Antibodies targeting epstein-BARR virus proteins and methods of use

Abstract

The present disclosure provides antibodies, and antigen binding fragments thereof, which bind an extracellular domain region of an Epstein-Barr virus (EBV) membrane protein, and related nucleic acids, vectors, pharmaceutical compositions, cells, and methods of use thereof. The antibodies, and antigen binding fragments thereof, as described herein can find utility as therapeutic and diagnostic agents for EBV infections and EBV-mediated diseases or as research agents.

Description

ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 ANTIBODIES TARGETING EPSTEIN-BARR VIRUS PROTEINS AND METHODS OF USE CROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 557,416, filed February 23, 2024, which is incorporated herein by reference in its entirety. SEQUENCE LISTING

[0002] The present application contains an electronically submitted Sequence Listing in XML format and the contents of the electronic Sequence Listing are herein incorporated by reference in its entirety. The name of the XML file containing the Sequence Listing is FLAT_002_01WO_SeqList_ST26.xml. The XML file is 302,465 bytes in size, was created on February 23, 2024, and is being submitted electronically via USPTO Patent Center. FIELD

[0003] The present disclosure generally relates to antibodies directed against the extracellular domain (ECD) regions of Epstein-Barr virus (EBV) membrane proteins, and related pharmaceutical compositions and methods of use thereof for treating EBV infections and EBV- mediated diseases such as lymphoproliferative disorders, cancers, and autoimmune diseases. BACKGROUND

[0004] The Epstein-Barr virus (EBV), also called human gammaherpesvirus 4, is one of the most common viruses in humans, infecting over 90% of adults globally. It is part of the -herpesviridae subfamily (Cohen, 2000; Knerr et al., 2021; Wang et al., 2001). It is the major cause of infectious mononucleosis, and is associated with various non-malignant, premalignant, and malignant EBV-mediated lymphoproliferative diseases, certain non-lymphoid cancers, and autoimmune diseases, among others. EBV was the first identified oncogenic virus and is linked to cancers of B, T or NK cells (Burkitt’s lymphoma (BL), Hodgkin’s lymphoma (HL), post-transplant lymphoproliferative disorders (PTLD) and Mature T- and NK-cell neoplasms (MTNKL) / peripheral T-cell lymphoma (PTCL)) (Ambinder & Cesarman, 2007; Hjalgrim et al., 2011; Siaghani et al., 2019). Some EBV-associated cancers are of epithelial origin (nasopharyngeal carcinoma (NPC), EBV-associated gastric carcinomas (EBVaGC), lymphoepithelioma-like carcinomas) and, very rarely, of mesenchymal -1- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 (leiomyosarcoma) origin (Ambinder & Cesarman, 2007; Hjalgrim et al., 2011). Moreover, a causative link between EBV and multiple sclerosis (MS) (Bjornevik et al., 2022; Guan et al., 2019; Hassani et al., 2018; Houen et al., 2020; Lanz et al., 2022), systemic lupus erythematosus (SLE) (Aygun et al., 2020; Draborg et al., 2012; Z. X. Li et al., 2019), and breast cancer (Farahmand et al., 2019; Hu et al., 2016; Jin et al., 2020; Sinclair et al., 2021) has been established. The global incidence of EBV-associated cancers is approximately 200,000 cases / year, and EBV-associated gastric carcinomas and nasopharyngeal carcinomas affect over 100,000 people per year (Knerr et al., 2021). Current attempts to treat EBV-mediated diseases include use of anti-EBV T cells, small molecule antivirals active against EBV, global B cell depleting agents such as anti-CD20 antibodies, and chemotherapeutics, among others. However, there is a need in the art for improved therapeutic strategies, in particular more targeted therapies, to manage the various pathologies associated with EBV infection. SUMMARY

[0005] The present disclosure provides an isolated antibody, or an antigen binding fragment thereof, which specifically binds to an extracellular domain (ECD) of the Epstein Barr Virus (EBV) membrane protein BILF-1.

[0006] In some embodiments of the isolated antibody or fragment thereof of the present disclosure, the antibody or fragment thereof specifically binds to one or more BILF-1 extracellular domains selected from the group consisting of ECD1, ECD2, ECD3, ECD4, and combinations thereof.

[0007] In some embodiments of the isolated antibody or fragment thereof of the present disclosure, the antibody or fragment thereof specifically binds to ECD1 of BILF-1 through contact with one or more amino acid residues within an epitope comprising SEQ ID NO: 2.

[0008] In some embodiments of the isolated antibody or fragment thereof of the present disclosure, the antibody or fragment thereof specifically binds to ECD2 of BILF-1 through contact with one or more amino acid residues within an epitope comprising SEQ ID NO: 3.

[0009] In some embodiments of the isolated antibody or fragment thereof of the present disclosure, the antibody or fragment thereof specifically binds to ECD3 of BILF-1 through contact with one or more amino acid residues within an epitope comprising SEQ ID NO: 4.

[0010] In some embodiments of the isolated antibody or fragment thereof of the present disclosure, the antibody or fragment thereof specifically binds to ECD4 of BILF-1 through contact with one or more amino acid residues within an epitope comprising SEQ ID NO: 5. -2- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004

[0011] In some embodiments of the isolated antibody or fragment thereof of the present disclosure, the antibody or fragment thereof specifically binds to the ECD of BILF-1 through contact with one or more amino acid residues relative to SEQ ID NO: 1 selected from the group consisting of L2, S3, T4, P7, S9, T10, L14, V15, N17, M18, T19, S20, V21, N22, A23, T24, T29, K30, S31, Y32, E90, F91, S92, G95, T160, M161, G 162, M173, E176, G177, P178, H183, T184, A191, T259, L262, V263, A264, R265, and G269.

[0012] In some embodiments of the isolated antibody or fragment thereof of the present disclosure, the antibody or fragment thereof specifically binds to the ECD of BILF-1 through contact with three or more amino acid residues relative to SEQ ID NO: 1 selected from the group consisting of L2, S3, T4, P7, S9, T10, L14, V15, N17, M18, T19, S20, V21, N22, A23, T24, T29, K30, S31, Y32, E90, F91, S92, G95, T160, M161, G 162, M173, E176, G177, P178, H183, T184, A191, T259, L262, V263, A264, R265, and G269.

[0013] In some embodiments of the isolated antibody or fragment thereof of the present disclosure, the antibody or fragment thereof specifically binds to the ECD of BILF-1 through contact with one or more amino acid residues relative to SEQ ID NO: 1 selected from the group consisting of M39, D164, A165, N166, L167, N168, R169, G170, P171, N172, R175, T179, K180, G181, M182, A185, V186, Q187, G188, L189, K190, A251, S253, L254, G255, F256, D257, C258, E260, S261, Y266, Y267, and P268.

[0014] In some embodiments of the isolated antibody or fragment thereof of the present disclosure, the antibody or fragment thereof specifically binds to the ECD of BILF-1 through contact with three or more amino acid residues relative to SEQ ID NO: 1 selected from the group consisting of M39, D164, A165, N166, L167, N168, R169, G170, P171, N172, R175, T179, K180, G181, M182, A185, V186, Q187, G188, L189, K190, A251, S253, L254, G255, F256, D257, C258, E260, S261, Y266, Y267, and P268.

[0015] In some embodiments of the isolated antibody or fragment thereof of the present disclosure, the antibody or fragment thereof specifically binds to amino acids proximal to the transmembrane region of the EBV membrane protein and the specific binding changes the conformational structure of BILF-1 and alters the function of BILF-1.

[0016] In some embodiments of the isolated antibody or fragment thereof of the present disclosure, the antibody or fragment thereof is a monoclonal antibody and / or a humanized antibody, or an antigen binding fragment thereof.

[0017] In some embodiments of the isolated antibody or fragment thereof of the present disclosure, the antibody or fragment thereof is a whole antibody, a fragment antigen binding -3- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 domain (Fab), a F(ab')2 domain, a single-chain variable fragment (scFv), a dimeric single-chain variable fragment (di-scFv), or a single domain antibody (sdAb).

[0018] In some embodiments of the isolated antibody or fragment thereof of the present disclosure, the isolated antibody or fragment thereof comprises an Fc region selected from the group consisting of IgA, IgD, IgE, IgG, and IgM Fc region and, optionally, the Fc region is a human Fc region. In some embodiments, the Fc region is selected from the group consisting of IgA1, IgA2, IgG1, IgG2, IgG3, and IgG4.

[0019] In some embodiments of the isolated antibody or fragment thereof of the present disclosure, the isolated antibody or fragment thereof comprises an IgG Fc region with high effector function in humans. In some embodiments, the Fc region is IgG1 or IgG3.

[0020] In some embodiments of the isolated antibody or fragment thereof of the present disclosure, the antibody or fragment thereof comprises a modified Fc region which has at least one altered effector function and / or pharmacokinetic (PK) characteristic relative to a wild-type Fc region. In some embodiments, the at least one altered effector function comprises increased engagement with natural killer (NK) cells, macrophages, neutrophils, and / or dendritic cells. Insome embodiments, the modified Fc region has incr In someembodiments, the modified Fc region is afucosylated.

[0021] In some embodiments of the isolated antibody or fragment thereof of the present disclosure, the isolated antibody or fragment thereof comprises a) a heavy chain (HC) complementarity determining region (CDR) 1 sequence of SEQ ID NO: 14, a HC CDR2 sequence of SEQ ID NO: 15, a HC CDR3 sequence of SEQ ID NO: 16; a HC CDR1 sequence of SEQ ID NO: 290, a HC CDR2 sequence of SEQ ID NO: 291, a HC CDR3 sequence of SEQ ID NO: 292; a HC CDR1 sequence of SEQ ID NO: 297, a HC CDR2 sequence of SEQ ID NO: 298, a HC CDR3 sequence of SEQ ID NO: 299; a HC CDR1 sequence of SEQ ID NO: 304, a HC CDR2 sequence of SEQ ID NO: 305, a HC CDR3 sequence of SEQ ID NO: 306; or a HC CDR1 sequence of SEQ ID NO: 311, a HC CDR2 sequence of SEQ ID NO: 312, a HC CDR3 sequence of SEQ ID NO: 313; and b) a light chain (LC) complementarity determining region (CDR) 1 sequence of SEQ ID NO: 17, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 19; -4- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 a LC CDR1 sequence of SEQ ID NO: 234, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 236; a LC CDR1 sequence of SEQ ID NO: 241, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 243; a LC CDR1 sequence of SEQ ID NO: 248, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 250; a LC CDR1 sequence of SEQ ID NO: 255, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 257; a LC CDR1 sequence of SEQ ID NO: 262, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 264; a LC CDR1 sequence of SEQ ID NO: 269, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 271; a LC CDR1 sequence of SEQ ID NO: 276, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 278; or a LC CDR1 sequence of SEQ ID NO: 283, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 285.

[0022] In some embodiments of the isolated antibody or fragment thereof of the present disclosure, the isolated antibody or fragment thereof comprises a) a heavy chain (HC) complementarity determining region (CDR) 1 sequence of SEQ ID NO: 14, a HC CDR2 sequence of SEQ ID NO: 15, a HC CDR3 sequence of SEQ ID NO: 16, a light chain (LC) CDR1 sequence of SEQ ID NO: 17, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 19; b) a HC CDR1 sequence of SEQ ID NO: 28, a HC CDR2 sequence of SEQ ID NO: 29, a HC CDR3 sequence of SEQ ID NO: 30, a LC CDR1 sequence of SEQ ID NO: 31, a LC CDR2 sequence of YAS, and a LC CDR3 sequence of SEQ ID NO: 33; c) a HC CDR1 sequence of SEQ ID NO: 42, a HC CDR2 sequence of SEQ ID NO: 43, a HC CDR3 sequence of SEQ ID NO: 44, a LC CDR1 sequence of SEQ ID NO: 45, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 47; d) a HC CDR1 sequence of SEQ ID NO: 56, a HC CDR2 sequence of SEQ ID NO: 57, a HC CDR3 sequence of SEQ ID NO: 58, a LC CDR1 sequence of SEQ ID NO: 59, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 61; -5- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 e) a HC CDR1 sequence of SEQ ID NO: 70, a HC CDR2 sequence of SEQ ID NO: 71, a HC CDR3 sequence of SEQ ID NO: 72, a LC CDR1 sequence of SEQ ID NO: 73, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 75; f) a HC CDR1 sequence of SEQ ID NO: 84, a HC CDR2 sequence of SEQ ID NO: 85, a HC CDR3 sequence of SEQ ID NO: 86, a LC CDR1 sequence of SEQ ID NO: 87, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 89; g) a HC CDR1 sequence of SEQ ID NO: 98, a HC CDR2 sequence of SEQ ID NO: 99, a HC CDR3 sequence of SEQ ID NO: 100, a LC CDR1 sequence of SEQ ID NO: 101, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 103; h) a HC CDR1 sequence of SEQ ID NO: 112, a HC CDR2 sequence of SEQ ID NO: 113, a HC CDR3 sequence of SEQ ID NO: 114, a LC CDR1 sequence of SEQ ID NO: 115, a LC CDR2 sequence of YAS, and a LC CDR3 sequence of SEQ ID NO: 117; i) a HC CDR1 sequence of SEQ ID NO: 126, a HC CDR2 sequence of SEQ ID NO: 127, a HC CDR3 sequence of SEQ ID NO: 128, a LC CDR1 sequence of SEQ ID NO: 129, a LC CDR2 sequence of YAS, and a LC CDR3 sequence of SEQ ID NO: 131; j) a HC CDR1 sequence of SEQ ID NO: 140, a HC CDR2 sequence of SEQ ID NO: 141, a HC CDR3 sequence of SEQ ID NO: 142, a LC CDR1 sequence of SEQ ID NO: 143, a LC CDR2 sequence of YAS, and a LC CDR3 sequence of SEQ ID NO: 145; k) a HC CDR1 sequence of SEQ ID NO: 154, a HC CDR2 sequence of SEQ ID NO: 155, a HC CDR3 sequence of SEQ ID NO: 156, a LC CDR1 sequence of SEQ ID NO: 157, a LC CDR2 sequence of WAS, and a LC CDR3 sequence of SEQ ID NO: 159; l) a HC CDR1 sequence of SEQ ID NO: 168, a HC CDR2 sequence of SEQ ID NO: 169, a HC CDR3 sequence of SEQ ID NO: 170, a LC CDR1 sequence of SEQ ID NO: 171, a LC CDR2 sequence of YAS, and a LC CDR3 sequence of SEQ ID NO: 173; m) a HC CDR1 sequence of SEQ ID NO: 182, a HC CDR2 sequence of SEQ ID NO: 183, a HC CDR3 sequence of SEQ ID NO: 184, a LC CDR1 sequence of SEQ ID NO: 185, a LC CDR2 sequence of YAS, and a LC CDR3 sequence of SEQ ID NO: 187; -6- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 n) a HC CDR1 sequence of SEQ ID NO: 196, a HC CDR2 sequence of SEQ ID NO: 197, a HC CDR3 sequence of SEQ ID NO: 198, a LC CDR1 sequence of SEQ ID NO: 199, a LC CDR2 sequence of AAS, and a LC CDR3 sequence of SEQ ID NO: 201; o) a HC CDR1 sequence of SEQ ID NO: 210, a HC CDR2 sequence of SEQ ID NO: 211, a HC CDR3 sequence of SEQ ID NO: 212, a LC CDR1 sequence of SEQ ID NO: 213, a LC CDR2 sequence of GTN, and a LC CDR3 sequence of SEQ ID NO: 215; p) a HC CDR1 sequence of SEQ ID NO: 14, a HC CDR2 sequence of SEQ ID NO: 15, a HC CDR3 sequence of SEQ ID NO: 16, a LC CDR1 sequence of SEQ ID NO: 234, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 236; q) a HC CDR1 sequence of SEQ ID NO: 14, a HC CDR2 sequence of SEQ ID NO: 15, a HC CDR3 sequence of SEQ ID NO: 16, a LC CDR1 sequence of SEQ ID NO: 241, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 243; r) a HC CDR1 sequence of SEQ ID NO: 14, a HC CDR2 sequence of SEQ ID NO: 15, a HC CDR3 sequence of SEQ ID NO: 16, a LC CDR1 sequence of SEQ ID NO: 248, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 250; s) a HC CDR1 sequence of SEQ ID NO: 14, a HC CDR2 sequence of SEQ ID NO: 15, a HC CDR3 sequence of SEQ ID NO: 16, a LC CDR1 sequence of SEQ ID NO: 255, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 257; t) a HC CDR1 sequence of SEQ ID NO: 14, a HC CDR2 sequence of SEQ ID NO: 15, a HC CDR3 sequence of SEQ ID NO: 16, a LC CDR1 sequence of SEQ ID NO: 262, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 264; u) a HC CDR1 sequence of SEQ ID NO: 14, a HC CDR2 sequence of SEQ ID NO: 15, a HC CDR3 sequence of SEQ ID NO: 16, a LC CDR1 sequence of SEQ ID NO: 269, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 271; v) a HC CDR1 sequence of SEQ ID NO: 14, a HC CDR2 sequence of SEQ ID NO: 15, a HC CDR3 sequence of SEQ ID NO: 16, a LC CDR1 sequence of SEQ ID NO: 276, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 278; or w) a HC CDR1 sequence of SEQ ID NO: 14, a HC CDR2 sequence of SEQ ID NO: 15, a HC CDR3 sequence of SEQ ID NO: 16, a LC CDR1 sequence of SEQ ID NO: 283, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 285. -7- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004

[0023] In some embodiments of the isolated antibody or fragment thereof of the present disclosure, the isolated antibody or fragment thereof comprises a) a HC CDR1 sequence of SEQ ID NO: 14, a HC CDR2 sequence of SEQ ID NO: 15, a HC CDR3 sequence of SEQ ID NO: 16, a HC FR1 sequence of SEQ ID NO: 6, a HC FR2 sequence of SEQ ID NO: 7, a HC FR3 sequence of SEQ ID NO: 8, a HC FR4 sequence of SEQ ID NO: 9; a HC CDR1 sequence of SEQ ID NO: 290, a HC CDR2 sequence of SEQ ID NO: 291, a HC CDR3 sequence of SEQ ID NO: 292, a HC FR1 sequence of SEQ ID NO: 286, a HC FR2 sequence of SEQ ID NO: 287, a HC FR3 sequence of SEQ ID NO: 288, a HC FR4 sequence of SEQ ID NO: 289; a HC CDR1 sequence of SEQ ID NO: 297, a HC CDR2 sequence of SEQ ID NO: 298, a HC CDR3 sequence of SEQ ID NO: 299, a HC FR1 sequence of SEQ ID NO: 293, a HC FR2 sequence of SEQ ID NO: 294, a HC FR3 sequence of SEQ ID NO: 295, a HC FR4 sequence of SEQ ID NO: 296; a HC CDR1 sequence of SEQ ID NO: 304, a HC CDR2 sequence of SEQ ID NO: 305, a HC CDR3 sequence of SEQ ID NO: 306, a HC FR1 sequence of SEQ ID NO: 300, a HC FR2 sequence of SEQ ID NO: 301, a HC FR3 sequence of SEQ ID NO: 302, a HC FR4 sequence of SEQ ID NO: 303; or a HC CDR1 sequence of SEQ ID NO: 311, a HC CDR2 sequence of SEQ ID NO: 312, a HC CDR3 sequence of SEQ ID NO: 313, a HC FR1 sequence of SEQ ID NO: 307, a HC FR2 sequence of SEQ ID NO: 308, a HC FR3 sequence of SEQ ID NO: 309, a HC FR4 sequence of SEQ ID NO: 310; and b) a LC CDR1 sequence of SEQ ID NO: 17, a LC CDR2 sequence of GTS, a LC CDR3 sequence of SEQ ID NO: 19, a LC FR1 sequence of SEQ ID NO: 10, a LC FR2 sequence of SEQ ID NO: 11, a LC FR3 sequence of SEQ ID NO: 12, and a LC FR4 sequence of SEQ ID NO: 13; a LC CDR1 sequence of SEQ ID NO: 234, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 236, a LC FR1 sequence of SEQ ID NO: 230, a LC FR2 sequence of SEQ ID NO: 231, a LC FR3 sequence of SEQ ID NO: 232, and a LC FR4 sequence of SEQ ID NO: 233; a LC CDR1 sequence of SEQ ID NO: 241, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 243, a LC FR1 sequence of SEQ ID NO: 237, a LC -8- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 FR2 sequence of SEQ ID NO: 238, a LC FR3 sequence of SEQ ID NO: 239, and a LC FR4 sequence of SEQ ID NO: 240; a LC CDR1 sequence of SEQ ID NO: 248, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 250, a LC FR1 sequence of SEQ ID NO: 244, a LC FR2 sequence of SEQ ID NO: 245, a LC FR3 sequence of SEQ ID NO: 246, and a LC FR4 sequence of SEQ ID NO: 247; a LC CDR1 sequence of SEQ ID NO: 255, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 257, a LC FR1 sequence of SEQ ID NO: 251, a LC FR2 sequence of SEQ ID NO: 252, a LC FR3 sequence of SEQ ID NO: 253, and a LC FR4 sequence of SEQ ID NO: 254; a LC CDR1 sequence of SEQ ID NO: 262, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 264, a LC FR1 sequence of SEQ ID NO: 258, a LC FR2 sequence of SEQ ID NO: 259, a LC FR3 sequence of SEQ ID NO: 260, and a LC FR4 sequence of SEQ ID NO: 261; a LC CDR1 sequence of SEQ ID NO: 269, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 271, a LC FR1 sequence of SEQ ID NO: 265, a LC FR2 sequence of SEQ ID NO: 266, a LC FR3 sequence of SEQ ID NO: 267, and a LC FR4 sequence of SEQ ID NO: 268; a LC CDR1 sequence of SEQ ID NO: 276, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 278, a LC FR1 sequence of SEQ ID NO: 272, a LC FR2 sequence of SEQ ID NO: 273, a LC FR3 sequence of SEQ ID NO: 274, and a LC FR4 sequence of SEQ ID NO: 275; or a LC CDR1 sequence of SEQ ID NO: 283, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 285, a LC FR1 sequence of SEQ ID NO: 279, a LC FR2 sequence of SEQ ID NO: 280, a LC FR3 sequence of SEQ ID NO: 281, and a LC FR4 sequence of SEQ ID NO: 282.

[0024] In some embodiments of the isolated antibody or fragment thereof of the present disclosure, the isolated antibody or fragment thereof comprises a) a heavy chain (HC) complementarity determining region (CDR) 1 sequence of SEQ ID NO: 14, a HC CDR2 sequence of SEQ ID NO: 15, a HC CDR3 sequence of SEQ ID NO: 16, a light chain (LC) CDR1 sequence of SEQ ID NO: 17, a LC CDR2 sequence of GTS, a LC CDR3 sequence of SEQ ID NO: 19, a HC framework region (FR) 1 sequence of SEQ ID NO: 6, a HC FR2 sequence of SEQ ID NO: 7, a HC FR3 -9- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 sequence of SEQ ID NO: 8, a HC FR4 sequence of SEQ ID NO: 9, a LC FR1 sequence of SEQ ID NO: 10, a LC FR2 sequence of SEQ ID NO: 11, a LC FR3 sequence of SEQ ID NO: 12, and a LC FR4 sequence of SEQ ID NO: 13; b) a HC CDR1 sequence of SEQ ID NO: 28, a HC CDR2 sequence of SEQ ID NO: 29, a HC CDR3 sequence of SEQ ID NO: 30, a LC CDR1 sequence of SEQ ID NO: 31, a LC CDR2 sequence of YAS, and a LC CDR3 sequence of SEQ ID NO: 33, a HC FR1 sequence of SEQ ID NO: 20, a HC FR2 sequence of SEQ ID NO: 21, a HC FR3 sequence of SEQ ID NO: 22, a HC FR4 sequence of SEQ ID NO: 23, a LC FR1 sequence of SEQ ID NO: 24, a LC FR2 sequence of SEQ ID NO: 25, a LC FR3 sequence of SEQ ID NO: 26, and a LC FR4 sequence of SEQ ID NO: 27; c) a HC CDR1 sequence of SEQ ID NO: 42, a HC CDR2 sequence of SEQ ID NO: 43, a HC CDR3 sequence of SEQ ID NO: 44, a LC CDR1 sequence of SEQ ID NO: 45, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 47, a HC FR1 sequence of SEQ ID NO: 34, a HC FR2 sequence of SEQ ID NO: 35, a HC FR3 sequence of SEQ ID NO: 36, a HC FR4 sequence of SEQ ID NO: 37, a LC FR1 sequence of SEQ ID NO: 38, a LC FR2 sequence of SEQ ID NO: 39, a LC FR3 sequence of SEQ ID NO: 40, and a LC FR4 sequence of SEQ ID NO: 41; d) a HC CDR1 sequence of SEQ ID NO: 56, a HC CDR2 sequence of SEQ ID NO: 57, a HC CDR3 sequence of SEQ ID NO: 58, a LC CDR1 sequence of SEQ ID NO: 59, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 61, a HC FR1 sequence of SEQ ID NO: 48, a HC FR2 sequence of SEQ ID NO: 49, a HC FR3 sequence of SEQ ID NO: 50, a HC FR4 sequence of SEQ ID NO: 51, a LC FR1 sequence of SEQ ID NO: 52, a LC FR2 sequence of SEQ ID NO: 53, a LC FR3 sequence of SEQ ID NO: 54, and a LC FR4 sequence of SEQ ID NO: 55; e) a HC CDR1 sequence of SEQ ID NO: 70, a HC CDR2 sequence of SEQ ID NO: 71, a HC CDR3 sequence of SEQ ID NO: 72, a LC CDR1 sequence of SEQ ID NO: 73, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 75, a HC FR1 sequence of SEQ ID NO: 62, a HC FR2 sequence of SEQ ID NO: 63, a HC FR3 sequence of SEQ ID NO: 64, a HC FR4 sequence of SEQ ID NO: 65, a LC FR1 sequence of SEQ ID NO: 66, a LC FR2 sequence of SEQ ID NO: 67, a LC FR3 sequence of SEQ ID NO: 68, and a LC FR4 sequence of SEQ ID NO: 69; f) a HC CDR1 sequence of SEQ ID NO: 84, a HC CDR2 sequence of SEQ ID NO: 85, a HC CDR3 sequence of SEQ ID NO: 86, a LC CDR1 sequence of SEQ ID NO: 87, -10- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 89, a HC FR1 sequence of SEQ ID NO: 76, a HC FR2 sequence of SEQ ID NO: 77, a HC FR3 sequence of SEQ ID NO: 78, a HC FR4 sequence of SEQ ID NO: 79, a LC FR1 sequence of SEQ ID NO: 80, a LC FR2 sequence of SEQ ID NO: 81, a LC FR3 sequence of SEQ ID NO: 82, and a LC FR4 sequence of SEQ ID NO: 83; g) a HC CDR1 sequence of SEQ ID NO: 98, a HC CDR2 sequence of SEQ ID NO: 99, a HC CDR3 sequence of SEQ ID NO: 100, a LC CDR1 sequence of SEQ ID NO: 101, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 103, a HC FR1 sequence of SEQ ID NO: 90, a HC FR2 sequence of SEQ ID NO: 91, a HC FR3 sequence of SEQ ID NO: 92, a HC FR4 sequence of SEQ ID NO: 93, a LC FR1 sequence of SEQ ID NO: 94, a LC FR2 sequence of SEQ ID NO: 95, a LC FR3 sequence of SEQ ID NO: 96, and a LC FR4 sequence of SEQ ID NO: 97; h) a HC CDR1 sequence of SEQ ID NO: 112, a HC CDR2 sequence of SEQ ID NO: 113, a HC CDR3 sequence of SEQ ID NO: 114, a LC CDR1 sequence of SEQ ID NO: 115, a LC CDR2 sequence of YAS, and a LC CDR3 sequence of SEQ ID NO: 117, a HC FR1 sequence of SEQ ID NO: 104, a HC FR2 sequence of SEQ ID NO: 105, a HC FR3 sequence of SEQ ID NO: 106, a HC FR4 sequence of SEQ ID NO: 107, a LC FR1 sequence of SEQ ID NO: 108, a LC FR2 sequence of SEQ ID NO: 109, a LC FR3 sequence of SEQ ID NO: 110, and a LC FR4 sequence of SEQ ID NO: 111; i) a HC CDR1 sequence of SEQ ID NO: 126, a HC CDR2 sequence of SEQ ID NO: 127, a HC CDR3 sequence of SEQ ID NO: 128, a LC CDR1 sequence of SEQ ID NO: 129, a LC CDR2 sequence of YAS, and a LC CDR3 sequence of SEQ ID NO: 131, a HC FR1 sequence of SEQ ID NO: 118, a HC FR2 sequence of SEQ ID NO: 119, a HC FR3 sequence of SEQ ID NO: 120, a HC FR4 sequence of SEQ ID NO: 121, a LC FR1 sequence of SEQ ID NO: 122, a LC FR2 sequence of SEQ ID NO: 123, a LC FR3 sequence of SEQ ID NO: 124, and a LC FR4 sequence of SEQ ID NO: 125; j) a HC CDR1 sequence of SEQ ID NO: 140, a HC CDR2 sequence of SEQ ID NO: 141, a HC CDR3 sequence of SEQ ID NO: 142, a LC CDR1 sequence of SEQ ID NO: 143, a LC CDR2 sequence of YAS, and a LC CDR3 sequence of SEQ ID NO: 145, a HC FR1 sequence of SEQ ID NO: 132, a HC FR2 sequence of SEQ ID NO: 133, a HC FR3 sequence of SEQ ID NO: 134, a HC FR4 sequence of SEQ ID NO: 135, a LC FR1 sequence of SEQ ID NO: 136, a LC FR2 sequence of SEQ ID NO: 137, a LC FR3 sequence of SEQ ID NO: 138, and a LC FR4 sequence of SEQ ID NO: 139; -11- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 k) a HC CDR1 sequence of SEQ ID NO: 154, a HC CDR2 sequence of SEQ ID NO: 155, a HC CDR3 sequence of SEQ ID NO: 156, a LC CDR1 sequence of SEQ ID NO: 157, a LC CDR2 sequence of WAS, and a LC CDR3 sequence of SEQ ID NO: 159, a HC FR1 sequence of SEQ ID NO: 146, a HC FR2 sequence of SEQ ID NO: 147, a HC FR3 sequence of SEQ ID NO: 148, a HC FR4 sequence of SEQ ID NO: 149, a LC FR1 sequence of SEQ ID NO: 150, a LC FR2 sequence of SEQ ID NO: 151, a LC FR3 sequence of SEQ ID NO: 152, and a LC FR4 sequence of SEQ ID NO: 153; l) a HC CDR1 sequence of SEQ ID NO: 168, a HC CDR2 sequence of SEQ ID NO: 169, a HC CDR3 sequence of SEQ ID NO: 170, a LC CDR1 sequence of SEQ ID NO: 171, a LC CDR2 sequence of YAS, and a LC CDR3 sequence of SEQ ID NO: 173, a HC FR1 sequence of SEQ ID NO: 160, a HC FR2 sequence of SEQ ID NO: 161, a HC FR3 sequence of SEQ ID NO: 162, a HC FR4 sequence of SEQ ID NO: 163, a LC FR1 sequence of SEQ ID NO: 164, a LC FR2 sequence of SEQ ID NO: 165, a LC FR3 sequence of SEQ ID NO: 166, and a LC FR4 sequence of SEQ ID NO: 167; m) a HC CDR1 sequence of SEQ ID NO: 182, a HC CDR2 sequence of SEQ ID NO: 183, a HC CDR3 sequence of SEQ ID NO: 184, a LC CDR1 sequence of SEQ ID NO: 185, a LC CDR2 sequence of YAS, and a LC CDR3 sequence of SEQ ID NO: 187, a HC FR1 sequence of SEQ ID NO: 174, a HC FR2 sequence of SEQ ID NO: 175, a HC FR3 sequence of SEQ ID NO: 176, a HC FR4 sequence of SEQ ID NO: 177, a LC FR1 sequence of SEQ ID NO: 178, a LC FR2 sequence of SEQ ID NO: 179, a LC FR3 sequence of SEQ ID NO: 180, and a LC FR4 sequence of SEQ ID NO: 181; n) a HC CDR1 sequence of SEQ ID NO: 196, a HC CDR2 sequence of SEQ ID NO: 197, a HC CDR3 sequence of SEQ ID NO: 198, a LC CDR1 sequence of SEQ ID NO: 199, a LC CDR2 sequence of AAS, and a LC CDR3 sequence of SEQ ID NO: 201, a HC FR1 sequence of SEQ ID NO: 188, a HC FR2 sequence of SEQ ID NO: 189, a HC FR3 sequence of SEQ ID NO: 190, a HC FR4 sequence of SEQ ID NO: 191, a LC FR1 sequence of SEQ ID NO: 192, a LC FR2 sequence of SEQ ID NO: 193, a LC FR3 sequence of SEQ ID NO: 194, and a LC FR4 sequence of SEQ ID NO: 195; o) a HC CDR1 sequence of SEQ ID NO: 210, a HC CDR2 sequence of SEQ ID NO: 211, a HC CDR3 sequence of SEQ ID NO: 212, a LC CDR1 sequence of SEQ ID NO: 213, a LC CDR2 sequence of GTN, and a LC CDR3 sequence of SEQ ID NO: 215, a HC FR1 sequence of SEQ ID NO: 202, a HC FR2 sequence of SEQ ID NO: 203, a HC FR3 sequence of SEQ ID NO: 204, a HC FR4 sequence of SEQ ID NO: 205, a LC FR1 -12- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 sequence of SEQ ID NO: 206, a LC FR2 sequence of SEQ ID NO: 207, a LC FR3 sequence of SEQ ID NO: 208, and a LC FR4 sequence of SEQ ID NO: 209; p) a HC CDR1 sequence of SEQ ID NO: 224, a HC CDR2 sequence of SEQ ID NO: 225, a HC CDR3 sequence of SEQ ID NO: 226, a LC CDR1 sequence of SEQ ID NO: 227, a LC CDR2 sequence of GAS, and a LC CDR3 sequence of SEQ ID NO: 229, a HC FR1 sequence of SEQ ID NO: 216, a HC FR2 sequence of SEQ ID NO: 217, a HC FR3 sequence of SEQ ID NO: 218, a HC FR4 sequence of SEQ ID NO: 219, a LC FR1 sequence of SEQ ID NO: 220, a LC FR2 sequence of SEQ ID NO: 221, a LC FR3 sequence of SEQ ID NO: 222, and a LC FR4 sequence of SEQ ID NO: 223; q) a HC CDR1 sequence of SEQ ID NO: 14, a HC CDR2 sequence of SEQ ID NO: 15, a HC CDR3 sequence of SEQ ID NO: 16, a LC CDR1 sequence of SEQ ID NO: 234, a LC CDR2 sequence of GTS, a LC CDR3 sequence of SEQ ID NO: 236, a HC FR1 sequence of SEQ ID NO: 6, a HC FR2 sequence of SEQ ID NO: 7, a HC FR3 sequence of SEQ ID NO: 8, a HC FR4 sequence of SEQ ID NO: 9, a LC FR1 sequence of SEQ ID NO: 230, a LC FR2 sequence of SEQ ID NO: 231, a LC FR3 sequence of SEQ ID NO: 232, and a LC FR4 sequence of SEQ ID NO: 233; r) a HC CDR1 sequence of SEQ ID NO: 14, a HC CDR2 sequence of SEQ ID NO: 15, a HC CDR3 sequence of SEQ ID NO: 16, a LC CDR1 sequence of SEQ ID NO: 241, a LC CDR2 sequence of GTS, a LC CDR3 sequence of SEQ ID NO: 243, a HC FR1 sequence of SEQ ID NO: 6, a HC FR2 sequence of SEQ ID NO: 7, a HC FR3 sequence of SEQ ID NO: 8, a HC FR4 sequence of SEQ ID NO: 9, a LC FR1 sequence of SEQ ID NO: 237, a LC FR2 sequence of SEQ ID NO: 238, a LC FR3 sequence of SEQ ID NO: 239, and a LC FR4 sequence of SEQ ID NO: 240; s) a HC CDR1 sequence of SEQ ID NO: 14, a HC CDR2 sequence of SEQ ID NO: 15, a HC CDR3 sequence of SEQ ID NO: 16, a LC CDR1 sequence of SEQ ID NO: 248, a LC CDR2 sequence of GTS, a LC CDR3 sequence of SEQ ID NO: 250, a HC FR1 sequence of SEQ ID NO: 6, a HC FR2 sequence of SEQ ID NO: 7, a HC FR3 sequence of SEQ ID NO: 8, a HC FR4 sequence of SEQ ID NO: 9, a LC FR1 sequence of SEQ ID NO: 244, a LC FR2 sequence of SEQ ID NO: 245, a LC FR3 sequence of SEQ ID NO: 246, and a LC FR4 sequence of SEQ ID NO: 247; t) a HC CDR1 sequence of SEQ ID NO: 14, a HC CDR2 sequence of SEQ ID NO: 15, a HC CDR3 sequence of SEQ ID NO: 16, a LC CDR1 sequence of SEQ ID NO: 255, a LC CDR2 sequence of GTS, a LC CDR3 sequence of SEQ ID NO: 257, a HC FR1 -13- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 sequence of SEQ ID NO: 6, a HC FR2 sequence of SEQ ID NO: 7, a HC FR3 sequence of SEQ ID NO: 8, a HC FR4 sequence of SEQ ID NO: 9, a LC FR1 sequence of SEQ ID NO: 251, a LC FR2 sequence of SEQ ID NO: 252, a LC FR3 sequence of SEQ ID NO: 253, and a LC FR4 sequence of SEQ ID NO: 254; u) a HC CDR1 sequence of SEQ ID NO: 14, a HC CDR2 sequence of SEQ ID NO: 15, a HC CDR3 sequence of SEQ ID NO: 16, a LC CDR1 sequence of SEQ ID NO: 262, a LC CDR2 sequence of GTS, a LC CDR3 sequence of SEQ ID NO: 264, a HC FR1 sequence of SEQ ID NO: 6, a HC FR2 sequence of SEQ ID NO: 7, a HC FR3 sequence of SEQ ID NO: 8, a HC FR4 sequence of SEQ ID NO: 9, a LC FR1 sequence of SEQ ID NO: 258, a LC FR2 sequence of SEQ ID NO: 259, a LC FR3 sequence of SEQ ID NO: 260, and a LC FR4 sequence of SEQ ID NO: 261; v) a HC CDR1 sequence of SEQ ID NO: 14, a HC CDR2 sequence of SEQ ID NO: 15, a HC CDR3 sequence of SEQ ID NO: 16, a LC CDR1 sequence of SEQ ID NO: 269, a LC CDR2 sequence of GTS, a LC CDR3 sequence of SEQ ID NO: 271, a HC FR1 sequence of SEQ ID NO: 6, a HC FR2 sequence of SEQ ID NO: 7, a HC FR3 sequence of SEQ ID NO: 8, a HC FR4 sequence of SEQ ID NO: 9, a LC FR1 sequence of SEQ ID NO: 265, a LC FR2 sequence of SEQ ID NO: 266, a LC FR3 sequence of SEQ ID NO: 267, and a LC FR4 sequence of SEQ ID NO: 268; w) a HC CDR1 sequence of SEQ ID NO: 14, a HC CDR2 sequence of SEQ ID NO: 15, a HC CDR3 sequence of SEQ ID NO: 16, a LC CDR1 sequence of SEQ ID NO: 276, a LC CDR2 sequence of GTS, a LC CDR3 sequence of SEQ ID NO: 278, a HC FR1 sequence of SEQ ID NO: 6, a HC FR2 sequence of SEQ ID NO: 7, a HC FR3 sequence of SEQ ID NO: 8, a HC FR4 sequence of SEQ ID NO: 9, a LC FR1 sequence of SEQ ID NO: 272, a LC FR2 sequence of SEQ ID NO: 273, a LC FR3 sequence of SEQ ID NO: 274, and a LC FR4 sequence of SEQ ID NO: 275; or x) a HC CDR1 sequence of SEQ ID NO: 14, a HC CDR2 sequence of SEQ ID NO: 15, a HC CDR3 sequence of SEQ ID NO: 16, a LC CDR1 sequence of SEQ ID NO: 283, a LC CDR2 sequence of GTS, a LC CDR3 sequence of SEQ ID NO: 285, a HC FR1 sequence of SEQ ID NO: 6, a HC FR2 sequence of SEQ ID NO: 7, a HC FR3 sequence of SEQ ID NO: 8, a HC FR4 sequence of SEQ ID NO: 9, a LC FR1 sequence of SEQ ID NO: 279, a LC FR2 sequence of SEQ ID NO: 280, a LC FR3 sequence of SEQ ID NO: 281, and a LC FR4 sequence of SEQ ID NO: 282. -14- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004

[0025] In some embodiments of the isolated antibody or fragment thereof of the present disclosure, the isolated antibody or fragment thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL), where the VH comprises an amino acid sequence set forth in any one of SEQ ID NOs: 314, 316, 318, 320, 322, 324, 326, 328, 330, 332, 334, 336, 338, 340, 342, 344, 354, 355, 356, 357, or an amino acid sequence that is at least 80% identical to the amino acid sequence set forth in any one of SEQ ID NOs: 314, 316, 318, 320, 322, 324, 326, 328, 330, 332, 334, 336, 338, 340, 342, 344, 354, 355, 356, 357; and where the VL comprises an amino acid sequence set forth in any one of SEQ ID NOs: 315, 317, 319, 321, 323, 325, 327, 329, 331, 333, 335, 337, 339, 341, 343, 345, 346, 347, 348, 349, 350, 351, 352, 353, or an amino acid sequence that is at least 80% identical to the amino acid sequence set forth in any one of SEQ ID NOs: 315, 317, 319, 321, 323, 325, 327, 329, 331, 333, 335, 337, 339, 341, 343, 345, 346, 347, 348, 349, 350, 351, 352, 353.

