Monoclonal antibodies for the prevention and treatment of herpes simplex virus infection

Abstract

Antibodies and antigen-binding fragments that bind to herpes simplex virus-2 (HSV-2), methods of using these antibodies and / or antigen-binding fragments, and pharmaceutical compositions comprising these antibodies and / or antigen-binding fragments are provided.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application Serial No. 62 / 820,495, filed on March 19, 2019, the contents of which are incorporated herein by reference in their entirety.

[0003] Government support statement

[0004] This invention was made with government support under Grant No. AI117321 awarded by the National Institutes of Health. The government has certain rights in this invention. Background Art

[0005] Herpes virus infection is a major health problem in humans. There are currently some small molecule antiviral treatments that have some efficacy against active infection, but there are no commercially available vaccines for HSV-1 or HSV-2 infection. In addition, there are no effective monoclonal antibodies for HSV treatment. Summary of the invention

[0006] Provided is an antibody or antigen-binding fragment, the antibody or antigen-binding fragment comprising:

[0007] A heavy chain variable region, the heavy chain variable region comprising

[0008] GYSFTTYD (SEQ ID NO: 1),

[0009] IYPREGST (SEQ ID NO: 2), and

[0010] ATYGSSRYYTMDY (SEQ ID NO: 3); and / or

[0011] A light chain variable region comprising

[0012] ESVDNFGISF (SEQ ID NO: 4),

[0013] AAS (SEQ ID NO: 5), and

[0014] QQSKEVPLT (SEQ ID NO: 6).

[0015] Provided is an antibody or antigen-binding fragment, the antibody or antigen-binding fragment comprising:

[0016] A heavy chain variable region, the heavy chain variable region comprising

[0017] GYSITNGNH (SEQ ID NO: 7),

[0018] IRSSGSS (SEQ ID NO: 8), and

[0019] ARGGGLRHYFDY (SEQ ID NO: 9); and / or

[0020] A light chain variable region comprising

[0021] GNIHNY (SEQ ID NO: 10),

[0022] HAE (SEQ ID NO: 11), and

[0023] QHFWSTPYT (SEQ ID NO: 12).

[0024] Provided is an antibody or antigen-binding fragment, the antibody or antigen-binding fragment comprising:

[0025] A heavy chain variable region, the heavy chain variable region comprising

[0026] GFTFTDYY (SEQ ID NO: 13),

[0027] IRNKANGYTT (SEQ ID NO:14), and

[0028] ACGNYVGYAMDY (SEQ ID NO: 15); and / or

[0029] A light chain variable region comprising

[0030] QSLLNSRTRKNY (SEQ ID NO: 16),

[0031] WAS (SEQ ID NO: 17), and

[0032] KQSYNLYT (SEQ ID NO: 18).

[0033] Provided is an antibody or antigen-binding fragment, the antibody or antigen-binding fragment comprising:

[0034] A heavy chain variable region, the heavy chain variable region comprising

[0035] GFSLSRHD (SEQ ID NO: 79),

[0036] IWGDGST (SEQ ID NO: 80), and

[0037] AKEDYGIFPY (SEQ ID NO: 81); and / or

[0038] A light chain variable region comprising

[0039] QDISSY (SEQ ID NO: 82),

[0040] RAN (SEQ ID NO: 83), and

[0041] LQYDEFPLT (SEQ ID NO: 84).

[0042] Provided is an antibody or antigen-binding fragment, the antibody or antigen-binding fragment comprising:

[0043] A heavy chain variable region, the heavy chain variable region comprising

[0044] GYTFTNYD (SEQ ID NO: 87),

[0045] IYPRDGST (SEQ ID NO: 88), and

[0046] ARGIFYVNYDVY (SEQ ID NO: 89); and / or

[0047] A light chain variable region comprising

[0048] DHINNW (SEQ ID NO: 90),

[0049] GAA (SEQ ID NO:91), and

[0050] QQYWSSPLT (SEQ ID NO:92).

[0051] Provided is an antibody or antigen-binding fragment, the antibody or antigen-binding fragment comprising:

[0052] A heavy chain variable region, the heavy chain variable region comprising

[0053] EYEFPSHD (SEQ ID NO: 93),

[0054] INSDGGST (SEQ ID NO: 94), and

[0055] ARHSSGYVLDY (SEQ ID NO: 95); and / or

[0056] A light chain variable region comprising

[0057] DHINHW (SEQ ID NO: 96),

[0058] GAT (SEQ ID NO:97), and

[0059] QQYWSTPYT (SEQ ID NO:98).

[0060] Provided is an antibody or antigen-binding fragment, the antibody or antigen-binding fragment comprising:

[0061] A heavy chain variable region, the heavy chain variable region comprising

[0062] EYEFPSHD (SEQ ID NO: 85),

[0063] INSDGGST (SEQ ID NO: 80), and

[0064] ARHSSGYVLDY (SEQ ID NO: 81); and / or

[0065] A light chain variable region comprising

[0066] DHINHW (SEQ ID NO: 86),

[0067] GAT (SEQ ID NO: 83), and

[0068] QQYWSTPYT (SEQ ID NO: 84).

[0069] A pharmaceutical composition comprising the antibody or antigen-binding fragment as described herein, and a pharmaceutically acceptable carrier or excipient.

[0070] A nucleic acid encoding a heavy chain variable region of an antibody, wherein the heavy chain variable region has an amino acid sequence comprising:

[0071] GYSFTTYD (SEQ ID NO: 1),

[0072] IYPREGST (SEQ ID NO: 2), and

[0073] ATYGSSRYYTMDY (SEQ ID NO: 3);

[0074] or

[0075] GYSITNGNH (SEQ ID NO: 7);

[0076] IRSSGSS (SEQ ID NO: 8), and

[0077] ARGGGLRHYFDY (SEQ ID NO: 9);

[0078] or

[0079] GFTFTDYY (SEQ ID NO: 13),

[0080] IRNKANGYTT (SEQ ID NO:14), and

[0081] ACGNYVGYAMDY (SEQ ID NO: 15);

[0082] or

[0083] GFSLSRHD (SEQ ID NO: 79),

[0084] IWGDGST (SEQ ID NO: 80), and

[0085] AKEDYGIFPY (SEQ ID NO: 81);

[0086] or

[0087] GFSLNNYD (SEQ ID NO: 85),

[0088] IWGDGST (SEQ ID NO: 80), and

[0089] AKEDYGIFPY (SEQ ID NO: 81);

[0090] or

[0091] GYTFTNYD (SEQ ID NO: 87),

[0092] IYPRDGST (SEQ ID NO: 88), and

[0093] ARGIFYVNYDVY (SEQ ID NO: 89);

[0094] or

[0095] EYEFPSHD (SEQ ID NO: 93),

[0096] INSDGGST (SEQ ID NO: 94), and

[0097] ARHSSGYVLDY (SEQ ID NO:95).

[0098] A nucleic acid encoding a light chain variable region of an antibody, wherein the light chain variable region has an amino acid sequence comprising:

[0099] ESVDNFGISF (SEQ ID NO: 4);

[0100] AAS (SEQ ID NO: 5); and

[0101] QQSKEVPLT (SEQ ID NO: 6),

[0102] or

[0103] GNIHNY (SEQ ID NO: 10);

[0104] HAE (SEQ ID NO: 11); and

[0105] QHFWSTPYT (SEQ ID NO: 12),

[0106] or

[0107] QSLLNSRTRKNY (SEQ ID NO: 16);

[0108] WAS (SEQ ID NO: 17); and

[0109] KQSYNLYT (SEQ ID NO: 18);

[0110] or

[0111] QDISSY (SEQ ID NO: 82),

[0112] RAN (SEQ ID NO: 83), and

[0113] LQYDEFPLT (SEQ ID NO: 84);

[0114] or

[0115] QDINSY (SEQ ID NO: 86),

[0116] RAN (SEQ ID NO: 83), and

[0117] LQYDEFPLT (SEQ ID NO: 84);

[0118] or

[0119] DHINNW (SEQ ID NO: 90),

[0120] GAA (SEQ ID NO:91), and

[0121] QQYWSSPLT (SEQ ID NO: 92);

[0122] or

[0123] DHINHW (SEQ ID NO: 96),

[0124] GAT (SEQ ID NO:97), and

[0125] QQYWSTPYT (SEQ ID NO:98).

[0126] A nucleic acid encoding the light chain complementarity determining regions (LCDRs) LCDR1, LCDR2 and LCDR3 of the light chain of an antibody as described herein.

[0127] A nucleic acid encoding the heavy chain complementarity determining regions (HCDRs) HCDR1, HCDR2 and HCDR3 of the heavy chain of an antibody as described herein.

[0128] A host cell comprising one or more nucleic acids described herein.

[0129] An antibody or antigen-binding fragment as described herein, linked or conjugated to a therapeutic agent.

[0130] A method of inhibiting herpes simplex virus-2 (HSV-2) activity in a subject, the method comprising administering an antibody or antigen-binding fragment described herein in an amount effective to inhibit HSV-2 activity in the subject.

[0131] A method for activating antibody-dependent cellular cytotoxicity (ADCC) of a cell infected with herpes simplex virus-2 (HSV-2), the method comprising contacting the cell with an isolated antibody or antigen-binding fragment described herein in an amount that affects cellular ADCC.

[0132] Use of an effective amount of an antibody or antigen-binding fragment described herein, or a pharmaceutical composition described herein, for treating or preventing a disease or condition associated with herpes simplex virus-2 (HSV-2) infection in a subject. BRIEF DESCRIPTION OF THE DRAWINGS

[0133] Those skilled in the art will appreciate that the drawings described below are for illustration purposes only and are not intended to limit the scope of the present teachings in any way.

[0134] The patent or application file contains at least one drawing executed in color. Copies of the patent or patent application disclosure with one or more color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

[0135] Figure 1: ELISA results show the binding of culture supernatants to HSV-2G infected cell lysates and uninfected Vero cell lysates. Germinal center (GC) B cells from inguinal lymph nodes of mice inoculated with ΔgD-2 were sorted directly into 96-well plates (1 cell / well). These GC B cells were then cultured in the presence of NB-21.2D9 feeder cells. After cultivation, the presence of IgG was first determined by ELISA, and then the reactivity of culture supernatant IgG to HSV-2G infected cell lysates (HSV-2G) and uninfected Vero lysates (control) was detected by ELISA.

[0136] Figure 2 : Distribution of VH gene segments obtained from d16-d17 GC B cells.

[0137] Figures 3A - 3B : Retention of recombinant antibodies (22D10, 32H6, 33B8 and 35H7) binding to HSV-2G lysate. The binding of recombinant antibodies to HSV-2G lysate was detected by ELISA. Heavy and light chain V(D)J rearrangements were amplified from selected single B cell culture wells (22D10, 32H6, 33B8 and 35H7) by standard RT-PCR. The V(D)J rearrangements of these clones were introduced into expression vectors. Recombinant antibodies were obtained by co-transfecting these expression vectors into Expi293F cells. ≥4 mg of purified IgG (not shown) were obtained. These antibodies did not bind to control, uninfected Vero lysates.

[0138] Figure 4 : Activation of FcγRIV by IgG1 and IgG2c isotypes of single mAbs. FcγRIV activation was determined using the Promega FcγRIV ADCC Reporter Bioassay at a concentration of 1 mg / mL. Statistical analysis was by ANOVA, **P<0.01, ****P<0.0001.

[0139] Figures 5A - 5B Binding of recombinant antibodies cloned from single bone marrow plasma cells and GC B cells (BMPC-23 and 19G7), respectively, to HSV-2G lysates is shown. Binding of recombinant antibodies to HSV-2-G infected and uninfected cell lysates was tested by ELISA.

[0140] Figures 6A - 6C : Passive transfer of mice with cloned HSV-reactive IgG2c antibodies (BMPC-23, 33B8, and 22D10) decreased overall survival ( Figure 6A ) and epithelium (Figure 6B ) and neural testing ( Figure 6C ) provided protection against lethal HSV-2 challenge.

[0141] Figures 7A - 7B Immunoprecipitation mass spectrometry (IP-MS) was performed to identify the binding targets of 22D10, 33B8 and BMPC-23 antibodies. Results Human herpesvirus glycoprotein B (gB) was identified as a target.

[0142] Figure 8 : shows the binding of recombinant antibodies to glycoprotein B of HSV-1 (gB-1) as measured by Luminex multiplex assay.

[0143] Figure 9A and 9B is a graph of median fluorescence intensity (MFI) versus IgG concentration (ng / ml) showing binding of various recombinant antibodies to gB-1 as measured by the Luminex multiplex assay.

[0144] Figures 10A - 10G The ability of gB-1-specific mouse monoclonal IgG antibody to inhibit the binding of BMPC-23 human IgG antibody to gB-1 was demonstrated. DETAILED DESCRIPTION

[0145] Prophylactic treatment with an anti-respiratory syncytial virus (RSV) F neutralizing monoclonal antibody (mAb) (palivizumab) has been shown to be effective in preventing serious complications of RSV infection in high-risk infants and young children and is now licensed and routinely used for this purpose. A commercially available anti-HSV-2 or anti-HSV-1 antibody therapy would be very useful but did not previously exist. Such a product would be particularly useful in immunocompromised patients or in premature patients whose immune responses have not developed.

[0146] Disclosed herein are antibodies, antigen-binding fragments, and nucleic acids encoding antibodies and antigen-binding fragments. The antibody or antigen-binding fragment binds to a herpes simplex virus-2 (HSV-2) antigen. The antibody or antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence comprising three heavy chain complementary determining regions (HCDRs); and a light chain variable region having an amino acid sequence comprising three light chain complementary determining regions (LCDRs), or a combination thereof. The antibody or antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence comprising heavy chain HCDR1, HCDR2, and HCDR3; a light chain variable region having an amino acid sequence comprising light chain LCDR1, LCDR2, and LCDR3; or a combination thereof.

[0147] Provided is an antibody or antigen-binding fragment, the antibody or antigen-binding fragment comprising:

[0148] A heavy chain variable region, the heavy chain variable region comprising

[0149] GYSFTTYD (SEQ ID NO: 1),

[0150] IYPREGST (SEQ ID NO: 2), and

[0151] ATYGSSRYYTMDY (SEQ ID NO: 3); and / or

[0152] A light chain variable region comprising

[0153] ESVDNFGISF (SEQ ID NO: 4),

[0154] AAS (SEQ ID NO: 5), and

[0155] QQSKEVPLT (SEQ ID NO: 6).

[0156] Provided is an antibody or antigen-binding fragment, the antibody or antigen-binding fragment comprising:

[0157] A heavy chain variable region, the heavy chain variable region comprising

[0158] GYSITNGNH (SEQ ID NO: 7),

[0159] IRSSGSS (SEQ ID NO: 8), and

[0160] ARGGGLRHYFDY (SEQ ID NO: 9); and / or

[0161] A light chain variable region comprising

[0162] GNIHNY (SEQ ID NO: 10),

[0163] HAE (SEQ ID NO: 11), and

[0164] QHFWSTPYT (SEQ ID NO: 12).

[0165] Provided is an antibody or an antigen-binding fragment thereof, the antibody or the antigen-binding fragment thereof comprising:

[0166] A heavy chain variable region, the heavy chain variable region comprising

[0167] GFTFTDYY (SEQ ID NO: 13),

[0168] IRNKANGYTT (SEQ ID NO:14), and

[0169] ACGNYVGYAMDY (SEQ ID NO: 15) and / or

[0170] A light chain variable region comprising

[0171] QSLLNSRTRKNY (SEQ ID NO: 16),

[0172] WAS (SEQ ID NO: 17), and

[0173] KQSYNLYT (SEQ ID NO: 18).

[0174] Provided is an antibody or antigen-binding fragment, the antibody or antigen-binding fragment comprising:

[0175] A heavy chain variable region, the heavy chain variable region comprising

[0176] GFSLSRHD (SEQ ID NO: 79),

[0177] IWGDGST (SEQ ID NO: 80), and

[0178] AKEDYGIFPY (SEQ ID NO: 81); and / or

[0179] A light chain variable region comprising

[0180] QDISSY (SEQ ID NO: 82),

[0181] RAN (SEQ ID NO: 83), and

[0182] LQYDEFPLT (SEQ ID NO:84)

[0183] Provided is an antibody or antigen-binding fragment, the antibody or antigen-binding fragment comprising:

[0184] A heavy chain variable region, the heavy chain variable region comprising

[0185] GFSLNNYD (SEQ ID NO: 85),

[0186] IWGDGST (SEQ ID NO: 80), and

[0187] AKEDYGIFPY (SEQ ID NO: 81); and / or

[0188] A light chain variable region comprising

[0189] QDINSY (SEQ ID NO: 86),

[0190] RAN (SEQ ID NO: 83), and

[0191] LQYDEFPLT (SEQ ID NO: 84).

[0192] Provided is an antibody or antigen-binding fragment, the antibody or antigen-binding fragment comprising:

[0193] A heavy chain variable region, the heavy chain variable region comprising

[0194] GYTFTNYD (SEQ ID NO: 87),

[0195] IYPRDGST (SEQ ID NO: 88), and

[0196] ARGIFYVNYDVY (SEQ ID NO: 89); and / or

[0197] A light chain variable region comprising

[0198] DHINNW (SEQ ID NO: 90),

[0199] GAA (SEQ ID NO:91), and

[0200] QQYWSSPLT (SEQ ID NO:92).

[0201] Provided is an antibody or antigen-binding fragment, the antibody or antigen-binding fragment comprising:

[0202] A heavy chain variable region, the heavy chain variable region comprising

[0203] EYEFPSHD (SEQ ID NO: 93),

[0204] INSDGGST (SEQ ID NO: 94), and

[0205] ARHSSGYVLDY (SEQ ID NO: 95); and / or

[0206] A light chain variable region comprising

[0207] DHINHW (SEQ ID NO: 96),

[0208] GAT (SEQ ID NO:97), and

[0209] QQYWSTPYT (SEQ ID NO:98).

[0210] Provided is an antibody or antigen-binding fragment, the antibody or antigen-binding fragment comprising:

[0211] A heavy chain variable region, the heavy chain variable region comprising

[0212] GYTFTNYW (SEQ ID NO: 99),

[0213] IHPNIGIT (SEQ ID NO: 100), and

[0214] ARGSDSGSAWFAY (SEQ ID NO: 101); and / or

[0215] A light chain variable region comprising

[0216] DHINNW (SEQ ID NO: 90),

[0217] GAT (SEQ ID NO:97), and

[0218] QQYWSTPLT (SEQ ID NO: 102).

[0219] Provided is an antibody or antigen-binding fragment, the antibody or antigen-binding fragment comprising:

[0220] A heavy chain variable region, the heavy chain variable region comprising

[0221] GYTFTSYW (SEQ ID NO: 103),

[0222] IHPNSGIT (SEQ ID NO: 104), and

[0223] ARGSNSGSAWFAY (SEQ ID NO: 105); and / or

[0224] A light chain variable region comprising

[0225] DHINNW (SEQ ID NO: 90),

[0226] GAT (SEQ ID NO:97), and

[0227] QQYWSTPLT (SEQ ID NO: 102).

[0228] Provided is an antibody or antigen-binding fragment, the antibody or antigen-binding fragment comprising:

[0229] A heavy chain variable region, the heavy chain variable region comprising

[0230] GYTFTSYW (SEQ ID NO: 103),

[0231] IHPNSGIT (SEQ ID NO: 104), and

[0232] ARGSNSGSAWFAY (SEQ ID NO: 105); and / or

[0233] A light chain variable region comprising

[0234] DHINNW (SEQ ID NO: 90),

[0235] GAA (SEQ ID NO:91), and

[0236] QQYWSSPLT (SEQ ID NO:92).

[0237] Provided is an antibody or antigen-binding fragment, the antibody or antigen-binding fragment comprising:

[0238] A heavy chain variable region, the heavy chain variable region comprising

[0239] GYTFTTYG (SEQ ID NO: 107),

[0240] INTYSGVS (SEQ ID NO: 108), and

[0241] AQLNYGMDY. (SEQ ID NO: 109); and / or

[0242] A light chain variable region comprising

[0243] QDVSTS (SEQ ID NO: 110),

[0244] SAS (SEQ ID NO: 111), and

[0245] HQHYSIPRT (SEQ ID NO: 112).

[0246] Provided is an antibody or antigen-binding fragment, the antibody or antigen-binding fragment comprising:

[0247] A heavy chain variable region, the heavy chain variable region comprising

[0248] GYTFTTYG (SEQ ID NO: 107),

[0249] INTYSGVS (SEQ ID NO: 108), and

[0250] AQVNYAMDY (SEQ ID NO: 113); and / or

[0251] A light chain variable region comprising

[0252] QDVSTA (SEQ ID NO: 114),

[0253] SAS (SEQ ID NO: 111), and

[0254] QQHYSTPRT (SEQ ID NO: 115).

[0255] Provided is an antibody or antigen-binding fragment, the antibody or antigen-binding fragment comprising:

[0256] A heavy chain variable region, the heavy chain variable region comprising

[0257] GYSITSGYD (SEQ ID NO: 116),

[0258] ISYSGLT (SEQ ID NO: 117), and

[0259] ARGPPWYFDV (SEQ ID NO: 118);

[0260] A light chain variable region comprising

[0261] QIVRAT (SEQ ID NO: 119),

[0262] LAS (SEQ ID NO: 120), and

[0263] LQYWNYPYT (SEQ ID NO: 121).

[0264] In some embodiments, the antibody or antigen-binding fragment thereof is an IgG antibody. In some embodiments, the antibody or antigen-binding fragment thereof is an IgG antibody having an IgG2c isotype.

[0265] In some embodiments, the antibody or fragment thereof is a humanized antibody.

[0266] In some embodiments, antibodies are provided. In some embodiments, antigen-binding fragments are provided. In some embodiments, the antigen is a herpes simplex virus-2 (HSV-2) antigen. For example, the HSV-2 antigen is glycoprotein B (gB).

