH CDR3 comprising or consisting of SEQ ID NO:186; a VLCDR1 comprising or consisting of SEQ ID NO:189, a VLCDR2 comprising or consisting of SEQ ID NO:191, and a VLCDR3 comprising or consisting of SEQ ID NO:193;vi) a VH CDR1 comprising or consisting of SEQ ID NO:196, a VH CDR2comprising or consisting of SEQ ID NO:198, a VH CDR3 comprising or consisting of SEQ ID NO:200; a VL CDR1 comprising or consisting of SEQ ID NO:203, a VL CDR2 comprising or consisting of SEQ ID NO:205, and a VL CDR3 comprising or consisting of SEQ ID NO:207;vii) a VH CDR1 comprising or consisting of SEQ ID NO:210, a VH CDR2comprising or consisting of SEQ ID NO:212, a VHCDR3 comprising or consisting of SEQ ID NO:214; a VL CDR1 comprising or consisting of SEQ ID NO:217, a VL CDR2 comprising or consisting of SEQ ID NO:219, and a VL CDR3 comprising or consisting of SEQ ID NO:221;viii) a VH CDR1 comprising or consisting of SEQ ID NO:224, a VH CDR2comprising or consisting of SEQ ID NO:226, a VHCDR3 comprising or consisting of SEQ ID NO:228; a VLCDR1 comprising or consisting of SEQ ID NO:231, a VLCDR2 comprising or consisting of SEQ ID NO:233, and a VLCDR3 comprising or consisting of SEQ ID NO:235; - 204 - 116104230Atty Docket No.40574-131ix) a VH CDR1 comprising or consisting of SEQ ID NO:238, a VH CDR2comprising or consisting of SEQ ID NO:240, a VH CDR3 comprising or consisting of SEQ ID NO:242; a VL CDR1 comprising or consisting of SEQ ID NO:245, a VL CDR2 comprising or consisting of SEQ ID NO:247, and a VL CDR3 comprising or consisting of SEQ ID NO:249;x) a VH CDR1 comprising or consisting of SEQ ID NO:252, a VH CDR2comprising or consisting of SEQ ID NO:254, a VHCDR3 comprising or consisting of SEQ ID NO:256; a VLCDR1 comprising or consisting of SEQ ID NO:259, a VLCDR2 comprising or consisting of SEQ ID NO:261, and a VL CDR3 comprising or consisting of SEQ ID NO:263;xi) a VH CDR1 comprising or consisting of SEQ ID NO:266, a VH CDR2comprising or consisting of SEQ ID NO:268, a VH CDR3 comprising or consisting of SEQ ID NO:270; a VLCDR1 comprising or consisting of SEQ ID NO:273, a VLCDR2 comprising or consisting of SEQ ID NO:275, and a VLCDR3 comprising or consisting of SEQ ID NO:277;xii) a VH CDR1 comprising or consisting of SEQ ID NO:280, a VH CDR2comprising or consisting of SEQ ID NO:282, a VH CDR3 comprising or consisting of SEQ ID NO:284, a VL CDR1 comprising or consisting of SEQ ID NO:287, a VL CDR2 comprising or consisting of SEQ ID NO:289, or a VL CDR3 comprising or consisting of SEQ ID NO:291;xiii) a VH CDR1 comprising or consisting of SEQ ID NO:294, a VH CDR2comprising or consisting of SEQ ID NO:296, a VHCDR3 comprising or consisting of SEQ ID NO:298, a VL CDR1 comprising or consisting of SEQ ID NO:301, a VL CDR2 comprising or consisting of SEQ ID NO:303, or a VL CDR3 comprising or consisting of SEQ ID NO:305;xiv) a VH CDR1 comprising or consisting of SEQ ID NO:308, a VH CDR2comprising or consisting of SEQ ID NO:310, a VHCDR3 comprising or consisting of SEQ ID NO:312, a VLCDR1 comprising or consisting of SEQ ID NO:315, a VLCDR2 comprising or consisting of SEQ ID NO:317, or a VLCDR3 comprising or consisting of SEQ ID NO:319; - 205 - 116104230Atty Docket No.40574-131xv) a VH CDR1 comprising or consisting of SEQ ID NO:322, a VH CDR2comprising or consisting of SEQ ID NO:324, a VH CDR3 comprising or consisting of SEQ ID NO:326, a VL CDR1 comprising or consisting of SEQ ID NO:329, a VL CDR2 comprising or consisting of SEQ ID NO:331, or a VL CDR3 