[0026] In some embodiments of the isolated antibody or fragment thereof of the present disclosure, the isolated antibody or fragment thereof is a bispecific antibody comprising: (a) a first antigen binding domain (ABD) that specifically binds to BILF-1; and (b) a second ABD domain that specifically binds to a cell surface receptor, where the cell surface receptor is expressed on an immune cell, can form a heterodimer with BILF-1, and / or is co-expressed with BILF-1.

[0027] In some embodiments of the isolated antibody or fragment thereof of the present disclosure, the isolated antibody or fragment thereof increases engagement of BILF-1 expressing cells with an immune cell. In some embodiments, the immune cell is a T cell or natural killer (NK) cell.

[0028] In some embodiments of the isolated antibody or fragment thereof of the present disclosure, the isolated antibody or fragment thereof binds a cell surface receptor, wherein the cell surface receptor is CD3, CD16, IL-8 receptor, CD19, BCMA, CD38, vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR), EBV latent membrane protein 1 (LMP1), or EBV latent membrane protein 2 (LMP2). In some embodiments, the cell surface receptor is CD3 or CD16. In some embodiments, the cell surface receptor is IL-8 receptor, CD19, BCMA, CD38, vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR), EBV latent membrane protein 1 (LMP1), or EBV latent membrane protein 2 (LMP2).

[0029] In some embodiments of the isolated antibody or fragment thereof of the present disclosure, the isolated antibody or fragment thereof is conjugated to a cytotoxic agent. In some -15- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 embodiments, the cytotoxic agent is monomethyl auristatin F (MMAF), monomethyl auristatin E (MMAE), or duocarmycin DM.

[0030] In some embodiments of the isolated antibody or fragment thereof of the present disclosure, the isolated antibody or fragment thereof is conjugated or fused to an immune activating agent. In some embodiments, the immune activating agent is a Toll-like receptor (TLR)- agonist, a Stimulation of interferon genes (STING)-agonist, or a cytokine. In some embodiments, the cytokine is interleukin-2 (IL-2), interleukin-15 (IL-15), or a TNF superfamily ligand. In some embodiments the TNF superfamily ligand is TRAIL, 4-1BBL, interleukin-21 (IL-21), IFN-alpha, IFN-beta, CD40, GITR-L, OX40L, or CD70.

[0031] In some embodiments of the isolated antibody or fragment thereof of the present disclosure, the isolated antibody or fragment thereof is a single-chain variable fragment (scFv), where the scFv is fused via a spacer (hinge) region to a transmembrane domain and an intracellular T-cell signaling domain, thereby forming a chimeric antigen receptor (CAR).

[0032] In some embodiments of the isolated antibody or fragment thereof of the present disclosure, the amino acid sequence of the antibody or fragment thereof comprises one or more mutations, where the one or more mutations improve the binding affinity, stability, and / or the pharmacokinetics of the antibody or fragment thereof. In some embodiments, the one or more mutations is in the light chain of the antibody or fragment thereof. In some embodiments, the one or more mutations comprises an amino acid substitution. In some embodiments, the one or more mutations is in an amino acid selected from asparagine, cysteine, and leucine. In some embodiments, the one or more mutations comprises an asparagine to histidine substitution, a cysteine to alanine substitution, an asparagine to arginine substitution, a leucine to isoleucine substitution, a cysteine to valine substitution, an asparagine to serine substitution, or an asparagine to alanine substitution. In some embodiments, an unpaired cysteine residue in the amino acid sequence of the antibody or fragment thereof is eliminated by the one or more mutations.

[0033] In some embodiments, the present disclosure provides isolated nucleic acid molecules comprising a nucleic acid sequence encoding the isolated antibody or fragment thereof described herein.

[0034] In some embodiments, the present disclosure provides a vector comprising the isolated nucleic acid molecules described herein. In some embodiments, the vector further comprises a heterologous promoter. In some embodiments, the heterologous promoter is an inducible promoter or a constitutive promoter. In some embodiments, the expression of the isolated antibody or fragment thereof is driven by the promoter. -16- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004

[0035] In some embodiments, the present disclosure provides an isolated cell comprising the isolated nucleic acid molecule or the vector described herein.

[0036] In some embodiments, the present disclosure provides a method of producing the isolated antibody or fragment thereof described herein. In some embodiments, the method comprises culturing the isolated cell described herein under culture conditions suitable for the expression of the antibody or fragment thereof and isolating the antibody or fragment thereof from the culture.

[0037] In some embodiments, the present disclosure provides a pharmaceutical composition comprising the antibody or fragment thereof described herein and a physiologically acceptable carrier. In some embodiments, the pharmaceutical composition comprises two or more antibodies or fragments thereof described herein. In some embodiments, the pharmaceutical composition further comprises a second antibody or antigen binding fragment thereof which specifically binds to LMP-1 and / or LMP-2. In some embodiments, the second antibody or antigen binding fragment thereof specifically binds to LMP-2.

[0038] In some embodiments, the pharmaceutical composition further comprises one or more therapeutic agents which increase expression of EBV membrane proteins in EBV-infected cells. In some embodiments, the EBV-infected cells comprise B cells. In some embodiments, the one or more therapeutic agents is selected from the group consisting of valproic acid, trichostatin A (TSA), 5-azacytidine (5-AZA), romidepsin, panabinostat, vorinostat, decitabine, nanatinostat, Deferasirox, rituximab, and combinations thereof.

[0039] In some embodiments, the present disclosure provides a method of treating a subject having, or at risk for having, one or more of an Epstein Barr Virus (EBV) infection or an EBV- mediated disease, comprising administering to the subject the pharmaceutical composition described herein.

[0040] In some embodiments of the method of treating a subject having, or at risk for having, one or more of an EBV infection or an EBV-mediated disease, the subject is EBV-positive and has a latent EBV infection. In some embodiments, the EBV infection is characterized as Latency 0, Latency I, Latency II, or Latency III. In some embodiments, the EBV infection is a chronic active EBV infection or an acute active EBV infection.

[0041] In some embodiments of the method of treating a subject having, or at risk for having, one or more of an EBV infection or an EBV-mediated disease, the EBV-mediated disease is one or more diseases selected from the group consisting of an EBV-mediated -17- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 lymphoproliferative disorder (LPD), an EBV-mediated cancer, an EBV-mediated autoimmune disease, infectious mononucleosis, and combinations thereof.

[0042] In some embodiments, the EBV-mediated disease is hemophagocytic lymphohistiocytosis (HLH), Hodgkin's lymphoma (HL), or non-Hodgkin's lymphoma (NHL). In some embodiments, the NHL is Burkitt's lymphoma, diffuse large B cell lymphoma, B cell NHL, T cell NHL, or NK cell NHL. In some embodiments, the T cell or NK cell NHL includes peripheral T cell lymphoma (PTCL), optionally angioimmunoblastic T cell lymphoma (AILT). In some embodiments, the EBV-mediated LPD is a post-transplant lymphoproliferative disorder (PTLD) or an HIV-related LPD.

[0043] In some embodiments, the EBV-mediated cancer is a non-lymphoid malignancy selected from the group consisting of nasopharyngeal carcinoma (NPC), gastric carcinoma (GC), Stomach adenocarcinoma and leiomyosarcoma.

[0044] In some embodiments, the EBV-mediated autoimmune disease is one or more diseases selected from the group consisting of multiple sclerosis (MS), systemic lupus erythematosus (SLE), Sjogren's Syndrome, type I diabetes (T1D), rheumatoid arthritis (RA), dermatomyositis, and combinations thereof.

[0045] In some embodiments of the method of treating a subject having, or at risk for having, one or more of an EBV infection or an EBV-mediated disease, the subject is immunocompromised.

[0046] In some embodiments of the method of treating a subject having, or at risk for having, one or more of an EBV infection or an EBV-mediated disease, the subject is about to undergo, is undergoing, or has undergone, an organ transplant procedure including therapeutic immunosuppression. In some embodiments, the organ transplant procedure is a bone marrow transplant.

[0047] In some embodiments of the method of treating a subject having, or at risk for having, one or more of an EBV infection or an EBV-mediated disease, the method comprises administering to the subject an additional therapeutic agent. In some embodiments, the additional therapeutic agent increases expression of EBV membrane proteins in EBV-infected cells. In some embodiments, the EBV-infected cells comprise B cells. In some embodiments, the additional therapeutic agent is selected from the group consisting of romidepsin, panabinostat, vorinostat, decitabine, nanatinostat, rituximab, and combinations thereof.

[0048] In some embodiments of the method of treating a subject having, or at risk for having, one or more of an EBV infection or an EBV-mediated disease, the antibody or fragment -18- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 thereof described herein increases killing of EBV-infected cells in the subject by at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 2000% or more relative to an untreated control. In some embodiments, the antibody or fragment thereof described herein reduces cell-free EBV DNA load in the subject by at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 2000% or more relative to an untreated control. In some embodiments, the antibody or fragment thereof described herein reduces EBV-positive cell counts, optionally EBV-positive cancer cell counts, by at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 2000% or more relative to an untreated control.

[0049] In some embodiments of the method of treating a subject having, or at risk for having, one or more of an EBV infection or an EBV-mediated disease, the antibody or fragment thereof or the pharmaceutical composition described herein increases the subject's overall survival, progression-free survival, time to progression, or any combination of the foregoing. In some embodiments, the antibody or fragment thereof or the pharmaceutical composition described herein reduces the number and / or severity of one or more adverse events in the subject.

[0050] In some embodiments of the method of treating a subject having, or at risk for having, one or more of an EBV infection or an EBV-mediated disease, where the subject has an EBV-mediated autoimmune disease, the antibody or fragment thereof or pharmaceutical composition described herein reduces the progression of disability in the subject, optionally as measured by a Kurtzke Expanded Disability Status Scale (EDSS) or an SLE Disease Activity Index (SLEDAI).

[0051] In some embodiments of the method of treating a subject having, or at risk for having, one or more of an EBV infection or an EBV-mediated disease, where the subject has EBV- mediated multiple sclerosis, the antibody or fragment thereof or pharmaceutical composition described herein reduces relapse rate and / or central nervous system (CNS) lesion load in the subject.

[0052] In some embodiments of the method of treating a subject having, or at risk for having, one or more of an EBV infection or an EBV-mediated disease, the method comprises administering the pharmaceutical composition to the subject by parenteral administration. In some embodiments, the parenteral administration is intravenous administration.

[0053] In some embodiments of the method of treating a subject having, or at risk for having, one or more of an EBV infection or an EBV-mediated disease, the method comprises -19- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 genotyping the EBV in the subject, and administering the pharmaceutical composition described herein to the subject if the EBV genotype is associated with a high risk of EBV-mediated disease.

[0054] In some embodiments of the method of treating a subject having, or at risk for having, one or more of an EBV infection or an EBV-mediated disease, where the subject has an autoimmune disease, the method comprises determining EBV protein expression in an activated B cell in the subject, and administering the pharmaceutical composition described herein to the subject if the activated B cell expresses one or more EBV proteins. In some embodiments, the one or more EBV proteins is selected from the group consisting of EBNA-1, EBNA-2, EBNA-3A, EBNA-3B, EBNA-3C, EBNA-LP, LMP-1, LMP-2A, LMP-2B, and combinations thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0055] FIG. 1A shows a schematic depiction of the amino acid sequence of BILF-1, annotating the intracellular, transmembrane, and extracellular domains. FIG. 1B shows a schematic depiction of BILF-1 interactions with cellular signaling pathways.

[0056] FIG. 2A shows tissue microarray (TMA) images of EBER1 and BILF1 in-situ hybridization (ISH) staining of Nasopharyngeal carcinoma (NPC) tissue, Lymphoma tissue, Post- transplant lympho-proliferative disorder (PTLD) tissue, and Stomach adenocarcinoma (STAD) tissue. FIG.2B provides graphs of statistical evaluation of the TMA ISH stainings.

[0057] FIG.3A provides a bar graph of BILF1 RNA expression of untreated P3HR1 cells and P3HR1 cells treated with Phorbol 12-Myristate 13-Acetate (PMA) with and without sodium butyrate (SB), a combination of 5-azacytidine (5-AZA) and decitabine with and without Nanatinostat, Deferasirox, Trichostatin A, or Romidepsin. FIG.3B provides a bar graph of BILF1 expression after treatment of P3HR1 cells with DMSO, 5-AZA and decitabine with or without Romidepsin, Romidepsin, and PMA with SB. FIG.3C provides a bar graph of BILF1 expression after treatment of P3HR1 cells with various concentrations of Romidepsin. FIG. 3D provides a bar graph of BILF1 expression after treatment of P3HR1 cells with various concentrations of Vorinostat, Belinostat, Panabinostat, and Romidepsin. DMSO treated P3HR1 cells and untreated P3HR1 cells were used as controls.

[0058] FIG. 4A shows flow cytometry density plots of anti-BILF-1 antibodies binding to BILF1-expressing B16 cells. FIG. 4B shows the non-specific binding of AXM1, AXM6 and AXM7 to live, fixed, or intracellularly stained peripheral blood mononuclear cells (PBMC). FIG. 4C shows flow cytometry density plots of anti-BILF-1 antibodies (AXM1 and AXM6) binding to -20- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 two different variants of BILF1 that have two mutations: BILF1 (R219K, V263A) and BILF1 (A6V, V11M). Each mutation is associated with BILF1 variants.

[0059] FIG. 5 provides graphs of binding curves of mAbs AXM1, AXM6 and AXM7 to BILF1 expressing cells and the equilibrium dissociation constant (KD) is indicated for each mAb.

[0060] FIG. 6A provides flow cytometry density plots showing the percentage of Sytox Blue-positive BILF1+ B16 cells after incubation with unconjugated mAb AXM1, AXM6, and isotype control and a cross-linking secondary antibody. FIG.6B provides flow cytometry density plots showing the percentage of BILF1+GFP+ B16 cells after incubation with unconjugated mAb AXM1, AXM6, and isotype control and a cross-linking secondary antibody. FIG. 6C provides flow cytometry density plots showing the percentage of BILF1+GFP+ B16 cells after incubation with unconjugated AXM1 and a cross-linking secondary antibody, PE / Texas Red-conjugated AXM1, and a cross-linking secondary antibody alone.

[0061] FIG.7A provides flow cytometry density plots showing the percentage of pHrodo red positive BILF-1+ B16 cells after incubation with AXM1 antibody and isotype control antibody conjugated with pH sensitive pHrodo red dye and co-staining with secondary anti-mouse Fab. FIG.7B and FIG.7C provide bar graphs showing the cell viability of BILF-1+ B16 cells (FIG. 7B) and B16 cells (FIG. 7C) after treatment with mAb AXM1 or isotype control, followed by anti-mouse secondary antibody (2nd Anti mouse) or anti-mouse secondary antibody conjugated with Monomethyl auristatin F (2nd Anti mouse-MMAF) or duocarmycin DM (2nd Anti mouse- DMDM). FIG. 7D provide a bar graph showing the cell viability of BILF-1+ B16 cells after treatment with AXM1, AXM6 and AXM7, followed by anti-mouse secondary antibody (2ndAnti mouse) or anti-mouse secondary antibody conjugated with duocarmycin DM (2ndAnti mouse- DMDM). FIG. 7E provide a bar graph showing the cell viability of BILF-1+ B16 cells after treatment with AXM1 directly conjugated with DMDM (AXM1 DMDM) or isotype control directly conjugated with DMDM (Isotype DMDM).

[0062] FIG. 8 provides Incucyte graphs showing the mean percentage of phase objective confluence of BILF1+ B16 cells (left panel) and B16 cells (right panel) versus time for a 5-day incubation with AXM1, Isotype control, AXM1-DMDM, or Isotype control-DMDM.

[0063] FIG.9A provides flow cytometry density plots showing the percentage of BILF-1+ EBV-positive Nasopharyngeal Carcinoma Cells (NPC) after staining with AXM1 followed by anti-mouse secondary antibody, Isotype control, or secondary antibody alone. FIG.9B provides an Incucyte graph showing the mean percentage of phase objective confluence of EBV-positive NPC cells vs time for a 4-day incubation with various concentrations of AXM1 directly -21- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 conjugated with DMDM (AXM1 DMDM) and isotype control-DMDM (Isotype DMDM). FIG. 9C provides a bar graph showing area under curve (AUC) of phase objective confluence of EBV- positive NPC cells for a 4-day incubation with various concentrations of AXM1 directly conjugated with DMDM (AXM1 DMDM) and isotype control-DMDM (Isotype DMDM). FIG. 10A provides flow cytometry density plots showing the percentage of BILF1-expressing GFP+ B16 cells after staining with fully human mAb AXM1 with a cysteine at position 91 in the CDR3 region of the light chain (Full human AXM1 (original C)) or fully human mAb AXM1 with serine replacement of the cysteine at position 91 (Full human AXM1 (C91S)) or isotype control. FIG.10B provides bar graphs showing the cell viability of B16 cells (left panel) or BILF-1+ B16 cells (right panel) after treatment with fully human (Hu) AXM1 (original C) or Hu AXM1 (C91S) with secondary antibody conjugated with duocarmycin DM (2nd-DMDM), 2nd-DMDM alone, AXM1-DMDM, or isotype control with secondary antibody conjugated with duocarmycin DM (Isotype-DMDM). FIG. 10C provides a binding curve of fully human mAb AXM1 (C91S) in BILF1 expressing B16 cells. FIG.10D provides binding curves of fully human AXM1 variants: AXM1-DQAHRFL (AXM1-N32D, C91A, N92H, N93R, W94F), AXM1-DQVHRWI (AXM1- N32D, C91V, N92H, N93R, L96I), AXM1-HQAHHFL (AXM1-N32H, C91A, N92H, N93H, W94F), AXM1-HQVARWI (AXM1-N32H, C91V, N92A, N93R, L96I), and AXM1-NQVNSWI (AXM1- C91V, N93S, L96I) to BILF1 expressing B16 cells. FIG. 10. E provides an Incucyte graph showing the mean percentage of phase objective confluence of BILF1+ B16 cells vs time for a 4-day incubation with AXM1 variants along with anti-human IgG DMDM. FIG. 10F provides flow cytometry density plot showing the percentage of BILF1-expressing GFP+ B16 cells binding to serial dilution of AXM1-HQAHHFL in neutral PH buffer (PBS + 2% FBS) and low PH buffer (PBS + 2% FBS + 50mM). FIG.10G provides ELISA data showing reactivity of AXM1 antibody variants against human insulin and LPS. Elotuzumab and Lenzilumab were used as control antibodies. FIG.10H provides binding curves of fully human AXM1 FAB antibody to BILF1 expressing B16 cells.

[0064] FIG. 11 displays flow cytometry data showing that both AXM1 C91 and AXM1 C91S specifically bind to BILF1 expressed by Romidepsin-induced Zebra+ SNU719 cells. To induce BILF1 expression, SNU719 cells were treated with 2.5 nM or 6.5 nM Romidepsin for 24 hours. Untreated SNU719 cells served as a control. After treatment, the cells were stained with AXM1(C91), AXM1(C91S), or an isotype control, followed by secondary anti-human IgG staining. The cells were subsequently stained with Anti-Zebra FITC or isotype-FITC for further analysis -22- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004

[0065] FIG.12 provides an Incucyte graph showing the mean percentage of phase objective confluence of EBV-positive NPC cells vs time for a 3-day incubation with fully human AXM1(C91S) conjugated with DMDM or fully human isotype conjugated with DMDM.

[0066] Female C57Bl / 6J mice (n = 6) were injected subcutaneously with BILF1+ B16 cells, randomized into two groups, and treated with 7 consecutive intravenous injections of Human AXM1 (C91S)-DMDM antibody or Human isotype-DMDM antibody. FIG. 13A provides a summary graph of average tumor size and FIG.13B provides a graph showing tumor size for each mouse measured over the course of 27 days. FIG.13C shows the survival curve for each of the two groups of mice. FIG. 13D presents a summary graph depicting the average tumor size, alongside individual tumor size data for each mouse treated with PBS, hu AXM1-MMAE, hu isotype-MMAE, hu AXM1-DX8951, and hu isotype-DX8951. FIG.13E shows a summary graph of the average tumor size for mice treated with PBS, hu AXM1-MMAE, and TA99-MMAE.

[0067] FIG. 14A provides a schematic depiction of different designs of bispecific CD3 T cell engagers in a knob-in-hole format.2C11-AXM1 is composed of AXM1-Fab-knob linked to 2C11-scFv-AXM1-hole and AXM1-2C11 is composed of AXM1-Fab-knob linked to AXM1- 2C11-scFv-hole, with either a GGGs linker or AAA linker connecting 2C11 with the CH2 of the Fc region. FIG. 14B provides flow cytometry density plots showing the percentage of BILF1+GFP+B16 cells (top panel) or GFP+B16 cells (bottom panel) positively stained with 2C11-AXM1, AXM1-2C11 (GGGs), AXM1-2C11 (AAA) bispecific antibodies, and secondary antibodies control. FIG. 14C provides flow cytometry density plots showing the percentage of CD3+ magnetically enriched mouse T cells positively stained with 2C11-AXM1, AXM1-2C11 (GGGs), AXM1-2C11 (AAA) bispecific antibodies, and secondary antibodies control.

[0068] FIG. 15A provides flow cytometry density plots showing the percentage of live (GFP+) control GFP+B16 cells or BILF1+GFP+B16 cells co-cultured for 24 hours with CD3 enriched mouse T cell and treated with 10 ug / ml, 2 ug / ml, or 0.4 ug / ml of 2C11-AXM1, AXM1- 2C11 (GGGs), or AXM1-2C11 (AAA) bispecific antibodies. FIG. 15B provides a bar graph showing optical density (OD) measurements of lactate dehydrogenase (LDH) in supernatants from the co-culture experiment described in FIG. 15A. FIG. 15C provides a graph showing the OD values of LDH in the supernatant of mouse T cell:BILF1+ B16 cell co-cultures treated with 2C11- AXM1, AXM1-2C11 (GGGs), and AXM1-2C11 (AAA) bispecific antibodies at concentrations ranging from 2 ug / ml to 0.00064 μg / ml using 5-fold serial dilutions.

[0069] FIG.16A provides a 11-point titration curve showing the OD values of LDH in the supernatant of mouse T cell:BILF1+ B16 cell co-cultures treated with various concentrations of -23- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 2C11-AXM1 bispecific antibody. The EC50 value of the 2C11-AXM1 bispecific antibody is indicated. FIG.16B provides flow cytometry density plots showing the percentage of live (GFP+) BILF1+GFP+B16 cells and CD8+ T cells in the mouse T cell: BILF1+ B16 cell co-cocultures treated with 14 different concentrations of the 2C11-AXM1 bispecific antibody or AXM1 alone or 2C11 alone.

[0070] Female C57Bl / 6J mice (n = 7) were injected subcutaneously with BILF1+ B16 cells, randomized into three groups, and treated with two intraperitoneal injections followed by 5 intravenous injection of PBS, 12.5 ug 2C11-AXM1 bispecific antibody or 12.5 ug 2C11 antibody. FIG.17A provides a summary graph of average tumor size for each of the three groups, measured over the course of 16 days. FIG.17B provides a graph showing tumor size for each mouse treated with PBS or 2C11-AXM1 bispecific antibody. FIG.17C provides a graph showing tumor size for each mouse treated with PBS or 2C11 alone. FIG. 17D provides a summary graph of average tumor size for mice treated with PBS, B21M-2C11 and AXM1-2C11.

[0071] FIG. 18A displays flow cytometry density plots illustrating the percentage of OVCAR3 cells, BILF1+GFP+ OVCAR3 cells, and BILF1+GFP+ B16 cells binding to AXM1(C91S), afucosylated AXM1(C91S) (AF-AXM1(C91S)), afucosylated trastuzumab (AF- Trastuzumab), and isotype control. FIG. 18B shows the percentage and mean fluorescence intensity (MFI) of BILF1+ OVCAR3 cells and BILF1+ B16 cells co-cultured with PBMCs at target-to-effector cell ratios of 1:40 and 1:20 (i.e., BILF1+ cells:PBMCs), in the presence of 5 μg / ml of AXM1(C91S), AF-AXM1(C91S), AF-Trastuzumab, or isotype control.

[0072] FIG. 19A presents two-phase decay graphs illustrating the half-life of hu AXM1(C91S) administered at doses of 100 μg / mouse and 500 μg / mouse in C57BL / 6 mice. Sera were collected from the mice at 15 minutes, 5 hours, 1 day, 2 days, 4 days, 9 days, and 14 days post-injection. Human IgG ELISA was used to measure the concentration of hu AXM1 at each time point. FIG. 19B shows in vivo IVIS images for each mouse, along with ROI fluorescent intensity graphs in the tumor and liver compartments, highlighting the biodistribution of AXM1 conjugated to the fluorescent dye IVISense-800 NHS (AXM1-IVIS 800) and control antibody conjugated to IVISense 800 NHS (control antibody-IVIS 800). To examine the biodistribution of anti-BILF1 in BILF1+ tumor-bearing mice, B6(Cg)-Tyrc-2 BILF1+ B16 cells, as described previously. The mice were then randomized and treated with either AXM1-IVIS 800 or control antibody-IVIS 800. Twenty-four hours post-injection, the mice were imaged using the IVIS in vivo imaging system. -24- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004

[0073] FIG.20A provides a 3D structural representation mapping antibody binding to the extracellular domain of BILF1, as measured by a flow cytometry-based alanine scan spanning all extracellular residues of BILF1. Residues of preferred AXM1 binding are shown in black and residues of preferred AXM6 binding are shown in white. FIG.20B provides a bar chart showing preferred AXM1 vs. AXM6 binding to residues on the BILF1 extracellular domain. Positive values indicate likely AXM1 epitope residues, and negative values indicate likely AXM6 epitope residues.

[0074] FIG. 21 presents a western blot analysis of BILF1-GS-GFP B16 cell lysates, including deglycosylated BILF1-GS-GFP lysates, probed with Anti-GFP and AXM1 antibodies. Membrane protein lysates from BILF1-GS-GFP B16 cells were first denatured at 100°C for 10 minutes. The lysates were then treated with PNGase F, O-glycosidase + neuraminidase, or O- glycosidase + neuraminidase + PNGase F for 1.5 hours or 4 hours at 37°C. After treatment, the samples were analyzed by western blotting using both Anti-GFP and AXM1 antibodies. FIG.21A shows western blot images for the 1.5-hour treatment, and FIG.21B shows the results for the 4- hour treatment. An untreated membrane protein lysate was included as a control. DETAILED DESCRIPTION Overview

[0075] The present disclosure provides antibodies, and antigen binding fragments thereof, which specifically bind an extracellular domain (ECD) of Epstein-Barr virus (EBV) membrane protein BILF-1, and related nucleic acids, vectors, pharmaceutical compositions, cells, and methods of use thereof, such as for treating EBV infections and EBV-mediated diseases. The antibodies, and antigen binding fragments thereof, as described herein can find utility as therapeutic, diagnostic, or research agents.

[0076] Similar to other herpesviruses, EBV has an active lytic and a dormant latent life cycle and thus causes a lifelong infection in the host, in which the virus can switch between latency and lytic reactivation (Babcock et al., 1998). EBV infects human B cells via the complement receptor CD21 and establishes life-long latency in B cells. Latency is classified in 4 stages (0, I, II, and III) and during latency only 0 to 8 proteins and a few short and micro-RNAs are expressed. The lytic infection, in which a host cell is hijacked to produce millions of new viruses, is crucial for the viral dissemination within the host and for transmission to a new host (Lukac & Yuan, -25- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 2007). This cycle is driven by temporally regulated gene expression of immediate-early (IE), early (E) and late (L) lytic genes that encode for lytic proteins (Lukac & Yuan, 2007) (Murata, 2018). Early genes are classified as being transcribed before viral replication and are subsequently essential for viral replication, as they, for instance, encode for the viral DNA polymerase (EBV- BALF5) (Lukac & Yuan, 2007). Moreover, early proteins can also interfere with host cell processes such as major histocompatibility complex I (MHC-I) or MHC-II surface expression, effectively evading the host immune system and, hence, ensuring viral survival (Quinn et al., 2014; Zuo et al., 2009, 2011). One of the early proteins is BILF1, a viral G protein-coupled receptor. BILF1 is not only expressed during lytic activation of EBV, but it also belongs to a set of genes that are highly expressed in EBV-positive tumors during the abortive lytic cycle (Yap et al., 2022) (FIG. 2). BILF1 is therefore highly expressed in many EBV-positive cancers and mediates cell transformation in vitro and tumor formation in vivo (Tierney et al., 2015). BILF1 has also been found to upregulate the intracellular adhesion molecule-1 (ICAM-I), which is vital in promoting cancer metastasis. Over-expression of BILF1 enhances VEGF secretion and signaling and promotes tumor foci formation in vitro and tumor engraftment as well as tumor growth in vivo (Lyngaa et al., 2010). BILF1 has been detected in various EBV+ cell lines and tissue samples in lytic and latent stages. Previously, BILF1 has been shown to be highly expressed in nasopharyngeal carcinoma (NPC) and stomach adenocarcinoma (STAD) (Yap et al., 2022) (Chakravorty et al., 2019) (Borozan et al., 2018). Therefore, BILF-1 is a promising target for antibody therapeutics.

[0077] The present disclosure provides antibodies, and antigen binding fragments thereof, which specifically bind an extracellular domain (ECD) of Epstein-Barr virus (EBV) membrane protein BILF-1. In some embodiments, the antibody or antigen binding fragment thereof described herein binds to EBV membrane protein BILF-1. In certain embodiments, the antibody or antigen binding fragment thereof binds to an ECD of BILF-1. In certain embodiments, the antibody or antigen binding fragment thereof binds to one or more of ECD1, ECD2, ECD3, or ECD4 of BILF- 1. In certain embodiments, the antibody or antigen binding fragment thereof binds to ECD1 of BILF-1. In certain embodiments, the antibody or antigen binding fragment thereof binds to ECD1 and ECD2 of BILF-1. In certain embodiments, the antibody or antigen binding fragment thereof binds to ECD1 and ECD3 of BILF-1. In certain embodiments, the antibody or antigen binding fragment thereof binds to ECD1 and ECD4 of BILF-1. In certain embodiments, the antibody or antigen binding fragment thereof binds to ECD1, ECD2, and ECD3 of BILF-1. In certain embodiments, the antibody or antigen binding fragment thereof binds to ECD1, ECD2, ECD3, -26- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 and ECD4 of BILF-1. In certain embodiments, the antibody or antigen binding fragment thereof binds to ECD2 of BILF-1. In certain embodiments, the antibody or antigen binding fragment thereof binds to ECD2 and ECD3 of BILF-1. In certain embodiments, the antibody or antigen binding fragment thereof binds to ECD2 and ECD4 of BILF-1. In certain embodiments, the antibody or antigen binding fragment thereof binds to ECD2, ECD3, and ECD4 of BILF-1. In certain embodiments, the antibody or antigen binding fragment thereof binds to ECD3 of BILF- 1. In certain embodiments, the antibody or antigen binding fragment thereof binds to ECD3 and ECD4 of BILF-1. Table 1: Amino acid sequences for BILF1 and BILF1 extracellular domains

[0078] The amino acid sequences of BILF-1 and its four extracellular domains are provided in Table 1. In some embodiments, the antibody or fragment thereof specifically binds to ECD1 of BILF-1 through contact with one or more amino acid residues within an epitope consisting of SEQ ID NO: 2. In some embodiments, the antibody or fragment thereof specifically binds to ECD2 of BILF-1 through contact with one or more amino acid residues within an epitope consisting of SEQ ID NO: 3. In some embodiments, the antibody or fragment thereof specifically binds to ECD3 of BILF-1 through contact with one or more amino acid residues within an epitope consisting of SEQ -27- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 ID NO: 4. In some embodiments, the antibody or fragment thereof specifically binds to ECD4 of BILF-1 through contact with one or more amino acid residues within an epitope consisting of SEQ ID NO: 5. In some embodiments, the antibody or fragment thereof specifically binds to one or more of ECD1, ECD2, ECD3, or ECD4 of BILF-1 through contact with one or more amino acid residues within the respective epitope, wherein the ECD1 epitope consists of SEQ ID NO: 2, the ECD2 epitope consists of SEQ ID NO: 3, the ECD3 epitope consists of SEQ ID NO: 4, and the ECD4 epitope consists of SEQ ID NO: 5.