[0267] In some embodiments, the antibody or fragment thereof comprises an Fc region that binds Fcγ receptor RIII (FcγRIII). In some embodiments, the antibody or fragment thereof comprises an Fc region that activates human FcγRIII when bound to human FcγRIII. In some embodiments, the human FcγRIII receptor is FcγRIIIa.

[0268] In some embodiments, the antibody or fragment thereof binds Fcγ receptor RIV (FcγRIV).

[0269] In some embodiments, the antibody or fragment thereof binds to an HSV-2 antigen.

[0270] In some embodiments, the framework regions of the light and / or heavy chains are human framework regions, or have 85% or greater identity thereto. In some embodiments, the framework regions of the light and / or heavy chains are human framework regions.

[0271] In some embodiments, the heavy chain V(D)J rearrangement is derived from the germline VH of IGHV1-85, the germline D of IGHD1-1, and the germline JH of IGHJ4. In some embodiments, the heavy chain V(D)J rearrangement is 95% or more identical to the germline VH of IGHV1-85, the germline D of IGHD1-1, and the germline JH of IGHJ4. In some embodiments, the light chain is derived from the germline VL of IGKV3-2 and the germline JL of IGKJ5. In some embodiments, the light chain is 95% or more identical to the germline VL of IGKV3-2 and the germline JL of IGKJ5.

[0272] In some embodiments, the heavy chain V(D)J rearrangement is derived from the germline VH of IGHV3-4, the germline D of IGHD2, and the germline JH of IGHJ4. In some embodiments, the heavy chain V(D)J rearrangement is 95% or more identical to the germline VH of IGHV3-4, the germline D of IGHD2, and the germline JH of IGHJ4. In some embodiments, the light chain is derived from the germline VL of IGKV12-41 and the germline JL of IGKJ2. In some embodiments, the light chain is 95% or more identical to the germline VL of IGKV12-41 and the germline JL of IGKJ2.

[0273] In some embodiments, the heavy chain V(D)J rearrangement is derived from the germline VH of IGHV7-3, the germline D of IGHD2-1, and the germline JH of IGHJ4. In some embodiments, the heavy chain V(D)J rearrangement is 95% or more identical to the germline VH of IGHV7-3, the germline D of IGHD2-1, and the germline JH of IGHJ4. In some embodiments, the light chain is derived from the germline VL of IGKV8-21 and the germline JL of IGKJ2. In some embodiments, the light chain is 95% or more identical to the germline VL of IGKV8-21 and the germline JL of IGKJ2.

[0274] In some embodiments, the heavy chain V(D)J rearrangement is derived from the germline VH of IGHV2-3, the germline D of IGHD2-1, and the germline JH of IGHJ3. In some embodiments, the heavy chain V(D)J rearrangement is 95% or more identical to the germline VH of IGHV2-3, the germline D of IGHD2-1, and the germline JH of IGHJ3. In some embodiments, the light chain is derived from the germline VL of IGKV14-111 and the germline JL of IGKJ5. In some embodiments, the light chain is 95% or more identical to the germline VL of IGKV14-111 and the germline JL of IGKJ5.

[0275] In some embodiments, the heavy chain V(D)J rearrangement is derived from the germline VH of IGHV1-85, the germline D of IGHD2-1, and the germline JH of IGHJ3. In some embodiments, the heavy chain V(D)J rearrangement is 95% or more identical to the germline VH of IGHV1-85, the germline D of IGHD2-1, and the germline JH of IGHJ3. In some embodiments, the light chain is derived from the germline VL of IGKV13-85 and the germline JL of IGKJ5. In some embodiments, the light chain is 95% or more identical to the germline VL of IGKV13-85 and the germline JL of IGKJ5.

[0276] In some embodiments, the heavy chain V(D)J rearrangement is derived from the germline VH of IGHV5-2, the germline D of IGHD3-2, and the germline JH of IGHJ4. In some embodiments, the heavy chain V(D)J rearrangement is 95% or more identical to the germline VH of IGHV5-2, the germline D of IGHD3-2, and the germline JH of IGHJ4. In some embodiments, the light chain is derived from the germline VL of IGKV13-85 and the germline JL of IGKJ2. In some embodiments, the light chain is 95% or more identical to the germline VL of IGKV13-85 and the germline JL of IGKJ2.

[0277] In some embodiments, the heavy chain V(D)J rearrangement is derived from the germline VH of IGHV1-64, the germline D of IGHD3-2, and the germline JH of IGHJ3. In some embodiments, the heavy chain V(D)J rearrangement is 95% or more identical to the germline VH of IGHV1-64, the germline D of IGHD3-2, and the germline JH of IGHJ3. In some embodiments, the light chain is derived from the germline VL of IGKV13-85 and the germline JL of IGKJ5. In some embodiments, the light chain is 95% or more identical to the germline VL of IGKV13-85 and the germline JL of IGKJ5.

[0278] In some embodiments, the heavy chain V(D)J rearrangement is derived from the germline VH of IGHV9-3, the germline D of IGHD2-12, and the germline JH of IGHJ4. In some embodiments, the heavy chain V(D)J rearrangement is 95% or more identical to the germline VH of IGHV9-3, the germline D of IGHD2-12, and the germline JH of IGHJ4. In some embodiments, the light chain is derived from the germline VL of IGKV6-17 and the germline JL of IGKJ1. In some embodiments, the light chain is 95% or more identical to the germline VL of IGKV6-17 and the germline JL of IGKJ1.

[0279] In some embodiments, the heavy chain V(D)J rearrangement is derived from the germline VH of IGHV3-1, the germline D of IGHD6-3, and the germline JH of IGHJ1. In some embodiments, the heavy chain V(D)J rearrangement is 95% or more identical to the germline VH of IGHV3-1, the germline D of IGHD6-3, and the germline JH of IGHJ1. In some embodiments, the light chain is derived from the germline VL of IGKV6-14 and the germline JL of IGKJ2. In some embodiments, the light chain is 95% or more identical to the germline VL of IGKV6-14 and the germline JL of IGKJ2.

[0280] A pharmaceutical composition is also provided, comprising an antibody or antigen binding fragment as described herein, and a pharmaceutically acceptable carrier or excipient. In some embodiments, the pharmaceutical composition further comprises an antiviral small molecule drug. The antiviral small molecule includes famciclovir, penciclovir, valacyclovir or a combination thereof. In some embodiments, the small molecule antiviral drug is acyclovir.

[0281] The following are exemplary nucleotide sequences and amino acid sequences of anti-HSV antibodies. The corresponding heavy or light chain CDRs (e.g., HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, LCDR3) are underlined in consecutive order. Table 4 provides a summary of the nucleotide sequences and amino acid sequences of exemplary anti-HSV antibodies, including the corresponding HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3.

[0282] BMPC-23_IgH

[0283] Nucleotides:

[0284] caggttcagctgcagcagtctggacctgagctggtgaagcctggggcttcagtgaagttgtcctgcaaggcttct ggctacagtttcacaacctacgatataaactgggtgaaggagaggcctggacagggacttgagtggattgggtgg atttatcctagagagggtagtacg aattacaatgagaagttcaggggcaaggccacattgactgcagacacatcctccagtacagcgtacatggagctccacagcctgacatctgaggactctgcggtctatttctgt gcaaccta cggtagtagtcgctactatactatggactac tggggtcaaggaacctcagtcaccgtctcctcagcc(SEQ IDNO:19)

[0285] Amino acids:

[0286] QVQLQQSGPELVKPGASVKLSCKAS GYSFTTYD INWVKERPGQGLEWIGW IYPREGST NYNEKFRGKATLTADTSSSTAYMELHSLTSEDSAVYFC ATYGSSRYYTMDY WGQGTSVTVSSA(SEQ ID NO:20)

[0287] BMPC - 23_IgL

[0288] Nucleotides

[0289] gacattgtgctgacccaatctccaacttctttggctgtgtctctagggcagagggccaccatctcctgcagagccagc gaaagtgttgataattttggcattagtttt atgaactggttccagcagaaaccaggacagccacccaaactcctcatctac gctgcatcc aacctaggatccggggtccctgccaggtttagtggcagtgggtctgggacagacttcagcctcaacatccatcctatggaggatgatgatactgcaatgtatttctgt cagcaaagtaaggaggt tccgctcacgttcggtgctgggaccaagctggagctgaaacgg(SEQ ID NO:21)

[0290] Amino acids:

[0291] DIVLTQSPTSLAVSLGQRATISCRAS ESVDNFGISF MNWFQQKPGQPPKLLIYAAS NLGSGVPARFSGSGSGTDFSLNIHPMEDDDTAMYFC QQSKEVPLT FGAGTKLELKR(SEQ ID NO:22)

[0292] 22D10_IgH

[0293] Nucleotide

[0294] gatgtacagcttcaggagtcaggacctgccctggtgaagccttctcagacagtgtccctcacctgcactgtcact ggctactctatcactaatggtaatcattgg tggaactggatccggcaggtttcaggaagcaaactggagtggttagggtac ataaggtccagtggtagctct gacagcaatccatctctcaaaagtcgaatctccatcactagagacacttccaagaaccagttattcctgcacttgaactctatgactactgaagatatagccacatattactgt gcaag aggggggggattacggcactactttgactac tggggccaaggcaccactctcacagtctcctcagcc(SEQ IDNO:23)

[0295] Amino acid:

[0296] DVQLQESGPALVKPSQTVSLTCTVT GYSITNGNHW WNWIRQVSGSKLEWLGY IRSSGSS DSNPSLKSRISITRDTSKNQLFLHLNSMTTEDIATYYC ARGGGLRHYFDY WGQGTTLTVSSA(SEQ ID NO:24)

[0297] 22D10_IgL

[0298] Nucleotide

[0299] gacatccagatgactcagtctccagcctccctatctgcatctgtgggagatactgtcaccatcacatgtcgagcaagt gggaatattcacaattat ttagcatggtatcaccagaaacagggaaaatctcctcaactcctggtctat catgcagaaaccttaacagatggtgtgccatcaaggttcagtggcagtggatcaggaacacaatattctctcaagatcaacagcctgcagcctgaagattttgggagttattactgt caacatttttggagtactccgtacaca ttcggaggggggaccaagctggaaataaaacgg(SEQ ID NO:25)

[0300] Amino acids:

[0301] DIQMTQSPASLSASVGDTVTITCRAS GNIHNY LAWYHQKQGKSPQLLVY HAE TLTDGVPSRFSGSGSGTQYSLKINSLQPEDFGSYYC QHFWSTPYT FGGGTKLEIKR(SEQ ID NO:26)

[0302] 33B8_IgH

[0303] Nucleotides

[0304] gaggtgaagctggtggagtctggaggaggcttggtacagcctgggggttctctgagtctctcctgtgcaacttct ggattcaccttcactgattactac atgaactgggtccgccagcctccagggaaggcacttgagtggttgggtttt attagaaacaaagctaatggttacacaacag agtacagtgcatctgtgaagggtcggttcaccatctccagagataattcccaaagcatcctctatcttcaaatgaattccctgagagctgaggacagtgccacttattactgt gc ttgtggtaactacgtaggctatgctatggactac tggggtcaaggaacctcagtcaccgtctcctcagcc(SEQ IDNO:27)

[0305] Amino acids:

[0306] EVKLVESGGGLVQPGGSLSLSCATS GFTFTDYY MNWVRQPPGKALEWLGF IRNKANGYTT EYSASVKGRFTISRDNSQSILYLQMNSLRAEDSATYYC ACGNYVGYAMDY WGQGTSVTVSSA(SEQ ID NO:28)

[0307] 33B8_IgL

[0308] Nucleotide

[0309] gacattgtgatgtcacagtctccatcctccctggctgtgtcagcaggagagaaggtcactatgagctgcaaatccagt cagagtctgctcaacagtagaacccgaaagaactac ttggcttggtaccagcagaaaccagggcagtctcctaaactgctgatctac tgggcatcc actagggaatctggggtccctgatcgcttcacaggcagtggatctgggacagatttcactctcaccatcagcagtgtgcaggctgaagacctggcagtttattactgc aagcaatcttataa tctgtacacg ttcggaggggggaccaagctggaaataaaacgg(SEQ ID NO:29)

[0310] Amino acid:

[0311] DIVMSQSPSSLAVSAGEKVTMSCKSS QSLLNSRTRKNY LAWYQQKPGQSPKLLIY WAS TRESGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYC KQSYNLYT FGGGTKLEIKR(SEQ ID NO:30)

[0312] HSV010-4_IgH

[0313] Nucleotide

[0314] caggtgcagctgaaggagtcaggacctggcctggtggcgccctcacagagcctgtccatcacatgcactgtctca gggttctcattaagcagacatgatg taagctgggttcgccagcctccaggaaagggtctggagtggctgggagta atatggggtgacgggagcaca aattatcattcagctctcatatccagactgagcatcagcaaagataactccaagagccaagttttcttaaaactgaacagtctgcaaaatgatgacacagccacgtactactgt gccaaagaagactatggtatttttccttac tggggccaagggactctggtcactgtctctgcagcc(SEQ ID NO:31) Amino acid

[0315] QVQLKESGPGLVAPSQSLSITCTVS GFSLSRHD VSWVRQPPGKGLEWLGV IWGDGST NYHSALISRLSISKDNSKSQVFLKLNSLQNDDTATYYC AKEDYGIFPY WGQGTLVTVSAA(SEQ ID NO:32)

[0316] HSV010 - 4_IgL

[0317] Nucleotide

[0318] gacatcaagatgacccagtctccatcttccatgtatgcatctctaggagagaaagtcactatcacttgcaaggcgagt caggacattagtagctat ttaagctggttccagcagaaaccagggaaatctcctaagaccctgatctat cgtgcaaac agattggtagatggggtcccatcaaggttcagtggcagtggatctgggcaagattattctctctccatcagcagcctggactatgaagatatgggaatttattattgt ctacagtatgatgagtttccgctcacg ttcggtgctgggaccaagctggagctgaaacgg(SEQ ID NO:33)

[0319] Amino acid

[0320] DIKMTQSPSSMYASLGEKVTITCKAS QDISSY LSWFQQKPGKSPKTLIY RAN RLVDGVPSRFSGSGSGQDYSLSISSLDYEDMGIYYC LQYDEFPLT FGAGTKLELKR(SEQ ID NO:34)

[0321] HSV010 - 7_IgH

[0322] Nucleotide

[0323] caggttcagctgcagcagtctggacctgagctggtgaagcctggggcttcagtgaagttgtcctgcaaggcttct ggctacaccttcacaaactacgat ataaactgggtgaagcagaggcctggacagggacttgagtggattggatgg atttatcctagagatggtagcact aaatacaatgagaaattcaagggcaaggccacattgactattgacacatcctccagcacagcgtacatggagctccacagcctgacatctgaggactctgcggtctatttctgt gcaagagg gatcttctatgttaactacgacgtttac tggggccaagggactctggtcactgtctctgcagcc(SEQ ID NO:35)

[0324] Amino acid

[0325] QVQLQQSGPELVKPGASVKLSCKAS GYTFTNYD INWVKQRPGQGLEWIGW IYPRDGST KYNEKFKGKATLTIDTSSSTAYMELHSLTSEDSAVYFC ARGIFYVNYDVY WGQGTLVTVSAA(SEQ ID NO:36)

[0326] HSV010-7_IgL

[0327] Nucleotide

[0328] gacatccagatgacacaatcttcatccttcttgtctgtatctctaggaggcagagtcaccattacttgcaaggcaagt gaccacattaataattg gttagcctggtatcagcagaaaccaggacatgctcctaggctcttaatatct ggtgcagcc agtttggaaactggggttccttcaagattcagtggcagtggatctggaaaggattacactctcaccattaccagtcttcagactgaagatgttgctacttattactgt caacagtattggagtagtccgctcacg ttcggtggtgggaccaagctggagctgaaacgg(SEQ ID NO:37)

[0329] Amino acid

[0330] DIQMTQSSSFLSVSLGGRVTITCKAS DHINNW LAWYQQKPGHAPRLLIS GAA SLETGVPSRFSGSGSGKDYTLTITSLQTEDVATYYC QQYWSSPLT FGGGTKLELKR(SEQ ID NO:38)

[0331] HSV010-34_IgH

[0332] Nucleotide

[0333] gaggtgcagctggtggagtctgggggaggcttagtgcagcctggagagtccctgaaactctcctgtgaatccaat gaatacgaattcccttcccatgac atgtcttgggtccgcaagactccggagaagaggctggagttggtcgcagcc attaatagtgatggtggtagcacc tactatccagacaccatggagagacgattcatcatctccagagacaataccaagaagaccctgtacctgcaaatgagcagtctgaggtctgaggacacagccttgtattactgt gcaagaca tagctcaggctatgttttggactac tggggtcaaggaacctcagtcaccgtctcctcagcc(SEQ ID NO:39)

[0334] Amino acid

[0335] EVQLVESGGGLVQPGESLKLSCESN EYEFPSHD MSWVRKTPEKRLELVAA INSDGGST YYPDTMERRFIISRDNTKKTLYLQMSSLRSEDTALYYC ARHSSGYVLDY WGQGTSVTVSSA(SEQ ID NO:40)

[0336] HSV010-34_IgL

[0337] Nucleotide

[0338] gacatccagatgacacaatcttcatcctacttgtctgtatctctaggaggcagagtcaccattacttgcaaggcaagt gaccacattaatcattg gttagcctggtatcagcagaaaccaggaaatgctcctaggctcttaatatct ggtgcaacc agtttggaaactggggttccttcaagattcagtggcagtggatctggaaaggattacactctcagcattgccagtcttcagactgaagatgttgctacttattactgt caacagtattggagtactccgtacacg ttcggaggggggaccaagctggaaataaaacgg(SEQ ID NO:41)

[0339] Amino acid

[0340] DIQMTQSSSYLSVSLGGRVTITCKAS DHINHW LAWYQQKPGNAPRLLIS GAT SLETGVPSRFSGSGSGKDYTLSIASLQTEDVATYYC QQYWSTPYT FGGGTKLEIKR(SEQ ID NO:42)

[0341] HSV010-6_IgH

[0342] Nucleotide

[0343] caggtccaactgcagcagcctggggctgagctggtaaagcctggggcttcagtgaagttgtcctgcaaggcttct ggctacactttcaccaactactgg atacactgggtgaagcagaggcctggacaaggccttgagtggattggaatg attcatcctaatattggtattact cactacagtgagaggttcaagagcaaggccacactgactgtagacaaatcctccaccacagcctacatgcaactcagcagcctgacatctgaggactctgcggtctattactgt gcaagagg gtcggactcaggctccgcctggtttgcttac tggggccaagggactctggtcactgtctctgcagcc(SEQ IDNO:43)

[0344] Amino acid

[0345] QVQLQQPGAELVKPGASVKLSCKAS GYTFTNYW IHWVKQRPGQGLEWIGM IHPNIGIT HYSERFKSKATLTVDKSSTTAYMQLSSLTSEDSAVYYC ARGSDSGSAWFAY WGQGTLVTVSAA(SEQ ID NO:44)

[0346] HSV010-6_IgL

[0347] Nucleotide

[0348] Gacatccagatgacacaatcttcatcctacttgtctgtttctctaggaggcagagtcaccattacttgcaaggcaagt gaccacattaataattg gttagcctggtatctgcagaaaccaggaaatgctcctagactcttaatgtct ggtgcaacc agtttggaaactggggttccttcaagattcagtggcagtggatctggaaaggattacactctcagcattaccagtcttcagactgaagatgttgctacttattactgt caacagtattggagtactccgctcacg ttcggtgctgggaccaagctggagctgaaacgg(SEQ ID NO:45)

[0349] Amino acid

[0350] DIQMTQSSSYLSVSLGGRVTITCKAS DHINNW LAWYLQKPGNAPRLLMS GAT SLETGVPSRFSGSGSGKDYTLSITSLQTEDVATYYC QQYWSTPLT FGAGTKLELKR(SEQ ID NO:46)

[0351] HSV010-9_IgH

[0352] Nucleotide

[0353] caggtccaactgcagcagcctggggctgagttggtaaagcctggggcttcagtgaagttgtcctgcaagtcttct ggctacactttcaccagctactgg atgcactgggtgaagcagaggcctggacaaggccttgagtggattggaatg attcatcctaatagtggtattact cactacaatgagaagttcaagaccaaggccacactgactgtagacaaatcctccagcacagcctacatgcaactcagcagcctgacatctgaggactctgcggtctcttactgt gcaagagg gtcgaactcaggctccgcctggtttgcttac tggggccaagggactctggtcactgtctctgcagcc(SEQ IDNO:47)

[0354] Amino acid

[0355] QVQLQQPGAELVKPGASVKLSCKSS GYTFTSYW MHWVKQRPGQGLEWIGM IHPNSGIT HYNEKFKTKATLTVDKSSSTAYMQLSSLTSEDSAVSYC ARGSNSGSAWFAY WGQGTLVTVSAA(SEQ ID NO:48)

[0356] HSV010-9_IgL

[0357] Nucleotide

[0358] Gacatccagatgacacaatcttcatcctacttgtctgtatctctaggaggcagagtcaccattacttgcaaggcaagt gaccacattaataatt ggttagcctggtatcagcagaaaccaggaaatgctcctaggctcttaatatct ggtgcaacc agtttggaaactggggttccttcaagattcagtggcagtggatctggaaaggattacactctcagcattaccagtcttcagactgaagatgttgctacttattactgt caacagtattggagtactccgctcacg ttcggtgctgggaccaagctggagctgaaacgg(SEQ ID NO:49)

[0359] Amino acid

[0360] DIQMTQSSSYLSVSLGGRVTITCKAS DHINNW LAWYQQKPGNAPRLLIS GAT SLETGVPSRFSGSGSGKDYTLSITSLQTEDVATYYC QQYWSTPLT FGAGTKLELKR(SEQ ID NO:50)

