Anti-HBV antibody and method of use

Abstract

This invention provides an anti-S-HBs antibody and a method for using the same. [Solution] The present invention provides an antibody that binds to S-HBs, is cross-reactive to each of the HBV proteins of a specific sequence, and / or, when measured in vitro, has a neutralization IC50 value of ≤1 ng / ml against HBV genome D.

Description

[Technical Field]

[0001] Technical field This invention relates to an antibody against hepatitis B virus (HBV) and a method for using the same. [Background technology]

[0002] background Chronic hepatitis B virus (HBV) infection remains a major health problem affecting more than 250 million people worldwide, despite the availability of effective vaccines (WHO, 2017). This infection leads to approximately one million deaths annually from HBV-associated cirrhosis, liver failure, and hepatocellular carcinoma (WHO, 2017). HBV is a DNA virus belonging to the family Hepadnaviridae, produced as infectious virions or Dane particles, but also as non-infectious subviral particles (Seeger et al., 2013). Virions and subviral particles exhibit three forms of HBV envelope glycoprotein or HBV surface antigen (HBsAg): L-HBs (large), M-HBs (medium), and S-HBs (small) on their surface. Therefore, defective particles, exceeding the number of infectious HBV virions, act as immune decoys (Seeger et al., 2013). Current treatments for chronic HBV rarely achieve functional cure, which is defined by HBsAg loss and seroconversion of anti-HBs antibodies. Nevertheless, HBV infection can be well controlled by the innate immune response in over 90% of patients infected as adults, and in about 1% of chronically infected patients who spontaneously cure the infection, known as HBV seroconversion or natural controllers (Bauer et al., 2011; Chu and Liaw, 2016; McMahon, 2009; Rehermann and Nascimbeni, 2005). Robust and multispecific HBV-specific CD4 + and CD8 +T cell responses are important immune effectors in controlling infection (Bauer et al., 2011). However, B cells and antibodies also play a role in long-term clearance after functional recovery and protection from viral rebound (Bertoletti and Ferrari, 2016; Corti et al., 2018; Rehermann and Nascimbeni, 2005). For example, HBsAg in patients - / Anti-HBs + Despite antibody seroconversion correlating with undetectable levels of HBV DNA (McMahon, 2009), functionally cured individuals undergoing B-cell depletion therapy to treat non-Hodgkin lymphoma are at high risk of HBV reactivation, which can rapidly lead to severe hepatic impairment (Kusumoto et al., 2019; Perrillo et al., 2015). Therefore, key immune components for controlling and ultimately eliminating HBV infection likely include a broad and robust antigen-specific T-cell response, as well as the development of neutralizing anti-HBs antibodies that mediate HBsAg clearance and lifelong protective immunity (Bertoletti and Ferrari, 2016; Corti et al., 2018).

[0003] Neutralizing antibodies produced in response to HBV infection target all three HBsAg forms. They recognize the S-HBs antigenic loop, interfere with the pre-attachment of heparan sulfate proteoglycans (HS) or L-HBs to the preS1 domain on hepatocytes, and block binding to the host cell receptor, sodium taurocholate cotransport polypeptide (NTCP) (Corti et al., 2018). Protection against HBV infection is conferred by IgG antibodies against the "a-determinant" portion of the S-HBs loop, induced by HBV vaccination (based on recombinant S-HBs immunogen) or administered to individuals at risk of exposure via polyclonal HBV immunoglobulin infusion (Samuel et al., 1993; West and Calandra, 1996). Several neutralizing anti-preS and anti-S-HBs antibodies have been isolated from immunized mice and a small number of human immunized donors (Corti et al., 2018). S-HBs neutralizing antibodies may contribute to viral clearance and long-term suppression in HBV seroconverted individuals, as well as to infection protection in vaccinated individuals. However, there has been no research on the memory B cell response to HBV in functionally cured HBV-infected individuals through the cloning and characterization of human HBsAg-specific antibodies. [Overview of the project]

[0004] overview This invention provides an anti-S-HBs antibody and a method for using the same. [Brief explanation of the drawing]