[0079] The present disclosure provides the distinct epitopes on BILF-1 to which the antibodies or antigen binding fragments thereof described herein specifically bind. Methods for mapping the epitope of an antibody on its target antigen are known in the art and include, but are not limited to, site-directed mutagenesis mapping, hydrogen-deuterium exchange mass spectrometry (HDX-MS), high-throughput shotgun mutagenesis epitope mapping, x-ray crystallography, and cryogenic electron microscopy. For example, an epitope may be determined by using alanine scanning mutagenesis, where systematic substitution of individual amino acid residues allows for identification of critical residues essential for antibody-antigen binding. In some embodiments, the anti-BILF1 antibodies or antigen binding fragments thereof of the present disclosure bind to BILF-1 through contact with one or more amino acid residues selected from the group consisting of L2, S3, T4, P7, S9, T10, L14, V15, N17, M18, T19, S20, V21, N22, A23, T24, T29, K30, S31, Y32, E90, F91, S92, G95, T160, M161, G 162, M173, E176, G177, P178, H183, T184, A191, T259, L262, V263, A264, R265, and G269 (the numbering of the amino acids is based on the full-length BILF-1 sequence set forth in SEQ ID NO: 1). In some embodiments, the antibodies or antigen binding fragments thereof of the present disclosure bind to BILF-1 through contact with at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 amino acid residues relative to SEQ ID NO: 1 selected from the group consisting of L2, S3, T4, P7, S9, T10, L14, V15, N17, M18, T19, S20, V21, N22, A23, T24, T29, K30, S31, Y32, E90, F91, S92, G95, T160, M161, G 162, M173, E176, G177, P178, H183, T184, A191, T259, L262, V263, A264, R265, and G269. In some embodiments, the antibodies or antigen binding fragments thereof of the present disclosure bind to BILF-1 through contact with three or more amino acid residues relative to SEQ ID NO: 1 selected from the group consisting of L2, S3, T4, P7, S9, T10, L14, V15, N17, M18, T19, S20, V21, N22, A23, T24, T29, K30, S31, Y32, E90, F91, S92, G95, T160, M161, G 162, M173, E176, G177, P178, H183, T184, A191, T259, L262, V263, A264, R265, and G269. In some embodiments, the antibodies or antigen binding fragments thereof of the present disclosure bind to BILF-1 through contact with one or more amino acid -28- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 residues relative to SEQ ID NO: 1 selected from the group consisting of M39, D164, A165, N166, L167, N168, R169, G170, P171, N172, R175, T179, K180, G181, M182, A185, V186, Q187, G188, L189, K190, A251, S253, L254, G255, F256, D257, C258, E260, S261, Y266, Y267, and P268. In some embodiments, the antibodies or antigen binding fragments thereof of the present disclosure bind to BILF-1 through contact with at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 amino acid residues relative to SEQ ID NO: 1 selected from the group consisting of M39, D164, A165, N166, L167, N168, R169, G170, P171, N172, R175, T179, K180, G181, M182, A185, V186, Q187, G188, L189, K190, A251, S253, L254, G255, F256, D257, C258, E260, S261, Y266, Y267, and P268. In some embodiments, the antibodies or antigen binding fragments thereof of the present disclosure bind to BILF-1 through contact with three or more amino acid residues relative to SEQ ID NO: 1 selected from the group consisting of M39, D164, A165, N166, L167, N168, R169, G170, P171, N172, R175, T179, K180, G181, M182, A185, V186, Q187, G188, L189, K190, A251, S253, L254, G255, F256, D257, C258, E260, S261, Y266, Y267, and P268.

[0080] The anti-BILF1 antibodies or antigen binding fragments thereof described herein have the potential to bind to a specific epitope of BILF1 and disrupt its conformational structure, thereby influencing its downstream signaling. In some embodiments, the anti-BILF-1 antibody or fragment thereof specifically binds to amino acids proximal to the transmembrane region of the EBV membrane protein BILF-1; and wherein the specific binding changes the conformational structure of BILF-1 and alters the function of BILF-1.

[0081] In some embodiments, the anti-BILF1 antibody or antigen binding fragment thereof described herein is a monoclonal antibody and / or a humanized antibody, or an antigen binding fragment thereof. In some embodiments, the anti-BILF1 antibody or antigen binding fragment thereof is a humanized antibody. In some embodiments, the anti-BILF1 antibody or antigen binding fragment thereof is a fully human antibody. In some embodiments, the anti-BILF1 antibody or antigen binding fragment thereof is a whole antibody, a fragment antigen binding domain (Fab), a F(ab’)2 domain, a single-chain variable fragment (scFv), a dimeric single-chain variable fragment (di-scFv), or a single domain antibody (sdAb). In some embodiments, the anti- BILF1 antibody or antigen binding fragment thereof is a whole antibody. In some embodiments, the anti-BILF1 antibody or antigen binding fragment thereof is a fragment antigen binding domain (Fab). In some embodiments, the anti-BILF1 antibody or antigen binding fragment thereof is a F(ab’)2 domain. In some embodiments, the anti-BILF1 antibody or antigen binding fragment thereof is a single-chain variable fragment (scFv). In some embodiments, the anti-BILF1 antibody -29- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 or antigen binding fragment thereof is a dimeric single-chain variable fragment (di-scFv). In some embodiments, the anti-BILF1 antibody or antigen binding fragment thereof is a single domain antibody (sdAb). (Fab), a F(ab’)2 domain, a single-chain variable fragment (scFv), a dimeric single-chain variable fragment

[0082] In some embodiments, the anti-BILF1 antibody or antigen binding fragment thereof of the present disclosure comprises an Fc region selected from the group consisting of IgA, IgD, IgE, IgG, and IgM Fc region. In some embodiments, the Fc region is IgA. In certain embodiments, the Fc region is IgA1. In certain embodiments, the Fc region is IgA2. In some embodiments, the Fc region is IgD. In some embodiments, the Fc region is IgE. In some embodiments, the Fc region is IgG. In certain embodiments, the Fc region is IgG1. In certain embodiments, the Fc region is IgG2. In certain embodiments, the Fc region is IgG3. In certain embodiments, the Fc region is IgG4. In certain embodiments, the Fc region is IgM. In some embodiments, the Fc region is a mouse Fc region. In some embodiments, the Fc region is a human Fc region.

[0083] expressed on the surface of effector immune cells. This interaction mediates a range of Fc effector functions and can enhance the therapeutic potential of clinical monoclonal antibodies for the treatment of inflammatory and neoplastic disorders (Nimmerjahn et al., Cancer Immun. 12, 13 (2012)). An Fc region can be modified to provide enhanced effector functions, such as enhanced binding affinity to Fc receptors, enhanced antibody-dependent cellular cytotoxicity (ADCC), or enhanced complement-dependent cytotoxicity (CDC). For the IgG class of antibodies, these effector functions are governed by engagement of the Fc region with a family of receptors referred and subsequent immune responses. Methods for optimizing the binding affinity of the F the antibody Fc region in order to enhance the effector functions are well known to persons skilled in the art. Non-limiting examples of such methods include modification of the Fc region of the antibody to enhance its interaction with relevant Fc receptors and increase its potential to facilitate antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cell-mediated phagocytosis (ADCP). Enhancements in ADCC activity have also been described following the modification of the oligosaccharide covalently attached to IgG1 antibodies at the conserved Asn297 in the Fc region. Methods for enhancing CDC activity can include isotype chimerism, in which portions of IgG3 subclass are introduced into corresponding regions of IgG1 subclass (e.g. Recombinant antibody composition, US2007148165). In some embodiments, the anti-BILF-1 -30- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 antibodies or antigen binding fragments thereof of the present disclosure comprise an IgG Fc region with high effector function in humans. In some embodiments, the anti-BILF-1 antibodies or antigen binding fragments thereof comprise a modified Fc region which has at least one altered effector function relative to a wild-type Fc region. In some embodiments, the anti-BILF-1 antibodies or antigen binding fragments thereof comprise a modified Fc region which has at least one altered pharmacokinetic (PK) characteristic relative to a wild-type Fc region. In some embodiments, the at least one altered effector function comprises increased engagement with one or more immune cells. In certain embodiments, the one or more immune cells is natural killer (NK) cells, macrophages, neutrophils, dendritic cells, or a combination thereof. In certain embodiments, the at least one altered effector function comprises increased engagement with NK cells. In certain embodiments, the at least one altered effector function comprises increased engagement with macrophages. In certain embodiments, the at least one altered effector function comprises increased engagement with neutrophils. In certain embodiments, the at least one altered effector function comprises increased engagement with dendritic cells. In some embodiments, the anti-BILF-1 antibodies or antigen binding fragments thereof comprise a modified Fc region which has increased affinity for one or more of or In certain embodiments, the anti-BILF-1 antibodies or antigen binding fragments thereof comprise a modified Fc region which has increased affinity for CD16. In certain embodiments, the anti-BILF- 1 antibodies or antigen binding fragments thereof comprise a modified Fc region which has increased affinity for . In some embodiments, the anti-BILF-1 antibodies or antigen binding fragments thereof described herein comprise one or more mutations in the Fc region that enhance FcyRIIIa binding and / or decreased FcyRIIIb binding. Nonlimiting examples of such mutations may be made at one or more amino acid positions selected from L234, L235, G236, S239, F243, H268, D270, R292, S298, Y300, V305, K326, A330, 1332, E333, K334, and P396. Nonlimiting exemplary mutations include L234Y, L235Q, G236W, S239D, S239M, F243L, H268D, D270E, R292P, S298A, Y300L, V305I, K326D, A330L, A330M, I332E, E333 A, K334A, K334E, and P396L.

[0084] Other exemplary Fc mutations include, but are not limited to, L234A / L235A (referred to as “LALA”) in human IgG1, L234A / L235A / P329G (referred to as “LALAPG”) in human IgG1, M252Y / S254T / T256E (referred to as “YTE”) in human IgG1, M428L / N434S (referred to as “LS”) in human IgG1, M252Y / S254T / T256E / H433K / N434F in human IgG1, and S241P in human IgG4. In some embodiments, the anti-BILF-1 antibodies or antigen binding fragments thereof described herein comprise a modified Fc region, wherein the modified Fc region -31- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 is a modified human IgG1 comprising mutations selected from L234A / L235A, L234A / L235A / P329G, M252Y / S254T / T256E, M428L / N434S, and M252Y / S254T / T256E / H433K / N434F relative to wild type IgG1. In certain embodiments, the modified Fc region is a modified human IgG1 comprising the L234A / L235A mutations. In certain embodiments, the modified Fc region is a modified human IgG1 comprising the L234A / L235A / P329G mutations. In certain embodiments, the modified Fc region is a modified human IgG1 comprising the M252Y / S254T / T256E mutations. In certain embodiments, the modified Fc region is a modified human IgG1 comprising the M428L / N434S mutations.

[0085] Fucose (6-deoxy-L-galactose) is a monosaccharide that is present in many glycoproteins and glycolipids present in vertebrates, invertebrates, plants, and bacteria. Fucosylation is the process of transferring a fucose residue to various proteins and oligosaccharides and is regulated by several molecules, including fucosyltransferases, guanosine diphosphate (GDP)-fucose synthetic enzymes, and GDP-fucose transporter(s). Human IgG1 antibody is a highly fucosylated glycoprotein. Two A-linked biantennary oligosaccharides consisting of core hepta-saccharide with variable addition of fucose, galactose, bisecting N- acetylglucosamine and sialic acid are present at Asn-297 of IgG1. Antibody glycosylation can lead to unique effector functions such as Antibody Dependent Cellular Cytotoxicity (ADCC) and Complement Dependent Cytotoxicity (CDC). The efficiency of ADCC is affected by the level of antibody fucosylation. In general, lower fucosylation is associated with a higher rate of ADCC. Therefore, afucosylated antibodies, or recombinant monoclonal antibodies with reduced fucose content, are known to exhibit increased binding affinity between the Fc region and Fc receptors, thereby enhancing immune responses, particularly through ADCC. Methods for reducing fucosylation in the Fc region of antibodies are known in the art. In some embodiments, the anti- BILF-1 antibodies or antigen binding fragments thereof described herein have reduced fucose content in the Fc region. In some embodiments, the oligosaccharides in the Fc region of the anti- BILF-1 antibodies or antigen binding fragments thereof do not have any fucoses. In some embodiments, the anti-BILF-1 antibodies or antigen binding fragments thereof described herein comprises an IgG1 Fc region, wherein the oligosaccharides in the IgG1 Fc region has reduced fucose content or does not have any fucoses. In some embodiments, the anti-BILF-1 antibodies or antigen binding fragments thereof described herein have a carbohydrate structure that lacks fucose attached (directly or indirectly) to an Fc region (i.e., afucosylated). The amount of fucose in such variants may be from 1% to 80%, from 1% to 65%, from 5% to 65% or from 20% to 40%. As an example, the amount of fucose may be determined by calculating the average amount of fucose -32- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 within the sugar chain at Asn297, relative to the sum of all glycostructures attached to Asn297 (for example, complex, hybrid and high mannose structures) as measured by MALDI-TOF mass spectrometry, as described in WO 2008 / 077546. Asn297 refers to the asparagine residue located at about position 297 in the Fc region (EU numbering of Fc region residues); however, Asn297 may also be located about ± 3 amino acids upstream or downstream of position 297, that is, between positions 294 and 300, due to minor sequence variations in antibodies. Complementarity Determining Regions (CDRs) and Framework Regions (FRs)

[0086] Natural antibodies are composed of two identical heavy chains (HC) and two identical light chains (LC). Each heavy chain is comprised of a heavy chain variable region (VH) and a heavy chain constant region. Each light chain is composed of a light chain variable region (VL) and a light chain constant region. The variable regions of each of the heavy and light chains are regions of hypervariability responsible for antigen binding specificity and contain three hypervariable loops termed complementary determining regions (CDRs). The three CDRs (CDR1, CDR2, and CDR3) are separated by regions that are more conserved, called framework regions - sheet structure which display these loops on the surface of the variable domain. Each VH or VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxyl-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. The amino acid sequences of the CDRs and FRs can be determined using various well-known definitions in the art, e.g., Kabat, Chothia, international ImMunoGeneTics database (IMGT), and AbM (see, e.g., Chothia & Lesk, 1987, Canonical structures for the hypervariable regions of immunoglobulins. J. Mol. Biol. 196, 901-917; Chothia C. et al., 1989, Conformations of immunoglobulin hypervariable regions. Nature 342, 877-883; Chothia C. et al., 1992, structural repertoire of the human VH segments J. Mol. Biol. 227, 799-817; Al-Lazikani et al., J. Mol. Biol 1997, 273(4)). Reference to CDRs as determined by Kabat numbering are based, for example, on Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institute of Health, Bethesda, Md. (1991). Chothia CDRs are determined as defined by Chothia (see, e.g., Chothia and Lesk J. Mol. Biol.196:901-917 (1987)). Unless otherwise indicated, the sequences of the CDRs described herein are determined according to the IMGT definition. The CDRs of the antibodies or fragments thereof described herein may therefore vary depending on the definition used for identification and may contain 1, 2, or 3 substitutions, additions, and / or deletions relative to any of the exemplified sequences. In some embodiments, the sequence of any one of the CDRs provided -33- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 herein comprises 1, 2, or 3 substitutions, additions, and / or deletions. The FRs of the antibodies or fragments thereof described herein may therefore also vary depending on the definition used for identification of the CDRs and may contain 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 substitutions, additions, and / or deletions relative to any of the exemplified sequences. In some embodiments, the sequence of any one of the FRs provided herein comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 substitutions, additions, and / or deletions.

[0087] In any of the embodiments described herein, the anti-BILF-1 antibodies or antigen- binding fragments thereof may comprise one or more amino acid substitutions (e.g., conservative substitutions), insertions, and / or deletions in any of the exemplary amino acid sequences, including, for example, one or more (e.g., one, two, or three) substitutions, insertions, and / or deletions in any of the exemplary CDR sequences. The present technology especially contemplates anti-BILF-1 antibodies or antigen-binding fragments thereof having one or more (e.g., one, two, or three) substitutions, insertions, and / or deletions compared to a reference CDR sequence as described herein that still maintain a certain level of binding affinity to BILF-1. In certain embodiments, the anti-BILF-1 antibody or antigen-binding fragment thereof having one or more (e.g., one, two, or three) substitutions, insertions, and / or deletions compared to a reference CDR sequence as described herein would maintain at least 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the binding affinity exhibited by the anti-BILF-1 antibody or antigen-binding fragment thereof having the reference CDR sequence, when tested under same or similar conditions. For example, the anti-BILF-1 antibody or antigen-binding fragment thereof having one or more (e.g., one, two, or three) substitutions, insertions, and / or deletions compared to a reference CDR sequence as described herein would bind to BILF-1 (e.g., human BILF-1) with an affinity (KD) of about 1x10-11-1x10-6M, e.g., about 1x10-11-1x10-8M, about 1x10-11-1x10-9M, about 1x10-11-1x10-10M, about 1x10-10-1x10-7M, about 1x10-10-1x10-8M, about 1x10-10-1x10-9M, about 1x10-11-1x10-7M, about 1x10-9-1x10-7M, about 1x10-9-1x10-8M, or about 1x10-8-1x10-7M.

[0088] An “Fc region” refers to the constant region of an antibody excluding the first constant region immunoglobulin domain. Thus, Fc refers to the last two constant region immunoglobulin domains of IgA, IgD, and IgG, and the last three constant region immunoglobulin domains of IgE and IgM, and the flexible hinge N-terminal to these domains. For IgA and IgM Fc undaries of the Fc region may vary. For example, the human IgG heavy chain Fc region is usually defined to comprise residues -34- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 C226 or P230 to its carboxyl-terminus, using the numbering according to the EU index as in Kabat et al. (1991, NIH Publication 91-3242, National Technical Information Service, Springfield, Va.).

[0089] Exemplary amino acid sequences for the CDRs and FRs of the anti-BILF-1 antibodies or antigen binding fragments of the present disclosure are presented in Table 2, Table 3, Table 4, and Table 5. Different anti-BILF-1 antibody clones were divided into 5 groups based on heavy chain sequence similarity. Table 2: Group 1 anti-BILF1 antibodies framework regions (FRs) and complementarity determining regions (CDRs) amino acid sequences-35- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004Table 3: Group 2 anti-BILF1 antibodies FRs and CDRs amino acid sequences -36- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004-37- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004Table 4: Group 3 anti-BILF1 antibodies FRs and CDRs amino acid sequences-38- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004Table 5: Group 4 anti-BILF1 antibodies FRs and CDRs amino acid sequencesTable 6: Group 5 anti-BILF1 antibodies FRs and CDRs amino acid sequences-39- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004

[0090] In some embodiments, the antibody or fragment thereof described herein comprises a heavy chain (HC) CDR1 sequence of SEQ ID NO: 14, a HC CDR2 sequence of SEQ ID NO: 15, a HC CDR3 sequence of SEQ ID NO: 16, a light chain (LC) CDR1 sequence of SEQ ID NO: 17, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 19.

[0091] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 28, a HC CDR2 sequence of SEQ ID NO: 29, a HC CDR3 sequence of SEQ ID NO: 30, a LC CDR1 sequence of SEQ ID NO: 31, a LC CDR2 sequence of YAS, and a LC CDR3 sequence of SEQ ID NO: 33.

[0092] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 42, a HC CDR2 sequence of SEQ ID NO: 43, a HC CDR3 sequence of SEQ ID NO: 44, a LC CDR1 sequence of SEQ ID NO: 45, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 47.

[0093] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 56, a HC CDR2 sequence of SEQ ID NO: 57, a HC CDR3 sequence of SEQ ID NO: 58, a LC CDR1 sequence of SEQ ID NO: 59, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 61.

[0094] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 70, a HC CDR2 sequence of SEQ ID NO: 71, a HC CDR3 sequence of SEQ ID NO: 72, a LC CDR1 sequence of SEQ ID NO: 73, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 75. -40- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004

[0095] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 84, a HC CDR2 sequence of SEQ ID NO: 85, a HC CDR3 sequence of SEQ ID NO: 86, a LC CDR1 sequence of SEQ ID NO: 87, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 89.

[0096] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 98, a HC CDR2 sequence of SEQ ID NO: 99, a HC CDR3 sequence of SEQ ID NO: 100, a LC CDR1 sequence of SEQ ID NO: 101, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 103.

[0097] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 112, a HC CDR2 sequence of SEQ ID NO: 113, a HC CDR3 sequence of SEQ ID NO: 114, a LC CDR1 sequence of SEQ ID NO: 115, a LC CDR2 sequence of YAS, and a LC CDR3 sequence of SEQ ID NO: 117.

[0098] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 126, a HC CDR2 sequence of SEQ ID NO: 127, a HC CDR3 sequence of SEQ ID NO: 128, a LC CDR1 sequence of SEQ ID NO: 129, a LC CDR2 sequence of YAS, and a LC CDR3 sequence of SEQ ID NO: 131.

[0099] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 140, a HC CDR2 sequence of SEQ ID NO: 141, a HC CDR3 sequence of SEQ ID NO: 142, a LC CDR1 sequence of SEQ ID NO: 143, a LC CDR2 sequence of YAS, and a LC CDR3 sequence of SEQ ID NO: 145.

[0100] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 154, a HC CDR2 sequence of SEQ ID NO: 155, a HC CDR3 sequence of SEQ ID NO: 156, a LC CDR1 sequence of SEQ ID NO: 157, a LC CDR2 sequence of WAS, and a LC CDR3 sequence of SEQ ID NO: 159.

[0101] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 168, a HC CDR2 sequence of SEQ ID NO: 169, a HC CDR3 sequence of SEQ ID NO: 170, a LC CDR1 sequence of SEQ ID NO: 171, a LC CDR2 sequence of YAS, and a LC CDR3 sequence of SEQ ID NO: 173.

[0102] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 182, a HC CDR2 sequence of SEQ ID NO: 183, a HC CDR3 sequence of SEQ ID NO: 184, a LC CDR1 sequence of SEQ ID NO: 185, a LC CDR2 sequence of YAS, and a LC CDR3 sequence of SEQ ID NO: 187. -41- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004

[0103] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 196, a HC CDR2 sequence of SEQ ID NO: 197, a HC CDR3 sequence of SEQ ID NO: 198, a LC CDR1 sequence of SEQ ID NO: 199, a LC CDR2 sequence of AAS, and a LC CDR3 sequence of SEQ ID NO: 201.

[0104] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 210, a HC CDR2 sequence of SEQ ID NO: 211, a HC CDR3 sequence of SEQ ID NO: 212, a LC CDR1 sequence of SEQ ID NO: 213, a LC CDR2 sequence of GTN, and a LC CDR3 sequence of SEQ ID NO: 215.

[0105] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 224, a HC CDR2 sequence of SEQ ID NO: 225, a HC CDR3 sequence of SEQ ID NO: 226, a LC CDR1 sequence of SEQ ID NO: 227, a LC CDR2 sequence of GAS, and a LC CDR3 sequence of SEQ ID NO: 229.

[0106] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 14, a HC CDR2 sequence of SEQ ID NO: 15, a HC CDR3 sequence of SEQ ID NO: 16, a light chain (LC) CDR1 sequence of SEQ ID NO: 17, a LC CDR2 sequence of GTS, a LC CDR3 sequence of SEQ ID NO: 19, a HC framework region (FR) 1 sequence of SEQ ID NO: 6, a HC FR2 sequence of SEQ ID NO: 7, a HC FR3 sequence of SEQ ID NO: 8, a HC FR4 sequence of SEQ ID NO: 9, a LC FR1 sequence of SEQ ID NO: 10, a LC FR2 sequence of SEQ ID NO: 11, a LC FR3 sequence of SEQ ID NO: 12, and a LC FR4 sequence of SEQ ID NO: 13.

[0107] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 28, a HC CDR2 sequence of SEQ ID NO: 29, a HC CDR3 sequence of SEQ ID NO: 30, a LC CDR1 sequence of SEQ ID NO: 31, a LC CDR2 sequence of YAS, a LC CDR3 sequence of SEQ ID NO: 33, a HC FR1 sequence of SEQ ID NO: 20, a HC FR2 sequence of SEQ ID NO: 21, a HC FR3 sequence of SEQ ID NO: 22, a HC FR4 sequence of SEQ ID NO: 23, a LC FR1 sequence of SEQ ID NO: 24, a LC FR2 sequence of SEQ ID NO: 25, a LC FR3 sequence of SEQ ID NO: 26, and a LC FR4 sequence of SEQ ID NO: 27.

[0108] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 42, a HC CDR2 sequence of SEQ ID NO: 43, a HC CDR3 sequence of SEQ ID NO: 44, a LC CDR1 sequence of SEQ ID NO: 45, a LC CDR2 sequence of GTS, a LC CDR3 sequence of SEQ ID NO: 47, a HC FR1 sequence of SEQ ID NO: 34, a HC FR2 sequence of SEQ ID NO: 35, a HC FR3 sequence of SEQ ID NO: 36, a HC FR4 sequence of -42- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 SEQ ID NO: 37, a LC FR1 sequence of SEQ ID NO: 38, a LC FR2 sequence of SEQ ID NO: 39, a LC FR3 sequence of SEQ ID NO: 40, and a LC FR4 sequence of SEQ ID NO: 41.

[0109] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 56, a HC CDR2 sequence of SEQ ID NO: 57, a HC CDR3 sequence of SEQ ID NO: 58, a LC CDR1 sequence of SEQ ID NO: 59, a LC CDR2 sequence of GTS, a LC CDR3 sequence of SEQ ID NO: 61, a HC FR1 sequence of SEQ ID NO: 48, a HC FR2 sequence of SEQ ID NO: 49, a HC FR3 sequence of SEQ ID NO: 50, a HC FR4 sequence of SEQ ID NO: 51, a LC FR1 sequence of SEQ ID NO: 52, a LC FR2 sequence of SEQ ID NO: 53, a LC FR3 sequence of SEQ ID NO: 54, and a LC FR4 sequence of SEQ ID NO: 55.

[0110] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 70, a HC CDR2 sequence of SEQ ID NO: 71, a HC CDR3 sequence of SEQ ID NO: 72, a LC CDR1 sequence of SEQ ID NO: 73, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 75, a HC FR1 sequence of SEQ ID NO: 62, a HC FR2 sequence of SEQ ID NO: 63, a HC FR3 sequence of SEQ ID NO: 64, a HC FR4 sequence of SEQ ID NO: 65, a LC FR1 sequence of SEQ ID NO: 66, a LC FR2 sequence of SEQ ID NO: 67, a LC FR3 sequence of SEQ ID NO: 68, and a LC FR4 sequence of SEQ ID NO: 69.

[0111] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 84, a HC CDR2 sequence of SEQ ID NO: 85, a HC CDR3 sequence of SEQ ID NO: 86, a LC CDR1 sequence of SEQ ID NO: 87, a LC CDR2 sequence of GTS, a LC CDR3 sequence of SEQ ID NO: 89, a HC FR1 sequence of SEQ ID NO: 76, a HC FR2 sequence of SEQ ID NO: 77, a HC FR3 sequence of SEQ ID NO: 78, a HC FR4 sequence of SEQ ID NO: 79, a LC FR1 sequence of SEQ ID NO: 80, a LC FR2 sequence of SEQ ID NO: 81, a LC FR3 sequence of SEQ ID NO: 82, and a LC FR4 sequence of SEQ ID NO: 83.

[0112] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 98, a HC CDR2 sequence of SEQ ID NO: 99, a HC CDR3 sequence of SEQ ID NO: 100, a LC CDR1 sequence of SEQ ID NO: 101, a LC CDR2 sequence of GTS, a LC CDR3 sequence of SEQ ID NO: 103, a HC FR1 sequence of SEQ ID NO: 90, a HC FR2 sequence of SEQ ID NO: 91, a HC FR3 sequence of SEQ ID NO: 92, a HC FR4 sequence of SEQ ID NO: 93, a LC FR1 sequence of SEQ ID NO: 94, a LC FR2 sequence of SEQ ID NO: 95, a LC FR3 sequence of SEQ ID NO: 96, and a LC FR4 sequence of SEQ ID NO: 97.

[0113] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 112, a HC CDR2 sequence of SEQ ID NO: 113, a HC CDR3 sequence of SEQ ID NO: 114, a LC CDR1 sequence of SEQ ID NO: 115, a LC CDR2 -43- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 sequence of YAS, a LC CDR3 sequence of SEQ ID NO: 117, a HC FR1 sequence of SEQ ID NO: 104, a HC FR2 sequence of SEQ ID NO: 105, a HC FR3 sequence of SEQ ID NO: 106, a HC FR4 sequence of SEQ ID NO: 107, a LC FR1 sequence of SEQ ID NO: 108, a LC FR2 sequence of SEQ ID NO: 109, a LC FR3 sequence of SEQ ID NO: 110, and a LC FR4 sequence of SEQ ID NO: 111.

[0114] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 126, a HC CDR2 sequence of SEQ ID NO: 127, a HC CDR3 sequence of SEQ ID NO: 128, a LC CDR1 sequence of SEQ ID NO: 129, a LC CDR2 sequence of YAS, a LC CDR3 sequence of SEQ ID NO: 131, a HC FR1 sequence of SEQ ID NO: 118, a HC FR2 sequence of SEQ ID NO: 119, a HC FR3 sequence of SEQ ID NO: 120, a HC FR4 sequence of SEQ ID NO: 121, a LC FR1 sequence of SEQ ID NO: 122, a LC FR2 sequence of SEQ ID NO: 123, a LC FR3 sequence of SEQ ID NO: 124, and a LC FR4 sequence of SEQ ID NO: 125.

[0115] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 140, a HC CDR2 sequence of SEQ ID NO: 141, a HC CDR3 sequence of SEQ ID NO: 142, a LC CDR1 sequence of SEQ ID NO: 143, a LC CDR2 sequence of YAS, a LC CDR3 sequence of SEQ ID NO: 145, a HC FR1 sequence of SEQ ID NO: 132, a HC FR2 sequence of SEQ ID NO: 133, a HC FR3 sequence of SEQ ID NO: 134, a HC FR4 sequence of SEQ ID NO: 135, a LC FR1 sequence of SEQ ID NO: 136, a LC FR2 sequence of SEQ ID NO: 137, a LC FR3 sequence of SEQ ID NO: 138, and a LC FR4 sequence of SEQ ID NO: 139.

[0116] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 154, a HC CDR2 sequence of SEQ ID NO: 155, a HC CDR3 sequence of SEQ ID NO: 156, a LC CDR1 sequence of SEQ ID NO: 157, a LC CDR2 sequence of WAS, a LC CDR3 sequence of SEQ ID NO: 159, a HC FR1 sequence of SEQ ID NO: 146, a HC FR2 sequence of SEQ ID NO: 147, a HC FR3 sequence of SEQ ID NO: 148, a HC FR4 sequence of SEQ ID NO: 149, a LC FR1 sequence of SEQ ID NO: 150, a LC FR2 sequence of SEQ ID NO: 151, a LC FR3 sequence of SEQ ID NO: 152, and a LC FR4 sequence of SEQ ID NO: 153.

[0117] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 168, a HC CDR2 sequence of SEQ ID NO: 169, a HC CDR3 sequence of SEQ ID NO: 170, a LC CDR1 sequence of SEQ ID NO: 171, a LC CDR2 sequence of YAS, a LC CDR3 sequence of SEQ ID NO: 173, a HC FR1 sequence of SEQ ID NO: -44- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 160, a HC FR2 sequence of SEQ ID NO: 161, a HC FR3 sequence of SEQ ID NO: 162, a HC FR4 sequence of SEQ ID NO: 163, a LC FR1 sequence of SEQ ID NO: 164, a LC FR2 sequence of SEQ ID NO: 165, a LC FR3 sequence of SEQ ID NO: 166, and a LC FR4 sequence of SEQ ID NO: 167.

[0118] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 182, a HC CDR2 sequence of SEQ ID NO: 183, a HC CDR3 sequence of SEQ ID NO: 184, a LC CDR1 sequence of SEQ ID NO: 185, a LC CDR2 sequence of YAS, a LC CDR3 sequence of SEQ ID NO: 187, a HC FR1 sequence of SEQ ID NO: 174, a HC FR2 sequence of SEQ ID NO: 175, a HC FR3 sequence of SEQ ID NO: 176, a HC FR4 sequence of SEQ ID NO: 177, a LC FR1 sequence of SEQ ID NO: 178, a LC FR2 sequence of SEQ ID NO: 179, a LC FR3 sequence of SEQ ID NO: 180, and a LC FR4 sequence of SEQ ID NO: 181.

[0119] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 196, a HC CDR2 sequence of SEQ ID NO: 197, a HC CDR3 sequence of SEQ ID NO: 198, a LC CDR1 sequence of SEQ ID NO: 199, a LC CDR2 sequence of AAS, a LC CDR3 sequence of SEQ ID NO: 201, a HC FR1 sequence of SEQ ID NO: 188, a HC FR2 sequence of SEQ ID NO: 189, a HC FR3 sequence of SEQ ID NO: 190, a HC FR4 sequence of SEQ ID NO: 191, a LC FR1 sequence of SEQ ID NO: 192, a LC FR2 sequence of SEQ ID NO: 193, a LC FR3 sequence of SEQ ID NO: 194, and a LC FR4 sequence of SEQ ID NO: 195.

[0120] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 210, a HC CDR2 sequence of SEQ ID NO: 211, a HC CDR3 sequence of SEQ ID NO: 212, a LC CDR1 sequence of SEQ ID NO: 213, a LC CDR2 sequence of GTN, a LC CDR3 sequence of SEQ ID NO: 215, a HC FR1 sequence of SEQ ID NO: 202, a HC FR2 sequence of SEQ ID NO: 203, a HC FR3 sequence of SEQ ID NO: 204, a HC FR4 sequence of SEQ ID NO: 205, a LC FR1 sequence of SEQ ID NO: 206, a LC FR2 sequence of SEQ ID NO: 207, a LC FR3 sequence of SEQ ID NO: 208, and a LC FR4 sequence of SEQ ID NO: 209.

[0121] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 224, a HC CDR2 sequence of SEQ ID NO: 225, a HC CDR3 sequence of SEQ ID NO: 226, a LC CDR1 sequence of SEQ ID NO: 227, a LC CDR2 sequence of GAS, a LC CDR3 sequence of SEQ ID NO: 229, a HC FR1 sequence of SEQ ID NO: 216, a HC FR2 sequence of SEQ ID NO: 217, a HC FR3 sequence of SEQ ID NO: 218, a HC FR4 -45- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 sequence of SEQ ID NO: 219, a LC FR1 sequence of SEQ ID NO: 220, a LC FR2 sequence of SEQ ID NO: 221, a LC FR3 sequence of SEQ ID NO: 222, and a LC FR4 sequence of SEQ ID NO: 223. Antibody variants

[0122] Antibody variants with superior features can be generated by introducing specific mutations into an antibody’s sequence. Non-limiting examples of superior features that can by introduced by specific mutations include enhanced stability, increased specificity, reduced glycosylation, decreased degradation, and increased shelf-life. In some embodiments of the anti- BILF-1 antibody or fragment thereof of the present disclosure, the variable domain in either the heavy or light chain or both is altered by at least one amino acid replacement. In some embodiments, amino acid replacement of CDR and framework residues by either a targeted or random mutagenesis approach may result in antibodies with enhanced binding, potency or specificity characteristics. In some embodiments, amino acid replacement of framework residues reduces potential immunogenicity by changing the framework residue to germline. In some embodiments, amino acid replacement of either framework or CDR residues may remove potential structural liabilities that may result in instability, aggregation, or heterogeneity of the antibody or fragment thereof described herein. Non-limiting examples of undesirable liabilities include unpaired cysteines (which may lead to disulfide bond scrambling, or variable sulfhydryl adduct formation), N-linked glycosylation sites (resulting in heterogeneity of structure and activity), as well as deamidation (e.g. NG, NS), isomerization (DG), oxidation (exposed methionine), and hydrolysis (DP) sites. In some embodiments, the amino acid sequence of the anti-BILF-1 antibody or fragment thereof of the present disclosure comprises one or more mutations. In some embodiments, the one or more mutations is in the light chain. In some embodiments, the one or more mutations comprises an amino acid substitution. In some embodiments, the one or more mutations comprise a mutation of an amino acid selected from asparagine, cysteine, and leucine. In some embodiments, the one or more mutations are selected from the group consisting of asparagine to histidine, cysteine to alanine, asparagine to arginine, leucine to isoleucine, cysteine to valine, asparagine to serine, and asparagine to alanine. In some embodiments, an unpaired cysteine residue in the amino acid sequence is eliminated by the one or more mutations. In some embodiments, the one or more mutations improve the binding affinity, stability, and / or the pharmacokinetics of the antibody or fragment thereof described herein. In some embodiments, the one or more mutations improve the binding affinity of the antibody or fragment thereof. In some -46- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 embodiments, the one or more mutations improve the stability of the antibody or fragment thereof. Table 7 and Table 8 provide exemplary sequences of antibody variants of anti-BILF-1 antibody clone AXM1 as described in Table 2.

