Herpes simplex virus antigen binding agents for mitigation of herpes simplex virus associated disease

Abstract

Provided herein are compositions for the prevention and treatment of genital herpes, comprising antigen binding agents to herpes simplex virus (HSV) glycoproteins, including those involved in virus entry and immune evasion, ribonucleic acids (RNAs) encoding these antigen binding agents, and methods of use thereof.

Description

P-636791-PC HERPES SIMPLEX VIRUS ANTIGEN BINDING AGENTS FOR MITIGATION OF HERPES SIMPLEX VIRUS ASSOCIATED DISEASE SEQUENCE LISTING STATEMENT

[0001] A Sequence Listing conforming to the rules of WIPO Standard ST.26 is hereby incorporated by reference. The Sequence Listing has been filed as an electronic document via PatentCenter encoded as XML in UTF-8 text. The electronic document, created on June 4, 2025, is entitled “P-636791-PC_ST26.xml”, and is 358 kilobytes in size. TECHNICAL FIELD

[0002] Provided herein are compositions for the prevention and treatment of genital herpes, comprising antigen binding agents directed to herpes simplex virus (HSV) glycoproteins, including those involved in virus entry and immune evasion, ribonucleic acids (RNAs) encoding these antigen binding agents, and methods of use thereof. Additionally, the present disclosure provides compositions comprising anti-glycoprotein D (gD) antigen binding agents or RNA encoding anti-gD antigen binding agents, anti-glycoprotein B (gB) antigen binding agents or RNA encoding anti-gB antigen binding agents, or a combination thereof and related methods of treating or preventing an HSV infection. Finally, the present disclosure provides compositions comprising bispecific antibodies that bind to one or more HSV glycoproteins, including those involved in virus entry and immune evasion, ribonucleic acids (RNAs) encoding these antigen binding agents, and methods of use thereof. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT

[0003] This invention was made with government support under AI139618 and AI018289 awarded by the National Institutes of Health. The government has certain rights in the invention. BACKGROUND

[0004] Herpes simplex viruses (HSV-1 and HSV-2) are double-stranded DNA viruses that are transmitted both orally and sexually and cause lifelong human diseases, including cold sores, eye and genital infections, meningitis, and encephalitis. Infection of neonates with HSV Page 1 of 242P-636791-PC is also of particular concern, as it can lead to severe morbidity and mortality. It is estimated that globally, 3.7 billion people under the age of 50 are infected with HSV-1 and 491 million people between the ages of 15–49 are infected with HSV-2, the leading cause of genital herpes.

[0005] Although anti-viral drugs, such as acyclovir, valacyclovir, cidofovir and foscarnet, that target DNA replication are available, HSV remains a significant human pathogen in part because it establishes latency within the sensory ganglia and can be reactivated, causing recurrent infections. Even when taken daily, the available drugs do not totally suppress virus shedding, which is a characteristic of reactivation. Therefore, HSV spread in the human population has been very difficult to control.

[0006] Another difficulty in treating HSV infection is that HSV acquires evasion of drugs by developing mutations, thereby conferring resistance. HSV employs multiple glycoproteins, glycoprotein D (gD), glycoprotein H / glycoprotein L (gH / gL) heterodimeric complex and glycoprotein B (gB) for entry into cells. The sequence of events leading to entry begins with the binding of gD to one of the cellular receptors (nectin-1 or HVEM) which causes conformational changes in gD. gD then activates the modulator of fusion, the heterodimer gH / gL, which in turn activates the fusogen, gB. These events then allow for the deposition of viral genome into the cell.

[0007] Passive transfer of neutralizing antibodies has shown promise in animal models; and placental transfer of anti-HSV monoclonal antibodies (Mabs) protects neonatal mice. In people, current immunotherapeutic strategies to fight HSV infections have also focused on the use of anti-HSV Mabs. However, while both UB-621 (E317), a Mab targeting glycoprotein D, and a gD-specific IgG1 isolated using a phage display library (HSV8) in combination with a broadly neutralizing anti-HIV antibody, were found to be safe and well tolerated in healthy individuals in phase I clinical trials, neither HSV Mab advanced to Phase II trials. Additional immuno- therapeutics to treat HSV infections are clearly needed. SUMMARY

[0008] Provided herein is a combination comprising: (a) a first polyribonucleotide encoding a first anti-Herpes Simplex Virus (HSV) glycoprotein antigen binding agent and (b) a second polyribonucleotide encoding a second anti-HSV glycoprotein antigen binding agent, wherein the first antigen binding agent and the second antigen binding agent bind to different epitopes. Page 2 of 242P-636791-PC

[0009] Also provided herein is a combination comprising: (a) a first anti-Herpes Simplex Virus (HSV) glycoprotein antigen binding agent and (b) a second anti-HSV glycoprotein antigen binding agent, wherein the first antigen binding agent and the second antigen binding agent bind to different epitopes on the same HSV glycoprotein.

[0010] Further provided herein is a composition comprising any of the above combinations.

[0011] Further provided herein is a polypeptide encoding an anti-Herpes Simplex Virus (HSV) glycoprotein B (gB) (anti-gB) antigen binding agent comprising a heavy chain variable region and a light chain variable region, wherein the polypeptide comprises (i) a heavy chain complementarity determining region 1 (CDRH1) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 33; (ii) a heavy chain complementarity determining region 2 (CDRH2) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 34; (iii) a heavy chain complementarity determining region 3 (CDRH3) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 35; (iv) a light chain complementarity determining region 1 (CDRL1) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 46, (v) a light chain complementarity determining region 2 (CDRL2) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 47; and (vi) a light chain complementarity determining region 3 (CDRL3) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 48.

[0012] Further provided herein is a polypeptide encoding an anti-Herpes Simplex Virus (HSV) glycoprotein D (gD) (anti-gD) antigen binding agent comprising a heavy chain variable region and a light chain variable region, wherein the polypeptide comprises (i) a heavy chain complementarity determining region 1 (CDRH1) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 162; (ii) a heavy chain complementarity determining region 2 (CDRH2) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 163; (iii) a heavy chain complementarity determining region 3 (CDRH3) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according Page 3 of 242P-636791-PC to SEQ ID NO: 164; (iv) a light chain complementarity determining region 1 (CDRL1) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 172, (v) a light chain complementarity determining region 2 (CDRL2) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 173; and (vi) a light chain complementarity determining region 3 (CDRL3) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 174.

[0013] Further provided herein is a polypeptide encoding an anti-Herpes Simplex Virus (HSV) glycoprotein D (gD) (anti-gD) antigen binding agent comprising a heavy chain variable region and a light chain variable region, wherein the polypeptide comprises (i) a heavy chain complementarity determining region 1 (CDRH1) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 206; (ii) a heavy chain complementarity determining region 2 (CDRH2) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 207; (iii) a heavy chain complementarity determining region 3 (CDRH3) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 208; (iv) a light chain complementarity determining region 1 (CDRL1) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 216, (v) a light chain complementarity determining region 2 (CDRL2) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 217; and (vi) a light chain complementarity determining region 3 (CDRL3) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 218.

[0014] Further provided herein is a polypeptide encoding an anti-Herpes Simplex Virus (HSV) glycoprotein D (gD) (anti-gD) antigen binding agent comprising a heavy chain variable region and a light chain variable region, wherein the polypeptide comprises (i) a heavy chain complementarity determining region 1 (CDRH1) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 229; (ii) a heavy chain complementarity determining region 2 (CDRH2) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% Page 4 of 242P-636791-PC identity to a nucleic acid sequence according to SEQ ID NO: 230; (iii) a heavy chain complementarity determining region 3 (CDRH3) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 231; (iv) a light chain complementarity determining region 1 (CDRL1) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 239, (v) a light chain complementarity determining region 2 (CDRL2) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 240; and (vi) a light chain complementarity determining region 3 (CDRL3) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 241.

[0015] Further provided herein is a polyribonucleotide encoding a polypeptide as described herein.

[0016] Also provided herein is a composition comprising a polypeptide or polyribonucleotide as described herein and a pharmaceutically acceptable carrier.

[0017] Further provided herein is a method of treating, suppressing, reducing, inhibiting, or preventing a Herpes Simplex Virus (HSV) infection or transmission in a subject, comprising administering to the subject a combination, composition, polypeptide, or polyribonucleotide as described herein.

[0018] Further provided herein is a method of treating, suppressing, reducing, inhibiting, or preventing a Herpes Simplex Virus (HSV) neurological infection or transmission in a subject, comprising administering to the subject a combination, composition, polypeptide, or polyribonucleotide as described herein.

[0019] Further provided herein is a method for neutralizing Herpes Simplex Virus (HSV) transmission or infection in a subject, comprising administering to the subject a combination, composition, polypeptide, or polyribonucleotide as described herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Some embodiments of the disclosure are herein described, by way of example only, with reference to the accompanying drawings. With specific reference now to the drawings in detail, it is stressed that the particulars shown are by way of example and for purposes of illustrative discussion of embodiments of the disclosure. In this regard, the description taken Page 5 of 242P-636791-PC with the drawings makes apparent to those skilled in the art how embodiments of the disclosure may be practiced.

[0021] Figures 1A-1C are a series of schematic drawings depicting some of the antigen binding agents provided herein, for example those which bind to a glycoprotein D (gD) or a glycoprotein B (gB) protein. Figure 1A is a schematic of an IgG monoclonal antibody (called IgG A), such as anti-gD2 MC2 or DL11, showing the light chain and the heavy chain with the variable regions (V) of the light chain (VL) and heavy chain (VH) and the constant regions (C) of the light chain (CL) and heavy chain (CL). The Fc region is also indicated (Cγ1, Cγ2, Cγ3). Figure 1B is a schematic of a second IgG monoclonal antibody (called IgG B), such as anti- gB2 (C226) or anti-gD2 (1D3). Figure 1C is a schematic of an scFv-Fc antibody (called scFv- Fc B), such as anti-gB2 (C226sc) or anti-gD2 (1D3 or 1D3sc).

[0022] Figures 1D-1H are a series of schematic drawings depicting the design of some antigen binding agents provided herein targeting two different epitopes. Exemplary bispecific antigen binding agent formats include: two Fabs (Figure 1D), one Fab / one scFv (Figure 1E and Figure 1F), or two single chains (scFv; Figure 1G) all fused to Fcs. Figure 1H is a schematic of a tetravalent bispecific antibody composed of two Fabs and two scFv components targeting two different epitopes.

[0023] Figures 1I-1J are schematic drawings depicting some antigen binding agents provided herein targeting two different epitopes and comprising a knob-in-hole (KiH) mutation to facilitate formation of bispecific antibodies.

[0024] Figures 2A-2E show the identification of gD2 and gB2 by MC2 IgG, C226sc, MC2+C226 (combination) and bispecific MC2 / C226 (BsAb) on native polyacrylamide gel electrophoresis (PAGE) (Figure 2A), as well as the effects of said binding agents on cell fusion (Figure 2B), HSV-2 virus entry (Figure 2C), HSV-1 virus entry (Figure 2D), and plaque neutralization (Figure 2E).

[0025] Figures 3A-3G show the effects of a combination of MC2 and C226sc (Mabs) and bi-specific MC2 C226sc (Bispecific) in an HSV-2 infection model on weight loss (Figure 3A), death (Figure 3B), viral replication after 2 days (Figure 3C) and 4 days (Figure 3D), and vaginal disease (Figure 3E) as expressed by days of disease (Figure 3F) and vaginal disease score (Figure 3G).

[0026] Figures 4A-4B show the design of RNA constructs combining MC2 IgG and C226sc scFV-Fc linked by a knob-in-hole (KiH) configuration (Figure 4A), and the formation of its Page 6 of 242P-636791-PC expressed protein product, the bispecific MC2-C226sc antigen binding agent construct (Figure 4B).

[0027] Figures 5A-5B show the production of recombinant bispecific MC2:C226sc antigen-binding agents in transfected cells (Figure 5A) and the effect of different MC2:C226sc concentration ratios on the agent’s yield (Figure 5B).

[0028] Figures 6A-6C show antigen binding agent production in animals immunized with RNA encoding MC2 antigen-binding agent (gB mAb), C226sc antigen-binding agent (gD2 mAb) or MC2 / C226sc antigen binding agent (bispecific). Mice were immunized and their blood and vaginal fluids analyzed over the course of 7 days (Figure 6A), IgG titers against gD2 (α-gD2) and gB (α-gB) were measured in serum (Figure 6B) and in vaginal fluid (Figure 6C). For Figures 6B and 6C, data is the mean of two animals per group.

[0029] Figures 7A-7J show a study to evaluate production of anti-HIV antibodies, and the prevention of genital disease following immunization with lipid nanoparticle (LNP) containing mRNA. Mice were inoculated with lipid nanoparticles containing mRNA encoding either a Luciferase control, MC2, C226sc, MC2 and C226sc each RNA formulated separately (“α-gD2 & gB Mix”), MC2 and C226sc co-formulated (“α-gD2-gB Co-form”) or MC2 and C226sc with KiH mutations co-formulated (“α-gD2-gB bispecific”), and after 2 days infected with HSV-2 (Figure 7A). MC2 containing antibodies were detected by ELISA using an anti-P2A antibody (Figure 7B). Further shown are ELISA results indicating the presence of gB2 antigen-binding agents 2, 8, and 28 days after immunization (Figure 7C) and gD2 antigen-binding agents 2, 8, and 28 days after immunization (Figure 7D) in serum. Also shown are ELISA results indicating the presence in serum of bispecific antigen-binding agent detecting gD (Figure 7E) and gB (Figure 7F). The reduction of viral titer 2 days and 4 days after treatment (Figure 7G), prevention of disease (Figure 7H) in treated mice, and neutralization of HSV2 (Figure 7I) and HSV1 (Figure 7J) by serum antigen-binding agents produced from RNA. n=5 mice / group; P value was calculated by Mann Whitney for non-parametric data was observed. P<0.05 was considered significant.

[0030] Figures 8A-8J show the generation and analysis of tetravalent bispecific antibodies. Figure 8A shows a Western blot demonstrating that BD Tetra Abs are successfully produced and run at the expected molecular weight ~200kDa. Figure 8B shows Western blots demonstrating that BD Tetra Abs recognize gB and gD run on the same gel. Figure 8C compares the blocking activity of the antibodies MC2, C226sc, the combination of MC2 and Page 7 of 242P-636791-PC C226sc, MC2 / C226sc bispecific Ab and BD Tetra on cell-cell fusion in B78 cells (effector cells) using a split luciferase assay. Figures 8D and 8E compare the effect of the antibodies MC2 / C226sc and BD Tetra on blocking cell-cell fusion in a split luciferase assay in B78 cells transfected with either type1 (Figure 8D) or type 2 (Figure 8E) glycoproteins. Figure 8F shows a penetration assay comparing the blocking effect of MC2, C226sc, the combination of MC2 and C226sc, MC2 / C226sc bispecific Ab and BD Tetra on HSV-1 (KOS) virus entry. Figure 8G shows penetration assay comparing MC2 / C226sc and BD Tetra blocking effect on HSV-2 (333) virus entry. Figure 8H shows a plaque neutralization assay comparing the combination of MC2 and C226sc, MC2 / C226sc and BD Tetra blocking effect on HSV-2 (333) virus entry. Figure 8I shows Surface Plasmon Resonance for binding soluble gB and gD proteins by MC2, C226sc, MC2 / C226sc BsAb, and BD Tetra Abs; arrows indicate the beginning of soluble gB1(730) and gD2(306) injection. Figure 8J shows Surface Plasmon Resonance for binding mouse Fc γ receptors RI and RIV by MC2, C226sc, MC2 / C226sc BsAb, and BD Tetra Abs.

[0031] Figures 9A-9B present sample curves showing theoretical binding activity of monoclonal antibody 1 (Mab1) (unfilled circles), Mab2 (filled gray circles), the combination of Mab1+Mab2 (black filled circles), and the predicted values for the two antibodies if they were additive (dashed line). Figure 9A provides an example of two antibodies whose combination is additive, as demonstrated in the graph by a close overlap between the experimentally determined (filled black circles) and theoretically determined (dashed gray line) curves for the combined antibodies. Figure 9B provides an example of two antibodies whose combination is antagonistic or “indifferent”, as demonstrated in the graph by the measured curve (filled black circles) more closely resembling that of the more active Mab (filled gray circles) than of the theoretically determined curve for the combined antibodies (dashed gray line).

[0032] Figures 9C-9L shows non-competing gD antibodies evaluated for their blocking activity in a split luciferase assay. MC2+MC5 (Figure 9C); MC2+MC3 (Figure 9D); MC2+DL11 (Figure 9E); MC2+1D3 (Figure 9F), MC5+MC23 (Figure 9G); MC5+DL11 (Figure 9H); MC5+1D3 (Figure 9I), MC23+DL11 (Figure 9J); MC23+1D3 (Figure 9K); and DL11 +1D3 (Figure 9L). The results from the first mAb of the pair are depicted with unfilled circles, the results from the second mAb of the pair are depicted with filled gray circles, and the results from the pair of antibodies are depicted in filled black circles. The calculated additive effect is marked by a dashed curve. Page 8 of 242P-636791-PC

[0033] Figure 10. Diagram of the expression and purification of recombinant antibodies. 293T cells were transfected with plasmids encoding for heavy (Hc) and light chains (Lc) to generate monospecific IgG A or IgG B. To generate a BsAb, A / B Hc+Lc for IgG A and Hc+Lc for IgG B were co-transfected. Monospecific antibodies were purified using ProA columns. BsAbs were purified on Nickel columns.

[0034] Figures 11A-11F. Blocking of cell–cell fusion by recombinant antibodies. Figures 11A-11C show the effect of combinations of recombinant Abs (black curves) on cell–cell fusion over a 2 h time course compared to monospecific Abs at the same concentrations: rMC5+rDL11 (Figure 11A); rMC2+rDL11 (Figure 11B); and rDL11+r1D3 (Figure 11C). Figures 11D-11F show comparisons of combinations of recombinant IgGs (black curves) and bispecific antibodies (gray curves) in cell–cell fusion: rMC5+rDL11 (Figure 11D); rMC2+rDL11 (Figure 11E); and rDL11+r1D3 (Figure 11F). Each antibody was used at a concentration of 5 µg / mL, either single or in combination. BsAbs were used at 10 µg / mL. At least three independent experiments were performed, each in duplicate. Representative graphs are shown.

[0035] Figures 12A-12F. Inhibition of virus activity by recombinant antibodies. Effect of MC5 / DL11 (Figure 12A), MC2 / DL11 (Figure 12B) or DL11 / 1D3 (Figure 12C) BsAbs on HSV-2 (333) β-galactosidase reporter virus infection of Vero cells using an entry assay. Virus was incubated with 2-fold dilutions of single IgGs starting at 6.25 µg / mL (single or in combination) or 12.5 µg / mL (BsAbs). Effect of MC5 / DL11 (Figure 12D), MC2 / DL11 (Figure 12E) or DL11 / 1D3 (Figure 12F) BsAbs on HSV-2 infection in a plaque assay. Antibodies were used at 6.25 µg / mL (single or in combination) or 12.5 µg / mL (BsAbs). Activity of each condition was expressed as % of no antibody control. p values of two-tailed Student t test to compare the activity of the combinations (black curves) and BsAbs (gray) are indicated in each graph.

[0036] Figure 13 is a graph depicting the results of comparing the effectiveness of the DL11 antigen binding agent and 1D3 antigen binding agent individually, in combination (DL11+1D3), and as a bispecific DL11 / 1D3 antigen binding agent (bispecific antigen binding agent). A split luciferase assay was used to determine efficacy of the groups on cell-cell fusion, by measuring luminescence (percentage of cells having no antigen binding agent) as a function of time (minutes; min). C10 cells (target cells) were transfected with HVEM and Rluc8 plasmids and B78 cells (effector cells) were transfected with gB, gD, gH, gL, and Rluc8 plasmids and treated with (a) no antigen binding agents, (b) 1D3 antigen binding agents alone, Page 9 of 242P-636791-PC (c) DL11 antigen binding agents alone, (d) a combination of individual DL11 and 1D3 antigen binding agents (DL11+1D3), or (e) the bispecific DL11 / 1D3 antigen binding agent.

[0037] Figures 14A-14B are graphs depicting the results of a penetration assay comparing the effectiveness of the DL11 and 1D3 antigen binding agents individually, in combination, (DL11+1D3), and as a bispecific DL11 / 1D3 antigen binding agent (bispecific antigen binding agent) on virus entry (percentage of cells having no antigen binding agent) as a function of antigen binding agent concentration (micrograms / milliliter; μg / ml). Vero cells were exposed to either HSV-1 (KOS) (Figure 14A) or HSV-2 (333) (Figure 14B). beta-galactosidase (β- galactosidase) reporter viruses were pre-incubated with serial 2-fold dilutions of (a) 1D3 antigen binding agents alone, (b) DL11 antigen binding agents alone, (c) a combination of individual DL11 and 1D3 antigen binding agents (DL11+1D3), or (d) the bispecific DL11 / 1D3 antigen binding agent.

[0038] Figures 15A-15B are graphs depicting the results of a plaque assay comparing the effectiveness of the DL11 and 1D3 antigen binding agents individually, in combination, (DL11+1D3), and as a bispecific DL11 / 1D3 antigen binding agent (bispecific antigen binding agent) on virus entry and spread, by measuring virus neutralization (percentage of plaques having no antigen binding agent) as a function of antigen binding agent concentration (micrograms / milliliter; μg / ml). Vero cells were exposed to 100 plaque forming units (pfu) of either HSV-1 (KOS) (Figure 15A) or HSV-2 (333) (Figure 15B) pre-incubated with serial 2- fold dilutions of (a) 1D3 antigen binding agents alone, (b) DL11 antigen binding agents alone, (c) a combination of individual DL11 and 1D3 antigen binding agents (DL11+1D3), or (d) the bispecific DL11 / 1D3 antigen binding agent.

[0039] Figures 16A-16D depict the effects of full length and single chain DL11 and / or 1D3 antigen binding agents on HSV-2 virus entry. Virus entry was determined by a penetration assay comparing the effectiveness of each individual antigen binding agent (1D3 antigen binding agents alone, DL11 antigen binding agents alone), a combination of the individual antigen binding agents (DL11+1D3), a bispecific antigen binding agent (DL11 / 1D3), a combination of the individual antigen binding agents (DL11+1D3sc), a bispecific antigen binding agent (DL11 / 1D3sc), a combination of the individual antigen binding agents (DL11sc+1D3sc), a bispecific antigen binding agent (DL11sc / 1D3sc) on virus entry as a function of antigen binding agent concentration (micrograms / milliliter; μg / ml). Vero cells were exposed to HSV-2 (333) beta-galactosidase (β-galactosidase) reporter viruses pre-incubated with serial 2-fold dilutions of the indicated antigen binding agents, beginning at 12.5 Page 10 of 242P-636791-PC micrograms / milliliter (μg / ml). Standard deviations from at least three independent experiments are shown. p values of two-tailed Student t test (p values) to compare DL11 and DL11+1D3 are indicated in each graph.

[0040] Figures 17A-17B are schematics depicting the design of a bispecific bicistronic antigen binding agent A and a bicistronic antigen binding agent B (Figure 17A), or bispecific bicistronic antigen binding agent A and a single chain antigen binding agent B (Figure 17B). For bicistronic antigen binding agents (Figure 17A and Figure 17B, left), the heavy chain and the light chain were linked by a P2A peptide that was cleaved post-translationally. In a bicistronic format, both the heavy chain and the light chain can be delivered with a single RNA. For single chain antigen binding agent B (Figure 17B), the variable regions of the heavy chain and the light chain were linked with a GS linker (e.g., (G4S)3) and delivered as a single RNA.

[0041] Figures 17C-17D depicts bispecific antibodies comprising the knob (D399R)-in- hole (K409D) mutations in the mouse IgG2a Fc portion of each antigen binding agent, which favor bispecific formation as shown. Here, Bicistronic A is shown with the knob (D399R) (center), which favors bispecific formation with Bicistronic B with a hole (K409D) (left) or single chain B with a hole (K409D) (right).

[0042] Figures 18A-18B are Western blots showing recombinant antigen binding agents produced in 293T cells transfected with RNAs encoding DL11 antigen binding agents, 1D3 antigen binding agents, a combination of DL11 and 1D3 antigen binding agents, and bispecific antigen binding agent. DL11, 1D3 and 1D3sc immunoglobulins (IgG) were constructed, either as wild-type constructs (Figure 18A) or knob-in-the-hole (KiH) constructs (Figure 18B). Stars indicate bispecific antigen binding agents (bispecific antigen binding agents). Figure 18A shows recombinant antigen binding agents produced in 293T cells transfected with non- mutated DL11; 1D3; 1D3sc; DL11 and 1D3; DL11 and 1D3sc. Figure 18B shows recombinant antigen binding agents produced in 293T cells transfected with knob (D399R)-into-hole (K409D) (KiH) mutated DL11; 1D3; 1D3sc; DL11 and 1D3; DL11 and 1D3sc, as shown in Figure 17D.

[0043] Figures 19A-19B are Western blots demonstrating that increasing the ratio of DL11 to either 1D3 or 1D3sc favors the production of bispecific antigen binding agents in 293T cells. RNAs for DL11, 1D3, and 1D3sc were transfected individually into 293T cells or RNAs in ratios of 1:1, 1:3, or 3:1 DL11 to 1D3 or 1D3sc were transfected into 293T cells. Figure 19A shows recombinant antigen binding agents produced in 293T cells transfected with DL11; 1D3; Page 11 of 242P-636791-PC 1D3sc; DL11 / 1D3 (1:1); DL11 / 1D3 (1:3); DL11 / 1D3 (3:1); DL11 / 1D3sc (1:1); DL11 / 1D3sc (1:3); and DL11 / 1D3sc (3:1). Figure 19B shows recombinant antigen binding agents produced in 293T cells transfected with DL11; 1D3; 1D3sc; DL11 / 1D3 (1:1); DL11 / 1D3 (1:3); DL11 / 1D3 (3:1); DL11 / 1D3cs (1:1); DL11 / 1D3sc (1:3); and DL11 / 1D3sc (3:1); each construct has the knob (D399R)-into-hole (K409D) mutations in the mouse IgG2a Fc, as shown in Figure 17D. The asterisks indicate the bispecific antibody band.

[0044] Figure 20 provides the levels of gD-binding antibodies following inoculation with mRNA-LNPs encoding 1D3 and DL11 antibodies, administered individually, co-formulated, or in bispecific form. Mice were inoculated with 30µg 1D3 IgG bicistronic and single chain Ab with and without knob in hole (KIH) mutations, DL11 IgG bicistronic with and without KIH (knob and hole) mutations, or with ID3 and DL11 with KIH mutations. When administered together, ratios of 1:1, 3:1, and 1:3 of 1D3 to DL11 were tested. Two days post administration, sera was collected and analyzed for binding to viral glycoprotein gD.

[0045] Figures 21A-21B provides the levels of neutralizing antibodies following inoculation with mRNA-LNPs encoding 1D3 and DL11 antibodies, administered individually, co-formulated, or in bispecific form. Mice were inoculated with 30µg 1D3 IgG bicistronic and single chain Ab with and without knob in hole (KIH) mutations DL11 IgG bicistronic with and without KIH mutations, or with ID3 and DL11 with KIH (knob and hole) mutation for bispecific Ab formation. Two days post administration, sera was collected and analyzed for its ability to neutralize HSV-1 (Figure 21A) and HSV-2 (Figure 21B).

[0046] Figure 22 shows the effects of inoculation with mRNA-LNPs encoding 1D3, DL11, MC2, and C226sc individually and 1D3-DL11 and MC2-C226 bispecific antibodies (1:1) on body mass after HSV-1 infection. mRNA constructs were bicistronic did not contain KIH mutations. Mice were inoculated with a total of 30µg and were intranasally administered 5X105PFU of HSV-1 strain H129 one day later. Weight was monitored for up to 15 days or until humane euthanization was needed.

[0047] Figure 23 demonstrates the effects of inoculation with mRNA-LNPs encoding 1D3, DL11, MC2, and C226sc individually and 1D3-DL11 and MC2-C226 bispecific antibodies (1:1) on survival after HSV-1 infection. mRNA constructs were bicistronic did not contain KIH mutations. Mice were inoculated with a total of 30µg mRNA and were intranasally administered 5X105PFU of HSV-1 strain H129 one day later. Page 12 of 242P-636791-PC

[0048] Figure 24 presents neurological disease in HSV-1-infected subjects inoculated with control mRNA-LNPs or mRNA-LNPs encoding 1D3, DL11, MC2, and C226sc antibodies individually or 1D3-DL11 and MC2-C226 bispecific antibodies (1:1) prior to HSV-1 infection. Mice were inoculated with a total of 30µg and were intranasally administered 5X105PFU of HSV-1 strain H129 one day later.

[0049] Figures 25A-25C shows HSV-1 viral titer in the olfactory bulbs (Figure 25A), trigeminal ganglia (Figure 25B), and the brains (Figure 25C) of HSV-1-infected mice inoculated with control mRNA-LNPs or mRNA-LNPs encoding 1D3, DL11, MC2, and C226sc antibodies individually or 1D3-DL11 and MC2-C226 bispecific antibodies (1:1) one day prior to HSV-1 infection. Mice were inoculated with a total of 30µg and were administered 5X105PFU of HSV-1 strain H129 intranasally one day later. The olfactory bulbs were harvested either at the end of the study or at the time of humane euthanasia. Cells were stained with crystal violet and the number of viral plaques forming units (PFU) were counted.

[0050] Figures 26A-26C shows HSV-1 viral titer in the olfactory bulbs (Figure 26A), trigeminal ganglia (Figure 26B), and the brains (Figure 26C) of HSV-1-infected mice inoculated with control mRNA-LNPs or mRNA-LNPs encoding 1D3, DL11, MC2, and C226sc antibodies individually or 1D3-DL11 and MC2-C226 bispecific antibodies (1:1) one day prior to HSV-1 infection. Mice were inoculated with a total of 30µg and were administered 5X105PFU of HSV-1 strain H129 intranasally one day later. The olfactory bulbs were harvested either at the end of the study or at the time of humane euthanasia. HSV-1 genomic copies were normalized to 105copies of mouse adipsin gene.

[0051] Figures 27A-27C shows HSV-1 gD (Figure 27A), HSV-2 gD (Figure 27B), and HSV-1 gB (Figure 27C) binding antibody responses in HSV-1-infected mice inoculated with control mRNA-LNPs or mRNA-LNPs encoding 1D3, DL11, MC2, and C226sc antibodies individually or 1D3-DL11 and MC2-C226 bispecific antibodies (1:1) one day prior to HSV-1 infection. Mice were inoculated with a total of 30µg mRNA and were administered 5X105PFU of HSV-1 strain H129 intranasally one day later.

[0052] Figures 28A-28B shows serum neutralizing antibody responses to HSV-1 (Figure 28A) and HSV-2 (Figure 28B) in HSV-1-infected mice inoculated with control mRNA-LNPs or mRNA-LNPs encoding 1D3, DL11, MC2, and C226sc antibodies individually or 1D3-DL11 and MC2-C226 bispecific antibodies (1:1) one day prior to HSV-1 infection. Mice were Page 13 of 242P-636791-PC inoculated with a total of 30µg mRNA and were administered 5X105PFU of HSV-1 strain H129 intranasally one day later. DETAILED DESCRIPTION

[0053] Provided herein are combinations and compositions for the prevention and treatment of genital herpes, comprising antigen binding agents directed to herpes simplex virus (HSV) glycoproteins, including those involved in virus entry and immune evasion, ribonucleic acids (RNAs) encoding these antigen binding agents, and methods of use thereof. Additionally, the present disclosure provides compositions comprising anti-glycoprotein D (gD) antigen binding agents or RNA encoding anti-gD antigen binding agents, anti-glycoprotein B (gB) antigen binding agents or RNA encoding anti-gB antigen binding agents, or a combination thereof and related methods of treating or preventing an HSV infection. Finally, the present disclosure provides compositions comprising bispecific antibodies that bind to one or more HSV glycoproteins, including those involved in virus entry and immune evasion, ribonucleic acids (RNAs) encoding these antigen binding agents, and methods of use thereof.

[0054] In some embodiments, the present disclosure provides an antigen binding agent (e.g., an antibody, alternate format antibody, or antigen binding fragment) that targets herpes simplex virus (HSV). In some embodiments, an antigen binding agent targets HSV glycoprotein D (gD) (e.g., HSV-1, HSV-2, or a combination thereof). In other embodiments, an antigen binding agent as described herein targets HSV glycoprotein B (gB) (e.g., HSV-1, HSV-2, or a combination thereof).

[0055] In some embodiments, a composition provided herein comprises or delivers an antigen binding agent as provided herein.

[0056] In some embodiments, an anti-gD antigen binding agent comprises a single-chain Fv (scFv). In some embodiments, an anti-gD antigen binding agent comprises two single-chain Fvs (scFvs). In some embodiments, two scFvs that are the same form a single monospecific antibody agent. In some embodiments, two different scFvs together form a single bispecific antibody agent.

[0057] In some embodiments, an anti-gD antigen binding agent comprises an antibody fragment and a single-chain Fv (scFv). In some embodiments, an anti-gD antigen binding agent Page 14 of 242P-636791-PC comprises an antibody fragment and a single-chain Fv (scFv). In some embodiments, an antibody fragment and a scFv together form a single bispecific antigen binding agent.

[0058] In some embodiments, an antigen binding agent is or comprises a bicistronic antigen binding agent, a single-chain variable fragment (scFv), or a combination thereof.

[0059] It will be appreciated that the term “modification” can encompass an amino acid modification such as an amino acid substitution, insertion, and / or deletion in a polypeptide sequence. Definitions

[0060] So that the present disclosure may be more readily understood, certain terms are defined below. Additional definitions for the following terms and other terms are set forth throughout the specification.

[0061] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art.

[0062] A, an, and the: As used herein, the singular form "a", "an" and "the" include plural references unless the context clearly dictates otherwise. For example, the term "a molecule" also includes a plurality of molecules.

[0063] About: The term “about”, when used herein in reference to a value, refers to a value that is similar, in context to the referenced value. In general, those skilled in the art, familiar with the context, will appreciate the relevant degree of variance encompassed by “about” in that context. For example, in some embodiments, the term “about” may encompass a range of values that within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less of the referred value.

[0064] Agent: As used herein, the term “agent,” may refer to a physical entity. In some embodiments, an agent may be characterized by a particular feature and / or effect. For example, as used herein, the term “therapeutic agent” refers to a physical entity that has a therapeutic effect and / or elicits a desired biological and / or pharmacological effect. In some embodiments, an agent may be a compound, molecule, or entity of any chemical class including, for example, a small molecule, polypeptide, nucleic acid, saccharide, lipid, metal, or a combination or complex thereof. Page 15 of 242P-636791-PC

[0065] Amino acid: In its broadest sense, as used herein, the term “amino acid” refers to a compound and / or substance that can be, is, or has been incorporated into a polypeptide chain, e.g., through formation of one or more peptide bonds. In some embodiments, an amino acid has the general structure H2N–C(H)(R)–COOH. In some embodiments, an amino acid is a naturally occurring amino acid. In some embodiments, an amino acid is a non-natural amino acid; in some embodiments, an amino acid is a D-amino acid; in some embodiments, an amino acid is an L-amino acid. “Standard amino acid” refers to any of the twenty standard L-amino acids commonly found in naturally occurring peptides. “Nonstandard amino acid” refers to any amino acid, other than the standard amino acids, regardless of whether it is prepared synthetically or obtained from a natural source. In some embodiments, an amino acid, including a carboxy- and / or amino-terminal amino acid in a polypeptide, can contain a structural modification as compared with the general structure above. For example, in some embodiments, an amino acid may be modified by methylation, amidation, acetylation, pegylation, glycosylation, phosphorylation, and / or substitution (e.g., of the amino group, the carboxylic acid group, one or more protons, and / or the hydroxyl group) as compared with the general structure. In some embodiments, such modification may, for example, alter the circulating half-life of a polypeptide containing the modified amino acid as compared with one containing an otherwise identical unmodified amino acid. In some embodiments, such modification does not significantly alter a relevant activity of a polypeptide containing the modified amino acid, as compared with one containing an otherwise identical unmodified amino acid. As will be clear from context, in some embodiments, the term “amino acid” may be used to refer to a free amino acid; in some embodiments it may be used to refer to an amino acid residue of a polypeptide.