[0361] HSV010-13_IgH

[0362] Nucleotide

[0363] caggtccaactgcagcagcctggggctgagctggtaaagcctggggcttcagtgaagttgtcctgcaaggcttct ggctacactttcaccagctactgg atacactgggtgaagcaggggcctggacaaggccttgagtggattggaatg attcatcctaatagtggtattact cactacaatgagaagttcaagaccaaggccacactgactgtagacaaatcctccagcacagcctacatgcaactcagcagcctgacatctgaggactctgcggtctgttactgt gcaagagg gtcgagctcaggctccgcctggtttgcttac tggggccaagggactctggtcactgtctctgcagcc(SEQ IDNO:51)

[0364] Amino acid

[0365] QVQLQQPGAELVKPGASVKLSCKAS GYTFTSYW IHWVKQGPGQGLEWIGM IHPNSGIT HYNEKFKTKATLTVDKSSSTAYMQLSSLTSEDSAVCYC ARGSSSGSAWFAY WGQGTLVTVSAA(SEQ ID NO:52)

[0366] HSV010-13_IgL

[0367] Nucleotide

[0368] gacatccagatgacacaatcttcatcctacttgtctgaatctctaggaggcagagtcaccattacttgcaaggcaagt gaccacattaataattg gttagcctggtatcagcagaaaccaggaaatgctcccaggctcttaatatct ggtgcaacc agtttggaaactggggttccttcaagattcagtggcagtggatctggaaaggattacactctcagcattaccagtcttcagactgaagatgttgctacttattactgt caacagtattggagtagtccgctcacg ttcggtgctgggaccaagctggagctgaaacgg(SEQ ID NO:53)

[0369] Amino acid

[0370] DIQMTQSSSYLSESLGGRVTITCKAS DHINNW LAWYQQKPGNAPRLLIS GAT SLETGVPSRFSGSGSGKDYTLSITSLQTEDVATYYC QQYWSSPLT FGAGTKLELKR(SEQ ID NO:54)

[0371] HSV010-14_IgH

[0372] Nucleotide

[0373] caggtccaactgcagcagcctggggctgagctggtaaagcctggggcttcagtgaagttgtcctgcaaggcttct ggctacactttcaccagctactgg atacactgggtgaagcagaggcctggccaaggccttgagtggattggaatg attcatcctaatagtggtattgct cactacagtgagaagttcaagagcacggccacactgactgtagacaaatcctccagcacagcctacatgcaactcagcagcctgacatctgaggactcttcggtctattactgt gcaagagg gtcgagctcaggctccgcctggtttgcttat tggggccaagggactctggtcactgtctctgcagcc(SEQ IDNO:55)

[0374] Amino acid

[0375] QVQLQQPGAELVKPGASVKLSCKAS GYTFTSYW IHWVKQRPGQGLEWIGM IHPNSGIA HYSEKFKSTATLTVDKSSSTAYMQLSSLTSEDSSVYYC ARGSSSGSAWFAY WGQGTLVTVSAA(SEQ ID NO:56)

[0376] HSV010-14_IgL

[0377] Nucleotide

[0378] gacatccagatgacacaatcttcatcctacttgtctgtttctctaggaggcagagtcaccattacttgcaaggcaggt gaccacattaataattg gttagcctggtatcagcagaaaccaggaaatgctcctaggctcttaatatct ggtgcaacc agtttggaaactggggttccttcaagattcagtggcagtggatctggaaaggattacactctcagcattaccagtcttcagactgaagatgttgctacttattactgt caacagtattggagtactccgctcacg ttcggtgctgggaccaagctggagctgaaacgg(SEQ ID NO:57)

[0379] Amino acid

[0380] DIQMTQSSSYLSVSLGGRVTITCKAG DHINNW LAWYQQKPGNAPRLLIS GAT SLETGVPSRFSGSGSGKDYTLSITSLQTEDVATYYC QQYWSTPLT FGAGTKLELKR(SEQ ID NO:58)

[0381] HSV010-28_IgH

[0382] Nucleotide

[0383] cagatccagttggtacagtctggacctgagctgaagaagcctggagagacagtcaagatctcctgcaaggcttct gggtataccttcacaacctatgga atgagctgggtgaaacaggctccaggaaagggtttaaagtggatgggctgg ataaacacctactctggagtgtca acatatgctgatgacttcaagggacggtttgccttctctttggaaacctctgccagcactgcctatttgcagatcaacaacctcaaaaatgaggacacggctacatatttctgt gctcaggt aaactatgctatggactactggggtcaaggaacctcagtcaccgtctcctcagcc(SEQ ID NO:59) Amino acid

[0384] QIQLVQSGPELKKPGETVKISCKAS GYTFTTYG MSWVKQAPGKGLKWMGW INTYSGVS TYADDFKGRFAFSLETSASTAYLQINNLKNEDTATYFC AQVNYAMDYW GQGTSVTVSSA(SEQ ID NO:60)

[0385] HSV010-28_IgL

[0386] Nucleotide

[0387] gacattgtgatgacccagtctcacaaattcttgtccacatcagtaggagactgggtcaccatcacctgcaaggccagt caggatgtgagtactgct gtagcctggtttcagcagaaaccaggacaatctcctaaagtactgatttac tcggcatcc taccggtacactggagtccctgatcgcttcactggcagtggatctgggacggatttcactttcaccatcagcagtgtgcaggctgaagacctggcagtttattactgt cagcaacattatagtactcctcggacg ttcggtggaggcaccaagctggaaatcaaacgg(SEQ ID NO:61)

[0388] Amino acid

[0389] DIVMTQSHKFLSTSVGDWVTITCKAS QDVSTA VAWFQQKPGQSPKVLIY SAS YRYTGVPDRFTGSGSGTDFTFTISSVQAEDLAVYYC QQHYSTPRT FGGGTKLEIKR(SEQ ID NO:62)

[0390] HSV010-20_IgH

[0391] Nucleotide

[0392] gatgtgcagcttcaggagtcaggacctggcatggtgagaccttctcagtcactttccctcacctgcactgtcact ggctactccatcaccagtggttatgac tggcactggatccgacattttccaggaaacaaactggagtggatgggctac ataagctacagtggtctcact aactacaacccatccctcagaagtcgattctccatcactcatgacacatctaagaaccatttcttcctgaagttgaattctgtgactactgaggacacagccacatattactgt gcaagagg tcctccctggtacttcgatgtc tggggcacagggaccacggtcaccgtctcctcagcc(SEQ ID NO:63)

[0393] Amino acid

[0394] DVQLQESGPGMVRPSQSLSLTCTVT GYSITSGYD WHWIRHFPGNKLEWMGY ISYSGLT NYNPSLRSRFSITHDTSKNHFFLKLNSVTTEDTATYYC ARGPPWYFDV WGTGTTVTVSSA(SEQ ID NO:64)

[0395] HSV010-20_IgL

[0396] Nucleotide

[0397] gacattgtgatgacccagtctcaaaaattcatgtccacatcagtaggaggcagggtcagcatcacctgcaaggccagt cagattgttcgtgctact gtagcctggtatcaacagaaaccagggcagtctcctaaaccactaatttac ttggcatcc aaccggcacactggagtccctgatcgcttcacaggcagtggatctgggacagatttcactctcaccattagcaatgtgcaatctgaagacctggcagattatttctgt ctgcaatattggaattatccgtacacg ttcggaggggggaccaagctggaaataaaacgg(SEQ ID NO:65)

[0398] Amino acid

[0399] DIVMTQSQKFMSTSVGGRVSITCKAS QIVRAT VAWYQQKPGQSPKPLIY LAS NRHTGVPDRFTGSGSGTDFTLTISNVQSEDLADYFC LQYWNYPYT FGGGTKLEIKR(SEQ ID NO:66)

[0400] HSV010-8_IgH

[0401] Nucleotide

[0402] caggtgcagctgaaggagtcaggacctggcctggtggcgccctcacagagcctgtcgatcacatgcactgtctca gggttctcattaaacaactatgatg taagctgggttcgccagcctccaggaaagggtctggagtggctgggagta atatggggtgacgggagcaca aattatcattcagctctcatatccagactgagcatcagcaaggataactccaagagccaagttttcttaaaactgaacagtctgcaaactgatgacacagccacgtactactgt gccaaagaaga ctatggtatttttccttac tggggccaagggactctggtcactgtctctgcagcc(SEQ ID NO:67)

[0403] Amino acid

[0404] QVQLKESGPGLVAPSQSLSITCTVS GFSLNNYD VSWVRQPPGKGLEWLGV IWGDGST NYHSALISRLSISKDNSKSQVFLKLNSLQTDDTATYYC AKEDYGIFPY WGQGTLVTVSAA(SEQ ID NO:68)

[0405] HSV010-8_IgL

[0406] Nucleotide

[0407] Gacatcaagatgacccagtctccatcttccatgtatgcatctctaggagagagagtcactatcacttgcaaggcgagt caggacattaatagctatttaagctggttccagcagaaaccagggaaatctcctaagaccctgatctat cgtgcaaac agattggtagatggggtcccatcaaggttcagtggcagtggatctgggcaagattattctctcaccatcagcagcctggaatatgaaaatatgggaatttattattgt ctacagtatgatgagtttccgctcacg ttcggtgctgggaccaagctggagctgaaacgg(SEQ ID NO:69)

[0408] Amino acid

[0409] DIKMTQSPSSMYASLGERVTITCKAS QDINSY LSWFQQKPGKSPKTLIY RAN RLVDGVPSRFSGSGSGQDYSLTISSLEYENMGIYYC LQYDEFPLT FGAGTKLELKR(SEQ ID NO:70)

[0410] HSV010-15_IgH

[0411] Nucleotide

[0412] caggtccaactgcagcagcctggggctgagctggtaaagcctggggcttcagtgaagttgtcctgcaaggcttctg gctacactttcaccagctactgg atacactgggtgcagcagaggcctggacaaggccttgagtggattggaatg attcatcctaatagtggtattact aactacagtgagaagttcaagagcaaggccacactgactttagacaagtcctccagcacagcctacatgcaactcatcagcctgacatctgaggactctgcggtctattactgt gcaagagg gtcgagttcaggctccgcctggtttgcttac tggggccaagggactctggtcactgtctctgcagcc(SEQ IDNO:71)

[0413] Amino acid

[0414] QVQLQQPGAELVKPGASVKLSCKAS GYTFTSYW IHWVQQRPGQGLEWIGM IHPNSGITNYSEKFKSKATLTLDKSSSTAYMQLISLTSEDSAVYYC ARGSSSGSAWFAY WGQGTLVTVSAA (SEQ ID NO:72)

[0415] HSV010-15_IgL

[0416] Nucleotide

[0417] gacatccagatgacacaatcttcatcctacttgtctgtttctctaggaggcagagtcaccattacttgcaaggcaagt gaccacattaataattggt taccttggtatcagcagaaaccaggaaatgctcctaggctcttaatttct ggtgcaacc agtttggaaactggggttccttcaagattcagtggcagtggatctggaaaggattacactctcagcattaccagtcttcagactgaagatgttgctacttattactgt caacagtattggagttctccgctcacg ttcggtgctgggaccaagctggagctgaaacgg(SEQ ID NO:3)

[0418] Amino acid

[0419] DIQMTQSSSYLSVSLGGRVTITCKAS DHINNW LPWYQQKPGNAPRLLIS GAT SLETGVPSRFSGSGSGKDYTLSITSLQTEDVATYYC QQYWSSPLT FGAGTKLELKR(SEQ ID NO:74)

[0420] HSV010-16_IgH

[0421] Nucleotide

[0422] cagatccagttggtacagtctggacctgagctgaagaagcctggagagacagtcaagatctcctgcaaggcttct gggtataccttcacaacctatgga atgagctgggtgaaacaggctccaggaaaggatttaaagtggatgggctgg ataaacacctactctggagtgtcaacatatggtgatgacttcaagggacggtttgccttgtctttggaaacctctgccagcactgcctatttacaaatcaacaacctcaaaaatgaggacacggctacatatttctgt gctcagtt aaactatggtatggactac tggggtcaaggaacctcagtcaccgtctcctcagcc(SEQ ID NO:75)

[0423] Amino acid

[0424] QIQLVQSGPELKKPGETVKISCKAS GYTFTTYG MSWVKQAPGKDLKWMGW INTYSGVS TYGDDFKGRFALSLETSASTAYLQINNLKNEDTATYFC AQLNYGMDY WGQGTSVTVSSA(SEQ ID NO:76)

[0425] HSV010-16_IgL

[0426] Nucleotide

[0427] gacattgtgatgacccagtctcacaaattcatgtccacatcagtaggagacagggtcagcatcacctgcaaggccagt caggatgtgagtacttct ttagcctggtatcaacagaaaccaggacaatctcctaaactactgatttat tcggcatcc taccggtacactggagtccctgatcgcttcactggcagtggatctgggacggatttcactttcaccatcagcagtgtgcaggctgaagacctggcagtttattactgt caccaacattatagtattcctcggacg ttcggtggaggcaccaagctggaaatcaaacgg(SEQ ID NO:77)

[0428] Amino acid

[0429] DIVMTQSHKFMSTSVGDRVSITCKAS QDVSTS LAWYQQKPGQSPKLLIY SAS YRYTGVPDRFTGSGSGTDFTFTISSVQAEDLAVYYC HQHYSIPRTFGGGTKLEIKR(SEQ ID NO:78)

[0430] In some embodiments, an antibody is provided that has a heavy chain HCDR1, HCDR2 and HCDR3 of one of the heavy chain amino acid sequences listed above and a light chain LCDR1, LCDR2 and LCDR3 of any of the light chain amino acid sequences listed above. In some embodiments, the heavy chain HCDR1, HCDR2 and HCDR3 and the light chain LCDR1, LCDR2 and LCDR3 are identical to the heavy chain HCDR and light chain LCDR of BMPC-23. In some embodiments, the heavy chain HCDR1, HCDR2 and HCDR3 and the light chain LCDR1, LCDR2 and LCDR3 are identical to the heavy chain HCDR and light chain LCDR of 33B8. In some embodiments, the heavy chain HCDR1, HCDR2 and HCDR3 and the light chain LCDR1, LCDR2 and LCDR3 are identical to the heavy chain HCDR and light chain LCDR of 22D10. In some embodiments, heavy chain HCDR1, HCDR2 and HCDR3 and light chain LCDR1, LCDR2 and LCDR3 are the same as the heavy chain HCDR and light chain LCDR of HSV010-4. In some embodiments, heavy chain HCDR1, HCDR2 and HCDR3 and light chain LCDR1, LCDR2 and LCDR3 are the same as the heavy chain HCDR and light chain LCDR of HSV010-8. In some embodiments, heavy chain HCDR1, HCDR2 and HCDR3 and light chain LCDR1, LCDR2 and LCDR3 are the same as the heavy chain HCDR and light chain LCDR of HSV010-7. In some embodiments, heavy chain HCDR1, HCDR2 and HCDR3 and light chain LCDR1, LCDR2 and LCDR3 are the same as the heavy chain HCDR and light chain LCDR of HSV010-34. In some embodiments, heavy chain HCDR1, HCDR2 and HCDR3 and light chain LCDR1, LCDR2 and LCDR3 are the same as the heavy chain HCDR and light chain LCDR of HSV010-6. In some embodiments, the heavy chain HCDR1, HCDR2 and HCDR3 and the light chain LCDR1, LCDR2 and LCDR3 are the same as the heavy chain HCDR and light chain LCDR of HSC010-9. In some embodiments, the heavy chain HCDR1, HCDR2 and HCDR3 and the light chain LCDR1, LCDR2 and LCDR3 are the same as the heavy chain HCDR and light chain LCDR of HSV010-13. In some embodiments, the heavy chain HCDR1, HCDR2 and HCDR3 and the light chain LCDR1, LCDR2 and LCDR3 are the same as the heavy chain HCDR and light chain LCDR of HSV010-14. In some embodiments, the heavy chain HCDR1, HCDR2 and HCDR3 and the light chain LCDR1, LCDR2 and LCDR3 are the same as the heavy chain HCDR and light chain LCDR of HSV010-15.In some embodiments, the heavy chain HCDR1, HCDR2 and HCDR3 and the light chain LCDR1, LCDR2 and LCDR3 are the same as the heavy chain HCDR and light chain LCDR of HSV010-16. In some embodiments, the heavy chain HCDR1, HCDR2 and HCDR3 and the light chain LCDR1, LCDR2 and LCDR3 are the same as the heavy chain HCDR and light chain LCDR of HSV010-28. In some embodiments, the heavy chain HCDR1, HCDR2 and HCDR3 and the light chain LCDR1, LCDR2 and LCDR3 are the same as the heavy chain HCDR and light chain LCDR of HSV010-20.

[0431] Provided is a nucleic acid encoding an antibody or an antigen-binding fragment thereof. Also provided is an isolated nucleic acid molecule encoding the antibody or the antigen-binding fragment thereof.

[0432] In some embodiments, a nucleic acid encoding a light chain of an antibody is provided. Specifically, the nucleic acid encodes a light chain variable region of the antibody. The light chain is a lambda chain or a kappa chain. In some embodiments, the nucleic acid also encodes a human framework region. The nucleic acid can be an isolated nucleic acid molecule.

[0433] In some embodiments, the nucleic acid encodes a light chain variable region of an antibody, the light chain having a nucleic acid sequence comprising: SEQ ID NO:21, SEQ ID NO:25, SEQ ID NO:29, SEQ ID NO:33, SEQ ID NO:69, SEQ ID NO:37, SEQ ID NO:41, SEQ ID NO:45, SEQ ID NO:49, SEQ ID NO:53, SEQ ID NO:57, SEQID NO:73, SEQ ID NO:77, SEQ ID NO:61, or SEQ ID NO:66. In some embodiments, the nucleic acid encodes a light chain variable region of an antibody, wherein the light chain has a nucleic acid sequence that is 95% or more identical to SEQ ID NO:21, SEQ ID NO:25, SEQ ID NO:29, SEQ ID NO:33, SEQ ID NO:69, SEQ ID NO:37, SEQ ID NO:41, SEQ ID NO:45, SEQ ID NO:49, SEQ ID NO:53, SEQ ID NO:57, SEQ ID NO:73, SEQ ID NO:77, SEQ ID NO:61, or SEQ ID NO:66.

[0434] In some embodiments, the nucleic acid encodes a light chain variable region of an antibody having an amino acid sequence comprising (LCDR1, LCDR2, and LCDR3 listed in their respective order):

[0435] ESVDNFGISF (SEQ ID NO: 4);

[0436] AAS (SEQ ID NO: 5); and

[0437] QQSKEVPLT (SEQ ID NO: 6),

[0438] or

[0439] GNIHNY (SEQ ID NO: 10);

[0440] HAE (SEQ ID NO: 11); and

[0441] QHFWSTPYT (SEQ ID NO: 12),

[0442] or

[0443] QSLLNSRTRKNY (SEQ ID NO: 16);

[0444] WAS (SEQ ID NO: 17); and

[0445] KQSYNLYT (SEQ ID NO: 18)

[0446] or

[0447] QDISSY (SEQ ID NO: 82);

[0448] RAN (SEQ ID NO:83); and

[0449] LQYDEFPLT (SEQ ID NO:84)

[0450] or

[0451] QDINSY (SEQ ID NO: 86);

[0452] RAN (SEQ ID NO:83); and

[0453] LQYDEFPLT (SEQ ID NO:84)

[0454] or

[0455] DHINNW (SEQ ID NO:90);

[0456] GAA (SEQ ID NO:91); and

[0457] QQYWSSPLT (SEQ ID NO:92)

[0458] or

[0459] DHINHW (SEQ ID NO:96)

[0460] GAT (SEQ ID NO:97)

[0461] QQYWSTPYT (SEQ ID NO:98)

[0462] or

[0463] DHINNW (SEQ ID NO:90);

[0464] GAT (SEQ ID NO:97); and

[0465] QQYWSTPLT (SEQ ID NO: 102)

[0466] or

[0467] DHINNW (SEQ ID NO:90);

[0468] GAT (SEQ ID NO:97); and

[0469] QQYWSSPLT (SEQ ID NO:92)

[0470] or

[0471] QDVSTS (SEQ ID NO: 110);

[0472] SAS (SEQ ID NO: 111); and

[0473] HQHYSIPRT (SEQ ID NO: 112)

[0474] or

[0475] QDVSTA (SEQ ID NO: 114);

[0476] SAS (SEQ ID NO: 111); and

[0477] QQHYSTPRT (SEQ ID NO: 115)

[0478] or

[0479] QIVRAT (SEQ ID NO: 119);

[0480] LAS (SEQ ID NO: 120); and

[0481] LQYWNYPYT (SEQ ID NO: 122).

[0482] In some embodiments, the nucleic acid further encodes a human framework region.In some embodiments, the light chain is a lambda chain or a kappa chain.

[0483] A nucleic acid encoding a heavy chain of an antibody is provided. Specifically, the nucleic acid encodes a light chain variable region of an antibody. In some embodiments, the nucleic acid also encodes a human framework region. The nucleic acid can be an isolated nucleic acid molecule.

[0484] In some embodiments, the nucleic acid encodes a heavy chain variable region of an antibody, wherein the heavy chain has a nucleic acid sequence comprising: SEQ ID NO:19, SEQ ID NO:23, SEQ ID NO:27, SEQ ID NO:31, SEQ ID NO:67, SEQ ID NO:35, SEQ ID NO:39, SEQ ID NO:43, SEQ ID NO:47, SEQ ID NO:51, SEQ ID NO:55, SEQID NO:71, SEQ ID NO:75, SEQ ID NO:59, or SEQ ID NO:63. In some embodiments, the nucleic acid encodes a heavy chain variable region of an antibody, wherein the heavy chain has a nucleic acid sequence that is 95% or more identical to SEQ ID NO:19, SEQ ID NO:23, SEQ ID NO:27, SEQ ID NO:31, SEQ ID NO:67, SEQ ID NO:35, SEQ ID NO:39, SEQ ID NO:43, SEQ ID NO:47, SEQ ID NO:51, SEQ ID NO:55, SEQ ID NO:71, SEQ ID NO:75, SEQ ID NO:59, or SEQ ID NO:63.