[0123] Table 7 provides exemplary light chain amino acid sequences for the CDRs and FRs of anti-BILF-1 antibodies that are variants of the anti-BILF-1 antibody clone AXM1 described in Table 2. Any one of the sets of three LC CDRs (CDR1, CDR2, and CDR3) and / or four LC FRs (FR1, FR2, FR3, and FR4) described in Table 7 may be used with any one of the sets of three HC CDRs (CDR1, CDR2, and CDR3) and / or four LC FRs (FR1, FR2, FR3, and FR4) of the present disclosure (e.g. as described in Table 2, Table 3, Table 4, Table 5, Table 6, and Table 8). Table 7: Amino acid sequences of AXM1 antibody variants with light chain mutations-47- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004

[0124] Table 8 provides exemplary heavy chain amino acid sequences for the CDRs and FRs of anti-BILF-1 antibodies that are variants of the anti-BILF-1 antibody clone AXM1 described in Table 2. Any one of the sets of three HC CDRs (CDR1, CDR2, and CDR3) and / or four HC FRs (FR1, FR2, FR3, and FR4) described in Table 8 may be used with any one of the sets of three LC CDRs and / or four LC FRs of the present disclosure (e.g. as described in Table 2, Table 3, Table 4, Table 5, Table 6, and Table 7). Table 8: Amino acid sequences of AXM1 antibody variants with heavy chain mutations-48- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004

[0125] Any one of the sets of three HC CDRs and / or four HC FRs of the present disclosure (e.g., as described in Table 2, Table 3, Table 4, Table 5, Table 6, and Table 8) may be used with any one of the sets of three LC CDRs and / or four LC FRs of the present disclosure (e.g. as described in Table 2, Table 3, Table 4, Table 5, Table 6, and Table 7).

[0126] In some embodiments, the antibody or fragment thereof described herein comprises: a. a HC CDR1 sequence of SEQ ID NO: 14, a HC CDR2 sequence of SEQ ID NO: 15, a HC CDR3 sequence of SEQ ID NO: 16; a HC CDR1 sequence of SEQ ID NO: 28, a HC CDR2 sequence of SEQ ID NO: 29, a HC CDR3 sequence of SEQ ID NO: 30; a HC CDR1 sequence of SEQ ID NO: 42, a HC CDR2 sequence of SEQ ID NO: 43, a HC CDR3 sequence of SEQ ID NO: 44; a HC CDR1 sequence of SEQ ID NO: 56, a HC CDR2 sequence of SEQ ID NO: 57, a HC CDR3 sequence of SEQ ID NO: 58; a HC CDR1 sequence of SEQ ID NO: 70, a HC CDR2 sequence of SEQ ID NO: 71, a HC CDR3 sequence of SEQ ID NO: 72; a HC CDR1 sequence of SEQ ID NO: 84, a HC CDR2 sequence of SEQ ID NO: 85, a HC CDR3 sequence of SEQ ID NO: 86; a HC CDR1 sequence of SEQ ID NO: 98, a HC CDR2 sequence of SEQ ID NO: 99, a HC CDR3 sequence of SEQ ID NO: 100; a HC CDR1 sequence of SEQ ID NO: 112, a HC CDR2 sequence of SEQ ID NO: 113, a HC CDR3 sequence of SEQ ID NO: 114; a HC CDR1 sequence of SEQ ID NO: 126, a HC CDR2 sequence of SEQ ID NO: 127, a HC CDR3 sequence of SEQ ID NO: 128; a HC CDR1 sequence of SEQ ID NO: 140, a HC CDR2 sequence of SEQ ID NO: 141, a HC CDR3 sequence of SEQ ID NO: 142; a HC CDR1 sequence of SEQ ID NO: 154, a HC CDR2 sequence of SEQ ID NO: 155, a HC CDR3 sequence of SEQ ID NO: 156; a HC CDR1 sequence of SEQ ID NO: 168, a HC CDR2 sequence of SEQ ID NO: 169, a HC CDR3 sequence of SEQ ID NO: 170; -49- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 a HC CDR1 sequence of SEQ ID NO: 182, a HC CDR2 sequence of SEQ ID NO: 183, a HC CDR3 sequence of SEQ ID NO: 184; a HC CDR1 sequence of SEQ ID NO: 196, a HC CDR2 sequence of SEQ ID NO: 197, a HC CDR3 sequence of SEQ ID NO: 198; a HC CDR1 sequence of SEQ ID NO: 210, a HC CDR2 sequence of SEQ ID NO: 211, a HC CDR3 sequence of SEQ ID NO: 212; a HC CDR1 sequence of SEQ ID NO: 224, a HC CDR2 sequence of SEQ ID NO: 225, a HC CDR3 sequence of SEQ ID NO: 226; a HC CDR1 sequence of SEQ ID NO: 290, a HC CDR2 sequence of SEQ ID NO: 291, a HC CDR3 sequence of SEQ ID NO: 292; a HC CDR1 sequence of SEQ ID NO: 297, a HC CDR2 sequence of SEQ ID NO: 298, a HC CDR3 sequence of SEQ ID NO: 299; a HC CDR1 sequence of SEQ ID NO: 304, a HC CDR2 sequence of SEQ ID NO: 305, a HC CDR3 sequence of SEQ ID NO: 306; or a HC CDR1 sequence of SEQ ID NO: 311, a HC CDR2 sequence of SEQ ID NO: 312, a HC CDR3 sequence of SEQ ID NO: 313; and b. a LC CDR1 sequence of SEQ ID NO: 17, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 19; a LC CDR1 sequence of SEQ ID NO: 31, a LC CDR2 sequence of YAS, and a LC CDR3 sequence of SEQ ID NO: 33; a LC CDR1 sequence of SEQ ID NO: 45, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 47; a LC CDR1 sequence of SEQ ID NO: 59, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 61; a LC CDR1 sequence of SEQ ID NO: 73, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 75; a LC CDR1 sequence of SEQ ID NO: 87, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 89; a LC CDR1 sequence of SEQ ID NO: 101, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 103; a LC CDR1 sequence of SEQ ID NO: 115, a LC CDR2 sequence of YAS, and a LC CDR3 sequence of SEQ ID NO: 117; -50- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 a LC CDR1 sequence of SEQ ID NO: 129, a LC CDR2 sequence of YAS, and a LC CDR3 sequence of SEQ ID NO: 131; a LC CDR1 sequence of SEQ ID NO: 143, a LC CDR2 sequence of YAS, and a LC CDR3 sequence of SEQ ID NO: 145; a LC CDR1 sequence of SEQ ID NO: 157, a LC CDR2 sequence of WAS, and a LC CDR3 sequence of SEQ ID NO: 159; a LC CDR1 sequence of SEQ ID NO: 171, a LC CDR2 sequence of YAS, and a LC CDR3 sequence of SEQ ID NO: 173; a LC CDR1 sequence of SEQ ID NO: 185, a LC CDR2 sequence of YAS, and a LC CDR3 sequence of SEQ ID NO: 187; a LC CDR1 sequence of SEQ ID NO: 199, a LC CDR2 sequence of AAS, and a LC CDR3 sequence of SEQ ID NO: 201; a LC CDR1 sequence of SEQ ID NO: 213, a LC CDR2 sequence of GTN, and a LC CDR3 sequence of SEQ ID NO: 215; a LC CDR1 sequence of SEQ ID NO: 227, a LC CDR2 sequence of GAS, and a LC CDR3 sequence of SEQ ID NO: 229; a LC CDR1 sequence of SEQ ID NO: 234, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 236; a LC CDR1 sequence of SEQ ID NO: 241, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 243; a LC CDR1 sequence of SEQ ID NO: 248, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 250; a LC CDR1 sequence of SEQ ID NO: 255, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 257; a LC CDR1 sequence of SEQ ID NO: 262, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 264; a LC CDR1 sequence of SEQ ID NO: 269, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 271; a LC CDR1 sequence of SEQ ID NO: 276, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 278; or a LC CDR1 sequence of SEQ ID NO: 283, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 285. -51- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004

[0127] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 14, a HC CDR2 sequence of SEQ ID NO: 15, a HC CDR3 sequence of SEQ ID NO: 16, a LC CDR1 sequence of SEQ ID NO: 234, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 236.

[0128] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 14, a HC CDR2 sequence of SEQ ID NO: 15, a HC CDR3 sequence of SEQ ID NO: 16, a LC CDR1 sequence of SEQ ID NO: 241, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 243.

[0129] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 14, a HC CDR2 sequence of SEQ ID NO: 15, a HC CDR3 sequence of SEQ ID NO: 16, a LC CDR1 sequence of SEQ ID NO: 248, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 250.

[0130] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 14, a HC CDR2 sequence of SEQ ID NO: 15, a HC CDR3 sequence of SEQ ID NO: 16, a LC CDR1 sequence of SEQ ID NO: 255, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 257.

[0131] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 14, a HC CDR2 sequence of SEQ ID NO: 15, a HC CDR3 sequence of SEQ ID NO: 16, a LC CDR1 sequence of SEQ ID NO: 262, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 264.

[0132] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 14, a HC CDR2 sequence of SEQ ID NO: 15, a HC CDR3 sequence of SEQ ID NO: 16, a LC CDR1 sequence of SEQ ID NO: 269, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 271.

[0133] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 14, a HC CDR2 sequence of SEQ ID NO: 15, a HC CDR3 sequence of SEQ ID NO: 16, a LC CDR1 sequence of SEQ ID NO: 276, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 278.

[0134] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 14, a HC CDR2 sequence of SEQ ID NO: 15, a HC CDR3 sequence of SEQ ID NO: 16, a LC CDR1 sequence of SEQ ID NO: 283, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 285. -52- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004

[0135] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 290, a HC CDR2 sequence of SEQ ID NO: 291, a HC CDR3 sequence of SEQ ID NO: 292, a LC CDR1 sequence of SEQ ID NO: 234, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 236.

[0136] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 290, a HC CDR2 sequence of SEQ ID NO: 291, a HC CDR3 sequence of SEQ ID NO: 292, a LC CDR1 sequence of SEQ ID NO: 241, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 243.

[0137] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 290, a HC CDR2 sequence of SEQ ID NO: 291, a HC CDR3 sequence of SEQ ID NO: 292, a LC CDR1 sequence of SEQ ID NO: 248, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 250.

[0138] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 290, a HC CDR2 sequence of SEQ ID NO: 291, a HC CDR3 sequence of SEQ ID NO: 292, a LC CDR1 sequence of SEQ ID NO: 255, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 257.

[0139] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 290, a HC CDR2 sequence of SEQ ID NO: 291, a HC CDR3 sequence of SEQ ID NO: 292, a LC CDR1 sequence of SEQ ID NO: 262, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 264.

[0140] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 290, a HC CDR2 sequence of SEQ ID NO: 291, a HC CDR3 sequence of SEQ ID NO: 292, a LC CDR1 sequence of SEQ ID NO: 269, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 271.

[0141] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 290, a HC CDR2 sequence of SEQ ID NO: 291, a HC CDR3 sequence of SEQ ID NO: 292, a LC CDR1 sequence of SEQ ID NO: 276, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 278.

[0142] In some embodiments, the antibody or fragment thereof described herein a HC CDR1 sequence of SEQ ID NO: 290, a HC CDR2 sequence of SEQ ID NO: 291, a HC CDR3 sequence of SEQ ID NO: 292, a LC CDR1 sequence of SEQ ID NO: 283, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 285. -53- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004

[0143] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 297, a HC CDR2 sequence of SEQ ID NO: 298, a HC CDR3 sequence of SEQ ID NO: 299, a LC CDR1 sequence of SEQ ID NO: 234, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 236.

[0144] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 297, a HC CDR2 sequence of SEQ ID NO: 298, a HC CDR3 sequence of SEQ ID NO: 299, a LC CDR1 sequence of SEQ ID NO: 241, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 243.

[0145] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 297, a HC CDR2 sequence of SEQ ID NO: 298, a HC CDR3 sequence of SEQ ID NO: 299, a LC CDR1 sequence of SEQ ID NO: 248, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 250.

[0146] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 297, a HC CDR2 sequence of SEQ ID NO: 298, a HC CDR3 sequence of SEQ ID NO: 299, a LC CDR1 sequence of SEQ ID NO: 255, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 257.

[0147] In some embodiments, the antibody or fragment thereof described herein a HC CDR1 sequence of SEQ ID NO: 297, a HC CDR2 sequence of SEQ ID NO: 298, a HC CDR3 sequence of SEQ ID NO: 299, a LC CDR1 sequence of SEQ ID NO: 262, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 264.

[0148] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 297, a HC CDR2 sequence of SEQ ID NO: 298, a HC CDR3 sequence of SEQ ID NO: 299, a LC CDR1 sequence of SEQ ID NO: 269, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 271.

[0149] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 297, a HC CDR2 sequence of SEQ ID NO: 298, a HC CDR3 sequence of SEQ ID NO: 299, a LC CDR1 sequence of SEQ ID NO: 276, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 278.

[0150] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 297, a HC CDR2 sequence of SEQ ID NO: 298, a HC CDR3 sequence of SEQ ID NO: 299, a LC CDR1 sequence of SEQ ID NO: 283, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 285. -54- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004

[0151] In some embodiments, the antibody or fragment thereof described herein a HC CDR1 sequence of SEQ ID NO: 304, a HC CDR2 sequence of SEQ ID NO: 305, a HC CDR3 sequence of SEQ ID NO: 306, a LC CDR1 sequence of SEQ ID NO: 234, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 236.

[0152] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 304, a HC CDR2 sequence of SEQ ID NO: 305, a HC CDR3 sequence of SEQ ID NO: 306, a LC CDR1 sequence of SEQ ID NO: 241, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 243.

[0153] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 304, a HC CDR2 sequence of SEQ ID NO: 305, a HC CDR3 sequence of SEQ ID NO: 306, a LC CDR1 sequence of SEQ ID NO: 248, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 250.

[0154] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 304, a HC CDR2 sequence of SEQ ID NO: 305, a HC CDR3 sequence of SEQ ID NO: 306, a LC CDR1 sequence of SEQ ID NO: 255, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 257.

[0155] In some embodiments, the antibody or fragment thereof described herein a HC CDR1 sequence of SEQ ID NO: 304, a HC CDR2 sequence of SEQ ID NO: 305, a HC CDR3 sequence of SEQ ID NO: 306, a LC CDR1 sequence of SEQ ID NO: 262, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 264.

[0156] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 304, a HC CDR2 sequence of SEQ ID NO: 305, a HC CDR3 sequence of SEQ ID NO: 306, a LC CDR1 sequence of SEQ ID NO: 269, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 271.

[0157] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 304, a HC CDR2 sequence of SEQ ID NO: 305, a HC CDR3 sequence of SEQ ID NO: 306, a LC CDR1 sequence of SEQ ID NO: 276, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 278.

[0158] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 304, a HC CDR2 sequence of SEQ ID NO: 305, a HC CDR3 sequence of SEQ ID NO: 306, a LC CDR1 sequence of SEQ ID NO: 283, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 285. -55- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004

[0159] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 311, a HC CDR2 sequence of SEQ ID NO: 312, a HC CDR3 sequence of SEQ ID NO: 313, a LC CDR1 sequence of SEQ ID NO: 234, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 236.

[0160] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 311, a HC CDR2 sequence of SEQ ID NO: 312, a HC CDR3 sequence of SEQ ID NO: 313, a LC CDR1 sequence of SEQ ID NO: 241, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 243.

[0161] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 311, a HC CDR2 sequence of SEQ ID NO: 312, a HC CDR3 sequence of SEQ ID NO: 313, a LC CDR1 sequence of SEQ ID NO: 248, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 250.

[0162] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 311, a HC CDR2 sequence of SEQ ID NO: 312, a HC CDR3 sequence of SEQ ID NO: 313, a LC CDR1 sequence of SEQ ID NO: 255, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 257.

[0163] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 311, a HC CDR2 sequence of SEQ ID NO: 312, a HC CDR3 sequence of SEQ ID NO: 313, a LC CDR1 sequence of SEQ ID NO: 262, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 264.

[0164] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 311, a HC CDR2 sequence of SEQ ID NO: 312, a HC CDR3 sequence of SEQ ID NO: 313, a LC CDR1 sequence of SEQ ID NO: 269, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 271.

[0165] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 311, a HC CDR2 sequence of SEQ ID NO: 312, a HC CDR3 sequence of SEQ ID NO: 313, a LC CDR1 sequence of SEQ ID NO: 276, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 278.

[0166] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 311, a HC CDR2 sequence of SEQ ID NO: 312, a HC CDR3 sequence of SEQ ID NO: 313, a LC CDR1 sequence of SEQ ID NO: 283, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 285.

[0167] In some embodiments, the antibody or fragment thereof described herein comprises: -56- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 a. a HC CDR1 sequence of SEQ ID NO: 14, a HC CDR2 sequence of SEQ ID NO: 15, a HC CDR3 sequence of SEQ ID NO: 16, a HC FR1 sequence of SEQ ID NO: 6, a HC FR2 sequence of SEQ ID NO: 7, a HC FR3 sequence of SEQ ID NO: 8, a HC FR4 sequence of SEQ ID NO: 9; a HC CDR1 sequence of SEQ ID NO: 290, a HC CDR2 sequence of SEQ ID NO: 291, a HC CDR3 sequence of SEQ ID NO: 292, a HC FR1 sequence of SEQ ID NO: 286, a HC FR2 sequence of SEQ ID NO: 287, a HC FR3 sequence of SEQ ID NO: 288, a HC FR4 sequence of SEQ ID NO: 289; a HC CDR1 sequence of SEQ ID NO: 297, a HC CDR2 sequence of SEQ ID NO: 298, a HC CDR3 sequence of SEQ ID NO: 299, a HC FR1 sequence of SEQ ID NO: 293, a HC FR2 sequence of SEQ ID NO: 294, a HC FR3 sequence of SEQ ID NO: 295, a HC FR4 sequence of SEQ ID NO: 296; a HC CDR1 sequence of SEQ ID NO: 304, a HC CDR2 sequence of SEQ ID NO: 305, a HC CDR3 sequence of SEQ ID NO: 306, a HC FR1 sequence of SEQ ID NO: 300, a HC FR2 sequence of SEQ ID NO: 301, a HC FR3 sequence of SEQ ID NO: 302, a HC FR4 sequence of SEQ ID NO: 303; or a HC CDR1 sequence of SEQ ID NO: 311, a HC CDR2 sequence of SEQ ID NO: 312, a HC CDR3 sequence of SEQ ID NO: 313, a HC FR1 sequence of SEQ ID NO: 307, a HC FR2 sequence of SEQ ID NO: 308, a HC FR3 sequence of SEQ ID NO: 309, a HC FR4 sequence of SEQ ID NO: 310; and b. a LC CDR1 sequence of SEQ ID NO: 234, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 236, a LC FR1 sequence of SEQ ID NO: 230, a LC FR2 sequence of SEQ ID NO: 231, a LC FR3 sequence of SEQ ID NO: 232, and a LC FR4 sequence of SEQ ID NO: 233; a LC CDR1 sequence of SEQ ID NO: 241, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 243, a LC FR1 sequence of SEQ ID NO: 237, a LC FR2 sequence of SEQ ID NO: 238, a LC FR3 sequence of SEQ ID NO: 239, and a LC FR4 sequence of SEQ ID NO: 240; a LC CDR1 sequence of SEQ ID NO: 248, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 250, a LC FR1 sequence of SEQ ID NO: 244, a LC FR2 sequence of SEQ ID NO: 245, a LC FR3 sequence of SEQ ID NO: 246, and a LC FR4 sequence of SEQ ID NO: 247; -57- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 a LC CDR1 sequence of SEQ ID NO: 255, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 257, a LC FR1 sequence of SEQ ID NO: 251, a LC FR2 sequence of SEQ ID NO: 252, a LC FR3 sequence of SEQ ID NO: 253, and a LC FR4 sequence of SEQ ID NO: 254; a LC CDR1 sequence of SEQ ID NO: 262, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 264, a LC FR1 sequence of SEQ ID NO: 258, a LC FR2 sequence of SEQ ID NO: 259, a LC FR3 sequence of SEQ ID NO: 260, and a LC FR4 sequence of SEQ ID NO: 261; a LC CDR1 sequence of SEQ ID NO: 269, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 271, a LC FR1 sequence of SEQ ID NO: 265, a LC FR2 sequence of SEQ ID NO: 266, a LC FR3 sequence of SEQ ID NO: 267, and a LC FR4 sequence of SEQ ID NO: 268; a LC CDR1 sequence of SEQ ID NO: 276, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 278, a LC FR1 sequence of SEQ ID NO: 272, a LC FR2 sequence of SEQ ID NO: 273, a LC FR3 sequence of SEQ ID NO: 274, and a LC FR4 sequence of SEQ ID NO: 275; or a LC CDR1 sequence of SEQ ID NO: 283, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 285, a LC FR1 sequence of SEQ ID NO: 279, a LC FR2 sequence of SEQ ID NO: 280, a LC FR3 sequence of SEQ ID NO: 281, and a LC FR4 sequence of SEQ ID NO: 282.

[0168] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 14, a HC CDR2 sequence of SEQ ID NO: 15, a HC CDR3 sequence of SEQ ID NO: 16, a LC CDR1 sequence of SEQ ID NO: 234, a LC CDR2 sequence of GTS, a LC CDR3 sequence of SEQ ID NO: 236, a HC FR1 sequence of SEQ ID NO: 6, a HC FR2 sequence of SEQ ID NO: 7, a HC FR3 sequence of SEQ ID NO: 8, a HC FR4 sequence of SEQ ID NO: 9, a LC FR1 sequence of SEQ ID NO: 230, a LC FR2 sequence of SEQ ID NO: 231, a LC FR3 sequence of SEQ ID NO: 232, and a LC FR4 sequence of SEQ ID NO: 233.

[0169] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 14, a HC CDR2 sequence of SEQ ID NO: 15, a HC CDR3 sequence of SEQ ID NO: 16, a LC CDR1 sequence of SEQ ID NO: 241, a LC CDR2 sequence of GTS, a LC CDR3 sequence of SEQ ID NO: 243, a HC FR1 sequence of SEQ ID NO: 6, a HC FR2 sequence of SEQ ID NO: 7, a HC FR3 sequence of SEQ ID NO: 8, a HC FR4 sequence of -58- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 SEQ ID NO: 9, a LC FR1 sequence of SEQ ID NO: 237, a LC FR2 sequence of SEQ ID NO: 238, a LC FR3 sequence of SEQ ID NO: 239, and a LC FR4 sequence of SEQ ID NO: 240.

[0170] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 14, a HC CDR2 sequence of SEQ ID NO: 15, a HC CDR3 sequence of SEQ ID NO: 16, a LC CDR1 sequence of SEQ ID NO: 248, a LC CDR2 sequence of GTS, a LC CDR3 sequence of SEQ ID NO: 250, a HC FR1 sequence of SEQ ID NO: 6, a HC FR2 sequence of SEQ ID NO: 7, a HC FR3 sequence of SEQ ID NO: 8, a HC FR4 sequence of SEQ ID NO: 9, a LC FR1 sequence of SEQ ID NO: 244, a LC FR2 sequence of SEQ ID NO: 245, a LC FR3 sequence of SEQ ID NO: 246, and a LC FR4 sequence of SEQ ID NO: 247.

[0171] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 14, a HC CDR2 sequence of SEQ ID NO: 15, a HC CDR3 sequence of SEQ ID NO: 16, a LC CDR1 sequence of SEQ ID NO: 255, a LC CDR2 sequence of GTS, a LC CDR3 sequence of SEQ ID NO: 257, a HC FR1 sequence of SEQ ID NO: 6, a HC FR2 sequence of SEQ ID NO: 7, a HC FR3 sequence of SEQ ID NO: 8, a HC FR4 sequence of SEQ ID NO: 9, a LC FR1 sequence of SEQ ID NO: 251, a LC FR2 sequence of SEQ ID NO: 252, a LC FR3 sequence of SEQ ID NO: 253, and a LC FR4 sequence of SEQ ID NO: 254.

[0172] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 14, a HC CDR2 sequence of SEQ ID NO: 15, a HC CDR3 sequence of SEQ ID NO: 16, a LC CDR1 sequence of SEQ ID NO: 262, a LC CDR2 sequence of GTS, a LC CDR3 sequence of SEQ ID NO: 264, a HC FR1 sequence of SEQ ID NO: 6, a HC FR2 sequence of SEQ ID NO: 7, a HC FR3 sequence of SEQ ID NO: 8, a HC FR4 sequence of SEQ ID NO: 9, a LC FR1 sequence of SEQ ID NO: 258, a LC FR2 sequence of SEQ ID NO: 259, a LC FR3 sequence of SEQ ID NO: 260, and a LC FR4 sequence of SEQ ID NO: 261.

[0173] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 14, a HC CDR2 sequence of SEQ ID NO: 15, a HC CDR3 sequence of SEQ ID NO: 16, a LC CDR1 sequence of SEQ ID NO: 269, a LC CDR2 sequence of GTS, a LC CDR3 sequence of SEQ ID NO: 271, a HC FR1 sequence of SEQ ID NO: 6, a HC FR2 sequence of SEQ ID NO: 7, a HC FR3 sequence of SEQ ID NO: 8, a HC FR4 sequence of SEQ ID NO: 9, a LC FR1 sequence of SEQ ID NO: 265, a LC FR2 sequence of SEQ ID NO: 266, a LC FR3 sequence of SEQ ID NO: 267, and a LC FR4 sequence of SEQ ID NO: 268.

[0174] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 14, a HC CDR2 sequence of SEQ ID NO: 15, a HC CDR3 sequence of SEQ ID NO: 16, a LC CDR1 sequence of SEQ ID NO: 276, a LC CDR2 sequence of -59- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 GTS, and a LC CDR3 sequence of SEQ ID NO: 278, a HC FR1 sequence of SEQ ID NO: 6, a HC FR2 sequence of SEQ ID NO: 7, a HC FR3 sequence of SEQ ID NO: 8, a HC FR4 sequence of SEQ ID NO: 9, a LC FR1 sequence of SEQ ID NO: 272, a LC FR2 sequence of SEQ ID NO: 273, a LC FR3 sequence of SEQ ID NO: 274, and a LC FR4 sequence of SEQ ID NO: 275.

[0175] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 14, a HC CDR2 sequence of SEQ ID NO: 15, a HC CDR3 sequence of SEQ ID NO: 16, a LC CDR1 sequence of SEQ ID NO: 283, a LC CDR2 sequence of GTS, a LC CDR3 sequence of SEQ ID NO: 285, a HC FR1 sequence of SEQ ID NO: 6, a HC FR2 sequence of SEQ ID NO: 7, a HC FR3 sequence of SEQ ID NO: 8, a HC FR4 sequence of SEQ ID NO: 9, a LC FR1 sequence of SEQ ID NO: 279, a LC FR2 sequence of SEQ ID NO: 280, a LC FR3 sequence of SEQ ID NO: 281, and a LC FR4 sequence of SEQ ID NO: 282.

[0176] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 290, a HC CDR2 sequence of SEQ ID NO: 291, a HC CDR3 sequence of SEQ ID NO: 292, a LC CDR1 sequence of SEQ ID NO: 234, a LC CDR2 sequence of GTS, a LC CDR3 sequence of SEQ ID NO: 236, a HC FR1 sequence of SEQ ID NO: 286, a HC FR2 sequence of SEQ ID NO: 287, a HC FR3 sequence of SEQ ID NO: 288, a HC FR4 sequence of SEQ ID NO: 289, a LC FR1 sequence of SEQ ID NO: 230, a LC FR2 sequence of SEQ ID NO: 231, a LC FR3 sequence of SEQ ID NO: 232, and a LC FR4 sequence of SEQ ID NO: 233.

[0177] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 290, a HC CDR2 sequence of SEQ ID NO: 291, a HC CDR3 sequence of SEQ ID NO: 292, a LC CDR1 sequence of SEQ ID NO: 241, a LC CDR2 sequence of GTS, a LC CDR3 sequence of SEQ ID NO: 243, a HC FR1 sequence of SEQ ID NO: 286, a HC FR2 sequence of SEQ ID NO: 287, a HC FR3 sequence of SEQ ID NO: 288, a HC FR4 sequence of SEQ ID NO: 289, a LC FR1 sequence of SEQ ID NO: 237, a LC FR2 sequence of SEQ ID NO: 238, a LC FR3 sequence of SEQ ID NO: 239, and a LC FR4 sequence of SEQ ID NO: 240.

[0178] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 290, a HC CDR2 sequence of SEQ ID NO: 291, a HC CDR3 sequence of SEQ ID NO: 292, a LC CDR1 sequence of SEQ ID NO: 248, a LC CDR2 sequence of GTS, a LC CDR3 sequence of SEQ ID NO: 250, a HC FR1 sequence of SEQ ID NO: 286, a HC FR2 sequence of SEQ ID NO: 287, a HC FR3 sequence of SEQ ID NO: 288, a HC FR4 sequence of SEQ ID NO: 289, a LC FR1 sequence of SEQ ID NO: 244, a LC FR2 sequence of -60- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 SEQ ID NO: 245, a LC FR3 sequence of SEQ ID NO: 246, and a LC FR4 sequence of SEQ ID NO: 247.

[0179] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 290, a HC CDR2 sequence of SEQ ID NO: 291, a HC CDR3 sequence of SEQ ID NO: 292, a LC CDR1 sequence of SEQ ID NO: 255, a LC CDR2 sequence of GTS, a LC CDR3 sequence of SEQ ID NO: 257, a HC FR1 sequence of SEQ ID NO: 286, a HC FR2 sequence of SEQ ID NO: 287, a HC FR3 sequence of SEQ ID NO: 288, a HC FR4 sequence of SEQ ID NO: 289, a LC FR1 sequence of SEQ ID NO: 251, a LC FR2 sequence of SEQ ID NO: 252, a LC FR3 sequence of SEQ ID NO: 253, and a LC FR4 sequence of SEQ ID NO: 254.

[0180] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 290, a HC CDR2 sequence of SEQ ID NO: 291, a HC CDR3 sequence of SEQ ID NO: 292, a LC CDR1 sequence of SEQ ID NO: 262, a LC CDR2 sequence of GTS, a LC CDR3 sequence of SEQ ID NO: 264, a HC FR1 sequence of SEQ ID NO: 286, a HC FR2 sequence of SEQ ID NO: 287, a HC FR3 sequence of SEQ ID NO: 288, a HC FR4 sequence of SEQ ID NO: 289, a LC FR1 sequence of SEQ ID NO: 258, a LC FR2 sequence of SEQ ID NO: 259, a LC FR3 sequence of SEQ ID NO: 260, and a LC FR4 sequence of SEQ ID NO: 261.

[0181] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 290, a HC CDR2 sequence of SEQ ID NO: 291, a HC CDR3 sequence of SEQ ID NO: 292, a LC CDR1 sequence of SEQ ID NO: 269, a LC CDR2 sequence of GTS, a LC CDR3 sequence of SEQ ID NO: 271, a HC FR1 sequence of SEQ ID NO: 286, a HC FR2 sequence of SEQ ID NO: 287, a HC FR3 sequence of SEQ ID NO: 288, a HC FR4 sequence of SEQ ID NO: 289, a LC FR1 sequence of SEQ ID NO: 265, a LC FR2 sequence of SEQ ID NO: 266, a LC FR3 sequence of SEQ ID NO: 267, and a LC FR4 sequence of SEQ ID NO: 268.

[0182] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 290, a HC CDR2 sequence of SEQ ID NO: 291, a HC CDR3 sequence of SEQ ID NO: 292, a LC CDR1 sequence of SEQ ID NO: 276, a LC CDR2 sequence of GTS, a LC CDR3 sequence of SEQ ID NO: 278, a HC FR1 sequence of SEQ ID NO: 286, a HC FR2 sequence of SEQ ID NO: 287, a HC FR3 sequence of SEQ ID NO: 288, a HC FR4 sequence of SEQ ID NO: 289, a LC FR1 sequence of SEQ ID NO: 272, a LC FR2 sequence of -61- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 SEQ ID NO: 273, a LC FR3 sequence of SEQ ID NO: 274, and a LC FR4 sequence of SEQ ID NO: 275.

[0183] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 290, a HC CDR2 sequence of SEQ ID NO: 291, a HC CDR3 sequence of SEQ ID NO: 292, a LC CDR1 sequence of SEQ ID NO: 283, a LC CDR2 sequence of GTS, a LC CDR3 sequence of SEQ ID NO: 285, a HC FR1 sequence of SEQ ID NO: 286, a HC FR2 sequence of SEQ ID NO: 287, a HC FR3 sequence of SEQ ID NO: 288, a HC FR4 sequence of SEQ ID NO: 289, a LC FR1 sequence of SEQ ID NO: 279, a LC FR2 sequence of SEQ ID NO: 280, a LC FR3 sequence of SEQ ID NO: 281, and a LC FR4 sequence of SEQ ID NO: 282.

[0184] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 297, a HC CDR2 sequence of SEQ ID NO: 298, a HC CDR3 sequence of SEQ ID NO: 299, a LC CDR1 sequence of SEQ ID NO: 234, a LC CDR2 sequence of GTS, a LC CDR3 sequence of SEQ ID NO: 236, a HC FR1 sequence of SEQ ID NO: 293, a HC FR2 sequence of SEQ ID NO: 294, a HC FR3 sequence of SEQ ID NO: 295, a HC FR4 sequence of SEQ ID NO: 296 NO: 313, a LC FR1 sequence of SEQ ID NO: 230, a LC FR2 sequence of SEQ ID NO: 231, a LC FR3 sequence of SEQ ID NO: 232, and a LC FR4 sequence of SEQ ID NO: 233.

[0185] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 297, a HC CDR2 sequence of SEQ ID NO: 298, a HC CDR3 sequence of SEQ ID NO: 299, a LC CDR1 sequence of SEQ ID NO: 241, a LC CDR2 sequence of GTS, a LC CDR3 sequence of SEQ ID NO: 243, a HC FR1 sequence of SEQ ID NO: 293, a HC FR2 sequence of SEQ ID NO: 294, a HC FR3 sequence of SEQ ID NO: 295, a HC FR4 sequence of SEQ ID NO: 296 NO: 313, a LC FR1 sequence of SEQ ID NO: 237, a LC FR2 sequence of SEQ ID NO: 238, a LC FR3 sequence of SEQ ID NO: 239, and a LC FR4 sequence of SEQ ID NO: 240.

[0186] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 297, a HC CDR2 sequence of SEQ ID NO: 298, a HC CDR3 sequence of SEQ ID NO: 299, a LC CDR1 sequence of SEQ ID NO: 248, a LC CDR2 sequence of GTS, a LC CDR3 sequence of SEQ ID NO: 250, a HC FR1 sequence of SEQ ID NO: 293, a HC FR2 sequence of SEQ ID NO: 294, a HC FR3 sequence of SEQ ID NO: 295, a HC FR4 sequence of SEQ ID NO: 296 NO: 313, a LC FR1 sequence of SEQ ID NO: 244, a LC FR2 -62- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 sequence of SEQ ID NO: 245, a LC FR3 sequence of SEQ ID NO: 246, and a LC FR4 sequence of SEQ ID NO: 247.

[0187] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 297, a HC CDR2 sequence of SEQ ID NO: 298, a HC CDR3 sequence of SEQ ID NO: 299, a LC CDR1 sequence of SEQ ID NO: 255, a LC CDR2 sequence of GTS, a LC CDR3 sequence of SEQ ID NO: 257, a HC FR1 sequence of SEQ ID NO: 293, a HC FR2 sequence of SEQ ID NO: 294, a HC FR3 sequence of SEQ ID NO: 295, a HC FR4 sequence of SEQ ID NO: 296 NO: 313, a LC FR1 sequence of SEQ ID NO: 251, a LC FR2 sequence of SEQ ID NO: 252, a LC FR3 sequence of SEQ ID NO: 253, and a LC FR4 sequence of SEQ ID NO: 254.