[0005] [Figure 1]S-HBs memory antibodies cloned from HBV vaccine recipients and controllers. (A) Mean S-HBsAg reactivity of serum IgG from HBV vaccine recipients (HBVv, n=6, lower curve) and controllers (HBVc, n=8, upper curve). Shaded area indicates range of values. Representative flow cytometry plots showing S-HBs-binding IgG+ memory B cells in HBV vaccine recipients and controllers (showing Bv4 and Bc3). nS-HBsAg and rS-HBsAg are human-derived natural and recombinant S-HBs antigens, respectively. (B) S-HBsAg-ELISA reactivity of S-HBsAg-captured IgG+ memory B cell antibodies (left) and percentage of S-HBs-specific monoclonal antibodies isolated from HBVv and HBVc (%S-HBsAg+) (right). %S-HBsAg+ by S-HBs antibody titer in HBVc (<150 and >900 IU / ml) is shown. (C) Capt-rHBAg, rHBAg capture ELISA. (C) Bubble plot showing the level of clonal proliferation by percentage of somatic mutations in the IgH and IgL chain variable domains of S-HBs-specific IgG antibodies. The size of the proliferators from each donor is shown in the bar graph below. (D) Volcano plot analysis comparing the immunoglobulin (Ig) gene repertoire of S-HBsAg-specific B cells from HBV-immunized donors and IgG memory B cells from healthy individuals (top). Dots above the dashed line indicate statistically significant differences between the two Ig gene repertoires. Comparison of VH(DH)JH rearrangement frequencies (bottom). pV, p-value; FC, magnification change. (E) Distribution of structure-dependent antibodies versus non-stereostructure antibodies among S-HBs memory IgG. The total number of antibodies tested is shown in the center of the pie chart. Infrared immunoblot shows anti-S-HBs IgG memory B cell antibodies reactive to denatured S-HBs protein (upper right). The ELISA binding curve for the peptide-reactive S-HBs antibody is shown (bottom right, mean ± SD of the four-cartridge). [Figure 2]Neutralizing activity of human S-HBs memory antibodies (A) Neutralizing activity of S-HBs IgG antibodies against in vitro infection of HepaRG cells with genotype D HBV. The 50% inhibitory concentration (IC50) values ​​(n=72) of each antibody (top left) and the distribution of neutralizing antibodies versus inactive antibodies (bottom left) are shown. (B) Neutralizing ability by bound S-HBs antigen (top right) and the percentage of somatic high-frequency mutations (%SHM) (bottom right) are shown. (C) In vitro neutralizing activity of selected S-HBs IgG antibodies against HDV using HDV RNA quantification in HepaRG cells by Northern blotting. ge, genomic equivalent. (D) In ​​vivo neutralizing activity of human S-HBs antibodies in AAV-HBV transduced mice. Circulating blood S-HBs levels were monitored in AAV-HBV transduced mice treated with a single IV dose of 0.5 mg of anti-S-HBs antibody PIBv4.104 (n=9), Bc1.187 (n=9), Bc1.263 (n=6), Bc4.204 (n=4), or mGO53 isotype control (n=5). The thick line represents the mean value. (E) This shows the Log10 change in S-HBs titer at the lowest point (2 days after injection, dpi2) after administration of 0.25 mg (white) and 0.5 mg (black) of antibody per mouse. The mean is shown by the line. (F) Circulating blood S-HBs and HBV DNA levels were monitored in AAV-HBV transduced mice (n=6) that received a single IV injection of 1 mg of anti-S-HBs antibody Bc1.187. The mean log10 changes over time in S-HBs and HBV DNA levels are shown on the right. [Figure 3]Cross-reactivity of human HBV neutralizing antibodies (A) Heatmap comparing the ELISA reactivity of HBV neutralizing antibodies against Adw and Ayw genotype D S-HBs protein (measured as AUC values ​​from Figure 14). The representative ELISA graph on the right shows the reactivity of selected antibodies against recombinant HBV vaccines Engerix-B (Ayw) and GenHevac (Adw). Error bars indicate SD for assay overlap. (B) Heatmap comparing the reactivity of HBV neutralizing antibodies against S-HBs antigens from genotypes shown in the phylogenetic tree (upper left) as percentage of bound S-HBs-expressing cells determined by flow cytometry. The data represents one of two independent experiments. HB1 and mGO53 are the positive and negative controls, respectively. The cytogram in the lower left shows the representative reactivity profile of the HB1 antibody. The ELISA graph on the right shows the reactivity of selected antibodies against recombinant S-HBs antigens from all genotypes except G. Error bars indicate SD for assay overlap. (C) This is the same as (B) except for the S-HBs mutant protein shown in the upper left figure. (D) This graph compares the neutralizing activity of Bc1.187 against infection of primary human hepatocytes by HBV virus genotypes A-D. Error bars show SEM of the three assays. (E) The graph shows the neutralization curves of HBV virus from genotypes A, C, and D by PIBv4.104 and Bc1.187, determined by the HepaRG neutralization assay. Error bars show SEM of the three assays. [Figure 4]Binding Characteristics of Human HBV Neutralizing Antibodies (A) Heatmap showing ELISA binding of selected HBV neutralizing antibodies to recombinant HBsAg mutant proteins. Color values ​​are proportional to the reactivity level. (B) Heatmap showing competition for HBV neutralizing antibodies for S-HBs binding. Brighter colors indicate stronger inhibition; black indicates no competition. (C) Graph