[0485] In some embodiments, the nucleic acid encodes a heavy chain variable region of an antibody having an amino acid sequence comprising (HCDR1, HCDR2, and HCDR3 listed in their respective order):

[0486] GYSFTTYD (SEQ ID NO: 1);

[0487] IYPREGST (SEQ ID NO: 2); and

[0488] ATYGSSRYYTMDY (SEQ ID NO: 3)

[0489] or

[0490] GYSITNGNH (SEQ ID NO: 7),

[0491] IRSSGSS (SEQ ID NO: 8); and

[0492] ARGGGLRHYFDY (SEQ ID NO: 9),

[0493] or

[0494] GFTFTDYY (SEQ ID NO: 13);

[0495] IRNKANGYTT (SEQ ID NO:14); and

[0496] ACGNYVGYAMDY (SEQ ID NO: 15)

[0497] or

[0498] GFSLSRHD (SEQ ID NO: 79);

[0499] IWGDGST (SEQ ID NO: 80); and

[0500] AKEDYGIFPY (SEQ ID NO:81)

[0501] or

[0502] GFSLNNYD (SEQ ID NO: 85);

[0503] IWGDGST (SEQ ID NO: 80); and

[0504] AKEDYGIFPY (SEQ ID NO:81)

[0505] or

[0506] GYTFTNYD (SEQ ID NO: 87);

[0507] IYPRDGST (SEQ ID NO: 88); and

[0508] ARGIFYVNYDVY (SEQ ID NO: 89)

[0509] or

[0510] EYEFPSHD (SEQ ID NO: 93);

[0511] INSDGGST (SEQ ID NO:94); and

[0512] ARHSSGYVLDY (SEQ ID NO:95)

[0513] or

[0514] GYTFTNYW (SEQ ID NO:99);

[0515] IHPNIGIT (SEQ ID NO:100); and

[0516] ARGSDSGSAWFAY (SEQ ID NO:101)

[0517] or

[0518] GYTFTSYW (SEQ ID NO:103);

[0519] IHPNSGIT (SEQ ID NO:104); and

[0520] ARGSNSGSAWFAY (SEQ ID NO:105)

[0521] or

[0522] GYTFTTYG (SEQ ID NO:107);

[0523] INTYSGVS (SEQ ID NO:108); and

[0524] AQLNYGMDY (SEQ ID NO:109)

[0525] or

[0526] GYTFTTYG (SEQ ID NO:107);

[0527] INTYSGVS (SEQ ID NO:108); and

[0528] AQVNYAMDY (SEQ ID NO:113)

[0529] or

[0530] GYSITSGYD (SEQ ID NO:116);

[0531] ISYSGLT (SEQ ID NO:117); and

[0532] ARGPPWYFDV (SEQ ID NO:118).

[0533] In some embodiments, the nucleic acid encodes the heavy chain variable region of an antibody having the nucleic acid sequence of SEQ ID NO: 19 and the light chain variable region of an antibody having the nucleic acid sequence of SEQ ID NO: 21. In some embodiments, the nucleic acid encodes the heavy chain variable region of an antibody having the nucleic acid sequence of SEQ ID NO: 23 and the light chain variable region of an antibody having the nucleic acid sequence of SEQ ID NO: 25. In some embodiments, the nucleic acid encodes the heavy chain variable region of an antibody having the nucleic acid sequence of SEQ ID NO: 27 and the light chain variable region of an antibody having the nucleic acid sequence of SEQ ID NO: 29. In some embodiments, the nucleic acid encodes the heavy chain variable region of an antibody having the nucleic acid sequence of SEQ ID NO: 31 and the light chain variable region of an antibody having the nucleic acid sequence of SEQ ID NO: 33. In some embodiments, the nucleic acid encodes the heavy chain variable region of an antibody having the nucleic acid sequence of SEQ ID NO: 67 and the light chain variable region of an antibody having the nucleic acid sequence of SEQ ID NO: 69. In some embodiments, the nucleic acid encodes the heavy chain variable region of an antibody having the nucleic acid sequence of SEQ ID NO: 35 and the light chain variable region of an antibody having the nucleic acid sequence of SEQ ID NO: 37. In some embodiments, the nucleic acid encodes the heavy chain variable region of an antibody having the nucleic acid sequence of SEQ ID NO:39 and the light chain variable region of an antibody having the nucleic acid sequence of SEQ ID NO:41. In some embodiments, the nucleic acid encodes the heavy chain variable region of an antibody having the nucleic acid sequence of SEQ ID NO:43 and the light chain variable region of an antibody having the nucleic acid sequence of SEQ ID NO:45. In some embodiments, the nucleic acid encodes the heavy chain variable region of an antibody having the nucleic acid sequence of SEQ ID NO:47 and the light chain variable region of an antibody having the nucleic acid sequence of SEQ ID NO:49. In some embodiments, the nucleic acid encodes the heavy chain variable region of an antibody having the nucleic acid sequence of SEQ ID NO:51 and the light chain variable region of an antibody having the nucleic acid sequence of SEQ ID NO:53. In some embodiments, the nucleic acid encodes the heavy chain variable region of an antibody having the nucleic acid sequence of SEQ ID NO:55 and the light chain variable region of an antibody having the nucleic acid sequence of SEQ ID NO:57. In some embodiments, the nucleic acid encodes the heavy chain variable region of an antibody having the nucleic acid sequence of SEQ ID NO:71 and the light chain variable region of an antibody having the nucleic acid sequence of SEQ ID NO:73. In some embodiments, the nucleic acid encodes a heavy chain variable region of an antibody having a nucleic acid sequence of SEQ ID NO: 75 and a light chain variable region of an antibody having a nucleic acid sequence of SEQ ID NO: 77. In some embodiments, the nucleic acid encodes a heavy chain variable region of an antibody having a nucleic acid sequence of SEQ ID NO: 59 and a light chain variable region of an antibody having a nucleic acid sequence of SEQ ID NO: 61.In some embodiments, the nucleic acid encodes a heavy chain variable region of an antibody having the nucleic acid sequence of SEQ ID NO:63 and a light chain variable region of an antibody having the nucleic acid sequence of SEQ ID NO:65.

[0534] In some embodiments, the nucleic acid further encodes a human Fc region. In some embodiments, the nucleic acid further encodes a human Fc region that binds to FcγRIII. In some embodiments, the antibody or antigen binding fragment comprises an Fc region that activates human FcγRIII when binding to human FcγRIII. In some embodiments, the human FcγRIII receptor is FcγRIIIa. In some embodiments, the heavy chain is a γ chain.

[0535] In some embodiments, the nucleic acids of the present disclosure encode polypeptides of less than 500 amino acids in length, less than 250 amino acids in length, or less than 120 amino acids in length. In some embodiments, the nucleic acids of the present disclosure encode polypeptides of 70 to 100 amino acids in length.

[0536] In embodiments of nucleic acids, the nucleic acid is DNA. In some embodiments, the nucleic acid is cDNA. In some embodiments, the nucleic acid is RNA.

[0537] The nucleic acids disclosed herein are suitable for recombinant production of the antibodies or antigen-binding fragments disclosed herein. Therefore, the present invention also relates to vectors and host cells containing nucleic acid sequences encoding antibodies or antigen-binding fragments.

[0538] Vectors encoding the nucleic acid molecules described herein are provided.

[0539] Also provided are host cells comprising one or more of the nucleic acids described herein or the vectors described herein.

[0540] The antibody or antigen binding fragment can be connected or coupled to a heterologous molecule. The heterologous molecule can be a therapeutic agent, such as a cytotoxic drug, a radioisotope, an immunomodulator, a second antibody, an antiviral small molecule, or a combination thereof. In some embodiments, the antibody or antigen binding fragment can be connected or coupled to a therapeutic agent.

[0541] A method of inhibiting HSV-2 activity in a subject, comprising administering an antibody or antigen binding fragment in an amount effective to inhibit HSV-2 activity in the subject. The antibody or antigen binding fragment can inhibit HSV-2 activity in a subject by clearing the virus from the subject, preventing the spread of HSV-2 in the subject, preventing the establishment of latency in the subject, and / or preventing the subject from becoming infected with HSV-2.

[0542] In some embodiments, the subject is infected with HSV-2. In some embodiments, the subject is not infected with HSV-2. In some embodiments, the subject is immunocompromised. In some embodiments, the immunocompromised patient has cancer, has received a transplant, or is taking immunosuppressive drugs. In some embodiments, the subject is pregnant. In some embodiments, the subject is a newborn.

[0543] In some embodiments, the subject is receiving or has received antiviral therapy. Antiviral therapy includes administering an antiviral small molecule to the subject. Antiviral small molecules include famciclovir, penciclovir, valacyclovir, or a combination thereof. In some embodiments, antiviral therapy includes administering acyclovir to the subject.

[0544] A method for activating antibody-dependent cellular cytotoxicity (ADCC) of cells infected with HSV-2 comprises contacting the cells with an isolated antibody or antigen-binding fragment in an amount that affects cellular ADCC.

[0545] In some embodiments, the cell is located in a subject infected with HSV-2.

[0546] Provided are antibodies or antigen-binding fragments described herein, or pharmaceutical compositions comprising the antibodies or antigen-binding fragments, for use in treating or preventing a disease or condition associated with herpes simplex virus-2 (HSV-2) infection in a subject.

[0547] Use of an effective amount of an antibody or antigen-binding fragment described herein in the manufacture of a medicament for treating or preventing a disease or condition associated with HSV-2 infection in a subject.

[0548] The one or more antibodies described herein may be isolated one or more antibodies. Similarly, the one or more antigen-binding fragments described herein may be isolated one or more antigen-binding fragments.

[0549] In some embodiments, the antibody or antigen-binding fragment thereof is chimeric or humanized. In some embodiments, the antibody or antigen-binding fragment thereof has a human sequence Fc region.

[0550] In some embodiments, the antibody or antigen-binding fragment comprises a monoclonal antibody, a scFv, a Fab fragment, a Fab' fragment, a F(ab')2 fragment, or a combination thereof.

[0551] In some embodiments, the isolated antibody, isolated antigen-binding fragment, antibody or antigen-binding fragment comprises a monoclonal antibody, scFv, Fab fragment, Fab' fragment, F(ab')2 fragment, or a combination thereof. It should be noted that although scFv is not an antibody fragment in the strict sense, but a fusion protein, as used herein, unless otherwise specified, the antigen-binding fragment of an antibody includes scFv.

[0552] In some embodiments, the methods are used to treat and prevent symptoms of neurological HSV-2 infection in a subject.

[0553] In some embodiments, the method is used to treat and prevent symptoms of epithelial HSV-2 infection.

[0554] In some embodiments, the antibodies or antigen-binding fragments thereof comprise a VH framework of a human germline framework sequence as named in Table 2 or Table 4 and / or (ii) a VL framework comprising a human germline framework sequence as named in Table 2 or Table 4. In some embodiments, the antibodies or antigen-binding fragments thereof comprise a VH framework with 95% or greater identity to a human germline framework sequence named in Table 2 or Table 4 and / or (ii) a VL framework with 95% or greater identity to a human germline framework sequence named in Table 2 or Table 4.

[0555] In some embodiments, the antibody or fragment thereof is present at about 1 x 10 -9 Mole (M) to about 1x 10 -12 The binding affinity (K D ) binds to HSV-2 surface antigen.

[0556] A method for producing an antibody or antigen-binding fragment thereof as described herein is provided, the method comprising culturing a host cell under conditions in which the antibody or antigen-binding fragment thereof is produced by the host cell. The term "host cell" refers to a cell into which an exogenous nucleic acid encoding an antibody or antigen-binding fragment has been introduced, including the progeny of such cells. Host cells include "transformants", "transformed cells", "transfectants", "transfected cells" and "transduced cells", including primary transformed / transfected / transduced cells and progeny derived therefrom, regardless of the number of passages. Progeny may not be completely identical to the parental cell in terms of nucleic acid content, but may contain mutations. Also included are mutant progeny with the same function or biological activity as screened or selected in the initially transformed cells.

[0557] The host cell can be a mammalian host cell. Examples of mammalian host cells for expressing antibodies or antigen-binding fragments thereof provided herein include Chinese hamster ovary (CHO cells), such as CHO-K1, CHO-S, CHO-K1SV, NSO myeloma cells, COS cells, HEK293 cells, HKB11 cells, BHK21 cells, CAP cells, EB66 cells, SP2 cells and Expi293F cells. In certain embodiments, the host cell is a Chinese hamster ovary (CHO) cell. In certain embodiments, the host cell is an Expi293F cell.

[0558] As used herein, the term "antibody" refers to an intact (complete) antibody, i.e., one with complete Fc and Fv regions. An intact antibody is a glycoprotein comprising at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds. Each heavy chain consists of a heavy chain variable region (V H ) and a heavy chain constant region. The heavy chain constant region is composed of three domains (CH1, CH2 and CH3). Each light chain is composed of a light chain variable region (V L ) and a light chain constant region. The light chain constant region consists of one domain (CL). H and V L The V regions are further subdivided into regions of hypervariability, called complementarity determining regions (CDRs), and more conserved regions, called framework regions (FRs), which are interspersed. H and V L It is composed of three CDRs and four FRs, which are arranged in the following order from amino-terminus to carboxyl-terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain a binding domain or binding portion that interacts with an antigen.

[0559] As used herein, the term "antigen binding fragment" or "antigen binding portion" refers to any portion of an antibody, or portions of an antibody linked together, that is smaller than an intact antibody but retains the ability to specifically bind to an antigen. Antigen binding fragments compete with fragments of intact antibodies for specific binding. In this case, the antigen is an HSV-2 antigen. The antigen may also be an HSV-1 antigen. An "antibody" or "fragment" thereof may comprise any class of immunoglobulins, such as IgG, IgM, IgA, IgD, and IgE. An exemplary class is IgG, and an exemplary isotype is IgG2c.

[0560] Examples of the term "antigen-binding fragment" or "antigen-binding portion" of an antibody include Fab fragments (composed of V L V H , C L and C H1domain), F(ab')2 fragment (a bivalent fragment comprising two Fab fragments linked by a disulfide bond in the hinge region), Fab' fragment (a monovalent fragment produced by reducing the F(ab')2 fragment, which has a free sulfhydryl group), V fragments consisting of a single arm of an antibody L and V H domain fragments, Fv fragments (comprising the V L and V H domains), single-chain fragments (scFv, light chain variable domain (VL) and heavy chain variable domain (VH) connected by a peptide linker), dAb fragments (composed of V H domain composition); isolated complementarity determining region (CDR), nanobodies (heavy chain variable region comprising a single variable domain and two constant domains), mutants thereof, naturally occurring variants, fusion proteins comprising an antibody portion having a desired specific antigen recognition site, humanized antibodies, chimeric antibodies and any other modified configuration of an immunoglobulin molecule comprising an antigen recognition site of desired specificity.

[0561] For example, antigen-binding fragments can be prepared by cutting whole antibodies or by recombinant means. See generally, Fundamental Immunology, Ch.7 (Paul, W., ed., 2nd ed. Raven Press, NY (1989)) [Basic Immunology, Chapter 7 (Paul, W., ed., 2nd edition, Raven Press, New York (1989))], which is incorporated herein by reference in its entirety. Antigen-binding fragments can be produced by recombinant DNA technology or by enzymatic or chemical cleavage of whole antibodies or by molecular biology techniques. In some embodiments, the fragment is Fab, Fab', F(ab')2, Fd, Fv, complementary determining region (CDR) fragment or single chain antibody (scFv). In the case of scFv fragments, V L and V HEncoded by a single gene, and connected together by a synthetic joint by a recombinant method, this enables them to be prepared as a single protein chain, wherein VL and VH regions are paired to form a monovalent molecule. In certain embodiments, scFv comprises a variable domain framework sequence with a sequence identical to human variable domain FR1, FR2, FR3 or FR4. In certain embodiments, scFv comprises a synthetic joint, which is a peptide with a length of 5 to 30 amino acid residues. For example, scFv comprises a joint peptide, which contains one or more glycine, serine and threonine residues. In certain embodiments, the joint length of scFv is 10-25 amino acid. In certain embodiments, the peptide joint comprises glycine, serine and / or threonine residues. (See, e.g., Bird et al., Science, 242:423-426 (1988) and Huston et al., Proc. Natl. Acad. Sci. USA, 85:5879-5883 (1988), each of which is incorporated herein by reference in its entirety).

[0562] The antigen binding fragment can be a polypeptide comprising at least a portion of an antibody that is sufficient to specifically bind an HSV-2 antigen to the polypeptide, including a bifunctional antibody. From the N-terminus to the C-terminus, the mature light chain and heavy chain variable domains each comprise the regional domains FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. The amino acid assignments for each domain are in accordance with Kabat, Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, Md. (1987 and 1991)), Chothia & Lesk, J. Mol. Biol. 196:901-917 (1987), or Chothia et al. (Nature 342:878-883 (1989), each of which is incorporated herein by reference in its entirety. As used herein, the term "polypeptide" includes polypeptide analogs of natural or artificial proteins, protein fragments and / or protein sequences. Polypeptides can be monomeric or polymeric. As used herein, Fd fragments refer to antibody fragments consisting of VH and CH1 domains; Fv fragments consisting of VL and VH domains of a single antibody arm; and dAb fragments consisting of VH domains (Ward et al., Nature 341: 544-546 (1989) [Ward et al., Nature 341: 544-546 (1989)] are incorporated herein by reference in their entirety). In some embodiments, the length of the fragment is at least 5, 6, 8 or 10 amino acids. In other embodiments, the length of the antigen-binding fragment is at least 14, at least 20, at least 50 or at least 70, 80, 90, 100, 150 or 200 amino acids.

[0563] The term "monoclonal antibody" (monoclonal antibody or mAb) as used herein refers to an antibody member obtained from a substantially homogeneous antibody population, i.e., the individual antibodies comprising the population are identical, except for possible mutations, such as naturally occurring mutations, which may be present in smaller amounts. Therefore, the modifier "monoclonal" indicates the characteristics of the antibody, rather than a mixture of discrete antibodies. Compared with polyclonal antibody preparations that typically include different antibodies for different antigenic determinants (epitopes), each monoclonal antibody of a monoclonal antibody preparation is directed to a single determinant on the antigen. In addition to their specificity, monoclonal antibody preparations are also advantageous in that they are typically not contaminated by other immunoglobulins. Therefore, once the sequence of a monoclonal antibody is identified, the determined monoclonal antibody can be produced by non-hybridoma technology, such as by appropriate recombinant means.

[0564] In the embodiments of the invention described herein, the antibodies are isolated. As used herein, the term "isolated antibody" refers to an antibody that, by virtue of its origin or source of derivation, has at least one (e.g., one, two, three, or four) of the following: (1) is not associated with naturally associated components that accompany it in its native state, (2) is free of other proteins from the same species, (3) is expressed by cells from a different species, or (4) is free of human manipulation that does not occur in nature.

[0565] In some embodiments, the antibody is humanized. As used herein, "humanized antibody" refers to an antibody form comprising sequences from humans and non-human (e.g., murine, rat) antibodies. Non-human (e.g., murine) antibodies of humanized form are chimeric antibodies, comprising minimal sequences derived from non-human immunoglobulins. In one embodiment, a humanized antibody is an antibody having a human immunoglobulin sequence (receptor antibody) but having residues from a murine hypervariable region (HVR) (or CDR). In some embodiments, the framework (FR) residues of murine mAb are replaced by corresponding human immunoglobulin variable domain framework (FR) residues. These humanized antibodies can be further modified to improve antibody performance. Humanized antibodies may include residues not found in receptor antibodies or donor antibodies. Alternatively, humanized antibodies do not include residues not found in receptor antibodies or donor antibodies. Typically, humanized antibodies will include substantially at least one and typically all of two variable domains, all or substantially all of its hypervariable loops corresponding to those of non-human immunoglobulins, and all or substantially all of FRs are those of human immunoglobulin sequences. The humanized antibody may optionally also include at least a portion of an immunoglobulin constant region (Fc), typically of a human immunoglobulin. See, e.g., Jones et al., Nature 321:522-525 (1986); Riechmann et al., Nature 332:323-329 (1988); Presta, Curr. Op. Struct. Biol. 2:593-596 (1992); Vaswani and Hamilton, Ann. Allergy, Asthma & Immunol. 1: 105-115 (1998); Harris, Biochem. Soc. Transactions 23: 1035-1038 (1995); Hurle and Gross, Curr. Op. Biotech. 5: 428-433 (1994); and U.S. Pat. Nos. 6,982,321 and 7,087,409, the contents of each of which are incorporated herein by reference in their entirety.In one embodiment, the humanized antibody comprises residues that are not found in the recipient antibody or in the donor antibody and the Fc region of the humanized antibody is modified as described in WO 99 / 58572, the contents of which are incorporated herein by reference in its entirety.