[0188] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 297, a HC CDR2 sequence of SEQ ID NO: 298, a HC CDR3 sequence of SEQ ID NO: 299, a LC CDR1 sequence of SEQ ID NO: 262, a LC CDR2 sequence of GTS, a LC CDR3 sequence of SEQ ID NO: 264, a HC FR1 sequence of SEQ ID NO: 293, a HC FR2 sequence of SEQ ID NO: 294, a HC FR3 sequence of SEQ ID NO: 295, a HC FR4 sequence of SEQ ID NO: 296 NO: 313, a LC FR1 sequence of SEQ ID NO: 258, a LC FR2 sequence of SEQ ID NO: 259, a LC FR3 sequence of SEQ ID NO: 260, and a LC FR4 sequence of SEQ ID NO: 261.

[0189] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 297, a HC CDR2 sequence of SEQ ID NO: 298, a HC CDR3 sequence of SEQ ID NO: 299, a LC CDR1 sequence of SEQ ID NO: 269, a LC CDR2 sequence of GTS, a LC CDR3 sequence of SEQ ID NO: 271, a HC FR1 sequence of SEQ ID NO: 293, a HC FR2 sequence of SEQ ID NO: 294, a HC FR3 sequence of SEQ ID NO: 295, a HC FR4 sequence of SEQ ID NO: 296 NO: 313, a LC FR1 sequence of SEQ ID NO: 265, a LC FR2 sequence of SEQ ID NO: 266, a LC FR3 sequence of SEQ ID NO: 267, and a LC FR4 sequence of SEQ ID NO: 268.

[0190] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 297, a HC CDR2 sequence of SEQ ID NO: 298, a HC CDR3 sequence of SEQ ID NO: 299, a LC CDR1 sequence of SEQ ID NO: 276, a LC CDR2 sequence of GTS, a LC CDR3 sequence of SEQ ID NO: 278, a HC FR1 sequence of SEQ ID NO: 293, a HC FR2 sequence of SEQ ID NO: 294, a HC FR3 sequence of SEQ ID NO: 295, a HC FR4 sequence of SEQ ID NO: 296 NO: 313, a LC FR1 sequence of SEQ ID NO: 272, a LC FR2 -63- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 sequence of SEQ ID NO: 273, a LC FR3 sequence of SEQ ID NO: 274, and a LC FR4 sequence of SEQ ID NO: 275.

[0191] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 297, a HC CDR2 sequence of SEQ ID NO: 298, a HC CDR3 sequence of SEQ ID NO: 299, a LC CDR1 sequence of SEQ ID NO: 283, a LC CDR2 sequence of GTS, a LC CDR3 sequence of SEQ ID NO: 285, a HC FR1 sequence of SEQ ID NO: 293, a HC FR2 sequence of SEQ ID NO: 294, a HC FR3 sequence of SEQ ID NO: 295, a HC FR4 sequence of SEQ ID NO: 296 NO: 313, a LC FR1 sequence of SEQ ID NO: 279, a LC FR2 sequence of SEQ ID NO: 280, a LC FR3 sequence of SEQ ID NO: 281, and a LC FR4 sequence of SEQ ID NO: 282.

[0192] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 304, a HC CDR2 sequence of SEQ ID NO: 305, a HC CDR3 sequence of SEQ ID NO: 306, a LC CDR1 sequence of SEQ ID NO: 234, a LC CDR2 sequence of GTS, a LC CDR3 sequence of SEQ ID NO: 236, a HC FR1 sequence of SEQ ID NO: 300, a HC FR2 sequence of SEQ ID NO: 301, a HC FR3 sequence of SEQ ID NO: 302, a HC FR4 sequence of SEQ ID NO: 303, a LC FR1 sequence of SEQ ID NO: 230, a LC FR2 sequence of SEQ ID NO: 231, a LC FR3 sequence of SEQ ID NO: 232, and a LC FR4 sequence of SEQ ID NO: 233.

[0193] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 304, a HC CDR2 sequence of SEQ ID NO: 305, a HC CDR3 sequence of SEQ ID NO: 306, a LC CDR1 sequence of SEQ ID NO: 241, a LC CDR2 sequence of GTS, a LC CDR3 sequence of SEQ ID NO: 243, a HC FR1 sequence of SEQ ID NO: 300, a HC FR2 sequence of SEQ ID NO: 301, a HC FR3 sequence of SEQ ID NO: 302, a HC FR4 sequence of SEQ ID NO: 303, a LC FR1 sequence of SEQ ID NO: 237, a LC FR2 sequence of SEQ ID NO: 238, a LC FR3 sequence of SEQ ID NO: 239, and a LC FR4 sequence of SEQ ID NO: 240.

[0194] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 304, a HC CDR2 sequence of SEQ ID NO: 305, a HC CDR3 sequence of SEQ ID NO: 306, a LC CDR1 sequence of SEQ ID NO: 248, a LC CDR2 sequence of GTS, a LC CDR3 sequence of SEQ ID NO: 250, a HC FR1 sequence of SEQ ID NO: 300, a HC FR2 sequence of SEQ ID NO: 301, a HC FR3 sequence of SEQ ID NO: 302, a HC FR4 sequence of SEQ ID NO: 303, a LC FR1 sequence of SEQ ID NO: 244, a LC FR2 sequence of -64- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 SEQ ID NO: 245, a LC FR3 sequence of SEQ ID NO: 246, and a LC FR4 sequence of SEQ ID NO: 247.

[0195] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 304, a HC CDR2 sequence of SEQ ID NO: 305, a HC CDR3 sequence of SEQ ID NO: 306, a LC CDR1 sequence of SEQ ID NO: 255, a LC CDR2 sequence of GTS, a LC CDR3 sequence of SEQ ID NO: 257, a HC FR1 sequence of SEQ ID NO: 300, a HC FR2 sequence of SEQ ID NO: 301, a HC FR3 sequence of SEQ ID NO: 302, a HC FR4 sequence of SEQ ID NO: 303, a LC FR1 sequence of SEQ ID NO: 251, a LC FR2 sequence of SEQ ID NO: 252, a LC FR3 sequence of SEQ ID NO: 253, and a LC FR4 sequence of SEQ ID NO: 254.

[0196] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 304, a HC CDR2 sequence of SEQ ID NO: 305, a HC CDR3 sequence of SEQ ID NO: 306, a LC CDR1 sequence of SEQ ID NO: 262, a LC CDR2 sequence of GTS, a LC CDR3 sequence of SEQ ID NO: 264, a HC FR1 sequence of SEQ ID NO: 300, a HC FR2 sequence of SEQ ID NO: 301, a HC FR3 sequence of SEQ ID NO: 302, a HC FR4 sequence of SEQ ID NO: 303, a LC FR1 sequence of SEQ ID NO: 258, a LC FR2 sequence of SEQ ID NO: 259, a LC FR3 sequence of SEQ ID NO: 260, and a LC FR4 sequence of SEQ ID NO: 261.

[0197] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 304, a HC CDR2 sequence of SEQ ID NO: 305, a HC CDR3 sequence of SEQ ID NO: 306, a LC CDR1 sequence of SEQ ID NO: 269, a LC CDR2 sequence of GTS, a LC CDR3 sequence of SEQ ID NO: 271, a HC FR1 sequence of SEQ ID NO: 300, a HC FR2 sequence of SEQ ID NO: 301, a HC FR3 sequence of SEQ ID NO: 302, a HC FR4 sequence of SEQ ID NO: 303, a LC FR1 sequence of SEQ ID NO: 265, a LC FR2 sequence of SEQ ID NO: 266, a LC FR3 sequence of SEQ ID NO: 267, and a LC FR4 sequence of SEQ ID NO: 268.

[0198] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 304, a HC CDR2 sequence of SEQ ID NO: 305, a HC CDR3 sequence of SEQ ID NO: 306, a LC CDR1 sequence of SEQ ID NO: 276, a LC CDR2 sequence of GTS, a LC CDR3 sequence of SEQ ID NO: 278, a HC FR1 sequence of SEQ ID NO: 300, a HC FR2 sequence of SEQ ID NO: 301, a HC FR3 sequence of SEQ ID NO: 302, a HC FR4 sequence of SEQ ID NO: 303, a LC FR1 sequence of SEQ ID NO: 272, a LC FR2 sequence of -65- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 SEQ ID NO: 273, a LC FR3 sequence of SEQ ID NO: 274, and a LC FR4 sequence of SEQ ID NO: 275.

[0199] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 304, a HC CDR2 sequence of SEQ ID NO: 305, a HC CDR3 sequence of SEQ ID NO: 306, a LC CDR1 sequence of SEQ ID NO: 283, a LC CDR2 sequence of GTS, a LC CDR3 sequence of SEQ ID NO: 285, a HC FR1 sequence of SEQ ID NO: 300, a HC FR2 sequence of SEQ ID NO: 301, a HC FR3 sequence of SEQ ID NO: 302, a HC FR4 sequence of SEQ ID NO: 303, a LC FR1 sequence of SEQ ID NO: 279, a LC FR2 sequence of SEQ ID NO: 280, a LC FR3 sequence of SEQ ID NO: 281, and a LC FR4 sequence of SEQ ID NO: 282.

[0200] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 311, a HC CDR2 sequence of SEQ ID NO: 312, a HC CDR3 sequence of SEQ ID NO: 313, a LC CDR1 sequence of SEQ ID NO: 234, a LC CDR2 sequence of GTS, a LC CDR3 sequence of SEQ ID NO: 236, a HC FR1 sequence of SEQ ID NO: 307, a HC FR2 sequence of SEQ ID NO: 308, a HC FR3 sequence of SEQ ID NO: 309, a HC FR4 sequence of SEQ ID NO: 310, a LC FR1 sequence of SEQ ID NO: 230, a LC FR2 sequence of SEQ ID NO: 231, a LC FR3 sequence of SEQ ID NO: 232, and a LC FR4 sequence of SEQ ID NO: 233.

[0201] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 311, a HC CDR2 sequence of SEQ ID NO: 312, a HC CDR3 sequence of SEQ ID NO: 313, a LC CDR1 sequence of SEQ ID NO: 241, a LC CDR2 sequence of GTS, a LC CDR3 sequence of SEQ ID NO: 243, a HC FR1 sequence of SEQ ID NO: 307, a HC FR2 sequence of SEQ ID NO: 308, a HC FR3 sequence of SEQ ID NO: 309, a HC FR4 sequence of SEQ ID NO: 310, a LC FR1 sequence of SEQ ID NO: 237, a LC FR2 sequence of SEQ ID NO: 238, a LC FR3 sequence of SEQ ID NO: 239, and a LC FR4 sequence of SEQ ID NO: 240.

[0202] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 311, a HC CDR2 sequence of SEQ ID NO: 312, a HC CDR3 sequence of SEQ ID NO: 313, a LC CDR1 sequence of SEQ ID NO: 248, a LC CDR2 sequence of GTS, a LC CDR3 sequence of SEQ ID NO: 250, a HC FR1 sequence of SEQ ID NO: 307, a HC FR2 sequence of SEQ ID NO: 308, a HC FR3 sequence of SEQ ID NO: 309, a HC FR4 sequence of SEQ ID NO: 310, a LC FR1 sequence of SEQ ID NO: 244, a LC FR2 sequence of -66- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 SEQ ID NO: 245, a LC FR3 sequence of SEQ ID NO: 246, and a LC FR4 sequence of SEQ ID NO: 247.

[0203] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 311, a HC CDR2 sequence of SEQ ID NO: 312, a HC CDR3 sequence of SEQ ID NO: 313, a LC CDR1 sequence of SEQ ID NO: 255, a LC CDR2 sequence of GTS, a LC CDR3 sequence of SEQ ID NO: 257, a HC FR1 sequence of SEQ ID NO: 307, a HC FR2 sequence of SEQ ID NO: 308, a HC FR3 sequence of SEQ ID NO: 309, a HC FR4 sequence of SEQ ID NO: 310, a LC FR1 sequence of SEQ ID NO: 251, a LC FR2 sequence of SEQ ID NO: 252, a LC FR3 sequence of SEQ ID NO: 253, and a LC FR4 sequence of SEQ ID NO: 254.

[0204] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 311, a HC CDR2 sequence of SEQ ID NO: 312, a HC CDR3 sequence of SEQ ID NO: 313, a LC CDR1 sequence of SEQ ID NO: 262, a LC CDR2 sequence of GTS, a LC CDR3 sequence of SEQ ID NO: 264, a HC FR1 sequence of SEQ ID NO: 307, a HC FR2 sequence of SEQ ID NO: 308, a HC FR3 sequence of SEQ ID NO: 309, a HC FR4 sequence of SEQ ID NO: 310, a LC FR1 sequence of SEQ ID NO: 258, a LC FR2 sequence of SEQ ID NO: 259, a LC FR3 sequence of SEQ ID NO: 260, and a LC FR4 sequence of SEQ ID NO: 261.

[0205] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 311, a HC CDR2 sequence of SEQ ID NO: 312, a HC CDR3 sequence of SEQ ID NO: 313, a LC CDR1 sequence of SEQ ID NO: 269, a LC CDR2 sequence of GTS, a LC CDR3 sequence of SEQ ID NO: 271, a HC FR1 sequence of SEQ ID NO: 307, a HC FR2 sequence of SEQ ID NO: 308, a HC FR3 sequence of SEQ ID NO: 309, a HC FR4 sequence of SEQ ID NO: 310, a LC FR1 sequence of SEQ ID NO: 265, a LC FR2 sequence of SEQ ID NO: 266, a LC FR3 sequence of SEQ ID NO: 267, and a LC FR4 sequence of SEQ ID NO: 268.

[0206] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 311, a HC CDR2 sequence of SEQ ID NO: 312, a HC CDR3 sequence of SEQ ID NO: 313, a LC CDR1 sequence of SEQ ID NO: 276, a LC CDR2 sequence of GTS, a LC CDR3 sequence of SEQ ID NO: 278, a HC FR1 sequence of SEQ ID NO: 307, a HC FR2 sequence of SEQ ID NO: 308, a HC FR3 sequence of SEQ ID NO: 309, a HC FR4 sequence of SEQ ID NO: 310, a LC FR1 sequence of SEQ ID NO: 272, a LC FR2 sequence of -67- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 SEQ ID NO: 273, a LC FR3 sequence of SEQ ID NO: 274, and a LC FR4 sequence of SEQ ID NO: 275.

[0207] In some embodiments, the antibody or fragment thereof described herein comprises a HC CDR1 sequence of SEQ ID NO: 311, a HC CDR2 sequence of SEQ ID NO: 312, a HC CDR3 sequence of SEQ ID NO: 313, a LC CDR1 sequence of SEQ ID NO: 283, a LC CDR2 sequence of GTS, a LC CDR3 sequence of SEQ ID NO: 285, a HC FR1 sequence of SEQ ID NO: 307, a HC FR2 sequence of SEQ ID NO: 308, a HC FR3 sequence of SEQ ID NO: 309, a HC FR4 sequence of SEQ ID NO: 310, a LC FR1 sequence of SEQ ID NO: 279, a LC FR2 sequence of SEQ ID NO: 280, a LC FR3 sequence of SEQ ID NO: 281, and a LC FR4 sequence of SEQ ID NO: 282. Table 9: Exemplary amino acid sequences for heavy chain variable regions (VH) and light chain variable regions (VL) of anti-BILF-1 antibodies-68- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004-69- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004-70- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004-71- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004

[0208] In some embodiments, exemplary amino acid sequences of the heavy and light chain variable regions of an antibody or fragment thereof described herein are provided in Table 9. In -72- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 some embodiments, the antibody or fragment thereof described herein comprises a heavy chain variable region (VH) comprising or consisting of an amino acid sequence set forth in any one of SEQ ID NOs: 314, 316, 318, 320, 322, 324, 326, 328, 330, 332, 334, 336, 338, 340, 342, 344, 354, 355, 356, 357, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in any one of SEQ ID NOs: 314, 316, 318, 320, 322, 324, 326, 328, 330, 332, 334, 336, 338, 340, 342, 344, 354, 355, 356, 357. In some embodiments, the antibody or fragment thereof described herein comprises a light chain variable region (VL) comprising or consisting of an amino acid sequence set forth in any one of SEQ ID NOs: 315, 317, 319, 321, 323, 325, 327, 329, 331, 333, 335, 337, 339, 341, 343, 345, 346, 347, 348, 349, 350, 351, 352, 353, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in any one of SEQ ID NOs: 315, 317, 319, 321, 323, 325, 327, 329, 331, 333, 335, 337, 339, 341, 343, 345, 346, 347, 348, 349, 350, 351, 352, 353.

[0209] In some embodiments, exemplary amino acid sequences of the heavy and light chain variable regions of an antibody or fragment thereof described herein are provided in Table 9. In some embodiments, the antibody or fragment thereof described herein comprises a heavy chain variable region (VH) comprising or consisting of an amino acid sequence set forth in any one of SEQ ID NOs: 314, 354, 355, 356, 357, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in any one of SEQ ID NOs: 314, 354, 355, 356, 357. In some embodiments, the antibody or fragment thereof described herein comprises a light chain variable region (VL) comprising or consisting of an amino acid sequence set forth in any one of SEQ ID NOs: 315, 346, 347, 348, 349, 350, 351, 352, 353, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in any one of SEQ ID NOs: 315, 346, 347, 348, 349, 350, 351, 352, 353.

[0210] In some embodiments, the antibody or fragment thereof described herein comprises: (i) a VH comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 314, or an -73- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 314; and / or (ii) a VL comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 315, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 315.

[0211] In some embodiments, the antibody or fragment thereof described herein comprises: (i) a VH comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 314, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 314; and / or (ii) a VL comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 346, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 346.

[0212] In some embodiments, the antibody or fragment thereof described herein comprises: (i) a VH comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 314, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 314; and / or (ii) a VL comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 347, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 347.

[0213] In some embodiments, the antibody or fragment thereof described herein comprises: (i) a VH comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 314, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID -74- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 NO: 314; and / or (ii) a VL comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 348, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 348.

[0214] In some embodiments, the antibody or fragment thereof described herein comprises: (i) a VH comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 314, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 314; and / or (ii) a VL comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 349, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 349.

[0215] In some embodiments, the antibody or fragment thereof described herein comprises: (i) a VH comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 314, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 314; and / or (ii) a VL comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 350, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 350.

[0216] In some embodiments, the antibody or fragment thereof described herein comprises: (i) a VH comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 314, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 314; and / or (ii) a VL comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 351, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about -75- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 351.

[0217] In some embodiments, the antibody or fragment thereof described herein comprises: (i) a VH comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 314, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 314; and / or (ii) a VL comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 352, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 352.

[0218] In some embodiments, the antibody or fragment thereof described herein comprises: (i) a VH comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 314, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 314; and / or (ii) a VL comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 352, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 353.

[0219] In some embodiments, the antibody or fragment thereof described herein comprises: (i) a VH comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 316, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 316; and / or (ii) a VL comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 317, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 317. -76- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004

[0220] In some embodiments, the antibody or fragment thereof described herein comprises: (i) a VH comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 318, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 318; and / or (ii) a VL comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 319, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 319.

[0221] In some embodiments, the antibody or fragment thereof described herein comprises: (i) a VH comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 320, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 320; and / or (ii) a VL comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 321, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 321.

[0222] In some embodiments, the antibody or fragment thereof described herein comprises: (i) a VH comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 322, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 322; and / or (ii) a VL comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 323, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 323.

[0223] In some embodiments, the antibody or fragment thereof described herein comprises: (i) a VH comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 324, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about -77- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 324; and / or (ii) a VL comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 325, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 325.

[0224] In some embodiments, the antibody or fragment thereof described herein comprises: (i) a VH comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 326, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 326; and / or (ii) a VL comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 327, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 327.

[0225] In some embodiments, the antibody or fragment thereof described herein comprises: (i) a VH comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 328, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 328; and / or (ii) a VL comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 329, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 329.

[0226] In some embodiments, the antibody or fragment thereof described herein comprises: (i) a VH comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 330, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 330; and / or (ii) a VL comprising or consisting of an amino acid sequence set forth in SEQ -78- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 ID NO: 331, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 331.

[0227] In some embodiments, the antibody or fragment thereof described herein comprises: (i) a VH comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 332, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 332; and / or (ii) a VL comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 333, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 333.

[0228] In some embodiments, the antibody or fragment thereof described herein comprises: (i) a VH comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 334, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 334; and / or (ii) a VL comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 335, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 335.

[0229] In some embodiments, the antibody or fragment thereof described herein comprises: (i) a VH comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 336, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 336; and / or (ii) a VL comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 337, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about -79- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 337.

[0230] In some embodiments, the antibody or fragment thereof described herein comprises: (i) a VH comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 338, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 338; and / or (ii) a VL comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 339, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 339.

[0231] In some embodiments, the antibody or fragment thereof described herein comprises: (i) a VH comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 340, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 340; and / or (ii) a VL comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 341, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 341.

[0232] In some embodiments, the antibody or fragment thereof described herein comprises: (i) a VH comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 342, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 342; and / or (ii) a VL comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 343, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 343. -80- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004

[0233] In some embodiments, the antibody or fragment thereof described herein comprises: (i) a VH comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 344, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 344; and / or (ii) a VL comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 345, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 345.

[0234] In some embodiments, the antibody or fragment thereof described herein comprises: (i) a VH comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 354, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 354; and / or (ii) a VL comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 315, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 315.

[0235] In some embodiments, the antibody or fragment thereof described herein comprises: (i) a VH comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 354, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 354; and / or (ii) a VL comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 346, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 346.

[0236] In some embodiments, the antibody or fragment thereof described herein comprises: (i) a VH comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 354, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about -81- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 354; and / or (ii) a VL comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 347, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 347.

[0237] In some embodiments, the antibody or fragment thereof described herein comprises: (i) a VH comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 354, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 354; and / or (ii) a VL comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 348, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 348.

[0238] In some embodiments, the antibody or fragment thereof described herein comprises: (i) a VH comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 354, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 354; and / or (ii) a VL comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 349, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 349.

[0239] In some embodiments, the antibody or fragment thereof described herein comprises: (i) a VH comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 354, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 354; and / or (ii) a VL comprising or consisting of an amino acid sequence set forth in SEQ -82- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 ID NO: 350, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 350.

[0240] In some embodiments, the antibody or fragment thereof described herein comprises: (i) a VH comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 354, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 354; and / or (ii) a VL comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 351, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 351.

[0241] In some embodiments, the antibody or fragment thereof described herein comprises: (i) a VH comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 354, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 354; and / or (ii) a VL comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 352, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 352.

[0242] In some embodiments, the antibody or fragment thereof described herein comprises: (i) a VH comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 354, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 354; and / or (ii) a VL comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 352, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about -83- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 353.

[0243] In some embodiments, the antibody or fragment thereof described herein comprises: (i) a VH comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 355, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 355; and / or (ii) a VL comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 315, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 315.

[0244] In some embodiments, the antibody or fragment thereof described herein comprises: (i) a VH comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 355, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 355; and / or (ii) a VL comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 346, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 346.

[0245] In some embodiments, the antibody or fragment thereof described herein comprises: (i) a VH comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 355, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 355; and / or (ii) a VL comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 347, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 347. -84- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004

[0246] In some embodiments, the antibody or fragment thereof described herein comprises: (i) a VH comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 355, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 355; and / or (ii) a VL comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 348, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 348.

[0247] In some embodiments, the antibody or fragment thereof described herein comprises: (i) a VH comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 355, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 355; and / or (ii) a VL comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 349, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 349.

[0248] In some embodiments, the antibody or fragment thereof described herein comprises: (i) a VH comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 355, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 355; and / or (ii) a VL comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 350, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 350.

[0249] In some embodiments, the antibody or fragment thereof described herein comprises: (i) a VH comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 355, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about -85- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 355; and / or (ii) a VL comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 351, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 351.

[0250] In some embodiments, the antibody or fragment thereof described herein comprises: (i) a VH comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 355, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 355; and / or (ii) a VL comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 352, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 352.

[0251] In some embodiments, the antibody or fragment thereof described herein comprises: (i) a VH comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 355, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 355; and / or (ii) a VL comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 352, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 353.

[0252] In some embodiments, the antibody or fragment thereof described herein comprises: (i) a VH comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 356, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 356; and / or (ii) a VL comprising or consisting of an amino acid sequence set forth in SEQ -86- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 ID NO: 315, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 315.

[0253] In some embodiments, the antibody or fragment thereof described herein comprises: (i) a VH comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 356, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 356; and / or (ii) a VL comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 346, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 346.

[0254] In some embodiments, the antibody or fragment thereof described herein comprises: (i) a VH comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 356, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 356; and / or (ii) a VL comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 347, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 347.

[0255] In some embodiments, the antibody or fragment thereof described herein comprises: (i) a VH comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 356, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 356; and / or (ii) a VL comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 348, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about -87- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 348.

[0256] In some embodiments, the antibody or fragment thereof described herein comprises: (i) a VH comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 356, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 356; and / or (ii) a VL comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 349, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 349.

[0257] In some embodiments, the antibody or fragment thereof described herein comprises: (i) a VH comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 356, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 356; and / or (ii) a VL comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 350, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 350.

[0258] In some embodiments, the antibody or fragment thereof described herein comprises: (i) a VH comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 356, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 356; and / or (ii) a VL comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 351, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 351. -88- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004

[0259] In some embodiments, the antibody or fragment thereof described herein comprises: (i) a VH comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 356, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 356; and / or (ii) a VL comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 352, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 352.

[0260] In some embodiments, the antibody or fragment thereof described herein comprises: (i) a VH comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 356, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 356; and / or (ii) a VL comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 352, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 353.

[0261] In some embodiments, the antibody or fragment thereof described herein comprises: (i) a VH comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 357, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 357; and / or (ii) a VL comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 315, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 315.

[0262] In some embodiments, the antibody or fragment thereof described herein comprises: (i) a VH comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 357, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about -89- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 357; and / or (ii) a VL comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 346, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 346.

[0263] In some embodiments, the antibody or fragment thereof described herein comprises: (i) a VH comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 357, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 357; and / or (ii) a VL comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 347, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 347.

[0264] In some embodiments, the antibody or fragment thereof described herein comprises: (i) a VH comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 357, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 357; and / or (ii) a VL comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 348, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 348.

[0265] In some embodiments, the antibody or fragment thereof described herein comprises: (i) a VH comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 357, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 357; and / or (ii) a VL comprising or consisting of an amino acid sequence set forth in SEQ -90- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 ID NO: 349, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 349.

[0266] In some embodiments, the antibody or fragment thereof described herein comprises: (i) a VH comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 357, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 357; and / or (ii) a VL comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 350, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 350.

[0267] In some embodiments, the antibody or fragment thereof described herein comprises: (i) a VH comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 357, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 357; and / or (ii) a VL comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 351, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 351.

[0268] In some embodiments, the antibody or fragment thereof described herein comprises: (i) a VH comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 357, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 357; and / or (ii) a VL comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 352, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about -91- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 352.

[0269] In some embodiments, the antibody or fragment thereof described herein comprises: (i) a VH comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 357, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 357; and / or (ii) a VL comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 352, or an amino acid sequence that is at least about 80% identical (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical) to the amino acid sequence set forth in SEQ ID NO: 353. Antibody drug conjugates

[0270] Chemotherapeutic agents often lack specificity for cancer cells, resulting in undesirable side effects due to toxicity to non-cancerous tissue. An antibody-drug-conjugate (ADC) is typically composed of an antibody conjugated to a payload such as a cytotoxic drug. The antibody specifically binds to a cell or tissue-specific antigen, allowing selective delivery of the cytotoxic agent to specific cells or tissues and reducing the systemic toxicity of traditional small-molecule chemotherapeutics. A successful ADC must bind to a target antigen and be internalized to deliver a toxic payload to a target cell without significant binding to non-target cells. BILF-1 has been shown to internalize in a constitutive manner, making it a promising target for ADC design. Disclosed herein are ADCs comprising an anti-BILF-1 antibody or antigen binding fragment thereof described herein and one or more payloads. In some embodiments, the anti-BILF-1 antibody or antigen binding fragment thereof described herein is conjugated to one or more payloads. Exemplary payloads include, but are not limited to, an alkylating agent, an anti- tumor antibiotic, a topoisomerase inhibitor, a mitotic inhibitor, a corticosteroid, a nitrosoureas, an antimetabolite, and any combination thereof. In some embodiments, the one or more payloads comprise a cytotoxic agent. In some embodiments, the cytotoxic agent is monomethyl auristatin F (MMAF), monomethyl auristatin E (MMAE), or duocarmycin DM (DMDM). In some embodiments, the anti-BILF-1 antibody or antigen binding fragment thereof described herein is conjugated to a cytotoxic agent. In some embodiments, the cytotoxic agent is duocarmycin DM. In some embodiments, the payload is released in target cells (e.g. BILF-1 positive cells). -92- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004

[0271] The anti-BILF-1 antibody or antigen binding fragment thereof described herein may be conjugated to a payload using a bifunctional crosslinking reagent or linker. The linker may directly or indirectly link the antibody or antigen binding fragment to the payload. The linker possesses at least two reactive groups, one of which is capable of reacting with an antibody, while the other one is capable of reacting with the payload to link the antibody with the payload, thereby forming a conjugate. The linker may join the payload to the antibody through chemical bonds, such that the payload and the antibody are chemically coupled (e.g., covalently bonded) to each other. Any suitable bifunctional linker can be used in connection with the anti-BILF-1 antibodies, antigen binding fragments thereof, and payload described herein, so long as the linker provides for retention of the payload, e.g., cytotoxicity, and targeting characteristics of the antibody or antigen binding fragment.

[0272] Attachment of a linker to an antibody can be accomplished in a variety of ways, such as through surface lysines, reductive coupling to oxidized carbohydrates, and through cysteine residues liberated by reducing interchain disulfide linkages. A variety of antibody drug conjugate linkage systems are known in the art, including hydrazone-, disulfide- and peptide-based linkages. Exemplary linkers may comprise, for example, a hydrazone moiety, a hydrazide moiety, a disulfide moiety, a -glucuronidase cleavable moiety, a cathepsin B cleavable moiety, a dipeptide containing moiety, an amide moiety, a maleimide moiety, a maleimidocaproyl (me) moiety, a para-ammo benzyloxycarbonyl (PABC) moiety, or a combination thereof.

[0273] In some embodiments, the linker is a cleavable linker. A cleavable linker is typically susceptible to cleavage under physiological conditions, in particular inside a cell by e.g., a lysosomal or endosomal protease to release the attached payload. In some embodiments, the cleavable linkers are designed to release the free payload in an unmodified form. Cleavable linkers may include, for example, disulfide linkers, acid labile linkers, peptidase labile linkers, glycosidase-sensitive linkers, photolabile linkers, and esterase labile linkers. Typically, a peptidyl linker is at least two amino acids long or at least three amino acids long. Cleavable linkers take advantage of the environmental differences between the systemic circulation and tumor cells to provide efficient, accurate release of free cytotoxic drugs. In some embodiments, the cleavable linkers are chemically cleaved via hydrazone or disulfide bonds. In other embodiments, the cleavable linkers are enzymatically cleaved via peptide or glucuronide bonds. Acid labile (pH- sensitive) linkers are relatively stable under neutral pH conditions, such as those in the blood, but are unstable at below pH 5.5 or 5.0. Acid-labile linkers include, e.g., hydrazone, semicarbazone, thiosemicarbazone, cis-aconitic amide, orthoester, acetal, ketal, and the like. Disulfide bond-based -93- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 linkers are chemically sensitive cleavable linkers, which are sensitive to reductive glutathione (GSH) under reducing conditions. GSH plays a crucial role during cell survival, cell proliferation and differentiation for the maintenance of the intracellular redox balance. In certain embodiments, disulfide bond-based linkers are be used in an ADC comprising an anti-BILF-1 antibody or antigen binding fragment thereof described herein to target cancer cells where the intracellular GSH levels may be considerably elevated compared to the levels in blood.

[0274] In some embodiments, the linker is a peptide-based linker comprising a peptidase- labile moiety sensitive to an intracellular protease, such as a lysosomal or endosomal protease. Exemplary proteases for payload release from ADCs include e.g., cathepsins Band D and plasmin, all of which are known to hydrolyze dipeptide drug derivatives resulting in the release of active drug inside target cells. In some embodiments, the peptidase labile linker comprises a dipeptide moiety. In some embodiments, the peptidase labile linker comprises a maleimidocaproyl (me) moiety or a para-amino benzyloxycarbonyl (PABC) moiety. In some embodiments, the peptidase labile linker is sensitive to cleavage by the thiol- dependent protease cathepsin B. Lysosomal proteases, such as cathepsin B, are generally overexpressed in cancer cells, and are therefore particularly suitable for payload release in cancer cells. Peptidyl linkers cleavable by intracellular proteases, such as cathepsin B, include, but are not limited to valine-citrulline (Val-Cit), phenylalanine-lysine (Phe-Lys), valine-alanine (Val-Ala), phenylalanine-leucine (Phe-Leu), phenylalanine-arginine (Phe-Lys), tetrapeptide linker Gly-Phe-Leu- Gly, and maleimidocaproyl- valine citrulline-p-aminobenzyloxycarbonyl (mc-vc-PABC). Additional peptidyl linkers include, but are not limited to Ala-Val, Val-Ala-Val, Lys-Lys, Pro-Val-Gly-Val-Val, Ala-Asn-Val, Val- Leu-Lys, Ala-Ala-Asn, Cit-Cit, Val-Lys, Lys, Cit, Ser, and Glu. In some embodiments, the linker is an mc-vc-PAB linker. Exemplary mc-vc-PAB linkers include mc-vc-PABC, mc-vc-PAB-PNP, mc-vc-PAB-NH2, and mc-vc-PAB-OH. Bispecific antibodies

[0275] Antibody specificity refers to selective recognition of the antibody for a particular epitope of an antigen. The term “bispecific” antibody as used herein denotes an antibody which have two different antigen-binding specificities. Bispecific antibodies of the present disclosure have two or more antigen-binding sites and bind to two different antigens or two different epitopes of the same antigen. In some embodiments, the anti-BILF-1 antibody or antigen binding fragment thereof of the present disclosure is a bispecific antibody. In some embodiments, the anti-BILF-1 antibody or fragment thereof is a bispecific antibody comprising a first antigen binding domain -94- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 (ABD) that specifically binds to BILF-1 and a second ABD domain that specifically binds to a cell surface receptor. In certain embodiments, the cell surface receptor is expressed on an immune cell, can form a heterodimer with BILF-1, is co-expressed with BILF-1, or a combination thereof. In some embodiments, the cell surface receptor is expressed on an immune cell. In some embodiments, the bispecific antibody or fragment thereof increases engagement of BILF-1 expressing cells with the immune cell. In certain embodiments, the immune cell is a T cell or a natural killer (NK) cell. In some embodiments, the immune cell is a T cell. In some embodiments, the immune cell is a NK cell. In some embodiments, the cell surface receptor to which the second ABD domain binds can form a heterodimer with BILF-1. In some embodiments, the cell surface receptor is co-expressed with BILF-1. In some embodiments, the cell surface receptor is CD3, CD16, IL-8 receptor, CD19, BCMA, CD38, vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR), EBV latent membrane protein 1 (LMP1), or EBV latent membrane protein 2 (LMP2). In certain embodiments, the cell surface receptor is CD3. In certain embodiments, the cell surface receptor is CD16. In certain embodiments, the cell surface receptor is IL-8. In certain embodiments, the cell surface receptor is CD19. In certain embodiments, the cell surface receptor is BCMA. In certain embodiments, the cell surface receptor is CD38. In certain embodiments, the cell surface receptor is VEGFR. In certain embodiments, the cell surface receptor is EGFR. In certain embodiments, the cell surface receptor is LMP1. In certain embodiments, the cell surface receptor is LMP2. In some embodiments, a mechanism referred to as “knob-in-hole” is used to facilitate the formation of heterodimers in bispecific antibody engineering. The “knob-in-hole” format refers to amino acid engineering that creates steric influences that promote heterodimeric formation and disfavor homodimeric formation, as described in Ridgway et al, Protein Engineering 9(7):6l7 (1996); Atwell et al, J. Mol. Biol.1997 270:26; US Patent No.8,216,805; and W01996 / 027011, all of which are hereby incorporated by reference in their entirety. For example, the hole-bearing heavy chain may comprise Y349C, T366S, L368A and Y407V mutations and the knob may comprise the S354C and T366W mutations. In some embodiments, the anti-BILF-1 antibody or antigen binding fragment thereof of the present disclosure is a bispecific antibody in a knob-in-hole format. In certain embodiments, the bispecific antibody described herein has a valence of 2 for BILF-1 and a valence of one for a second antigen binding domain. Antibody “valency” as used herein refers to the total number of antigen-binding sites of an antibody.