comprising or consisting of SEQ ID NO:333;xvi) a VH CDR1 comprising or consisting of SEQ ID NO:336, a VH CDR2comprising or consisting of SEQ ID NO:338, a VHCDR3 comprising or consisting of SEQ ID NO:340, a VLCDR1 comprising or consisting of SEQ ID NO:343, a VLCDR2 comprising or consisting of SEQ ID NO:345, or a VL CDR3 comprising or consisting of SEQ ID NO:347;xvii) a VH CDR1 comprising or consisting of SEQ ID NO:350, a VH CDR2comprising or consisting of SEQ ID NO:352, a VH CDR3 comprising or consisting of SEQ ID NO:354, a VLCDR1 comprising or consisting of SEQ ID NO:357, a VLCDR2 comprising or consisting of SEQ ID NO:359, or a VLCDR3 comprising or consisting of SEQ ID NO:361;xviii) a VH CDR1 comprising or consisting of SEQ ID NO:364, a VH CDR2comprising or consisting of SEQ ID NO:366, a VH CDR3 comprising or consisting of SEQ ID NO:368, a VL CDR1 comprising or consisting of SEQ ID NO:371, a VL CDR2 comprising or consisting of SEQ ID NO:373, or a VL CDR3 comprising or consisting of SEQ ID NO:375;xix) a VH CDR1 comprising or consisting of SEQ ID NO:378, a VH CDR2comprising or consisting of SEQ ID NO:380, a VHCDR3 comprising or consisting of SEQ ID NO:382, a VL CDR1 comprising or consisting of SEQ ID NO:385, a VL CDR2 comprising or consisting of SEQ ID NO:387, or a VL CDR3 comprising or consisting of SEQ ID NO:389;xx) a VH CDR1 comprising or consisting of SEQ ID NO:392, a VH CDR2comprising or consisting of SEQ ID NO:394, a VHCDR3 comprising or consisting of SEQ ID NO:396, a VLCDR1 comprising or consisting of SEQ ID NO:399, a VLCDR2 comprising or consisting of SEQ ID NO:401, or a VLCDR3 comprising or consisting of SEQ ID NO:403; - 206 - 116104230Atty Docket No.40574-131xxi) a VH CDR1 comprising or consisting of SEQ ID NO:406, a VH CDR2comprising or consisting of SEQ ID NO:408, a VH CDR3 comprising or consisting of SEQ ID NO:410, a VL CDR1 comprising or consisting of SEQ ID NO:413, a VL CDR2 comprising or consisting of SEQ ID NO:415, or a VL CDR3 comprising or consisting of SEQ ID NO:417;xxii) a VH CDR1 comprising or consisting of SEQ ID NO:420, a VH CDR2comprising or consisting of SEQ ID NO:422, a VHCDR3 comprising or consisting of SEQ ID NO:424, a VLCDR1 comprising or consisting of SEQ ID NO:427, a VLCDR2 comprising or consisting of SEQ ID NO:429, or a VL CDR3 comprising or consisting of SEQ ID NO:431;xxiii) a VH CDR1 comprising or consisting of SEQ ID NO:434, a VH CDR2comprising or consisting of SEQ ID NO:436, a VH CDR3 comprising or consisting of SEQ ID NO:438, a VLCDR1 comprising or consisting of SEQ ID NO:441, a VLCDR2 comprising or consisting of SEQ ID NO:443, or a VLCDR3 comprising or consisting of SEQ ID NO:445;xxiv) a VH CDR1 comprising or consisting of SEQ ID NO:448, a VH CDR2comprising or consisting of SEQ ID NO:450, a VH CDR3 comprising or consisting of SEQ ID NO:452, a VL CDR1 comprising or consisting of SEQ ID NO:455, a VL CDR2 comprising or consisting of SEQ ID NO:457, or a VL CDR3 comprising or consisting of SEQ ID NO:459;xxv) a VH CDR1 comprising or consisting of SEQ ID NO:462, a VH CDR2comprising or consisting of SEQ ID NO:464, a VHCDR3 comprising or consisting of SEQ ID NO:466, a VL CDR1 comprising or consisting of SEQ ID NO:469, a VL CDR2 comprising or consisting of SEQ ID NO:471, or a VL CDR3 comprising or consisting of SEQ ID NO:473;xxvi) a VH CDR1 comprising or consisting of SEQ ID NO:476, a VH CDR2comprising or consisting of SEQ ID NO:478, a VHCDR3 comprising or consisting of SEQ ID NO:480, a VLCDR1 