[0066] Antibody: As used herein, the term “antibody” refers to an immunoglobulin molecule, or fragment thereof, that binds specifically to an epitope (e.g., of an antigen) having two heavy chains and two light chains, each of which includes a variable domain and a constant region. In some embodiments, an antigen binding agent may include one or more constant region sequences that are characteristic of mouse, rabbit, primate, or human antibodies. In some embodiments, an antigen binding agent may include one or more sequence elements that are humanized, primatized, chimeric, etc. In some embodiments, the term “antigen binding agent” is used to refer to one or more of the art-known or developed constructs or formats for utilizing antibody structural and functional features in alternative presentation. For example, in some embodiments, an antigen biding agent utilized in accordance with the present disclosure is in a Page 16 of 242P-636791-PC format selected from, but not limited to, intact IgA, IgG, IgE or IgM antibodies; bi- or multi- specific antibodies (e.g., Zybodies®, etc.); CrossMabs (e.g., CrossMabCH1-CL; CrossMabCH1-CLcv; bispecific CrossMabCH1-CL with knob-in-hole); antibody fragments such as Fab fragments, Fab' fragments, F(ab')2 fragments, Fd' fragments, Fd fragments, and isolated complementarity determining regions (CDRs) or sets thereof; single chain Fvs (scFvs); scFv-Fc fusions; polypeptide-Fc fusions; single domain antibodies (e.g., shark single domain antibodies such as IgNAR or fragments thereof); cameloid antibodies; masked antibodies (e.g., Probodies®); Small Modular ImmunoPharmaceuticals (“SMIPsTM”); single chain or Tandem diabodies (TandAb®); VHHs; Anticalins®; Nanobodies® minibodies; BiTE®s; ankyrin repeat proteins or DARPINs®; Avimers®; DARTs; TCR-like antibodies; Adnectins®; Affilins®; Trans-bodies®; Affibodies®; TrimerX®; MicroProteins; Fynomers®, Centyrins®; and KALBITOR®s.

[0067] Antigen: Those skilled in the art, reading the present specification, will appreciate that the term “antigen” refers to a molecule that is recognized by the immune system, e.g., in particular embodiments the adaptive immune system, such that it elicits an antigen-specific immune response. In some embodiments, an antigen-specific immune response may be or comprise generation of antigen binding agents and / or antigen-specific T cells. In some embodiments, an antigen is a peptide or polypeptide that comprises at least one epitope against which an immune response can be generated. In some embodiments, an antigen is presented by cells of the immune system such as antigen presenting cells like dendritic cells or macrophages. In some embodiments, an antigen or a processed product thereof such as a T- cell epitope is bound by a T- or B-cell receptor, or by an immunoglobulin molecule such as an antigen binding agent. Accordingly, an antigen or a processed product thereof may react specifically with antigen binding agents or T lymphocytes (T cells). In some embodiments, an antigen is a parasitic antigen. In accordance with the present disclosure, in some embodiments, an antigen may be delivered by RNA molecules as provided herein. In some embodiments, a peptide or polypeptide antigen can be 2-100 amino acids, including for example, 5 amino acids, 10 amino acids, 15 amino acids, 20 amino acids, 25 amino acids, 30 amino acids, 35 amino acids, 40 amino acids, 45 amino acids, or 50 amino acids in length. In some embodiments, a peptide or polypeptide antigen can be greater than 50 amino acids. In some embodiments, a peptide or polypeptide antigen can be greater than 100 amino acids. In some embodiments, an antigen is recognized by an immune effector cell. In some embodiments, an antigen if recognized by an immune effector cell is able to induce in the presence of appropriate co- Page 17 of 242P-636791-PC stimulatory signals, stimulation, priming and / or expansion of the immune effector cell carrying an antigen receptor recognizing the antigen. In the context of the embodiments of the present disclosure, in some embodiments, an antigen can be presented or present on the surface of a cell, e.g., an antigen presenting cell. In some embodiments, an antigen is presented by a diseased cell such as a virus-infected cell. In some embodiments, an antigen receptor is a TCR which binds to an epitope of an antigen presented in the context of MHC. In some embodiments, binding of a TCR when expressed by T cells and / or present on T cells to an antigen presented by cells such as antigen presenting cells results in stimulation, priming and / or expansion of said T cells. In some embodiments, binding of a TCR when expressed by T cells and / or present on T cells to an antigen presented on diseased cells results in cytolysis and / or apoptosis of the diseased cells, wherein said T cells preferably release cytotoxic factors, e.g. perforins and granzymes.

[0068] Antigen binding agent: As used herein, an “antigen binding agent,” an “antigen- binding fragment,” an “antigen-binding site,” or “affinity reagent,” is a molecule that binds to an antigen or receptor or another molecule. In some embodiments, the “antigen binding agent” refers to any polypeptide or polypeptide complex that includes immunoglobulin structural elements sufficient to confer specific binding to a particular antigen. Exemplary antigen binding agents include but are not limited to monoclonal antibodies or polyclonal antibodies. In other embodiments, an antigen binding agent may be an antibody, alternate format antibody, or antigen binding fragment.

[0069] In some embodiments, the term “antigen binding agent” encompasses the structure that constitutes the natural biological form of an antigen binding agent. In most mammals, including humans, and mice, this form is a tetramer and consists of two identical pairs of two immunoglobulin chains, each pair having one light and one heavy chain, each light chain comprising immunoglobulin domains VL and CL, and each heavy chain comprising immunoglobulin domains VH, C-gamma-1 (Cγ1), C-gamma-2 (Cγ2), and C-gamma-3 (Cγ3). In each pair, the light and heavy chain variable regions (VL and VH) are together responsible for binding to an antigen, and the constant regions (CL, Cγ1, Cγ2, and Cγ3, particularly Cγ2, and Cγ3) are responsible for antigen binding agent effector functions. In some mammals, for example in camels and llamas, full-length antigen binding agents may consist of only two heavy chains, each heavy chain comprising immunoglobulin domains VH, Cγ2, and Cγ3. By “immunoglobulin (Ig)” herein is meant a protein consisting of one or more polypeptides substantially encoded by immunoglobulin genes. Immunoglobulins include but are not limited Page 18 of 242P-636791-PC to antigen binding agents. Immunoglobulins may have a number of structural forms, including but not limited to full-length antigen binding agents, antigen binding agent fragments, and individual immunoglobulin domains including but not limited to VH, Cγ1, Cγ2, Cγ3, VL, and CL.

[0070] The term “antigen binding agent” is meant to include full-length antigen binding agents and may refer to a natural antigen binding agent from any organism, an engineered antigen binding agent, or an antigen binding agent generated recombinantly for experimental, therapeutic, or other purposes as further defined below. Furthermore, full-length antigen binding agents comprise conjugates as provided and exemplified herein. As used herein, the term “antigen binding agent” comprises monoclonal antigen binding agents (mAb, moAb, Mab) and polyclonal antigen binding agents. Antigen binding agents can be antagonists, agonists, neutralizing, inhibitory, or stimulatory. Specifically included within the definition of “antigen binding agent” are full-length antigen binding agents provided and exemplified herein. By “full length antigen binding agent” herein is meant the structure that constitutes the natural biological form of an antigen binding agent, including variable and constant regions.

[0071] A “monoclonal antigen binding agent” (mAb, moAb, Mab) is an antigen binding agent made by cloning a unique white blood cell. All subsequent antigen binding agents derived this way trace back to a unique parent cell. Monoclonal antigen binding agents can have monovalent affinity, binding only to the same epitope (the part of an antigen that is recognized by the antigen binding agent). In contrast, “polyclonal antigen binding agents” bind to multiple epitopes and are usually made by several different antigen binding agent secreting plasma cell lineages. “Bispecific monoclonal antigen binding agents” can also be engineered, by increasing the therapeutic targets of one monoclonal antigen binding agent to two epitopes.

[0072] Depending on the amino acid sequence of the constant domain of their heavy chains, intact antigen binding agents can be assigned to different “classes”. There are five-major classes (isotypes) of intact antigen binding agents: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into “subclasses”, e.g., IgG1, IgG2, IgG3, IgG4, IgA, and IgA2. The heavy-chain constant domains that correspond to the different classes of antigen binding agents are called alpha, delta, epsilon, gamma, and mu, respectively. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are known to one skilled in the art. Page 19 of 242P-636791-PC

[0073] Associated: Two events or entities are “associated” with one another, as that term is used herein, if the presence, level, degree, type and / or form of one is correlated with that of the other. For example, a particular entity (e.g., polypeptide, genetic signature, metabolite, microbe, etc.) is considered to be associated with a particular disease, disorder, or condition, if its presence, level and / or form correlates with incidence of, susceptibility to, severity of, stage of, etc. the disease, disorder, or condition (e.g., across a relevant population). In some embodiments, two or more entities are physically “associated” with one another if they interact, directly or indirectly, so that they are and / or remain in physical proximity with one another. In some embodiments, two or more entities that are physically associated with one another are covalently linked to one another; in some embodiments, two or more entities that are physically associated with one another are not covalently linked to one another but are non-covalently associated, for example by means of hydrogen bonds, van der Waals interaction, hydrophobic interactions, magnetism, and combinations thereof.

[0074] Binding: Those skilled in the art, reading the present specification, will appreciate that the term “binding” typically refers to a non-covalent association between or among entities or moieties. In some embodiments, binding data are expressed in terms of “IC50”. As is understood in the art, IC50 is the concentration of an assessed agent in a binding assay at which 50% inhibition of binding of reference agent known to bind the relevant binding partner is observed. In some embodiments, assays are run under conditions in which the assays are run (e.g., limiting binding target and reference concentrations), these values approximate KDvalues. Assays for determining binding are well known in the art and are provided in detail, for example, in PCT publications WO 94 / 20127 and WO 94 / 03205, and other publications such Sidney et al., Current Protocols in Immunology 18.3.1 (1998); Sidney, et al., J. Immunol. 154:247 (1995); and Sette, et al., Mol. Immunol.31:813 (1994). Alternatively, binding can be expressed relative to binding by a reference standard peptide. For example, can be based on its IC50, relative to the IC50of a reference standard peptide. Binding can also be determined using other assay systems including those using: live cells (e.g., Ceppellini et al., Nature 339:392 (1989); Christnick et al., Nature 352:67 (1991); Busch et al., Int. Immunol. 2:443 (1990); Hill et al., J. Immunol. 147:189 (1991); del Guercio et al., J. Immunol. 154:685 (1995)), cell free systems using detergent lysates (e.g., Cerundolo et al., J. Immunol 21:2069 (1991)), immobilized purified MHC (e.g., Hill et al., J. Immunol. 152, 2890 (1994); Marshall et al., J. Immunol. 152:4946 (1994)), ELISA systems (e.g., Reay et al., EMBO J. 11:2829 (1992)), surface plasmon resonance (e.g., Khilko et al., J. Biol. Chem. 268:15425 (1993)); high flux Page 20 of 242P-636791-PC soluble phase assays (Hammer et al., J. Exp. Med.180:2353 (1994)), and measurement of class I MHC stabilization or assembly (e.g., Ljunggren et al., Nature 346:476 (1990); Schumacher et al., Cell 62:563 (1990); Townsend et al., Cell 62:285 (1990); Parker et al., J. Immunol. 149:1896 (1992)).

[0075] Cap: As used herein, the term “cap” refers to a structure comprising or essentially consisting of a nucleoside-5 '-triphosphate that is typically joined to a 5'-end of an uncapped RNA (e.g., an uncapped RNA having a 5'- diphosphate). In some embodiments, a cap is or comprises a guanine nucleotide. In some embodiments, a cap is or comprises a naturally- occurring RNA 5’ cap, including, e.g., but not limited to a 7- methylguanosine cap, which has a structure designated as “m7G.” In some embodiments, a cap is or comprises a synthetic cap analog that resembles an RNA cap structure and possesses the ability to stabilize RNA if attached thereto, including, e.g., but not limited to anti-reverse cap analogs (ARCAs) known in the art). Those skilled in the art will appreciate that methods for joining a cap to a 5’ end of an RNA are known in the art. For example, in some embodiments, a capped RNA may be obtained by in vitro capping of RNA that has a 5' triphosphate group or RNA that has a 5' diphosphate group with a capping enzyme system (including, e.g., but not limited to vaccinia capping enzyme system or Saccharomyces cerevisiae capping enzyme system). Alternatively, a capped RNA can be obtained by in vitro transcription (IVT) of a single-stranded DNA template in the presence of a dinucleotide or trinucleotide cap analog.

[0076] Cell-mediated immunity: “Cell-mediated immunity,” “cellular immunity,” “cellular immune response,” or similar terms are meant to include a cellular response directed to cells characterized by expression of an antigen, in particular characterized by presentation of an antigen with class I or class II MHC. A cellular response relates to immune effector cells, in particular to T cells or T lymphocytes which act as either “helpers” or “killers.” The helper T cells (also termed CD4+T cells or CD4 T cells) play a central role by regulating the immune response and the killer cells (also termed cytotoxic T cells, cytolytic T cells, CD8+T cells, CD8 T cells, or CTLs) kill diseased cells such as virus-infected cells, preventing the production of more diseased cells.

[0077] Co-administration: As used herein, the term “co-administration” refers to use of a composition (e.g., a pharmaceutical composition) described herein and one or more additional therapeutic agents. In some embodiments, one or more additional therapeutic agents comprises at least one polyribonucleotide encoding another antigen binding agent (e.g., an anti-HSV (gD, gB and / or gD / gB)). The combined use of a composition (e.g., a pharmaceutical composition) Page 21 of 242P-636791-PC described herein and an additional therapeutic agent may be performed concurrently or separately (e.g., sequentially in any order). In some embodiments, a composition (e.g., a pharmaceutical composition) described herein and an additional therapeutic agent may be combined in one pharmaceutically acceptable excipient, or they may be placed in separate excipient and delivered to a target cell or administered to a subject at different times. Each of these situations is contemplated as falling within the meaning of “co-administration” or “combination,” provided that a composition (e.g., a pharmaceutical composition) described herein and an additional therapeutic agent are delivered or administered sufficiently close in time that there is at least some temporal overlap in biological effect(s) generated by each on a target cell or a subject being treated.

[0078] Codon-optimized: As used herein, the term “codon-optimized” refers to alteration of codons in a coding region of a nucleic acid molecule to reflect the typical codon usage of a host organism without preferably altering the amino acid sequence encoded by the nucleic acid molecule. Within the context of the present disclosure, in some embodiments coding regions are codon-optimized for optimal expression in a subject to be treated using the RNA molecules provided herein. In some embodiments, codon-optimization may be performed such that codons for which frequently occurring tRNAs are available are inserted in place of “rare codons.” In some embodiments, codon-optimization may include increasing guanosine / cytosine (G / C) content of a coding region of RNA provided herein as compared to the G / C content of the corresponding coding sequence of a wild-type RNA, wherein the amino acid sequence encoded by the RNA is preferably not modified compared to the amino acid sequence.

[0079] Combination therapy: As used herein, the term “combination therapy” refers to those situations in which a subject is simultaneously exposed to two or more therapeutic regimens (e.g., two or more therapeutic agents (e.g., two or more antigen binding agents)). In some embodiments, the two or more regimens may be administered simultaneously; in some embodiments, such regimens may be administered sequentially (e.g., all “doses” of a first regimen are administered prior to administration of any doses of a second regimen); in some embodiments, such agents are administered in overlapping dosing regimens. In some embodiments, administration of combination therapy may involve administration of one or more agent(s) or modality(ies) to a subject receiving the other agent(s) or modality(ies) in the combination. For clarity, combination therapy does not require that individual agents be administered together in a single composition (or even necessarily at the same time), although Page 22 of 242P-636791-PC in some embodiments, two or more agents, or active moieties thereof, may be administered together in a combination composition. In some embodiments, a combination therapy comprises polyribonucleotides encoding two or more antigen binding agents.

[0080] Comparable: As used herein, the term “comparable” refers to two or more agents, entities, situations, sets of conditions, etc., that may not be identical to one another but that are sufficiently similar to permit comparison there between so that one skilled in the art will appreciate that conclusions may reasonably be drawn based on differences or similarities observed. In some embodiments, comparable sets of conditions, circumstances, individuals, or populations are characterized by a plurality of substantially identical features and one or a small number of varied features. Those of ordinary skill in the art will understand, in context, what degree of identity is required in any given circumstance for two or more such agents, entities, situations, sets of conditions, etc. to be considered comparable. For example, those of ordinary skill in the art will appreciate that sets of circumstances, individuals, or populations are comparable to one another when characterized by a sufficient number and type of substantially identical features to warrant a reasonable conclusion that differences in results obtained or phenomena observed under or with different sets of circumstances, individuals, or populations are caused by or indicative of the variation in those features that are varied.

[0081] "Comprises", "comprising", "includes", "including", “having” The terms "comprises", "comprising", "includes", "including", “having” and their conjugates encompass "including but not limited to".

[0082] Consisting of: The term “consisting of” means “including and limited to”. “Consisting of” shall thus mean excluding more than traces of other elements. The skilled artisan would appreciate that while, in some embodiments the term “comprising” is used, such a term may be replaced by the term “consisting of”, wherein such a replacement would narrow the scope of inclusion of elements not specifically recited.

[0083] Consisting essentially of: As used herein, the term “consisting essentially of” means that consisting largely, but not necessarily entirely, of a recited element. The term "consisting essentially of" means that the composition, method or structure may include additional ingredients, steps and / or parts, but only if the additional ingredients, steps and / or parts do not materially alter the basic and novel characteristics of the claimed composition, method or structure. Page 23 of 242P-636791-PC

[0084] Corresponding to: As used herein, the term “corresponding to” refers to a relationship between two or more entities. For example, the term “corresponding to” may be used to designate the position / identity of a structural element in a compound or composition relative to another compound or composition (e.g., to an appropriate reference compound or composition). For example, in some embodiments, a monomeric residue in a polymer (e.g., an amino acid residue in a polypeptide or a nucleic acid residue in a polynucleotide) may be identified as “corresponding to” a residue in an appropriate reference polymer. For example, those of ordinary skill will appreciate that, for purposes of simplicity, residues in a polypeptide are often designated using a canonical numbering system based on a reference related polypeptide, so that an amino acid “corresponding to” a residue at position 190, for example, need not actually be the 190th amino acid in a particular amino acid chain but rather corresponds to the residue found at 190 in the reference polypeptide; those of ordinary skill in the art readily appreciate how to identify “corresponding” amino acids. For example, those skilled in the art will be aware of various sequence alignment strategies, including software programs such as, for example, BLAST, CS-BLAST, CUSASW++, DIAMOND, FASTA, GGSEARCH / GLSEARCH, Genoogle, HMMER, HHpred / HHsearch, IDF, Infernal, KLAST, USEARCH, parasail, PSI-BLAST, PSI-Search, ScalaBLAST, Sequilab, SAM, SSEARCH, SWAPHI, SWAPHI-LS, SWIMM, or SWIPE that can be utilized, for example, to identify “corresponding” residues in polypeptides and / or nucleic acids in accordance with the present disclosure. Those of skill in the art will also appreciate that, in some instances, the term “corresponding to” may be used to describe an event or entity that shares a relevant similarity with another event or entity (e.g., an appropriate reference event or entity). To give but one example, a gene or protein in one organism may be described as “corresponding to” a gene or protein from another organism in order to indicate, in some embodiments, that it plays an analogous role or performs an analogous function and / or that it shows a particular degree of sequence identity or homology, or shares a particular characteristic sequence element.

[0085] Derived: In the context of an amino acid sequence (peptide or polypeptide) “derived from” a designated amino acid sequence (peptide or polypeptide), it refers to a structural analogue of a designated amino acid sequence. In some embodiments, an amino acid sequence which is derived from a particular amino acid sequence has an amino acid sequence that is identical, essentially identical or homologous to that particular sequence or a fragment thereof. Amino acid sequences derived from a particular amino acid sequence may be variants of that particular sequence or a fragment thereof. For example, antigen binding agents utilized Page 24 of 242P-636791-PC according to the present disclosure may include amino acid sequences (e.g., CDRs, variable domains, constant regions, etc.) derived from other antibodies, e.g., naturally produced antibodies.

[0086] Designed: As used herein, the term “designed” refers to an agent (i) whose structure is or was selected by the hand of man; (ii) that is produced by a process requiring the hand of man; and / or (iii) that is distinct from natural substances and other known agents.

[0087] Detecting: The term “detecting” is used broadly herein to include appropriate means of determining the presence or absence of an entity of interest or any form of measurement of an entity of interest in a sample. Thus, “detecting” may include determining, measuring, assessing, or assaying the presence or absence, level, amount, and / or location of an entity of interest. Quantitative and qualitative determinations, measurements or assessments are included, including semi-quantitative. Such determinations, measurements or assessments may be relative, for example when an entity of interest is being detected relative to a control reference, or absolute. As such, the term “quantifying” when used in the context of quantifying an entity of interest can refer to absolute or to relative quantification. Absolute quantification may be accomplished by correlating a detected level of an entity of interest to known control standards (e.g., through generation of a standard curve). Alternatively, relative quantification can be accomplished by comparison of detected levels or amounts between two or more different entities of interest to provide a relative quantification of each of the two or more different entities of interest, i.e., relative to each other.

[0088] Dosing regimen: Those skilled in the art will appreciate that the term “dosing regimen” may be used to refer to a set of unit doses (typically more than one) that are administered individually to a subject, typically separated by periods of time. In some embodiments, a given therapeutic agent has a recommended dosing regimen, which may involve one or more doses. In some embodiments, a dosing regimen comprises a plurality of doses each of which is separated in time from other doses. In some embodiments, individual doses are separated from one another by a time period of the same length; in some embodiments, a dosing regimen comprises a plurality of doses and at least two different time periods separating individual doses. In some embodiments, all doses within a dosing regimen are of the same unit dose amount. In some embodiments, different doses within a dosing regimen are of different amounts. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount different from the first dose amount. In some embodiments, a dosing regimen comprises a first Page 25 of 242P-636791-PC dose in a first dose amount, followed by one or more additional doses in a second dose amount same as the first dose amount. In some embodiments, a dosing regimen is correlated with a desired or beneficial outcome when administered across a relevant population (i.e., is a therapeutic dosing regimen).

[0089] Encode: As used herein, the term “encode” or “encoding” refers to sequence information of a first molecule that guides production of a second molecule having a defined sequence of nucleotides (e.g., a polyribonucleotide) or a defined sequence of amino acids. For example, a DNA molecule can encode an RNA molecule (e.g., by a transcription process that includes a DNA-dependent RNA polymerase enzyme). An RNA molecule can encode a polypeptide (e.g., by a translation process). Thus, a gene, a cDNA, or an RNA molecule encodes a polypeptide if transcription and translation of RNA corresponding to that gene produces the polypeptide in a cell or other biological system. In some embodiments, a coding region of a polyribonucleotide encoding a target antigen refers to a coding strand, the nucleotide sequence of which is identical to the polyribonucleotide sequence of such a target antigen. In some embodiments, a coding region of a polyribonucleotide encoding a target antigen refers to a non-coding strand of such a target antigen, which may be used as a template for transcription of a gene or cDNA.

[0090] Encoding: As used herein, “encoding” refers to a polyribonucleotide that comprises sequence that encodes a protein of interest, or a fragment thereof. In some embodiments, a polyribonucleotide comprises a protein coding sequence that encodes a protein of interest, or a fragment thereof. In some embodiments, one or more other proteins, or a fragment thereof is also encoded. In some embodiments, a protein of interest, or a fragment thereof, is the only protein encoded. “Encoding” refers, in some embodiments, to an RNA that contains a gene that encodes the protein of interest. In other embodiments, RNA comprises a protein coding sequence that encodes the protein of interest. In other embodiments, one or more other proteins is also encoded. In other embodiments, a protein of interest is the only protein encoded.

[0091] Engineered: In general, the term “engineered” refers to the aspect of having been manipulated by the hand of man. For example, a polynucleotide is considered to be “engineered” when two or more sequences that are not linked together in that order in nature are manipulated by the hand of man to be directly linked to one another in the engineered polynucleotide and / or when a particular residue in a polynucleotide is non-naturally occurring and / or is caused through action of the hand of man to be linked with an entity or moiety with which it is not linked in nature. Page 26 of 242P-636791-PC

[0092] Epitope: The term “epitope” as used herein refers to a region of the antigen that binds to the antigen binding agent. It is the region of an antigen recognized by a first antigen binding agent wherein the binding of the first antigen binding agent to the region prevents binding of a second antigen binding agent or other bivalent molecule to the region. The region encompasses a particular core sequence or sequences selectively recognized by a class of antigen binding agents. In general, epitopes are comprised by local surface structures that can be formed by contiguous or noncontiguous amino acid sequences. In some embodiments, the term “epitope” refers to a moiety that is specifically recognized by an immunoglobulin (e.g., antibody or receptor) binding component. For example, an epitope may be recognized by a T cell, a B cell, or an antibody. In some embodiments, an epitope is comprised of a plurality of chemical atoms or groups on an antigen. In some embodiments, such chemical atoms or groups are surface- exposed when the antigen adopts a relevant three-dimensional conformation. In some embodiments, such chemical atoms or groups are physically near to each other in space when the antigen adopts such a conformation. In some embodiments, at least some such chemical atoms are groups are physically separated from one another when the antigen adopts an alternative conformation (e.g., is linearized). Accordingly, in some embodiments, an epitope of an antigen may include a continuous or discontinuous portion of the antigen. In some embodiments, an epitope is or comprises a T cell epitope. In some embodiments, an epitope may have a length of about 5 to about 30 amino acids, or about 10 to about 25 amino acids, or about 5 to about 15 amino acids, or about 5 to 12 amino acids, or about 6 to about 9 amino acids.

[0093] Essentially free of: The phrase "essentially free of" is used to indicate the indicated component, if present, is present in an amount that does not contribute, or contributes only in a de minimus fashion, to the properties of the composition. In various embodiments, where a composition is essentially free of a particular component, the component is present in less than a functional amount. In various embodiments, the component may be present in trace amounts. Particular limits will vary depending on the nature of the component, but may be, for example, selected from less than 10% by weight, less than 9% by weight, less than 8% by weight, less than 7% by weight, less than 6% by weight, less than 5% by weight, less than 4% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, or less than 0.5% by weight. Unless indicated otherwise, percentage (%) of ingredients refer to total % by weight.

[0094] Expression: As used herein, the term “expression” of a nucleic acid sequence refers to the generation of a gene product from the nucleic acid sequence. In some embodiments, a Page 27 of 242P-636791-PC gene product can be a transcript, e.g., a polyribonucleotide as provided herein. In some embodiments, a gene product can be a polypeptide. In some embodiments, expression of a nucleic acid sequence involves one or more of the following: (1) production of an RNA template from a DNA sequence (e.g., by transcription); (2) processing of an RNA transcript (e.g., by splicing, editing, etc.); (3) translation of an RNA into a polypeptide or protein; and / or (4) post-translational modification of a polypeptide or protein.

[0095] Five prime untranslated region: As used herein, the terms “five prime untranslated region” or “5' UTR” refer to a sequence of an RNA molecule between a transcription start site and a start codon of a coding region of an RNA. In some embodiments, “5’ UTR” refers to a sequence of an RNA molecule that begins at a transcription start site and ends one nucleotide (nt) before a start codon (usually AUG) of a coding region of an RNA molecule, e.g., in its natural context.

[0096] Fragment: The term "fragment" as used herein refers to any portion of the full-length amino acid sequence of protein of a polypeptide of the disclosure which has less amino acids than the full-length amino acid sequence of a polypeptide of the disclosure. The fragment may or may not possess a functional activity of such polypeptides.

[0097] Homology: As used herein, the term "homology" refers to the similarity between two or more polynucleotide or polypeptide sequences. This similarity is often measured by comparing nucleotide sequences using algorithms such as BLAST (Basic Local Alignment Search Tool) or sequence alignment methods like Needleman-Wunsch or Smith-Waterman. Thus, at least 80% homology implies that when the two sequences (DNA, RNA, or protein) are aligned and compared by any of those methods, at least 80% of their positions exhibit identical or similar nucleotides or amino acids. In some embodiments, the term “homology” or “homolog” refers to the overall relatedness between polynucleotide molecules (e.g., DNA molecules and / or RNA molecules) and / or between polypeptide molecules. In some embodiments, polynucleotide molecules (e.g., DNA molecules and / or RNA molecules) and / or polypeptide molecules are considered to be “homologous” to one another if their sequences are at least 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical. In some embodiments, polynucleotide molecules (e.g., DNA molecules and / or RNA molecules) and / or polypeptide molecules are considered to be “homologous” to one another if their sequences are at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% similar (e.g., containing residues with related chemical properties at corresponding positions). For example, as is well known by Page 28 of 242P-636791-PC those of ordinary skill in the art, certain amino acids are typically classified as similar to one another as “hydrophobic” or “hydrophilic” amino acids, and / or as having “polar” or “non- polar” side chains. Substitution of one amino acid for another of the same type may often be considered a “homologous” substitution.

[0098] Homolog: In some embodiments, “homolog” encompasses a gene or a polypeptide (a protein) that is related to a second gene or polypeptide (protein), respectively, by descent from a common ancestral DNA or polypeptide (protein) sequence, respectively. Thus, a homolog of a gene, in some embodiments, comprises a similar nucleotide sequence to the gene. In some embodiments, a gene homolog encodes an identical polypeptide as is encoded by the gene. In some embodiments, a gene homolog encodes a polypeptide with the same functional properties as is encoded by the gene. In some embodiments, a gene homolog encodes a polypeptide that comprises a similar amino acid sequence as the polypeptide encoded by the gene. In one embodiment, the polypeptide homolog comprises a similar amino acid sequence as the polypeptide. In some embodiments, the polypeptide homolog comprises the same functional properties as the polypeptide. In some embodiments, the polypeptide homolog comprises similar functional properties as the polypeptide. In some embodiments, the polypeptide homolog comprises a same domain(s) as the polypeptide. In some embodiments, the polypeptide homolog comprises a similar domain(s) as the polypeptide. The similarity between two sequences (DNA, RNA, or amino acid) can be expressed as percent sequence identity and / or percent positive substitutions.

[0099] Homology: In a further embodiment, the amino acid sequences or nucleic acid sequences of the disclosure may be homologues, variants, isoforms, or fragments of the sequences presented. The term "homolog" as used herein refers to a polypeptide having a sequence homology of a certain amount, namely of at least 70%, e.g., at least 80%, 90%, 95%, 96%, 97%, 98%, 99% of the amino acid sequence it is referred to. Homology refers to the magnitude of identity between two sequences. Homolog sequences have the same or similar characteristics, in particular, have the same or similar property of the sequence as identified. The term 'variant' as used herein refers to a polypeptide wherein the amino acid sequence exhibits substantially 70, 80, 95, or 99% homology with the amino acid sequence as set forth in the sequence listing. It should be appreciated that the variant may result from a modification of the native amino acid sequences, or by modifications including insertion, substitution or deletion of one or more amino acids. Page 29 of 242P-636791-PC

[0100] Humoral immunity: As used herein, the term “humoral immunity” or “humoral immune response” refers to antigen binding agent production and the accessory processes that accompany it, including: Th2 activation and cytokine production, germinal center formation and isotype switching, affinity maturation and memory cell generation. It also refers to the effector functions of antigen binding agents, which include pathogen neutralization, classical complement activation, and opsonin promotion of phagocytosis and pathogen elimination.

[0101] Identity: The term “identity” refers to the overall relatedness between polynucleotide molecules (e.g., DNA molecules and / or RNA molecules) and / or between polypeptide molecules. In some embodiments, polynucleotide molecules (e.g., DNA molecules and / or RNA molecules) and / or between polypeptide molecules are considered to be “substantially identical” to one another if their sequences are at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical. Calculation of the percent identity of two nucleic acid or polypeptide sequences, for example, can be performed by aligning the two sequences for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second sequence for optimal alignment and non-identical sequences can be disregarded for comparison purposes). In certain embodiments, the length of a sequence aligned for comparison purposes is at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or substantially 100% of the length of a reference sequence. The nucleotides at corresponding positions are then compared. When a position in the first sequence is occupied by the same residue (e.g., nucleotide or amino acid) as the corresponding position in the second sequence, then the molecules are identical at that position. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which needs to be introduced for optimal alignment of the two sequences. The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. For example, the percent identity between two nucleotide sequences can be determined using the algorithm of Meyers and Miller, 1989, which has been incorporated into the ALIGN program (version 2.0). In some exemplary embodiments, nucleic acid sequence comparisons made with the ALIGN program use a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4. The percent identity between two nucleotide sequences can, alternatively, be determined using the GAP program in the GCG software package using an NWSgapdna.CMP matrix. Page 30 of 242P-636791-PC

[0102] In some embodiments herein, the terms “homology” and “identity” are used herein interchangeably. However, “homology” can be also understood to provide “similarity”, meaning that the positions are either the same or similar enough to have the same function and structure.

[0103] Immunoglobulin G: As used herein, the term “immunoglobulin G” or “IgG” refers to a polypeptide belonging to the class of antigen binding agents that are substantially encoded by a recognized immunoglobulin gamma gene. In humans this class comprises IgG1, IgG2, IgG3, and IgG4. In mice this class comprises IgG1, IgG2a, IgG2b, IgG3. As used herein, the term “modified immunoglobulin G” refers to a molecule that is derived from an antigen binding agent of the “G” class. As used herein, the term “antigen binding agent” refers to a protein consisting of one or more polypeptides substantially encoded by all or part of the recognized immunoglobulin genes. The recognized immunoglobulin genes, for example in humans, include the kappa (κ), lambda (λ), and heavy chain genetic loci, which together comprise the myriad variable region genes, and the constant region genes mu (μ), delta (δ), gamma (γ), sigma (σ), and alpha (α) which encode the IgM, IgD, IgG, IgE, and IgA isotypes or classes, respectively.

[0104] In some embodiments, chains and / or fragments of antibodies and fragments may be used in combination, e.g., a scFv-Fc arm with a conventional antibody arm. In some embodiments, an antigen binding agent may lack a covalent modification (e.g., attachment of a glycan) that it (or its relevant fragment) would have if produced naturally. In some embodiments, an antigen binding agent may contain a covalent modification (e.g., attachment of a glycan, a payload (e.g., a detectable moiety, a therapeutic moiety, a catalytic moiety, etc.), or other pendant group (e.g., poly-ethylene glycol, etc.)). In many embodiments, an antigen binding agent is or comprises a polypeptide whose amino acid sequence includes one or more structural elements recognized by those skilled in the art as a complementarity determining region (CDR); in some embodiments an antigen binding agent is or comprises a polypeptide whose amino acid sequence includes at least one CDR (e.g., at least one heavy chain CDR and / or at least one light chain CDR) that is substantially identical to one found in a reference antibody. In some embodiments an included CDR is substantially identical to a reference CDR in that it is either identical in sequence or contains between 1-5 amino acid substitutions as compared with the reference CDR. In some embodiments an included CDR is substantially identical to a reference CDR in that it shows at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the reference Page 31 of 242P-636791-PC CDR. In some embodiments, an included CDR is substantially identical to a reference CDR in that it shows at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the reference CDR. In some embodiments an included CDR is substantially identical to a reference CDR in that at least one amino acid within the included CDR is deleted, added, or substituted as compared with the reference CDR but the included CDR has an amino acid sequence that is otherwise identical with that of the reference CDR. In some embodiments an included CDR is substantially identical to a reference CDR in that 1-5 amino acids within the included CDR are deleted, added, or substituted as compared with the reference CDR but the included CDR has an amino acid sequence that is otherwise identical to the reference CDR. In some embodiments, an included CDR is substantially identical to a reference CDR in that at least one amino acid within the included CDR is substituted as compared with the reference CDR but the included CDR has an amino acid sequence that is otherwise identical with that of the reference CDR. In some embodiments, an included CDR is substantially identical to a reference CDR in that 1-5 amino acids within the included CDR are deleted, added, or substituted as compared with the reference CDR but the included CDR has an amino acid sequence that is otherwise identical to the reference CDR. In some embodiments, an antigen binding agent is or comprises a polypeptide whose amino acid sequence includes structural elements recognized by those skilled in the art as an immunoglobulin variable domain. In some embodiments, an antigen binding agent is a polypeptide protein having a binding domain which is homologous or largely homologous to an immunoglobulin-binding domain.