[0276] In some embodiments, the anti-BILF-1 antibody or fragment thereof described herein comprises a linker. A linker may be used, for example, to fuse a scFv moiety to a Fc region. -95- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 In some embodiments, the scFv moiety is fused to the CH2 of the Fc region. In some embodiments, the linker is a peptide linker. In some embodiments, the linker is a glycine-serine linker. In some embodiments, the linker comprises the sequence of GGGS (SEQ ID NO: 358). In some embodiments, the linker comprises the sequence of AAA. T cell engagers

[0277] A T cell engager is a molecule that acts as a bridge between a target cell and a T cell. A bispecific T cell engager (BiTE) is a T cell engager with bispecific affinity to two antigens. A wide variety of molecules have been developed which are based on the basic concept of having two antibody-like binding domains. BiTEs are a class of bispecific antibody-type molecules that have been developed, primarily for the use as anti-cancer drugs. They direct a host's immune system, more specifically the T cells' cytotoxic activity, against a target cell, such as a cancer cell. In these molecules, one binding domain binds to a T cell, for example via the CD3 receptor, and the other binding domain binds to a target cell such as a tumor cell (via targeting of a tumor specific antigen). Since the bispecific molecule binds both the target cell and the T cell, it brings the target cell into proximity with the T cell, so that the T cell can exert its effect, for example, a cytotoxic effect on a cancer cell. The formation of the T cell:bispecific Ab:cancer cell complex induces signaling in the T cell leading to, for example, the release of cytotoxic mediators. Ideally, the agent only induces the desired signaling in the presence of the target cell, leading to selective killing. The terms “bispecific T cell engager” or “BiTE” or “BiTEs” in the present disclosure refers to a molecule with two antigen binding domains, which may bind the same or different antigens. In some embodiments, the anti-BILF-1 antibody or fragment thereof of the present disclosure is a T cell engager. In certain embodiments, the anti-BILF-1 antibody or fragment thereof is a BiTE. In some embodiments, the T cell engager comprises an anti-BILF-1 binding domain and an anti-CD3 binding domain. In some embodiments, the T cell engager comprises an anti-BILF-1 binding domain and an anti-CD28 binding domain. Other T cell engagers include, but are not limited to, a trispecific T cell engager (TriTE), a dual affinity retargeting antibody (DART), a TeTriTE, and a quadrispecific T cell engagers. Immune Activating Agents

[0278] An immune activating agent is a molecule that triggers immune activation. Non- limiting examples of immune activating agents include Toll-like receptor (TLR)-agonists, Stimulation of interferon genes (STING)-agonists, and cytokines such as IL-2, IL-15, or a TNF -96- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 superfamily ligand. In some embodiments, the anti-BILF-1 antibody or fragment thereof of the present disclosure is conjugated or fused to an immune activating agent. In some embodiments, the immune activating agent is a TLR agonist, a STING agonist, or a cytokine. In some embodiments, the immune activating agent is a TLR agonist. Non-limiting examples of TLR agonists include TLR-3, TLR-7, TLR-9, and TLR-9 agonists. In some embodiments, the immune activating agent is a STING agonist. In some embodiments, the immune activating agent is a cytokine. In certain embodiments, the cytokine is IL-2. In certain embodiments, the cytokine is IL-15. In certain embodiments, the cytokine is a TNF superfamily ligand. Non-limiting examples of TNF superfamily ligands include TRAIL, 4-1BBL, interleukin-21 (IL-21), IFN-alpha, IFN- beta, CD40, GITR-L, OX40L, and CD70. Chimeric Antigen Receptors

[0279] A chimeric antigen receptor (CAR) is generally designed in a modular fashion that includes at least an extracellular target-binding domain, a transmembrane domain that anchors the CAR to the cell membrane, and one or more intracellular signaling domains (also known as costimulatory domains) that transmit activation signals within the cell. The domains present within a CAR construct are operably linked with suitable linker sequences. As used herein, "chimeric antigen receptor" or "CAR" indicates an artificial, recombinant polypeptide comprising at least an extracellular domain that binds to a particular antigen, a transmembrane domain, and an intracellular signaling domain. The extracellular domain of a CAR can target a tumor- specific antigen or a tumor-associated antigen. An immune cell, such as a T lymphocyte, can be genetically engineered to express the CAR. Binding of the extracellular antigen-binding domain of the CAR to the targeted antigen causes the CAR-expressing cell to kill cells expressing the targeted antigen. The extracellular domain of a CAR can be derived from an antibody. In some embodiments, the extracellular domain of a CAR can be derived from the anti-BILF-1 antibody or fragment thereof of the present disclosure. CAR T cells which targets BILF-1 could effectively kill cells infected with EBV, such as EBV+ B cells or cancer cells. In some embodiments, the anti-BILF-1 antibody or fragment thereof of the present disclosure is fused to a transmembrane domain and an intracellular signaling domain to form a CAR. In certain embodiments, the anti-BILF-1 antibody or fragment thereof is a single-chain variable fragment (scFv). In some embodiments, the anti- BILF-1 antibody or fragment thereof of the present disclosure is a scFv, which is fused via a spacer (hinge) region to a transmembrane domain and an intracellular T-cell signaling domain, to form CAR. -97- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 Nucleic Acids and Vectors

[0280] The present disclosure also provides isolated nucleic acid molecules comprising a nucleic acid sequence encoding an anti-BILF-1 antibody or fragment thereof described herein. The isolated nucleic acids described herein are prepared using standard techniques well known to those of skill in the art. The amino acid sequences of the anti-BILF-1 antibodies or fragments thereof described herein may be used to determine appropriate nucleic acid sequences encoding the particular antibody disclosed thereby. The nucleic acid sequence may be optimized to reflect particular codon “preferences” for various expression systems according to standard methods well known to those of skill in the art.

[0281] In some embodiments, the isolated nucleic acid molecules described herein encodes the amino acid sequence of any one of the sequences provided in Table 2, Table 3, Table 4, Table 5, Table 6, Table 7, Table 8, and Table 9. In some embodiments, the isolated nucleic acid molecules described herein encodes the amino acid sequence of any one of the sets of three CDR sequences provided in Table 2, Table 3, Table 4, Table 5, Table 6, Table 7, Table 8, and Table 9.

[0282] In some embodiments, the isolated nucleic acid molecule described herein encodes the amino acid sequences of SEQ ID NO: 14, SEQ ID NO: 15, and SEQ ID NO: 16.

[0283] In some embodiments, the isolated nucleic acid molecule described herein encodes the amino acid sequences of SEQ ID NO: 17, GTS, and SEQ ID NO: 19.

[0284] In some embodiments, the isolated nucleic acid molecule described herein encodes the amino acid sequences of SEQ ID NO: 28, SEQ ID NO: 29, and SEQ ID NO: 30.

[0285] In some embodiments, the isolated nucleic acid molecule described herein encodes the amino acid sequences of SEQ ID NO: 31, YAS, and SEQ ID NO: 33.

[0286] In some embodiments, the isolated nucleic acid molecule described herein encodes the amino acid sequences of SEQ ID NO: 42, SEQ ID NO: 43, and SEQ ID NO: 44.

[0287] In some embodiments, the isolated nucleic acid molecule described herein encodes the amino acid sequences of SEQ ID NO: 45, GTS, and SEQ ID NO: 47.

[0288] In some embodiments, the isolated nucleic acid molecule described herein encodes the amino acid sequences of SEQ ID NO: 56, SEQ ID NO: 57, and SEQ ID NO: 58.

[0289] In some embodiments, the isolated nucleic acid molecule described herein encodes the amino acid sequences of SEQ ID NO: 59, GTS, and SEQ ID NO: 61.

[0290] In some embodiments, the isolated nucleic acid molecule described herein encodes the amino acid sequences of SEQ ID NOs: 70, SEQ ID NO: 71, and SEQ ID NO: 72. -98- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004

[0291] In some embodiments, the isolated nucleic acid molecule described herein encodes the amino acid sequences of SEQ ID NO: 73, GTS, and SEQ ID NO: 75.

[0292] In some embodiments, the isolated nucleic acid molecule described herein encodes the amino acid sequences of SEQ ID NOs: 84, SEQ ID NO: 85, and SEQ ID NO: 86.

[0293] In some embodiments, the isolated nucleic acid molecule described herein encodes the amino acid sequences of SEQ ID NO: 87, GTS, and SEQ ID NO: 89.

[0294] In some embodiments, the isolated nucleic acid molecule described herein encodes the amino acid sequences of SEQ ID NO: 98, SEQ ID NO: 99, and SEQ ID NO: 100.

[0295] In some embodiments, the isolated nucleic acid molecule described herein encodes the amino acid sequences of SEQ ID NO: 101, GTS, and SEQ ID NO: 103.

[0296] In some embodiments, the isolated nucleic acid molecule described herein encodes the amino acid sequences of SEQ ID NOs: 112, SEQ ID NO: 113, and SEQ ID NO: 114.

[0297] In some embodiments, the isolated nucleic acid molecule described herein encodes the amino acid sequences of SEQ ID NO: 115, YAS, and SEQ ID NO: 117.

[0298] In some embodiments, the isolated nucleic acid molecule described herein encodes the amino acid sequences of SEQ ID NO: 126, SEQ ID NO: 127, and SEQ ID NO: 128.

[0299] In some embodiments, the isolated nucleic acid molecule described herein encodes the amino acid sequences of SEQ ID NO: 129, YAS, and SEQ ID NO: 131.

[0300] In some embodiments, the isolated nucleic acid molecule described herein encodes the amino acid sequences of SEQ ID NO: 140, SEQ ID NO: 141, and SEQ ID NO: 142.

[0301] In some embodiments, the isolated nucleic acid molecule described herein encodes the amino acid sequences of SEQ ID NO: 143, YAS, and SEQ ID NO: 145.

[0302] In some embodiments, the isolated nucleic acid molecule described herein encodes the amino acid sequences of SEQ ID NO: 154, SEQ ID NO: 155, and SEQ ID NO: 156.

[0303] In some embodiments, the isolated nucleic acid molecule described herein encodes the amino acid sequences of SEQ ID NO: 157, WAS, and SEQ ID NO: 159.

[0304] In some embodiments, the isolated nucleic acid molecule described herein encodes the amino acid sequences of SEQ ID NO: 168, SEQ ID NO: 169, and SEQ ID NO: 170.

[0305] In some embodiments, the isolated nucleic acid molecule described herein encodes the amino acid sequences of SEQ ID NO: 171, YAS, and SEQ ID NO: 173.

[0306] In some embodiments, the isolated nucleic acid molecule described herein encodes the amino acid sequences of SEQ ID NO: 182, SEQ ID NO: 183, and SEQ ID NO: 184. -99- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004

[0307] In some embodiments, the isolated nucleic acid molecule described herein encodes the amino acid sequences of SEQ ID NO: 185, YAS, and SEQ ID NO: 187.

[0308] In some embodiments, the isolated nucleic acid molecule described herein encodes the amino acid sequences of SEQ ID NO: 196, SEQ ID NO: 197, and SEQ ID NO: 198.

[0309] In some embodiments, the isolated nucleic acid molecule described herein encodes the amino acid sequences of SEQ ID NO: 199, AAS, and SEQ ID NO: 201.

[0310] In some embodiments, the isolated nucleic acid molecule described herein encodes the amino acid sequences of SEQ ID NO: 210, SEQ ID NO: 211, and SEQ ID NO: 212.

[0311] In some embodiments, the isolated nucleic acid molecule described herein encodes the amino acid sequences of SEQ ID NO: 213, GTN, and SEQ ID NO: 215.

[0312] In some embodiments, the isolated nucleic acid molecule described herein encodes the amino acid sequences of SEQ ID NO: 224, SEQ ID NO: 225, and SEQ ID NO: 226.

[0313] In some embodiments, the isolated nucleic acid molecule described herein encodes the amino acid sequences of SEQ ID NO: 227, GAS, and SEQ ID NO: 229.

[0314] In some embodiments, the isolated nucleic acid molecule described herein encodes the amino acid sequences of SEQ ID NO: 234, GTS, and SEQ ID NO: 236.

[0315] In some embodiments, the isolated nucleic acid molecule described herein encodes the amino acid sequences of SEQ ID NO: 241, GTS, and SEQ ID NO: 243.

[0316] In some embodiments, the isolated nucleic acid molecule described herein encodes the amino acid sequences of SEQ ID NO: 248, GTS, and SEQ ID NO: 250.

[0317] In some embodiments, the isolated nucleic acid molecule described herein encodes the amino acid sequences of SEQ ID NO: 255, GTS, and SEQ ID NO: 257.

[0318] In some embodiments, the isolated nucleic acid molecule described herein encodes the amino acid sequences of SEQ ID NO: 262, GTS, and SEQ ID NO: 264.

[0319] In some embodiments, the isolated nucleic acid molecule described herein encodes the amino acid sequences of SEQ ID NO: 269, GTS, and SEQ ID NO: 271.

[0320] In some embodiments, the isolated nucleic acid molecule described herein encodes the amino acid sequences of SEQ ID NO: 276, GTS, and SEQ ID NO: 278.

[0321] In some embodiments, the isolated nucleic acid molecule described herein encodes the amino acid sequences of SEQ ID NO: 283, GTS, and SEQ ID NO: 285.

[0322] In some embodiments, the isolated nucleic acid molecule described herein encodes the amino acid sequences of SEQ ID NO: 290, SEQ ID NO: 291, and SEQ ID NO: 292. -100- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004

[0323] In some embodiments, the isolated nucleic acid molecule described herein encodes the amino acid sequences of SEQ ID NO: 297, SEQ ID NO: 298, and SEQ ID NO: 299.

[0324] In some embodiments, the isolated nucleic acid molecule described herein encodes the amino acid sequences of SEQ ID NO: 304, SEQ ID NO: 305, and SEQ ID NO: 306.

[0325] In some embodiments, the isolated nucleic acid molecule described herein encodes the amino acid sequences of SEQ ID NO: 311, SEQ ID NO: 312, and SEQ ID NO: 313.

[0326] In some embodiments, the isolated nucleic acid molecule described herein encodes the amino acid sequences of any one of SEQ ID NOs: 314 - 357.

[0327] In some embodiments, the isolated nucleic acid comprises a heterologous promoter which drives the expression of the antibody or fragment thereof described herein. Non-limiting examples of heterologous promoters include cytomegalovirus (CMV), CMV-immediately early(CMV-IE), CMV / EF1- In some embodiments, thepromoter is an inducible promoter. In some embodiments, the promoter is a constitutive promoter.

[0328] The present disclosure also provides plasmids or vectors comprising one or more isolated nucleic acid molecules described herein. The vector can be any non-viral or viral vector known in the art or described herein.

[0329] Suitable vectors can be chosen or constructed, containing appropriate regulatory sequences, including promoter sequences, terminator sequences, polyadenylation sequences, enhancer sequences, marker genes and other sequences as appropriate.

[0330] In some embodiments, the vector is suitable for directing the production of a protein product in a cell. In some embodiments, the vector is a non-viral vector. Non-limiting examples of non-viral vectors include a transposon vector, naked DNA (e.g., a DNA plasmid), a liposome, or a lipid nanoparticle.

[0331] In some embodiments, the vector is a viral vector. In some embodiments the viral vector is an adeno-associated virus vector (AAV), an adenoviral vector (AV), a lentiviral vector (LV), a retroviral vector (RV), a herpes simplex virus vector (HSV), or a poxvirus vector.

[0332] For example, viral and non-viral vectors and delivery systems are described in Sung & Kim 2019, Biomaterials Research 23:8; Mali, 2013, Indian Journal of Human Genetics, 19(1):3- 8; Hardee et al., 2017, Genes 8:65; Bulcha et al., 2020, Signal Transduction and Targeted Therapy; Ghosh et al., 2020, Applied Biosafety: Journal of ABSA International 25(1):7-18, the disclosures of each of which are hereby incorporated by reference herein in their entireties.

[0333] In some embodiments, the vector is a recombinant vector. In some embodiments, the vector comprises a transposon system. Non-limiting examples of transposon systems include -101- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 PiggyBac, Sleeping Beauty, Frog Prince, Himarl, Passport, Minos, hAT, Toll, Tol2, AciDs, PIF, Harbinger, Harbinger3-DR, and Hsmarl, and any of their respective derivatives with equal, lower and / or higher transposition activity. In some embodiments, the transposon system comprises two elements: a DNA element flanked by two terminal inverted repeats, and a transposase that catalyzes the transposon’s mobilization.

[0334] In some embodiments, the vector comprises an inducible expression system. Non- limiting examples of inducible expression systems include cumate, tetracycline, rapamycin, FKCsA, abscisic acid, tamoxifen, blue light, and riboswitch-inducible expression systems. In some embodiments, the inducible expression system comprises a cumate switch combined with -CymR repressor-T2A-Puro cassette. The cumate switch system provides tight control through the binding of the CmR repressor in the absence of cumate.

[0335] In some embodiments, the vector comprises a target-specific nuclease. Non-limiting examples of target-specific nucleases include zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), meganucleases, and clustered regularly interspaced short palindromic repeats (CRISPR) associated (Cas) nucleases.

[0336] In some embodiments, the vector comprises a CRISPR nuclease and "single guide RNA" or "sgRNA" that guides the Cas nuclease to a desired nucleic acid sequence. In some embodiments, the Cas nuclease has DNA cleavage activity.

[0337] Non-limiting examples of Cas nucleases include Casl, CaslB, Cas2, Cas3, Cas4, Cas5, Cas6, Cas7, Cas8, Cas9 (also known as Csnl and Csxl2), CaslO, , Cpfl, C2c3, C2c2 and C2clCsyl, Csy2, Csy3, Csel, Cse2, Cscl, Csc2, Csa5, Csn2, Csm2, Csm3, Csm4, Csm5, Csm6, Cmrl, Cmr3, Cmr4, Cmr5, Cmr6, Cpfl, Csbl, Csb2, Csb3, Csxl7, Csxl4, CsxlO, Csxl6, CsaX, Csx3, Csxl, Csxl5, Csfl, Csf2, Csf3, Csf4, homologs thereof, variants thereof, mutants thereof, and derivatives thereof. There are three main types of Cas nucleases (type I, type II, and type III), and 10 subtypes including 5 type I, 3 type II, and 2 type III proteins (see, e.g., Hochstrasser and Doudna, Trends Biochem Sci, 2015:40(l):58-66). Type II Cas nucleases include, but are not limited to, Casl, Cas2, Csn2, and Cas9. These Cas nucleases are known to those skilled in the art. For example, the amino acid sequence of the Streptococcus pyogenes wild type Cas9 polypeptide is set forth, e.g., in NBCI Ref. Seq. No. NP 269215, and the amino acid sequence of Streptococcus thermophilus wild type Cas9 polypeptide is set forth, e.g., in NBCI Ref. Seq. No. WP_011681470.

[0338] In some embodiments, the vector comprises one or more promoters, one or more poly-A sequences, one or more selectable markers, and / or an origin. Selection for cells comprising the vector is facilitated by incorporation into the vector of a gene whose product allows the -102- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 transfected cells to survive and grow under selective conditions. A number of such genes have been identified. These include, among others: (1) neo, a prokaryotic gene which encodes resistance to the aminoglycoside antibiotic G418; (2) E. coli guanine phosphoribosyl transferase (gpt), which encodes resistance to mycophenolic acid (MPA) in the presence of xanthine, [Mulligan et al , Proc. Nat. Acad. Sci. USA, 78:2072-2076 (1981)]; (3) dihydrofolate reductase (DHFR), which allows for growth of DHFR" cells in the absence of nucleosides and gene amplification in the presence of increasing concentration of methotrexate; (4) the hisD gene of Salmonella typhimurium which allows growth in the presence of histidinol (Hartman et al. , Proc. Nat. Acad. Sci. USA, 85:8047-8051, (1988)); (5) the trpB gene of E. coli (Hartman et al., Proc. Nat. Acad. Sci. USA, 85:8047-8051, (1988)), which allows growth in the presence of indole (without tryptophan); (6) the glutamine synthetase gene, which allows growth in media lacking glutamine, (7) a puromycin resistance gene (e.g., N-acetyltransferase [pac]), and 8) an ampicillin resistance gene (e.g., bla). The availability of these selective markers, either alone or in various combinations, provides flexibility in the generation of mammalian cell lines which express recombinant products at high levels. Cells

[0339] The present disclosure also provides cells comprising one or more isolated nucleic acid molecules, plasmids, or vectors described herein. In some embodiments, the cell is a prokaryotic cell. In some embodiments, the cell is a eukaryotic cell. In some embodiments, the cell is a mammalian cell (e.g., a murine, bovine, simian, porcine, equine, bovine, or human cell). In some embodiments, the cell is a human cell. In some embodiments, the cell is suited for the manufacture of therapeutic proteins, such as Chinese hamster ovary (CHO) cells, HEK cells, or mouse myeloma cells. In some embodiments, the cell is a CHO cell. In some embodiments, the cells is a HEK 293 cell. In some embodiments, the cell is a Expi293F cells, a derivative of a HEK 293 cell.

[0340] The nucleic acid molecules, plasmids and / or vectors described herein can be introduced into a cell by any method known in the art. Non-limiting examples of such methods are transfection, viral infection, conjugation, protoplast fusion, lipofection, electroporation, nucleofection, calcium phosphate precipitation, polyethyleneimine (PEI)-mediated transfection, DEAE-dextran mediated transfection, liposome-mediated transfection, particle gun technology, calcium phosphate precipitation, direct micro-injection, nanoparticle-mediated nucleic acid delivery, and the like. In some embodiments, the nucleic acid molecules, plasmids and / or vectors -103- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 described herein are introduced into a cell by lipofection. In some embodiments, the nucleic acid molecules, plasmids and / or vectors described herein are introduced into a cell by electroporation. In some embodiments, the nucleic acid molecules, plasmids and / or vectors described herein are introduced into a cell by nucleofection. In some embodiments, the nucleic acid molecules, plasmids and / or vectors are introduced into a cell by transfection. The transfection protocol may be any known in the art (e.g., those described in Kim and Eberwine. Anal Bioanal Chem.2010; 397(8):3173-3178). In some embodiments, two or more of the nucleic acid molecules, plasmids and / or vectors described herein are introduced into the same cell. In some embodiments, two or more of the nucleic acid molecules, plasmids and / or vectors described herein are co-transfected into a cell. In some embodiments, the nucleic acid molecules, plasmids and / or vectors are introduced using a method that comprises integration of the nucleic acid sequence or a portion thereof into the genome of the cell. In some embodiments, the polynucleotide or a portion thereof is stably integrated, (e.g., covalently inserted into a chromosome by homologous recombination, non-homologous end joining, transposition, etc.).

[0341] In some embodiments, the nucleic acid molecules, plasmids and / or vectors described herein direct the production of a protein product in the cell. In some embodiments, the nucleic acid molecules, plasmids and / or vectors described herein direct the production of the anti-BILF- 1 antibody or fragment thereof of the present disclosure in the cell.

[0342] After introduction to a cell of one or more nucleic acid molecules, plasmids and / or vectors described herein, cells are grown under conditions suitable for expression of the encoded polypeptide(s). In some embodiments, the cells are grown under conditions suitable for expression of the anti-BILF-1 antibody or fragment thereof of the present disclosure. Suitable cell culturing methods for protein production are known in the art. Cells can be cultured according to the manufacturer’s instructions and / or according to an optimized protocol. In some embodiments, the cells are grown in suspension. In some embodiments, the cells are grown in serum-free media. In some embodiments the cells are grown in the presence of serum. Purification

[0343] The anti-BILF-1 antibodies or fragments thereof described herein may be isolated from cells by an appropriate purification scheme using standard protein purification techniques. A variety of purification techniques for antibodies or antibody fragments are known in the art.

[0344] The purification process may comprise a step to clear the cell lysate. For example, the cell culture may be passed through a filter (e.g., a 0.22 or 0.44 μM filter) to yield a cleared cell -104- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 lysate. The purification process may comprise a binding step in which the antibody or fragment thereof is contacted with a first surface that interacts with it based on a first property of the antibody or fragment thereof (e.g., charge, size, hydrophobicity, or affinity). The purification process may additionally comprise a wash step, in which a first buffer is applied to the first surface, wherein the first buffer selectively removes polypeptides from the first surface while not disrupting the interaction between the first surface and the antibody or fragment thereof. The purification process may additionally comprise an elution step, in which a second buffer is applied to the first surface that disrupts the interaction between the first surface and the antibody or fragment thereof. Optionally, the purification process may additionally comprise further steps in which the antibody or fragment thereof is contacted with a second surface that interacts with it based on a second property of the antibody or fragment thereof. The purification process may also comprise further wash steps and elution steps. In some embodiments, purification of the anti- BILF-1 antibody or fragment thereof of the present disclosure comprises affinity chromatography. Non-limiting examples of affinity chromatography for antibody purification include magnetic or non-magnetic beads or resin covalently bound with recombinant protein G, recombinant protein A, and / or recombinant protein L. In some embodiments, purification of the anti-BILF-1 antibody or fragment thereof comprises binding the antibody or fragment thereof to recombinant Protein G. Pharmaceutical Compositions

[0345] The present disclosure also provides pharmaceutical compositions comprising one or more of the anti-BILF-1 antibodies or antigen binding fragments thereof disclosed herein. In some embodiments, the pharmaceutical composition comprises two or more anti-BILF-1 antibodies or fragments thereof described herein. In some embodiments, the pharmaceutical composition further comprises a second antibody or antigen binding fragment thereof which specifically binds to LMP-1 and / or LMP-2. In some embodiments, the pharmaceutical composition further comprises a second antibody or antigen binding fragment thereof which specifically binds to LMP-2. In some embodiments, the pharmaceutical composition further comprises one or more therapeutic agents which increase expression of EBV membrane proteins in EBV-infected cells. In some embodiments, the EBV-infected cells comprise B cells. In some embodiments, the one or more therapeutic agent which increase expression of EBV membrane proteins in EBV-infected cells is selected from the group consisting of valproic acid, trichostatin A (TSA), 5-azacytidine (5-AZA), romidepsin, panabinostat, vorinostat, decitabine, nanatinostat, -105- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 Deferasirox, rituximab, and combinations thereof. In some embodiments, the one or more therapeutic agents which increase expression of EBV membrane proteins in EBV-infected cells comprise romidepsin. In some embodiments, the one or more therapeutic agents comprise decitabine. In some embodiments, the one or more therapeutic agent comprise 5-AZA. In some embodiments, the one or more therapeutic agent comprise nanatinostat. In some embodiments, the one or more therapeutic agent comprise Deferasirox. In some embodiments, the one or more therapeutic agent comprise TSA. In some embodiments, the one or more therapeutic agent comprise decitabine, 5-AZA, and romidepsin. In some embodiments, the one or more therapeutic agent comprise panabinostat.

[0346] In some embodiments, the pharmaceutical composition additionally comprises a pharmaceutically acceptable diluent, carrier, or excipient. In some embodiments, the pharmaceutical composition additionally comprises a pharmaceutically acceptable excipient. Pharmaceutically acceptable carriers, diluents, and excipients may be any known in the art. In some embodiments, pharmaceutically acceptable carriers, diluents, and excipients are those that are useful in preparing a formulation that is generally safe, non-toxic, and desirable, and includes excipients that are acceptable for mammalian, e.g., human or primate, use. Such excipients can be solid, liquid, semisolid, or, in the case of an aerosol composition, gaseous. Examples of such carriers, diluents and excipients include, but are not limited to, water, saline, Ringer’s solutions, dextrose solution, and 5% human serum albumin. Supplementary active compounds can also be incorporated into the formulations. Solutions or suspensions used for the formulations can include a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial compounds such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating compounds such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetates, citrates or phosphates; detergents such as Tween 20 to prevent aggregation; and compounds for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. In some embodiments, the pharmaceutical compositions are sterile.

[0347] Pharmaceutical compositions may further include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, or phosphate buffered saline (PBS). In some cases, the composition is sterile and should be fluid such that it can be drawn into a syringe or delivered to a subject from a syringe. -106- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 In certain embodiments, it is stable under the conditions of manufacture and storage and is preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be, e.g., a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, sodium chloride in the composition. Prolonged absorption of the internal compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

[0348] Sterile solutions can be prepared by incorporating one or more of the anti-BILF-1 antibodies or fragments thereof described herein in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Methods of Treatment

[0349] The present disclosure also provides methods of treating a subject having, or at risk for having, one or more of an EBV infection or an EBV-mediated disease or condition, comprising administering one or more of the anti-BILF-1 antibody or fragment thereof and / or one or more of the pharmaceutical compositions disclosed herein to the subject. The anti-BILF-1 antibody or fragment thereof and / or the pharmaceutical compositions described herein are administered in an amount sufficient to improve symptoms of an EBV infection or EBV-mediated disease or condition.

[0350] Symptoms of an EBV infection or EBV-mediated disease or condition described herein can be evaluated using standard methods known to those of skill in the art and may be reduced (e.g., the subject's condition may be improved) by 5% or more (e.g., 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%) compared to symptoms prior to administration of the anti-BILF-1 antibody or fragment thereof and / or the pharmaceutical compositions described herein. These effects may occur, for example, within 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 15 weeks, 20 weeks, 25 weeks, or more, following administration of the anti-BILF-1 antibody or fragment thereof and / or the pharmaceutical -107- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 compositions described herein. The patient may be evaluated 1 month, 2 months, 3 months, 4 months, 5 months, 6 months or more following administration of the anti-BILF-1 antibody or fragment thereof and / or the pharmaceutical compositions depending on the dose and route of administration used for treatment.

[0351] In some embodiments of the methods of treating a subject having, or at risk for having, one or more of an EBV infection or an EBV-mediated disease or condition, the subject is EBV-positive. In some embodiments, the subject has a latent EBV infection. In certain embodiments, the EBV infection is characterized as Latency 0, Latency I, Latency II, or Latency III. In certain embodiments, the EBV infection is a chronic active EBV infection or an acute active EBV infection.

[0352] In some embodiments of the methods of treating a subject having, or at risk for having, one or more of an EBV infection or an EBV-mediated disease or condition, the EBV- mediated disease is one or more diseases selected from the group consisting of an EBV-mediated lymphoproliferative disorder (LPD), an EBV-mediated cancer, an EBV-mediated autoimmune disease, infectious mononucleosis, and combinations thereof.

[0353] In some embodiments, the one or more EBV-mediated diseases comprise hemophagocytic lymphohistiocytosis (HLH), Hodgkin’s lymphoma (HL), or non-Hodgkin’s lymphoma (NHL). In certain embodiments, the NHL is Burkitt’s lymphoma, diffuse large B cell lymphoma, B cell NHL, T cell NHL, or NK cell NHL. In certain embodiments, the T cell or NK cell NHL comprises peripheral T cell lymphoma (PTCL) and / or angioimmunoblastic T cell lymphoma (AILT).

[0354] In some embodiments, the one or more EBV-mediated diseases comprise an EBV- mediated LPD. In certain embodiments, the EBV-mediated LPD is a post-transplant lymphoproliferative disorder (PTLD) or an HIV-related LPD.

[0355] In some embodiments, the one or more EBV-mediated diseases comprise an EBV- mediated cancer. In certain embodiments, the EBV-mediated cancer is a non-lymphoid malignancy selected from the group consisting of nasopharyngeal carcinoma (NPC), gastric carcinoma (GC), Stomach adenocarcinoma and leiomyosarcoma.

[0356] In some embodiments, the one or more EBV-mediated diseases comprise an EBV- mediated autoimmune disease. In certain embodiments, the EBV-mediated autoimmune disease is one or more diseases selected from the group consisting of multiple sclerosis (MS), systemic lupus erythematosus (SLE), Sjogren’s Syndrome, type I diabetes (T1D), rheumatoid arthritis (RA), dermatomyositis, and combinations thereof. -108- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004

[0357] In some embodiments, the one or more EBV-mediated diseases comprise infectious mononucleosis.

[0358] In some embodiments of the methods of treating a subject having, or at risk for having, one or more of an EBV infection or an EBV-mediated disease or condition, the subject is immunocompromised. In some embodiments, the subject is about to undergo, is undergoing, or has undergone, an organ transplant procedure comprising therapeutic immunosuppression. In certain embodiments, the organ transplant procedure is a bone marrow transplant.

[0359] Various drugs have previously been shown to induce lytic stage in EBV+ cells, which can lead to upregulation of EBV membrane proteins in the EBV+ cells (EBV-infected cells). In some embodiments of the methods of treating a subject having, or at risk for having, one or more of an EBV infection or an EBV-mediated disease or condition, the methods comprise administering to the subject one or more of an anti-BILF-1 antibody or fragment thereof disclosed herein and one or more of an additional therapeutic agent. In some embodiments, the one or more therapeutic agent increases expression of EBV membrane proteins in EBV-infected cells. In some embodiments, the EBV-infected cells comprise B cells. In some embodiments, the one or more additional therapeutic agent is selected from the group consisting of valproic acid, trichostatin A (TSA), 5-azacytidine (5-AZA), romidepsin, panabinostat, vorinostat, decitabine, nanatinostat, Deferasirox, rituximab, and combinations thereof. In some embodiments, the one or more therapeutic agent comprise decitabine. In some embodiments, the one or more therapeutic agent comprise 5-AZA. In some embodiments, the one or more therapeutic agent comprise nanatinostat. In some embodiments, the one or more therapeutic agent comprise Deferasirox. In some embodiments, the one or more therapeutic agent comprise TSA. In some embodiments, the one or more therapeutic agent comprise romidepsin. In some embodiments, the one or more therapeutic agent comprise decitabine, 5-AZA, and romidepsin. In some embodiments, the one or more therapeutic agent comprise panabinostat.

[0360] In some embodiments of the methods of treating a subject having, or at risk for having, one or more of an EBV infection or an EBV-mediated disease or condition, the one or more antibody or fragment thereof or pharmaceutical composition described herein that is administered to the subject increases killing of EBV-infected cells in the subject by at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 2000% or more relative to an untreated control. In some embodiments, the one or more antibody or fragment thereof or pharmaceutical composition described herein reduces cell-free EBV DNA load in the subject by at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 200, 300, -109- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 400, 500, 600, 700, 800, 900, 1000, 2000% or more relative to an untreated control. In some embodiments, the one or more antibody or fragment thereof or pharmaceutical composition described herein reduces EBV-positive cell counts, optionally EBV-positive cancer cell counts, by at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 2000% or more relative to an untreated control. In some embodiments, the one or more antibody or fragment thereof or pharmaceutical composition described herein increases the subject’s overall survival, progression-free survival, time to progression, or any combination of the foregoing. In some embodiments, the one or more antibody or fragment thereof or pharmaceutical composition described herein reduces the number and / or severity of one or more adverse events in the subject.

[0361] In some embodiments of the methods of treatment described herein, the subject has an EBV-mediated autoimmune disease and the one or more antibody or fragment thereof or pharmaceutical composition disclosed herein reduces the progression of disability in the subject, optionally as measured by a Kurtzke Expanded Disability Status Scale (EDSS) or an SLE Disease Activity Index (SLEDAI).

[0362] In some embodiments of the methods of treatment described herein, the subject has EBV-mediated multiple sclerosis, and the one or more antibody or fragment thereof or pharmaceutical composition disclosed herein reduces relapse rate and / or central nervous system (CNS) lesion load in the subject.

[0363] In some embodiments of the methods of treating a subject having, or at risk for having, one or more of an EBV infection or an EBV-mediated disease or condition, the methods comprise genotyping the EBV in the subject, and administering the pharmaceutical composition to the subject if the EBV genotype is associated with a high risk of EBV-mediated disease. In some embodiments, the methods comprise determining EBV protein expression in an activated B cell in a subject who has an autoimmune disease, and administering the pharmaceutical composition to the subject if the activated B cell expresses one or more EBV proteins. In certain embodiments, the one or more EBV proteins is selected from the group consisting of EBNA-1, EBNA-2, EBNA-3A, EBNA-3B, EBNA-3C, EBNA-LP, LMP-1, LMP-2A, LMP-2B, and combinations thereof.

[0364] The anti-BILF-1 antibody or fragment thereof and / or the pharmaceutical compositions described herein may be administered to a subject by any mode of delivery, including, for example, by parenteral injection (e.g. subcutaneously, intraperitoneally, intravenously, intramuscularly, or to the interstitial space of a tissue), or by rectal, oral (e.g. tablet, -110- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 spray), vaginal, topical, transdermal (e.g. see WO99 / 27961) or transcutaneous, intranasal, ocular, aural, pulmonary or other mucosal administration and / or inhalation of powder compositions. Multiple doses can be administered by the same or different routes. In some embodiments of the methods of treatment described herein, the methods comprise administering one or more of the pharmaceutical compositions disclosed herein to the subject by parenteral administration. In some embodiments, the parenteral administration is intravenous administration.