comprising or consisting of SEQ ID NO:483, a VLCDR2 comprising or consisting of SEQ ID NO:485, or a VLCDR3 comprising or consisting of SEQ ID NO:487; - 207 - 116104230Atty Docket No.40574-131xxvii) a VH CDR1 comprising or consisting of SEQ ID NO:490, a VH CDR2comprising or consisting of SEQ ID NO:492, a VH CDR3 comprising or consisting of SEQ ID NO:494, a VL CDR1 comprising or consisting of SEQ ID NO:497, a VL CDR2 comprising or consisting of SEQ ID NO:499, or a VL CDR3 comprising or consisting of SEQ ID NO:501;xxviii) a VH CDR1 comprising or consisting of SEQ ID NO:504, a VH CDR2comprising or consisting of SEQ ID NO:506, a VHCDR3 comprising or consisting of SEQ ID NO:508, a VLCDR1 comprising or consisting of SEQ ID NO:511, a VLCDR2 comprising or consisting of SEQ ID NO:513, or a VL CDR3 comprising or consisting of SEQ ID NO:515;xxix) a VH CDR1 comprising or consisting of SEQ ID NO:518, a VH CDR2comprising or consisting of SEQ ID NO:520, a VH CDR3 comprising or consisting of SEQ ID NO:522, a VLCDR1 comprising or consisting of SEQ ID NO:525, a VLCDR2 comprising or consisting of SEQ ID NO:527, or a VLCDR3 comprising or consisting of SEQ ID NO:529;xxx) a VH CDR1 comprising or consisting of SEQ ID NO:532, a VH CDR2comprising or consisting of SEQ ID NO:534, a VH CDR3 comprising or consisting of SEQ ID NO:536, a VL CDR1 comprising or consisting of SEQ ID NO:539, a VL CDR2 comprising or consisting of SEQ ID NO:541, or a VL CDR3 comprising or consisting of SEQ ID NO:543;xxxi) a VH CDR1 comprising or consisting of SEQ ID NO:546, a VH CDR2comprising or consisting of SEQ ID NO:548, a VHCDR3 comprising or consisting of SEQ ID NO:550, a VL CDR1 comprising or consisting of SEQ ID NO:553, a VL CDR2 comprising or consisting of SEQ ID NO:555, or a VL CDR3 comprising or consisting of SEQ ID NO:557;xxxii) a VH CDR1 comprising or consisting of SEQ ID NO:560, a VH CDR2comprising or consisting of SEQ ID NO:562, a VHCDR3 comprising or consisting of SEQ ID NO:564, a VLCDR1 comprising or consisting of SEQ ID NO:567, a VLCDR2 comprising or consisting of SEQ ID NO:569, or a VLCDR3 comprising or consisting of SEQ ID NO:571; - 208 - 116104230Atty Docket No.40574-131 xxxiii) a VH CDR1 comprising or consisting of SEQ ID NO:574, a VH CDR2comprising or consisting of SEQ ID NO:576, a VH CDR3 comprising or consisting of SEQ ID NO:578, a VL CDR1 comprising or consisting of SEQ ID NO:581, a VL CDR2 comprising or consisting of SEQ ID NO:583, or a VL CDR3 comprising or consisting of SEQ ID NO:585; xxxiv) a VH CDR1 comprising or consisting of SEQ ID NO:588, a VH CDR2comprising or consisting of SEQ ID NO:590, a VHCDR3 comprising or consisting of SEQ ID NO:592, a VLCDR1 comprising or consisting of SEQ ID NO:595, a VLCDR2 comprising or consisting of SEQ ID NO:597, or a VL CDR3 comprising or consisting of SEQ ID NO:599; xxxv) a VH CDR1 comprising or consisting of SEQ ID NO:602, a VH CDR2comprising or consisting of SEQ ID NO:604, a VH CDR3 comprising or consisting of SEQ ID NO:606, a VLCDR1 comprising or consisting of SEQ ID NO:609, a VLCDR2 comprising or consisting of SEQ ID NO:611, or a VLCDR3 comprising or consisting of SEQ ID NO:613; or xxxvi) a VH CDR1 comprising or consisting of SEQ ID NO:616, a VH CDR2comprising or consisting of SEQ ID NO:618, a VH CDR3 comprising or consisting of SEQ ID NO:620, a VL CDR1 comprising or consisting of SEQ ID NO:623, a VL CDR2 comprising or consisting of SEQ ID NO:625, or a VL CDR3 comprising or consisting of SEQ ID NO:627.