[0566] Techniques for humanizing monoclonal antibodies are well known and described, for example, in U.S. Pat. Nos. 4,816,567, 5,807,715, 5,866,692, 6,331,415, 5,530,101, 5,693,761, 5,693,762, 5,585,089 and 6,180,370, the contents of each of which are incorporated herein by reference in their entirety. Many "humanized" antibody molecules comprising an antigen binding site derived from a non-human immunoglobulin have been described, including antibodies having rodent or modified rodent V regions and their associated complementarity determining regions (CDRs) fused to human constant domains. See, for example, Winter et al. Nature 349:293-299 (1991), Lobuglio et al. Proc. Nat. Acad. Sci. USA 86:4220-4224 (1989), Shaw et al. J. Immunol. 138:4534-4538 (1987), and Brown et al. Cancer. Res.47:3577-3583 (1987) [Brown et al., Cancer Research 47:3577-3583 (1987)], the contents of each of which are incorporated herein by reference in their entirety. Other references describe the situation in which rodent hypervariable regions or CDRs are fused to suitable human antibody constant domains, such as supporting framework regions (FRs). See, for example, Riechmann et al. Nature 332:323-327 (1988), Verhoeyen et al. Science 239:1534-1536 (1988), and Jones et al. Nature 321:522-525 (1986), the contents of each of which are incorporated herein by reference in their entirety. Another reference describes rodent CDRs supported by recombinantly veneered rodent framework regions—European Patent Publication No. 0519596 (incorporated herein by reference in its entirety). These "humanized" molecules are designed to minimize unwanted immune responses to rodent anti-human antibody molecules, which limits the duration and effectiveness of therapeutic applications of these moieties in human recipients.The antibody constant region can be engineered to be immunologically inert (e.g., not triggering complement lysis). See, for example, PCT Publication No. WO 99 / 58572; British Patent Application No. 9809951.8. Daugherty et al., Nucl. Acids Res. 19:2471-2476 (1991) and U.S. Pat. Nos. 6,180,377, 6,054,297, 5,997,867, 5,866,692, 6,210,671 and 6,350,861 and PCT Publication No. WO 01 / 27160 disclose other methods of humanizing antibodies that can also be used (each of which is incorporated herein by reference in its entirety).

[0567] In some embodiments, the antibodies or fragments herein can be recombinantly produced, e.g., antibodies expressed using a recombinant expression vector transfected into a host cell, antibodies isolated from a recombinant, combinatorial human antibody library, antibodies isolated from an animal (e.g., a mouse) transgenic for human immunoglobulin genes.

[0568] The "variable region" or "variable domain" of an antibody refers to the amino terminal domain of the heavy or light chain of an antibody. The variable domain of the heavy chain may be referred to as "VH". The variable domain of the light chain may be referred to as "VL". These domains are generally the most variable parts of the antibody and contain the antigen binding site. The term "variable" refers to certain parts of the variable domain that differ greatly in sequence between antibodies and are used for the binding and specificity of each specific antibody to its specific antigen. However, the variability is not evenly distributed throughout the variable domain of an antibody. It is concentrated in three parts called hypervariable regions (HVRs) (or domain CDRs) in the light and heavy chain variable domains. The highly conserved parts of the variable domains are called framework regions (FRs). The variable domains of native heavy and light chains each contain four FR regions, which mainly adopt a β-folded structure, connected by three CDRs, forming loops connecting and, in some cases, forming part of the β-folded structure. The CDRs in each chain are tightly linked together by the FR regions and, together with the CDRs from the other chain, contribute to the formation of the antibody antigen-binding site (see Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, National Institute of Health, Bethesda, Md. (1991)). The constant domains are not directly involved in the binding of antibodies to antigens, but exhibit various effector functions, such as participation of antibodies in antibody-dependent cellular toxicity.

[0569] The "light chains" of antibodies (immunoglobulins) from any vertebrate species can be assigned to one of two clearly distinct types, called kappa (κ) and lambda (λ), based on the amino acid sequences of their constant domains.

[0570] "Framework" or "FR" residues are those variable domain residues other than the HVR residues herein defined.

[0571] In certain embodiments, the antibodies herein have a human Fc region. The term "Fc region" herein is used to define the C-terminal region of an immunoglobulin heavy chain, including a native sequence Fc region and a variant Fc region. Although the boundaries of an immunoglobulin heavy chain Fc region may be different, a human IgG heavy chain Fc region is generally defined as extending from an amino acid residue at a Cys226 or Pro230 position to its carboxyl terminus. For example, during the production or purification of an antibody, or by recombinant engineering of a nucleic acid encoding the heavy chain of an antibody, the C-terminal lysine in the Fc region may be removed. Therefore, a complete antibody as used herein may be an antibody with or without an additional C-terminal lysine.

[0572] Compositions or pharmaceutical compositions comprising antibodies, scFvs or antibody fragments disclosed herein preferably contain stabilizers to prevent the loss of activity or structural integrity of the protein due to denaturation, oxidation or aggregation over a period of time during storage and transportation before use. The composition or pharmaceutical composition may include one or more of any combination of salts, surfactants, pH regulators and tonicity agents (e.g., sugars) that can help overcome aggregation problems. When the composition or pharmaceutical composition of the present invention is used as an injection, it is ideal to keep the pH value within a pH range of approximately neutral pH, and minimizing the level of surfactant is also beneficial to avoid bubbles in the formulation, which are harmful to injection into the subject. In some embodiments, the composition or pharmaceutical composition is in liquid form and stably supports high concentrations of biologically active antibodies in solution and is suitable for inhalation or parenteral administration. In some embodiments, the composition or pharmaceutical composition is formulated for mammalian subjects, particularly human subjects. In some embodiments, the composition or pharmaceutical composition is formulated for intravenous, intramuscular, intraperitoneal, intradermal and / or subcutaneous injection. In some embodiments, the composition or pharmaceutical composition can be in liquid form and minimizes the risk of bubble formation and allergic side effects. In some embodiments, the composition or pharmaceutical composition is isotonic. In one embodiment, the pH of the composition or pharmaceutical composition is 6.8 to 7.4.

[0573] In some embodiments, the scFv or antibody fragments disclosed herein are lyophilized and / or freeze-dried and reconstituted for use.

[0574] Examples of pharmaceutically acceptable carriers include, but are not limited to, phosphate buffered saline, sterile water (including water for injection USP), emulsions such as oil / water emulsions, and various types of wetting agents. Exemplary diluents for aerosol or parenteral administration are phosphate buffered saline or physiological (0.9%) saline, such as 0.9% sodium chloride solution (USP). Compositions comprising such carriers are prepared by well-known conventional methods (see, e.g., Remington's Pharmaceutical Sciences, 18th edition, A. Gennaro, ed., Mack Publishing Co., Easton, Pa., 1990 [Remington Pharmaceutical Sciences, 18th edition, A. Gennaro edited, Mack Publishing Co., Easton, Pennsylvania, 1990]; and Remington, The Science and Practice of Pharmacy 20th Ed. Mack Publishing, 2000 [Remington, the science and practice of pharmacy, 20th edition, Mack Publishing, 2000], the contents of each of which are incorporated herein by reference in their entirety). In non-limiting examples, it may include one or more of disodium hydrogen phosphate, potassium chloride, potassium dihydrogen phosphate, polysorbate 80 (e.g., ethyl 2-[2-[3,5-bis(2-hydroxyethoxy)oxolan-2-yl]-2-(2-hydroxyethoxy)ethoxy]ethyl (E)-octadec-9-enoate), edetate disodium dehydrate, sucrose, sodium dihydrogen phosphate monohydrate, and sodium dihydrogen phosphate dihydrate.

[0575] The antibodies, or antibody fragments, or compositions, or pharmaceutical compositions described herein may also be lyophilized or provided in any suitable form, including but not limited to injectable or inhalable solutions, gel forms, and tablet forms.

[0576] The present invention encompasses substitution variants of antibodies. The substitution variant removes at least one amino acid residue in the antibody molecule and inserts a different residue in its place. The sites of greatest interest for substitution mutations include hypervariable regions, but framework changes are also contemplated. These conservative substitutions are shown under the heading "conservative substitutions" in Table 1. If such substitutions result in changes in biological activity, then more substantial changes named "exemplary substitutions" in Table 1 or as further described below with reference to amino acid classes may be introduced and the product screened.

[0577] Table 1: Amino Acid Substitutions

[0578]

[0579]

[0580] Substantial modification in the biological properties of antibodies is accomplished by selecting substitutions that differ significantly in maintaining: (a) the structure of the polypeptide backbone in the area of ​​the substitution, e.g., β-sheet or helical conformation; (b) the charge or hydrophobicity of the molecule at the target site; or (c) the bulk of the side chain. Based on common side chain properties, naturally occurring residues are divided into the following groups:

[0581] (1) Non-polar: norleucine, Met, Ala, Val, Leu, Ile;

[0582] (2) Polarity: uncharged: Cys, Ser, Thr, Asn, Gln;

[0583] (3) Acidic (negatively charged): Asp, Glu;

[0584] (4) Basic (positively charged): Lys, Arg;

[0585] (5) Residues that affect chain orientation: Gly, Pro; and

[0586] (6) Aromatic: Trp, Tyr, Phe, His.

[0587] Non-conservative substitutions are made by exchanging a member of one of these classes for another class.

[0588] For example, a type of substitution that can be performed is to change one or more cysteines (which may be chemically reactive) in the antibody to another residue, such as, but not limited to, alanine or serine. For example, atypical cysteine ​​can be substituted. Substitution can be performed in the CDR or framework region of the variable domain or the constant region of the antibody. In certain embodiments, cysteine ​​is typical. It is also common to replace any cysteine ​​residues that do not participate in maintaining the correct conformation of the antibody with serine, to improve the oxidative stability of the molecule and to prevent abnormal cross-linking. On the contrary, one or more cysteine ​​bonds can be added to the antibody to improve its stability, particularly when the antibody is an antibody fragment (e.g., Fv fragment).

[0589] Antibodies can also be modified, for example in the variable domains of the heavy and / or light chains, for example to alter the binding properties of the antibody. Changes in the variable regions can alter binding affinity and / or specificity. In some embodiments, no more than one to five conservative amino acid substitutions are made within the CDR domains. In other embodiments, no more than one to three conservative amino acid substitutions are made within the CDR domains.

[0590] The antibodies described herein can be produced recombinantly. Antibodies produced in eukaryotic expression systems contain glycosylation at the residue in the Fc portion corresponding to Asn297.

[0591] In some embodiments, a composition or pharmaceutical composition comprising an antibody or antigen-binding fragment thereof as described herein is substantially pure with respect to the antibody or antigen-binding fragment thereof. A composition or pharmaceutical composition comprising an antibody or antigen-binding fragment thereof as described herein is "substantially pure" with respect to the antibody or fragment when at least 60% to 75% of a sample of the composition or pharmaceutical composition exhibits an antibody or antigen-binding fragment thereof of a single species. A substantially pure composition or pharmaceutical composition comprising an antibody or antigen-binding fragment thereof as described herein may comprise 60%, 70%, 80% or 90%, more typically about 95%, preferably greater than 99% of an antibody or antigen-binding fragment of a single species in its portion as an antibody or antigen-binding fragment. Purity or homogeneity may be detected by a variety of methods known in the art, such as polyacrylamide gel electrophoresis or HPLC.

[0592] In embodiments of these methods, the subject is a mammal.

[0593] In some embodiments, the mammal is a human.

[0594] All combinations of the various elements described herein are within the scope of the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

[0595] The terms used herein are only for the purpose of describing specific embodiments, and are not intended to be limiting. As used herein, unless the content clearly indicates otherwise, the singular forms "a and an" and "the" are intended to include plural forms, including "at least one". "At least one" should not be interpreted as limiting "one" (a and an). "Or" means "and / or". As used herein, the term "and / or" includes any and all combinations of one or more of the related listed items. The terms "comprise", "include" and "have" are intended to be inclusive and mean that there may be other elements in addition to the listed elements.

[0596] Pharmaceutically acceptable: As used herein, the term "pharmaceutically acceptable" refers to other recognized pharmacopeias approved by a regulatory agency of a federal or state government or listed in the U.S. Pharmacopeia, in addition to other formulations that are safe for use in animals, more particularly in humans and / or non-human mammals. Pharmaceutically acceptable carrier; As used herein, the term "pharmaceutically acceptable carrier" refers to excipients, diluents, preservatives, solubilizers, emulsifiers, adjuvants and / or excipients, administered with the antibodies or fragments of the present invention. Such carriers can be sterile liquids, such as water and oils, including those from petroleum, animal, plant or synthetic sources, such as peanut oil, soybean oil, mineral oil, sesame oil, etc., polyethylene glycol, glycerol, propylene glycol or other synthetic solvents. Antibacterial agents, such as benzyl alcohol or methyl parabens; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; and agents for adjusting tonicity, such as sodium chloride or glucose, can also be carriers. Methods for producing compositions in combination with carriers are known to those skilled in the art. In some embodiments, the term "pharmaceutically acceptable carrier" is intended to include any and all solvents, dispersion media, coatings, isotonic agents, and absorption delaying agents, etc., that are compatible with drug administration. The use of such media and agents for pharmaceutical actives is well known in the art. See, e.g., Remington, The Science and Practice of Pharmacy. 20"'ed. (Lippincott, Williams and Wilkins 2003). Unless any conventional media or agents are incompatible with the active compound, such use in the composition is contemplated.

[0597] It should be understood that the aspects and embodiments of the present invention described herein include "consisting of" and / or "consisting essentially of" the aspects and embodiments.

[0598] Throughout this disclosure, various aspects of the present invention may be presented in the format of a range. It should be understood that the description in the range format is only for convenience and brevity, and should not be interpreted as a hard limit to the scope of the present invention. Therefore, the description of the range should be regarded as having clearly disclosed all possible sub-ranges and individual numerical values ​​within the range. For example, the description of a range such as 1 to 6 should be regarded as having clearly disclosed sub-ranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, and individual numbers within the range, such as 1, 2, 3, 4, 5 and 6. This applies regardless of the width of the range.

[0599] Other objects, advantages and features of the present invention will become apparent from the following description taken in conjunction with the accompanying drawings.

[0600] Although the present disclosure has been described with reference to various embodiments, it will be appreciated by those skilled in the art that various changes may be made and elements thereof may be substituted with a variety of equivalents without departing from the scope of the present disclosure. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the present disclosure without departing from its essential scope. Therefore, it is intended that the present disclosure is not limited to the specific embodiments disclosed as the best mode contemplated for carrying out the present disclosure, but that the present disclosure will include all embodiments falling within the scope of the appended claims.

[0601] All cited patents, patent applications, and other references are incorporated herein by reference in their entirety. However, if a term in the present application contradicts or conflicts with a term in the incorporated reference, the term from the present application takes precedence over the conflicting term from the incorporated reference.

[0602] The present invention can be better understood from the following experimental details.

[0603] Experimental details

[0604] A candidate HSV-2 single-cycle viral vaccine deleted in the immunodominant envelope glycoprotein D (designated ΔgD-2) induces high titer antibodies that are able to actively and passively protect mice from HSV disease in a murine model. These antibodies are weakly neutralizing but can effectively activate murine Fcγ receptor IV (FcγRIV) to activate antibody-dependent cell-mediated cytotoxicity (ADCC). The present disclosure has analyzed, cloned, sequenced and tested monoclonal antibodies (mAbs) isolated from germinal center B cells of immunized mice, and identified several mAbs that passively protected mice from viral diseases. Certain mAbs have sufficient activity to be used for the prevention and treatment of patients with HSV (e.g., humanized forms) or at risk for disseminated disease (e.g., neonates, immunocompromised hosts).

[0605] Mice were prime-boosted with ΔgD-2, and spleens, draining lymph nodes, or bone marrow were isolated. Germinal center (GC) B cells were then cultured on NB-21.2D9 cells (Nojima culture). After culture, supernatants were screened for the presence of IgG that binds HSV lysate by ELISA. V(D)J rearrangements amplified from selected GC B cell cultures were sequenced for B cell antigen receptor (BCR) repertoire analysis in GC B cell clones from individual mice. Reconstituted antibodies from selected single GC B cell cultures and single bone marrow plasma cells were then evaluated for their ability to activate mFcγRIV in vitro and protect mice in a passive transfer model.

[0606] Briefly, mice were inoculated with ΔgD-2 and then 16 days after inoculation, the draining inguinal lymph nodes were removed. GC B cells were isolated from these tissues and cultured in Nojima culture. Although the overall cloning efficiency of GC B cells from these (transported) tissues was lower than those from freshly isolated tissues (6% domain vs. 20% domain), 50 GC clones specific for HSV-2G strain (HSV-2G or HSV2-G) lysates were obtained. ELISA analysis was performed on HSV-2G lysates and uninfected Vero lysates (control), and the results are shown in Figure 1 GC B cells from inguinal lymph nodes of mice vaccinated with ΔgD-2 were sorted directly into 96-well plates (1 cell / well). These GC B cells were then cultured in the presence of NB-21.2D9 feeder cells. After culture, the presence of IgG was first determined by ELISA, and then the reactivity of culture supernatant IgG to HSV-2G lysate (HSV-2G) and uninfected Vero lysate was tested by ELISA.

[0607] The molecular genetics of GC B cells were analyzed ( Figure 2 ). V(D)J rearrangements were amplified from cDNA of HSV-2G lysate reactive, IgG+ cultures, then cloned and sequenced. Rearranged V, D, and J gene segments were determined using IMGT V-QUEST (see the World Wide Web at imgt.org / ). HSV2-specific GC B cells used a different set of VH gene segments. VH1-64 and VH1-26 appeared more frequently (~10%) than the other gene segments.

[0608] Based on the V(D)J sequences obtained from each B cell culture, paired heavy and light chains were re-expressed in Expi293F cells (as recombinant mouse IgG1 and IgG2c antibodies) (Kuraoka et al. Immunity 2016; DiLillo et al. Nature Medicine 2013). Then, 4 independent, HSV-2G lysate-reactive IgG+ single B cell cultures were selected from GC B cells on day 16. As expected, all recombinant antibodies reacted specifically with HSV-2G lysate (Figure 3). Clone 32H6 bound most tightly to the lysate, followed by 35H7, 22D10 and 33B8. Figure 3 shows the retention of HSV-2G lysate binding by the recombinant antibodies. The binding of the recombinant antibodies to the HSV-2G lysate was detected by ELISA. Heavy and light chain V(D)J rearrangements were amplified from selected individual B cell culture wells (22D10, 32H6, 33B8, and 35H7) by standard RT-PCR. The V(D)J rearrangements of these clones were introduced into expression vectors. Recombinant antibodies were obtained by co-transfecting these expression vectors into Expi293F cells. ≥4 mg of purified IgG was obtained (not shown). These antibodies did not bind to control, uninfected Vero lysates. In vitro FcγRIV activation assay (Promega FcγRIV ADCC Reporter Gene Bioassay Kit) ( Figure 4 These recombinant antibodies (≥4 mg each) were tested for antigenic identity in in vitro and in vivo protection assays.

[0609] ΔgD-2 prime-boost vaccination established a long-lasting, HSV-reactive (and protective) serum IgG response in mice, as shown by the results that mice were still protected from HSV challenge 8 months after the boost. These results suggest that vaccination successfully established long-lived plasma cells. It is hypothesized that HSV-reactive plasma cells can be isolated and these plasma cells can produce protective IgG from the bone marrow of mice that have received prime-boost vaccination. In experiments in which bone marrow plasma cells were isolated from ΔgD-2-vaccinated mice, mice vaccinated with ΔgD-2 contained a 4-fold higher frequency of surface IgM-CD138hiB220lo / -FSChi plasma cells in the bone marrow compared to unvaccinated mice.

[0610] To analyze the molecular genetics of bone marrow plasma cells, single sIgM - CD138 hi B220 lo / - FSC hiV(D)J rearrangements were amplified from cDNA of plasma cells, and the amplified products were cloned and sequenced. The rearranged V, D, and J gene segments were determined using IMGT V-QUEST (available on the World Wide Web at imgt.org / ). We recovered 21 pairs of heavy and light chains and 4 heavy chain-only clones from 96 individual cells (Table 1). The 25 heavy chain sequences consisted of four IgG3 (16%), nine IgG1 (36%), seven IgG2b (28%), four IgG2c (16%), and one IgA (4%) isotypes. Twenty individual clones (80%) had a V(D)J rearrangement. H The gene fragments carried at least one nucleotide substitution (an average of 4.4 V H mutation). A summary of V(D)J rearrangements recovered from bone marrow plasma cells of ΔgD: mice inoculated with HSV is provided in Table 2 below. As shown in Table 2, CDR3 shows conserved residues (C, W for HDCR, C, F for LCDR). In addition to BMPC-7, IgG2b or IgG2c clones (grey rows in Table 2) carry V H and V L mutations, indicating that these plasma cell clones were generated through GC reactions.

[0611]

[0612]

[0613] Protection by serum antibodies elicited by ΔgD-2 vaccination depended on activation of FcγRIV. We focused on IgG2c antibodies that preferentially bind to activating FcγRs. Based on the V(D)J sequences obtained from each plasma cell, paired heavy and light chains were re-expressed in Expi293F cells (as recombinant mouse IgG1 and IgG2c antibodies) as described above. Nine clones bearing IgG2b and IgG2c constant regions were selected (BMPC-1, BMPC-12, BMPC-7, BMPC-8, BMPC-9, BMPC-23, BMPC-26, BMPC-57, and BMPC-61). Of these nine antibodies, BMPC-23, but not the others, reacted with HSV-2G lysate ( Figure 5A and 5B , data not shown). Binding of BMPC-23 was comparable to that of 19G7, another HSV-2G lysate-reactive IgG cloned from GCB cells of ΔgD-2-vaccinated mice. IgG1 and IgG2c isotypes of BMPC-23 were detected in an in vitro FcγRIV activation assay ( Figure 4 ) and in vivo protection assays (see description below, Figures 6A to 6C ) for analysis. Figure 4As shown, BMPC-23IgG2c showed the highest level of FcγR activation.

[0614] The reproducibility of the in vivo protection assays was evaluated for IgG1 and IgG2c formats of 22D10, 33B8, and BMPC-23 antibodies (≥4 mg each), as well as any dependence on Ig isotype for protection. Representative experiments are shown in Figures 6A-6C In short, the overall results from 2 independent experiments showed that the IgG2c version of BMPC-23 protected 8 / 10 mice, 22D10 protected 5 / 10 mice, and 33B8 protected 4 / 10 mice from lethal challenge. The three monoclonal antibodies BMPC-23, 22D10, and 33B8 (as IgG2c) provided significant protection against HSV-2. To test the role of Ig isotype on the ability to provide protection, IgG1 and IgG2c isotypes of these three antibodies were generated and evaluated for the ability to activate mFcγRIV signaling (as a measure of ADCC), as well as for in vivo protection assays. The results are shown in Figure 4 middle.