[0365] The anti-BILF-1 antibody or fragment thereof and / or the pharmaceutical compositions described herein may be administered to a subject once, or more than once. For example, the anti-BILF-1 antibody or fragment thereof and / or the pharmaceutical compositions described herein may be administered one, two, three, four, five, six, seven, eight, nine, ten, or more times. Doses may be administered at any known interval. For example, doses may be administered every six hours, every eight hours, every 12 hours, every 18 hours, daily, every two days, twice weekly, weekly, twice monthly, or monthly.

[0366] The dose and dosage regimen may depend upon a variety of factors readily determined by a physician, such as the nature of the disease or condition, the characteristics of the subject, and the subject's history. In some embodiments, the effective amount of the anti-BILF-1 antibody or fragment thereof is about 10 mg to about 10,000 mg per day. In some embodiments, the effective amount of the anti-BILF-1 antibody or fragment thereof is about 100 mg to about 5,000 mg per day. In some embodiments, the effective amount of the anti-BILF-1 antibody or fragment thereof is about 1,000 mg to about 3,000 mg per day. In some embodiments, the effective amount of the anti-BILF-1 antibody or fragment thereof is about 0.1 mg / kg to about 300 mg / kg mg per day. In some embodiments, the effective amount of the anti-BILF-1 antibody or fragment thereof is about 1 mg / kg to about 100 mg / kg mg per day. In some embodiments, the effective amount of the anti-BILF-1 antibody or fragment thereof is about 10 mg / kg to about 30 mg / kg. Methods of Use

[0367] The anti-BILF-1 antibody or fragment thereof described herein can be used as a research agent. For example, the antibody or fragment thereof can be attached to a non-fluorescent or fluorescent material. Non-limiting examples of non-fluorescent materials include resin, non- magnetic or magnetic beads and streptavidin. The antibody or fragment thereof can be attached to a fluorescent dye using methods well known in the arts or using a commercially available antibody labeling kit. The labeled antibody or fragment thereof can be used to identify EBV+ cells. Non- limiting examples of research applications where the anti-BILF-1 antibody or fragment thereof -111- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 described herein can be used include flow cytometry, fluorescence-activated cell sorting, histology, western blot, ELISA, ELISpot, immunohistochemistry, immunoprecipitation, peptide array, and inhibition assays. Terms and concepts

[0368] A number of terms and concepts are discussed below. They are intended to facilitate the understanding of various embodiments of the invention in conjunction with the rest of the present document and the accompanying figures. These terms and concepts may be further clarified and understood based on the accepted conventions in the fields of the present invention, as well as the description provided throughout the present document and / or the accompanying figures. Some other terms can be explicitly or implicitly defined in other sections of this document and in the accompanying figures and may be used and understood based on the accepted conventions in the fields of the present invention, the description provided throughout the present document and / or the accompanying figures. The terms not explicitly defined can also be defined and understood based on the accepted conventions in the fields of the present invention and interpreted in the context of the present document and / or the accompanying figures.

[0369] Unless otherwise dictated by context, singular terms shall include pluralities, and plural terms shall include the singular. Generally, nomenclatures used in connection with, and techniques of, cell and tissue culture, molecular biology, immunology, microbiology, genetics and protein and nucleic acid chemistry are those well-known and commonly used. Known methods and techniques are generally performed according to conventional methods well-known and as described in various general and more specific references, unless otherwise indicated. Standard techniques may be used for recombinant technology, molecular biology, microbiology, chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients. The nomenclatures used in connection with the laboratory procedures and techniques described in the present disclosure are those well-known and commonly used.

[0370] The terms "a", "an", and "the" can refer to one or more unless specifically noted otherwise. The use of the term "or" is used to mean "and / or," unless explicitly indicated to refer to alternatives only, or the alternatives are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and "and / or." As used herein "another" can mean at least a second or more.

[0371] The term “or” as used herein, including the claims, is used to mean “and / or” unless explicitly indicated to refer to alternatives only or the alternatives are mutually exclusive. -112- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004

[0372] The terms “about” and “approximately” are used as equivalents. Any numerals used in this application with or without about / approximately are meant to cover any normal fluctuations appreciated by one of ordinary skill in the relevant art. In certain embodiments, the term “approximately” or “about” refers to a quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length that varies by as much as 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the stated reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length unless otherwise stated or otherwise evident from the context (except where such number would exceed 100% of a possible value).

[0373] An “agonist” refers to biological structure (e.g., antibody) or chemical agent that increases or enhances the physiological action of another agent or molecule. In some instances, the agonist specifically binds to the other agent or molecule. Included are full and partial agonists.

[0374] As used herein, the term “amino acid” is intended to mean both naturally occurring and non-naturally occurring amino acids as well as amino acid analogs and mimetics. Naturally occurring amino acids include the 20 (L)-amino acids utilized during protein biosynthesis as well as others such as 4-hydroxyproline, hydroxylysine, desmosine, isodesmosine, homocysteine, citrulline and ornithine, for example. Non-naturally occurring amino acids include, for example, (D)-amino acids, norleucine, norvaline, p-fluorophenylalanine, ethionine and the like, which are known to a person skilled in the art. Amino acid analogs include modified forms of naturally and non-naturally occurring amino acids. Such modifications can include, for example, substitution or replacement of chemical groups and moieties on the amino acid or by derivatization of the amino acid. Amino acid mimetics include, for example, organic structures which exhibit functionally similar properties such as charge and charge spacing characteristic of the reference amino acid. For example, an organic structure which mimics arginine (Arg or R) would have a positive charge moiety located in similar molecular space and having the same degree of mobility as the e-amino group of the side chain of the naturally occurring Arg amino acid. Mimetics also include constrained structures so as to maintain optimal spacing and charge interactions of the amino acid or of the amino acid functional groups. Those skilled in the art know or can determine what structures constitute functionally equivalent amino acid analogs and amino acid mimetics.

[0375] As used herein, the term “antibody” encompasses not only intact polyclonal or monoclonal antibodies, but also fragments thereof (such as dAb, Fab, Fab’, F(ab’)2, Fv), single chain (scFv), synthetic variants thereof, naturally occurring variants, fusion proteins comprising -113- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 an antibody portion with an antigen binding fragment of the required specificity, humanized antibodies, chimeric antibodies, and any other modified configuration of the immunoglobulin molecule that comprises an antigen binding site or fragment (epitope recognition site) of the required specificity. Certain features and characteristics of antibodies (and antigen binding fragments thereof) are described in greater detail herein.

[0376] An antibody, or antigen binding fragment thereof, can be of essentially any type. As is well known in the art, an antibody is an immunoglobulin molecule capable of specific binding to a target through at least one epitope recognition site, located in the variable region of the immunoglobulin molecule.

[0377] As used herein, the term “complementarity determining region” (“CDR”) describes the non-contiguous antigen combining sites (also known as antigen binding regions) found within the variable region of both heavy and light chain polypeptides. CDRs are also referred to as “hypervariable regions” and that term is used interchangeably herein with the term “CDR” in reference to the portions of the variable region that form the antigen binding regions.

[0378] The term “antigen binding fragment” as used herein refers to a polypeptide fragment that contains at least one CDR of an immunoglobulin heavy and / or light chain that binds to the antigen of interest (e.g. BILF-1). In this regard, an antigen binding fragment of the herein described antibodies may comprise 1, 2, 3, 4, 5, or all 6 CDRs of a VH and VL region from antibodies that bind to a target molecule (e.g. BILF-1).

[0379] The term “antigen” refers to a molecule or a portion of a molecule capable of being bound by a selective binding agent, such as an antibody, and additionally capable of being used in an animal to produce antibodies capable of binding to an epitope of that antigen. An antigen may have one or more epitopes. As used herein, the term “antigen” includes substances that are capable, under appropriate conditions, of inducing an immune response to the substance and of reacting with the products of the immune response. More broadly, the term “antigen” includes any substance to which an antibody binds, or for which antibodies are desired, regardless of whether the substance is immunogenic. For such antigens, antibodies can be identified by recombinant methods, independently of any immune response.

[0380] An “epitope” includes that portion of an antigen or other macromolecule capable of forming a binding interaction that interacts with the variable region binding pocket of an antibody, or antigen binding fragment thereof. Such binding interaction can be manifested as an intermolecular contact with one or more amino acid residues of a CDR. Antigen binding can involve a CDR3 or a CDR3 pair. An epitope can be a linear peptide sequence (i.e., “continuous”) -114- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 or can be composed of noncontiguous amino acid sequences (i.e., “conformational” or “discontinuous”). An antibody, or antigen binding fragment thereof, can recognize one or more amino acid sequences. Therefore, an epitope can define more than one distinct amino acid sequence. Epitopes can be determined, for example, by peptide mapping and sequence analysis techniques well known to one of skill in the art. In particular embodiments, an epitope comprises, consists, or consists essentially of about, at least about, or no more than about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 contiguous amino acids (i.e., a linear epitope) or non- contiguous amino acids (i.e., conformational epitope) of a reference sequence or target molecule described herein.

[0381] The binding properties of antibodies or antigen binding fragments thereof can be quantified using methods well known in the art (Davies et al., 2003). In some embodiments, an antibody, or antigen binding fragment thereof, specifically binds to a target molecule, for example, a cell surface receptor, a cancer or immunomodulatory antigen, or an epitope or complex thereof, -6 M to about 10- 11 M. In some embodiments, the equilibrium dissociation constant is about or ranges from about --10 M. In certain embodiments, an antibody, or antigen binding fragmentthereof, has an affinity (KD or EC50) for a target molecule (to which it specifically binds) of about, at least about, or less than about, 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, or 50 nM.

[0382] A molecule such as a polypeptide or antibody is said to exhibit “specific binding” or “preferential binding” if it reacts or associates more frequently, more rapidly, with greater duration and / or with greater affinity with a particular cell(s), substance(s), or particular epitope(s) than it does with alternative cells or substances, or epitopes. An antibody “specifically binds” or “preferentially binds” to a target molecule (e.g. BILF-1) or epitope if it binds with greater affinity, avidity, more readily, and / or with greater duration than it binds to other substances or epitopes, for example, by a statistically significant amount. Typically, one member of the pair of molecules that exhibit specific binding has an area on its surface, or a cavity, which specifically binds to and is therefore complementary to a particular spatial and / or polar organization of the other member of the pair of molecules. Thus, the members of the pair have the property of binding specifically to each other. For instance, an antibody that specifically or preferentially binds to a specific epitope is an antibody that binds that specific epitope with greater affinity, avidity, more readily, and / or with greater duration than it binds to other epitopes. It is also understood by reading this -115- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 definition that, for example, an antibody (or moiety or epitope) that specifically or preferentially binds to a first target may or may not specifically or preferentially bind to a second target. The term is also applicable where, for example, an antibody is specific for a particular epitope which is carried by a number of antigens, in which case the specific binding member carrying the antigen binding fragment or domain will be able to bind to the various antigens carrying the epitope; for example, it may be cross reactive to a number of different forms of a target antigen from multiple species that share a common epitope.

[0383] Immunological binding generally refers to the non-covalent interactions of the type which occur between an immunoglobulin molecule and an antigen for which the immunoglobulin is specific, for example by way of illustration and not limitation, as a result of electrostatic, ionic, hydrophilic and / or hydrophobic attractions or repulsion, steric forces, hydrogen bonding, van der Waals forces, and other interactions. The strength, or affinity of immunological binding interactions can be expressed in terms of the dissociation constant (KD) of the interaction, wherein a smaller KD represents a greater affinity. Immunological binding properties of selected polypeptides can be quantified using methods well known in the art. One such method entails measuring the rates of antigen binding site / antigen complex formation and dissociation, wherein those rates depend on the concentrations of the complex partners, the affinity of the interaction, and on geometric parameters that equally influence the rate in both directions. Thus, both the “on rate constant” (Kon) and the “off rate constant” (Koff) can be determined by calculation of the concentrations and the actual rates of association and dissociation. The ratio of Koff / Kon enables cancellation of all parameters not related to affinity and is thus equal to the dissociation constant KD. As used herein, the term “affinity” includes the equilibrium constant for the reversible binding of two agents and is expressed as KD or EC50. Affinity of a binding protein to a ligand such as affinity of an antibody for an epitope can be, for example, from about 100 nanomolar (nM) to about 0.1 nM, from about 100 nM to about 1 picomolar (pM), or from about 100 nM to about 1 femtomolar (fM). As used herein, the term “avidity” refers to the resistance of a complex of two or more agents to dissociation after dilution. In some embodiments, affinity is expressed in the terms of the half maximal effective concentration (EC50), which refers to the concentration of an agent, such as an antibody, as disclosed herein, which induces a response halfway between the baseline and maximum after a specified exposure time. The EC50 is commonly used as a measure of an antibody’s potency.

[0384] Antibodies may be prepared by any of a variety of techniques known to those of ordinary skill in the art. See, e.g., Harlow and Lane, Antibodies: A Laboratory Manual, Cold -116- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 Spring Harbor Laboratory, 1988. Monoclonal antibodies specific for a polypeptide of interest may be prepared, for example, using the technique of (Köhler & Milstein, 1976), and improvements thereto. Also included are methods that utilize transgenic animals such as mice to express human antibodies. See, e.g., (Neuberger, 1996); Lonberg et al., Handbook of Experimental Pharmacology 113:49-101, 1994; and (Lonberg & Huszar, 1995). Particular examples include the VELOCIMMUNE® platform by REGENEREX® (see, e.g., U.S. Patent No.6,596,541).

[0385] Antibodies can also be generated or identified by the use of phage display or yeast display libraries (see, e.g., U.S. Patent No.7,244,592; (Chao et al., 2006)). Non-limiting examples of available libraries include cloned or synthetic libraries, such as the Human Combinatorial Antibody Library (HuCAL), in which the structural diversity of the human antibody repertoire is represented by seven heavy chain and seven light chain variable region genes. The combination of these genes gives rise to 49 frameworks in the master library. By superimposing highly variable genetic cassettes (CDRs = complementarity determining regions) on these frameworks, the vast human antibody repertoire can be reproduced. Also included are human libraries designed with human-donor-sourced fragments encoding a light-chain variable region, a heavy-chain CDR-3, synthetic DNA encoding diversity in heavy-chain CDR-1, and synthetic DNA encoding diversity in heavy-chain CDR-2. Other libraries suitable for use will be apparent to persons skilled in the art.

[0386] In certain embodiments, antibodies or antigen binding fragments thereof as described herein include a heavy chain and a light chain CDR set, respectively interposed between a heavy chain and a light chain framework region (FR) set which provide support to the CDRs and define the spatial relationship of the CDRs relative to each other. As used herein, the term “CDR set” refers to the three hypervariable regions of a heavy or light chain V region. Proceeding from the N-terminus of a heavy or light chain, these regions are denoted as “CDR1,” “CDR2,” and “CDR3” respectively. An antigen binding site, therefore, includes six CDRs, comprising the CDR set from each of a heavy and a light chain V region. A polypeptide comprising a single CDR, (e.g., a CDR1, CDR2 or CDR3) is referred to herein as a “molecular recognition unit.” Crystallographic analysis of a number of antigen-antibody complexes has demonstrated that the amino acid residues of CDRs form extensive contact with bound antigen, wherein the most extensive antigen contact is with the heavy chain CDR3. Thus, the molecular recognition units are primarily responsible for the specificity of an antigen binding site.

[0387] As used herein, the term “FR set” refers to the four flanking amino acid sequences which frame the CDRs of a CDR set of a heavy or light chain V region. Some FR residues may -117- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 contact bound antigen; however, FRs are primarily responsible for folding the V region into the antigen binding site, particularly the FR residues directly adjacent to the CDRs. Within FRs, certain amino residues and certain structural features are very highly conserved. In this regard, all V region sequences contain an internal disulfide loop of around 90 amino acid residues. When the V regions fold into a binding-site, the CDRs are displayed as projecting loop motifs which form an antigen binding surface. It is generally recognized that there are conserved structural regions of FRs which influence the folded shape of the CDR loops into certain “canonical” structures— regardless of the precise CDR amino acid sequence. Further, certain FR residues are known to participate in non-covalent interdomain contacts which stabilize the interaction of the antibody heavy and light chains.

[0388] The structures and locations of immunoglobulin variable domains may be determined by reference to Kabat, E. A. et al., Sequences of Proteins of Immunological Interest. 4th Edition. US Department of Health and Human Services.1987, and updates thereof.

[0389] Also included are “monoclonal” antibodies, which refer to a homogeneous antibody population wherein the monoclonal antibody is comprised of amino acids (naturally occurring and non-naturally occurring) that are involved in the selective binding of an epitope. Monoclonal antibodies are highly specific, being directed against a single epitope. The term “monoclonal antibody” encompasses not only intact monoclonal antibodies and full-length monoclonal antibodies, but also fragments thereof (such as Fab, Fab’, F(ab’)2, Fv), single chain (ScFv), variants thereof, fusion proteins comprising an antigen binding portion, humanized monoclonal antibodies, chimeric monoclonal antibodies, and any other modified configuration of the immunoglobulin molecule that comprises an antigen binding fragment (epitope recognition site) of the required specificity and the ability to bind to an epitope. It is not intended to be limited as regards the source of the antibody or the manner in which it is made (e.g., by hybridoma, phage selection, recombinant expression, transgenic animals). The term includes whole immunoglobulins as well as the fragments etc. described above under the definition of “antibody.”

[0390] The proteolytic enzyme papain preferentially cleaves IgG molecules to yield several fragments, two of which (the F(ab) fragments) each comprise a covalent heterodimer that includes an intact antigen binding site. The enzyme pepsin is able to cleave IgG molecules to provide several fragments, including the F(ab’)2 fragment which comprises both antigen binding sites. An Fv fragment for use according to certain embodiments can be produced by preferential proteolytic cleavage of an IgM, and on rare occasions of an IgG or IgA immunoglobulin molecule. Fv fragments are, however, more commonly derived using recombinant techniques known in the art. -118- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 The Fv fragment includes a non-covalent VH::VL heterodimer including an antigen binding site which retains much of the antigen recognition and binding capabilities of the native antibody molecule. See (Inbar et al., 1972); (Hochman et al., 1976) and (Matsueda et al., 1980).

[0391] In certain embodiments, single chain Fv (scFV) antibodies are contemplated. For example, Kappa bodies (Ill et al., 1997); minibodies (Martin et al., 1994); diabodies; (Holliger et al., 1993); or Janusins (Traunecker et al., 1991); and (Traunecker et al., 1992), may be prepared using standard molecular biology techniques following the teachings of the present application with regard to selecting antibodies having the desired specificity.

[0392] A single chain Fv (scFv) polypeptide is a covalently linked VH::VL heterodimer which is expressed from a gene fusion including VH- and VL-encoding genes linked by a peptide- encoding linker. (Huston et al., 1988). A number of methods have been described to discern chemical structures for converting the naturally aggregated—but chemically separated—light and heavy polypeptide chains from an antibody V region into an scFv molecule which will fold into a three-dimensional structure substantially similar to the structure of an antigen binding site. See, e.g., U.S. Pat. Nos. 5,091,513 and 5,132,405, to Huston et al.; and U.S. Pat. No. 4,946,778, to Ladner et al.

[0393] Certain embodiments include “probodies”, or antibodies where the binding site(s) are masked or otherwise inert until activated by proteolytic cleavage in target or disease tissue. Certain of these and related embodiments comprise one or more masking moieties that sterically hinder the antigen binding site(s) of the antibody, and which are fused to the antibody via one or more proteolytically-cleavable linkers (see, for example, (Polu & Lowman, 2014)).

[0394] In certain embodiments, an antibody as described herein is in the form of a diabody. Diabodies are multimers of polypeptides, each polypeptide comprising a first domain comprising a binding region of an immunoglobulin light chain and a second domain comprising a binding region of an immunoglobulin heavy chain, the two domains being linked (e.g., by a peptide linker) but unable to associate with each other to form an antigen binding site: antigen binding sites are formed by the association of the first domain of one polypeptide within the multimer with the second domain of another polypeptide within the multimer (WO94 / 13804).

[0395] A dAb fragment of an antibody consists of a VH domain (Ward et al., 1989).

[0396] Where bispecific or multi-specific antibodies are to be used, these may be conventional bispecific antibodies, which can be manufactured in a variety of ways (Holliger & Winter, 1993) e.g., prepared chemically or from hybrid hybridomas, or may be any of the bispecific antibody fragments mentioned above. Diabodies and scFv can be constructed without -119- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 an Fc region, using only variable domains, potentially reducing the effects of anti-idiotypic reaction. Bispecific whole antibodies may be made by knobs-into-holes engineering (Ridgway et al., 1996).

[0397] Bispecific diabodies, as opposed to bispecific whole antibodies, may also be particularly useful because they can be readily constructed and expressed in E. coli. Diabodies (and many other polypeptides such as antibody fragments) of appropriate binding specificities can be readily selected using phage display (WO94 / 13804) from libraries. If one arm of the diabody is to be kept constant, for instance, with a specificity directed against antigen X, then a library can be made where the other arm is varied and an antibody of appropriate specificity selected.

[0398] In certain embodiments, the antibodies described herein may be provided in the form of a UniBody®. A UniBody® is an IgG4 antibody with the hinge region removed (see GenMab Utrecht, The Netherlands; see also, e.g., US20090226421). This proprietary antibody technology creates a stable, smaller antibody format with an anticipated longer therapeutic window than current small antibody formats. IgG4 antibodies are considered inert and thus do not interact with the immune system. Fully human IgG4 antibodies may be modified by eliminating the hinge region of the antibody to obtain half-molecule fragments having distinct stability properties relative to the corresponding intact IgG4 (GenMab, Utrecht). Halving the IgG4 molecule leaves only one area on the UniBody® that can bind to cognate antigens (e.g., disease targets) and the UniBody® therefore binds univalently to only one site on target cells. For certain cancer cell surface antigens, this univalent binding may not stimulate the cancer cells to grow as may be seen using bivalent antibodies having the same antigen specificity, and hence UniBody® technology may afford treatment options for some types of cancer that may be refractory to treatment with conventional antibodies. The small size of the UniBody® can be a great benefit when treating some forms of cancer, allowing for better distribution of the molecule over larger solid tumors and potentially increasing efficacy.

[0399] In certain embodiments, the antibodies of the present disclosure may take the form of a Nanobody®. Nanobodies® are encoded by single genes and are efficiently produced in almost all prokaryotic and eukaryotic hosts e.g. E. coli (see e.g. U.S. Pat. No. 6,765,087), molds (for example Aspergillus or Trichoderma) and yeast (for example Saccharomyces, Kluyvermyces, Hansenula or Pichia (see e.g. U.S. Pat. No. 6,838,254). The production process is scalable and multi-kilogram quantities of Nanobodies® have been produced. Nanobodies may be formulated as a ready-to-use solution having a long shelf life. The Nanoclone® method (see, e.g., WO -120- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 06 / 079372) is a proprietary method for generating Nanobodies against a desired target, based on automated high-throughput selection of B-cells.

[0400] In certain embodiments, the antibodies or antigen binding fragments thereof described herein are humanized. These embodiments refer to a chimeric molecule, generally prepared using recombinant techniques, having an antigen binding site derived from an immunoglobulin from a non-human species and the remaining immunoglobulin structure of the molecule based upon the structure and / or sequence of a human immunoglobulin. The antigen binding site may comprise either complete variable domains fused onto constant domains or only the CDRs grafted onto appropriate framework regions in the variable domains. Epitope binding sites may be wild type or modified by one or more amino acid substitutions. This eliminates the constant region as an immunogen in human individuals, but the possibility of an immune response to the foreign variable region remains ((Lobuglio et al., 1989); (Queen et al., 1989); (Riechmann et al., 1988)). Illustrative methods for humanization of antibodies include the methods described in U.S. Patent No.7,462,697.

[0401] Another approach focuses not only on providing human-derived constant regions but modifying the variable regions as well so as to reshape them as closely as possible to human form. It is known that the variable regions of both heavy and light chains contain three complementarity-determining regions (CDRs) which vary in response to the epitopes in question and determine binding capability, flanked by four framework regions (FRs) which are relatively conserved in a given species and which putatively provide a scaffolding for the CDRs. When nonhuman antibodies are prepared with respect to a particular epitope, the variable regions can be “reshaped” or “humanized” by grafting CDRs derived from nonhuman antibody on the FRs present in the human antibody to be modified. Application of this approach to various antibodies has been reported by (Sato et al., 1993);(Riechmann et al., 1988); (Verhoeyen et al., 1988); (Kettleborough et al., 1991); (Maeda et al., 1991); (Gorman et al., 1991); (Tempest...

Claims

ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 CLAIMS I / We claim:

1. An isolated antibody, or an antigen binding fragment thereof, which specifically binds to an extracellular domain (ECD) of the Epstein Barr Virus (EBV) membrane protein BILF-1.

2. The isolated antibody or fragment thereof of claim 1, wherein the antibody or fragment thereof specifically binds to one or more BILF-1 extracellular domains selected from the group consisting of ECD1, ECD2, ECD3, ECD4, and combinations thereof.

3. The isolated antibody or fragment thereof of claim 2, wherein the antibody or fragment thereof specifically binds to ECD1 of BILF-1 through contact with one or more amino acid residues within an epitope comprising SEQ ID NO:

2.

4. The isolated antibody or fragment thereof of claim 2 or claim 3, wherein the antibody or fragment thereof specifically binds to ECD2 of BILF-1 through contact with one or more amino acid residues within an epitope comprising of SEQ ID NO:

3.

5. The isolated antibody or fragment thereof of any one of claims 2 – 4, wherein the antibody or fragment thereof specifically binds to ECD3 of BILF-1 through contact with one or more amino acid residues within an epitope comprising of SEQ ID NO:

4.

6. The isolated antibody or fragment thereof of any one of claims 2 – 5, wherein the antibody or fragment thereof specifically binds to ECD4 of BILF-1 through contact with one or more amino acid residues within an epitope comprising of SEQ ID NO:

5.

7. The isolated antibody or fragment thereof of any one of claims 1 – 6, wherein the antibody or fragment thereof specifically binds to the ECD of BILF-1 through contact with one or more amino acid residues relative to SEQ ID NO: 1 selected from the group consisting of L2, S3, T4, P7, S9, T10, L14, V15, N17, M18, T19, S20, V21, N22, A23, T24, T29, K30, S31, Y32, E90, F91, S92, G95, T160, M161, G 162, M173, E176, G177, P178, H183, T184, A191, T259, L262, V263, A264, R265, and G269. -146- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 8. The isolated antibody or fragment thereof of claim 7, wherein the antibody or fragment thereof specifically binds to the ECD of BILF-1 through contact with three or more amino acid residues relative to SEQ ID NO: 1 selected from the group consisting of L2, S3, T4, P7, S9, T10, L14, V15, N17, M18, T19, S20, V21, N22, A23, T24, T29, K30, S31, Y32, E90, F91, S92, G95, T160, M161, G 162, M173, E176, G177, P178, H183, T184, A191, T259, L262, V263, A264, R265, and G269.

9. The isolated antibody or fragment thereof of any one of claims 1 – 6, wherein the antibody or fragment thereof specifically binds to the ECD of BILF-1 through contact with one or more amino acid residues relative to SEQ ID NO: 1 selected from the group consisting of M39, D164, A165, N166, L167, N168, R169, G170, P171, N172, R175, T179, K180, G181, M182, A185, V186, Q187, G188, L189, K190, A251, S253, L254, G255, F256, D257, C258, E260, S261, Y266, Y267, and P268.

10. The isolated antibody or fragment thereof of claim 9, wherein the antibody or fragment thereof specifically binds to the ECD of BILF-1 through contact with three or more amino acid residues relative to SEQ ID NO: 1 selected from the group consisting of M39, D164, A165, N166, L167, N168, R169, G170, P171, N172, R175, T179, K180, G181, M182, A185, V186, Q187, G188, L189, K190, A251, S253, L254, G255, F256, D257, C258, E260, S261, Y266, Y267, and P268.

11. The isolated antibody or fragment thereof of any one of claims 1 – 10, wherein the antibody or fragment thereof specifically binds to amino acids proximal to the transmembrane region of the EBV membrane protein; and wherein the specific binding changes the conformational structure of BILF-1 and alters the function of BILF-1.

12. The isolated antibody or fragment thereof of any one of claims 1 – 11, wherein the antibody or fragment thereof is a monoclonal antibody and / or a humanized antibody, or an antigen binding fragment thereof.

13. The isolated antibody or fragment thereof of any one of claims 1 – 12, wherein the antibody or fragment thereof is a whole immunoglobulin, a fragment antigen binding domain (Fab), a F(ab’)2 domain, a single-chain variable fragment (scFv), a dimeric single- chain variable fragment (di-scFv), or a single domain antibody (sdAb). -147- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 14. The isolated antibody or fragment thereof of any one of claims 1 – 13, comprising an Fc region selected from the group consisting of IgA, IgD, IgE, IgG, and IgM Fc region; and optionally wherein the Fc region is a human Fc region.

15. The isolated antibody or fragment thereof of claim 14, comprising an Fc region selected from the group consisting of IgA1, IgA2, IgG1, IgG2, IgG3, and IgG4.

16. The isolated antibody or fragment thereof of claim 14 or claim 15, comprising an IgG Fc region with high effector function in humans.

17. The isolated antibody or fragment thereof of claim 16, wherein the IgG Fc region is IgG1 or IgG3.

18. The isolated antibody or fragment thereof of any one of claims 1 – 17, comprising a modified Fc region which has at least one altered effector function and / or pharmacokinetic (PK) characteristic relative to a wild type Fc region.

19. The isolated antibody or fragment thereof of claim 18, wherein the at least one altered effector function comprises increased engagement with natural killer (NK) cells, macrophages, neutrophils, and / or dendritic cells.

20. The isolated antibody or fragment thereof of claim 18 or claim 19, wherein the modified Fc , optionally wherein the modified Fc region is afucosylated.

21. The isolated antibody or fragment thereof of any one of claims 1 – 20, wherein the antibody or fragment thereof comprises: a) a heavy chain (HC) complementarity determining region (CDR) 1 sequence of SEQ ID NO: 14, a HC CDR2 sequence of SEQ ID NO: 15, a HC CDR3 sequence of SEQ ID NO: 16; a HC CDR1 sequence of SEQ ID NO: 290, a HC CDR2 sequence of SEQ ID NO: 291, a HC CDR3 sequence of SEQ ID NO: 292; a HC CDR1 sequence of SEQ ID NO: 297, a HC CDR2 sequence of SEQ ID NO: 298, a HC CDR3 sequence of SEQ ID NO: 299; -148- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 a HC CDR1 sequence of SEQ ID NO: 304, a HC CDR2 sequence of SEQ ID NO: 305, a HC CDR3 sequence of SEQ ID NO: 306; or a HC CDR1 sequence of SEQ ID NO: 311, a HC CDR2 sequence of SEQ ID NO: 312, a HC CDR3 sequence of SEQ ID NO: 313; and b) a light chain (LC) complementarity determining region (CDR) 1 sequence of SEQ ID NO: 17, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 19; a LC CDR1 sequence of SEQ ID NO: 234, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 236; a LC CDR1 sequence of SEQ ID NO: 241, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 243; a LC CDR1 sequence of SEQ ID NO: 248, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 250; a LC CDR1 sequence of SEQ ID NO: 255, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 257; a LC CDR1 sequence of SEQ ID NO: 262, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 264; a LC CDR1 sequence of SEQ ID NO: 269, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 271; a LC CDR1 sequence of SEQ ID NO: 276, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 278; or a LC CDR1 sequence of SEQ ID NO: 283, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO:

285.

22. The isolated antibody or fragment thereof of any one of claims 1-20, wherein the antibody or fragment thereof comprises: a) a heavy chain (HC) complementarity determining region (CDR) 1 sequence of SEQ ID NO: 14, a HC CDR2 sequence of SEQ ID NO: 15, a HC CDR3 sequence of SEQ ID NO: 16, a light chain (LC) CDR1 sequence of SEQ ID NO: 17, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 19; b) a HC CDR1 sequence of SEQ ID NO: 28, a HC CDR2 sequence of SEQ ID NO: 29, a HC CDR3 sequence of SEQ ID NO: 30, a LC CDR1 sequence of SEQ ID NO: 31, a LC CDR2 sequence of YAS, and a LC CDR3 sequence of SEQ ID NO: 33; -149- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 c) a HC CDR1 sequence of SEQ ID NO: 42, a HC CDR2 sequence of SEQ ID NO: 43, a HC CDR3 sequence of SEQ ID NO: 44, a LC CDR1 sequence of SEQ ID NO: 45, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 47; d) a HC CDR1 sequence of SEQ ID NO: 56, a HC CDR2 sequence of SEQ ID NO: 57, a HC CDR3 sequence of SEQ ID NO: 58, a LC CDR1 sequence of SEQ ID NO: 59, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 61; e) a HC CDR1 sequence of SEQ ID NO: 70, a HC CDR2 sequence of SEQ ID NO: 71, a HC CDR3 sequence of SEQ ID NO: 72, a LC CDR1 sequence of SEQ ID NO: 73, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 75; f) a HC CDR1 sequence of SEQ ID NO: 84, a HC CDR2 sequence of SEQ ID NO: 85, a HC CDR3 sequence of SEQ ID NO: 86, a LC CDR1 sequence of SEQ ID NO: 87, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 89; g) a HC CDR1 sequence of SEQ ID NO: 98, a HC CDR2 sequence of SEQ ID NO: 99, a HC CDR3 sequence of SEQ ID NO: 100, a LC CDR1 sequence of SEQ ID NO: 101, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 103; h) a HC CDR1 sequence of SEQ ID NO: 112, a HC CDR2 sequence of SEQ ID NO: 113, a HC CDR3 sequence of SEQ ID NO: 114, a LC CDR1 sequence of SEQ ID NO: 115, a LC CDR2 sequence of YAS, and a LC CDR3 sequence of SEQ ID NO: 117; i) a HC CDR1 sequence of SEQ ID NO: 126, a HC CDR2 sequence of SEQ ID NO: 127, a HC CDR3 sequence of SEQ ID NO: 128, a LC CDR1 sequence of SEQ ID NO: 129, a LC CDR2 sequence of YAS, and a LC CDR3 sequence of SEQ ID NO: 131; j) a HC CDR1 sequence of SEQ ID NO: 140, a HC CDR2 sequence of SEQ ID NO: 141, a HC CDR3 sequence of SEQ ID NO: 142, a LC CDR1 sequence of SEQ ID NO: 143, a LC CDR2 sequence of YAS, and a LC CDR3 sequence of SEQ ID NO: 145; k) a HC CDR1 sequence of SEQ ID NO: 154, a HC CDR2 sequence of SEQ ID NO: 155, a HC CDR3 sequence of SEQ ID NO: 156, a LC CDR1 sequence of SEQ ID NO: 157, a LC CDR2 sequence of WAS, and a LC CDR3 sequence of SEQ ID NO: 159; l) a HC CDR1 sequence of SEQ ID NO: 168, a HC CDR2 sequence of SEQ ID NO: 169, a HC CDR3 sequence of SEQ ID NO: 170, a LC CDR1 sequence of SEQ ID -150- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 NO: 171, a LC CDR2 sequence of YAS, and a LC CDR3 sequence of SEQ ID NO: 173; m) a HC CDR1 sequence of SEQ ID NO: 182, a HC CDR2 sequence of SEQ ID NO: 183, a HC CDR3 sequence of SEQ ID NO: 184, a LC CDR1 sequence of SEQ ID NO: 185, a LC CDR2 sequence of YAS, and a LC CDR3 sequence of SEQ ID NO: 187; n) a HC CDR1 sequence of SEQ ID NO: 196, a HC CDR2 sequence of SEQ ID NO: 197, a HC CDR3 sequence of SEQ ID NO: 198, a LC CDR1 sequence of SEQ ID NO: 199, a LC CDR2 sequence of AAS, and a LC CDR3 sequence of SEQ ID NO: 201; o) a HC CDR1 sequence of SEQ ID NO: 210, a HC CDR2 sequence of SEQ ID NO: 211, a HC CDR3 sequence of SEQ ID NO: 212, a LC CDR1 sequence of SEQ ID NO: 213, a LC CDR2 sequence of GTN, and a LC CDR3 sequence of SEQ ID NO: 215; p) a HC CDR1 sequence of SEQ ID NO: 14, a HC CDR2 sequence of SEQ ID NO: 15, a HC CDR3 sequence of SEQ ID NO: 16, a LC CDR1 sequence of SEQ ID NO: 234, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 236; q) a HC CDR1 sequence of SEQ ID NO: 14, a HC CDR2 sequence of SEQ ID NO: 15, a HC CDR3 sequence of SEQ ID NO: 16, a LC CDR1 sequence of SEQ ID NO: 241, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 243; r) a HC CDR1 sequence of SEQ ID NO: 14, a HC CDR2 sequence of SEQ ID NO: 15, a HC CDR3 sequence of SEQ ID NO: 16, a LC CDR1 sequence of SEQ ID NO: 248, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 250; s) a HC CDR1 sequence of SEQ ID NO: 14, a HC CDR2 sequence of SEQ ID NO: 15, a HC CDR3 sequence of SEQ ID NO: 16, a LC CDR1 sequence of SEQ ID NO: 255, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 257; t) a HC CDR1 sequence of SEQ ID NO: 14, a HC CDR2 sequence of SEQ ID NO: 15, a HC CDR3 sequence of SEQ ID NO: 16, a LC CDR1 sequence of SEQ ID NO: 262, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 264; u) a HC CDR1 sequence of SEQ ID NO: 14, a HC CDR2 sequence of SEQ ID NO: 15, a HC CDR3 sequence of SEQ ID NO: 16, a LC CDR1 sequence of SEQ ID NO: 269, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 271; -151- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 v) a HC CDR1 sequence of SEQ ID NO: 14, a HC CDR2 sequence of SEQ ID NO: 15, a HC CDR3 sequence of SEQ ID NO: 16, a LC CDR1 sequence of SEQ ID NO: 276, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 278; or w) a HC CDR1 sequence of SEQ ID NO: 14, a HC CDR2 sequence of SEQ ID NO: 15, a HC CDR3 sequence of SEQ ID NO: 16, a LC CDR1 sequence of SEQ ID NO: 283, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO:

285.