[0105] In order: As used herein with reference to a polynucleotide or polyribonucleotide, “in order” refers to the order of features from 5' to 3' along the polynucleotide or polyribonucleotide. As used herein with reference to a polypeptide, “in order” refers to the order of features moving from the N-terminal-most of the features to the C-terminal-most of the features along the polypeptide. “In order” does not mean that no additional features can be present among the listed features. For example, if Features A, B, and C of a polynucleotide are described herein as being “in order, Feature A, Feature B, and Feature C,” this description does not exclude, e.g., Feature D being located between Features A and B.

[0106] Increased, Induced, or Reduced: As used herein, these terms or grammatically comparable comparative terms, indicate values that are relative to a comparable reference measurement. For example, in some embodiments, an assessed value achieved with a provided composition (e.g., a pharmaceutical composition) may be “increased” relative to that obtained with a comparable reference composition. Alternatively or additionally, in some embodiments, Page 32 of 242P-636791-PC an assessed value achieved in a subject may be “increased” relative to that obtained in the same subject under different conditions (e.g., prior to or after an event; or presence or absence of an event such as administration of a composition (e.g., a pharmaceutical composition) as described herein, or in a different, comparable subject (e.g., in a comparable subject that differs from the subject of interest in prior exposure to a condition, e.g., absence of administration of a composition (e.g., a pharmaceutical composition) as described herein.). In some embodiments, comparative terms refer to statistically relevant differences (e.g., that are of a prevalence and / or magnitude sufficient to achieve statistical relevance). Those skilled in the art will be aware, or will readily be able to determine, in a given context, a degree and / or prevalence of difference that is required or sufficient to achieve such statistical significance. In some embodiments, the term “reduced”, or equivalent terms refers to a reduction in the level of an assessed value by at least 5%, at least 10%, at least 20%, at least 50%, at least 75% or higher, as compared to a comparable reference. In some embodiments, the term “reduced”, or equivalent terms refers to a complete or essentially complete inhibition, i.e., a reduction to zero or essentially to zero. In some embodiments, the term “increased” or “induced” refers to an increase in the level of an assessed value by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 80%, at least 100%, at least 200%, at least 500%, or higher, as compared to a comparable reference.

[0107] Ionizable: The term “ionizable” refers to a compound or group or atom that is charged at a certain pH. In the context of an ionizable amino lipid, such a lipid or a function group or atom thereof bears a positive charge at a certain pH. In some embodiments, an ionizable amino lipid is positively charged at an acidic pH. In some embodiments, an ionizable amino lipid is predominately neutral at physiological pH values, e.g., in some embodiments about 7.0-7.4, but becomes positively charged at lower pH values. In some embodiments, an ionizable amino lipid may have a pKa within a range of about 5 to about 7.

[0108] Isoform: The term “isoform” as used herein refers to variants of a polypeptide that are encoded by the same gene, but that differ in their isoelectric point (pI) or molecular weight (MW), or both. Such isoforms can differ in their amino acid composition (e.g., as a result of alternative splicing or limited proteolysis) and in addition, or in the alternative, may arise from differential post-translational modification (e.g., glycosylation, acylation, phosphorylation deamidation, or sulphation). As used herein, the term “isoform” also refers to a protein that exists in only a single form, i.e., it is not expressed as several variants. Page 33 of 242P-636791-PC

[0109] Isolated: The term “isolated” means altered or removed from the natural state. For example, a nucleic acid or a peptide naturally present in a living animal is not “isolated,” but the same nucleic acid or peptide partially or completely separated from the coexisting materials of its natural state is “isolated.” An isolated nucleic acid or protein can exist in substantially purified form, or can exist in a non-native environment such as, for example, a host cell.

[0110] Knob-in-hole: In some embodiments, the antigen binding agent comprises a “knob- into-hole” (“knob-in-hole”, KiH) pair of mutations either to enhance, or to inhibit or reduce, assembly, e.g., to enhance binding of two electrostatically or physically complementary moieties while inhibiting or reducing binding of two electrostatically or physically non- complementary moieties. In a non-limiting example, to generate a bicistronic or bispecific antigen binding agent, the constant region of the Fc portion of a first antigen binding agent can be mutated to form a knob, while the constant region of the of the Fc portion of a second antigen binding agent can be mutated to form a hole. During assembly of antigen binding agents in a mixture of the first antigen binding agent and the second antigen binding agent, the assembly of one Fc portion of a first antigen binding agent and one Fc portion of a second antigen binding agent is electrostatically and / or physically favored over assembly of either two Fc portions of the first antigen binding agent and / or two Fc portions of the second antigen binding agent.

[0111] Lipid: As used herein, the terms “lipid” and “lipid-like material” are broadly defined as molecules which comprise one or more hydrophobic moieties or groups and optionally also one or more hydrophilic moieties or groups. Molecules comprising hydrophobic moieties and hydrophilic moieties are also typically denoted as amphiphiles.

[0112] Lipidoid: As used herein, a “lipidoid” refers to a lipid-like molecule. In some embodiments, a lipoid is an amphiphilic molecule with one or more lipid-like physical properties. In the context of the present disclosure, the term lipid is considered to encompass lipidoids.

[0113] Modification: It will be appreciated that the term “modification” can encompass an amino acid modification such as an amino acid substitution, insertion, and / or deletion in a polypeptide sequence.

[0114] Nanoparticle: As used herein, the term “nanoparticle” refers to a particle having an average size suitable for parenteral administration. In some embodiments, a nanoparticle has a longest dimension (e.g., a diameter) of less than 1,000 nanometers (nm). In some embodiments, a nanoparticle may be characterized by a longest dimension (e.g., a diameter) of less than 300 Page 34 of 242P-636791-PC nm. In some embodiments, a nanoparticle may be characterized by a longest dimension (e.g., a diameter) of less than 100 nm. In many embodiments, a nanoparticle may be characterized by a longest dimension between about 1 nm and about 100 nm, or between about 1 µm and about 500 nm, or between about 1 nm and 1,000 nm. In many embodiments, a population of nanoparticles is characterized by an average size (e.g., longest dimension) that is below about 1,000 nm, about 500 nm, about 100 nm, about 50 nm, about 40 nm, about 30 nm, about 20 nm, or about 10 nm and often above about 1 nm. In many embodiments, a nanoparticle may be substantially spherical so that its longest dimension may be its diameter. In some embodiments, a nanoparticle has a diameter of less than 100 nm as defined by the National Institutes of Health.

[0115] Naturally occurring: The term “naturally occurring” as used herein refers to an entity that can be found in nature. For example, a peptide or nucleic acid that is present in an organism (including viruses) and can be isolated from a source in nature and which has not been intentionally modified by man in the laboratory is naturally occurring.

[0116] Neutralization: As used herein, the term “neutralization” refers to an event in which binding agents such as antigen binding agents bind to a biological active site of a virus such as a receptor binding protein, thereby inhibiting the parasitic infection of cells. In some embodiments, the term “neutralization” refers to an event in which binding agents eliminate or significantly reduce ability of infecting cells.

[0117] Nucleic acid particle: A “nucleic acid particle” can be used to deliver nucleic acid to a target site of interest (e.g., cell, tissue, organ, and the like). A nucleic acid particle may comprise at least one cationic or cationically ionizable lipid or lipid-like material, at least one cationic polymer such as protamine, or a mixture thereof and nucleic acid. In some embodiments, a nucleic acid particle is a lipid nanoparticle. In some embodiments, a nucleic acid particle is a lipoplex particle.

[0118] Nucleic acid / Polynucleotide: As used herein, the term “nucleic acid” refers to a polymer of at least 10 nucleotides or more. In some embodiments, a nucleic acid is or comprises DNA. In some embodiments, a nucleic acid is or comprises RNA. In some embodiments, a nucleic acid is or comprises peptide nucleic acid (PNA). In some embodiments, a nucleic acid is or comprises a single stranded nucleic acid. In some embodiments, a nucleic acid is or comprises a double-stranded nucleic acid. In some embodiments, a nucleic acid comprises both single and double-stranded portions. In some embodiments, a nucleic acid comprises a backbone that comprises one or more phosphodiester linkages. In some embodiments, a nucleic Page 35 of 242P-636791-PC acid comprises a backbone that comprises both phosphodiester and non-phosphodiester linkages. For example, in some embodiments, a nucleic acid may comprise a backbone that comprises one or more phosphorothioate or 5'-N-phosphoramidite linkages and / or one or more peptide bonds, e.g., as in a “peptide nucleic acid”. In some embodiments, a nucleic acid comprises one or more, or all, natural residues (e.g., adenine, cytosine, deoxyadenosine, deoxycytidine, deoxyguanosine, deoxythymidine, guanine, thymine, uracil). In some embodiments, a nucleic acid comprises on or more, or all, non-natural residues. In some embodiments, a non-natural residue comprises a nucleoside analog (e.g., 2-aminoadenosine, 2- thiothymidine, inosine, pyrrolo-pyrimidine, 3 -methyl adenosine, 5-methylcytidine, C-5 propynyl-cytidine, C-5 propynyl-uridine, 2-aminoadenosine, C5-bromouridine, C5- fluorouridine, C5-iodouridine, C5-propynyl-uridine, C5 -propynyl-cytidine, C5- methylcytidine, 2-aminoadenosine, 7-deazaadenosine, 7-deazaguanosine, 8-oxoadenosine, 8- oxoguanosine, 6-O-methylguanine, 2-thiocytidine, methylated bases, intercalated bases, and combinations thereof). In some embodiments, a non-natural residue comprises one or more modified sugars (e.g., 2'-fluororibose, ribose, 2'-deoxyribose, arabinose, and hexose) as compared to those in natural residues. In some embodiments, a nucleic acid has a nucleotide sequence that encodes a functional gene product such as an RNA or polypeptide. In some embodiments, a nucleic acid has a nucleotide sequence that comprises one or more introns. In some embodiments, a nucleic acid may be prepared by isolation from a natural source, enzymatic synthesis (e.g., by polymerization based on a complementary template, e.g., in-vivo or in-vitro), reproduction in a recombinant cell or system, or chemical synthesis. In some embodiments, a nucleic acid is at least 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 20, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 600, 700, 800, 900, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 5500, 6000, 6500, 7000, 7500, 8000, 8500, 9000, 9500, 10,000, 10,500, 11,000, 11,500, 12,000, 12,500, 13,000, 13,500, 14,000, 14,500, 15,000, 15,500, 16,000, 16,500, 17,000, 17,500, 18,000, 18,500, 19,000, 19,500, or 20,000 or more residues or nucleotides long.

[0119] Nucleotide: As used herein, the term “nucleotide” refers to its art-recognized meaning. When a number of nucleotides is used as an indication of size, e.g., of a polynucleotide, a certain number of nucleotides refers to the number of nucleotides on a single strand, e.g., of a polynucleotide. Page 36 of 242P-636791-PC

[0120] Patient: As used herein, the term “patient” refers to any organism who is suffering or at risk of a disease or disorder or condition. Typical patients include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and / or humans). In some embodiments, a patient is a human. In some embodiments, a patient is suffering from or susceptible to one or more diseases or disorders or conditions. In some embodiments, a patient displays one or more symptoms of a disease or disorder or condition. In some embodiments, a patient has been diagnosed with one or more diseases or disorders or conditions. In some embodiments, a disease or disorder or condition that is amenable to provided technologies is or includes an HSV infection. In some embodiments, a patient is receiving or has received certain therapy to diagnose and / or to treat a disease, disorder, or condition. In some embodiments, a patient is a patient suffering from or susceptible to an HSV infection.

[0121] PEG-conjugated lipid: The term “PEG-conjugated lipid" refers to a molecule comprising a lipid portion and a polyethylene glycol portion.

[0122] Percent homology: The terms “percent homology” or “percent identity” may be determined, for example but no limited to, using BlastP software of the National Center of Biotechnology Information (NCBI) using default parameters. The homolog may also refer to an ortholog, a deletion, insertion, or substitution variant, including an amino acid substitution. In some embodiments, sequence identity or homology can be determined using any protein or nucleic acid sequence alignment algorithm such as Blast, ClustalW, MUSCLE, and HHpred.

[0123] Pharmaceutical composition: As used herein, the term “pharmaceutical composition” refers to an active agent, formulated together with one or more pharmaceutically acceptable carriers. In some embodiments, active agent is present in unit dose amount appropriate for administration in a therapeutic regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. In some embodiments, pharmaceutical compositions may be specially formulated for parenteral administration, for example, by subcutaneous, intramuscular, or intravenous injection as, for example, a sterile solution or suspension formulation.

[0124] Pharmaceutically effective amount: The term “pharmaceutically effective amount” or “therapeutically effective amount” refers to the amount which achieves a desired reaction or a desired effect alone or together with further doses. In the case of the treatment of a particular disease (e.g., herpes), a desired reaction in some embodiments relates to inhibition of the course of the disease (e.g., herpes). In some embodiments, such inhibition may comprise slowing Page 37 of 242P-636791-PC down the progress of a disease (e.g., herpes herpes) and / or interrupting or reversing the progress of the disease (e.g., herpes). In some embodiments, a desired reaction in a treatment of a disease (e.g., herpes) may be or comprise delay or prevention of the onset of a disease (e.g., herpes) or a condition (e.g., an HSV associated condition). An effective amount of a composition (e.g., a pharmaceutical composition) described herein will depend, for example, on disease (e.g., herpes) or a condition (e.g., an HSV associated condition) to be treated, the severity of such a disease (e.g., herpes) or a condition (e.g., an HSV associated condition), individual parameters of the patient, including, e.g., age, physiological condition, size and weight, the duration of treatment, the type of an accompanying therapy (if present), the specific route of administration and similar factors. Accordingly, doses of a composition (e.g., a pharmaceutical composition) described herein may depend on various of such parameters. In the case that a reaction in a patient is insufficient with an initial dose, higher doses (or effectively higher doses achieved by a different, more localized route of administration) may be used.

[0125] Poly(A) sequence: As used herein, the term “poly(A) sequence” or “poly-A tail” refers to an uninterrupted or interrupted sequence of adenylate residues which is typically located at the 3'-end of an RNA molecule. Poly(A) sequences are known to those of skill in the art and may follow the 3’-UTR in the RNAs provided herein. An uninterrupted poly(A) sequence is characterized by consecutive adenylate residues. In nature, an uninterrupted poly(A) sequence is typical. RNAs disclosed herein can have a poly(A) sequence attached to the free 3'-end of the RNA by a template-independent RNA polymerase after transcription or a poly(A) sequence encoded by DNA and transcribed by a template-dependent RNA polymerase.

[0126] Polypeptide: As used herein, the term “polypeptide” refers to a polymeric chain of amino acids. In some embodiments, a polypeptide has an amino acid sequence that occurs in nature. In some embodiments, a polypeptide has an amino acid sequence that does not occur in nature. In some embodiments, a polypeptide has an amino acid sequence that is engineered in that it is designed and / or produced through action of the hand of man. In some embodiments, a polypeptide may comprise or consist of natural amino acids, non-natural amino acids, or both. In some embodiments, a polypeptide may comprise or consist of only natural amino acids or only non-natural amino acids. In some embodiments, a polypeptide may comprise D-amino acids, L-amino acids, or both. In some embodiments, a polypeptide may comprise only D- amino acids. In some embodiments, a polypeptide may comprise only L-amino acids. In some Page 38 of 242P-636791-PC embodiments, a polypeptide may include one or more pendant groups or other modifications, e.g., modifying or attached to one or more amino acid side chains, at the polypeptide’s N- terminus, at the polypeptide’s C-terminus, or any combination thereof. In some embodiments, such pendant groups or modifications comprise acetylation, amidation, lipidation, methylation, pegylation, etc., including combinations thereof. In some embodiments, a polypeptide may be cyclic, and / or may comprise a cyclic portion. In some embodiments, a polypeptide is not cyclic and / or does not comprise any cyclic portion. In some embodiments, a polypeptide is linear. In some embodiments, a polypeptide may be or comprise a stapled polypeptide. In some embodiments, the term “polypeptide” may be appended to a name of a reference polypeptide, activity, or structure; in such instances it is used herein to refer to polypeptides that share the relevant activity or structure and thus can be considered to be members of the same class or family of polypeptides. For each such class, the present specification provides and / or those skilled in the art will be aware of exemplary polypeptides within the class whose amino acid sequences and / or functions are known; in some embodiments, such exemplary polypeptides are reference polypeptides for the polypeptide class or family. In some embodiments, a member of a polypeptide class or family shows significant sequence homology or identity with, shares a common sequence motif (e.g., a characteristic sequence element) with, and / or shares a common activity (in some embodiments at a comparable level or within a designated range) with a reference polypeptide of the class; in some embodiments with all polypeptides within the class). For example, in some embodiments, a member polypeptide shows an overall degree of sequence homology or identity with a reference polypeptide that is at least about 30-40%, and is often greater than about 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more and / or includes at least one region (e.g., a conserved region that may in some embodiments be or comprise a characteristic sequence element) that shows very high sequence identity, often greater than 90% or even 95%, 96%, 97%, 98%, or 99%. Such a conserved region usually encompasses at least 3-4 and often up to 35 or more amino acids; in some embodiments, a conserved region encompasses at least one stretch of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or more contiguous amino acids. In some embodiments, a relevant polypeptide may comprise or consist of a fragment of a parent polypeptide.

[0127] Prevent: As used herein, the term “prevent” or “prevention” when used in connection with the occurrence of a disease, disorder, and / or condition, refers to reducing the risk of developing the disease, disorder and / or condition and / or to delaying onset of one or more Page 39 of 242P-636791-PC characteristics or symptoms of the disease, disorder or condition. Prevention may be considered complete when onset of a disease, disorder or condition has been delayed for a predefined period of time.

[0128] Recombinant: The term “recombinant” in the context of the present disclosure means “made through genetic engineering”. In some embodiments, a “recombinant” entity such as a recombinant nucleic acid in the context of the present disclosure is not naturally occurring.

[0129] Reference: As used herein, the term “reference” describes a standard or control relative to which a comparison is performed. For example, in some embodiments, an agent, animal, individual, population, sample, sequence or value of interest is compared with a reference or control agent, animal, individual, population, sample, sequence or value. In some embodiments, a reference or control is tested and / or determined substantially simultaneously with the testing or determination of interest. In some embodiments, a reference or control is a historical reference or control, optionally embodied in a tangible medium. Typically, as would be understood by those skilled in the art, a reference or control is determined or characterized under comparable conditions or circumstances to those under assessment. Those skilled in the art will appreciate when sufficient similarities are present to justify reliance on and / or comparison to a particular possible reference or control.

[0130] Risk: As will be understood from context, “risk” of a disease, disorder, and / or condition refers to a likelihood that a particular individual will develop the disease, disorder, and / or condition. In some embodiments, risk is expressed as a percentage. In some embodiments, risk is from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90 up to 100%. In some embodiments risk is expressed as a risk relative to a risk associated with a reference sample or group of reference samples. In some embodiments, a reference sample or group of reference samples have a known risk of a disease, disorder, condition and / or event. In some embodiments a reference sample or group of reference samples are from individuals comparable to a particular individual. In some embodiments, relative risk is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more. In some embodiments, risk may reflect one or more genetic attributes, e.g., which may predispose an individual toward development (or not) of a particular disease, disorder and / or condition. In some embodiments, risk may reflect one or more epigenetic events or attributes and / or one or more lifestyle or environmental events or attributes.

[0131] Ribonucleic acid (RNA) or Polyribonucleotide: As used herein, the term “ribonucleic acid,” “RNA,” or “polyribonucleotide” refers to a polymer of ribonucleotides. Page 40 of 242P-636791-PC “Ribonucleic acid,” “RNA,” or “polyribonucleotide” are used interchangeably herein. In some embodiments, an RNA is single stranded. In some embodiments, an RNA is double stranded. In some embodiments, an RNA comprises both single and double stranded portions. In some embodiments, an RNA can comprise a backbone structure as described in the definition of “Nucleic acid / Polynucleotide” above. An RNA can be a regulatory RNA (e.g., siRNA, microRNA, etc.), or a messenger RNA (mRNA). In some embodiments, an RNA is a mRNA. In some embodiments, where an RNA is a mRNA, an RNA typically comprises at its 3' end a poly(A) region. In some embodiments, where an RNA is a mRNA, an RNA typically comprises at its 5' end an art-recognized cap structure, e.g., for recognizing and attachment of a mRNA to a ribosome to initiate translation. In some embodiments, an RNA is a synthetic RNA. Synthetic RNAs include RNAs that are synthesized in vitro (e.g., by enzymatic synthesis methods and / or by chemical synthesis methods).

[0132] Ribonucleotide: As used herein, the term “ribonucleotide” encompasses unmodified ribonucleotides and modified ribonucleotides. For example, unmodified ribonucleotides include the purine bases adenine (A) and guanine (G), and the pyrimidine bases cytosine (C) and uracil (U). Modified ribonucleotides may include one or more modifications including, but not limited to, for example, (a) end modifications, e.g., 5' end modifications (e.g., phosphorylation, dephosphorylation, conjugation, inverted linkages, etc.), 3' end modifications (e.g., conjugation, inverted linkages, etc.), (b) base modifications, e.g. , replacement with modified bases, stabilizing bases, destabilizing bases, or bases that base pair with an expanded repertoire of partners, or conjugated bases, (c) sugar modifications (e.g., at the 2' position or 4' position) or replacement of the sugar, and (d) internucleoside linkage modifications, including modification or replacement of the phosphodiester linkages. The term “ribonucleotide” also encompasses ribonucleotide triphosphates including modified and non-modified ribonucleotide triphosphates.

[0133] RNA lipid nanoparticle: As used herein, the term “lipid nanoparticle” or “RNA lipid nanoparticle” refers to a nanoparticle comprising at least one lipid and RNA molecule(s), e.g., one or more polyribonucleotides as provided herein. In some embodiments, an RNA lipid nanoparticle comprises at least one cationic amino lipid. In some embodiments, an RNA lipid nanoparticle comprises at least one cationic amino lipid, at least one helper lipid, and at least one polymer-conjugated lipid (e.g., PEG-conjugated lipid). In various embodiments, RNA lipid nanoparticles as described herein can have an average size (e.g., Z-average) of about 100 nm to 1000 nm, or about 200 nm to 900 nm, or about 200 nm to 800 nm, or about 250 nm to Page 41 of 242P-636791-PC about 700 nm. In some embodiments of the present disclosure, RNA lipid nanoparticles can have a particle size (e.g., Z-average) of about 30 nm to about 200 nm, or about 30 nm to about 150 nm, about 40 nm to about 150 nm, about 50 nm to about 150 nm, about 60 nm to about 130 nm, about 70 nm to about 110 nm, about 70 nm to about 100 nm, about 80 nm to about 100 nm, about 90 nm to about 100 nm, about 70 to about 90 nm, about 80 nm to about 90 nm, or about 70 nm to about 80 nm. In some embodiments, an average size of lipid nanoparticles is determined by measuring the average particle diameter. In some embodiments, RNA lipid nanoparticles may be prepared by mixing lipids with RNA molecules described herein.

[0134] RNA lipoplex particle: As used herein, the term “RNA lipoplex particle” refers to a complex comprising liposomes, in particular cationic liposomes, and RNA molecules. Without wishing to bound by a particular theory, electrostatic interactions between positively charged liposomes and negatively charged RNA results in complexation and spontaneous formation of RNA lipoplex particles. In some embodiments, positively charged liposomes may comprise a cationic lipid, such as in some embodiments DOTMA, and additional lipids, such as in some embodiments DOPE. In some embodiments, an RNA lipoplex particle is a nanoparticle.

[0135] Selective or specific: The term “selective” or “specific,” when used herein in reference to an agent having an activity, is understood by those skilled in the art to mean that the agent discriminates between potential target entities, states, or cells. For example, in some embodiments, an agent is said to bind “specifically” to its target if it binds preferentially with that target in the presence of one or more competing alternative targets. In many embodiments, specific interaction is dependent upon the presence of a particular structural feature of the target entity (e.g., an epitope, a cleft, a binding site). It is to be understood that specificity need not be absolute. In some embodiments, specificity may be evaluated relative to that of a target- binding moiety for one or more other potential target entities (e.g., competitors). In some embodiments, specificity is evaluated relative to that of a reference specific binding moiety. In some embodiments, specificity is evaluated relative to that of a reference non-specific binding moiety.

[0136] Stable: As used herein, the term “stable” in the context of the present disclosure refers to a pharmaceutical composition (e.g., immunogenic composition, e.g., vaccine) as a whole and / or components thereof meeting or exceeding pre-determined acceptance criteria. For example, in some embodiments, a stable pharmaceutical composition (e.g., immunogenic composition, e.g., vaccine) exhibits no unacceptable levels of microbial growth, and substantially no or no breakdown or degradation of the active biological molecule Page 42 of 242P-636791-PC component(s). In some embodiments, a stable pharmaceutical composition (e.g., immunogenic composition, e.g., vaccine) refers to the integrity of RNA molecules being maintained at least above 90% or more. In some embodiments, a stable pharmaceutical composition (e.g., immunogenic composition, e.g., vaccine) refers to at least 90% or more (including, e.g., at least 95%, at least 96%, at least 97%, or more) of RNA molecules being maintained to be encapsulated within lipid nanoparticles. In some embodiments, a stable pharmaceutical composition (e.g., immunogenic composition, e.g., vaccine) refers to a formulation that remains capable of eliciting a desired immunologic response when administered to a subject. In some embodiments, a pharmaceutical composition (e.g., immunogenic composition, e.g., vaccine) remains stable for a specified period of time under certain conditions.

[0137] Subject: As used herein, the term “subject” refers to an organism to be administered with a composition described herein, e.g., for experimental, diagnostic, prophylactic, and / or therapeutic purposes. Typical subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, domestic pets, etc.) and humans. In some embodiments, a subject is a human subject. In some embodiments, a subject is suffering from a disease, disorder, or condition (e.g., HSV, an HSV -associated condition, etc.). In some embodiments, a subject is susceptible to a disease, disorder, or condition (e.g., HSV, an HSV-associated condition, etc.). In some embodiments, a subject displays one or more symptoms or characteristics of a disease, disorder, or condition (e.g., HSV, an HSV-associated condition, etc.). In some embodiments, a subject displays one or more non-specific symptoms of a disease, disorder, or condition (e.g., HSV, an HSV-associated condition, etc.). In some embodiments, a subject does not display any symptom or characteristic of a disease, disorder, or condition (e.g., HSV, an HSV- associated condition, etc.). In some embodiments, a subject is someone with one or more features characteristic of susceptibility to or risk of a disease, disorder, or condition (e.g., HSV, an HSV-associated condition, etc.). In some embodiments, a subject is a patient. In some embodiments, a subject is an individual to whom diagnosis and / or therapy is and / or has been administered.

[0138] Suffering from: An individual who is “suffering from” a disease, disorder, and / or condition (e.g., HSV, an HSV-associated condition, etc.) has been diagnosed with and / or displays one or more symptoms of a disease, disorder, and / or condition.

[0139] Susceptible to: An individual who is “susceptible to” a disease, disorder, and / or condition (e.g., HSV, an HSV-associated condition, etc.) is one who has a higher risk of developing the disease, disorder, and / or condition (e.g., HSV, an HSV-associated condition, Page 43 of 242P-636791-PC etc.) than does a member of the general public. In some embodiments, an individual who is susceptible to a disease, disorder and / or condition (e.g., HSV, an HSV-associated condition, etc.) may not have been diagnosed with the disease, disorder, and / or condition (e.g., HSV, an HSV-associated condition, etc.). In some embodiments, an individual who is susceptible to a disease, disorder, and / or condition (e.g., HSV, an HSV-associated condition, etc.) may exhibit symptoms of the disease, disorder, and / or condition (e.g., HSV, an HSV-associated condition, etc.). In some embodiments, an individual who is susceptible to a disease, disorder, and / or condition (e.g., HSV, an HSV-associated condition, etc.) may not exhibit symptoms of the disease, disorder, and / or condition (e.g., HSV, an HSV-associated condition, etc.). In some embodiments, an individual who is susceptible to a disease, disorder, and / or condition (e.g., HSV, an HSV-associated condition, etc.) will develop the disease, disorder, and / or condition (e.g., HSV, an HSV-associated condition, etc.). In some embodiments, an individual who is susceptible to a disease, disorder, and / or condition (e.g., HSV, an HSV-associated condition, etc.) will not develop the disease, disorder, and / or condition (e.g., HSV, an HSV-associated condition, etc.).

[0140] Symptoms: In some embodiments, “symptoms” may be any manifestation of an HSV infection, comprising blisters, ulcerations, or lesions on the urethra, cervix, upper thigh, and / or anus in women and on the penis, urethra, scrotum, upper thigh, and anus in men, inflammation, swelling, fever, flu-like symptoms, sore mouth, sore throat, pharyngitis, pain, blisters on tongue, mouth or lips, ulcers, cold sores, neck pain, enlarged lymph nodes, reddening, bleeding, itching, dysuria, headache, muscle pain, etc., or a combination thereof.

[0141] Synthetic: As used herein, the term “synthetic” refers to an entity that is artificial, or that is made with human intervention, or that results from synthesis rather than naturally occurring. For example, in some embodiments, a synthetic nucleic acid or polynucleotide refers to a nucleic acid molecule that is chemically synthesized, e.g., in some embodiments by solid- phase synthesis. In some embodiments, the term “synthetic” refers to an entity that is made outside of biological cells. For example, in some embodiments, a synthetic nucleic acid or polynucleotide refers to a nucleic acid molecule (e.g., an RNA) that is produced by in vitro transcription using a template.

[0142] Tetravalent antibody: In some embodiments, a tetravalent antibody refers to an engineered antibody molecule that possesses four antigen-binding sites as opposed to the two binding sites found in conventional IgG antibodies. In some embodiments, a tetravalent antibody has enhanced binding strength, is able to simultaneously engage with multiple targets, Page 44 of 242P-636791-PC or a combination thereof. In some embodiments, the tetravalent antibody is a bispecific antibody and bind two different antigens or two distinct epitopes on the same antigen, in some embodiments, concurrently.

[0143] Three prime untranslated region: As used herein, the terms “three prime untranslated region” or “3' UTR” refer to a sequence of an RNA molecule that begins following a stop codon of a coding region of an open reading frame sequence. In some embodiments, the 3' UTR begins immediately after a stop codon of a coding region of an open reading frame sequence, e.g., in its natural context. In other embodiments, the 3' UTR does not begin immediately after stop codon of the coding region of an open reading frame sequence, e.g., in its natural context.

[0144] Treating: In some embodiments, “treating” refers to either therapeutic treatment or prophylactic or preventative measures, wherein the object is to prevent or lessen the targeted pathologic condition or disorder as described hereinabove. Thus, in some embodiments, treating may include directly affecting or curing, suppressing, inhibiting, preventing, reducing the severity of, delaying the onset of, reducing symptoms associated with the disease, disorder or condition, or a combination thereof. Thus, in some embodiments, “treating” refers inter alia to delaying progression, expediting remission, inducing remission, augmenting remission, speeding recovery, increasing efficacy of or decreasing resistance to alternative therapeutics, or a combination thereof. In some embodiments, “preventing” refers, inter alia, to delaying the onset of symptoms, preventing relapse to a disease, decreasing the number or frequency of relapse episodes, increasing latency between symptomatic episodes, or a combination thereof. In some embodiments, “suppressing” or “inhibiting”, refers inter alia to reducing the severity of symptoms, reducing the severity of an acute episode, reducing the number of symptoms, reducing the incidence of disease-related symptoms, reducing the latency of symptoms, ameliorating symptoms, reducing secondary symptoms, reducing secondary infections, prolonging patient survival, or a combination thereof.

[0145] Therapy: The term “therapy” refers to an administration or delivery of an agent or intervention that has a therapeutic effect and / or elicits a desired biological and / or pharmacological effect (e.g., has been demonstrated to be statistically likely to have such effect when administered to a relevant population). In some embodiments, a therapeutic agent or therapy is any substance that can be used to alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of, and / or reduce incidence of one or more symptoms or features of a disease, disorder, and / or condition (e.g., HSV, an HSV-associated condition, etc.). In some Page 45 of 242P-636791-PC embodiments, a therapeutic agent or therapy is a medical intervention (e.g., surgery, radiation, phototherapy) that can be performed to alleviate, relieve, inhibit, present, delay onset of, reduce severity of, and / or reduce incidence of one or more symptoms or features of a disease, disorder, and / or condition.

[0146] Threshold level (e.g., acceptance criteria): As used herein, the term “threshold level” refers to a level that are used as a reference to attain information on and / or classify the results of a measurement, for example, the results of a measurement attained in an assay. For example, in some embodiments, a threshold level means a value measured in an assay that defines the dividing line between two subsets of a population (e.g. a batch that satisfy quality control criteria vs. a batch that does not satisfy quality control criteria). Thus, a value that is equal to or higher than the threshold level defines one subset of the population, and a value that is lower than the threshold level defines the other subset of the population. A threshold level can be determined based on one or more control samples or across a population of control samples. A threshold level can be determined prior to, concurrently with, or after the measurement of interest is taken. In some embodiments, a threshold level can be a range of values.

[0147] Treat: As used herein, the term “treat,” “treatment,” or “treating” refers to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of, and / or reduce incidence of one or more symptoms or features of a disease, disorder, and / or condition (e.g., HSV, an HSV-associated condition, etc.). Treatment may be administered to a subject who does not exhibit signs of a disease, disorder, and / or condition (e.g., HSV, an HSV-associated condition, etc.). In some embodiments, treatment may be administered to a subject who exhibits only early signs of the disease, disorder, and / or condition (e.g., HSV, an HSV-associated condition, etc.), for example for the purpose of decreasing the risk of developing pathology associated with the disease, disorder, and / or condition. In some embodiments, treatment may be administered to a subject at a later-stage of disease, disorder, and / or condition (e.g., HSV, an HSV-associated condition, etc.).

[0148] Vaccination: As used herein, the term “vaccination” refers to the administration of a composition intended to generate an immune response, for example to a disease-associated (e.g., disease-causing) agent. In some embodiments, vaccination can be administered before, during, and / or after exposure to a disease-associated agent, and in certain embodiments, before, during, and / or shortly after exposure to the agent. In some embodiments, vaccination includes multiple administrations, appropriately spaced in time, of a vaccine composition. In some embodiments, vaccination generates an immune response to an infectious agent. Page 46 of 242P-636791-PC

[0149] Vaccine: As used herein, the term “vaccine” refers to a composition that induces an immune response upon administration to a subject. In some embodiments, an induced immune response provides protective immunity.

[0150] Variable region: The “variable region” of an antigen binding agent contains the antigen binding determinants of the molecule, and thus determines the specificity of an antigen binding agent for its target antigen. The variable region is so named because it is the most distinct in sequence from other antigen binding agents within the same isotype. The majority of sequence variability occurs in the complementarity determining regions (CDRs). There are 6 CDRs total, three each per heavy and light chain, designated VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3. The variable region outside of the CDRs is referred to as the framework (FR) region. Although not as diverse as the CDRs, sequence variability does occur in the FR region between different antigen binding agents. Overall, this characteristic architecture of antigen binding agents provides a stable scaffold (the FR region) upon which substantial antigen binding diversity (the CDRs) can be explored by the immune system to obtain specificity for a broad array of antigens.