comparing the binding of selected HBV neutralizing antibodies and their germline counterparts to S-HBs as measured by flow cytometry (top) and ELISA (bottom). (D) Neutralizing activity of germline versions of genotype D HBV virus Bc1.187, Bc4.204, and PIBv4.104 as determined by HepaRG neutralization assay. Error bars indicate SD of the triple assay. (E) Reactivity profiles of selected S-HBs human antibodies on a human protein microarray. Each spot corresponds to the z-score given to a single protein by the reference antibody (Ref: mGO53, y-axis) and the test antibody (x-axis). The label indicates an immunoreactive protein (z>5). [Figure 5] In vivo treatment with potent HBV cross-neutralizing antibody Bc1.187. (A) Occurrence of HBV infection over time in AAV-HBV transduction mice (n=7 per group) treated every 2 days for 16 days with 0.5 mg IV of anti-S-HBs Bc1.187 or isotype control mGO53 chimeric antibody. Circulating blood HBsAg, HBeAg, and HBV DNA levels are shown. Thick lines indicate mean values. (B) Occurrence of HBV infection over time in HUHEP mice administered IV human anti-S-HBs antibody Bc1.187 (20 mg / kg ~ 0.4 mg, n=7, straight line; 50 mg / kg ~ 1 mg, n=5, dotted line) weekly for 3 weeks. Circulating blood HBsAg, HBeAg, and HBV DNA levels (left) and Δlog10 values ​​compared to baseline (right) are shown. Thick lines indicate mean values. [Figure 6] This table shows the clinical and immunovirological characteristics of HBV immune donors. [Figure 7] Figures 7A and 7B are tables showing the immunoglobulin gene repertoire and neutralizing activity of human anti-S-HBs antibodies. [Figure 8]Binding of purified serum IgG and blood IgG+ memory B cells to S-HBs antigen. (A) Representative ELISA graph showing the reactivity of purified serum IgG antibodies from HBV vaccinated individuals (HBVv) and controllers (HBVc) to recombinant (rS-HBs) and human-derived natural (nS-HBs) S-HBs particles. Error bars indicate double-sequence SEM values. (B) Flow cytometry cytogram showing the gating strategy used to sort single-cell IgG+ memory B cells that bind to fluorescently labeled rS-HBs and nS-HBs proteins used as bait. S-HBs-reactive IgG+ memory B cell populations are shown for all donors. [Figure 9] S-HBs reactivity of S-HBs-capturing IgG+ memory B cell antibodies. (A) Heatmap showing the ELISA reactivity of S-HBs-binding memory antibodies cloned from HBV vaccinated individuals and seroconverted individuals against nS-HBs and rS-HBs (fixed and captured). The average of three sets of optical density values ​​is shown. (B) Violin plot showing the cumulative ELISA optical density (COD) values ​​for the binding shown in (A). The percentage of S-HBs-specific antibodies cloned from S-HBs-capturing IgG+ memory B cells is shown for each donor (right). [Figure 10]Immunoglobulin gene repertoire of S-HBs-specific IgG+ memory B cells. (A) Pie chart comparing the distribution of VH / JH gene usage in blood S-HBs-specific IgG+ memory B cells and IgG+ memory B cells (IgG.mB) from healthy individuals (Prigent et al., 2016). The number of antibody sequences analyzed is shown in the center of each pie chart. (B) Bar graph comparing the distribution of single immunoglobulin VH genes expressed by S-HBs-specific IgG+ memory B cells and control IgG+ memory B cells. (C) Amino acid alignment of the CDRH2 region of VH1-69 expressing S-HBs antibodies (defined by Kabat). Gray residues indicate substitutions compared to germline VH genes (top). (D) Same as (B) except for IgG subtype (left) and κ-vs-λ-Ig chain usage (right). (E) Same as (B) except for CDRH3 length and number of positive charges. The average length of CDRH3 is shown below each histogram. (F) Same as (A), except for the use of Vκ / Jκ and Vλ / Jλ genes. (G) Violin plots comparing the number of mutations in the VH, Vκ, and Vλ genes in S-HBs-specific IgG+ memory B cells and control IgG+ memory B cells. The mean number of mutations (mut.) is shown below each dot plot. The number of mutations across antibody groups was compared using an independent Student's t-test corrected by Welch. (H) Graph showing Bayesian estimation of antigen-driven selection based on anti-S-HBs IgH and IgL sequences. Groups were compared using 2×2 and 2×5 Fisher's direct tests (in A, B, D, E, and F). [Figure 11]Reactivity of human anti-S-HBs antibodies against denatured S-HBsAg and S-HBsAg peptides. (A) ELISA reactivity of anti-S-HBs antibodies against transmembrane domain deletion S-HBsAg protein (ΔTM-rS-HBsAg). HB1 and mGO53 are positive and negative controls, respectively. The dotted line indicates the cutoff OD405nm for positive reactivity. (B) Same as (A), except for the cyclic peptides corresponding to the putative S-HBsAg loops 122-137 and 139-148. (C) Heatmap reactivity of anti-S-HBs antibodies against S-HBsAg duplicated linear peptides. The amino acid sequence of the S-HBsAg peptide (right) and the overall mean of the hydroxyl (GRAVY) (bottom) are shown. [Figure 12] Figures 12A and 12B show in vitro HBV neutralization by human S-HBs antibodies. The graph shows the neutralization curves for genotype D HBV virus by selected human S-HBs antibodies, measured by an in vitro HepaRG assay. The dotted horizontal line represents 50% neutralization, from which the IC50 value can be derived from the antibody