[0615] IP-MS was performed to identify the targets of 22D10, 33B8 and BMPC-23 antibodies. The results are shown in Figure 7A and 7B In this study, human herpesvirus glycoprotein B (gB) was identified as a target.

[0616] BMPC-23 binds to HSV-1 gB (gB-1). The gB-1 binding of the antibody was determined by Luminex multiplex analysis. A mixture of antigen (gB-1) coupled microspheres (1,000 counts each) was added to each well of a 96-well filter plate (Millipore). After washing with PBS containing 1% BSA, 0.05% Tween 20 and 0.05% NaN3, serial dilutions of recombinant antibodies (5E7, 19G7, 18G4, 22E10, 3A2, 17G3, 22D10, 32H6, 33B8, 25H7, BMPC-23 and S5V2-29) were added to the plate and incubated at room temperature for 2 hours while gently agitating the plate. The samples were diluted in PBS containing 1% milk, 1% BSA, 0.05% Tween 20 and 0.05% NaN3. After washing, PE goat anti-mouse IgG was added to the plate and incubated for 1 hour at room temperature with gentle agitation. After washing, the microspheres were resuspended in PBS containing 1% BSA, 0.05% Tween 20, and 0.05% NaN3 and The fluorescence signal from each microsphere is measured in a 3D machine. Figure 8 As shown, the only antibody that demonstrated substantial binding to gB-1 was BMPC-23.

[0617] Searching for gB-1-specific HSV antibodies. HSV-specific antibodies were cloned from germinal center B cells after Nojima culture (single B cell culture) and tested for binding to HSV-1 gB-1 by Luminex multiplex analysis as described above. Figure 9A and 9B The gB-1 binding results of 10 antibodies compared to BMPC-23 are shown. The cell sources and isolation methods of the antibodies tested are shown in Table 3. Except for BMPC-23, the antibodies in Table 3 are from germinal center B cells (lymph nodes) collected 15-17 days after the initial vaccination with ΔgD-2. BMPC-23 is derived from bone marrow plasma cells collected 2 weeks after boosting with ΔgD-2. The nucleotide sequences and amino acid sequences of the heavy and light chains, as well as the amino acid sequences of the light and heavy chain CDR1, CDR2 and CDR3 are shown in Table 4.

[0618] Searching for BMPC-like antibodies. The ability of 9 of the 10 gB-1-specific mouse monoclonal IgG antibodies in Figure 3 to inhibit the binding of BMPC-23 human IgG antibodies to gB-1 was detected. Serial dilutions of gB-1-specific mouse monoclonal antibodies or unrelated control mouse antibodies (H33Lγ1) were incubated with gB-1-coupled Luminex beads. After incubation, a fixed concentration (2ng / ml) of BMPC-23 human IgG antibodies was added to each well. After washing, mouse anti-human IgG-PE was added to detect the binding of human BMPC-23 antibodies. The y-axis represents the MFI percentage of maximum binding, which is determined as the average MFI in the presence of control IgG and H33Lγ1 that do not bind to gB-1. Figure 10A BMPC-23 mouse IgG (222 ng / ml) was shown to inhibit human BMPC by >99%. Strong inhibition of HSV010-4 (>95% at 222 ng / ml), HSV010-7 (>90% at 222 ng / ml), and HSV010-34 (>80% at 222 ng / ml) was shown. Figure 10B , 10F and 10G, respectively, indicating that these antibodies bind to epitopes on gB-1 that closely overlap with the epitopes recognized by BMPC-23. Therefore, it is expected that these antibodies have similar protective efficacy as BMPC-23 (experiments in progress). HSV010-28 ( Figure 10D 30% inhibition at 222ng / ml) and HSV010-6, 9, 13, 14 ( Figure 10E The mild inhibition of 32%-48% at 222 ng / ml in 1% sera (32%-48% at 222 ng / ml) indicates that the epitopes on gB-1 recognized by these antibodies partially overlap with the epitopes recognized by BMPC-23. Figure 10CAs shown, HSV010-20 has no inhibitory effect, indicating that the epitope recognized by this antibody does not overlap with the epitope recognized by BMPC-23. It is necessary to detect the protective efficacy of these antibodies (experiments in progress). The above data are also summarized in Table 3 below.

[0619] Additional experiments. Determination of the target antigens of antibodies 22D10 and 33B8 will be performed using methods similar to those used for antigen determination of BMPC-23 antibodies. For example, methods such as mass spectrometry of proteins bound by 22D10 or 33B8 antibodies and / or screening of 22D10 or 33B8 against other non-gB purified antigens from HSV-1 can be used.

[0620] The ability of the 12 untested antibodies in Table 3 to protect against ocular infection caused by HSV-1 will be evaluated using the methods described above.

[0621] The structural determination of the epitopes of the HSV-1 binding antibodies in Table 3 will be performed. Such methods include co-crystallization of the Fab fragment of the antibody with an HSV-1 protein (e.g., gB-1), X-ray diffraction, and analysis by XDS. (See, e.g., Watanabe et al, 2019, Cell, 177, 1124-1135 [Watanabe et al, 2019, Cell, 177: 1124-1135]).

[0622] Table 3

[0623]

[0624]

[0625]

[0626]