[0151] Furthermore, antigen binding agents may exist in a variety of other forms including, for example, Fv, Fab, and (Fab’)2, as well as bi-functional (i.e., bi-specific) hybrid antigen binding agents (e.g., Lanzavecchia et al., (1987) Eur. J. Immunol.17:105) and in single chains (e.g., Huston et al. (1988) Proc. Natl. Acad. Sci. U.S.A. 85: 5879-5883 and Bird et al. (1988) Science 242: 423-426 (and related Erratum (1989) Science 244: 409), which are incorporated herein by reference). (See, generally, Hood et al., “Immunology”, Benjamin, N.Y., 2nd ed. (1984), and Hunkapiller et al. 1(1986) Nature 323: 15-16). Bispecific antigen binding agents are a technique for creating a single polypeptide that binds to two different determinants. Bispecific antigen binding agents may be made in many different formats, including but not limited to quadroma, F(ab')2, tetravalent, heterodimeric scFv, bispecific scFv, tandem scFv, diabody and minibody formats, or scFvs appended to or recombinantly fused with whole antigen binding agents.

[0152] Variant: As used herein in the context of molecules, e.g., nucleic acids, proteins, or small molecules, the term “variant” refers to a molecule that shows significant structural identity with a reference molecule but differs structurally from the reference molecule, e.g., in the presence or absence or in the level of one or more chemical moieties as compared to the reference entity. In some embodiments, a variant also differs functionally from its reference molecule. In general, whether a particular molecule is properly considered to be a “variant” of Page 47 of 242P-636791-PC a reference molecule is based on its degree of structural identity with the reference molecule. As will be appreciated by those skilled in the art, any biological or chemical reference molecule has certain characteristic structural elements. A variant, by definition, is a distinct molecule that shares one or more such characteristic structural elements but differs in at least one aspect from the reference molecule. In some embodiments, a variant polypeptide or nucleic acid may differ from a reference polypeptide or nucleic acid as a result of one or more differences in amino acid or nucleotide sequence and / or one or more differences in chemical moieties (e.g., carbohydrates, lipids, phosphate groups) that are covalently components of the polypeptide or nucleic acid (e.g., that are attached to the polypeptide or nucleic acid backbone). In some embodiments, a variant polypeptide or nucleic acid shows an overall sequence identity with a reference polypeptide or nucleic acid that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, or 99%. In some embodiments, a variant polypeptide or nucleic acid does not share at least one characteristic sequence element with a reference polypeptide or nucleic acid. In some embodiments, a reference polypeptide or nucleic acid has one or more biological activities. In some embodiments, a variant polypeptide or nucleic acid shares one or more of the biological activities of the reference polypeptide or nucleic acid. In some embodiments, a variant polypeptide or nucleic acid lacks one or more of the biological activities of the reference polypeptide or nucleic acid. In some embodiments, a variant polypeptide or nucleic acid shows a reduced level of one or more biological activities as compared to the reference polypeptide or nucleic acid. In some embodiments, a polypeptide or nucleic acid of interest is considered to be a “variant” of a reference polypeptide or nucleic acid if it has an amino acid or nucleotide sequence that is identical to that of the reference but for a small number of sequence alterations at particular positions. Typically, fewer than about 20%, about 15%, about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, or about 2% of the residues in a variant are substituted, inserted, or deleted, as compared to the reference. In some embodiments, a variant polypeptide or nucleic acid comprises about 10, about 9, about 8, about 7, about 6, about 5, about 4, about 3, about 2, or about 1 substituted residues as compared to a reference. Often, a variant polypeptide or nucleic acid comprises a very small number (e.g., fewer than about 5, about 4, about 3, about 2, or about 1) number of substituted, inserted, or deleted, functional residues (i.e., residues that participate in a particular biological activity) relative to the reference. In some embodiments, a variant polypeptide or nucleic acid comprises not more than about 5, about 4, about 3, about 2, or about 1 addition or deletion, and, in some embodiments, comprises no additions or deletions, as compared to the reference. In some embodiments, a variant polypeptide or nucleic acid comprises fewer than Page 48 of 242P-636791-PC about 25, about 20, about 19, about 18, about 17, about 16, about 15, about 14, about 13, about 10, about 9, about 8, about 7, about 6, and commonly fewer than about 5, about 4, about 3, or about 2 additions or deletions as compared to the reference. In some embodiments, a reference polypeptide or nucleic acid is one found in nature.

[0153] Vector: as used herein, refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. One type of vector is a “plasmid”, which refers to a circular double stranded DNA loop into which additional DNA segments may be ligated. Another type of vector is a viral vector, wherein additional DNA segments may be ligated into the viral genome. Certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors). Other vectors (e.g., non-episomal mammalian vectors) can be integrated into the genome of a host cell upon introduction into the host cell, and thereby are replicated along with the host genome. Moreover, certain vectors are capable of directing the expression of genes to which they are operatively linked. Such vectors are referred to herein as “expression vectors.” In some embodiments, known techniques may be used, for example, for generation or manipulation of recombinant DNA, for oligonucleotide synthesis, and for tissue culture and transformation (e.g., electroporation, lipofection). Enzymatic reactions and purification techniques may be performed according to manufacturer's specifications or as commonly accomplished in the art or as provided herein. The foregoing techniques and procedures may be generally performed according to conventional methods well known in the art and as provided in various general and more specific references that are cited and discussed throughout the present specification. See e.g., Sambrook et al., Molecular Cloning: A Laboratory Manual (4th ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (2012)), which is incorporated herein by reference for any purpose. Polyribonucleotides encoding antigen binding agents

[0154] The present disclosure, among other things, utilizes RNA technologies as a modality to express antigen binding agents directly in a subject as a novel class of antibody-based therapeutics. In some embodiments, a polyribonucleotide as described herein encodes an antigen binding agent (e.g., an antibody, alternate format antibody, or antigen binding fragment). Page 49 of 242P-636791-PC

[0155] In some embodiments, the antigen binding agent targets a Herpes Simplex Virus (HSV). In some embodiments, an antigen binding agent targeting HSV specifically binds to a particular epitope of an HSV polypeptide.

[0156] In some embodiments, provided herein is a polyribonucleotide encoding an anti-HSV gB antigen binding agent or an anti-HSV gD antigen binding agent.

[0157] In other embodiments, provided herein is a combination comprising: (a) a first polyribonucleotide encoding a first anti-Herpes Simplex Virus (HSV) glycoprotein antigen binding agent and (b) a second polyribonucleotide encoding a second anti-HSV glycoprotein antigen binding agent.

[0158] In some embodiments, each antigen binding agent targets a distinct epitope. In some embodiments, the antigen binding agent targets a distinct epitope on the same HSV glycoprotein. In other embodiments, the antigen binding agent targets a distinct epitope on different HSV glycoproteins.

[0159] Non-limiting examples of polyribonucleotide encoding antigen binding agents and portions thereof, including antigen-binding fragments, epitopes, CDR, FR, linkers, and tags, can be found in Tables 1-5 and 11.

[0160] In some embodiments, the polyribonucleotide encodes an anti-gB antigen binding agent. In some embodiments, the polyribonucleotide encoding an anti-gB antigen binding agent has a sequence as disclosed in Table 1 or in the sequence listing provided herewith. In some embodiments, the polyribonucleotide encodes an antigen binding agent comprising a heavy chain. In some embodiments, the polyribonucleotide encoding a heavy chain of an anti- gB antigen binding agent has a sequence as disclosed in Table 1 or in the sequence listing provided herewith. In other embodiments, the polyribonucleotide encodes an antigen binding agent comprising a light chain. In some embodiments, the polyribonucleotide encoding a light chain has a sequence as disclosed in Table 1 or in the sequence listing provided herewith. In other embodiments, the polyribonucleotide encodes an antigen binding agent comprising both a heavy chain and a light chain.

[0161] In some embodiments the heavy chain comprises a heavy chain variable region, which in some embodiments, comprises at least one heavy chain complementarity determining regions (CDRHs). In some embodiments, the heavy chain variable region comprises three CDRHs, referred to as CDRH1, CDRH2, and CDRH3. In some embodiments, the polyribonucleotide encodes a heavy chain variable region comprising one or more CDRHs, Page 50 of 242P-636791-PC CDRH1, CDRH2, and CDRH3 as set forth in Table 1 or in the sequence listing provided herewith.

[0162] In some embodiments the light chain comprises a light chain variable region, which in some embodiments, comprises at least one light chain complementarity determining regions (CDRLs). In some embodiments, the light chain variable region comprises three CDRLs, referred to as CDRL1, CDRL2, and CDRL3. In some embodiments, the polyribonucleotide encodes a light chain variable region comprising one or more CDRLs, CDRL1, CDRL2, and CDRL3 as set forth in Table 1 or in the sequence listing provided herewith. Table 1. Nucleic acid sequences for antigen binding agent C226 Sequence Sequence SEQ ID description NO:Page 51 of 242P-636791-PC C226sc UGGAUCUCCACCAUCACCGGCGAGUCCACCUACGCCGA 34 Heavy Chain GGAGUUCAAGGGCC DR2Page 52 of 242P-636791-PC CGCGCUUUGGCGGCACCGGCAGCGGCACCGAUUUUACC CUGAACAUUCAUCCGGUGGAAGAAGAAGAUGCGGCGAC A A A A AA AAA APage 53 of 242P-636791-PC UACUGGGGCCAGGGCACCUCCGUGACCGUGUCCUCCGG CGGCGGCGGCUCCGGCGGCGGCGGCUCCGGCGGCGGCG A A A APage 54 of 242P-636791-PC GUCCUGCGACAAGACCCACACCUGCCCCCCCUGCCCCGC CCCCGAGCUGCUGGGCGGCCCCUCCGUGUUCCUGUUCCC AA AA A A A A APage 55 of 242P-636791-PC AGGACCCCGAGGUGAAGUUCAACUGGUACGUGGACGGC GUGGAGGUGCACAACGCCAAGACCAAGCCCCGCGAGGA A A AA A A APage 56 of 242P-636791-PC ACCGAAGGAGCUAACCGCUUUUUUGCACAACAUGGGGG AUCAUGUAACUCGCCUUGAUCGUUGGGAACCGGAGCUG AA AA A A AAA A A A A A A

[0163] In some embodiments, the polyribonucleotide encoding anti-HSV gB antigen binding agent comprises: (i) a heavy chain complementarity determining region 1 (CDRH1) comprising a nucleic acid sequence according to SEQ ID NO: 33, (ii) a heavy chain complementarity determining region 2 (CDRH2) comprising a nucleic acid sequence according to SEQ ID NO: 34, (iii) a heavy chain complementarity determining region 3 (CDRH3) comprising a nucleic acid sequence according to SEQ ID NO: 35, (iv) a light chain complementarity determining Page 57 of 242P-636791-PC region 1 (CDRL1) comprising a nucleic acid sequence according to SEQ ID NO: 46, (v) a light chain complementarity determining region 2 (CDRL2) comprising a nucleic acid sequence according to SEQ ID NO: 47, (vii) a light chain complementarity determining region 3 (CDRL3) comprising a nucleic acid sequence according to SEQ ID NO: 48, or a combination thereof.

[0164] In some embodiments, an anti-Herpes Simplex Virus (HSV) glycoprotein B (gB) (anti-gB) antigen binding agent comprises a heavy chain variable region and a light chain variable region. In some embodiments, an anti-gB antigen binding agent comprises a heavy chain complementarity determining region 1 (CDRH1) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 33. In some embodiments, an anti-gB antigen binding agent comprises a heavy chain complementarity determining region 2 (CDRH2) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 34. In some embodiments, an anti-gB antigen binding agent comprises a heavy chain complementarity determining region 3 (CDRH3) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 35. In some embodiments, an anti-gB antigen binding agent comprises a CDRL1 comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 46. In some embodiments, an anti-gB antigen binding agent comprises a CDRL2 comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 47. In some embodiments, an anti-gB antigen binding agent comprises a CDRL3 comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 48. In some embodiments, an anti-gB antigen binding agent comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and / or CDRL3 belonging to a C226 antigen binding agent.

[0165] In some embodiments, the polynucleotide encoding the anti-HSV gB antigen binding agent encodes a heavy chain variable region comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 32 or SEQ ID NO: 278; wherein the polynucleotide encodes a light chain variable region comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 45, or a combination thereof. Page 58 of 242P-636791-PC

[0166] In some embodiments, the polynucleotide encoding the anti-HSV gB antigen binding agent encodes a heavy chain comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 31; wherein the polynucleotide encodes a light chain comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 44, or a combination thereof.

[0167] In some embodiments, the polynucleotide encoding the anti-HSV gB antigen binding agent comprises a nucleic acid sequence has at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 57, SEQ ID NO: 58, or SEQ ID NO: 59.

[0168] In some embodiments, an anti-gB antigen binding agent comprises a C226 antigen binding agent. In some embodiments, an anti-gB antigen binding agent comprises parts, in particular the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 of the C226 antigen binding agent. In some embodiments, an anti-gB antigen binding agent comprises the VH and VL domains of C226.

[0169] In some embodiments, an anti-gB antigen binding agent is termed herein C226sc. In other embodiments, an anti-gB antigen binding agent as described herein is any antigen binding agent that is known in the art.

[0170] In other embodiments the polyribonucleotide encodes an anti-gD antigen binding agent. In some embodiments, the polyribonucleotide encoding an anti-gD antigen binding agent comprises a sequence as disclosed in Table 2, Table 3, or Table 4 or in the sequence listing provided herewith. In some embodiments, the polyribonucleotide encodes an antigen binding agent comprising a heavy chain. In some embodiments, the polyribonucleotide encoding a heavy chain of an anti-gD antigen binding agent comprises a sequence as disclosed in Table 2, Table 3, or Table 4 or in the sequence listing provided herewith. In other embodiments, the polyribonucleotide encodes an antigen binding agent comprising a light chain. In some embodiments, the polyribonucleotide encoding a light chain comprises a sequence as disclosed in Table 2, Table 3, or Table 4 or in the sequence listing provided herewith. In other embodiments, the polyribonucleotide encodes an antigen binding agent comprising both a heavy chain and a light chain.

[0171] In some embodiments the heavy chain comprises a heavy chain variable region, which in some embodiments, comprises at least one heavy chain complementarity determining Page 59 of 242P-636791-PC regions (CDRHs). In some embodiments, the heavy chain variable region comprises three CDRHs, referred to as CDRH1, CDRH2, and CDRH3. In some embodiments, the polyribonucleotide encoding one or more CDRHs, CDRH1, CDRH2, and CDRH3 comprises a sequence as set forth in Table 2, Table 3, or Table 4 or in the sequence listing provided herewith.

[0172] In some embodiments the light chain comprises a light chain variable region, which in some embodiments, comprises at least one light chain complementarity determining regions (CDRLs). In some embodiments, the light chain variable region comprises three CDRLs, referred to as CDRL1, CDRL2, and CDRL3. In some embodiments, the polyribonucleotide encoding a light chain variable region, one or more CDRLs, CDRL1, CDRL2, and CDRL3 comprises a sequence as set forth in Table 2, Table 3, or Table 4 or in the sequence listing provided herewith. Table 2. Nucleic acid sequences for antigen binding agent MC2 Sequence Sequence SEQ ID description NO:Page 60 of 242P-636791-PC GGCCCUGCCCGCCCCCAUCGAGAAGACCAUCUCCAAGGC CAAGGGCCAGCCCCGCGAGCCCCAGGUGUACGUGUACC A A A AA AA APage 61 of 242P-636791-PC GGCGGCCCCUCCGUGUUCCUGUUCCCCCCCAAGCCCAAG GACACCCUGAUGAUCUCCCGCACCCCCGAGGUGACCUG A A A A A APage 62 of 242P-636791-PC CUUCGCCCUGGUGUCCAAGCUGACCGUGGACAAGUCCC GCUGGCAGCAGGGCAACGUGUUCUCCUGCUCCGUGAUG A A A AA A A A A AAPage 63 of 242P-636791-PC UGUACUUCGACUUCUGGGGCCAGGGCACCACCCUGACC GUGUCCUCCPage 64 of 242P-636791-PC GAUCAAGCGCACCGUGGCCGCCCCCUCCGUGUUCAUCU UCCCCCCCUCCGACGAGCAGCUGAAGUCCGGCACCGCCU AA AA A APage 65 of 242P-636791-PC CGGCGCCCUGACCUCCGGCGUGCACACCUUCCCCGCCGU GCUGCAGUCCUCCGGCCUGUACUCCCUGUCCUCCGUGG A A A A A APage 66 of 242P-636791-PC CCGUGGACACCUCCUCCUCCACCGCCUACAUGCAGUUCU CCUCCCUGACCACCGAGGACUCCGCCAUCUACUACUGCG A A A APage 67 of 242P-636791-PC Anti-gD CCCCAGGCUUUACACUUUAUGCUUCCGGCUCGUAUGUU 30 plasmid / MC GUGUGGAAUUGUGAGCGGAUAACAAUUUCACACAGGAA 2 ACAGCUAUGACCAUGAUUACGAAUUGUAAUACGACUCAPage 68 of 242P-636791-PC CAGAAGCCCGGCCAGCCCCCCAAGCUGCUGAUCUACGCC GCCUCCAACCUGGAGUCCGGCAUCCCCGCCCGCUUCUCC A A A AA A APage 69 of 242P-636791-PC AGGAGCUAACCGCUUUUUUGCACAACAUGGGGGAUCAU GUAACUCGCCUUGAUCGUUGGGAACCGGAGCUGAAUGA A A A AAA A A A A A ATable 3. Nucleic acid sequences for antigen binding agent 1D3 Sequence Sequence SEQ IDPage 70 of 242P-636791-PC 1D3 Heavy AUGGGCUGGAGCUGCAUUAUUCUGUUUCUGGUGGCGAC 95 Chain (rev. CGCGACCGGCGUGCAUAGCGAUGUGCAGCUGCAGGAAA l AAA A A A APage 71 of 242P-636791-PC CCCCUGGCCCCCGUGUGCGGCGACACCACCGGCUCCUCC GUGACCCUGGGCUGCCUGGUGAAGGGCUACUUCCCCGA A A AAPage 72 of 242P-636791-PC 1D3 Heavy UACAACCCCUCCCUGACCUCCCGCAUCUCCAUCACCCGC 107 Chain (FR3) GACACCUCCAAGAACCAGUUCUUCCUGCAGCUGAACUC A A A A A A APage 73 of 242P-636791-PC CCUGAAGAUCUCCCGCGUGGAGGCCGAGGACCUGGGCG UGUACUUCUGCGAGCUGGGCAUCACCACCGUGGUGGGC A A A A A AAPage 74 of 242P-636791-PC GCCGGCGCCGAUUGAACGCACCAUUAGCAAACCGAAAG GCAGCGUGCGCGCGCCGCAGGUGUAUGUGCUGCCGCCG AA AA AAA A AAAAAA A A APage 75 of 242P-636791-PC GCGGCCCCACCAUCAAGCCCUGCCCCCCCUGCAAGUGCC CCGCCCCCAACCUGCUGGGCGGCCCCUCCGUGUUCAUCU AA A AA A A APage 76 of 242P-636791-PC UGACCGUGAGCAGCGCGAAAACCACCGCGCCGAGCGUG UAUCCGCUGGCGCCGGUGUGCGGCGAUACCACCGGCAG A A AAA APage 77 of 242P-636791-PC (K409D hole CCGGCCCCGGCCUGGUGAAGCCCUCCCAGUCCCUGUCCC mut) (signal) UGACCUGCACCGUGACCGGCUACUCCAUCACCUCCGAC A AA A A AA AAPage 78 of 242P-636791-PC AACGUGAAGUGGAAGAUCGACGGCUCCGAGCGCCAGAA CGGCGUGCUGAACUCCUGGACCGACCAGGACUCCAAGG A A A A A A A APage 79 of 242P-636791-PC CCGGCAAGGGCUCCGGCGCCACCAACUUCUCCCUGCUG AAGCAGGCCGGCGACGUGGAGGAGAACCCCGGCCCCAU A A APage 80 of 242P-636791-PC CCCCGAAGAACGUUUUCCAAUGAUGAGCACUUUUAAAG UUCUGCUAUGUGGCGCGGUAUUAUCCCGUAUUGACGCC AA A AA A A A A APage 81 of 242P-636791-PC UAUAAGCAUAAAAGUCUCAACACAACAUAUACAAAACA AACGAAUCUCAAGCAAUCAAGCAUUCUACUUCUAUUGC A AA AAA A AAA AAAA AAPage 82 of 242P-636791-PC GCACCGACUUCACCCUGAAGAUCUCCCGCGUGGAGGCC GAGGACCUGGGCGUGUACUCUGCUCCCAGUCCACCUAC A A A AA A APage 83 of 242P-636791-PC CGUGACACCACGAUGCCUGUAGCAAUGGCAACAACGUU GCGCAAACUAUUAACUGGCGAACUACUUACUCUAGCUU AA AA AA A A A A A AAAPage 84 of 242P-636791-PC GGCAGCGATGTGGTGATGACCCAGACCCCGCTGAGCCTG CCGGTGAGCCTGGGCGATCAGGCGAGCATTAGCTGCCGC A A A A T T ATAA AA AA A TATPage 85 of 242P-636791-PC CCCAAGATCAAGGACGTGCTGATGATCTCCCTGTCCCCCA TCGTGACCTGCGTGGTGGTGGACGTGTCCGAGGACGACC A T A AT T T TT T AA AA T APage 86 of 242P-636791-PC CCGAACTGAACTATAAAAACACCGAACCGGTGCTGGATA GCGATGGCAGCTATTTTATGTATAGCGATCTGCGCGTGGA AAAAAAAAA T T AA AA A TATA T ATable 4. Nucleic acid sequences for antigen binding agent DL11 Sequence Sequence SEQ IDPage 87 of 242P-636791-PC AUGGGCUGGAGCUGCAUUAUUCUGUUUCUGGUGGCGAC CGCGACCGGCGUGCAUAGCCAGGUGCAGCUGCAGCAGA AA AAA A AAAPage 88 of 242P-636791-PC GCGACACCACCGGCUCCUCCGUGACCCUGGGCUGCCUG GUGAAGGGCUACUUCCCCGAGCCCGUGACCCUGACCUG AA A APage 89 of 242P-636791-PC ACCGCGUGGUGUCCGUGCUGACCGUGCUGCACCAGGAC UGGCUGAACGGCAAGGAGUACAAGUGCAAGGUGUCCAA AA A A AA A A AAPage 90 of 242P-636791-PC CUGACCUUUGGCGCGGGCACCAAACUGGAACUGAAACG CGCGGAUGCGGCGCCGACCGUGAGCAUUUUUCCGCCGA A AA A A A APage 91 of 242P-636791-PC DL11 Light UGGCUGCAGCAGAAGCCCGACGGCACCAUCAAGCGCCU Chain (FR2) GAUCUAC 85Page 92 of 242P-636791-PC GCAGCAGAAACCGGAUGGCACCAUUAAACGCCUGAUUU AUGCGGCGAGCACCCUGGAUAGCGGCGUGCCGAAACGC A A A A A A A APage 93 of 242P-636791-PC GUGGUGCACGAGGGCCUGCACAACCACCACACCACCAA GUCCUUCUCCCGCACCCCCGGCAAGGGCUCCGGCGCCAC AA AA A A APage 94 of 242P-636791-PC CACCAUUAGCAAACCGAAAGGCAGCGUGCGCGCGCCGC AGGUGUAUGUGCUGCCGCCGCCGGAAGAAGAAAUGACC AAAAAA A A A A A APage 95 of 242P-636791-PC GCGGCCCCUCCGUGUUCAUCUUCCCCCCCAAGAUCAAG GACGUGCUGAUGAUCUCCCUGUCCCCCAUCGUGACCUG A A A A APage 96 of 242P-636791-PC UCCACCAAGUACAACGAGAAGUUCAUGGGCAAGACCAU CCUGACCGCCGACAAGUCCUCCUCCACCGCCUACAUGCU A A A A APage 97 of 242P-636791-PC AAGUCCUUCAACCGCAACGAGUGCUGAUGAACUAGUAG UGACUGACUAGGAUCUGGUUACCACUAAACCAGCCUCA A AA A AA A AA A A AA A APage 98 of 242P-636791-PC GUGAAGAUCCUUUUUGAUAAUCUCAUGACCAAAAUCCC UUAACGUGAGUUUUCGUUCCACUGAGCGUCAGACCCCG A AAAA A AAA A A APage 99 of 242P-636791-PC UCCUCCGUGACCGUGACCUCCUCCACCUGGCCCUCCCAG UCCAUCACCUGCAACGUGGCCCACCCCGCCUCCUCCACC AA A AA AA A A A APage 100 of 242P-636791-PC UCGUUUUACAACGUCGUGACUGGGAAAACCCUGGCGUU ACCCAACUUAAUCGCCUUGCAGCACAUCCCCCUUUCGCC A AA A AA A A APage 101 of 242P-636791-PC GAUAGUUACCGGAUAAGGCGCAGCGGUCGGGCUGAACG GGGGGUUCGUGCACACAGCCCAGCUUGGAGCGAACGAC A A AA A A A A A A A APage 102 of 242P-636791-PC UUUAUGCCGGAAGAUAUUUAUGUGGAAUGGACCAACAA CGGCAAAACCGAACUGAACUAUAAAAACACCGAACCGG A A A A A A A A AAA[ ] n some em o ments, a nuc ec ac sequence as prov e ere n s at east , at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the nucleic acid sequence listed in Table 1, Table 2, Table 3, Table 4, Table 5, or Table 11. In some embodiments, an HSV-2 gD antigenic fragment has a nucleic acid sequence that is identical to the amino acid sequence listed in Table 1, Table 2, Table 3, Table 4, Table 5, or Table 11.

[0174] In some embodiments, the anti-HSV glycoprotein antigen binding agent comprises an anti-HSV glycoprotein D (anti-HSV gD) antigen binding agent.

[0175] In some embodiments, the polynucleotide encoding the anti-HSV gD antigen binding agent comprises: (i) a CDRH1 comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 5, (ii) a CDRH2 comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 6, (iii) a CDRH3 comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 7, (iv) a CDRL1 comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 17, (v) a CDRL2 comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 18, (vi) a CDRL3 comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 19, or a combination thereof.

[0176] In some embodiments, the polyribonucleotide encoding the anti-HSV gD antigen binding agent comprises: (i) a CDRH1 comprising a nucleic acid sequence according to SEQ ID NO: 5, (ii) a CDRH2 comprising a nucleic acid sequence according to SEQ ID NO: 6, (iii) a CDRH3 comprising a nucleic acid sequence according to SEQ ID NO: 7, (iv) a CDRL1 comprising a nucleic acid sequence according to SEQ ID NO: 17, (v) a CDRL2 comprising a Page 103 of 242P-636791-PC nucleic acid sequence according to SEQ ID NO: 18, (vi) a CDRL3 comprising a nucleic acid sequence according to SEQ ID NO: 19, or a combination thereof.

[0177] In other embodiments, the polynucleotide encoding the anti-HSV gD antigen binding agent comprises: (i) a CDRH1 comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 65, (ii) a CDRH2 comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 66, (iii) a CDRH3 comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 67, (iv) a CDRL1 comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 78, (v) a CDRL2 comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 79, (vi) a CDRL3 comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 80, or a combination thereof.

[0178] In other embodiments, the polynucleotide encoding the anti-HSV gD antigen binding agent comprises: (i) a CDRH1 comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 98, (ii) a CDRH2 comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 99, (iii) a CDRH3 comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 100, (iv) a CDRL1 comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 112, (v) a CDRL2 comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 113, (vi) a CDRL3 comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 114, or a combination thereof.

[0179] In some embodiments, the polyribonucleotide encoding the anti-HSV gD antigen binding agent comprises: (i) a CDRH1 comprising a nucleic acid sequence according to SEQ ID NO: 98, (ii) a CDRH2 comprising a nucleic acid sequence according to SEQ ID NO: 99, (iii) a CDRH3 comprising a nucleic acid sequence according to SEQ ID NO: 100, (iv) a CDRL1 comprising a nucleic acid sequence according to SEQ ID NO: 112, (v) a CDRL2 comprising a Page 104 of 242P-636791-PC nucleic acid sequence according to SEQ ID NO: 113, (vi) a CDRL3 comprising a nucleic acid sequence according to SEQ ID NO: 114, or a combination thereof.

[0180] In some embodiments, the polyribonucleotide encoding the anti-HSV gD antigen binding agent comprises: (i) a CDRH1 comprising a nucleic acid sequence according to SEQ ID NO: 65, (ii) a CDRH2 comprising a nucleic acid sequence according to SEQ ID NO: 6, (iii) a CDRH3 comprising a nucleic acid sequence according to SEQ ID NO: 7, (iv) a CDRL1 comprising a nucleic acid sequence according to SEQ ID NO: 17, (v) a CDRL2 comprising a nucleic acid sequence according to SEQ ID NO: 18, (vi) a CDRL3 comprising a nucleic acid sequence according to SEQ ID NO: 19, or a combination thereof.

[0181] In some embodiments, the polynucleotide encoding the anti-HSV gD antigen binding agent encodes a heavy chain variable region comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 4 or SEQ ID NO: 276; wherein a polynucleotide encoding the anti-HSV gD antigen binding agent encodes a light chain variable region comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 16 or SEQ ID NO: 277, or a combination thereof.

[0182] In other embodiments, the polynucleotide encoding the anti-HSV gD antigen binding agent encodes a heavy chain variable region comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 63; wherein a polynucleotide encoding the anti-HSV gD antigen binding agent encodes a light chain variable region comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 77, or a combination thereof.

[0183] In other embodiments, the polynucleotide encoding the anti-HSV gD antigen binding agent encodes a heavy chain variable region comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 97; wherein a polynucleotide encoding the anti-HSV gD antigen binding agent encodes a light chain variable region comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 111, or a combination thereof.

[0184] In some embodiments, the polynucleotide encoding the anti-HSV gD antigen binding agent encodes a heavy chain comprising a nucleic acid sequence having at least 80%, at least Page 105 of 242P-636791-PC 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 2 or SEQ ID NO: 3; a polynucleotide encoding the anti-HSV gD antigen binding agent encodes a light chain comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 15, or a combination thereof.

[0185] In other embodiments, the polynucleotide encoding the anti-HSV gD antigen binding agent encodes a heavy chain comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 61 or SEQ ID NO: 62; a polynucleotide encoding the anti-HSV gD antigen binding agent encodes a light chain comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 73, or a combination thereof.

[0186] In other embodiments, the polynucleotide encoding the anti-HSV gD antigen binding agent encodes a heavy chain comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 96; a polynucleotide encoding the anti-HSV gD antigen binding agent encodes a light chain comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 110, or a combination thereof.

[0187] In some embodiments, the polynucleotide encoding the anti-HSV gD antigen binding agent comprises a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to any one of SEQ ID NO: 28, SEQ ID NO: 29 or SEQ ID NO: 30.

[0188] In other embodiments, the polynucleotide encoding the anti-HSV gD antigen binding agent comprises a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to any one of SEQ ID NOs: 89-93.

[0189] In other embodiments, the polynucleotide encoding the anti-HSV gD antigen binding agent comprises a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to any one of SEQ ID NOs: 122-127 or 143-147.

[0190] In some embodiments, the combination is in the form of a bispecific antigen binding agent, which in some embodiments, is a bispecific antibody. In some embodiments, a bispecific antigen binding agent is a recombinant protein that includes two different antigen-binding Page 106 of 242P-636791-PC fragments or complementarity determining regions (CDRs) and thereby binds two different epitopes (e.g., on the same or different antigens).

[0191] In some embodiments, the bispecific antibody comprises a tetravalent bispecific antibody. In some embodiments, the polynucleotide encoding said tetravalent bispecific antibody comprises a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 280. In other embodiments, the present disclosure provides a polynucleotide encoding a polyribonucleotide encoding an anti-HSV gB antigen binding agent comprises: (i) a CDRH1 comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 33, (ii) a CDRH2 comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 34, (iii) a CDRH3 comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 35, (iv) a CDRL1 comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 46, (v) a CDRL2 comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 47, (vii) a CDRL3 comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 48, or a combination thereof.

[0192] In some embodiments, the first and second polynucleotides are formulated as a bispecific antibody. In other embodiments, the first and second polynucleotides are formulated as a tetravalent bispecific antibody. In some embodiments, the polynucleotide encoding said tetravalent bispecific antibody comprises a nucleic acid sequence having at least 80% identity to SEQ ID NO: 280 (see Table 11). Table 5. Additional exemplary nucleic acid sequences Sequence Sequence SEQ IDPage 107 of 242P-636791-PC UGUAGCCAUUCGUAUCUGCUCCUAAUAAAAAGAAAGUU UCUUCACAUUCUPage 108 of 242P-636791-PC GAGCUGGCCCCCGAGGACCCCGAGGACUCCGCCCUGCU GGAGGACCCCGUGGGCACCGUGGCCCCCCAGAUCCCCCC AA A A A A A APage 109 of 242P-636791-PC ACCAGCUGACCGACCCCCCCGGCGUGCGCCGCGUGUACC ACAUCCAGGCCGGCCUGCCCGACCCCUUCCAGCCCCCCU A A A A A

[0193] In some embodiments, at least one of the polynucleotides encoding the anti-HSV glycoprotein antigen binding agents further comprises a signal sequence. Page 110 of 242P-636791-PC

[0194] In some embodiments, one or more of said polyribonucleotides comprises at least one in-frame signal sequence encoding at least one signal peptide.

[0195] In some embodiments, one or more of said polyribonucleotides further encodes an in- frame marker sequence or detectable tag sequence encoding a marker or detectable tag.

[0196] In some embodiments, one or more of said polyribonucleotides further comprises a poly-A tail.

[0197] In some embodiments, one or more of said polyribonucleotides further comprise a cap. In some embodiments, the cap comprises an m7GpppG cap, 3′-O-methyl-m7GpppG cap, or anti-reverse cap analog. In some embodiments, one or more polyribonucleotides further comprise a cap-independent translational enhancer.

[0198] In some embodiments, one or more polyribonucleotides further comprise 5′ untranslated regions, 3′ untranslated regions, or a combination thereof.

[0199] In some embodiments, the present disclosure provides an RNA construct comprising one or more coding sequences, a 5’UTR, a 3’UTR, a polyA tail, a cap, or any combinations thereof. In some embodiments, the 5’UTR is from tobacco etch virus. In some embodiments, the 3’UTR is from Xenopus beta globin. Antigen binding agents, antigen-binding sites, and other immunogens

[0200] Non-limiting examples of antigen binding agents and portions thereof, including antigen-binding fragments, epitopes, CDR, FR, linkers, and tags, can be found in Tables 6-9 and 11.

[0201] In some embodiments, provided herein is a polypeptide encoding an anti-HSV gB antigen binding agent or an anti-HSV gD antigen binding agent.

[0202] In other embodiments, provided herein is a combination comprising: (a) a first anti- Herpes Simplex Virus (HSV) glycoprotein antigen binding agent and (b) a second anti-HSV glycoprotein antigen binding agent.

[0203] In some embodiments, each antigen binding agent targets a distinct epitope. In some embodiments, the antigen binding agent targets a distinct epitope on the same HSV glycoprotein. In other embodiments, the antigen binding agent targets a distinct epitope on different HSV glycoproteins. Page 111 of 242P-636791-PC

[0204] In some embodiments, the claimed combination excludes the combination of an anti- gD antigen binding agent and an anti-gH, antigen binding agent, the combination of an anti- gD antigen binding agent and an anti-gL antigen binding agent, the combination of an anti-gD antigen binding agent and an anti-gB antigen binding agent, or a combination thereof.