concentration on the x-axis. [Figure 13] Passive administration of human S-HBs antibody in HBV-AAV mice. (A) In vivo neutralizing activity of human S-HBs antibody in AAV-HBV transduced mice. Circulating blood HBsAg levels were monitored in AAV-HBV transduced mice treated with a single IV dose of 0.25 mg of anti-S-HBs antibody Bv4.104 (n=6), Bc1.187 (n=6), Bc1.263 (n=6), Bc4.204 (n=6), or mGO53 isotype control (n=5). The thick line shows the mean. The graph shows the time course of Log10 change in HBsAg titer (Δlog10 S-HBs) after administration of 0.25 mg IV of antibody per mouse. (B) Graph showing the time course of human IgG titer development in mice treated once with 0.25 mg (left) and 0.5 mg (right) of S-HBs antibody. The thick line represents the average. [Figure 14]Binding of HBV neutralizing antibodies to recombinant serotype-specific S-HBs proteins. Representative ELISA graphs showing the binding of selected HBV neutralizing antibodies to purified recombinant Adw (linear) and Ayw (dotted) S-HBs proteins. HB1 and mGO53 are positive and negative controls, respectively. Mean ± SEM values ​​of assay overlaps from one of two independent experiments are shown. [Figure 15] Cross-reactivity of HBV neutralizing antibodies against genotype-specific S-HBs proteins. (A)(B) Amino acid alignment of consensus S-HBs protein sequences from different HBV genotypes used. Residual mutations are highlighted in gray. (B) Cytogram comparing the reactivity profiles of selected HBV neutralizing antibodies against genotype-specific S-HBs antigens. Data represent one of two independent experiments. HB1 and mGO53 are positive and negative controls, respectively. Ctr, untransfected cell control (bottom); FI, fluorescence intensity. [Figure 16] Reactivity of HBV neutralizing antibodies against S-HBs mutant proteins. (A) Cytogram comparing the reactivity of selected HBV neutralizing antibodies against genotype D S-HBs mutant proteins exhibiting naturally occurring escape mutations (T126A, M133T, Y134V, or G145R) or mutations in the S-HBs N-glycosylation site (N126S). Data represent one of two independent experiments. HB1 and mGO53 are positive and negative controls, respectively. Ctr, untransfected cell control (bottom); FI, fluorescence intensity. [Figure 17](A) Reactivity profiles of selected human S-HBs antibodies (n=8) on a human protein microarray. For each protein spot, the mean fluorescence intensity (MFI) obtained by the reference (Ref: mGO53) and the test is shown on the y and x axes, respectively. Each dot represents the mean of the double array protein. The diagonal line indicates equal binding for the reference antibody and the test antibody. Labeled dots indicate immunoreactive proteins with a z score > 5. (B) Frequency histogram showing log10 protein substitutions (σ) of the MFI signal for S-HBs antibodies compared to the non-reactive antibody mGO53. The polyreactivity index (PI) corresponds to the Gaussian mean of all array protein substitutions. (C) Binding of selected S-HBs antibodies to HEp2-expressing autoantigen was assayed by IFA and ELISA. Ctr+, positive control of the kit. mGO53 and ED38 are negative and positive control antibodies, respectively. Scale bars represent 40 μM. The bar graph in the lower right shows HEp-2 reactivity measured by ELISA. It shows the mean ± SD of values ​​from two independent experiments conducted in a double-chain fashion. [Figure 18]Passive administration of neutralizing antibodies in chronically HBV-infected mice. (A) Time course of circulating blood HBsAg levels in AAV-HBV transduced mice (n=7) treated with 0.5 mg ip of human anti-S-HBs antibody Bc1.187 or mGO53 isotype control every 3-4 days for 17 days. Mean Δlog10 HBsAg value is shown (right). Shaded area indicates antibody treatment period. (B) Mouse anti-human IgG antibody levels in the treated mice shown in (A), measured by ELISA. (C) IgG concentration of passively administered chimeric Bc1.187 antibody (0.5 mg iv) in B6 mice (n=4). Half-life (t1 / 2) of muBc1.187 antibody is shown in the upper right. (D) Time course of Δlog10 S-HBs levels in C57BL / 6J mice administered weekly IV injections (0.5 mg) of chimeric anti-S-HBs antibody Bc1.187 and mGO53 isotype control. The thick line shows the mean value. (E) Time course of Δlog10 HBsAg and HBV DNA levels in AAV-HBV transduced mice (n=7) treated every 2 days for 16 days with 0.5 mg IV of chimeric anti-S-HBs antibody Bc1.187 or mGO53 isotype control. The thick line shows the mean value. The shaded area indicates the duration of antibody treatment. [Figure 19] Treatment of HBV-infected HUHEP mice with Bc1.187 antibody. (A) Time course of serum HBsAg, HBeAg, and HBV DNA levels in each HUHEP mouse infected with genotype D HBV and treated with anti-HBs Bc1.187 for 3 weeks by intravenous administration of either 20 mg / kg or 50 mg / kg of human antibody. (B) Time course of HBV infection in HUHEP mice treated with non-HBV isotype control mGO53 (20 mg / kg ip) or entecavir (ETV) every 3-4 days for 3 weeks. Shows serum levels of HBsAg, HBeAg, and HBV DNA. (C) Graph (shaded area) showing time course of human serum albumin levels when infected HUHEP mice were treated with 20 mg / kg (straight line) and 50 mg / kg (dotted line) of Bc1.187 for 17 days via ip. [Modes for carrying out the invention]