[0627] Sequence Listing <110> Albert Einstein College of Medicine Duke University <120> Monoclonal antibodies for the prevention and treatment of herpes simplex virus infection <130> EIC0008PCT <150> 62 / 820,495 <151> 2019-03-19 <160> 163 <170> PatentIn Version 3.5 <210> 1 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Antibody heavy chain CDR1 <400> 1 Gly Tyr Ser Phe Thr Thr Tyr Asp 1 5 <210> 2 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Antibody heavy chain CDR2 <400> 2 Ile Tyr Pro Arg Glu Gly Ser Thr 1 5 <210> 3 <211> 13 <212> PRT <213> Artificial sequence <220> <223> Antibody heavy chain CDR3 <400> 3 Ala Thr Tyr Gly Ser Ser Arg Tyr Tyr Thr Met Asp Tyr 1 5 10 <210> 4 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Antibody light chain CDR1 <400> 4 Glu Ser Val Asp Asn Phe Gly Ile Ser Phe 1 5 10 <210> 5 <211> 3 <212> PRT <213> Artificial sequence <220> <223> Antibody light chain CDR2 <400> 5 Ala Ala Ser 1 <210> 6 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Antibody light chain CDR3 <400> 6 Gln Gln Ser Lys Glu Val Pro Leu Thr 1 5 <210> 7 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Antibody heavy chain CDR1 <400> 7 Gly Tyr Ser Ile Thr Asn Gly Asn His 1 5 <210> 8 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Antibody heavy chain CDR2 <400> 8 Ile Arg Ser Ser Gly Ser Ser 1 5 <210> 9 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Antibody heavy chain CDR3 <400> 9 Ala Arg Gly Gly Gly Leu Arg His Tyr Phe Asp Tyr 1 5 10 <210> 10 <211> 6 <212> PRT <213> Artificial sequence <220> <223> Antibody light chain CDR1 <400> 10 Gly Asn Ile His Asn Tyr 1 5 <210> 11 <211> 3 <212> PRT <213> Artificial sequence <220> <223> Antibody light chain CDR2 <400> 11 His Ala Glu 1 <210> 12 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Antibody light chain CDR3 <400> 12 Gln His Phe Trp Ser Thr Pro Tyr Thr 1 5 <210> 13 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Antibody heavy chain CDR1 <400> 13 Gly Phe Thr Phe Thr Asp Tyr Tyr 1 5 <210> 14 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Antibody heavy chain CDR2 <400> 14 Ile Arg Asn Lys Ala Asn Gly Tyr Thr Thr 1 5 10 <210> 15 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Antibody heavy chain CDR3 <400> 15 Ala Cys Gly Asn Tyr Val Gly Tyr Ala Met Asp Tyr 1 5 10 <210> 16 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Antibody light chain CDR1 <400> 16 Gln Ser Leu Leu Asn Ser Arg Thr Arg Lys Asn Tyr 1 5 10 <210> 17 <211> 3 <212> PRT <213> Artificial sequence <220> <223> Antibody light chain CDR2 <400> 17 Trp Ala Ser 1 <210> 18 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Antibody light chain CDR3 <400> 18 Lys Gln Ser Tyr Asn Leu Tyr Thr 1 5 <210> 19 <211> 363 <212> DNA <213> Artificial sequence <220> <223> BMPC-23_IgH heavy chain <400> 19 caggttcagc tgcagcagtc tggacctgag ctggtgaagc ctggggcttc agtgaagttg 60 tcctgcaagg cttctggcta cagtttcaca acctacgata taaactgggt gaaggagagg 120 cctggacagg gacttgagtg gattgggtgg atttatccta gagagggtag tacgaattac 180 aatgagaagt tcaggggcaa ggccacattg actgcagaca catcctccag tacagcgtac 240 atggagctcc acagcctgac atctgaggac tctgcggtct atttctgtgc aacctacggt 300 agtagtcgct actatactat ggactactgg ggtcaaggaa cctcagtcac cgtctcctca 360 gcc 363 <210> 20 <211> 121 <212> PRT <213> Artificial sequence <220> <223> BMPC-23_IgH heavy chain <400> 20 Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Thr Tyr 20 25 30 Asp Ile Asn Trp Val Lys Glu Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Trp Ile Tyr Pro Arg Glu Gly Ser Thr Asn Tyr Asn Glu Lys Phe 50 55 60 Arg Gly Lys Ala Thr Leu Thr Ala Asp Thr Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu His Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95 Ala Thr Tyr Gly Ser Ser Arg Tyr Tyr Thr Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Ser Val Thr Val Ser Ser Ala 115 120 <210> 21 <211> 336 <212> DNA <213> Artificial Sequence <220> <223> BMPC-23_IgL light chain <400> 21 gacattgtgc tgacccaatc tccaacttct ttggctgtgt ctctagggca gagggccacc 60 atctcctgca gagccagcga aagtgttgat aattttggca ttagttttat gaactggttc 120 cagcagaaac caggacagcc acccaaactc ctcatctacg ctgcatccaa cctaggatcc 180 ggggtccctg ccaggtttag tggcagtggg tctgggacag acttcagcct caacatccat 240 cctatggagg atgatgatac tgcaatgtat ttctgtcagc aaagtaagga ggttccgctc 300 acgttcggtg ctgggaccaa gctggagctg aaacgg 336 <210> 22 <211> 112 <212> PRT <213> Artificial Sequence <220> <223> BMPC-23_IgL Light Chain <400> 22 Asp Ile Val Leu Thr Gln Ser Pro Thr Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Phe 20 25 30 Gly Ile Ser Phe Met Asn Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro 35 40 45 Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Gly Ser Gly Val Pro Ala 50 55 60 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Ser Leu Asn Ile His 65 70 75 80 Pro Met Glu Asp Asp Asp Thr Ala Met Tyr Phe Cys Gln Gln Ser Lys 85 90 95 Glu Val Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg 100 105 110 <210> 23 <211> 363 <212> DNA <213> Artificial sequence <220> <223> 22D10 heavy chain <400> 23 gatgtacagc ttcaggagtc aggacctgcc ctggtgaagc cttctcagac agtgtccctc 60 acctgcactg tcactggcta ctctatcact aatggtaatc attggtggaa ctggatccgg 120 caggtttcag gaagcaaact ggagtggtta gggtacataa ggtccagtgg tagctctgac 180 agcaatccat ctctcaaaag tcgaatctcc atcactagag acacttccaa gaaccagtta 240 ttcctgcact tgaactctat gactactgaa gatatagcca catattactg tgcaagaggg 300 gggggattac ggcactactt tgactactgg ggccaaggca ccactctcac agtctcctca 360 gcc 363 <210> 24 <211> 121 <212> PRT <213> Artificial sequence <220> <223> 22D10 heavy chain <400> 24 Asp Val Gln Leu Gln Glu Ser Gly Pro Ala Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Val Ser Leu Thr Cys Thr Val Thr Gly Tyr Ser Ile Thr Asn Gly 20 25 30 Asn His Trp Trp Asn Trp Ile Arg Gln Val Ser Gly Ser Lys Leu Glu 35 40 45 Trp Leu Gly Tyr Ile Arg Ser Ser Gly Ser Ser Asp Ser Asn Pro Ser 50 55 60 Leu Lys Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Leu 65 70 75 80 Phe Leu His Leu Asn Ser Met Thr Thr Glu Asp Ile Ala Thr Tyr Tyr 85 90 95 Cys Ala Arg Gly Gly Gly Leu Arg His Tyr Phe Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Thr Leu Thr Val Ser Ser Ala 115 120 <210> 25 <211> 324 <212> DNA <213> Artificial Sequence <220> <223> 22D10 Light Chain <400> 25 gacatccaga tgactcagtc tccagcctcc ctatctgcat ctgtgggaga tactgtcacc 60 atcacatgtc gagcaagtgg gaatattcac aattatttag catggtatca ccagaaacag 120 ggaaaatctc ctcaactcct ggtctatcat gcagaaacct taacagatgg tgtgccatca 180 aggttcagtg gcagtggatc aggaacacaa tattctctca agatcaacag cctgcagcct 240 gaagattttg ggagttatta ctgtcaacat ttttggagta ctccgtacac attcggaggg 300 gggaccaagc tggaaataaa acgg 324 <210> 26 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> 22D10 Light Chain <400> 26 Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Thr Val Thr Ile Thr Cys Arg Ala Ser Gly Asn Ile His Asn Tyr 20 25 30 Leu Ala Trp Tyr His Gln Lys Gln Gly Lys Ser Pro Gln Leu Leu Val 35 40 45 Tyr His Ala Glu Thr Leu Thr Asp Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Gln Tyr Ser Leu Lys Ile Asn Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Gly Ser Tyr Tyr Cys Gln His Phe Trp Ser Thr Pro Tyr 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg 100 105 <210> 27 <211> 366 <212> DNA <213> Artificial sequence <220> <223> 33B8 heavy chain <400> 27 gaggtgaagc tggtggagtc tggaggaggc ttggtacagc ctgggggttc tctgagtctc 60 tcctgtgcaa cttctggatt caccttcact gattactaca tgaactgggt ccgccagcct 120 ccagggaagg cacttgagtg gttgggtttt attagaaaca aagctaatgg ttacacaaca 180 gagtacagtg catctgtgaa gggtcggttc accatctcca gagataattc ccaaagcatc 240 ctctatcttc aaatgaattc cctgagagct gaggacagtg ccacttatta ctgtgcttgt 300 ggtaactacg taggctatgc tatggactac tggggtcaag gaacctcagt caccgtctcc 360 tcagcc 366 <210> 28 <211> 122 <212> PRT <213> Artificial sequence <220> <223> 33B8 heavy chain <400> 28 Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Ser Leu Ser Cys Ala Thr Ser Gly Phe Thr Phe Thr Asp Tyr 20 25 30 Tyr Met Asn Trp Val Arg Gln Pro Pro Gly Lys Ala Leu Glu Trp Leu 35 40 45 Gly Phe Ile Arg Asn Lys Ala Asn Gly Tyr Thr Thr Glu Tyr Ser Ala 50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Gln Ser Ile 65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Ser Ala Thr Tyr 85 90 95 Tyr Cys Ala Cys Gly Asn Tyr Val Gly Tyr Ala Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Ser Val Thr Val Ser Ser Ala 115 120 <210> 29 <211> 339 <212> DNA <213> Artificial Sequence <220> <223> 33B8 Light Chain <400> 29 gacattgtga tgtcacagtc tccatcctcc ctggctgtgt cagcaggaga gaaggtcact 60 atgagctgca aatccagtca gagtctgctc aacagtagaa cccgaaagaa ctacttggct 120 tggtaccagc agaaaccagg gcagtctcct aaactgctga tctactgggc atccactagg 180 gaatctgggg tccctgatcg cttcacaggc agtggatctg ggacagattt cactctcacc 240 atcagcagtg tgcaggctga agacctggca gtttattact gcaagcaatc ttataatctg 300 tacacgttcg gaggggggac caagctggaa ataaaacgg 339 <210> 30 <211> 113 <212> PRT <213> Artificial sequence <220> <223> 33B8 light chain <400> 30 Asp Ile Val Met Ser Gln Ser Pro Ser Ser Leu Ala Val Ser Ala Gly 1 5 10 15 Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser 20 25 30 Arg Thr Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Lys Gln 85 90 95 Ser Tyr Asn Leu Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 Arg <210> 31 <211> 351 <212> DNA <213> Artificial sequence <220> <223> HSV010-4 heavy chain <400> 31 caggtgcagc tgaaggagtc aggacctggc ctggtggcgc cctcacagag cctgtccatc 60 acatgcactg tctcagggtt ctcattaagc agacatgatg taagctgggt tcgccagcct 120 ccaggaaagg gtctggagtg gctgggagta atatggggtg acgggagcac aaattatcat 180 tcagctctca tatccagact gagcatcagc aaagataact ccaagagcca agttttctta 240 aaactgaaca gtctgcaaaa tgatgacaca gccacgtact actgtgccaa agaagactat 300 ggtatttttc cttactgggg ccaagggact ctggtcactg tctctgcagc c 351 <210> 32 <211> 117 <212> PRT <213> Artificial sequence <220> <223> HSV010-4 heavy chain <400> 32 Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Arg His 20 25 30 Asp Val Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Gly Asp Gly Ser Thr Asn Tyr His Ser Ala Leu Ile 50 55 60 Ser Arg Leu Ser Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Phe Leu 65 70 75 80 Lys Leu Asn Ser Leu Gln Asn Asp Asp Thr Ala Thr Tyr Tyr Cys Ala 85 90 95 Lys Glu Asp Tyr Gly Ile Phe Pro Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ala Ala 115 <210> 33 <211> 324 <212> DNA <213> Artificial sequence <220> <223> HSV010-4 light chain <400> 33 gacatcaaga tgacccagtc tccatcttcc atgtatgcat ctctaggaga gaaagtcact 60 atcacttgca aggcgagtca ggacattagt agctatttaa gctggttcca gcagaaacca 120 gggaaatctc ctaagaccct gatctatcgt gcaaacagat tggtagatgg ggtcccatca 180 aggttcagtg gcagtggatc tgggcaagat tattctctct ccatcagcag cctggactat 240 gaagatatgg gaatttatta ttgtctacag tatgatgagt ttccgctcac gttcggtgct 300 gggaccaagc tggagctgaa acgg 324 <210> 34 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> HSV010-4 Light Chain <400> 34 Asp Ile Lys Met Thr Gln Ser Pro Ser Ser Met Tyr Ala Ser Leu Gly 1 5 10 15 Glu Lys Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Ile Ser Ser Tyr 20 25 30 Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys Ser Pro Lys Thr Leu Ile 35 40 45 Tyr Arg Ala Asn Arg Leu Val Asp Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Gln Asp Tyr Ser Leu Ser Ile Ser Ser Leu Asp Tyr 65 70 75 80 Glu Asp Met Gly Ile Tyr Tyr Cys Leu Gln Tyr Asp Glu Phe Pro Leu 85 90 95 Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg 100 105 <210> 35 <211> 360 <212> DNA <213> Artificial Sequence <220> <223> HSV010-7 Heavy Chain <400> 35 caggttcagc tgcagcagtc tggacctgag ctggtgaagc ctggggcttc agtgaagttg 60 tcctgcaagg cttctggcta caccttcaca aactacgata taaactgggt gaagcagagg 120 cctggacagg gacttgagtg gattggatgg atttatccta gagatggtag cactaaatac 180 aatgagaaat tcaagggcaa ggccacattg actattgaca catcctccag cacagcgtac 240 atggagctcc acagcctgac atctgaggac tctgcggtct atttctgtgc aagagggatc 300 ttctatgtta actacgacgt ttactggggc caagggactc tggtcactgt ctctgcagcc 360 <210> 36 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> HSV010-7 Heavy Chain <400> 36 Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30 Asp Ile Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Trp Ile Tyr Pro Arg Asp Gly Ser Thr Lys Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ile Asp Thr Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu His Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95 Ala Arg Gly Ile Phe Tyr Val Asn Tyr Asp Val Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ala Ala 115 120 <210> 37 <211> 324 <212> DNA <213> Artificial Sequence <220> <223> HSV010-7 Light Chain <400> 37 gacatccaga tgacacaatc ttcatccttc ttgtctgtat ctctaggagg cagagtcacc 60 attacttgca aggcaagtga ccacattaat aattggttag cctggtatca gcagaaacca 120 ggacatgctc ctaggctctt aatatctggt gcagccagtt tggaaactgg ggttccttca 180 agattcagtg gcagtggatc tggaaaggat tacactctca ccattaccag tcttcagact 240 gaagatgttg ctacttatta ctgtcaacag tattggagta gtccgctcac gttcggtggt 300 gggaccaagc tggagctgaa acgg 324 <210> 38 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> HSV010-7 Light Chain <400> 38 Asp Ile Gln Met Thr Gln Ser Ser Ser Phe Leu Ser Val Ser Leu Gly 1 5 10 15 Gly Arg Val Thr Ile Thr Cys Lys Ala Ser Asp His Ile Asn Asn Trp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly His Ala Pro Arg Leu Leu Ile 35 40 45 Ser Gly Ala Ala Ser Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Lys Asp Tyr Thr Leu Thr Ile Thr Ser Leu Gln Thr 65 70 75 80 Glu Asp Val Ala Thr Tyr Tyr Cys Gln Gln Tyr Trp Ser Ser Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Leu Lys Arg 100 105 <210> 39 <211> 357 <212> DNA <213> Artificial Sequence <220> <223> HSV010-34 Heavy Chain <400> 39 gaggtgcagc tggtggagtc tgggggaggc ttagtgcagc ctggagagtc cctgaaactc 60 tcctgtgaat ccaatgaata cgaattccct tcccatgaca tgtcttgggt ccgcaagact 120 ccggagaaga ggctggagtt ggtcgcagcc attaatagtg atggtggtag cacctactat 180 ccagacacca tggagagacg attcatcatc tccagagaca ataccaagaa gaccctgtac 240 ctgcaaatga gcagtctgag gtctgaggac acagccttgt attactgtgc aagacatagc 300 tcaggctatg ttttggacta ctggggtcaa ggaacctcag tcaccgtctc ctcagcc 357 <210> 40 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> HSV010-34 Heavy Chain <400> 40 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Glu 1 5 10 15 Ser Leu Lys Leu Ser Cys Glu Ser Asn Glu Tyr Glu Phe Pro Ser His 20 25 30 Asp Met Ser Trp Val Arg Lys Thr Pro Glu Lys Arg Leu Glu Leu Val 35 40 45 Ala Ala Ile Asn Ser Asp Gly Gly Ser Thr Tyr Tyr Pro Asp Thr Met 50 55 60 Glu Arg Arg Phe Ile Ile Ser Arg Asp Asn Thr Lys Lys Thr Leu Tyr 65 70 75 80 Leu Gln Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Arg His Ser Ser Gly Tyr Val Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Ser Val Thr Val Ser Ser Ala 115 <210> 41 <211> 324 <212> DNA <213> Artificial Sequence <220> <223> HSV010-34 Light Chain <400> 41 gacatccaga tgacacaatc ttcatcctac ttgtctgtat ctctaggagg cagagtcacc 60 attacttgca aggcaagtga ccacattaat cattggttag cctggtatca gcagaaacca 120 ggaaatgctc ctaggctctt aatatctggt gcaaccagtt tggaaactgg ggttccttca 180 agattcagtg gcagtggatc tggaaaggat tacactctca gcattgccag tcttcagact 240 gaagatgttg ctacttatta ctgtcaacag tattggagta ctccgtacac gttcggaggg 300 gggaccaagc tggaaataaa acgg 324 <210> 42 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> HSV010-34 Light Chain <400> 42 Asp Ile Gln Met Thr Gln Ser Ser Ser Tyr Leu Ser Val Ser Leu Gly 1 5 10 15 Gly Arg Val Thr Ile Thr Cys Lys Ala Ser Asp His Ile Asn His Trp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Asn Ala Pro Arg Leu Leu Ile 35 40 45 Ser Gly Ala Thr Ser Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Lys Asp Tyr Thr Leu Ser Ile Ala Ser Leu Gln Thr 65 70 75 80 Glu Asp Val Ala Thr Tyr Tyr Cys Gln Gln Tyr Trp Ser Thr Pro Tyr 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg 100 105 <210> 43 <211> 363 <212> DNA <213> Artificial Sequence <220> <223> HSV010-6 Heavy Chain <400> 43 caggtccaac tgcagcagcc tggggctgag ctggtaaagc ctggggcttc agtgaagttg 60 tcctgcaagg cttctggcta cactttcacc aactactgga tacactgggt gaagcagagg 120 cctggacaag gccttgagtg gattggaatg attcatccta atattggtat tactcactac 180 agtgagaggt tcaagagcaa ggccacactg actgtagaca aatcctccac cacagcctac 240 atgcaactca gcagcctgac atctgaggac tctgcggtct attactgtgc aagagggtcg 300 gactcaggct ccgcctggtt tgcttactgg ggccaaggga ctctggtcac tgtctctgca 360 gcc 363 <210> 44 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> HSV010-6 Heavy Chain <400> 44 Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30 Trp Ile His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Met Ile His Pro Asn Ile Gly Ile Thr His Tyr Ser Glu Arg Phe 50 55 60 Lys Ser Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Thr Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Ser Asp Ser Gly Ser Ala Trp Phe Ala Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ala Ala 115 120 <210> 45 <211> 324 <212> DNA <213> Artificial sequence <220> <223> HSV010-6 light chain <400> 45 gacatccaga tgacacaatc ttcatcctac ttgtctgttt ctctaggagg cagagtcacc 60 attacttgca aggcaagtga ccacattaat aattggttag cctggtatct gcagaaacca 120 ggaaatgctc ctagactctt aatgtctggt gcaaccagtt tggaaactgg ggttccttca 180 agattcagtg gcagtggatc tggaaaggat tacactctca gcattaccag tcttcagact 240 gaagatgttg ctacttatta ctgtcaacag tattggagta ctccgctcac gttcggtgct 300 gggaccaagc tggagctgaa acgg 324 <210> 46 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> HSV010-6 Light Chain <400> 46 Asp Ile Gln Met Thr Gln Ser Ser Ser Tyr Leu Ser Val Ser Leu Gly 1 5 10 15 Gly Arg Val Thr Ile Thr Cys Lys Ala Ser Asp His Ile Asn Asn Trp 20 25 30 Leu Ala Trp Tyr Leu Gln Lys Pro Gly Asn Ala Pro Arg Leu Leu Met 35 40 45 Ser Gly Ala Thr Ser Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Lys Asp Tyr Thr Leu Ser Ile Thr Ser Leu Gln Thr 65 70 75 80 Glu Asp Val Ala Thr Tyr Tyr Cys Gln Gln Tyr Trp Ser Thr Pro Leu 85 90 95 Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg 100 105 <210> 47 <211> 363 <212> DNA <213> Artificial Sequence <220> <223> HSV010-9 Heavy Chain <400> 47 caggtccaac tgcagcagcc tggggctgag ttggtaaagc ctggggcttc agtgaagttg 60 tcctgcaagt cttctggcta cactttcacc agctactgga tgcactgggt gaagcagagg 120 cctggacaag gccttgagtg gattggaatg attcatccta atagtggtat tactcactac 180 aatgagaagt tcaagaccaa ggccacactg actgtagaca aatcctccag cacagcctac 240 atgcaactca gcagcctgac atctgaggac tctgcggtct cttactgtgc aagagggtcg 300 aactcaggct ccgcctggtt tgcttactgg ggccaaggga ctctggtcac tgtctctgca 360 gcc 363 <210> 48 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> HSV010-9 Heavy Chain <400> 48 Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ser Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Met Ile His Pro Asn Ser Gly Ile Thr His Tyr Asn Glu Lys Phe 50 55 60 Lys Thr Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Ser Tyr Cys 85 90 95 Ala Arg Gly Ser Asn Ser Gly Ser Ala Trp Phe Ala Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ala Ala 115 120 <210> 49 <211> 324 <212> DNA <213> Artificial sequence <220> <223> HSV010-9 light chain <400> 49 gacatccaga tgacacaatc ttcatcctac ttgtctgtat ctctaggagg cagagtcacc 60 attacttgca aggcaagtga ccacattaat aattggttag cctggtatca gcagaaacca 120 ggaaatgctc ctaggctctt aatatctggt gcaaccagtt tggaaactgg ggttccttca 180 agattcagtg gcagtggatc tggaaaggat tacactctca gcattaccag tcttcagact 240 gaagatgttg ctacttatta ctgtcaacag tattggagta ctccgctcac gttcggtgct 300 gggaccaagc tggagctgaa acgg 324 <210> 50 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> HSV010-9 Light Chain <400> 50 Asp Ile Gln Met Thr Gln Ser Ser Ser Tyr Leu Ser Val Ser Leu Gly 1 5 10 15 Gly Arg Val Thr Ile Thr Cys Lys Ala Ser Asp His Ile Asn Asn Trp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Asn Ala Pro Arg Leu Leu Ile 35 40 45 Ser Gly Ala Thr Ser Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Lys Asp Tyr Thr Leu Ser Ile Thr Ser Leu Gln Thr 65 70 75 80 Glu Asp Val Ala Thr Tyr Tyr Cys Gln Gln Tyr Trp Ser Thr Pro Leu 85 90 95 Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg 100 105 <210> 51 <211> 363 <212> DNA <213> Artificial Sequence <220> <223> HSV010-13 Heavy Chain <400> 51 caggtccaac tgcagcagcc tggggctgag ctggtaaagc ctggggcttc agtgaagttg 60 tcctgcaagg cttctggcta cactttcacc agctactgga tacactgggt gaagcagggg 120 cctggacaag gccttgagtg gattggaatg attcatccta atagtggtat tactcactac 180 aatgagaagt tcaagaccaa ggccacactg actgtagaca aatcctccag cacagcctac 240 atgcaactca gcagcctgac atctgaggac tctgcggtct gttactgtgc aagagggtcg 300 agctcaggct ccgcctggtt tgcttactgg ggccaaggga ctctggtcac tgtctctgca 360 gcc 363 <210> 52 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> HSV010-13 Heavy Chain <400> 52 Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Trp Ile His Trp Val Lys Gln Gly Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Met Ile His Pro Asn Ser Gly Ile Thr His Tyr Asn Glu Lys Phe 50 55 60 Lys Thr Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Cys Tyr Cys 85 90 95 Ala Arg Gly Ser Ser Ser Gly Ser Ala Trp Phe Ala Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ala Ala 115 120 <210> 53 <211> 324 <212> DNA <213> Artificial Sequence <220> <223> HSV010-13 Light Chain <400> 53 gacatccaga tgacacaatc ttcatcctac ttgtctgaat ctctaggagg cagagtcacc 60 attacttgca aggcaagtga ccacattaat aattggttag cctggtatca gcagaaacca 120 ggaaatgctc ccaggctctt aatatctggt gcaaccagtt tggaaactgg ggttccttca 180 agattcagtg gcagtggatc tggaaaggat tacactctca gcattaccag tcttcagact 240 gaagatgttg ctacttatta ctgtcaacag tattggagta gtccgctcac gttcggtgct 300 gggaccaagc tggagctgaa acgg 324 <210> 54 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> HSV010-13 Light Chain <400> 54 Asp Ile Gln Met Thr Gln Ser Ser Ser Tyr Leu Ser Glu Ser Leu Gly 1 5 10 15 Gly Arg Val Thr Ile Thr Cys Lys Ala Ser Asp His Ile Asn Asn Trp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Asn Ala Pro Arg Leu Leu Ile 35 40 45 Ser Gly Ala Thr Ser Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Lys Asp Tyr Thr Leu Ser Ile Thr Ser Leu Gln Thr 65 70 75 80 Glu Asp Val Ala Thr Tyr Tyr Cys Gln Gln Tyr Trp Ser Ser Pro Leu 85 90 95 Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg 100 105 <210> 55 <211> 363 <212> DNA <213> Artificial sequence <220> <223> HSV010-14 heavy chain <400> 55 caggtccaac tgcagcagcc tggggctgag ctggtaaagc ctggggcttc agtgaagttg 60 tcctgcaagg cttctggcta cactttcacc agctactgga tacactgggt gaagcagagg 120 cctggccaag gccttgagtg gattggaatg attcatccta atagtggtat tgctcactac 180 agtgagaagt tcaagagcac ggccacactg actgtagaca aatcctccag cacagcctac 240 atgcaactca gcagcctgac atctgaggac tcttcggtct attactgtgc aagagggtcg 300 agctcaggct ccgcctggtt tgcttattgg ggccaaggga ctctggtcac tgtctctgca 360 gcc 363 <210> 56 <211> 121 <212> PRT <213> Artificial sequence <220> <223> HSV010-14 heavy chain <400> 56 Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Trp Ile His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Met Ile His Pro Asn Ser Gly Ile Ala His Tyr Ser Glu Lys Phe 50 55 60 Lys Ser Thr Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ser Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Ser Ser Ser Gly Ser Ala Trp Phe Ala Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ala Ala 115 120 <210> 57 <211> 324 <212> DNA <213> Artificial sequence <220> <223> HSV010-14 light chain <400> 57 gacatccaga tgacacaatc ttcatcctac ttgtctgttt ctctaggagg cagagtcacc 60 Asp Ile Gln Met Thr Gln Ser Ser Ser Tyr Leu Ser Val Ser Leu Gly 1 5 10 15 attacttgca aggcaggtga ccacattaat aattggttag cctggtatca gcagaaacca 120 Gly Arg Val Thr Ile Thr Cys Lys Ala Gly Asp His Ile Asn Asn Trp 20 25 30 ggaaatgctc ctaggctctt aatatctggt gcaaccagtt tggaaactgg ggttccttca 180 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Asn Ala Pro Arg Leu Leu Ile 35 40 45 agattcagtg gcagtggatc tggaaaggat tacactctca gcattaccag tcttcagact 240 Ser Gly Ala Thr Ser Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 gaagatgttg ctacttatta ctgtcaacag tattggagta ctccgctcac gttcggtgct 300 gggaccaagc tggagctgaa acgg 324 <210> 58 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> HSV010-14 Light Chain <400> 58 Asp Ile Gln Met Thr Gln Ser Ser Ser Tyr Leu Ser Val Ser Leu Gly 1 5 10 15 Gly Arg Val Thr Ile Thr Cys Lys Ala Gly Asp His Ile Asn Asn Trp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Asn Ala Pro Arg Leu Leu Ile 35 40 45 Ser Gly Ala Thr Ser Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Lys Asp Tyr Thr Leu Ser Ile Thr Ser Leu Gln Thr 65 70 75 80 Glu Asp Val Ala Thr Tyr Tyr Cys Gln Gln Tyr Trp Ser Thr Pro Leu 85 90 95 Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg 100 105 <210> 59 <211> 351 <212> DNA <213> Artificial sequence <220> <223> HSV010-28 heavy chain <400> 59 cagatccagt tggtacagtc tggacctgag ctgaagaagc ctggagagac agtcaagatc 60 tcctgcaagg cttctgggta taccttcaca acctatggaa tgagctgggt gaaacaggct 120 ccaggaaagg gtttaaagtg gatgggctgg ataaacacct actctggagt gtcaacatat 180 gctgatgact tcaagggacg gtttgccttc tctttggaaa cctctgccag cactgcctat 240 ttgcagatca acaacctcaa aaatgaggac acggctacat atttctgtgc tcaggtaaac 300 tatgctatgg actactgggg tcaaggaacc tcagtcaccg tctcctcagc c 351 <210> 60 <211> 117 <212> PRT <213> Artificial sequence <220> <223> HSV010-28 heavy chain <400> 60 Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu 1 5 10 15 Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Thr Tyr 20 25 30 Gly Met Ser Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met 35 40 45 Gly Trp Ile Asn Thr Tyr Ser Gly Val Ser Thr Tyr Ala Asp Asp Phe 50 55 60 Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys 85 90 95 Ala Gln Val Asn Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val 100 105 110 Thr Val Ser Ser Ala 115 <210> 61 <211> 324 <212> DNA <213> Artificial sequence <220> <223> HSV010-28 light chain <400> 61 gacattgtga tgacccagtc tcacaaattc ttgtccacat cagtaggaga ctgggtcacc 60 atcacctgca aggccagtca ggatgtgagt actgctgtag cctggtttca gcagaaacca 120 ggacaatctc ctaaagtact gatttactcg gcatcctacc ggtacactgg agtccctgat 180 cgcttcactg gcagtggatc tgggacggat ttcactttca ccatcagcag tgtgcaggct 240 gaagacctgg cagtttatta ctgtcagcaa cattatagta ctcctcggac gttcggtgga 300 ggcaccaagc tggaaatcaa acgg 324 <210> 62 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> HSV010-28 Light Chain <400> 62 Asp Ile Val Met Thr Gln Ser His Lys Phe Leu Ser Thr Ser Val Gly 1 5 10 15 Asp Trp Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Thr Ala 20 25 30 Val Ala Trp Phe Gln Gln Lys Pro Gly Gln Ser Pro Lys Val Leu Ile 35 40 45 Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Val Gln Ala 65 70 75 80 Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln His Tyr Ser Thr Pro Arg 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg 100 105 <210> 63 <211> 354 <212> DNA <213> Artificial sequence <220> <223> HSV010-20 heavy chain <400> 63 gatgtgcagc ttcaggagtc aggacctggc atggtgagac cttctcagtc actttccctc 60 acctgcactg tcactggcta ctccatcacc agtggttatg actggcactg gatccgacat 120 tttccaggaa acaaactgga gtggatgggc tacataagct acagtggtct cactaactac 180 aacccatccc tcagaagtcg attctccatc actcatgaca catctaagaa ccatttcttc 240 ctgaagttga attctgtgac tactgaggac acagccacat attactgtgc aagaggtcct 300 ccctggtact tcgatgtctg gggcacaggg accacggtca ccgtctcctc agcc 354 <210> 64 <211> 118 <212> PRT <213> Artificial sequence <220> <223> HSV010-20 heavy chain <400> 64 Asp Val Gln Leu Gln Glu Ser Gly Pro Gly Met Val Arg Pro Ser Gln 1 5 10 15 Ser Leu Ser Leu Thr Cys Thr Val Thr Gly Tyr Ser Ile Thr Ser Gly 20 25 30 Tyr Asp Trp His Trp Ile Arg His Phe Pro Gly Asn Lys Leu Glu Trp 35 40 45 Met Gly Tyr Ile Ser Tyr Ser Gly Leu Thr Asn Tyr Asn Pro Ser Leu 50 55 60 Arg Ser Arg Phe Ser Ile Thr His Asp Thr Ser Lys Asn His Phe Phe 65 70 75 80 Leu Lys Leu Asn Ser Val Thr Thr Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95 Ala Arg Gly Pro Pro Trp Tyr Phe Asp Val Trp Gly Thr Gly Thr Thr 100 105 110 Val Thr Val Ser Ser Ala 115 <210> 65 <211> 324 <212> DNA <213> Artificial sequence <220> <223> HSV010-20 light chain <400> 65 gacattgtga tgacccagtc tcaaaaattc atgtccacat cagtaggagg cagggtcagc 60 atcacctgca aggccagtca gattgttcgt gctactgtag cctggtatca acagaaacca 120 gggcagtctc ctaaaccact aatttacttg gcatccaacc ggcacactgg agtccctgat 180 cgcttcacag gcagtggatc tgggacagat ttcactctca ccattagcaa tgtgcaatct 240 gaagacctgg cagattattt ctgtctgcaa tattggaatt atccgtacac gttcggaggg 300 gggaccaagc tggaaataaa acgg 324 <210> 66 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> HSV010-20 Light Chain <400> 66 Asp Ile Val Met Thr Gln Ser Gln Lys Phe Met Ser Thr Ser Val Gly 1 5 10 15 Gly Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Ile Val Arg Ala Thr 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Pro Leu Ile 35 40 45 Tyr Leu Ala Ser Asn Arg His Thr Gly Val Pro Asp Arg Phe Thr Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asn Val Gln Ser 65 70 75 80 Glu Asp Leu Ala Asp Tyr Phe Cys Leu Gln Tyr Trp Asn Tyr Pro Tyr 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg 100 105 <210> 67 <211> 351 <212> DNA <213> Artificial Sequence <220> <223> HSV010-8 Heavy Chain <400> 67 caggtgcagc tgaaggagtc aggacctggc ctggtggcgc cctcacagag cctgtcgatc 60 acatgcactg tctcagggtt ctcattaaac aactatgatg taagctgggt tcgccagcct 120 ccaggaaagg gtctggagtg gctgggagta atatggggtg acgggagcac aaattatcat 180 tcagctctca tatccagact gagcatcagc aaggataact ccaagagcca agttttctta 240 aaactgaaca gtctgcaaac tgatgacaca gccacgtact actgtgccaa agaagactat 300 ggtatttttc cttactgggg ccaagggact ctggtcactg tctctgcagc c 351 <210> 68 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> HSV010-8 heavy chain <400> 68 Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Asn Asn Tyr 20 25 30 Asp Val Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Gly Asp Gly Ser Thr Asn Tyr His Ser Ala Leu Ile 50 55 60 Ser Arg Leu Ser Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Phe Leu 65 70 75 80 Lys Leu Asn Ser Leu Gln Thr Asp Asp Thr Ala Thr Tyr Tyr Cys Ala 85 90 95 Lys Glu Asp Tyr Gly Ile Phe Pro Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ala Ala 115 <210> 69 <211> 324 <212> DNA <213> Artificial Sequence <220> <223> HSV010-8 light chain <400> 69 gacatcaaga tgacccagtc tccatcttcc atgtatgcat ctctaggaga gagagtcact 60 atcacttgca aggcgagtca ggacattaat agctatttaa gctggttcca gcagaaacca 120 gggaaatctc ctaagaccct gatctatcgt gcaaacagat tggtagatgg ggtcccatca 180 aggttcagtg gcagtggatc tgggcaagat tattctctca ccatcagcag cctggaatat 240 gaaaatatgg gaatttatta ttgtctacag tatgatgagt ttccgctcac gttcggtgct 300 gggaccaagc tggagctgaa acgg 324 <210> 70 <211> 108 <212> PRT <213> Artificial sequence <220> <223> HSV010-8 light chain <400> 70 Asp Ile Lys Met Thr Gln Ser Pro Ser Ser Met Tyr Ala Ser Leu Gly 1 5 10 15 Glu Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Ile Asn Ser Tyr 20 25 30 Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys Ser Pro Lys Thr Leu Ile 35 40 45 Tyr Arg Ala Asn Arg Leu Val Asp Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Gln Asp Tyr Ser Leu Thr Ile Ser Ser Leu Glu Tyr 65 70 75 80 Glu Asn Met Gly Ile Tyr Tyr Cys Leu Gln Tyr Asp Glu Phe Pro Leu 85 90 95 Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg 100 105 <210> 71 <211> 363 <212> DNA <213> Artificial sequence <220> <223> HSV010-15 heavy chain <400> 71 caggtccaac tgcagcagcc tggggctgag ctggtaaagc ctggggcttc agtgaagttg 60 tcctgcaagg cttctggcta cactttcacc agctactgga tacactgggt gcagcagagg 120 cctggacaag gccttgagtg gattggaatg attcatccta atagtggtat tactaactac 180 agtgagaagt tcaagagcaa ggccacactg actttagaca agtcctccag cacagcctac 240 atgcaactca tcagcctgac atctgaggac tctgcggtct attactgtgc aagagggtcg 300 agttcaggct ccgcctggtt tgcttactgg ggccaaggga ctctggtcac tgtctctgca 360 gcc 363 <210> 72 <211> 121 <212> PRT <213> Artificial sequence <220> <223> HSV010-15 heavy chain <400> 72 Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Trp Ile His Trp Val Gln Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Met Ile His Pro Asn Ser Gly Ile Thr Asn Tyr Ser Glu Lys Phe 50 55 60 Lys Ser Lys Ala Thr Leu Thr Leu Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ile Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Ser Ser Ser Gly Ser Ala Trp Phe Ala Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ala Ala 115 120 <210> 73 <211> 324 <212> DNA <213> Artificial sequence <220> <223> HSV010-15 light chain <400> 73 gacatccaga tgacacaatc ttcatcctac ttgtctgttt ctctaggagg cagagtcacc 60 gacatccaga tgacacaatc ttcatcctac ttgtctgttt ctctaggagg cagagtcacc 60 attacttgca aggcaagtga ccacattaat aattggttac cttggtatca gcagaaacca 120 attacttgca aggcaagtga ccacattaat aattggttac cttggtatca gcagaaacca 120 ggaaatgctc ctaggctctt aatttctggt gcaaccagtt tggaaactgg ggttccttca 180 ggaaatgctc ctaggctctt aatttctggt gcaaccagtt tggaaactgg ggttccttca 180 agattcagtg gcagtggatc tggaaaggat tacactctca gcattaccag tcttcagact 240 agattcagtg gcagtggatc tggaaaggat tacactctca gcattaccag tcttcagact 240 gaagatgttg ctacttatta ctgtcaacag tattggagtt ctccgctcac gttcggtgct 300 gaagatgttg ctacttatta ctgtcaacag tattggagtt ctccgctcac gttcggtgct 300 gggaccaagc tggagctgaa acgg 324 gggaccaagc tggagctgaa acgg 324 <210> 74<210> 74 <211> 108<211> 108 <212> PRT<212> PRT <213> Artificial Sequence<213> Artificial Sequence <220><220> <223> HSV010-15 Light Chain<223> HSV010-15 Light Chain <400> 74<400> 74 Asp Ile Gln Met Thr Gln Ser Ser Ser Tyr Leu Ser Val Ser Leu Gly Asp Ile Gln Met Thr Gln Ser Ser Ser Tyr Leu Ser Val Ser Leu Gly 1 5 10 15 1 5 10 15 Gly Arg Val Thr Ile Thr Cys Lys Ala Ser Asp His Ile Asn Asn Trp Gly Arg Val Thr Ile Thr Cys Lys Ala Ser Asp His Ile Asn Asn Trp 20 25 30 20 25 30 Leu Pro Trp Tyr Gln Gln Lys Pro Gly Asn Ala Pro Arg Leu Leu Ile Leu Pro Trp Tyr Gln Gln Lys Pro Gly Asn Ala Pro Arg Leu Leu Ile 35 40 45 35 40 45 Ser Gly Ala Thr Ser Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ala Thr Ser Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 50 55 60 Ser Gly Ser Gly Lys Asp Tyr Thr Leu Ser Ile Thr Ser Leu Gln Thr 65 70 75 80 Glu Asp Val Ala Thr Tyr Tyr Cys Gln Gln Tyr Trp Ser Ser Pro Leu 85 90 95 Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg 100 105 <210> 75 <211> 351 <212> DNA <213> Artificial sequence <220> <223> HSV010-16 heavy chain <400> 75 cagatccagt tggtacagtc tggacctgag ctgaagaagc ctggagagac agtcaagatc 60 tcctgcaagg cttctgggta taccttcaca acctatggaa tgagctgggt gaaacaggct 120 ccaggaaagg atttaaagtg gatgggctgg ataaacacct actctggagt gtcaacatat 180 ggtgatgact tcaagggacg gtttgccttg tctttggaaa cctctgccag cactgcctat 240 ttacaaatca acaacctcaa aaatgaggac acggctacat atttctgtgc tcagttaaac 300 tatggtatgg actactgggg tcaaggaacc tcagtcaccg tctcctcagc c 351 <210> 76 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> HSV010-16 Heavy Chain <400> 76 Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu 1 5 10 15 Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Thr Tyr 20 25 30 Gly Met Ser Trp Val Lys Gln Ala Pro Gly Lys Asp Leu Lys Trp Met 35 40 45 Gly Trp Ile Asn Thr Tyr Ser Gly Val Ser Thr Tyr Gly Asp Asp Phe 50 55 60 Lys Gly Arg Phe Ala Leu Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys 85 90 95 Ala Gln Leu Asn Tyr Gly Met Asp Tyr Trp Gly Gln Gly Thr Ser Val 100 105 110 Thr Val Ser Ser Ala 115 <210> 77 <211> 324 <212> DNA <213> Artificial Sequence <220> <223> HSV010-16 Light Chain <400> 77 gacattgtga tgacccagtc tcacaaattc atgtccacat cagtaggaga cagggtcagc 60 Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly atcacctgca aggccagtca ggatgtgagt acttctttag cctggtatca acagaaacca 120 Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Thr Ser Leu Ala Trp Tyr Gln Gln Lys Pro ggacaatctc ctaaactact gatttattcg gcatcctacc ggtacactgg agtccctgat 180 Gly Gln Ser Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Asp cgcttcactg gcagtggatc tgggacggat ttcactttca ccatcagcag tgtgcaggct 240 Arg Phe Thr Gly Ala Val Asp Leu Gly Thr Asp Phe Thr Phe His Ser Ser Cys Ala Ala gaagacctgg cagtttatta ctgtcaccaa cattatagta ttcctcggac gttcggtgga 300 Glu Asp Leu Ala Phe Tyr Tyr Cys Thr Lys His Tyr Ser Tyr Pro Arg Arg Phe Gly Gly ggcaccaagc tggaaatcaa acgg 324 Gly Thr Ser Leu Glu Ile Lys Thr <210> 78 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> HSV010-16 Light Chain <400> 78 Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly 1 5 10 15 Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Thr Ser 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Val Gln Ala 65 70 75 80 Glu Asp Leu Ala Val Tyr Tyr Cys His Gln His Tyr Ser Ile Pro Arg 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg 100 105 <210> 79 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR1 <400> 79 Gly Phe Ser Leu Ser Arg His Asp 1 5 <210> 80 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR2 <400> 80 Ile Trp Gly Asp Gly Ser Thr 1 5 <210> 81 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR3 <400> 81 Ala Lys Glu Asp Tyr Gly Ile Phe Pro Tyr 1 5 10 <210> 82 <211> 6 <212> PRT <213> Artificial sequence <220> <223> Light chain CDR1 <400> 82 Gln Asp Ile Ser Ser Tyr 1 5 <210> 83 <211> 3 <212> PRT <213> Artificial sequence <220> <223> Light chain CDR2 <400> 83 Arg Ala Asn 1 <210> 84 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Light chain CDR3 <400> 84 Leu Gln Tyr Asp Glu Phe Pro Leu Thr 1 5 <210> 85 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR1 <400> 85 Gly Phe Ser Leu Asn Asn Tyr Asp 1 5 <210> 86 <211> 6 <212> PRT <213> Artificial sequence <220> <223> Light chain CDR1 <400> 86 Gln Asp Ile Asn Ser Tyr 1 5 <210> 87 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR1 <400> 87 Gly Tyr Thr Phe Thr Asn Tyr Asp 1 5 <210> 88 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR2 <400> 88 Ile Tyr Pro Arg Asp Gly Ser Thr 1 5 <210> 89 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR3 <400> 89 Ala Arg Gly Ile Phe Tyr Val Asn Tyr Asp Val Tyr 1 5 10 <210> 90 <211> 6 <212> PRT <213> Artificial sequence <220> <223> Light chain CDR1 <400> 90 Asp His Ile Asn Asn Trp 1 5 <210> 91 <211> 3 <212> PRT <213> Artificial sequence <220> <223> Light chain CDR2 <400> 91 Gly Ala Ala 1 <210> 92 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Light chain CDR3 <400> 92 Gln Gln Tyr Trp Ser Ser Pro Leu Thr 1 5 <210> 93 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR1 <400> 93 Glu Tyr Glu Phe Pro Ser His Asp 1 5 <210> 94 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR2 <400> 94 Ile Asn Ser Asp Gly Gly Ser Thr 1 5 <210> 95 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR3 <400> 95 Ala Arg His Ser Ser Gly Tyr Val Leu Asp Tyr 1 5 10 <210> 96 <211> 6 <212> PRT <213> Artificial sequence <220> <223> Light chain CDR1 <400> 96 Asp His Ile Asn His Trp 1 5 <210> 97 <211> 3 <212> PRT <213> Artificial sequence <220> <223> Light chain CDR2 <400> 97 Gly Ala Thr 1 <210> 98 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Light chain CDR3 <400> 98 Gln Gln Tyr Trp Ser Thr Pro Tyr Thr 1 5 <210> 99 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR1 <400> 99 Gly Tyr Thr Phe Thr Asn Tyr Trp 1 5 <210> 100 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR2 <400> 100 Ile His Pro Asn Ile Gly Ile Thr 1 5 <210> 101 <211> 13 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR3 <400> 101 Ala Arg Gly Ser Asp Ser Gly Ser Ala Trp Phe Ala Tyr 1 5 10 <210> 102 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR3 <400> 102 Gln Gln Tyr Trp Ser Thr Pro Leu Thr 1 5 <210> 103 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR1 <400> 103 Gly Tyr Thr Phe Thr Ser Tyr Trp 1 5 <210> 104 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR2 <400> 104 Ile His Pro Asn Ser Gly Ile Thr 1 5 <210> 105 <211> 13 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR3 <400> 105 Ala Arg Gly Ser Asn Ser Gly Ser Ala Trp Phe Ala Tyr 1 5 10 <210> 106 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR2 <400> 106 Ile His Pro Asn Ser Gly Ile Ala 1 5 <210> 107 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR1 <400> 107 Gly Tyr Thr Phe Thr Thr Tyr Gly 1 5 <210> 108 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR2 <400> 108 Ile Asn Thr Tyr Ser Gly Val Ser 1 5 <210> 109 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR3 <400> 109 Ala Gln Leu Asn Tyr Gly Met Asp Tyr 1 5 <210> 110 <211> 6 <212> PRT <213> Artificial sequence <220> <223> Light chain CDR1 <400> 110 Gln Asp Val Ser Thr Ser 1 5 <210> 111 <211> 3 <212> PRT <213> Artificial sequence <220> <223> Light chain CDR2 <400> 111 Ser Ala Ser 1 <210> 112 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Light chain CDR2 <400> 112 His Gln His Tyr Ser Ile Pro Arg Thr 1 5 <210> 113 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR3 <400> 113 Ala Gln Val Asn Tyr Ala Met Asp Tyr 1 5 <210> 114 <211> 6 <212> PRT <213> Artificial sequence <220> <223> Light chain CDR1 <400> 114 Gln Asp Val Ser Thr Ala 1 5 <210> 115 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Light chain CDR3 <400> 115 Gln Gln His Tyr Ser Thr Pro Arg Thr 1 5 <210> 116 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR1 <400> 116 Gly Tyr Ser Ile Thr Ser Gly Tyr Asp 1 5 <210> 117 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR2 <400> 117 Ile Ser Tyr Ser Gly Leu Thr 1 5 <210> 118 <400> 118 000 <210> 119 <211> 6 <212> PRT <213> Artificial sequence <220> <223> Light chain CDR1 <400> 119 Gln Ile Val Arg Ala Thr 1 5 <210> 120 <211> 3 <212> PRT <213> Artificial sequence <220> <223> Light chain CDR2 <400> 120 Leu Ala Ser 1 <210> 121 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Light chain CDR3 <400> 121 Leu Gln Tyr Trp Asn Tyr Pro Tyr Thr 1 5 <210> 122 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR3 <400> 122 Cys Ala Arg Gly Thr Tyr Trp 1 5 <210> 123 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Light chain CDR3 <400> 123 Cys Gln Gln Trp Ser Gly Tyr Pro Phe Thr Phe 1 5 10 <210> 124 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR3 <400> 124 Cys Val Arg Leu Asp Ala Met Asp Tyr Trp 1 5 10 <210> 125 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Light chain CDR3 <400> 125 Cys Ser Gln Ser Thr His Val Pro Tyr Thr Phe 1 5 10 <210> 126 <211> 15 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR3 <400> 126 Cys Ala Thr Tyr Gly Ser Ser Arg Tyr Tyr Thr Met Asp Tyr Trp 1 5 10 15 <210> 127 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Light chain CDR3 <400> 127 Cys Gln Gln Trp Ser Ser Tyr Pro Pro Thr Phe 1 5 10 <210> 128 <211> 16 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR3 <400> 128 Cys Ala Arg Glu Gly Asp Ser Asn Tyr Asp Trp Tyr Phe Asp Val Trp 1 5 10 15 <210> 129 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Light chain CDR3 <400> 129 Cys Gln His Phe Trp Ser Pro Val Thr Phe 1 5 10 <210> 130 <211> 17 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR3 <400> 130 Cys Thr Arg Ala Tyr Tyr Ser Asn Tyr Val Gly Leu Gly Phe Pro Tyr 1 5 10 15 Trp <210> 131 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Light chain CDR3 <400> 131 Cys Met Gln His Leu Glu Tyr Pro Tyr Thr Phe 1 5 10 <210> 132 <211> 13 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR3 <400> 132 Cys Ala Arg Gly Gly Tyr Tyr Tyr Thr Met Asp Tyr Trp 1 5 10 <210> 133 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Light chain CDR3 <400> 133 Cys Gln Gln Ser Asn Glu Asp Pro Arg Thr Phe 1 5 10 <210> 134 <211> 13 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR3 <400> 134 Cys Ala Arg Ser Ser Asn Tyr Gly Phe Phe Asp Val Trp 1 5 10 <210> 135 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Light chain CDR3 <400> 135 Cys Gln Gln Tyr Tyr Arg Tyr Pro Arg Thr Phe 1 5 10 <210> 136 <211> 13 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR3 <400> 136 Cys Ala Arg Asp Arg Thr Gly Tyr Gly Met Asp Tyr Trp 1 5 10 <210> 137 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Light chain CDR3 <400> 137 Cys Leu Gln Tyr Asp Glu Phe Arg Thr Phe 1 5 10 <210> 138 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR3 <400> 138 Cys Thr Tyr Asp Tyr Asp Gly Gly Phe Asp Tyr Trp 1 5 10 <210> 139 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Light chain CDR3 <400> 139 Cys Leu Gln Tyr Asp Glu Phe Pro Tyr Thr Phe 1 5 10 <210> 140 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR3 <400> 140 Cys Ala Ser Asp Gln Gly Gly Ala Met Asp His Trp 1 5 10 <210> 141 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Light chain CDR3 <400> 141 Cys Leu Gln Thr Asp Asn Phe Pro Leu Thr Phe 1 5 10 <210> 142 <211> 15 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR3 <400> 142 Cys Thr Arg Ser Phe Gln Ala Thr Ser Phe Ala Met Asp Tyr Trp 1 5 10 15 <210> 143 <211> 15 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR3 <400> 143 Cys Ala Arg Ser Phe Gln Ala Thr Ser Phe Ala Met Asp Tyr Trp 1 5 10 15 <210> 144 <211> 13 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR3 <400> 144 Cys Ala Ser Gly Asp Asp Tyr Gly Arg Met Asp Tyr Trp 1 5 10 <210> 145 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Light chain CDR3 <400> 145 Cys Gln Gln Tyr Asn Ser Tyr Pro Leu Thr Phe 1 5 10 <210> 146 <211> 15 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR3 <400> 146 Cys Ala Ser Pro Ile Tyr Tyr Gly Ile Ser Trp Phe Ala Tyr Trp 1 5 10 15 <210> 147 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Light chain CDR3 <400> 147 Cys Gln Gln Gly Gln Ser Tyr Pro Tyr Thr Phe 1 5 10 <210> 148 <211> 13 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR3 <400> 148 Cys Ala Arg Ile Trp Pro Asp Trp Tyr Phe Asp Val Trp 1 5 10 <210> 149 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Light chain CDR3 <400> 149 Cys Leu Gln Ser Asp Asn Met Pro Phe Thr Phe 1 5 10 <210> 150 <211> 15 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR3 <400> 150 Cys Ala Thr Tyr Gly Ser Ser Arg Tyr Tyr Thr Met Asp Tyr Trp 1 5 10 15 <210> 151 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Light chain CDR3 <400> 151 Cys Gln Gln Ser Lys Glu Val Pro Leu Thr Phe 1 5 10 <210> 152 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR3 <400> 152 Cys Ala Arg Leu Asp Ala Met Asp Tyr Trp 1 5 10 <210> 153 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Light chain CDR3 <400> 153 Cys Leu Gln Tyr Asp Asn Leu Trp Thr Phe 1 5 10 <210> 154 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR3 <400> 154 Cys Thr Arg Arg Ala Thr Gly Asp Tyr Trp 1 5 10 <210> 155 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Light chain CDR3 <400> 155 Cys Ala Gln Asn Leu Glu Leu Pro Arg Thr Phe 1 5 10 <210> 156 <211> 18 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR3 <400> 156 Cys Ala Arg Cys Gly Asn Tyr Tyr Gly Ser Ser Tyr Trp Tyr Phe Asp 1 5 10 15 Val Trp <210> 157 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR3 <400> 157 Cys Ala Arg Gly Gly Tyr Trp 1 5 <210> 158 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Light chain CDR3 <400> 158 Cys Gln Gln Trp Asn Ile Tyr Pro Phe Thr Phe 1 5 10 <210> 159 <211> 14 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR3 <400> 159 Cys Ala Arg Trp Leu Leu Arg Gly Gly Tyr Phe Asp Tyr Trp 1 5 10 <210> 160 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Light chain CDR3 <400> 160 Cys Gln Gln His Tyr Ser Ile Pro Phe Thr Phe 1 5 10 <210> 161 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Light chain CDR3 <400> 161 Cys Gln Gln Trp Ser Ser Phe Pro Phe Thr Phe 1 5 10 <210> 162 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Light chain CDR3 <400> 162 Cys His Gln Gly Gln Ser Tyr Pro Tyr Thr Phe 1 5 10 <210> 163 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR3 <400> 163 Cys Ala Arg Gly Val Thr Thr Leu Trp 1 5