[0205] In some embodiments, an anti-HSV glycoprotein binding agent comprises an anti-gB antigen binding agent. In some embodiments, the polyribonucleotide sequence encoding the anti-gB antigen binding agent is disclosed in Table 6 or in the sequence listing provided herewith. In some embodiments, the anti-gB glycoprotein binding agent comprises a heavy chain. In some embodiments, the anti-gB glycoprotein binding agent comprises a heavy chain which sequence is disclosed in Table 6 or in the sequence listing provided herewith. In other embodiments, the anti-gB glycoprotein binding agent comprises a light chain. In some embodiments, the anti-gB glycoprotein binding agent comprises a light chain which sequence is disclosed in Table 6 or in the sequence listing provided herewith. In other embodiments, the anti-gB glycoprotein binding agent comprises both a heavy chain and a light chain.

[0206] In some embodiments the heavy chain comprises a heavy chain variable region, which in some embodiments, comprises at least one heavy chain complementarity determining regions (CDRHs). In some embodiments, the heavy chain variable region comprises three CDRHs, referred to, in some embodiments, as CDRH1, CDRH2, and CDRH3. In some embodiments, the anti-gB glycoprotein binding agent comprises a heavy chain variable region, one or more CDRHs, CDRH1, CDRH2, and CDRH3 as set forth in Table 6 or in the sequence listing provided herewith.

[0207] In some embodiments the light chain comprises a light chain variable region, which in some embodiments, comprises at least one light chain complementarity determining regions (CDRLs). In some embodiments, the light chain variable region comprises three CDRLs, referred to, in some embodiments, as CDRL1, CDRL2, and CDRL3. In some embodiments, the polyribonucleotide encodes a light chain variable region, one or more CDRLs, CDRL1, CDRL2, and CDRL3 as set forth in Table 6 or in the sequence listing provided herewith. Table 6. Amino acid sequences for antigen binding agent C226sc Sequence Sequence SEQ IDPage 112 of 242P-636791-PC EFKGRFAFSLETSASTAYLQINNLKNEDTAIYFCASKGKYDY YAMDYWGQGTSVTVSSAKTTAPSVYPLAPVCGDTTGSSVTPage 113 of 242P-636791-PC C226sc Heavy ChainRFAFSLETSASTAYLQINNLKNEDTAIYFCAS190Page 114 of 242P-636791-PC YAMDYWGQGTSVTVSSGGGGSGGGGSGGGGSDIVLTQSPA SLAVSLGQRATISCRASQSVSTSTYNYIHWFQQKPGQPPKLL

[0208] The present disclosure also provides antigen binding agents as described herein. In some embodiments, the antigen binding agents are encoded by the polyribonucleotides described herein.

[0209] In some embodiments, provided herein is a combination comprising: (a) a first anti- Herpes Simplex Virus (HSV) glycoprotein antigen binding agent and (b) a second anti-HSV glycoprotein antigen binding agent, wherein the first antigen binding agent and the second antigen binding agent bind to different epitopes.

[0210] In some embodiments, provided herein is a combination comprising: (a) a first anti- Herpes Simplex Virus (HSV) glycoprotein antigen binding agent and (b) a second anti-HSV Page 115 of 242P-636791-PC glycoprotein antigen binding agent, wherein the first antigen binding agent and the second antigen binding agent bind to different epitopes, wherein the first antigen binding agent and the second antigen binding agent bind to different epitopes on the same HSV glycoprotein.

[0211] In some embodiments, provided herein is a combination comprising: (a) a first anti- Herpes Simplex Virus (HSV) glycoprotein antigen binding agent and (b) a second anti-HSV glycoprotein antigen binding agent, wherein the first antigen binding agent and the second antigen binding agent bind to different epitopes, wherein the first antigen binding agent and the second antigen binding agent bind to different epitopes on different HSV glycoproteins.

[0212] In some embodiments, provided herein is a combination comprising: (a) a first anti- Herpes Simplex Virus (HSV) glycoprotein antigen binding agent and (b) a second anti-HSV glycoprotein antigen binding agent, wherein the first antigen binding agent and the second antigen binding agent bind to different epitopes, optionally wherein (i) the first antigen binding agent and the second antigen binding agent bind to different epitopes on the same HSV glycoprotein, or (ii) the first antigen binding agent and the second antigen binding agent bind to different epitopes on different HSV glycoproteins.

[0213] In some embodiments, provided herein is a combination comprising: (a) a first anti- Herpes Simplex Virus (HSV) glycoprotein antigen binding agent and (b) a second anti-HSV glycoprotein antigen binding agent, wherein the first antigen binding agent and the second antigen binding agent bind to different epitopes. In some embodiments, the first antigen binding agent and the second antigen binding agent bind to different epitopes on the same HSV glycoprotein. In other embodiments, the first antigen binding agent and the second antigen binding agent bind to different epitopes on different HSV glycoproteins.

[0214] In some embodiments, the first and / or second anti-HSV glycoprotein antigen binding agent comprises an anti-HSV glycoprotein B (anti-HSV gB) antigen binding agent.

[0215] In some embodiments, the anti-HSV gB antigen binding agent comprises: (i) a heavy chain complementarity determining region 1 (CDRH1) comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 184, (ii) a heavy chain complementarity determining region 2 (CDRH2) comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 185, (iii) a heavy chain complementarity determining region 3 (CDRH3) comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 186, (iv) a Page 116 of 242P-636791-PC light chain complementarity determining region 1 (CDRL1) comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 194, (v) a light chain complementarity determining region 2 (CDRL2) comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 195, (vi) a light chain complementarity determining region 3 (CDRL3) comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 196, or a combination thereof.

[0216] In some embodiments, the anti-HSV gB antigen binding agent comprises: (i) a heavy chain complementarity determining region 1 (CDRH1) comprising an amino acid sequence according to SEQ ID NO: 184, (ii) a heavy chain complementarity determining region 2 (CDRH2) comprising an amino acid sequence according to SEQ ID NO: 185, (iii) a heavy chain complementarity determining region 3 (CDRH3) comprising an amino acid sequence according to SEQ ID NO: 186, (iv) a CDRL1) comprising an amino acid sequence according to SEQ ID NO: 194, (v) a CDRL2) comprising an amino acid sequence according to SEQ ID NO: 195, (vi) a CDRL3 comprising an amino acid sequence according to SEQ ID NO: 196, or a combination thereof.

[0217] In some embodiments, the anti-HSV gB antigen binding agent comprises a heavy chain variable region comprising an amino acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 183; the anti- HSV gB antigen binding agent comprises a light chain variable region comprising an amino acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 193, or a combination thereof.

[0218] In some embodiments, the anti-HSV gB antigen binding agent comprises a heavy chain comprising an amino acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 182; the anti-HSV gB antigen binding agent comprises a light chain comprising an amino acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 192, or a combination thereof.

[0219] In some embodiments, the anti-HSV gB antigen binding agent comprises an amino acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 202 or SEQ ID NO: 203. Page 117 of 242P-636791-PC

[0220] In some embodiments, the anti-HSV gB antigen binding agent comprises a tetravalent bispecific antibody, which comprises an amino acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 281 or 282.

[0221] In some embodiments, an anti-HSV glycoprotein binding agent comprises an anti-gD antigen binding agent. In some embodiments, an anti-HSV glycoprotein binding agent comprises an anti-gD antigen binding agent which sequence is disclosed in Table 7, Table 8, or Table 9 or in the sequence listing provided herewith. In some embodiments, the anti-gD glycoprotein binding agent comprises a heavy chain. In some embodiments, the anti-gD glycoprotein binding agent comprises a heavy chain which sequence is disclosed in Table 7, Table 8, or Table 9 or in the sequence listing provided herewith. In other embodiments, the anti-gD glycoprotein binding agent comprises a light chain. In some embodiments, the anti-gD glycoprotein binding agent comprises a light chain which sequence is disclosed in Table 7, Table 8, or Table 9 or in the sequence listing provided herewith. In other embodiments, the anti-gD glycoprotein binding agent comprises both a heavy chain and a light chain.

[0222] In some embodiments the heavy chain comprises a heavy chain variable region, which in some embodiments, comprises at least one heavy chain complementarity determining regions (CDRHs). In some embodiments, the heavy chain variable region comprises three CDRHs, referred to, in some embodiments, as CDRH1, CDRH2, and CDRH3. In some embodiments, the anti-gD glycoprotein binding agent comprises a heavy chain variable region, one or more CDRHs, CDRH1, CDRH2, and CDRH3 as set forth in Table 7, Table 8, or Table 9 or in the sequence listing provided herewith.

[0223] In some embodiments the light chain comprises a light chain variable region, which in some embodiments, comprises at least one light chain complementarity determining regions (CDRLs). In some embodiments, the light chain variable region comprises three CDRLs, referred to, in some embodiments, as CDRL1, CDRL2, and CDRL3. In some embodiments, the polyribonucleotide encodes a light chain variable region, one or more CDRLs, CDRL1, CDRL2, and CDRL3 as set forth in Table 7, Table 8, or Table 9 or in the sequence listing provided herewith. Table 7. Amino acid sequences for antigen binding agent MC2 Sequence Sequence SEQ IDPage 118 of 242P-636791-PC MGWSCIILFLVATATGVHSQGQIQQSGTELVKPGASVKLSC KTSGFTFSSSYISWLKQRPGQSLEWIAWIYAGTGGSNYNRRFPage 119 of 242P-636791-PC MC2 Heavy ChainLTTALYFDF164Page 120 of 242P-636791-PC MC2 Light RADAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWK Chain IDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEYERHN 175Table 8. Amino acid sequences for antigen binding agent DL11 Sequence Sequence SEQ ID description NO:Page 121 of 242P-636791-PC DL11 Heavy ChainWIYPGHSSTKYNEKFMG207Page 122 of 242P-636791-PC DL11 Light ChainLQYASYPLT218Page 123 of 242P-636791-PC TEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLH NHHTTKSFSRTPGKa e . mno ac sequences or an gen n ng agen Sequence Sequence SEQ ID description NO:Page 124 of 242P-636791-PC AKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTW NSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNPage 125 of 242P-636791-PC 1D3 LightDVVMTQTPLSLPVSLGDQASISC243Chain (FR1)Page 126 of 242P-636791-PC IEPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPI VTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNS

[0224] In some embod ments, an am no ac d sequence as prov ded ere n s at east 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence listed in Table 6, Table 7, Table 8, Table 9, Table 10, or Table 11. In some embodiments, an HSV-2 gD antigenic fragment or an HSV-2 gB antigenic fragment has an amino acid sequence that is identical to an amino acid sequence listed in Table 6, Table 7, Table 8, Table 9, Table 10, or Table 11.

[0225] In some embodiments, the anti-HSV gD antigen binding agent comprises: (i) a CDRH1 comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 162, (ii) a CDRH2 comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 163, (iii) a CDRH3 comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 164, (iv) a CDRL1 comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 172, (v) a CDRL2 comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 173, (iv) a CDRL3 comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 174, or a combination thereof.

[0226] In some embodiments, the anti-HSV gD antigen binding agent comprises: (i) a CDRH1 comprising an amino acid sequence according to SEQ ID NO: 162, (ii) a CDRH2 comprising an amino acid sequence according to SEQ ID NO: 163, (iii) a CDRH3 comprising an amino acid sequence according to SEQ ID NO: 164, (iv) a CDRL1 comprising an amino acid sequence according to SEQ ID NO: 172, (v) a CDRL2 comprising an amino acid sequence according to SEQ ID NO: 173, (vi) a CDRL3 comprising an amino acid sequence according to SEQ ID NO: 174, or a combination thereof. Page 127 of 242P-636791-PC

[0227] In some embodiments, an anti-gD antigen binding agent comprises a CDRH1 comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 206. In some embodiments, an anti-gD antigen binding agent comprises a CDRH2 comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 207. In some embodiments, an anti-gD antigen binding agent comprises a CDRH3 comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 208. In some embodiments, an anti-gD antigen binding agent comprises a CDRL1 comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 216. In some embodiments, an anti-gD antigen binding agent comprises a CDRL2 comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 217. In some embodiments, an anti-gD antigen binding agent comprises a CDRL3 comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 218. In some embodiments, an anti-gD antigen binding agent comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and / or CDRL3 belonging to a DL11 antigen binding agent.

[0228] In some embodiments, the anti-HSV gD antigen binding agent comprises a heavy chain variable region comprising an amino acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 161; the anti- HSV gD antigen binding agent comprises a light chain variable region comprising an amino acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 171, or a combination thereof.

[0229] In some embodiments, the anti-HSV gD antigen binding agent comprises a heavy chain comprising an amino acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 159 or 160; the anti-HSV gD antigen binding agent comprises a light chain comprising an amino acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 170, or a combination thereof.

[0230] In some embodiments, the anti-gD antigen binding agent comprises: (i) a CDRH1 comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 206, (ii) a CDRH2 comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence Page 128 of 242P-636791-PC according to SEQ ID NO: 207, (iii) a CDRH3 comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 208, (iv) a CDRL1 comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 216, (v) a CDRL2 comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 217, (vi) a CDRL3 comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 218, or a combination thereof.

[0231] In some embodiments, the anti-gD antigen binding agent comprises a heavy chain variable region comprising an amino acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 205; the anti-gD antigen binding agent comprises a light chain variable region comprising an amino acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 215, or a combination thereof.

[0232] In some embodiments, the anti-gD antigen binding agent comprises a heavy chain comprising an amino acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 204; the anti-gD antigen binding agent comprises a light chain comprising an amino acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 214, or a combination thereof.

[0233] In some embodiments, the anti-gD antigen binding agent comprises: (i) a CDRH1 comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 229, (ii) a CDRH2 comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 230, (iii) a CDRH3 comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 231, (iv) a CDRL1 comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 239, (v) a CDRL2 comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 240, (vi) a CDRL3 comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 241, or a combination thereof. Page 129 of 242P-636791-PC

[0234] In some embodiments, the anti-gD antigen binding agent comprises: (i) a CDRH1 comprising an amino acid sequence as set forth in SEQ ID NO: 229, (ii) a CDRH2 comprising an amino acid sequence as set forth in SEQ ID NO: 230, (iii) a CDRH3 comprising an amino acid sequence as set forth in SEQ ID NO: 231, (iv) a CDRL1 comprising an amino acid sequence as set forth in SEQ ID NO: 239, (v) a CDRL2 comprising an amino acid sequence as set forth in SEQ ID NO: 240, (vi) a CDRL3 comprising an amino acid sequence as set forth in SEQ ID NO: 241, or a combination thereof.

[0235] In some embodiments, an anti-gD antigen binding agent comprises a CDRH1 comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 229. In some embodiments, an anti-gD antigen binding agent comprise a CDRH2 comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 230. In some embodiments, an anti-gD antigen binding agent comprises a CDRH3 comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 231. In some embodiments, an anti-gD antigen binding agent comprises a CDRL1 comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 239. In some embodiments, an anti-gD antigen binding agent comprises a CDRL2 comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 240. In some embodiments, an anti-gD antigen binding agent comprises a CDRL3 comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 241. In some embodiments, an anti-gD antigen binding agent comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and / or CDRL3 belonging to a 1D3 antigen binding agent.

[0236] In some embodiments, the anti-gD antigen binding agent comprises a heavy chain variable region comprising an amino acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 228; the anti-gD antigen binding agent comprises a light chain variable region comprising an amino acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 238, or a combination thereof.

[0237] In some embodiments, the anti-gD antigen binding agent comprises a heavy chain comprising an amino acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 227; the anti-gD antigen binding Page 130 of 242P-636791-PC agent comprises a light chain comprising an amino acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 237, or a combination thereof.

[0238] In some embodiments, the anti-gD antigen binding agent comprises an amino acid sequence having at least 80%, at least 90%, or at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 247 or SEQ ID NO: 248. Table 10. Additional amino acid sequences Sequence Sequence SEQ ID description NO:Page 131 of 242P-636791-PC YDEFVLATGDFVYMSPFYGYREGSHTEHTSYAADRFKQVD GFYARDLTTKARATAPTTRNLLTTPKFTVAWDWVPKRPSVPage 132 of 242P-636791-PC HPPATPNNMGLIAGAVGGSLLAALVICGIVYWMHRRTRKA PKRIRLPHIREDDQPSSHQPLFYPage 133 of 242P-636791-PC TQPRWSYYDSFSAVSEDNLGFLMHAPAFETAGTYLRLVKIN DWTEITQFILEHRARASCKYALPLRIPPAACLTSKAYQQGVT

[0239] In some embodiments, at least one of the anti-HSV glycoprotein antigen binding agents further comprises a signal peptide. In some embodiments, the signal peptide comprises the mouse Ig heavy chain signal. In some embodiments, the signal peptide comprises amino acid sequence MGWSCIILFLVATATGVHS (SEQ ID NO: 255). In other embodiments, the signal peptide comprises amino acid sequence MGRLTSGVGTAALLVVAVGLRVVCA (SEQ ID NO: 253). In other embodiments, the signal peptide comprises amino acid sequence MGRLTSGVGTAALLVVAVGLRVVCA (SEQ ID NO: 254). In other embodiments, the signal peptide comprises the amino acid of a signal peptide that is known in the art.

[0240] In some embodiments, at least one of the anti-HSV glycoprotein antigen binding agents further comprises a marker sequence or detectable tag sequence. In some embodiments, at least one of the anti-HSV glycoprotein antigen binding agents further comprises a marker sequence. In some embodiments, at least one of the anti-HSV glycoprotein antigen binding agents further comprises a detectable tag sequence.

[0241] In some embodiments, at least one of the anti-HSV glycoprotein antigen binding agents is attached to the cytotoxic molecule or the therapeutic agent. In some embodiments, at least one of the anti-HSV glycoprotein antigen binding agents is attached to the cytotoxic Page 134 of 242P-636791-PC molecule. In some embodiments, at least one of the anti-HSV glycoprotein antigen binding agents is attached to the therapeutic agent.

[0242] In some embodiments, a composition provided herein comprises or delivers an antigen binding agent as provided herein.

[0243] In some embodiments, the epitope target of the anti-gD antigen binding agent as described herein comprises an epitope target as described in Atanasiu et al, J Virol, 2018, which is incorporated herein by reference in its entirety.

[0244] In some embodiments, the epitope target of the anti-gB antigen binding agent as described herein comprises an epitope target as described in Bender et al., 2007, J Virol.81(8): 3827-3841, which is incorporated herein by reference in its entirety.

[0245] Simultaneous blocking of gB and gD can seem counterintuitive, as these proteins are seemingly at the opposite ends of the viral entry cascade. The experimental data provided herein surprisingly shows the opposite, that simultaneous blocking of gB and gD has a synergistic effect on blocking HSV entry.

[0246] In some embodiments, an anti-gD antigen binding agent and an anti-gB antigen binding agent are a single bispecific antigen binding agent directed to gD and gB. In other words, provided herein is a composition comprising one or more RNAs encoding a bispecific antigen binding agent that binds gD and gB (e.g., HSV-1, HSV-2, or a combination thereof).

[0247] In some embodiments, a composition comprises a single RNA molecule encoding an anti-gD binding agent, an anti-gB antigen binding agent, or a combination thereof. In some embodiments, a composition comprises a single RNA molecule encoding an anti-gD and anti- gB bispecific antigen binding agent (e.g., a bispecific antibody). In some embodiments, a composition comprises 2, 3, 4, 5, or more RNAs encoding an anti-gD and anti-gB antibodies. In some embodiments, the composition comprises 2, 3, 4, 5, or more RNA molecules molecule encoding an anti-gD and anti-gB bispecific antigen binding agent (e.g., a bispecific antibody).

[0248] In some embodiments, an anti-gD antigen binding agent comprises an Anti-HSV-1 gD antigen binding agent (ab6502) (Abcam), or a fragment thereof. In some embodiments, an anti-gD antigen binding agent comprises an Anti-HSV-2 gD (ab8936) (Abcam), or a fragment thereof. In some embodiments, an anti-gD antigen binding agent comprises an Anti-HSV gD antigen binding agent (B11) (Santa Cruz Biotech), or a fragment thereof. In some embodiments, an anti-gD antigen binding agent is an Anti-HSV-1 gD antigen binding agent (ab8397) (Abcam), or a fragment thereof. In some embodiments, an anti-gD antigen binding Page 135 of 242P-636791-PC agent is an Anti-HSV gD antigen binding agent (NB110-57524) (Novus Biologicals), or a fragment thereof.

[0249] In some embodiments, an anti-gB antigen binding agent comprises an Anti-HSV-1 gB antigen binding agent (ab6506) (Abcam), or a fragment thereof. In some embodiments, an anti-gB antigen binding agent comprises an Anti-HSV gB antigen binding agent (NB110- 57527) (Novus Biologicals), or a fragment thereof. In some embodiments, an anti-gB antigen binding agent comprises an Anti-HSV gB antigen binding agent (B25) (Santa Cruz Biotechnology), or a fragment thereof. In some embodiments, an anti-gB antigen binding agent comprises an Anti-HSV-1 / 2 gB antigen binding agent (MAB858) (R&D Systems), or a fragment thereof. In some embodiments, an anti-gB antigen binding agent comprises an Anti- HSV-1 gB antigen binding agent (ab6507) (Abcam), or a fragment thereof.

[0250] In some embodiments, CDRs are experimentally determined through DNA sequencing and protein sequencing. Said methods can include isolating the mRNA from the hybridoma cells producing the monoclonal antibody and sequencing it. In some embodiments, CDRs are identified based on established definitions, such as the Kabat, Chothia, or IMGT numbering schemes, which specify the positions of the CDRs within the variable domain sequences. The identified CDR sequences can then be further validated through structural modeling and comparison with known antibody structures to ensure their accuracy.

[0251] In some embodiments, the tetravalent bispecific antibody comprises an amino acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 281 or 282.

[0252] In some embodiments, the tetravalent bispecific antibody comprises an amino acid sequence according to SEQ ID NO: 281. In some embodiments, the tetravalent bispecific antibody comprises an amino acid sequence according to SEQ ID NO: 282 (see Table 11). Table 11. BD Tetravalent antibody nucleic acid and amino acid sequences Sequence Sequence SEQ IDPage 136 of 242P-636791-PC UACAUCUCCUGGCUGAAGCAGCGCCCCGGCCAGUCCCU GGAGUGGAUCGCCUGGAUCUACGCCGGCACCGGCGGCUPage 137 of 242P-636791-PC GGCGGCUCCGGCGGCGGCGGCUCCCAGAUCCAGCUGGU GCAGUCCGGCCCCGAGCUGAAGAAGCCCGGCGAGACCGMGWSCIILFLVATATGVHSQGQIQQSGTELVKPGASVKLSC BD T tPage 138 of 242P-636791-PC VKGYFPEPVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTV TSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPCPPCKCPPage 139 of 242P-636791-PC

[0253] In some embodiments, the first anti-HSV glycoprotein antigen binding agent and the second anti-HSV glycoprotein antigen binding agent together form a single bispecific antigen binding agent. In some embodiments, the bispecific antigen binding agent comprises an IgG antibody fragment and an scFv-Fc. In some embodiments, the IgG antibody fragment comprises a single heavy chain and a single light chain.

[0254] In some embodiments, the bispecific antigen binding agent comprises a tetravalent bispecific antibody.

[0255] In some embodiments, the first anti-HSV antibody is linked to the second anti-HSV antibody, optionally wherein the first anti-HSV antibody is linked to the second anti-HSV antibody by a covalent bond, a hydrogen bond, an ionic bond, or an electrostatic interaction, further optionally wherein the first anti-HSV antibody is linked to the second anti-HSV antibody by a peptide linker.

[0256] In some embodiments, the first anti-HSV antibody is linked to the second anti-HSV antibody. In some embodiments, the first anti-HSV antibody is linked to the second anti-HSV antibody by a covalent bond, a hydrogen bond, an ionic bond, or an electrostatic interaction. In some embodiments, the first anti-HSV antibody is linked to the second anti-HSV antibody by a peptide linker.

[0257] A linker, may in some embodiments, comprise a linear amino acid sequence. In some embodiments, a linear amino acid sequence (“linker”) comprises an enzyme cleavage site and may, in some embodiments, be termed a “cleavable linker” or a “cleavable peptide”. In some embodiments, a linker may be a cleavable linker. In some embodiments, a linker may be a non- cleavable linker. In some embodiments, the linker is a G4S linker. In some embodiments, the linker is a (G4S)3 linker.

[0258] In some embodiments, the combination further comprises a linker wherein at least one of the anti-HSV glycoprotein antigen binding agents comprises a heavy chain or heavy chain variable region, a linker, and a light chain or a light chain variable region.

[0259] In some embodiments, the linker comprises a 2A peptide linker.

[0260] In some embodiments, the linker comprises a GS linker.

[0261] In some embodiments, the antibody or antigen-binding agent comprises a “knob-into- hole” (“knob-in-hole,” KiH) pair of mutations either to enhance, or to inhibit or reduce, assembly, e.g., to enhance binding of two electrostatically or physically complementary Page 140 of 242P-636791-PC moieties while inhibiting or reducing binding of two electrostatically or physically non- complementary moieties. In a non-limiting example, to generate a bicistronic or bispecific antibody, the constant region of the Fc portion of a first antibody can be mutated to form a knob, while the constant region of the Fc portion of a second antibody can be mutated to form a hole. During assembly of antibodies in a mixture of the first antibody and the second antibody, the assembly of one Fc portion of a first antibody and one Fc portion of a second antibody is electrostatically and / or physically favored over assembly of either two Fc portions of the first antibody and / or two Fc portions of the second antibody.

[0262] In some embodiments, the anti-HSV glycoprotein antigen binding agent comprises a knob-in-hole (KiH) mutation. KiH is a specific type of mutation used in the design and engineering of bispecific antibodies that facilitates the formation of a bispecific antigen binding agent (e.g., a bispecific antibody). The KiH approach is used when an antigen binding agent comprises two heavy chains. The KiH approach comprises engineering one heavy chain of an antigen binding agent with a "knob" mutation, and the other heavy chain with a complementary "hole" mutation. These mutations introduce steric hindrance, promoting preferential pairing of a knob-containing heavy chain with a hole-containing heavy chain, thereby increasing the likelihood of correct assembly into a bispecific antigen binding agent (e.g., a bispecific antibody).

[0263] In some embodiments, a knob mutation comprises the substitution to a Tryptophan (W) or Arginine (R). The bulky side chain of these amino acids provide the steric bulk necessary for the knob interaction. In some embodiments, a hole mutation comprises the substitution to a Glycine (G) or aspartic acid (D). The small side chain of these amino acids and can create a cavity that complements the knob. In some embodiments, a KiH mutation comprises a mutation in the mouse IgG2a Fc portion of each were engineered binding agent. In some embodiments, a KiH comprises a D399R in MC2 Fc (knob) and a K409D in C226 Fc (hole).

[0264] In some embodiments, at least one of the antigen binding agents comprises a first and second immunoglobulin chain, wherein the first immunoglobulin chain comprises a first variable region and a first constant region, and the second immunoglobulin chain comprises a second variable region and a second constant region, wherein the first constant region comprises a first modification and the second constant region comprises a second modification, wherein the second modification is electrostatically or physically complementary to the first Page 141 of 242P-636791-PC modification to increase, enhance, or promote binding, electrostatic attraction, or other association of the first immunoglobulin chain with the immunoglobulin chain.

[0265] In some embodiments, the polynucleotide encoding the first immunoglobulin chain has at least 80%, at least 90%, at least 95%, or 100% identity to the nucleic acid sequence according to SEQ ID NO: 91 and the polynucleotide encoding the second immunoglobulin chain has at least 80%, at least 90%, at least 95%, or 100% identity to the nucleic acid sequence according to SEQ ID NO: 58, SEQ ID NO: 125, SEQ ID NO: 144, or SEQ ID NO: 145.

[0266] In some embodiments, the first immunoglobulin chain comprises an amino acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 226 or SEQ ID NO: 160; and the second immunoglobulin chain comprises an amino acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 247, SEQ ID NO: 251, SEQ ID NO: 252, or SEQ ID NO: 203.

[0267] In addition to the foregoing, other embodiments include use or modification and use of known gD antigen binding agents. These antigen binding agents may be used in bispecific embodiments of the disclosure. Non-limiting examples include those in Table 12. Table 12. Exemplary additional gD antigen binding agents and activities thereof Name Target Activity nPage 142 of 242P-636791-PC

[0268] In some embodiments, at least one of the anti-HSV glycoprotein antigen binding agents comprises a single-chain Fv (scFv). In some embodiments, an anti-gB antigen binding agent is or comprises a single-chain Fv (scFv). In some embodiments, an anti-gD antigen binding agent is or comprises a single-chain Fv (scFv). In some embodiments, an scFv is a fusion polypeptide comprising the variable heavy chain (VH) and variable light chain (VL) regions of an immunoglobulin, connected by a short linker peptide of, for example but not limited to, ten to about 25 amino acids.

[0269] In other embodiments, at least one of the anti-HSV glycoprotein antigen binding agents comprises an IgG antibody.

[0270] In some embodiments, an anti-gD binding agent, an anti-gB antigen binding agent, or a combination thereof comprises an IgG heavy chain constant region. In some embodiments, an antigen binding agent that includes an IgG heavy chain constant region can be referred to as an IgG antigen binding agent. In some embodiments, an antibody that includes an IgG heavy chain constant region can be referred to as an IgG antibody.

[0271] In some embodiments, the IgG antibody comprises an IgG1, IgG2, or IgG4 constant region. In some embodiments, the first anti-HSV glycoprotein antigen binding agent and the second anti-HSV glycoprotein antigen binding agent together form a single bispecific antigen binding agent. In some embodiments, the bispecific antigen binding agent comprises an IgG antibody fragment and an scFv-Fc. In some embodiments, the IgG antibody fragment comprises a single heavy chain and a single light chain. In some embodiments, the bispecific antigen binding agent comprises a tetravalent bispecific antibody.

[0272] In other embodiments, at least one of the anti-HSV glycoprotein antigen binding agents comprises a single-chain Fv-Fc (scFv-Fc). In some embodiments, a canonical antibody (e.g., an IgG antibody) is composed of two identical heavy chains and two identical light chains, linked together by disulfide bonds, each chain consists of constant (C) and variable (V) regions. In some embodiments, an antibody fragment comprises only one “half” of a canonical antibody, e.g., comprises only one heavy chain and one light chain.

[0273] In some embodiments, an anti-gD antigen binding agent comprises an antibody fragment (e.g., one heavy chain and one light chain) and an anti-gB antigen binding agent comprises a scFv. In some embodiments, a bispecific antigen binding agent comprises an anti- gD IgG antibody fragment (e.g., one heavy chain and one light chain) and an anti-gB scFv. Page 143 of 242P-636791-PC

[0274] In some embodiments, at least one of said anti-HSV glycoprotein antigen binding agent comprises a single-chain Fv (scFv). In some embodiments, at least one of said anti-HSV glycoprotein antigen binding agent comprises a single-chain Fv-Fc (scFv-Fc).

[0275] In other embodiments, at least one of the anti-HSV glycoprotein antigen binding agents comprises a bicistronic antigen binding agent.

[0276] There are a number of antibody formats, e.g., in clinical or pre-clinical use. In some embodiments, an anti-gD binding agent, an anti-gB antigen binding agent, or a combination thereof is or comprises an IgG heavy chain constant region. In some embodiments, an anti-gD binding agent, an anti-gB antigen binding agent, or a combination thereof is or comprises a single-chain variable fragment (scFv). In some embodiments, an anti-gD binding agent, an anti-gB antigen binding agent, or a combination thereof is or comprises a minibody. In some embodiments, an anti-gD binding agent, an anti-gB antigen binding agent, or a combination thereof is or comprises a nanobody. In some embodiments, an anti-gD binding agent, an anti- gB antigen binding agent, or a combination thereof is or comprises a VHH. In some embodiments, an anti-gD binding agent, an anti-gB antigen binding agent, or a combination thereof is or comprises a single-domain antibody. In some embodiments, an anti-gD binding agent, an anti-gB antigen binding agent, or a combination thereof is or comprises a Fragment antigen binding (Fab). In some embodiments, an anti-gD binding agent, an anti-gB antigen binding agent, or a combination thereof is or comprises a diabody. In some embodiments, an anti-gD binding agent, an anti-gB antigen binding agent, or a combination thereof is or comprises a triabody. Nucleic acids

[0277] In some embodiments, nucleic acid comprises a ribonucleic acid (RNA) or a deoxyribonucleic acid (DNA). In some embodiments, the nucleic acid is double-stranded (ds); in some embodiments, the nucleic acid is single-stranded (ss). In some embodiments, the nucleic acid comprises an antisense nucleic acid or a portion thereof. In some embodiments, the nucleic acid comprises an oligonucleotide.

[0278] In some embodiments, the nucleic acid comprises a deoxyribonucleic acid (DNA). In some embodiments, the DNA comprises a genomic DNA or a portion thereof or a complementary DNA (cDNA) or a portion thereof. In some embodiments, the DNA is double- stranded; in some embodiments, the DNA is single-stranded. In some embodiments, the nucleic acid comprises an antisense DNA. In some embodiments, the nucleic acid comprises a single- Page 144 of 242P-636791-PC stranded antisense DNA. In some embodiments, the sense strand of the DNA and the antisense strand of the DNA each comprise a 5’ end and a 3’ end.

[0279] In some embodiments, the nucleic acid comprises a ribonucleic acid (RNA). In some embodiments, the RNA comprises a messenger RNA (RNA), a small interfering RNA (siRNA), or a microRNA (miRNA). In some embodiments, the RNA is double-stranded; in some embodiments, the RNA is single-stranded. In some embodiments, a strand of the RNA comprises a 5’ end and a 3’ end. In certain embodiments, the nucleic acid comprises an siRNA moiety comprised of a sense strand and an antisense strand; the sense strand comprising a 3' end and a 5' end; and the antisense strand comprising a 3' end and a 5' end.

[0280] The term “construct” may encompass an artificially assembled or isolated nucleic acid molecule which includes the polynucleotide of interest. In general, a construct may include the polynucleotide or polynucleotides of interest, a marker gene which in some cases can also be a gene of interest and appropriate regulatory sequences. It should be appreciated that the inclusion of regulatory sequences in a construct is optional, for example, such sequences may not be required in situations where the regulatory sequences of a host cell are to be used. The term “construct” includes vectors but should not be seen as being limited thereto.

[0281] The term “expression” may encompass the production of a functional end-product e.g., an RNA or a protein.

[0282] “Antisense” nucleic acids refer to nucleic acids that specifically hybridize (e.g., bind) with a complementary sense nucleic acid, e.g., cellular RNA and / or genomic DNA, under cellular conditions so as to inhibit expression (e.g., by inhibiting transcription and / or translation). The binding may be by conventional base pair complementarity or, for example, in the case of binding to DNA duplexes, through specific interactions in the major groove of the double helix.

[0283] Antisense technology is the process in which an antisense RNA or DNA molecule interacts with a target sense DNA or RNA strand. A sense strand is a 5' to 3' RNA molecule or DNA molecule. The complementary strand, or mirror strand, to the sense is called an antisense. When an antisense strand interacts with a sense RNA strand, the double helix is recognized as foreign to the cell and will be degraded, resulting in reduced or absent protein production. Although DNA is already a double-stranded molecule, antisense technology can be applied to it, building a triplex formation. Page 145 of 242P-636791-PC

[0284] The terms “complementary” or “complement thereof” are used herein to encompass the sequences of polynucleotides which is capable of forming Watson & Crick base pairing with another specified polynucleotide throughout the entirety of the complementary region. This term is applied to pairs of polynucleotides based solely upon their sequences and not any particular set of conditions under which the two polynucleotides would actually bind.

[0285] RNA antisense strands can be either catalytic or non-catalytic. The catalytic antisense strands, also called ribozymes, cleave the RNA molecule at specific sequences. A non-catalytic RNA antisense strand blocks further RNA processing.

[0286] Antisense modulation of cells and / or tissue levels of the globulin genes of interest and / or desaturase genes of interest or any combination thereof may be effected by transforming the organism’s cells or tissues with at least one antisense compound, including antisense DNA, antisense RNA, a ribozyme, DNAzyme, a locked nucleic acid (LNA) and an aptamer. In some embodiments the molecules are chemically modified. In other embodiments the antisense molecule is antisense DNA or an antisense DNA analog.