23. The isolated antibody or fragment thereof of any one of claims 1-20, wherein the antibody or fragment thereof comprises a) a HC CDR1 sequence of SEQ ID NO: 14, a HC CDR2 sequence of SEQ ID NO: 15, a HC CDR3 sequence of SEQ ID NO: 16, a HC FR1 sequence of SEQ ID NO: 6, a HC FR2 sequence of SEQ ID NO: 7, a HC FR3 sequence of SEQ ID NO: 8, a HC FR4 sequence of SEQ ID NO: 9; a HC CDR1 sequence of SEQ ID NO: 290, a HC CDR2 sequence of SEQ ID NO: 291, a HC CDR3 sequence of SEQ ID NO: 292, a HC FR1 sequence of SEQ ID NO: 286, a HC FR2 sequence of SEQ ID NO: 287, a HC FR3 sequence of SEQ ID NO: 288, a HC FR4 sequence of SEQ ID NO: 289; a HC CDR1 sequence of SEQ ID NO: 297, a HC CDR2 sequence of SEQ ID NO: 298, a HC CDR3 sequence of SEQ ID NO: 299, a HC FR1 sequence of SEQ ID NO: 293, a HC FR2 sequence of SEQ ID NO: 294, a HC FR3 sequence of SEQ ID NO: 295, a HC FR4 sequence of SEQ ID NO: 296; a HC CDR1 sequence of SEQ ID NO: 304, a HC CDR2 sequence of SEQ ID NO: 305, a HC CDR3 sequence of SEQ ID NO: 306, a HC FR1 sequence of SEQ ID NO: 300, a HC FR2 sequence of SEQ ID NO: 301, a HC FR3 sequence of SEQ ID NO: 302, a HC FR4 sequence of SEQ ID NO: 303; or a HC CDR1 sequence of SEQ ID NO: 311, a HC CDR2 sequence of SEQ ID NO: 312, a HC CDR3 sequence of SEQ ID NO: 313, a HC FR1 sequence of SEQ ID NO: 307, a HC FR2 sequence of SEQ ID NO: 308, a HC FR3 sequence of SEQ ID NO: 309, a HC FR4 sequence of SEQ ID NO: 310; and b) a LC CDR1 sequence of SEQ ID NO: 17, a LC CDR2 sequence of GTS, a LC CDR3 sequence of SEQ ID NO: 19, a LC FR1 sequence of SEQ ID NO: 10, a LC FR2 sequence of SEQ ID NO: 11, a LC FR3 sequence of SEQ ID NO: 12, and a LC FR4 sequence of SEQ ID NO: 13; -152- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 a LC CDR1 sequence of SEQ ID NO: 234, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 236, a LC FR1 sequence of SEQ ID NO: 230, a LC FR2 sequence of SEQ ID NO: 231, a LC FR3 sequence of SEQ ID NO: 232, and a LC FR4 sequence of SEQ ID NO: 233; a LC CDR1 sequence of SEQ ID NO: 241, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 243, a LC FR1 sequence of SEQ ID NO: 237, a LC FR2 sequence of SEQ ID NO: 238, a LC FR3 sequence of SEQ ID NO: 239, and a LC FR4 sequence of SEQ ID NO: 240; a LC CDR1 sequence of SEQ ID NO: 248, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 250, a LC FR1 sequence of SEQ ID NO: 244, a LC FR2 sequence of SEQ ID NO: 245, a LC FR3 sequence of SEQ ID NO: 246, and a LC FR4 sequence of SEQ ID NO: 247; a LC CDR1 sequence of SEQ ID NO: 255, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 257, a LC FR1 sequence of SEQ ID NO: 251, a LC FR2 sequence of SEQ ID NO: 252, a LC FR3 sequence of SEQ ID NO: 253, and a LC FR4 sequence of SEQ ID NO: 254; a LC CDR1 sequence of SEQ ID NO: 262, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 264, a LC FR1 sequence of SEQ ID NO: 258, a LC FR2 sequence of SEQ ID NO: 259, a LC FR3 sequence of SEQ ID NO: 260, and a LC FR4 sequence of SEQ ID NO: 261; a LC CDR1 sequence of SEQ ID NO: 269, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 271, a LC FR1 sequence of SEQ ID NO: 265, a LC FR2 sequence of SEQ ID NO: 266, a LC FR3 sequence of SEQ ID NO: 267, and a LC FR4 sequence of SEQ ID NO: 268; a LC CDR1 sequence of SEQ ID NO: 276, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 278, a LC FR1 sequence of SEQ ID NO: 272, a LC FR2 sequence of SEQ ID NO: 273, a LC FR3 sequence of SEQ ID NO: 274, and a LC FR4 sequence of SEQ ID NO: 275; or a LC CDR1 sequence of SEQ ID NO: 283, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 285, a LC FR1 sequence of SEQ ID NO: 279, a LC FR2 sequence of SEQ ID NO: 280, a LC FR3 sequence of SEQ ID NO: 281, and a LC FR4 sequence of SEQ ID NO:

282. -153- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 24. The isolated antibody or fragment thereof of any one of claims 1-20, wherein the antibody or fragment thereof comprises a) a heavy chain (HC) complementarity determining region (CDR) 1 sequence of SEQ ID NO: 14, a HC CDR2 sequence of SEQ ID NO: 15, a HC CDR3 sequence of SEQ ID NO: 16, a light chain (LC) CDR1 sequence of SEQ ID NO: 17, a LC CDR2 sequence of GTS, a LC CDR3 sequence of SEQ ID NO: 19, a HC framework region (FR) 1 sequence of SEQ ID NO: 6, a HC FR2 sequence of SEQ ID NO: 7, a HC FR3 sequence of SEQ ID NO: 8, a HC FR4 sequence of SEQ ID NO: 9, a LC FR1 sequence of SEQ ID NO: 10, a LC FR2 sequence of SEQ ID NO: 11, a LC FR3 sequence of SEQ ID NO: 12, and a LC FR4 sequence of SEQ ID NO: 13; b) a HC CDR1 sequence of SEQ ID NO: 28, a HC CDR2 sequence of SEQ ID NO: 29, a HC CDR3 sequence of SEQ ID NO: 30, a LC CDR1 sequence of SEQ ID NO: 31, a LC CDR2 sequence of YAS, and a LC CDR3 sequence of SEQ ID NO: 33, a HC FR1 sequence of SEQ ID NO: 20, a HC FR2 sequence of SEQ ID NO: 21, a HC FR3 sequence of SEQ ID NO: 22, a HC FR4 sequence of SEQ ID NO: 23, a LC FR1 sequence of SEQ ID NO: 24, a LC FR2 sequence of SEQ ID NO: 25, a LC FR3 sequence of SEQ ID NO: 26, and a LC FR4 sequence of SEQ ID NO: 27; c) a HC CDR1 sequence of SEQ ID NO: 42, a HC CDR2 sequence of SEQ ID NO: 43, a HC CDR3 sequence of SEQ ID NO: 44, a LC CDR1 sequence of SEQ ID NO: 45, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 47, a HC FR1 sequence of SEQ ID NO: 34, a HC FR2 sequence of SEQ ID NO: 35, a HC FR3 sequence of SEQ ID NO: 36, a HC FR4 sequence of SEQ ID NO: 37, a LC FR1 sequence of SEQ ID NO: 38, a LC FR2 sequence of SEQ ID NO: 39, a LC FR3 sequence of SEQ ID NO: 40, and a LC FR4 sequence of SEQ ID NO: 41; d) a HC CDR1 sequence of SEQ ID NO: 56, a HC CDR2 sequence of SEQ ID NO: 57, a HC CDR3 sequence of SEQ ID NO: 58, a LC CDR1 sequence of SEQ ID NO: 59, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 61, a HC FR1 sequence of SEQ ID NO: 48, a HC FR2 sequence of SEQ ID NO: 49, a HC FR3 sequence of SEQ ID NO: 50, a HC FR4 sequence of SEQ ID NO: 51, a LC FR1 sequence of SEQ ID NO: 52, a LC FR2 sequence of SEQ ID NO: 53, a LC FR3 sequence of SEQ ID NO: 54, and a LC FR4 sequence of SEQ ID NO: 55; e) a HC CDR1 sequence of SEQ ID NO: 70, a HC CDR2 sequence of SEQ ID NO: 71, a HC CDR3 sequence of SEQ ID NO: 72, a LC CDR1 sequence of SEQ ID NO: 73, -154- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 75, a HC FR1 sequence of SEQ ID NO: 62, a HC FR2 sequence of SEQ ID NO: 63, a HC FR3 sequence of SEQ ID NO: 64, a HC FR4 sequence of SEQ ID NO: 65, a LC FR1 sequence of SEQ ID NO: 66, a LC FR2 sequence of SEQ ID NO: 67, a LC FR3 sequence of SEQ ID NO: 68, and a LC FR4 sequence of SEQ ID NO: 69; f) a HC CDR1 sequence of SEQ ID NO: 84, a HC CDR2 sequence of SEQ ID NO: 85, a HC CDR3 sequence of SEQ ID NO: 86, a LC CDR1 sequence of SEQ ID NO: 87, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 89, a HC FR1 sequence of SEQ ID NO: 76, a HC FR2 sequence of SEQ ID NO: 77, a HC FR3 sequence of SEQ ID NO: 78, a HC FR4 sequence of SEQ ID NO: 79, a LC FR1 sequence of SEQ ID NO: 80, a LC FR2 sequence of SEQ ID NO: 81, a LC FR3 sequence of SEQ ID NO: 82, and a LC FR4 sequence of SEQ ID NO: 83; g) a HC CDR1 sequence of SEQ ID NO: 98, a HC CDR2 sequence of SEQ ID NO: 99, a HC CDR3 sequence of SEQ ID NO: 100, a LC CDR1 sequence of SEQ ID NO: 101, a LC CDR2 sequence of GTS, and a LC CDR3 sequence of SEQ ID NO: 103, a HC FR1 sequence of SEQ ID NO: 90, a HC FR2 sequence of SEQ ID NO: 91, a HC FR3 sequence of SEQ ID NO: 92, a HC FR4 sequence of SEQ ID NO: 93, a LC FR1 sequence of SEQ ID NO: 94, a LC FR2 sequence of SEQ ID NO: 95, a LC FR3 sequence of SEQ ID NO: 96, and a LC FR4 sequence of SEQ ID NO: 97; h) a HC CDR1 sequence of SEQ ID NO: 112, a HC CDR2 sequence of SEQ ID NO: 113, a HC CDR3 sequence of SEQ ID NO: 114, a LC CDR1 sequence of SEQ ID NO: 115, a LC CDR2 sequence of YAS, and a LC CDR3 sequence of SEQ ID NO: 117, a HC FR1 sequence of SEQ ID NO: 104, a HC FR2 sequence of SEQ ID NO: 105, a HC FR3 sequence of SEQ ID NO: 106, a HC FR4 sequence of SEQ ID NO: 107, a LC FR1 sequence of SEQ ID NO: 108, a LC FR2 sequence of SEQ ID NO: 109, a LC FR3 sequence of SEQ ID NO: 110, and a LC FR4 sequence of SEQ ID NO: 111; i) a HC CDR1 sequence of SEQ ID NO: 126, a HC CDR2 sequence of SEQ ID NO: 127, a HC CDR3 sequence of SEQ ID NO: 128, a LC CDR1 sequence of SEQ ID NO: 129, a LC CDR2 sequence of YAS, and a LC CDR3 sequence of SEQ ID NO: 131, a HC FR1 sequence of SEQ ID NO: 118, a HC FR2 sequence of SEQ ID NO: 119, a HC FR3 sequence of SEQ ID NO: 120, a HC FR4 sequence of SEQ ID NO: 121, a LC FR1 sequence of SEQ ID NO: 122, a LC FR2 sequence of SEQ ID NO: 123, a LC FR3 sequence of SEQ ID NO: 124, and a LC FR4 sequence of SEQ ID NO: 125; -155- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 j) a HC CDR1 sequence of SEQ ID NO: 140, a HC CDR2 sequence of SEQ ID NO: 141, a HC CDR3 sequence of SEQ ID NO: 142, a LC CDR1 sequence of SEQ ID NO: 143, a LC CDR2 sequence of YAS, and a LC CDR3 sequence of SEQ ID NO: 145, a HC FR1 sequence of SEQ ID NO: 132, a HC FR2 sequence of SEQ ID NO: 133, a HC FR3 sequence of SEQ ID NO: 134, a HC FR4 sequence of SEQ ID NO: 135, a LC FR1 sequence of SEQ ID NO: 136, a LC FR2 sequence of SEQ ID NO: 137, a LC FR3 sequence of SEQ ID NO: 138, and a LC FR4 sequence of SEQ ID NO: 139; k) a HC CDR1 sequence of SEQ ID NO: 154, a HC CDR2 sequence of SEQ ID NO: 155, a HC CDR3 sequence of SEQ ID NO: 156, a LC CDR1 sequence of SEQ ID NO: 157, a LC CDR2 sequence of WAS, and a LC CDR3 sequence of SEQ ID NO: 159, a HC FR1 sequence of SEQ ID NO: 146, a HC FR2 sequence of SEQ ID NO: 147, a HC FR3 sequence of SEQ ID NO: 148, a HC FR4 sequence of SEQ ID NO: 149, a LC FR1 sequence of SEQ ID NO: 150, a LC FR2 sequence of SEQ ID NO: 151, a LC FR3 sequence of SEQ ID NO: 152, and a LC FR4 sequence of SEQ ID NO: 153; l) a HC CDR1 sequence of SEQ ID NO: 168, a HC CDR2 sequence of SEQ ID NO: 169, a HC CDR3 sequence of SEQ ID NO: 170, a LC CDR1 sequence of SEQ ID NO: 171, a LC CDR2 sequence of YAS, and a LC CDR3 sequence of SEQ ID NO: 173, a HC FR1 sequence of SEQ ID NO: 160, a HC FR2 sequence of SEQ ID NO: 161, a HC FR3 sequence of SEQ ID NO: 162, a HC FR4 sequence of SEQ ID NO: 163, a LC FR1 sequence of SEQ ID NO: 164, a LC FR2 sequence of SEQ ID NO: 165, a LC FR3 sequence of SEQ ID NO: 166, and a LC FR4 sequence of SEQ ID NO: 167; m) a HC CDR1 sequence of SEQ ID NO: 182, a HC CDR2 sequence of SEQ ID NO: 183, a HC CDR3 sequence of SEQ ID NO: 184, a LC CDR1 sequence of SEQ ID NO: 185, a LC CDR2 sequence of YAS, and a LC CDR3 sequence of SEQ ID NO: 187, a HC FR1 sequence of SEQ ID NO: 174, a HC FR2 sequence of SEQ ID NO: 175, a HC FR3 sequence of SEQ ID NO: 176, a HC FR4 sequence of SEQ ID NO: 177, a LC FR1 sequence of SEQ ID NO: 178, a LC FR2 sequence of SEQ ID NO: 179, a LC FR3 sequence of SEQ ID NO: 180, and a LC FR4 sequence of SEQ ID NO: 181; n) a HC CDR1 sequence of SEQ ID NO: 196, a HC CDR2 sequence of SEQ ID NO: 197, a HC CDR3 sequence of SEQ ID NO: 198, a LC CDR1 sequence of SEQ ID NO: 199, a LC CDR2 sequence of AAS, and a LC CDR3 sequence of SEQ ID NO: 201, a HC FR1 sequence of SEQ ID NO: 188, a HC FR2 sequence of SEQ ID NO: 189, a HC FR3 sequence of SEQ ID NO: 190, a HC FR4 sequence of SEQ ID NO: 191, a LC FR1 -156- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 sequence of SEQ ID NO: 192, a LC FR2 sequence of SEQ ID NO: 193, a LC FR3 sequence of SEQ ID NO: 194, and a LC FR4 sequence of SEQ ID NO: 195; o) a HC CDR1 sequence of SEQ ID NO: 210, a HC CDR2 sequence of SEQ ID NO: 211, a HC CDR3 sequence of SEQ ID NO: 212, a LC CDR1 sequence of SEQ ID NO: 213, a LC CDR2 sequence of GTN, and a LC CDR3 sequence of SEQ ID NO: 215, a HC FR1 sequence of SEQ ID NO: 202, a HC FR2 sequence of SEQ ID NO: 203, a HC FR3 sequence of SEQ ID NO: 204, a HC FR4 sequence of SEQ ID NO: 205, a LC FR1 sequence of SEQ ID NO: 206, a LC FR2 sequence of SEQ ID NO: 207, a LC FR3 sequence of SEQ ID NO: 208, and a LC FR4 sequence of SEQ ID NO: 209; p) a HC CDR1 sequence of SEQ ID NO: 224, a HC CDR2 sequence of SEQ ID NO: 225, a HC CDR3 sequence of SEQ ID NO: 226, a LC CDR1 sequence of SEQ ID NO: 227, a LC CDR2 sequence of GAS, and a LC CDR3 sequence of SEQ ID NO: 229, a HC FR1 sequence of SEQ ID NO: 216, a HC FR2 sequence of SEQ ID NO: 217, a HC FR3 sequence of SEQ ID NO: 218, a HC FR4 sequence of SEQ ID NO: 219, a LC FR1 sequence of SEQ ID NO: 220, a LC FR2 sequence of SEQ ID NO: 221, a LC FR3 sequence of SEQ ID NO: 222, and a LC FR4 sequence of SEQ ID NO: 223; q) a HC CDR1 sequence of SEQ ID NO: 14, a HC CDR2 sequence of SEQ ID NO: 15, a HC CDR3 sequence of SEQ ID NO: 16, a LC CDR1 sequence of SEQ ID NO: 234, a LC CDR2 sequence of GTS, a LC CDR3 sequence of SEQ ID NO: 236, a HC FR1 sequence of SEQ ID NO: 6, a HC FR2 sequence of SEQ ID NO: 7, a HC FR3 sequence of SEQ ID NO: 8, a HC FR4 sequence of SEQ ID NO: 9, a LC FR1 sequence of SEQ ID NO: 230, a LC FR2 sequence of SEQ ID NO: 231, a LC FR3 sequence of SEQ ID NO: 232, and a LC FR4 sequence of SEQ ID NO: 233; r) a HC CDR1 sequence of SEQ ID NO: 14, a HC CDR2 sequence of SEQ ID NO: 15, a HC CDR3 sequence of SEQ ID NO: 16, a LC CDR1 sequence of SEQ ID NO: 241, a LC CDR2 sequence of GTS, a LC CDR3 sequence of SEQ ID NO: 243, a HC FR1 sequence of SEQ ID NO: 6, a HC FR2 sequence of SEQ ID NO: 7, a HC FR3 sequence of SEQ ID NO: 8, a HC FR4 sequence of SEQ ID NO: 9, a LC FR1 sequence of SEQ ID NO: 237, a LC FR2 sequence of SEQ ID NO: 238, a LC FR3 sequence of SEQ ID NO: 239, and a LC FR4 sequence of SEQ ID NO: 240; s) a HC CDR1 sequence of SEQ ID NO: 14, a HC CDR2 sequence of SEQ ID NO: 15, a HC CDR3 sequence of SEQ ID NO: 16, a LC CDR1 sequence of SEQ ID NO: 248, a LC CDR2 sequence of GTS, a LC CDR3 sequence of SEQ ID NO: 250, a HC FR1 -157- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 sequence of SEQ ID NO: 6, a HC FR2 sequence of SEQ ID NO: 7, a HC FR3 sequence of SEQ ID NO: 8, a HC FR4 sequence of SEQ ID NO: 9, a LC FR1 sequence of SEQ ID NO: 244, a LC FR2 sequence of SEQ ID NO: 245, a LC FR3 sequence of SEQ ID NO: 246, and a LC FR4 sequence of SEQ ID NO: 247; t) a HC CDR1 sequence of SEQ ID NO: 14, a HC CDR2 sequence of SEQ ID NO: 15, a HC CDR3 sequence of SEQ ID NO: 16, a LC CDR1 sequence of SEQ ID NO: 255, a LC CDR2 sequence of GTS, a LC CDR3 sequence of SEQ ID NO: 257, a HC FR1 sequence of SEQ ID NO: 6, a HC FR2 sequence of SEQ ID NO: 7, a HC FR3 sequence of SEQ ID NO: 8, a HC FR4 sequence of SEQ ID NO: 9, a LC FR1 sequence of SEQ ID NO: 251, a LC FR2 sequence of SEQ ID NO: 252, a LC FR3 sequence of SEQ ID NO: 253, and a LC FR4 sequence of SEQ ID NO: 254; u) a HC CDR1 sequence of SEQ ID NO: 14, a HC CDR2 sequence of SEQ ID NO: 15, a HC CDR3 sequence of SEQ ID NO: 16, a LC CDR1 sequence of SEQ ID NO: 262, a LC CDR2 sequence of GTS, a LC CDR3 sequence of SEQ ID NO: 264, a HC FR1 sequence of SEQ ID NO: 6, a HC FR2 sequence of SEQ ID NO: 7, a HC FR3 sequence of SEQ ID NO: 8, a HC FR4 sequence of SEQ ID NO: 9, a LC FR1 sequence of SEQ ID NO: 258, a LC FR2 sequence of SEQ ID NO: 259, a LC FR3 sequence of SEQ ID NO: 260, and a LC FR4 sequence of SEQ ID NO: 261; v) a HC CDR1 sequence of SEQ ID NO: 14, a HC CDR2 sequence of SEQ ID NO: 15, a HC CDR3 sequence of SEQ ID NO: 16, a LC CDR1 sequence of SEQ ID NO: 269, a LC CDR2 sequence of GTS, a LC CDR3 sequence of SEQ ID NO: 271, a HC FR1 sequence of SEQ ID NO: 6, a HC FR2 sequence of SEQ ID NO: 7, a HC FR3 sequence of SEQ ID NO: 8, a HC FR4 sequence of SEQ ID NO: 9, a LC FR1 sequence of SEQ ID NO: 265, a LC FR2 sequence of SEQ ID NO: 266, a LC FR3 sequence of SEQ ID NO: 267, and a LC FR4 sequence of SEQ ID NO: 268; w) a HC CDR1 sequence of SEQ ID NO: 14, a HC CDR2 sequence of SEQ ID NO: 15, a HC CDR3 sequence of SEQ ID NO: 16, a LC CDR1 sequence of SEQ ID NO: 276, a LC CDR2 sequence of GTS, a LC CDR3 sequence of SEQ ID NO: 278, a HC FR1 sequence of SEQ ID NO: 6, a HC FR2 sequence of SEQ ID NO: 7, a HC FR3 sequence of SEQ ID NO: 8, a HC FR4 sequence of SEQ ID NO: 9, a LC FR1 sequence of SEQ ID NO: 272, a LC FR2 sequence of SEQ ID NO: 273, a LC FR3 sequence of SEQ ID NO: 274, and a LC FR4 sequence of SEQ ID NO: 275; or -158- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 x) a HC CDR1 sequence of SEQ ID NO: 14, a HC CDR2 sequence of SEQ ID NO: 15, a HC CDR3 sequence of SEQ ID NO: 16, a LC CDR1 sequence of SEQ ID NO: 283, a LC CDR2 sequence of GTS, a LC CDR3 sequence of SEQ ID NO: 285, a HC FR1 sequence of SEQ ID NO: 6, a HC FR2 sequence of SEQ ID NO: 7, a HC FR3 sequence of SEQ ID NO: 8, a HC FR4 sequence of SEQ ID NO: 9, a LC FR1 sequence of SEQ ID NO: 279, a LC FR2 sequence of SEQ ID NO: 280, a LC FR3 sequence of SEQ ID NO: 281, and a LC FR4 sequence of SEQ ID NO:

282.

25. The isolated antibody or fragment thereof of any one of claims 1 – 20, wherein the antibody or fragment thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises an amino acid sequence set forth in any one of SEQ ID NOs: 314, 316, 318, 320, 322, 324, 326, 328, 330, 332, 334, 336, 338, 340, 342, 344, 354, 355, 356, 357, or an amino acid sequence that is at least 80% identical to the amino acid sequence set forth in any one of SEQ ID NOs: 314, 316, 318, 320, 322, 324, 326, 328, 330, 332, 334, 336, 338, 340, 342, 344, 354, 355, 356, 357; and wherein the VL comprises an amino acid sequence set forth in any one of SEQ ID NOs: 315, 317, 319, 321, 323, 325, 327, 329, 331, 333, 335, 337, 339, 341, 343, 345, 346, 347, 348, 349, 350, 351, 352, 353, or an amino acid sequence that is at least 80% identical to the amino acid sequence set forth in any one of SEQ ID NOs: 315, 317, 319, 321, 323, 325, 327, 329, 331, 333, 335, 337, 339, 341, 343, 345, 346, 347, 348, 349, 350, 351, 352, 353.

26. The isolated antibody or fragment thereof of any one of claims 1 – 25, wherein the antibody or fragment thereof is a bispecific antibody, comprising: a) a first antigen binding domain (ABD) that specifically binds to BILF-1; and b) a second ABD domain that specifically binds to a cell surface receptor, wherein the cell surface receptor is expressed on an immune cell, can form a heterodimer with BILF-1, and / or is co-expressed with BILF-1. -159- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 27. The isolated antibody or fragment thereof of claim 26, wherein the antibody or fragment thereof increases engagement of BILF-1 expressing cells with the immune cell.

28. The isolated antibody or fragment thereof of claim 26 or claim 27, wherein the immune cell is a T cell or natural killer (NK) cell.

29. The isolated antibody or fragment thereof of any one of claims 26 – 28, wherein the cell surface receptor is CD3, CD16, IL-8 receptor, CD19, BCMA, CD38, vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR), EBV latent membrane protein 1 (LMP1), or EBV latent membrane protein 2 (LMP2).

30. The isolated antibody or fragment thereof of claim 29, wherein the cell surface receptor is CD3 or CD16.

31. The isolated antibody or fragment thereof of claim 29, wherein the cell surface receptor is IL-8 receptor, CD19, BCMA, CD38, vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR), EBV latent membrane protein 1 (LMP1), or EBV latent membrane protein 2 (LMP2).

32. The isolated antibody or fragment thereof of any one of claims 1 – 31, wherein the antibody or fragment thereof is conjugated to a cytotoxic agent.

33. The isolated antibody or fragment thereof of claim 32, wherein the cytotoxic agent is monomethyl auristatin F (MMAF), monomethyl auristatin E (MMAE), or duocarmycin DM (DMDM).

34. The isolated antibody or fragment thereof of any one of claims 1 – 33, wherein the antibody or fragment thereof is conjugated or fused to an immune activating agent.

35. The isolated antibody or fragment thereof of claim 34, wherein the immune activating agent is a Toll-like receptor (TLR)-agonist, a Stimulation of interferon genes (STING)- agonist, or a cytokine.

36. The isolated antibody or fragment thereof of claim 35, wherein the cytokine is interleukin- 2 (IL-2), interleukin-15 (IL-15), or a TNF superfamily ligand. -160- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 37. The isolated antibody or fragment thereof of claim 36, wherein the TNF superfamily ligand is TRAIL, 4-1BBL, interleukin-21 (IL-21), IFN-alpha, IFN-beta, CD40, GITR-L, OX40L, or CD70.

38. The isolated antibody or fragment thereof of any one of claims 1 – 25, wherein the antibody or fragment thereof is a single-chain variable fragment (scFv), wherein the scFv is fused via a spacer (hinge) region to a transmembrane domain and an intracellular T-cell signaling domain, thereby forming a chimeric antigen receptor (CAR).

39. The isolated antibody or fragment thereof of any one of claims 1 – 38, wherein the amino acid sequence of the antibody or fragment thereof comprises one or more mutations, wherein the one or more mutations improve the binding affinity, stability, and / or the pharmacokinetics of the antibody or fragment thereof.

40. The isolated antibody or fragment thereof of claim 39, wherein the one or more mutations is in the light chain.

41. The isolated antibody or fragment thereof of claim 39 or claim 40, wherein the one or more mutations comprise an amino acid substitution.

42. The isolated antibody or fragment thereof of any one of claims 39 – 41, wherein the one or more mutations is in an amino acid selected from asparagine, cysteine, and leucine.

43. The isolated antibody or fragment thereof of claim 41 or claim 42, wherein the one or more mutations comprise an asparagine to histidine substitution, a cysteine to alanine substitution, an asparagine to arginine substitution, a leucine to isoleucine substitution, a cysteine to valine substitution, an asparagine to serine substitution, and an asparagine to alanine substitution.

44. The isolated antibody or fragment thereof of any one of claims 39 – 43, wherein an unpaired cysteine residue in the amino acid sequence is eliminated by the one or more mutations.

45. An isolated nucleic acid molecule comprising a nucleic acid sequence encoding the isolated antibody or fragment thereof of any one of claims 1 – 44. -161- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 46. A vector comprising the isolated nucleic acid molecules of claim 45.

47. The vector of claim 46, comprising a heterologous promoter.

48. The vector of claim 47, wherein the heterologous promoter is an inducible promoter or a constitutive promoter.

49. The vector of claim 47 or 48, wherein the expression of the isolated antibody or fragment thereof is driven by the promoter.

50. An isolated cell comprising the isolated nucleic acid molecule of claim 45 or the vector of any one of claims 46 – 49.

51. A method of producing an antibody or fragment thereof, comprising culturing the cell of claim 50 under culture conditions suitable for the expression of the antibody or fragment thereof and isolating the antibody or fragment thereof from the culture.

52. A pharmaceutical composition, comprising the antibody or fragment thereof of any one of claims 1 – 44 and a physiologically acceptable carrier.

53. The pharmaceutical composition of claim 52, comprising two or more antibodies or fragments thereof of any one of claims 1 – 44.

54. The pharmaceutical composition of claim 52 or claim 53, further comprising a second antibody or antigen binding fragment thereof which specifically binds to LMP-1 and / or LMP-2.

55. The pharmaceutical composition of claim 52 or claim 53, further comprising a second antibody or antigen binding fragment thereof which specifically binds to LMP-2.

56. The pharmaceutical composition of any one of claims 52 – 55, further comprising one or more therapeutic agents which increase expression of EBV membrane proteins in EBV- infected cells.

57. The pharmaceutical composition of claim 56, wherein the EBV-infected cells comprise B cells. -162- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 58. The pharmaceutical composition of claim 56 or claim 57, wherein the one or more therapeutic agents is selected from the group consisting of valproic acid, trichostatin A (TSA), 5-azacytidine (5-AZA), romidepsin, panabinostat, vorinostat, decitabine, nanatinostat, Deferasirox, rituximab, and combinations thereof.

59. A method of treating a subject having, or at risk for having, one or more of an Epstein Barr Virus (EBV) infection or an EBV-mediated disease, comprising administering to the subject the pharmaceutical composition of any one of claims 52 – 58.

60. The method of claim 59, wherein the subject is EBV-positive and has a latent EBV infection.

61. The method of claim 60, wherein the EBV infection is characterized as Latency 0, Latency I, Latency II, or Latency III.

62. The method of claim 61, wherein the EBV infection is a chronic active EBV infection or an acute active EBV infection.

63. The method of any one of claims 59 – 62, wherein the EBV-mediated disease is one or more diseases selected from the group consisting of an EBV-mediated lymphoproliferative disorder (LPD), an EBV-mediated cancer, an EBV-mediated autoimmune disease, infectious mononucleosis, and combinations thereof.

64. The method of claim 63, wherein the EBV-mediated disease is hemophagocytic lymphohistiocytosis (HLH), Hodgkin’s lymphoma (HL), or non-Hodgkin’s lymphoma (NHL).

65. The method of claim 64, wherein the NHL is Burkitt’s lymphoma, diffuse large B cell lymphoma, B cell NHL, T cell NHL, or NK cell NHL.

66. The method of claim 65, wherein the T cell or NK cell NHL comprises peripheral T cell lymphoma (PTCL), optionally angioimmunoblastic T cell lymphoma (AILT).

67. The method of claim 63, wherein the EBV-mediated LPD is a post-transplant lymphoproliferative disorder (PTLD) or an HIV-related LPD. -163- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 68. The method of claim 63, wherein the EBV-mediated cancer is a non-lymphoid malignancy selected from the group consisting of nasopharyngeal carcinoma (NPC), gastric carcinoma (GC), Stomach adenocarcinoma and leiomyosarcoma.

69. The method of claim 63, wherein the EBV-mediated autoimmune disease is one or more diseases selected from the group consisting of multiple sclerosis (MS), systemic lupus erythematosus (SLE), Sjogren’s Syndrome, type I diabetes (T1D), rheumatoid arthritis (RA), dermatomyositis, and combinations thereof.

70. The method of any one of claims 59 – 69, wherein the subject is immunocompromised.

71. The method of any one of claims 59 – 70, wherein the subject is about to undergo, is undergoing, or has undergone, an organ transplant procedure comprising therapeutic immunosuppression.

72. The method of claim 71, wherein the organ transplant procedure is a bone marrow transplant.

73. The method of any one of claims 59 – 72, comprising administering to the subject an additional therapeutic agent.

74. The method of claim 73, wherein the additional therapeutic agent increases expression of EBV membrane proteins in EBV-infected cells.

75. The method of claim 74, wherein the EBV-infected cells comprise B cells.

76. The method of claim 74 or 75, wherein the additional therapeutic agent is selected from the group consisting of romidepsin, panabinostat, vorinostat, decitabine, nanatinostat, rituximab, and combinations thereof.

77. The method of any one of claims 59 – 76, wherein the antibody or fragment thereof increases killing of EBV-infected cells in the subject by at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 2000% or more relative to an untreated control. -164- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 78. The method of any one of claims 59 – 77, wherein the antibody or fragment thereof reduces cell-free EBV DNA load in the subject by at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 2000% or more relative to an untreated control.

79. The method of any one of claims 59 – 78, wherein the antibody or fragment thereof reduces EBV-positive cell counts, optionally EBV-positive cancer cell counts, by at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 2000% or more relative to an untreated control.

80. The method of any one of claims 59 – 79, wherein the antibody or fragment thereof increases the subject’s overall survival, progression-free survival, time to progression, or any combination of the foregoing.

81. The method of any one of claims 59 – 80, wherein the antibody or fragment thereof reduces the number and / or severity of one or more adverse events in the subject.

82. The method of any one of claims 59 – 81, wherein the subject has an EBV-mediated autoimmune disease, and wherein the antibody or fragment thereof reduces the progression of disability in the subject, optionally as measured by a Kurtzke Expanded Disability Status Scale (EDSS) or an SLE Disease Activity Index (SLEDAI).

83. The method of any one of claims 59 – 82, wherein the subject has EBV-mediated multiple sclerosis, and wherein the antibody or fragment thereof reduces relapse rate and / or central nervous system (CNS) lesion load in the subject.

84. The method of any one of claims 59 – 83, comprising administering the pharmaceutical composition to the subject by parenteral administration.

85. The method of claim 84, wherein the parenteral administration is intravenous administration.

86. The method of any one of claims 59 – 85, comprising genotyping the EBV in the subject, and administering the pharmaceutical composition to the subject if the EBV genotype is associated with a high risk of EBV-mediated disease. -165- 315153392 v1ATTORNEY DOCKET NO.: FLAT-002 / 01WO 334521-2004 87. The method of any one of claims 59 – 86, comprising determining EBV protein expression in an activated B cell in the subject, and administering the pharmaceutical composition to the subject if the activated B cell expresses one or more EBV proteins, and wherein the subject has an autoimmune disease.

88. The method of claim 87, wherein the one or more EBV proteins is selected from the group consisting of EBNA-1, EBNA-2, EBNA-3A, EBNA-3B, EBNA-3C, EBNA-LP, LMP-1, LMP-2A, LMP-2B, and combinations thereof. -166- 315153392 v1

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