85. The antibody or antigen-binding fragment thereof of any one of claims 1-36 or 64-84,wherein the antibody or antigen-binding fragment thereof is selected from the group consisting of 1E11, 2A09, 5H03, 5C10, and 1A09-H.

86. The antibody or antigen-binding fragment thereof of any one of claims 1-36 or 64-85,wherein the antibody or antigen-binding fragment is a humanized antibody.

87. The antibody or antigen-binding fragment thereof according to any one of claims 1-36 or64-86, wherein the antibody or antigen-binding fragment thereof is isolated.

88. The antibody or antigen-binding fragment thereof according to any one of claims 1-36 and64-87, wherein the antibody or antigen-binding fragment thereof is complexed with an EV-D68 virion. - 209 - 116104230Atty Docket No.40574-13189. The antibody or antigen-binding fragment thereof according to claims 1-36 and 64-88,wherein the antibody or antigen-binding fragment thereof inhibits binding of an EV-D68-228 antibody to an EV-D68 virion.

90. A composition comprising at least one of the antibody or antigen-binding fragment thereofaccording to claims 1-36 or 64-89, wherein the composition comprises a plurality of antibodies or antigen-binding fragments thereof.

91. The composition according to claim 90, wherein the composition further comprises at leastone therapeutic compound.

92. The composition according to claim 91, wherein the at least one therapeutic compoundcomprises an antiviral compound, an antibiotic, a steroid, rupintrivir–vemurafenib, vemurafenib– pleconaril, rupintrivir–pleconaril, or rupintrivir–cycloheximide.

93. A method of protecting an individual against infection with an enterovirus, treating anindividual having an enterovirus infection, or reducing disease symptoms in an individual infected with an enterovirus, comprising administering to the individual an antibody or antigen-binding fragment thereof according to claims 1-36 and 64-89 or the composition according to claims 90- 92.

94. The method according to claim 93, wherein the individual is administered a compositioncomprising the antibody or antigen-binding fragment thereof according to claims 1-36 and 64-89.

95. The method according to claim 93 or claim 94, wherein the composition further comprisesat least one therapeutic agent.

96. The method according to claim 95, wherein the at least one therapeutic agent comprises anantiviral compound, an antibiotic, a steroid, rupintrivir–vemurafenib, vemurafenib–pleconaril, rupintrivir–pleconaril or rupintrivir–cycloheximide.

97. The method according to claim 93, wherein the individual is administered the antibody orantigen-binding fragment thereof of claim 1-36 to 64-89 by one route of administration and at least one therapeutic agent by another route of administration.

98. The method according to claim 97, wherein the at least one therapeutic agent comprises anantiviral compound, an antibiotic, a steroid, rupintrivir–vemurafenib, vemurafenib–pleconaril, rupintrivir–pleconaril or rupintrivir–cycloheximide. - 210 - 116104230

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