[0287] Antisense modulation of cells and / or tissue levels of the globulin genes of interest and / or desaturase genes of interest or any combination thereof may be effected by transforming the organism’s cells or tissues with at least one antisense compound, including antisense DNA, antisense RNA, a ribozyme, DNAzyme, a locked nucleic acid (LNA), and an aptamer. In some embodiments, the molecules are chemically modified. In other embodiments, the antisense molecule is antisense DNA or an antisense DNA analog.

[0288] The term “RNA interference” or “RNAi” refers to the silencing or decreasing of gene expression mediated by small double stranded RNAs. It is the process of sequence-specific, post-transcriptional gene silencing in animals and plants, initiated by inhibitory RNA (iRNA) that is homologous in its duplex region to the sequence of the silenced gene. The gene may be endogenous or exogenous to the organism, present integrated into a chromosome or present in a transfection vector that is not integrated into the genome. The expression of the gene is either completely or partially inhibited. RNAi may also be considered to inhibit the function of a target RNA; the function of the target RNA may be complete or partial.

[0289] The term “RNAi molecule” refers to single- or double-stranded RNA molecules comprising both a sense and antisense sequence. For example, the RNA interference molecule can be a double-stranded polynucleotide molecule comprising self-complementary sense and antisense regions, wherein the antisense region comprises complementarity to a target nucleic Page 146 of 242P-636791-PC acid molecule. Alternatively the RNAi molecule can be a single-stranded hairpin polynucleotide having self-complementary sense and antisense regions, wherein the antisense region comprises complementarity to a target nucleic acid molecule or it can be a circular single-stranded polynucleotide having two or more loop structures and a stem comprising self- complementary sense and antisense regions, wherein the antisense region comprises complementarity to a target nucleic acid molecule, and wherein the circular polynucleotide can be processed either in vivo or in vitro to generate an active molecule capable of mediating RNAi.

[0290] RNAi refers to the introduction of homologous double-stranded RNA (dsRNA) to target a specific gene product, resulting in post transcriptional silencing of that gene. This phenomenon was first reported in Caenorhabditis elegans by Guo and Kemphues (1995, Cell, 81(4):611-620) and subsequently Fire et al. (1998, Nature 391:806-811) discovered that it is the presence of dsRNA, formed from the annealing of sense and antisense strands present in the in vitro RNA preps, that is responsible for producing the interfering activity.

[0291] In both plants and animals, RNAi is mediated by RNA-induced silencing complex (RISC), a sequence-specific, multicomponent nuclease that destroys messenger RNAs homologous to the silencing trigger. RISC is known to contain short RNAs (approximately 22 nucleotides) derived from the double-stranded RNA trigger. The short-nucleotide RNA sequences are homologous to the target gene that is being suppressed. Thus, the short- nucleotide sequences appear to serve as guide sequences to instruct a multicomponent nuclease, RISC, to destroy the specific RNAs.

[0292] The dsRNA used to initiate RNAi, may be isolated from native source or produced by known means, e.g., transcribed from DNA. Plasmids and vectors for generating RNAi molecules against target sequence are now readily available from commercial sources.

[0293] The dsRNA can be transcribed from the vectors as two separate strands. In other embodiments, the two strands of DNA used to form the dsRNA may belong to the same or two different duplexes in which they each form with a DNA strand of at least partially complementary sequence. When the dsRNA is thus produced, the DNA sequence to be transcribed is flanked by two promoters, one controlling the transcription of one of the strands, and the other that of the complementary strand. These two promoters may be identical or different. Alternatively, a single promoter can derive the transcription of single-stranded Page 147 of 242P-636791-PC hairpin polynucleotide having self-complementary sense and antisense regions that anneal to produce the dsRNA.

[0294] The terms “promoter element,” “promoter,” or “promoter sequence” may encompass a DNA sequence that is located at the 5' end (i.e., precedes) the coding region of a DNA polymer. The location of most promoters known in nature precedes the transcribed region. The promoter functions as a switch, activating the expression of a gene. If the gene is activated, it is said to be transcribed, or participating in transcription. Transcription involves the synthesis of RNA from the gene. The promoter, therefore, serves as a transcriptional regulatory element and also provides a site for initiation of transcription of the gene into RNA.

[0295] Inhibition is sequence-specific in that nucleotide sequences corresponding to the duplex region of the RNA are targeted for genetic inhibition. RNA molecules containing a nucleotide sequence identical to a portion of the target gene are preferred for inhibition. RNA sequences with insertions, deletions, and single point mutations relative to the target sequence have also been found to be effective for inhibition. Thus, sequence identity may be optimized by sequence comparison and alignment algorithms known in the art (see Gribskov and Devereux, Sequence Analysis Primer, Stockton Press, 1991, and references cited therein) and calculating the percent difference between the nucleotide sequences by, for example, the Smith-Waterman algorithm as implemented in the BESTFITTM software program using default parameters (e.g., University of Wisconsin Genetic Computing Group). Greater than 90% sequence identity, or even 100% sequence identity, between the inhibitory RNA and the portion of the target gene is preferred. Alternatively, the duplex region of the RNA may be defined functionally as a nucleotide sequence that is capable of hybridizing with a portion of the target gene transcript. The length of the identical nucleotide sequences may be at least 25, 50, 100, 200, 300 or 400 bases. There is no upper limit on the length of the dsRNA that can be used. For example, the dsRNA can range from about 21 base pairs (bp) of the gene to the full- length of the gene or more.

[0296] In some embodiments, the composition comprises a small interfering RNA (siRNA). The siRNA moiety may further include a guanosine at the 5'-end.

[0297] The sense and / or antisense strands of the siRNA moiety may be equal to or less than 30, 25, 24, 23, 22, 21, 20, 19, 18 or 17 nucleotides in length. An siRNA moiety may include one or more overhangs. For example, the siRNA moiety may include one or two 3' overhangs of 2-3 nucleotides. In certain embodiments, the disclosure relates to any of the compositions Page 148 of 242P-636791-PC provided herein, wherein the siRNA moiety is composed of 21-nt sense and 21-nt antisense strands, paired in a manner to have a 19-nucleotide duplex region and a 2-nt 3' overhang at each 3' terminus. In certain embodiments, the disclosure relates to any of the compositions describe herein, wherein the 2-nt 3' overhang is either UU or dTdT. Symmetric 3'-overhangs ensure that the sequence-specific endonuclease complexes (siRNPs) are formed with approximately equal ratios of sense and antisense target RNA cleaving siRNPs. The 3'- overhang in the sense strand provides no contribution to recognition as it is believed the antisense siRNA strand guides target recognition. Therefore, the UU or dTdT 3'-overhang of the antisense sequences is complementary to the target RNA but the symmetrical UU or dTdT 3'-overhang of the sense siRNA oligo does not need to correspond to the RNA. The use of deoxythymidines in both 3'-overhangs may increase nuclease resistance, although siRNA duplexes with either UU or dTdT overhangs work equally well. 2'-Deoxynucleotides in the 3' overhangs are as efficient as ribonucleotides, but are often cheaper to synthesize.

[0298] The targeted region in the RNA, and hence the sequence in the siRNA duplex, are chosen using the following guidelines. The open reading frame (ORF) region from the cDNA sequence is recommended for targeting, preferably at least 50 to 100 nucleotides downstream of the start codon, most preferably at least 75-100. Both the 5' and 3' untranslated regions (UTRs) and regions near the start codon are not recommended for targeting as these may be richer in regulatory protein binding sites. UTR-binding proteins and / or translation initiation complexes may interfere with binding of the siRNP endonuclease complex.

[0299] The sequence of the RNA or cDNA is searched seeking the sequence AA(N19)TT. Sequences with approximately 50% G / C-content (30% to 70%) are used. If no suitable sequences are found, the search is extended to sequences AA(N21). The sequence of the sense siRNA corresponds to 5'-(N19)dTdT-3' or N21, respectively. In the latter case, the 3' end of the sense siRNA is converted to dTdT. The rationale for this sequence conversion is to generate a symmetric duplex with respect to the sequence composition of the sense and antisense 3' overhangs. It is believed that symmetric 3' overhangs help to ensure that the siRNPs are formed with approximately equal ratios of sense and antisense target RNA-cleaving siRNPs. The modification of the overhang of the sense sequence of the siRNA duplex is not expected to affect targeted RNA recognition, as the antisense siRNA strand glides target recognition.

[0300] If the target RNA does not contain a suitable AA(N21) sequence, it is recommended to search for NA(N21) The sequence of the sense and antisense strand may still be synthesized Page 149 of 242P-636791-PC as 5' (N19)TT as the sequence of the 3' most nucleotide of the antisense siRNA does not appear to contribute to specificity.

[0301] It is further recommended to search the selected siRNA sequence against EST libraries in appropriate databases (e.g., NCBI BLAST database search) to ensure that only one gene is targeted.

[0302] The appropriately designed siRNAs are either obtained from commercial sources (such as DHARMACON RESEARCHTM, Lafayette, Colo.; XERGONTM, Huntsville, Ala.; AMBIONTM, Austin, Tex.) or chemically synthesized used appropriately protected ribonucleoside phosphoramidites and a conventional DNA / RNA synthesizer according to standard protocols. The RNA oligonucleotides are 2'-deprotected, desalted and the two strands annealed, according to manufacturer's specifications or conventional protocols, depending on how the siRNAs are obtained. All handling steps are conducted under strict sterile, RNase-free conditions.

[0303] In some embodiments, a nucleic acid aptamer is included. Nucleic acid aptamers are nucleic acid oligomers that bind other macromolecules specifically; such aptamers that bind specifically to other macromolecules can be readily isolated from libraries of such oligomers by technologies such as SELEX. In some embodiments, an oligosaccharide is included. Certain oligosaccharides are known ligands for certain extracellular or cell surface receptors.

[0304] The term “homology” encompasses similarity of sequence attributed to descent from a common ancestor. Homologous biological components (genes, proteins, structures) are called homologs. The extent to which nucleotide or protein sequences are related. The similarity between two sequences (DNA, RNA, or amino acid) can be expressed as percent sequence identity and / or percent positive substitutions.

[0305] The term “homolog” encompasses a gene or a polypeptide (a protein) that is related to a second gene or polypeptide (protein), respectively, by descent from a common ancestral DNA or polypeptide (protein) sequence, respectively. Thus, a homolog of a gene, in some embodiments, comprises a similar nucleotide sequence to the gene. In some embodiments, a gene homolog encodes an identical polypeptide as is encoded by the gene. In some embodiments, a gene homolog encodes a polypeptide with the same functional properties as is encoded by the gene. In some embodiments, a gene homolog encodes a polypeptide that comprises a similar amino acid sequence as the polypeptide encoded by the gene. In one embodiment, the polypeptide homolog comprises a similar amino acid sequence as the Page 150 of 242P-636791-PC polypeptide. In some embodiments, the polypeptide homolog comprises the same functional properties as the polypeptide. In some embodiments, the polypeptide homolog comprises similar functional properties as the polypeptide. In some embodiments, the polypeptide homolog comprises a same domain(s) as the polypeptide. In some embodiments, the polypeptide homolog comprises a similar domain(s) as the polypeptide.

[0306] The terms “percent homology” or “percent identity” may be determined, for example but no limited to, using BlastP software of the National Center of Biotechnology Information (NCBI) using default parameters. The homolog may also refer to an ortholog, a deletion, insertion, or substitution variant, including an amino acid substitution. In some embodiments, sequence identity or homology can be determined using any protein or nucleic acid sequence alignment algorithm such as Blast, ClustalW, MUSCLE, and HHpred.

[0307] In some embodiments, gene homology and / or polypeptide homology can be based on shared motifs, for example but not limited to pfam domains, COG domains, DUF domains, transmembrane domains, and nuclease domains. In some embodiments, similarities of shared motifs are combined with the conserved size of the gene or the expression product in the different subtypes and the location of the gene in the gene cluster. Modified RNAs

[0308] In some embodiments, an RNA is a modified RNA as described herein below. In some embodiments, the present disclosure provides a composition or combination comprising one or more nucleoside-modified RNAs, wherein each of said modified RNAs encodes an anti- gD antigen binding agent, an anti-gB antigen binding agent, or a combination thereof.

[0309] In some embodiments, the present disclosure provides compositions comprising modified RNAs and methods of use thereof. In some embodiments, the modified RNA comprises one or more modified nucleoside residues. For example, in some embodiments, an RNA comprising a nucleotide sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to a sequence listed in any of Tables 1-5 and 11 comprises one or more modified nucleoside residues.

[0310] In some embodiments, an RNA as provided herein refers to a messenger RNA.

[0311] In some embodiments, all uridine residues are modified as provided herein. In some embodiments, one or more of the RNAs as provided herein are nucleoside-modified RNAs. In Page 151 of 242P-636791-PC other embodiments, two or more of the RNAs as provided herein are nucleoside-modified RNAs. In other embodiments, three or more of the RNAs as provided herein are nucleoside- modified RNAs.

[0312] In another embodiment, the modified nucleoside of the methods and compositions of the present disclosure is m5C (5-methylcytidine). In another embodiment, the modified nucleoside is m5U (5-methyluridine). In another embodiment, the modified nucleoside is m6A (N6-methyladenosine). In another embodiment, the modified nucleoside is s2U (2-thiouridine). In another embodiment, the modified nucleoside is Ψ (pseudouridine). In another embodiment, the modified nucleoside is Um (2'-O-methyluridine).

[0313] In other embodiments, the modified nucleoside is m1A (1-methyladenosine), m2A (2-methyladenosine), m6A (N6-methyladenosine), Am (2'-O-methyladenosine), ms2m6A (2- methylthio-N6-methyladenosine), i6A (N6-isopentenyladenosine), ms2i6A (2-methylthio-N6- isopentenyladenosine), io6A (N6-(cis-hydroxyisopentenyl)adenosine), ms2io6A (2-methylthio- N6-(cis-hydroxyisopentenyl) adenosine), g6A (N6-glycinylcarbamoyladenosine), t6A (N6- threonylcarbamoyladenosine), ms2t6A (2-methylthio-N6-threonyl carbamoyladenosine), m6t6A (N6-methyl-N6-threonylcarbamoyladenosine), hn6A (N6- hydroxynorvalylcarbamoyladenosine), ms2hn6A (2-methylthio-N6-hydroxynorvalyl carbamoyladenosine), Ar(p) (2'-O-ribosyladenosine (phosphate)), I (inosine), m1I (1- methylinosine), m1Im (1,2'-O-dimethylinosine), m3C (3-methylcytidine), m5C (5- methylcytidine), Cm (2'-O-methylcytidine), s2C (2-thiocytidine), ac4C (N4-acetylcytidine), f5C (5-formylcytidine), m5Cm (5,2'-O-dimethylcytidine), ac4Cm (N4-acetyl-2'-O-methylcytidine), k2C (lysidine), m1G (1-methylguanosine), m2G (N2-methylguanosine), m7G (7- methylguanosine), Gm (2'-O-methylguanosine), m22G (N2,N2-dimethylguanosine), m2Gm (N2,2'-O-dimethylguanosine), m22Gm (N2,N2,2'-O-trimethylguanosine), Gr(p) (2'-O- ribosylguanosine (phosphate)), yW (wybutosine), o2yW (peroxywybutosine), OHyW (hydroxywybutosine), OHyW* (undermodified hydroxywybutosine), imG (wyosine), mimG (methylwyosine), Q (queuosine), oQ (epoxyqueuosine), galQ (galactosyl-queuosine), manQ (mannosyl-queuosine), preQ0 (7-cyano-7-deazaguanosine), preQ1 (7-aminomethyl-7- deazaguanosine), G+(archaeosine), Ψ (pseudouridine), D (dihydrouridine), m5U (5- methyluridine), Um (2'-O-methyluridine), m5Um (5,2'-O-dimethyluridine), m1Ψ (1- methylpseudouridine), Ψm (2'-O-methylpseudouridine), s2U (2-thiouridine), s4U (4- thiouridine), m5s2U (5-methyl-2-thiouridine), s2Um (2-thio-2'-O-methyluridine), acp3U (3-(3- amino-3-carboxypropyl)uridine), ho5U (5-hydroxyuridine), mo5U (5-methoxyuridine), cmo5U Page 152 of 242P-636791-PC (uridine 5-oxyacetic acid), mcmo5U (uridine 5-oxyacetic acid methyl ester), chm5U (5- (carboxyhydroxymethyl)uridine), mchm5U (5-(carboxyhydroxymethyl)uridine methyl ester), mcm5U (5-methoxycarbonylmethyluridine), mcm5Um (5-methoxycarbonylmethyl-2'-O- methyluridine), mcm5s2U (5-methoxycarbonylmethyl-2-thiouridine), nm5s2U (5- aminomethyl-2-thiouridine), mnm5U (5-methylaminomethyluridine), mnm5s2U (5- methylaminomethyl-2-thiouridine), mnm5se2U (5-methylaminomethyl-2-selenouridine), ncm5U (5-carbamoylmethyluridine), ncm5Um (5-carbamoylmethyl-2'-O-methyluridine), cmnm5U (5-carboxymethylaminomethyluridine), cmnm5Um (5-carboxymethylaminomethyl- 2'-O-methyluridine), cmnm5s2U (5-carboxymethylaminomethyl-2-thiouridine), m62A (N6,N6- dimethyladenosine), Im (2'-O-methylinosine), m4C (N4-methylcytidine), m4Cm (N4,2'-O- dimethylcytidine), hm5C (5-hydroxymethylcytidine), m3U (3-methyluridine), m1acp3Ψ (1- methyl-3-(3-amino-3-carboxypropyl) pseudouridine), cm5U (5-carboxymethyluridine), m6Am (N6,2'-O-dimethyladenosine), m62Am (N6,N6,2'-O-trimethyladenosine), m2,7G (N2,7- dimethylguanosine), m2,2,7G (N2,N2,7-trimethylguanosine), m3Um (3,2'-O-dimethyluridine), m5D (5-methyldihydrouridine), m3Ψ (3-methylpseudouridine), f5Cm (5-formyl-2'-O- methylcytidine), m1Gm (1,2'-O-dimethylguanosine), m1Am (1,2'-O-dimethyladenosine), τm5U (5-taurinomethyluridine), τm5s2U (5-taurinomethyl-2-thiouridine), imG-14 (4- demethylwyosine), imG2 (isowyosine), ac6A (N6-acetyladenosine), inm5U (5- (isopentenylaminomethyl)uridine), inm5s2U (5-(isopentenylaminomethyl)- 2-thiouridine), inm5Um (5-(isopentenylaminomethyl)- 2'-O-methyluridine), m2,7Gm (N2,7,2'-O- trimethylguanosine), m42Cm (N4,N4,2'-O-trimethylcytidine), C+(agmatidine), m8A (8- methyladenosine), gmnm5s2U (geranylated 5-methylaminomethyl-2-thiouridine), gcmnm5s2U (geranylated 5-carboxymethylaminomethyl-2-thiouridine), or cnm5U (5-cyanomethyl- uridine).

[0314] In some embodiments, the modified nucleoside residues are pseudouridine or pseudouridine family residues.

[0315] In some embodiments, the modified RNA comprises pseudouridine residues. In some embodiments, pseudouridine refers to the C-glycoside isomer of the nucleoside uridine. In some embodiments, pseudouridine residues comprise m1acp3Ψ (1-methyl-3-(3-amino-5- carboxypropyl)pseudouridine, m1Ψ (1-methylpseudouridine), Ψm (2′-O-methylpseudouridine, m5D (5-methyldihydrouridine), m3Ψ (3-methylpseudouridine), or a combination thereof. In some embodiments, said pseudouridine residues comprise 1-methylpseudouridine residues instead of uridine. Page 153 of 242P-636791-PC

[0316] In some embodiments, the modified nucleoside residues are pseudouridine analogues. In some embodiments, a "pseudouridine analog" is any modification, variant, isoform or derivative of pseudouridine. For example, pseudouridine analogs include but are not limited to 1-carboxymethyl-pseudouridine, 1-propynyl-pseudouridine, 1-taurinomethyl- pseudouridine, 1-taurinomethyl-4-thio-pseudouridine, 1-methylpseudouridine (m1Ψ), 1- methyl-4-thio-pseudouridine (m1s4Ψ), 4-thio-1-methyl-pseudouridine, 3-methyl- pseudouridine (m3Ψ), 2-thio-1-methyl-pseudouridine, 1-methyl-1-deaza-pseudouridine, 2- thio-1-methyl-1-deaza-pseudouridine, dihydropseudouridine, 2-thio-dihydropseudouridine, 2- methoxyuridine, 2-methoxy-4-thio-uridine, 4-methoxy-pseudouridine, 4-methoxy-2-thio- pseudouridine, N1-methyl-pseudouridine, 1-methyl-3-(3-amino-3- carboxypropyl)pseudouridine (acp3Ψ), and 2'-O-methyl-pseudouridine (Ψm).

[0317] In some embodiments, the modified nucleobase is a modified uracil. Exemplary nucleobases and nucleosides having a modified uracil include pseudouridine (Ψ), pyridin-4- one ribonucleoside, 5-aza-uridine, 6-aza-uridine, 2-thio-5-aza-uridine, 2-thio-uridine (s2U), 4- thio-uridine (s4U), 4-thio-pseudouridine, 2-thio-pseudouridine, 5-hydroxy-uridine (ho5U), 5- aminoallyl-uridine, 5-halo-uridine (e.g., 5-iodo-uridine or 5-bromo-uridine), 3-methyl-uridine (m3U), 5-methoxy-uridine (mo5U), uridine 5-oxyacetic acid (cmo5U), uridine 5-oxyacetic acid methyl ester (mcmo5U), 5-carboxymethyl-uridine (cm5U), 1-carboxymethyl-pseudouridine, 5- carboxyhydroxymethyl-uridine (chm5U), 5-carboxyhydroxymethyl-uridine methyl ester (mchm5U), 5-methoxycarbonylmethyl-uridine (mcm5U), 5-methoxycarbonylmethyl-2-thio- uridine (mcm5s2U), 5-aminomethyl-2-thio-uridine (nm5s2U), 5-methylaminomethyl-uridine (mnm5U), 5-methylaminomethyl-2-thio-uridine (mnm5s2U), 5-methylaminomethyl-2-seleno- uridine (mnm5se2U), 5-carbamoylmethyl-uridine (ncm5U), 5-carboxymethylaminomethyl- uridine (cmnm5U), 5-carboxymethylaminomethyl-2-thio-uridine (cmnm5s2U), 5-propynyl- uridine, 1-propynyl-pseudouridine, 5-taurinomethyl-uridine (τcm5U), 1-taurinomethyl- pseudouridine, 5-taurinomethyl-2-thio-uridine (τrm5s2U), 1-taurinomethyl-4-thio- pseudouridine, 5-methyl-uridine (m5U, i.e., having the nucleobase deoxythymine), 1- methylpseudouridine (m1Ψ), 5-methyl-2-thio-uridine (m5s2U), 1-methyl-4-thio-pseudouridine (m1s4Ψ), 4-thio-1-methyl-pseudouridine, 3-methyl-pseudouridine (m3Ψ), 2-thio-1-methyl- pseudouridine, 1-methyl-1-deaza-pseudouridine, 2-thio-1-methyl-1-deaza-pseudouridine, dihydrouridine (D), dihydropseudouridine, 5,6-dihydrouridine, 5-methyl-dihydrouridine (m5D), 2-thio-dihydrouridine, 2-thio-dihydropseudouridine, 2-methoxy-uridine, 2-methoxy-4- thio-uridine, 4-methoxy-pseudouridine, 4-methoxy-2-thio-pseudouridine, N1-methyl- Page 154 of 242P-636791-PC pseudouridine (also known as 1-methylpseudouridine (m1Ψ), 3-(3-amino-3- carboxypropyl)uridine (acp3U), 1-methyl-3-(3-amino-3-carboxypropyl)pseudouridine (acp3Ψ), 5-(isopentenylaminomethyl)uridine (inm5U), 5-(isopentenylaminomethyl)-2-thio- uridine (inm5s2U), α-thio-uridine, 2'-O-methyl-uridine (Um), 5,2'-O-dimethyl-uridine (m5Um), 2'-O-methyl-pseudouridine (Ψm), 2-thio-2'-O-methyl-uridine (s2Um), 5- methoxycarbonylmethyl-2'-O-methyl-uridine (mcm5Um), 5-carbamoylmethyl-2'-β-methyl- uridine (ncm5Um), 5-carboxymethylaminomethyl-2'-O-methyl-uridine (cmnm5Um), 3,2'-O- dimethyl-uridine (m3Um), 5-(isopentenylaminomethyl)-2'-β-methyl-uridine (inm5Um), 1-thio- uridine, deoxythymidine, 2'-F-ara-uridine, 2'-F-uridine, 2'-OH-ara-uridine, 5-(2- carbomethoxyvinyl)uridine, and 5-[3-(1-E-propenylamino)uridine.

[0318] In some embodiments, the modified nucleobase is a modified cytosine. Exemplary nucleobases and nucleosides having a modified cytosine include 5-aza-cytidine, 6-aza- cytidine, pseudoisocytidine, 3-methyl-cytidine (m3C), N4-acetyl-cytidine (ac4C), 5-formyl- cytidine (f5C), N4-methyl-cytidine (m4C), 5-methyl-cytidine (m5C), 5-halo-cytidine (e.g., 5- iodo-cytidine), 5-hydroxymethyl-cytidine (hm5C), 1-methyl-pseudoisocytidine, pyrrolo- cytidine, pyrrolo-pseudoisocytidine, 2-thio-cytidine (s2C), 2-thio-5-methyl-cytidine, 4-thio- pseudoisocytidine, 4-thio-1-methyl-pseudoisocytidine, 4-thio-1-methyl-1-deaza- pseudoisocytidine, 1-methyl-1-deaza-pseudoisocytidine, zebularine, 5-aza-zebularine, 5- methyl-zebularine, 5-aza-2-thio-zebularine, 2-thio-zebularine, 2-methoxy-cytidine, 2- methoxy-5-methyl-cytidine, 4-methoxy-pseudoisocytidine, 4-methoxy-1-methyl- pseudoisocytidine, lysidine (k2C), α-thio-cytidine, 2'-O-methyl-cytidine (Cm), 5,2'-O- dimethyl-cytidine (m5Cm), N4-acetyl-2'-O-methyl-cytidine (ac4Cm), N4,2'-O-dimethyl- cytidine (m4Cm), 5-formyl-2'-O-methyl-cytidine (f5Cm), N4,N4,2'-O-trimethyl-cytidine (m42Cm), 1-thio-cytidine, 2'-F-ara-cytidine, 2'-F-cytidine, and 2'-OH-ara-cytidine.

[0319] In some embodiments, the modified nucleobase is a modified adenine. Exemplary nucleobases and nucleosides having a modified adenine include 2-amino-purine, 2,6- diaminopurine, 2-amino-6-halo-purine (e.g., 2-amino-6-chloro-purine), 6-halo-purine (e.g., 6- chloro-purine), 2-amino-6-methyl-purine, 8-azido-adenosine, 7-deaza-adenine, 7-deaza-8-aza- adenine, 7-deaza-2-amino-purine, 7-deaza-8-aza-2-amino-purine, 7-deaza-2,6-diaminopurine, 7-deaza-8-aza-2,6-diaminopurine, 1-methyl-adenosine (m1A), 2-methyl-adenine (m2A), N6- methyl-adenosine (m6A), 2-methylthio-N6-methyl-adenosine (ms2m6A), N6-isopentenyl- adenosine (i6A), 2-methylthio-N6-isopentenyl-adenosine (ms2i6A), N6-(cis- hydroxyisopentenyl)adenosine (io6A), 2-methylthio-N6-(cis-hydroxyisopentenyl)adenosine Page 155 of 242P-636791-PC (ms2io6A), N6-glycinylcarbamoyl-adenosine (g6A), N6-threonylcarbamoyl-adenosine (t6A), N6-methyl-N6-threonylcarbamoyl-adenosine (m6t6A), 2-methylthio-N6-threonylcarbamoyl- adenosine (ms2g6A), N6,N6-dimethyl-adenosine (m62A), N6-hydroxynorvalylcarbamoyl- adenosine (hn6A), 2-methylthio-N6-hydroxynorvalylcarbamoyl-adenosine (ms2hn6A), N6- acetyl-adenosine (ac6A), 7-methyl-adenine, 2-methylthio-adenine, 2-methoxy-adenine, α-thio- adenosine, 2'-O-methyl-adenosine (Am), N6,2'-O-dimethyl-adenosine (m6Am), N6,N6,2'-O- trimethyl-adenosine (m62Am), 1,2'-O-dimethyl-adenosine (m1Am), 2'-β-ribosyladenosine (phosphate) (Ar(p)), 2-amino-N6-methyl-purine, 1-thio-adenosine, 8-azido-adenosine, 2'-F- ara-adenosine, 2'-F-adenosine, 2'-OH-ara-adenosine, and N6-(19-amino-pentaoxanonadecyl)- adenosine.

[0320] In some embodiments, the modified nucleobase is a modified guanine. Exemplary nucleobases and nucleosides having a modified guanine include inosine (I), 1-methyl-inosine (m1I), wyosine (imG), methylwyosine (mimG), 4-demethyl-wyosine (imG-14), isowyosine (imG2), wybutosine (yW), peroxywybutosine (o2yW), hydroxywybutosine (OHyW), undermodified hydroxywybutosine (OHyW*), 7-deaza-guanosine, queuosine (Q), epoxyqueuosine (oQ), galactosyl-queuosine (galQ), mannosyl-queuosine (manQ), 7-cyano-7- deaza-guanosine (preQ0), 7-aminomethyl-7-deaza-guanosine (preQ1), archaeosine (G+), 7- deaza-8-aza-guanosine, 6-thio-guanosine, 6-thio-7-deaza-guanosine, 6-thio-7-deaza-8-aza- guanosine, 7-methyl-guanosine (m7G), 6-thio-7-methyl-guanosine, 7-methyl-inosine, 6- methoxy-guanosine, 1-methyl-guanosine (m1G), N2-methyl-guanosine (m2G), N2,N2- dimethyl-guanosine (m22G), N2,7-dimethyl-guanosine (m2,7G), N2,N2,7-dimethyl-guanosine (m2,2,7G), 8-oxo-guanosine, 7-methyl-8-oxo-guanosine, 1-methyl-6-thio-guanosine, N2- methyl-6-thio-guanosine, N2,N2-dimethyl-6-thio-guanosine, α-thio-guanosine, 2'-O-methyl- guanosine (Gm), N2-methyl-2'-O-methyl-guanosine (m2Gm), N2,N2-dimethyl-2'-O-methyl- guanosine (m22Gm), 1-methyl-2'-O-methyl-guanosine (m1Gm), N2,7-dimethyl-2'-O-methyl- guanosine (m2'7Gm), 2'-O-methyl-inosine (Im), 1,2'-O-dimethyl-inosine (m1Im), and 2'-O- ribosylguanosine (phosphate) (Gr(p)).

[0321] The nucleobase of the nucleotide can be independently selected from a purine, a pyrimidine, a purine or pyrimidine analog. For example, the nucleobase can each be independently selected from adenine, cytosine, guanine, uracil, or hypoxanthine. In another embodiment, the nucleobase can also include, for example, naturally-occurring and synthetic derivatives of a base, including pyrazolo[3,4-d]pyrimidines, 5-methylcytosine (5-me-C), 5- hydroxymethyl cytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-methyl and other alkyl Page 156 of 242P-636791-PC derivatives of adenine and guanine, 2-propyl and other alkyl derivatives of adenine and guanine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-propynyl uracil and cytosine, 6-azo uracil, cytosine and thymine, 5-uracil (pseudouracil), 4-thiouracil, 8-halo (e.g., 8-bromo), 8- amino, 8-thiol, 8-thioalkyl, 8-hydroxyl and other 8-substituted adenines and guanines, 5-halo particularly 5-bromo, 5-trifluoromethyl and other 5-substituted uracils and cytosines, 7- methylguanine and 7-methyladenine, 8-azaguanine and 8-azaadenine, deazaguanine, 7- deazaguanine, 3-deazaguanine, deazaadenine, 7-deazaadenine, 3-deazaadenine, pyrazolo[3,4- d]pyrimidine, imidazo[1,5-a]1,3,5 triazinones, 9-deazapurines, imidazo[4,5-d]pyrazines, thiazolo[4,5-d]pyrimidines, pyrazin-2-ones, 1,2,4-triazine, pyridazine; and 1,3,5 triazine. When the nucleotides are depicted using the shorthand A, G, C, T or U, each letter refers to the representative base and / or derivatives thereof, e.g., A includes adenine or adenine analogs, e.g., 7-deaza adenine).

[0322] Modifications on the Internucleoside Linkage

[0323] The modified nucleotides, which may be incorporated into a polynucleotide, primary construct, or RNA molecule, can be modified on the internucleoside linkage (e.g., phosphate backbone). Herein, in the context of the polynucleotide backbone, the phrases "phosphate" and "phosphodiester" are used interchangeably. Backbone phosphate groups can be modified by replacing one or more of the oxygen atoms with a different substituent. Further, the modified nucleosides and nucleotides can include the wholesale replacement of an unmodified phosphate moiety with another internucleoside linkage as provided herein. Examples of modified phosphate groups include, but are not limited to, phosphorothioate, phosphoroselenates, boranophosphates, boranophosphate esters, hydrogen phosphonates, phosphoramidates, phosphorodiamidates, alkyl or aryl phosphonates, and phosphotriesters. Phosphorodithioates have both non-linking oxygens replaced by sulfur. The phosphate linker can also be modified by the replacement of a linking oxygen with nitrogen (bridged phosphoramidates), sulfur (bridged phosphorothioates), and carbon (bridged methylene-phosphonates).

[0324] The α-thio substituted phosphate moiety is provided to confer stability to RNA and DNA polymers through the unnatural phosphorothioate backbone linkages. Phosphorothioate DNA and RNA have increased nuclease resistance and subsequently a longer half-life in a cellular environment. Phosphorothioate linked polynucleotides, primary constructs, or modified RNA molecules are expected to also reduce the innate immune response through weaker binding / activation of cellular innate immune molecules. Page 157 of 242P-636791-PC

[0325] In specific embodiments, a modified nucleoside includes an alpha-thio-nucleoside (e.g., 5'-O-(1-thiophosphate)-adenosine, 5'-O-(1-thiophosphate)-cytidine (α-thio-cytidine), 5'- O-(1-thiophosphate)-guanosine, 5'-O-(1-thiophosphate)-uridine, or 5'-O-(1-thiophosphate)- pseudouridine).

[0326] Other internucleoside linkages that may be employed according to the present disclosure, including internucleoside linkages which do not contain a phosphorous atom, are provided herein below.

[0327] Combinations of Modified Sugars, Nucleobases, and Internucleoside Linkages

[0328] The polynucleotides, primary constructs, and modified RNA of the disclosure can include a combination of modifications to the sugar, the nucleobase, and / or the internucleoside linkage.

[0329] In some embodiments, purified preparation of RNA, oligoribonucleotide, or polyribonucleotide of the methods and compositions of the present disclosure comprises a combination of two or more of the above-provided modifications. In some embodiments, purified preparation of an RNA or oligoribonucleotide comprises a combination of three or more of the above-provided modifications. In some embodiments, a purified preparation of an RNA or oligoribonucleotide comprises a combination of more than three of the above-provided modifications.

[0330] In some embodiments, modified RNAs comprise in vitro-synthesized modified RNAs.

[0331] In some embodiments, the present disclosure comprises one or more modified RNAs encoding an anti-glycoprotein D (gD) antigen binding agent. In some embodiments, a modified RNA comprises pseudouridine or pseudouridine family residues. In some embodiments, modified RNAs of the present disclosure direct protein expression of HSV glycoproteins encoded thereon.

[0332] In some embodiments, the present disclosure provides an in vitro-transcribed RNA molecule encoding an an anti-glycoprotein D (gD) antigen binding agent, comprising a pseudouridine. In some embodiments, the present disclosure provides a synthetic RNA molecule encoding an anti-glycoprotein D (gD) antigen binding agent, comprising a pseudouridine.