Claims

1. A herpes simplex virus-2 (HSV-2) glycoprotein B (gB) binding antibody or antigen-binding fragment, the antibody or antigen-binding fragment comprising: A heavy chain variable region, the heavy chain variable region including a complementarity determining region CDR, the heavy chain variable region CDR is: GYSFTTYD (SEQ ID NO: 1), IYPREGST (SEQ ID NO: 2), and ATYGSSRYYTMDY (SEQ ID NO: 3); and A light chain variable region, the light chain variable region includes a complementarity determining region CDR, and the light chain variable region CDR is as follows: ESVDNFGISF (SEQ ID NO: 4), AAS (SEQ ID NO: 5), and QQSKEVPLT (SEQ ID NO: 6).

2. The antibody or antigen-binding fragment of claim 1, which has an IgG2c isotype.

3. The antibody or antigen-binding fragment of claim 1 or 2, which is a humanized antibody.

4. The antibody or antigen-binding fragment of claim 1 or 2, comprising an Fc region that binds to human Fcγ receptor RIII (FcγRIII).

5. The antibody or antigen-binding fragment of claim 1 or 2, wherein the framework region of the light chain, the framework region of the heavy chain, or a combination thereof is a human framework region, or has 85% or higher identity with the human framework region.

6. The antibody or antigen-binding fragment of claim 5, wherein the framework region of the light chain, the framework region of the heavy chain, or a combination thereof is the human framework region.

7. A nucleic acid encoding the herpes simplex virus-2 (HSV-2) glycoprotein B (gB) binding antibody or antigen-binding fragment as described in claim 1.

8. The nucleic acid of claim 7, further comprising a nucleic acid sequence encoding a human heavy chain framework region.

9. The nucleic acid of claim 7, further comprising a nucleic acid sequence encoding a human Fc region.

10. The nucleic acid of claim 7, further comprising a nucleic acid sequence encoding a human light chain framework region.

11. A host cell comprising one or more nucleic acids according to any one of claims 7 to 10.

12. Use of the antibody or antigen-binding fragment of any one of claims 1 to 6 in the preparation of a medicament for inhibiting herpes simplex virus-2 (HSV-2) infection in a subject, wherein: The antibody or antigen-binding fragment of any one of claims 1 to 6 is administered in an amount effective to inhibit HSV-2 activity in a subject.

13. The use of claim 12, wherein the subject is infected with HSV-2.

14. The use of claim 12, wherein the subject is not yet infected with HSV-2.

15. The use according to any one of claims 12 to 14, wherein the subject is immunocompromised.

16. The method of any one of claims 12 to 14, wherein the subject is pregnant or is a newborn.

17. The use according to any one of claims 12 to 14, wherein the subject is receiving or has received an antiviral drug.

18. The use of claim 17, wherein the antiviral drug comprises acyclovir.

19. A pharmaceutical composition comprising: The antibody or antigen-binding fragment of any one of claims 1 to 6; and Pharmaceutically acceptable carrier or excipient.

20. The pharmaceutical composition of claim 19, further comprising a small molecule antiviral drug.

21. The pharmaceutical composition of claim 20, wherein the small molecule antiviral drug is acyclovir.

22. The pharmaceutical composition of any one of claims 19 to 21, wherein the antibody or antigen-binding fragment is present in an amount effective to treat or prevent herpes simplex virus-2 (HSV-2) infection in a subject.

23. Use of an effective amount of the antibody or antigen-binding fragment of any one of claims 1-6 in the manufacture of a medicament for treating or preventing herpes simplex virus-2 (HSV-2) infection in a subject.

24. An anti-HSV-2 glycoprotein B antibody or antigen-binding fragment, wherein the antibody comprises a heavy chain variable region shown in SEQ ID NO: 20 and a light chain variable region shown in SEQ ID NO:

22.

25. A nucleic acid encoding the anti-HSV-2 glycoprotein B antibody or antigen-binding fragment of claim 24, wherein the nucleic acid comprises a nucleic acid sequence of SEQ ID NO: 19, which encodes a heavy chain variable region shown in SEQ ID NO: 20, and a nucleic acid sequence of SEQ ID NO: 21, which encodes a light chain variable region shown in SEQ ID NO: 22.

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