[0333] In some embodiments, an in vitro-transcribed RNA molecule of the methods and compositions of the present disclosure is synthesized by T7 phage RNA polymerase. In some Page 158 of 242P-636791-PC embodiments, a molecule is synthesized by SP6 phage RNA polymerase. In some embodiments, a molecule is synthesized by T3 phage RNA polymerase. In some embodiments, a molecule is synthesized by a polymerase selected from the above polymerases. In some embodiments, an RNA is synthesized chemically on a column similar to DNA.

[0334] In some embodiments, a nucleoside that is modified in an RNA, oligoribonucleotide, or polyribonucleotide of the methods and compositions of the present disclosure is uridine (U). In some embodiments, a modified nucleoside is cytidine (C). In some embodiments, the modified nucleoside is adenine (A). In some embodiments, a modified nucleoside is guanine (G).

[0335] In some embodiments, an RNA of the methods and compositions of the present disclosure further comprises a poly-A tail. In some embodiments, an RNA of the methods and compositions of the present disclosure does not comprise a poly-A tail. Each possibility represents a separate embodiment of the present disclosure.

[0336] In some embodiments, an RNA of the methods and compositions of the present disclosure comprises a cap. In some embodiments, the cap is a 5’ cap. In some embodiments, the 5’ cap comprises a trinucleotide cap. In some embodiments, the 5’ cap generates a Cap 1 structure.

[0337] In some embodiments, the cap comprises an m7GpppG cap. In some embodiments, RNA of the methods and compositions of the present disclosure does not comprise an m7GpppG cap. In some embodiments, an RNA of the methods and compositions of the present disclosure comprises a 3′-O-methyl-m7GpppG. In some embodiments, an RNA of methods and compositions of the present disclosure comprises a non-reversible cap analog, which, in some embodiments, is added during transcription of the RNA. In some embodiments, an RNA of methods and compositions of the present disclosure comprises an anti-reverse cap analog. Each possibility represents a separate embodiment of the present disclosure.

[0338] In some embodiments, an RNA of the methods and compositions of the present disclosure further comprises a cap-independent translational enhancer. In some embodiments, an RNA of the methods and compositions of the present disclosure does not comprise a cap- independent translational enhancer. In some embodiments, the cap-independent translational enhancer is a tobacco etch virus (TEV) cap-independent translational enhancer. In some embodiments, the cap-independent translational enhancer is any other cap-independent Page 159 of 242P-636791-PC translational enhancer known in the art. Each possibility represents a separate embodiment of the present disclosure.

[0339] In some embodiments, “pseudouridine” refers to m1acp3Ψ (1-methyl-3-(3-amino-5- carboxypropyl)pseudouridine. In some embodiments, the term refers to m1Ψ (1- methylpseudouridine). In some embodiments, the term refers to Ψm (2′-O- methylpseudouridine. In some embodiments, the term refers to m5D (5-methyldihydrouridine). In some embodiments, the term refers to m3Ψ (3-methylpseudouridine). In some embodiments, the modified nucleoside is 4' (pseudouridine). In some embodiments, the term refers to a pseudouridine moiety that is not further modified. In some embodiments, the term refers to a monophosphate, diphosphate, or triphosphate of any of the above pseudouridines. In some embodiments, the term refers to any other pseudouridine known in the art. Each possibility represents a separate embodiment of the present disclosure.

[0340] In some embodiments, a modified RNA comprises a modified nucleoside, which in some embodiments, comprises m5C, m5U, m6A, s2U, Ψ, 2'-O-methyl-U, 2’-O- methylpseudouridine, or a combination thereof.

[0341] In some embodiments, the present disclosure provides a method for delivering a recombinant protein to a subject, the method comprising the step of contacting the subject with an RNA of the methods and compositions of the present disclosure, thereby delivering a recombinant protein to a subject.

[0342] In some embodiments, a method of the present disclosure comprises increasing the number, percentage, or frequency of modified uridine nucleosides in the RNA molecule to decrease immunogenicity or increase efficiency of translation. In some embodiments, the number of modified uridine residues in an RNA, oligoribonucleotide, or polyribonucleotide molecule determines the magnitude of the effects observed in the present disclosure.

[0343] In some embodiments, between 0.1% and 100% of the uridine residues in the modified RNAs of the methods and compositions of the present disclosure are modified (e.g. by the presence of pseudouridine). In some embodiments, 0.1% of the residues are modified. In some embodiments, 0.2%. In some embodiments, the fraction is 0.3%. In some embodiments, the fraction is 0.4%. In some embodiments, the fraction is 0.5%. In some embodiments, the fraction is 0.6%. In some embodiments, the fraction is 0.8%. In some embodiments, the fraction is 1%. In some embodiments, the fraction is 1.5%. In some embodiments, the fraction is 2%. In some embodiments, the fraction is 2.5%. In some Page 160 of 242P-636791-PC embodiments, the fraction is 3%. In some embodiments, the fraction is 4%. In some embodiments, the fraction is 5%. In some embodiments, the fraction is 6%. In some embodiments, the fraction is 8%. In some embodiments, the fraction is 10%. In some embodiments, the fraction is 12%. In some embodiments, the fraction is 14%. In some embodiments, the fraction is 16%. In some embodiments, the fraction is 18%. In some embodiments, the fraction is 20%. In some embodiments, the fraction is 25%. In some embodiments, the fraction is 30%. In some embodiments, the fraction is 35%. In some embodiments, the fraction is 40%. In some embodiments, the fraction is 45%. In some embodiments, the fraction is 50%. In some embodiments, the fraction is 60%. In some embodiments, the fraction is 70%. In some embodiments, the fraction is 80%. In some embodiments, the fraction is 90%. In some embodiments, the fraction is 100%.

[0344] In some embodiments, the fraction is less than 5%. In some embodiments, the fraction is less than 3%. In some embodiments, the fraction is less than 1%. In some embodiments, the fraction is less than 2%. In some embodiments, the fraction is less than 4%. In some embodiments, the fraction is less than 6%. In some embodiments, the fraction is less than 8%. In some embodiments, the fraction is less than 10%. In some embodiments, the fraction is less than 12%. In some embodiments, the fraction is less than 15%. In some embodiments, the fraction is less than 20%. In some embodiments, the fraction is less than 30%. In some embodiments, the fraction is less than 40%. In some embodiments, the fraction is less than 50%. In some embodiments, the fraction is less than 60%. In some embodiments, the fraction is less than 70%

[0345] In some embodiments, 0.1% of the residues of a given uridine nucleotide are modified. In some embodiments, the fraction of the nucleotide is 0.2%. In some embodiments, the fraction is 0.3%. In some embodiments, the fraction is 0.4%. In some embodiments, the fraction is 0.5%. In some embodiments, the fraction is 0.6%. In some embodiments, the fraction is 0.8%. In some embodiments, the fraction is 1%. In some embodiments, the fraction is 1.5%. In some embodiments, the fraction is 2%. In some embodiments, the fraction is 2.5%. In some embodiments, the fraction is 3%. In some embodiments, the fraction is 4%. In some embodiments, the fraction is 5%. In some embodiments, the fraction is 6%. In some embodiments, the fraction is 8%. In some embodiments, the fraction is 10%. In some embodiments, the fraction is 12%. In some embodiments, the fraction is 14%. In some embodiments, the fraction is 16%. In some embodiments, the fraction is 18%. In some embodiments, the fraction is 20%. In some embodiments, the fraction is 25%. In some Page 161 of 242P-636791-PC embodiments, the fraction is 30%. In some embodiments, the fraction is 35%. In some embodiments, the fraction is 40%. In some embodiments, the fraction is 45%. In some embodiments, the fraction is 50%. In some embodiments, the fraction is 60%. In some embodiments, the fraction is 70%. In some embodiments, the fraction is 80%. In some embodiments, the fraction is 90%. In some embodiments, the fraction is 100%.

[0346] In some embodiments, the fraction of the given uridine nucleotide is less than 8%. In some embodiments, the fraction is less than 10%. In some embodiments, the fraction is less than 5%. In some embodiments, the fraction is less than 3%. In some embodiments, the fraction is less than 1%. In some embodiments, the fraction is less than 2%. In some embodiments, the fraction is less than 4%. In some embodiments, the fraction is less than 6%. In some embodiments, the fraction is less than 12%. In some embodiments, the fraction is less than 15%. In some embodiments, the fraction is less than 20%. In some embodiments, the fraction is less than 30%. In some embodiments, the fraction is less than 40%. In some embodiments, the fraction is less than 50%. In some embodiments, the fraction is less than 60%. In some embodiments, the fraction is less than 70%.

[0347] In some embodiments, the terms “ribonucleotide,” “oligoribonucleotide,” and polyribonucleotide refers to, in some embodiments, compounds comprising nucleotides in which the sugar moiety is ribose. In some embodiments, the term includes both RNA and RNA derivates in which the backbone is modified. Numerous RNA backbone modifications are known in the art and contemplated in the present disclosure. In some embodiments, modified RNA is a PNA (peptide nucleic acid). PNA contain peptide backbones and nucleotide bases and are able to bind, in some embodiments, to both DNA and RNA molecules. In some embodiments, the nucleotide is modified by replacement of one or more phosphodiester bonds with a phosphorothioate bond. In some embodiments, the artificial nucleic acid contains any other variant of the phosphate backbone of native nucleic acids known in the art. Each nucleic acid derivative represents a separate embodiment of the present disclosure.

[0348] Methods for production of nucleic acids having modified backbones are well known in the art, and are provided, for example in U.S. Pat. Nos. 5,723,335 and 5,663,153 issued to Hutcherson et al. and related PCT publication WO95 / 26204. Each method represents a separate embodiment of the present disclosure.

[0349] The nucleic acid of interest can be purified by any method known in the art, or any method to be developed, so long as the method of purification removes contaminants from the Page 162 of 242P-636791-PC nucleic acid preparation and thereby substantially reduces the immunogenicity potential of the nucleic acid preparation. In some embodiments, the nucleic acid of interest is purified using high-performance liquid chromatography (HPLC). In some embodiments, a nucleic acid of interest is purified by contacting the nucleic acid of interest with the bacterial enzyme RNase III. In other various embodiments, any method of nucleic acid purification that substantially reduces the immunogenicity of the nucleic acid preparation can be used. Non-limiting examples of purification methods that can be used with the compositions and methods of the disclosure include liquid chromatography separation and enzyme digestion, each used alone or in any combination, simultaneously or in any order. Non-limiting examples of liquid chromatography separation include HPLC and fast protein liquid chromatography (FPLC). Materials useful in the HPLC and FPLC methods of the disclosure include, but are not limited to, cross-linked polystyrene / divinylbenzene (PS / DVB), PS / DVB-C18, PS / DVB-alkylated, Helix DNA columns (Varian), Eclipse dsDNA Analysis Columns (Agilent Technologies), Reverse-phase 5 (RPC-5) exchange material, DNAPac, ProSwift, and bio-inert UltiMate.RTM. 3000 Titanium columns (Dionex). Enzymes useful in the enzyme digestion methods of the disclosure include any enzyme able to digest any contaminant in a nucleic acid preparation of the disclosure, such as, for example a dsRNA contaminant, and include but are not limited to, RNase III, RNase V1, Dicer, and Chipper (see Fruscoloni et al., 2002, PNAS 100:1639) Non- limiting examples of assays for assessing the purity of the nucleic acid of interest include a dot- blot assay, a Northern blot assay, and a dendritic cell activation assay, as provided elsewhere herein.

[0350] In some embodiments, the modified RNA of the methods and compositions of the present disclosure is significantly less immunogenic than an unmodified in vitro-synthesized RNA molecule with the same sequence. In some embodiments, the modified RNA molecule is 2-fold less immunogenic than its unmodified counterpart. In some embodiments, immunogenicity is reduced by a 3-fold factor. In some embodiments, immunogenicity is reduced by a 5-fold factor. In some embodiments, immunogenicity is reduced by a 7-fold factor. In some embodiments, immunogenicity is reduced by a 10-fold factor. In some embodiments, immunogenicity is reduced by a 15-fold factor. In some embodiments, immunogenicity is reduced by a fold factor. In some embodiments, immunogenicity is reduced by a 50-fold factor. In some embodiments, immunogenicity is reduced by a 100-fold factor. In some embodiments, immunogenicity is reduced by a 200-fold factor. In some embodiments, immunogenicity is reduced by a 500-fold factor. In some embodiments, immunogenicity is Page 163 of 242P-636791-PC reduced by a 1000-fold factor. In some embodiments, immunogenicity is reduced by a 2000- fold factor. In some embodiments, immunogenicity is reduced by another fold difference.

[0351] In some embodiments, “significantly less immunogenic” refers to a detectable decrease in immunogenicity. In some embodiments, the term refers to a fold decrease in immunogenicity (e.g. 1 of the fold decreases enumerated above). In some embodiments, the term refers to a decrease such that an effective amount of the modified RNA can be administered without triggering a detectable immune response. In some embodiments, the term refers to a decrease such that the modified RNA can be repeatedly administered without eliciting an immune response sufficient to detectably reduce expression of the recombinant protein. In some embodiments, the decrease is such that the modified RNA can be repeatedly administered without eliciting an immune response sufficient to eliminate detectable expression of the recombinant protein.

[0352] Methods of determining immunogenicity are well known in the art, and provided in detail in U. S. Patent 8,278,036 which is hereby incorporated by reference herein.

[0353] In some embodiments, the modified RNA of the methods and compositions of the present disclosure is translated in the cell more efficiently than an unmodified RNA molecule with the same sequence. In some embodiments, the modified RNA exhibits enhanced ability to be translated by a target cell. In some embodiments, translation is enhanced by a factor of 2- fold relative to its unmodified counterpart. In some embodiments, translation is enhanced by a 3-fold factor. In some embodiments, translation is enhanced by a 5-fold factor. In some embodiments, translation is enhanced by a 7-fold factor. In some embodiments, translation is enhanced by a 10-fold factor. In some embodiments, translation is enhanced by a 15-fold factor. In some embodiments, translation is enhanced by a 20-fold factor. In some embodiments, translation is enhanced by a 50-fold factor. In some embodiments, translation is enhanced by a 100-fold factor. In some embodiments, translation is enhanced by a 200-fold factor. In some embodiments, translation is enhanced by a 500-fold factor. In some embodiments, translation is enhanced by a 1000-fold factor. In some embodiments, translation is enhanced by a 2000- fold factor. In some embodiments, the factor is 10-1000-fold. In some embodiments, the factor is 10-100-fold. In some embodiments, the factor is 10-200-fold. In some embodiments, the factor is 10-300-fold. In some embodiments, the factor is 10-500-fold. In some embodiments, the factor is 20-1000-fold. In some embodiments, the factor is 30-1000-fold. In some embodiments, the factor is 50-1000-fold. In some embodiments, the factor is 100-1000-fold. In some embodiments, the factor is 200-1000-fold. In some embodiments, translation is Page 164 of 242P-636791-PC enhanced by any other significant amount or range of amounts. Each possibility represents a separate embodiment of the present disclosure.

[0354] Methods of determining translation efficiency are well known in the art, and include, e.g. measuring the activity of an encoded reporter protein (e.g luciferase or renilla or green fluorescent protein [Wall A A, Phillips A M et al., Effective translation of the second cistron in two Drosophila dicistronic transcripts is determined by the absence of in-frame AUG codons in the first cistron. J Biol Chem 2005; 280(30): 27670-8]), or measuring radioactive label incorporated into the translated protein (Ngosuwan J, Wang N M et al, Roles of cytosolic Hsp70 and Hsp40 molecular chaperones in post-translational translocation of pre-secretory proteins into the endoplasmic reticulum. J Biol Chem 2003; 278(9): 7034-42). Each method represents a separate embodiment of the present disclosure.

[0355] In some embodiments, a target cell of the method of the present disclosure is a dendritic cell. In some embodiments, a target cell of the method of the present disclosure is a macrophage. In some embodiments, a target cell of the method of the present disclosure is a B cell. In some embodiments, a target cell of the method of the present disclosure is another antigen presenting cell. In some embodiments, a target cell of methods of the present disclosure is a mucosal cell. In some embodiments, a target cell of methods of the present disclosure is an epithelial cell. In some embodiments, a cell is a skin cell. In some embodiments, a cell is an epidermal cell. In some embodiments, the cell is a keratinocyte. In some embodiments, a cell is a Merkel cell, melanocyte or Langerhans cell. Each possibility represents a separate embodiment of the present disclosure.

[0356] Codon Optimization and GC Enrichment

[0357] The present disclosure also provides codon optimized nucleotide sequences.

[0358] As used herein, the term “codon-optimized” refers to alteration of codons in a coding region of a nucleic acid molecule (e.g., a nucleotide sequence) to reflect the typical codon usage of a host organism (e.g., a subject receiving a nucleic acid molecule (e.g., a nucleotide sequence)) preferably without altering the amino acid sequence encoded by the nucleic acid molecule. Within the context of the present disclosure, in some embodiments, coding regions are codon-optimized for optimal expression in a subject to be treated using the RNA molecules provided herein. In some embodiments, codon-optimization may be performed such that codons for which frequently occurring tRNAs are available are inserted in place of “rare codons.” In some embodiments, codon-optimization may include increasing Page 165 of 242P-636791-PC guanosine / cytosine (G / C) content of a coding region of RNA provided herein as compared to the G / C content of the corresponding coding sequence of a wild type RNA, wherein the amino acid sequence encoded by the RNA is preferably not modified compared to the amino acid sequence.

[0359] In some embodiments, a coding sequence (also referred to as a “coding region”) is codon optimized for expression in the subject to whom a composition (e.g., a pharmaceutical composition) is to be administered (e.g., a human). Thus, in some embodiments, sequences in such a polynucleotide (e.g., a nucleotide sequence) may differ from wild type sequences encoding the relevant antigen, fragment or epitope thereof, even when the amino acid sequence of the antigen, fragment or epitope thereof is wild type.

[0360] In some embodiments, codons are optimized for expression in a relevant subject (e.g., a human), and even, in some cases, for expression in a particular cell or tissue.

[0361] In some embodiments, a polynucleotide (e.g., a polyribonucleotide or a nucleotide sequence) of the present disclosure is codon optimized, wherein the codons in the polynucleotide (e.g., the polyribonucleotide) are adapted to human codon usage (herein referred to as “human codon optimized polynucleotide”). In some embodiments, a portion of a nucleotide sequence is codon optimized (e.g., a portion of or the portion encoding a glycoprotein or a portion of or the portion encoding a signal sequence). In some embodiments, the entire nucleotide sequence is codon optimized. Codons encoding the same amino acid occur at different frequencies in a subject, e.g., a human. Accordingly, in some embodiments, the coding sequence of a polynucleotide of the present disclosure is modified such that the frequency of the codons encoding the same amino acid corresponds to the naturally occurring frequency of that codon according to the human codon usage. Lipid Nanoparticles

[0362] In some embodiments of the combination of the present disclosure, one or more of the polyribonucleotides are formulated with a nanoparticle, lipid, polymer, cholesterol, cell penetrating peptide, or any combination thereof.

[0363] In some embodiments, one or more of the polyribonucleotides are formulated with a nanoparticle. In some embodiments, one or more of the polyribonucleotides are formulated with a lipid. In some embodiments, one or more of the polyribonucleotides are formulated with a polymer. In some embodiments, one or more of the polyribonucleotides are formulated with Page 166 of 242P-636791-PC cholesterol. In some embodiments, one or more of the polyribonucleotides are formulated with a cell penetrating peptide.

[0364] In some embodiments, the nanoparticle comprises a lipid nanoparticle.

[0365] In some embodiments, one or more of the polyribonucleotides are fully or partially encapsulated within lipid nanoparticles.

[0366] In some embodiments, the lipid nanoparticles comprise (a) a polymer-conjugated lipid; (b) a cationic lipid; and (c) one or more neutral lipids. In some embodiments, the lipid nanoparticles comprise a polymer-conjugated lipid. In some embodiments, the lipid nanoparticles comprise a cationic lipid. In some embodiments, the lipid nanoparticles comprise one or more neutral lipids.

[0367] In some embodiments, the combination further comprises polyplexes (PLX), lipidated polyplexes (LPLX), or liposomes. In some embodiments, the combination further comprises polyplexes (PLX). In some embodiments, the combination further comprises lipidated polyplexes (LPLX). In some embodiments, the combination further comprises liposomes. In some embodiments, one or more of the ribonucleotides is fully encapsulated within the lipid nanoparticle, polyplexes (PLX), lipidated polyplex (LPLX), or liposome. In some embodiments, one or more of the ribonucleotides is partially encapsulated within the lipid nanoparticle, polyplexes (PLX), lipidated polyplex (LPLX), or liposome.

[0368] In some embodiments, the lipid nanoparticle comprises a polymer-conjugated lipid. In some embodiments, the polymer-conjugated lipid comprises a PEG-conjugated lipid. In other embodiments, the polymer-conjugated lipid comprises 2-[(polyethylene glycol)-2000]- N,N-ditetradecylacetamide.

[0369] In other embodiments, the lipid nanoparticle comprises one or more neutral lipids. In some embodiments, the one or more neutral lipids comprises (2R)-2,3- Bis(octadecanoyloxy)propyl 2-(trimethylazaniumyl)ethyl phosphate. In other embodiments, the one or more neutral lipids comprises cholesterol.

[0370] In other embodiments, the lipid nanoparticle comprises a cationic lipid. In some embodiments, the cationic lipid comprises [(4-Hydroxybutyl)azanediyl]di(hexane-6,1-diyl) bis(2-hexyldecanoate).

[0371] In some embodiments, the lipid nanoparticle comprises: (a) 2-[(polyethylene glycol)- 2000]-N,N-ditetradecylacetamide; (b) (2R)-2,3-Bis(octadecanoyloxy)propyl 2- Page 167 of 242P-636791-PC (trimethylazaniumyl)ethyl phosphate; (c) cholesterol; and (d) [(4- Hydroxybutyl)azanediyl]di(hexane-6,1-diyl) bis(2-hexyldecanoate.

[0372] In some embodiments, nanoparticles used in the compositions and methods of the present disclosure comprise lipid nanoparticles as provided in Cullis, P., & Hope, M. (n.d.). Lipid Nanoparticle Systems for Enabling Gene Therapies. Molecular therapy., 25(7), which is incorporated by reference herein in its entirety.

[0373] In some embodiments, delivery of RNA (e.g., nucleoside modified RNA) comprises any suitable delivery method, including RNA transfection methods. In some embodiments, delivery of a nucleoside-modified RNA to a subject comprises mixing the nucleoside-modified RNA with a transfection reagent prior to the step of contacting the subject. In some embodiments, a method of present disclosure further comprises administering nucleoside- modified RNA together with the transfection reagent. In some embodiments, the transfection reagent is a cationic lipid reagent.

[0374] In some embodiments, a composition comprises a lipid nanoparticle (LNP) and one or more nucleic acid molecules provided herein. For example, in some embodiments, a composition comprises an LNP and one or more nucleoside-modified polyribonucleotides encoding one or more antigen binding agents, adjuvants, or a combination thereof.

[0375] The term “lipid nanoparticle” refers to a particle having at least one dimension on the order of nanometers (e.g., 1-1,000 nm) which includes one or more lipids, for example a lipid of Formula (I), (II) or (III), as provided in WO2016176330A1, which is incorporated by reference herein in its entirety.

[0376] In some embodiments, lipid nanoparticles are included in a formulation comprising a nucleoside-modified RNA as provided herein. In some embodiments, such lipid nanoparticles comprise a cationic lipid and one or more excipients such as neutral lipids, charged lipids, steroids and polymer conjugated lipids. In some embodiments, the nucleoside- modified RNA is encapsulated in the lipid portion of the lipid nanoparticle or an aqueous space enveloped by some or all of the lipid portion of the lipid nanoparticle, thereby protecting it from enzymatic degradation or other undesirable effects induced by the mechanisms of the host organism or cells e.g. an adverse immune response.

[0377] In various embodiments, the lipid nanoparticles have a mean diameter of from about 30 nm to about 150 nm, from about 40 nm to about 150 nm, from about 50 nm to about 150 nm, from about 60 nm to about 130 nm, from about 70 nm to about 110 nm, from about 70 nm Page 168 of 242P-636791-PC to about 100 nm, from about 80 nm to about 100 nm, from about 90 nm to about 100 nm, from about 70 to about 90 nm, from about 80 nm to about 90 nm, from about 70 nm to about 80 nm, or about 30 nm, 35 nm, 40 nm, 45 nm, 50 nm, 55 nm, 60 nm, 65 nm, 70 nm, 75 nm, 80 nm, 85 nm, 90 nm, 95 nm, 100 nm, 105 nm, 110 nm, 115 nm, 120 nm, 125 nm, 130 nm, 135 nm, 140 nm, 145 nm, or 150 nm, and are substantially non-toxic. In certain embodiments, the nucleoside-modified RNA, when present in the lipid nanoparticles, is resistant in aqueous solution to degradation with a nuclease.

[0378] The LNP may comprise any lipid capable of forming a particle to which the one or more nucleic acid molecules are attached, or in which the one or more nucleic acid molecules are encapsulated. The term “lipid” refers to a group of organic compounds that are derivatives of fatty acids (e.g., esters) and are generally characterized by being insoluble in water but soluble in many organic solvents. Lipids are usually divided in at least three classes: (1) “simple lipids” which include fats and oils as well as waxes; (2) “compound lipids” which include phospholipids and glycolipids; and (3) “derived lipids” such as steroids.

[0379] In some embodiments, the LNP comprises one or more cationic lipids, and one or more stabilizing lipids. Stabilizing lipids include neutral lipids and pegylated lipids. As used herein, the term “cationic lipid” refers to a lipid that is cationic or becomes cationic (protonated) as the pH is lowered below the pK of the ionizable group of the lipid, but is progressively more neutral at higher pH values. At pH values below the pK, the lipid is then able to associate with negatively charged nucleic acids. In certain embodiments, the cationic lipid comprises a zwitterionic lipid that assumes a positive charge on pH decrease.

[0380] In certain embodiments, the cationic lipid comprises any of a number of lipid species which carry a net positive charge at a selective pH, such as physiological pH. Such lipids include, but are not limited to, N,N-dioleyl-N,N-dimethylammonium chloride (DODAC); N- (2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium chloride (DOTMA); N,N-distearyl-N,N- dimethylammonium bromide (DDAB); N-(2,3- dioleoyloxy)propyl)-N,N,N- trimethylammonium chloride (DOTAP); 3-(N— (Ν’,Ν’- dimethylaminoethane)- carbamoyl)cholesterol (DC-Choi), N-(l-(2,3-dioleoyloxy)propyl)- N-2- (sperminecarboxamido)ethyl)-N,N-dimethylammonium trifluoracetate (DOSPA), dioctadecylamidoglycyl carboxy spermine (DOGS), l,2-dioleoyl-3-dimethylammonium propane (DODAP), N,N-dimethyl-2,3-dioleoyloxy)propylamine (DODMA), and N-(l,2- dimyristyloxyprop-3-yl)-N,N-dimethyl-N-hydroxyethyl ammonium bromide (DMRIE). Additionally, a number of commercial preparations of cationic lipids are available which can Page 169 of 242P-636791-PC be used in the present disclosure. These include, for example, LIPOFECTIN® (commercially available cationic liposomes comprising DOTMA and l,2-dioleoyl-sn-3- phosphoethanolamine (DOPE), from GIBCO / BRL, Grand Island, N.Y.); LIPOFECTAMINE® (commercially available cationic liposomes comprising N-(l-(2,3- dioleyloxy)propyl)-N-(2- (sperminecarboxamido)ethyl)-N,N-dimethylammonium trifluoroacetate (DOSPA) and (DOPE), from GIBCO / BRL); and TRANSFECTAM® (commercially available cationic lipids comprising dioctadecylamidoglycyl carboxyspermine (DOGS) in ethanol from Promega Corp., Madison, Wis.). The following lipids are cationic and have a positive charge at below physiological pH:

[0381] DODAP, DODMA, DMDMA, l,2-dilinoleyloxy-N,N-dimethylaminopropane (DLinDMA), 1 ,2-dilinolenyloxy-N,N-dimethylaminopropane (DLenDMA).

[0382] In some embodiments, the cationic lipid is an amino lipid. Suitable amino lipids useful in the disclosure include those provided in WO 2012 / 016184, incorporated herein by reference in its entirety. Representative amino lipids include, but are not limited to, l,2- dilinoleyoxy-3-(dimethylamino)acetoxypropane (Dlin-DAC), l,2-dilinoleyoxy-3- morpholinopropane (Dlin-MA), l,2-dilinoleoyl-3-dimethylaminopropane (DLinDAP), l,2- dilinoleylthio-3-dimethylaminopropane (Dlin-S-DMA), l-linoleoyl-2-linoleyloxy-3- dimethylaminopropane (Dlin-2-DMAP), l,2-dilinoleyloxy-3-trimethylaminopropane chloride salt (Dlin-TMA.Cl), l,2-dilinoleoyl-3-trimethylaminopropane chloride salt (Dlin-TAP.Cl), l,2- dilinoleyloxy-3-(N-methylpiperazino)propane (Dlin-MPZ), 3-(N,N- dilinoleylamino)-l,2- propanediol (DlinAP), 3-(N,N-dioleylamino)-l,2-propanediol (DOAP), l,2-dilinoleyloxo-3-(2- N,N-dimethylamino)ethoxypropane (Dlin-EG-DMA), and 2,2-dilinoleyl-4- dimethylaminomethyl-[l,3]-dioxolane (Dlin-K-DMA).

[0383] In certain embodiments, the cationic lipid is present in the LNP in an amount from about 30 to about 95 mole percent. In some embodiments, the cationic lipid is present in the LNP in an amount from about 30 to about 70 mole percent. In some embodiments, the cationic lipid is present in the LNP in an amount from about 40 to about 60 mole percent. In some embodiments, the cationic lipid is present in the LNP in an amount of about 50 mole percent. In some embodiments, the LNP comprises only cationic lipids. In certain embodiments, the LNP comprises one or more additional lipids which stabilize the formation of particles during their formation. Page 170 of 242P-636791-PC

[0384] Suitable stabilizing lipids include neutral lipids and anionic lipids. In some embodiments, the term “neutral lipid” refers to any one of a number of lipid species that exist in either an uncharged or neutral zwitterionic form at physiological pH. Representative neutral lipids include diacylphosphatidylcholines, diacylphosphatidylethanolamines, ceramides, sphingomyelins, dihydro sphingomyelins, cephalins, and cerebrosides.

[0385] Exemplary neutral lipids include, for example, distearoylphosphatidylcholine (DSPC), dioleoylphosphatidylcholine (DOPC), dipalmitoylphosphatidylcholine (DPPC), dioleoylphosphatidylglycerol (DOPG), dipalmitoylphosphatidylglycerol (DPPG), dioleoyl- phosphatidylethanolamine (DOPE), palmitoyloleoylphosphatidylcholine (POPC), palmitoyloleoyl-phosphatidylethanolamine (POPE) and dioleoyl-phosphatidylethanolamine 4- (N-maleimidomethyl)-cyclohexane-l- carboxylate (DOPE-mal), dipalmitoyl phosphatidyl ethanolamine (DPPE), dimyristoylphosphoethanolamine (DMPE), distearoyl- phosphatidylethanolamine (DSPE), 16-O-monomethyl PE, 16-O-dimethyl PE, 18-1-trans PE, l-stearioyl-2-oleoyl- phosphatidyethanol amine (SOPE), and l,2-dielaidoyl-sn-glycero-3- phophoethanolamine (transDOPE). In some embodiments, the neutral lipid is l,2-distearoyl- sn-glycero-3- phosphocholine (DSPC).

[0386] In some embodiments, the LNPs comprise a neutral lipid selected from DSPC, DPPC, DMPC, DOPC, POPC, DOPE and SM. In various embodiments, the molar ratio of the cationic lipid (e.g., lipid of Formula (I)) to the neutral lipid ranges from about 2 : 1 to about 8: 1.

[0387] In various embodiments, the LNPs further comprise a steroid or steroid analogue.

[0388] In certain embodiments, the steroid or steroid analogue is cholesterol. In some of these embodiments, the molar ratio of the cationic lipid (e.g., lipid of Formula (I)) to cholesterol ranges from about 2:1 to 1:1.

[0389] The term “anionic lipid” refers to any lipid that is negatively charged at physiological pH. These lipids include phosphatidylglycerol, cardiolipin, diacylphosphatidylserine, diacylphosphatidic acid, N- dodecanoylphosphatidylethanolamines, N- succinylphosphatidylethanolamines, N- glutarylphosphatidylethanolamines, lysylphosphatidylglycerols, palmitoyloleyolphosphatidylglycerol (POPG), and other anionic modifying groups joined to neutral lipids.

[0390] In certain embodiments, the LNP comprises glycolipids (e.g., monosialoganglioside Gmi). In certain embodiments, the LNP comprises a sterol, such as cholesterol. Page 171 of 242P-636791-PC

[0391] In some embodiments, the LNPs comprise a polymer conjugated lipid. The term “polymer conjugated lipid” refers to a molecule comprising both a lipid portion and a polymer portion. An example of a polymer conjugated lipid is a pegylated lipid. The term “pegylated lipid” refers to a molecule comprising both a lipid portion and a polyethylene glycol portion. Pegylated lipids are known in the art and include l-(monomethoxy-polyethyleneglycol)-2,3- dimyristoylglycerol (PEG-s- DMG) and the like.

[0392] In certain embodiments, the LNP comprises an additional, stabilizing lipid which is a polyethylene glycol-lipid (pegylated lipid). Suitable polyethylene glycol- lipids include PEG- modified phosphatidylethanolamine, PEG-modified phosphatidic acid, PEG-modified ceramides (e.g., PEG-CerC14 or PEG-CerC20), PEG-modified dialkylamines, PEG-modified diacylglycerols, PEG-modified dialkylglycerols.

[0393] Representative polyethylene glycol-lipids include PEG-c-DOMG, PEG-c-DMA, and PEG-s-DMG. In some embodiments, the polyethylene glycol-lipid is N-[(methoxy poly(ethylene glycol)2ooo)carbamyl]-l,2-dimyristyloxlpropyl-3-amine (PEG-c-DMA). In some embodiments, the polyethylene glycol-lipid is PEG-c-DOMG). In other embodiments, the LNPs comprise a pegylated diacylglycerol (PEG-DAG) such as l-(monomethoxy- polyethyleneglycol)-2,3-dimyristoylglycerol (PEG-DMG), a pegylated phosphatidylethanoloamine (PEG-PE), a PEG succinate diacylglycerol (PEG-S-DAG) such as 4-0-(2’,3’-di(tetradecanoyloxy)propyl-l-0-(co- methoxy(polyethoxy)ethyl)butanedioate (PEG-S-DMG), a pegylated ceramide (PEG- cer), or a PEG dialkoxypropylcarbamate such as Q-methoxy(polyethoxy)ethyl-N-(2,3- di(tetradecanoxy)propyl)carbamate or 2,3- di(tetradecanoxy)propyl-N-(co- methoxy(polyethoxy)ethyl)carbamate. In various embodiments, the molar ratio of the cationic lipid to the pegylated lipid ranges from about 100: 1 to about 25: 1.

[0394] In certain embodiments, the additional lipid is present in the LNP in an amount from about 1 to about 10 mole percent. In some embodiments, the additional lipid is present in the LNP in an amount from about 1 to about 5 mole percent. In some embodiments, the additional lipid is present in the LNP in about 1 mole percent or about 1.5 mole percent.

[0395] In certain embodiments, the LNP comprises one or more targeting moieties which are capable of targeting the LNP to a cell or cell population. For example, in some embodiments, the targeting moiety is a ligand which directs the LNP to a receptor found on a cell surface. Page 172 of 242P-636791-PC

[0396] In certain embodiments, the LNP comprises one or more internalization domains. For example, in some embodiments, the LNP comprises one or more domains which bind to a cell to induce the internalization of the LNP. For example, in some embodiments, the one or more internalization domains bind to a receptor found on a cell surface to induce receptor- mediated uptake of the LNP. In certain embodiments, the LNP is capable of binding a biomolecule in vivo, where the LNP-bound biomolecule can then be recognized by a cell- surface receptor to induce internalization. For example, in some embodiments, the LNP binds systemic ApoE, which leads to the uptake of the LNP and associated cargo.

[0397] Other exemplary LNPs and their manufacture are provided in the art, for example in WO2016176330A1, U.S. Patent Application Publication No. US20120276209, Semple et al., 2010, Nat Biotechnol., 28(2): 172-176; Akinc et al., 2010, Mol Ther., 18(7): 1357-1364; Basha et al., 2011, Mol Ther, 19(12): 2186-2200; Leung et al., 2012, J Phys Chem C Nanomater Interfaces, 116(34): 18440-18450; Lee et al., 2012, Int J Cancer., 131(5): E781-90; Belliveau et al., 2012, Mol Ther nucleic Acids, 1 : e37; Jayaraman et al., 2012, Angew Chem Int Ed Engl., 51(34): 8529-8533; Mui et al., 2013, Mol Ther Nucleic Acids.2, el39; Maier et al., 2013, Mol Ther., 21(8): 1570-1578; and Tarn et al., 2013, Nanomedicine, 9(5): 665-74, each of which are incorporated by reference in their entirety. Polypeptides

[0398] In some embodiments, provided herein is a polypeptide encoding an anti-Herpes Simplex Virus (HSV) glycoprotein B (gB) (anti-gB) antigen binding agent comprising (i) a heavy chain complementarity determining region 1 (CDRH1) comprising an amino acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 184, (ii) a heavy chain complementarity determining region 2 (CDRH2) comprising an amino acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 185, (iii) a heavy chain complementarity determining region 3 (CDRH3) comprising an amino acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 186, (iv) a light chain complementarity determining region 1 (CDRL1) comprising an amino acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 194, (v) a light chain complementarity determining region 2 (CDRL2) comprising an amino acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to an amino acid sequence according Page 173 of 242P-636791-PC to SEQ ID NO: 195, (vi) a light chain complementarity determining region 3 (CDRL3) comprising an amino acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 196, or a combination thereof.

[0399] In some embodiments, provided herein is a polypeptide encoding an anti-Herpes Simplex Virus (HSV) glycoprotein D (gD) (anti-gD) antigen binding agent comprising (i) a CDRH1 comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 162, (ii) a CDRH2 comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 163, (iii) a CDRH3 comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 164, (iv) a CDRL1 comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 172, (v) a CDRL2 comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 173, (vi) a CDRL3 comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 174, or a combination thereof.

[0400] In some embodiments, provided herein is a polypeptide encoding an anti-Herpes Simplex Virus (HSV) glycoprotein D (gD) (anti-gD) antigen binding agent comprising (i) a CDRH1 comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 206, (ii) a CDRH2 comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 207, (iii) a CDRH3 comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 208, (iv) a CDRL1 comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 216, (v) a CDRL2 comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 217, (vi) a CDRL3 comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 218, or a combination thereof.

[0401] In some embodiments, provided herein is a polypeptide encoding an anti-Herpes Simplex Virus (HSV) glycoprotein D (gD) (anti-gD) antigen binding agent comprising (i) a CDRH1 comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 229, (ii) a CDRH2 comprising an amino Page 174 of 242P-636791-PC acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 230, (iii) a CDRH3 comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 231, (iv) a CDRL1 comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 239, (v) a CDRL2 comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 240, (vi) a CDRL3 comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 241, or a combination thereof.

[0402] In some embodiments, the anti-gB antigen binding agent or the anti-gD antigen binding agent comprises one or more amino acid substitutions.

[0403] In some embodiments, the one or more amino acid substitutions are in a heavy chain constant region.

[0404] In some embodiments, the one or more amino acid substitutions comprises (a) D399R with reference to SEQ ID NO: 159, SEQ ID NO: 180, or SEQ ID NO: 225, or (b) K409D with reference to SEQ ID NO: 202, SEQ ID NO: 246, or SEQ ID NO: 250.

[0405] In some embodiments, the anti-gD antigen binding agent is an anti-gD IgG.

[0406] In some embodiments, the anti-gD antigen binding agent comprises an anti-gD scFv.

[0407] In some embodiments, the anti-gD antigen binding agent is an anti-gD scFv-Fc.

[0408] In some embodiments, provided is a polyribonucleotide encoding the polypeptide described herein. Polyribonucleotides

[0409] In some embodiments, provided herein is a polyribonucleotide encoding an anti- Herpes Simplex Virus (HSV) glycoprotein B (gB) (anti-gB) antigen binding agent comprising (i) a heavy chain complementarity determining region 1 (CDRH1) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 33, (ii) a heavy chain complementarity determining region 2 (CDRH2) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 34, (iii) a heavy chain complementarity determining region 3 (CDRH3) comprising a nucleic acid sequence having Page 175 of 242P-636791-PC at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 35, (iv) a light chain complementarity determining region 1 (CDRL1) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 46, (v) a light chain complementarity determining region 2 (CDRL2) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 47, (vi) a light chain complementarity determining region 3 (CDRL3) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 48, or a combination thereof.

[0410] In some embodiments, provided herein is a polyribonucleotide encoding an anti- HSV glycoprotein D (gD) (anti-gD) antigen binding agent comprising (i) a CDRH1 comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 5, (ii) a CDRH2 comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 6, (iii) a CDRH3 comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 7, (iv) a CDRL1 comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 17, (v) a CDRL2 comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 18, (vi) a CDRL3 comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 19, or a combination thereof.

[0411] In some embodiments, provided herein is a polyribonucleotide encoding an anti-gD antigen binding agent comprising (i) a CDRH1 comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 65, (ii) a CDRH2 comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 66, (iii) a CDRH3 comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 67, (iv) a CDRL1 comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 78, (v) a CDRL2 comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a Page 176 of 242P-636791-PC nucleic acid sequence according to SEQ ID NO: 79, (vi) a CDRL3 comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 80, or a combination thereof.

[0412] In some embodiments, provided herein is a polyribonucleotide encoding an anti-gD antigen binding agent comprising (i) a CDRH1 comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 98, (ii) a CDRH2 comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 99, (iii) a CDRH3 comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 100, (iv) a CDRL1 comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 112, (v) a CDRL2 comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 113, (vi) a CDRL3 comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 114, or a combination thereof. Compositions

[0413] In some embodiments, provided herein is a composition comprising the combination described herein and a pharmaceutically acceptable carrier.

[0414] In some embodiments, the composition is formulated for intramuscular, subcutaneous, intradermal, intranasal, intravaginal, intrarectal, or topical administration. In some embodiments, the composition is formulated for intramuscular administration. In some embodiments, the composition is formulated for subcutaneous administration. In some embodiments, the composition is formulated for intradermal administration. In some embodiments, the composition is formulated for intranasal administration. In some embodiments, the composition is formulated for intravaginal administration. In some embodiments, the composition is formulated for intrarectal administration. In some embodiments, the composition is formulated for topical administration.

[0415] In some embodiments, provided herein is a composition comprising the polypeptide described herein or the polyribonucleotide described herein and a pharmaceutically acceptable carrier. In some embodiments, provided herein is a composition comprising the polypeptide described herein and a pharmaceutically acceptable carrier. In some embodiments, provided Page 177 of 242P-636791-PC herein is a composition comprising the polyribonucleotide described herein and a pharmaceutically acceptable carrier.

[0416] In some embodiments, provided herein is a pharmaceutical composition comprising bis...

Claims

P-636791-PC CLAIMS What is claimed is:

1. A combination comprising: a. a first polyribonucleotide encoding a first anti-Herpes Simplex Virus (HSV) glycoprotein antigen binding agent and b. a second polyribonucleotide encoding a second anti-HSV glycoprotein antigen binding agent; wherein the first antigen binding agent and the second antigen binding agent bind to different epitopes.

2. The combination of claim 1, wherein the first antigen binding agent and the second antigen binding agent bind to different epitopes on the same HSV glycoprotein.

3. The combination of claim 1, wherein the first antigen binding agent and the second antigen binding agent bind to different epitopes on different HSV glycoproteins.

4. The combination of claim 3, wherein one of said anti-HSV glycoprotein antigen binding agents comprises an anti-gB antigen binding agent and one of said anti-HSV glycoprotein antigen binding agents comprises an anti-gD antigen binding agent.

5. The combination of claim 4, wherein the polyribonucleotide encoding the anti-HSV gD antigen binding agent comprises: (i) a heavy chain complementarity determining region 1 (CDRH1) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 5, (ii) a heavy chain complementarity determining region 2 (CDRH2) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 6, (iii) a heavy chain complementarity determining region 3 (CDRH3) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 7, (iv) a light chain complementarity determining region 1 (CDRL1) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% Page 221 of 242P-636791-PC identity to a nucleic acid sequence according to SEQ ID NO: 17, (v) a light chain complementarity determining region 2 (CDRL2) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 18, and / or (vi) a light chain complementarity determining region 3 (CDRL3) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO:

19.

6. The combination of claim 4 or claim 5, wherein the polyribonucleotide encoding the anti-HSV gB antigen binding agent comprises: (i) a heavy chain complementarity determining region 1 (CDRH1) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 33, (ii) a heavy chain complementarity determining region 2 (CDRH2) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 34, (iii) a heavy chain complementarity determining region 3 (CDRH3) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 35, (iv) a light chain complementarity determining region 1 (CDRL1) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 46, (v) a light chain complementarity determining region 2 (CDRL2) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 47, and / or (vi) a light chain complementarity determining region 3 (CDRL3) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO:

48.

7. The combination of any one of claims 4-6, wherein the anti-HSV gD antigen binding agent comprises: (i) a heavy chain complementarity determining region 1 (CDRH1) comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an Page 222 of 242P-636791-PC amino acid sequence according to SEQ ID NO: 162, (ii) a heavy chain complementarity determining region 2 (CDRH2) comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 163, (iii) a heavy chain complementarity determining region 3 (CDRH3) comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 164, (iv) a light chain complementarity determining region 1 (CDRL1) comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 172, (v) a light chain complementarity determining region 2 (CDRL2) comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 173, and / or (vi) a light chain complementarity determining region 3 (CDRL3) comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO:

174.

8. The combination of any one of claims 4-7, wherein the anti-HSV gB antigen binding agent comprises: (i) a heavy chain complementarity determining region 1 (CDRH1) comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 184, (ii) a heavy chain complementarity determining region 2 (CDRH2) comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 185, (iii) a heavy chain complementarity determining region 3 (CDRH3) comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 186, (iv) a light chain complementarity determining region 1 (CDRL1) comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 194, (v) a light chain complementarity determining region 2 (CDRL2) comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 195, and / or Page 223 of 242P-636791-PC (vi) a light chain complementarity determining region 3 (CDRL3) comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO:

196.

9. The combination of any one of claims 4-8, wherein said combination is in the form of a bispecific antigen binding agent.

10. The combination of claim 9, wherein the bispecific antigen binding agent comprises a tetravalent bispecific antigen binding agent.

11. The combination of claim 10, wherein the polynucleotide encoding said tetravalent bispecific antigen binding agent comprises a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO:

280.

12. The combination of claim 10, wherein the tetravalent bispecific antigen binding agent comprises an amino acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 281 or 282.

13. A combination comprising: a. a first anti-Herpes Simplex Virus (HSV) glycoprotein antigen binding agent and b. a second anti-HSV glycoprotein antigen binding agent, wherein the first antigen binding agent and the second antigen binding agent bind to different epitopes, wherein the first antigen binding agent and the second antigen binding agent bind to different epitopes on the same HSV glycoprotein.

14. The combination of any one of claims 1-3 or claim 13, wherein at least one of said anti-HSV glycoprotein antigen binding agents comprises an anti-HSV glycoprotein B (anti-HSV gB) antigen binding agent.

15. The combination of claim 14, wherein a polynucleotide encoding the anti-HSV gB antigen binding agent comprises: (i) a heavy chain complementarity determining region 1 (CDRH1) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% Page 224 of 242P-636791-PC identity to a nucleic acid sequence according to SEQ ID NO: 33, (ii) a heavy chain complementarity determining region 2 (CDRH2) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 34, (iii) a heavy chain complementarity determining region 3 (CDRH3) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 35, (iv) a light chain complementarity determining region 1 (CDRL1) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 46, (v) a light chain complementarity determining region 2 (CDRL2) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 47, and (vi) a light chain complementarity determining region 3 (CDRL3) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO:

48.

16. The combination of any one of claims 14-15, wherein a polynucleotide encoding the anti-HSV gB antigen binding agent encodes a heavy chain variable region comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 32 or SEQ ID NO: 278; and wherein the polynucleotide encodes a light chain variable region comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO:

45.

17. The combination of any one of claims 14-16, wherein a polynucleotide encoding the anti-HSV gB antigen binding agent encodes a heavy chain comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 33; and wherein the polynucleotide encodes a light chain comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO:

44.

18. The combination of any one of claims 14-17, wherein a polynucleotide encoding the anti-HSV gB antigen binding agent comprises a nucleic acid sequence has at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according Page 225 of 242P-636791-PC to SEQ ID NO: 57, SEQ ID NO: 58, or SEQ ID NO:

59.

19. The combination of one of claims 14-18, wherein the anti-HSV gB antigen binding agent comprises: (i) a heavy chain complementarity determining region 1 (CDRH1) comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 184, (ii) a heavy chain complementarity determining region 2 (CDRH2) comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 185, (iii) a heavy chain complementarity determining region 3 (CDRH3) comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 186, (iv) a light chain complementarity determining region 1 (CDRL1) comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 194, (v) a light chain complementarity determining region 2 (CDRL2) comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 195, and (vi) a light chain complementarity determining region 3 (CDRL3) comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO:

196.

20. The combination of claim any one of claims 14-19, wherein the anti-HSV gB antigen binding agent comprises a heavy chain variable region comprising an amino acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 183; and the anti-HSV gB antigen binding agent comprises a light chain variable region comprising an amino acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO:

193.

21. The combination of any one of claims 14-20, wherein the anti-HSV gB antigen binding agent comprises a heavy chain comprising an amino acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to an amino acid sequence according Page 226 of 242P-636791-PC to SEQ ID NO: 182; and the anti-HSV gB antigen binding agent comprises a light chain comprising an amino acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO:

192.

22. The combination of any one of claims 14-21, wherein the anti-HSV gB antigen binding agent comprises an amino acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 202 or SEQ ID NO:

203.

23. The combination of any one of claims 1-3 and 13-22, wherein at least one of said anti- HSV glycoprotein antigen binding agents comprises an anti-HSV glycoprotein D (anti-HSV gD) antigen binding agent.

24. The combination of claim 23, wherein a polynucleotide encoding the anti-HSV gD antigen binding agent comprises: (i) a heavy chain complementarity determining region 1 (CDRH1) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 5, (ii) a heavy chain complementarity determining region 2 (CDRH2) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 6, (iii) a heavy chain complementarity determining region 3 (CDRH3) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 7, (iv) a light chain complementarity determining region 1 (CDRL1) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 17, (v) a light chain complementarity determining region 2 (CDRL2) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 18, and (vi) a light chain complementarity determining region 3 (CDRL3) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO:

19.

25. The combination of claim 23 or claim 24, wherein a polynucleotide encoding the anti- HSV gD antigen binding agent encodes a heavy chain variable region comprising a Page 227 of 242P-636791-PC nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 4 or SEQ ID NO: 276; and wherein a polynucleotide encoding the anti-HSV gD antigen binding agent encodes a light chain variable region comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 16 or SEQ ID NO:

277.

26. The combination of any one of claims 23-25, wherein a polynucleotide encoding the anti-HSV gD antigen binding agent encodes a heavy chain comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 2 or SEQ ID NO: 3; and a polynucleotide encoding the anti-HSV gD antigen binding agent encodes a light chain comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO:

15.

27. The combination of any one of claims 23-26, wherein a polynucleotide encoding the anti-HSV gD antigen binding agent comprises a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to any one of SEQ ID NO: 28, SEQ ID NO: 29 or SEQ ID NO:

30.

28. The combination of any one of claims 23-27, wherein the anti-HSV gD antigen binding agent comprises: (i) a heavy chain complementarity determining region 1 (CDRH1) comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 162, (ii) a heavy chain complementarity determining region 2 (CDRH2) comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 163, (iii) a heavy chain complementarity determining region 3 (CDRH3) comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 164, (iv) a light chain complementarity determining region 1 (CDRL1) comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 172, Page 228 of 242P-636791-PC (v) a light chain complementarity determining region 2 (CDRL2) comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 173, and (vi) a light chain complementarity determining region 3 (CDRL3) comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO:

174.

29. The combination of any one of claims 23-28, wherein the anti-HSV gD antigen binding agent comprises a heavy chain variable region comprising an amino acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 161; and the anti-HSV gD antigen binding agent comprises a light chain variable region comprising an amino acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO:

171.

30. The combination of any one of claims 23-29, wherein the anti-HSV gD antigen binding agent comprises a heavy chain comprising an amino acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 159 or 160; and the anti-HSV gD antigen binding agent comprises a light chain comprising an amino acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO:

170.

31. The combination of any one of claims 23-30, wherein a polynucleotide encoding the anti-HSV gD antigen binding agent comprises: (i) a heavy chain complementarity determining region 1 (CDRH1) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 65, (ii) a heavy chain complementarity determining region 2 (CDRH2) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 66, (iii) a heavy chain complementarity determining region 3 (CDRH3) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 67, (iv) a light chain complementarity determining region 1 (CDRL1) comprising a Page 229 of 242P-636791-PC nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 78, (v) a light chain complementarity determining region 2 (CDRL2) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 79, and (vi) a light chain complementarity determining region 3 (CDRL3) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO:

80.

32. The combination of any one of claims 23-31, wherein a polynucleotide encoding the anti-gD antigen binding agent encodes a heavy chain variable region comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 63; and a polynucleotide encoding the anti-gD antigen binding agent encodes a light chain variable region comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO:

77.

33. The combination of any one of claims 23-32, wherein a polynucleotide encoding the anti-gD antigen binding agent encodes a heavy chain comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 61 or 62; and a polynucleotide encoding the anti-gD antigen binding agent encodes a light chain comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO:

76.

34. The combination of any one of claims 23-33, wherein a polynucleotide encoding the anti-gD antigen binding agent comprises a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to any one of SEQ ID NOs: 89-93.

35. The combination of any one of claims 23-34, wherein the anti-gD antigen binding agent comprises: (i) a heavy chain complementarity determining region 1 (CDRH1) comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an Page 230 of 242P-636791-PC amino acid sequence according to SEQ ID NO: 206, (ii) a heavy chain complementarity determining region 2 (CDRH2) comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 207, (iii) a heavy chain complementarity determining region 3 (CDRH3) comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 208, (iv) a light chain complementarity determining region 1 (CDRL1) comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 216, (v) a light chain complementarity determining region 2 (CDRL2) comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 217, and (vi) a light chain complementarity determining region 3 (CDRL3) comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO:

218.

36. The combination of any one of claims 23-35, wherein the anti-gD antigen binding agent comprises a heavy chain variable region comprising an amino acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 205; and the anti-gD antigen binding agent comprises a light chain variable region comprising an amino acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO:

215.

37. The combination of any one of claims 23-36, wherein the anti-gD antigen binding agent comprises a heavy chain comprising an amino acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 204; and the anti-gD antigen binding agent comprises a light chain comprising an amino acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO:

214.

38. The combination of any one of claims 23-37, wherein a polynucleotide encoding the anti-HSV gD antigen binding agent comprises: (i) a heavy chain complementarity determining region 1 (CDRH1) comprising a Page 231 of 242P-636791-PC nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 98, (ii) a heavy chain complementarity determining region 2 (CDRH2) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 99, (iii) a heavy chain complementarity determining region 3 (CDRH3) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 100, (iv) a light chain complementarity determining region 1 (CDRL1) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 112, (v) a light chain complementarity determining region 2 (CDRL2) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 113, and (vi) a light chain complementarity determining region 3 (CDRL3) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO:

114.

39. The combination of any one of claims 23-38, wherein a polynucleotide encoding the anti-gD antigen binding agent encodes a heavy chain variable region comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 97; and wherein a polynucleotide encoding the anti-gD antigen binding agent encodes a light chain variable region comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO:

111.

40. The combination of any one of claims 23-39, wherein a polynucleotide encoding the anti-gD antigen binding agent encodes a heavy chain comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 96; and a polynucleotide encoding the anti- gD antigen binding agent encodes a light chain comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO:

110. Page 232 of 242P-636791-PC 41. The combination of any one of claims 23-40, wherein a polynucleotide encoding the anti-gD antigen binding agent comprises a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 123, SEQ ID NO: 125, SEQ ID NO: 126, or SEQ ID NO:

127.

42. The combination of any one of claims 23-41, wherein the anti-gD antigen binding agent comprises: (i) a heavy chain complementarity determining region 1 (CDRH1) comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 229, (ii) a heavy chain complementarity determining region 2 (CDRH2) comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 230, (iii) a heavy chain complementarity determining region 3 (CDRH3) comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 231, (iv) a light chain complementarity determining region 1 (CDRL1) comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 239, (v) a light chain complementarity determining region 2 (CDRL2) comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 240, and (vi) a light chain complementarity determining region 3 (CDRL3) comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO:

241.

43. The combination of any one of claims 23-42, wherein the anti-gD antigen binding agent comprises a heavy chain variable region comprising an amino acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 228; and the anti-gD antigen binding agent comprises a light chain variable region comprising an amino acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO:

238. Page 233 of 242P-636791-PC 44. The combination of any one of claims 23-43, wherein the anti-gD antigen binding agent comprises a heavy chain comprising an amino acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 227; and the anti-gD antigen binding agent comprises a light chain comprising an amino acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO:

237.

45. The combination of any one of claims 23-44, wherein the anti-gD antigen binding agent comprises an amino acid sequence having at least 80%, at least 90%, or at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 247 or SEQ ID NO:

248.

46. The combination of any one of claims 1-45, wherein the first anti-HSV antibody is linked to the second anti-HSV antibody, optionally wherein the first anti-HSV antibody is linked to the second anti-HSV antibody by a covalent bond, a hydrogen bond, an ionic bond, or an electrostatic interaction, further optionally wherein the first anti-HSV antibody is linked to the second anti-HSV antibody by a peptide linker.

47. The combination of any one of claims 1-46, wherein at least one of said anti-HSV glycoprotein antigen binding agent comprises a single-chain Fv (scFv).

48. The combination of any one of claims 1-47, wherein at least one of said anti-HSV glycoprotein antigen binding agent comprises a single-chain Fv-Fc (scFv-Fc).

49. The combination of any one of claims 1-48, wherein at least one of said anti-HSV glycoprotein antigen binding agent comprises a bicistronic antigen binding agent.

50. The combination of any one of claims 1-49, wherein at least one of said anti-HSV glycoprotein antigen binding agent comprises an IgG antibody.

51. The combination of claim 50, wherein the IgG antibody comprises an IgG1, IgG2, or IgG4 constant region.

52. The combination of any one of claims 1-51, wherein the first anti-HSV glycoprotein antigen binding agent and the second anti-HSV glycoprotein antigen binding agent together form a single bispecific antigen binding agent.

53. The combination of claim 52, wherein said bispecific antigen binding agent comprises an IgG antibody fragment and an scFv-Fc.

54. The combination of claim 53, wherein the IgG antibody fragment comprises a single heavy chain and a single light chain. Page 234 of 242P-636791-PC 55. The combination of any one of claims 52-54, wherein said bispecific antigen binding agent comprises a tetravalent bispecific antibody.

56. The combination of any one of claims 1-55, further comprising a linker wherein at least one of the anti-HSV glycoprotein antigen binding agents comprises a heavy chain or heavy chain variable region, a linker, and a light chain or a light chain variable region.

57. The combination of claim 56, wherein the linker comprises a 2A peptide linker.

58. The combination of claim 56, wherein the linker comprises a GS linker.

59. The combination of any one of claims 1-58, wherein at least one of the antigen binding agents comprises a first and second immunoglobulin chain, wherein the first immunoglobulin chain comprises a first variable region and a first constant region, and the second immunoglobulin chain comprises a second variable region and a second constant region, wherein the first constant region comprises a first modification and the second constant region comprises a second modification, wherein the second modification is electrostatically or physically complementary to the first modification to increase, enhance, or promote binding, electrostatic attraction, or other association of the first immunoglobulin chain with the immunoglobulin chain.

60. The combination of claim 59, wherein the polynucleotide encoding the first immunoglobulin chain has at least 80%, at least 90%, at least 95%, or 100% identity to the nucleic acid sequence according to SEQ ID NO: 91 and the polynucleotide encoding the second immunoglobulin chain has at least 80%, at least 90%, at least 95%, or 100% identity to the nucleic acid sequence according to SEQ ID NO: 58, SEQ ID NO: 125, SEQ ID NO: 144, or SEQ ID NO:

145.

61. The combination of claim 59 or claim 60, wherein the first immunoglobulin chain comprises an amino acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 226 or SEQ ID NO: 160; and the second immunoglobulin chain comprises an amino acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 247, SEQ ID NO: 251, SEQ ID NO: 252, or SEQ ID NO:

203.

62. The combination of any one of claims 1-61, wherein at least one of the anti-HSV glycoprotein antigen binding agents further comprises a signal sequence.

63. The combination of any one of claims 1-62, wherein at least one of the anti-HSV glycoprotein antigen binding agents further comprises a marker sequence or detectable Page 235 of 242P-636791-PC tag sequence.

64. The combination of any one of claims 1-63, wherein at least one of the anti-HSV glycoprotein antigen binding agents is attached to the cytotoxic molecule or the therapeutic agent.

65. The combination of any one of claims 1-3 and 14-64, wherein a single polyribonucleotide comprises said first and second polyribonucleotides.

66. The combination of any one of claims 1-3 and 14-65, wherein one or more of said polyribonucleotides comprise one or more ribonucleic acids that are nucleoside modified.

67. The combination of claim 66, wherein the one or more nucleoside modified ribonucleic acids comprise one or more m5D (5-methyldihydrouridine) residues.

68. The combination of claim 66, wherein the one or more nucleoside modified ribonucleic acids comprise one or more pseudouridine residues.

69. The combination of claim 68, wherein said one or more pseudouridine residues comprise m1Ψ (1-methylpseudouridine).

70. The combination of claim 68, wherein said one or more pseudouridine residues comprise m1acp3Ψ (1-methyl-3-(3-amino-5-carboxypropyl)pseudouridine, Ψm (2′-O- methylpseudouridine, m3Ψ (3-methylpseudouridine), or any combination thereof.

71. The combination of any one of claims 1-3 and 14-70, wherein one or more of said polyribonucleotides is a codon optimized polyribonucleotide.

72. The combination of any one of claims 1-3 and 14-71, wherein one or more of said polyribonucleotides comprises at least one in-frame signal sequence encoding at least one signal peptide.

73. The combination of any one of claims 1-3 and 14-72, wherein one or more of said polyribonucleotides further encodes an in-frame marker sequence or detectable tag sequence encoding a marker or detectable tag.

74. The combination of any one of claims 1-3 and 14-73, wherein one or more of said polyribonucleotides further comprises a poly-A tail.

75. The combination of any one of claims 1-3 and 14-74, wherein one or more of said polyribonucleotides further comprise a cap.

76. The combination of claim 75, wherein the cap comprises an m7GpppG cap, 3′-O- methyl-m7GpppG cap, or anti-reverse cap analog.

77. The combination of any one of claims 1-3 and 14-76, wherein one or more of said polyribonucleotides further comprises a cap-independent translational enhancer. Page 236 of 242P-636791-PC 78. The combination of any one of claims 1-3 and 14-77, wherein one or more of said polyribonucleotides further comprises 5′ untranslated regions, 3′ untranslated regions, or a combination thereof.

79. The combination of any one of claims 1-3 and 14-78, wherein one or more of said polyribonucleotides are formulated with a nanoparticle, lipid, polymer, cholesterol, cell penetrating peptide, or any combination thereof.

80. The combination of claim 79, wherein said nanoparticle comprises a lipid nanoparticle.

81. The combination of claim 79 or claim 80, wherein one or more of said polyribonucleotides are fully or partially encapsulated within lipid nanoparticles.

82. The combination of claim 80 or claim 81, wherein the lipid nanoparticles comprise (a) a polymer-conjugated lipid; (b) a cationic lipid; and (c) one or more neutral lipids.

83. The combination of any one of claims 1-3 and 14-82, wherein said composition further comprises polyplexes (PLX), lipidated polyplexes (LPLX), or liposomes.

84. The combination of any one of claims 1-83, wherein the anti-HSV glycoprotein antigen binding agent binds to an HSV-1 glycoprotein, an HSV-2 glycoprotein, or a combination thereof.

85. A composition comprising the polypeptides encoded by the combination of any one of claims 1-84.

86. A composition comprising the combination of any one of claims 1-85 and a pharmaceutically acceptable carrier.

87. The composition of claim 86, wherein said composition is formulated for intramuscular, subcutaneous, intradermal, intranasal, intravaginal, intrarectal, or topical administration.

88. A polypeptide encoding an anti-Herpes Simplex Virus (HSV) glycoprotein B (gB) (anti-gB) antigen binding agent comprising a heavy chain variable region and a light chain variable region, wherein the polypeptide comprises: (i) a heavy chain complementarity determining region 1 (CDRH1) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 33, (ii) a heavy chain complementarity determining region 2 (CDRH2) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 34, (iii) a heavy chain complementarity determining region 3 (CDRH3) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% Page 237 of 242P-636791-PC identity to a nucleic acid sequence according to SEQ ID NO: 35, (iv) a light chain complementarity determining region 1 (CDRL1) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 46, (v) a light chain complementarity determining region 2 (CDRL2) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO: 47, and (vi) a light chain complementarity determining region 3 (CDRL3) comprising a nucleic acid sequence having at least 80%, at least 90%, at least 95%, or 100% identity to a nucleic acid sequence according to SEQ ID NO:

48.

89. A polypeptide encoding an anti-Herpes Simplex Virus (HSV) glycoprotein D (gD) (anti-gD) antigen binding agent comprising a heavy chain variable region and a light chain variable region, wherein the polypeptide comprises: (i) a heavy chain complementarity determining region 1 (CDRH1) comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 162, (ii) a heavy chain complementarity determining region 2 (CDRH2) comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 163, (iii) a heavy chain complementarity determining region 3 (CDRH3) comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 164, (iv) a light chain complementarity determining region 1 (CDRL1) comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 172, (v) a light chain complementarity determining region 2 (CDRL2) comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 173, and (vi) a light chain complementarity determining region 3 (CDRL3) comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO:

174. Page 238 of 242P-636791-PC 90. A polypeptide encoding an anti-Herpes Simplex Virus (HSV) glycoprotein D (gD) (anti-gD) antigen binding agent comprising a heavy chain variable region and a light chain variable region, wherein the polypeptide comprises: (i) a heavy chain complementarity determining region 1 (CDRH1) comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 206, (ii) a heavy chain complementarity determining region 2 (CDRH2) comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 207, (iii) a heavy chain complementarity determining region 3 (CDRH3) comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 208, (iv) a light chain complementarity determining region 1 (CDRL1) comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 216, (v) a light chain complementarity determining region 2 (CDRL2) comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 217, and (vi) a light chain complementarity determining region 3 (CDRL3) comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO:

218.

91. A polypeptide encoding an anti-Herpes Simplex Virus (HSV) glycoprotein D (gD) (anti-gD) antigen binding agent comprising a heavy chain variable region and a light chain variable region, wherein the polypeptide comprises: (i) a heavy chain complementarity determining region 1 (CDRH1) comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 229, (ii) a heavy chain complementarity determining region 2 (CDRH2) comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 230, (iii) a heavy chain complementarity determining region 3 (CDRH3) comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an Page 239 of 242P-636791-PC amino acid sequence according to SEQ ID NO: 231, (iv) a light chain complementarity determining region 1 (CDRL1) comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 239, (v) a light chain complementarity determining region 2 (CDRL2) comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO: 240, and (vi) a light chain complementarity determining region 3 (CDRL3) comprising an amino acid sequence having at least 90%, at least 95%, or 100% identity to an amino acid sequence according to SEQ ID NO:

241.

92. The polypeptide of any one of claims 88-91, wherein the anti-gB antigen binding agent or the anti-gD antigen binding agent comprises one or more amino acid substitutions.

93. The polypeptide of claim 92, wherein the one or more amino acid substitutions are in a heavy chain constant region.

94. The polypeptide of claim 93, wherein the one or more amino acid substitutions comprises (a) D399R with reference to SEQ ID NO: 159, SEQ ID NO: 180, or SEQ ID NO: 225, or (b) K409D with reference to SEQ ID NO: 202, SEQ ID NO: 246, or SEQ ID NO:

250.

95. The polypeptide of any one of claims 88-94, wherein the anti-gD antigen binding agent is an anti-gD IgG.

96. The polypeptide of any one of claims 88-94, wherein the anti-gD antigen binding agent comprises an anti-gD scFv.

97. The polypeptide of any one of claims 88-94, wherein the anti-gD antigen binding agent is an anti-gD scFv-Fc.

98. A polyribonucleotide encoding the polypeptide according to any one of claims 88-97.

99. A composition comprising the polypeptide of any one of claims 88-98 or the polyribonucleotide of claim 92 and a pharmaceutically acceptable carrier.

100. The combination of any one of claims 1-85, the composition of any one of claims 86- 87 or 99, the polypeptide of any one of claims 88-97, or the polyribonucleotide of claim 98 for use in a method of treating, suppressing, reducing, inhibiting, or preventing a Herpes Simplex Virus (HSV) infection or transmission in a subject.

101. The combination of any one of claims 1-85, the composition of any one of claims 86- 87 or 99, the polypeptide of any one of claims 88-97, or the polyribonucleotide of Page 240 of 242P-636791-PC claim 98 for use in a method of treating, suppressing, reducing, inhibiting, or preventing a Herpes Simplex Virus (HSV) neurological infection or transmission in a subject.

102. The combination of any one of claims 1-85, the composition of any one of claims 86- 87 or 99, the polypeptide of any one of claims 88-97, or the polyribonucleotide of claim 98 for use in a method for neutralizing Herpes Simplex Virus (HSV) transmission or infection in a subject.

103. The combination, composition, polypeptide or polyribonucleotide for use of any one of claims 100-102, wherein the HSV infection or transmission comprises HSV-1 infection or transmission.

104. The combination, composition, polypeptide or polyribonucleotide for use of any one of claims 100-102, wherein the HSV infection or transmission comprises HSV-2 infection or transmission.

105. The combination, composition, polypeptide or polyribonucleotide for use of any one of claims 100-104, wherein the HSV infection comprises a primary HSV infection.

106. The combination, composition, polypeptide or polyribonucleotide for use of any one of claims 100-104, wherein the HSV infection comprises a flare, recurrence, or HSV labialis following a primary HSV infection.

107. The combination, composition, polypeptide or polyribonucleotide for use of any one of claims 100-104, wherein the HSV infection comprises a reactivation of a latent HSV infection.

108. The combination, composition, polypeptide or polyribonucleotide for use of any one of claims 100-107, wherein the HSV infection comprises an HSV encephalitis, HSV keratitis, an HSV neonatal infection, a genital HSV infection, an oral HSV infection, or a mucosal HSV infection.

109. The combination, composition, polypeptide or polyribonucleotide for use of any one of claims 100-108, wherein the composition, combination, or polypeptide is formulated for administration by intramuscular administration, subcutaneous administration, or intradermal administration.

110. The combination, composition, polypeptide or polyribonucleotide for use of any one of claims 100-108, wherein the composition, combination, or polypeptide is formulated for administration by intranasal administration, intravaginal administration, or intrarectal administration. Page 241 of 242

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