[0006] Detailed explanation I. Definition For the purposes of this specification, “acceptor human framework” is a framework comprising the amino acid sequence of a light chain variable domain (VL) framework or a heavy chain variable domain (VH) framework derived from a human immunoglobulin framework or a human consensus framework, as defined below. An acceptor human framework “derived” from a human immunoglobulin framework or a human consensus framework may contain the same amino acid sequence or may contain a modification of the amino acid sequence. In some embodiments, the number of amino acid modifications is 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less. In some embodiments, the VL acceptor human framework is sequence-identical to the VL human immunoglobulin framework sequence or the human consensus framework sequence.

[0007] "Affinity" refers to the sum of the strength of non-covalent interactions between a single binding site between a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless otherwise indicated, as used herein, "binding affinity" refers to the intrinsic binding affinity that reflects the 1:1 interaction between the members of a binding pair (e.g., an antibody and an antigen). The affinity of molecule X for its partner Y is generally expressed by the dissociation constant (K). D ) can be expressed by. Affinity can be measured by methods common in the art, including those described herein. Specific illustrative and exemplary methods for measuring binding affinity are described below.

[0008] An "affinity-matured" antibody is an antibody that, compared to an unmodified parent antibody, has one or more modifications in one or more complementarity-determining regions (CDRs), and such modifications improve the antibody's affinity for the antigen.

[0009] The terms "anti-S-HBs antibody" and "antibody that binds to S-HBs" refer to antibodies that can bind to S-HBs with sufficient affinity such that they are useful as diagnostic and / or therapeutic agents targeting S-HBs. In one embodiment, the degree of binding of an anti-S-HBs antibody to an irrelevant non-S-HBs protein is less than about 10% of the binding of the antibody to S-HBs when measured, for example, by surface plasmon resonance (SPR) or using an ELISA or flow cytometry disclosed herein. In certain embodiments, an antibody that binds to S-HBs has a dissociation constant (K -8 ) of ≤ 1 μM, ≤ 100 nM, ≤ 10 nM, ≤ 1 nM, ≤ 0.1 nM, ≤ 0.01 nM or ≤ 0.001 nM (e.g., 10 -8 M or less, e.g., 10 -13 M to 10 -9 M, e.g., 10 -13 M). When an antibody has a K D of ≤ 1 μM and / or the degree of binding of an anti-S-HBs antibody to an irrelevant non-S-HBs protein is less than about 10% of the binding of the antibody to S-HBs as measured, for example, by surface plasmon resonance (SPR) or flow cytometry or an ELISA assay described herein, the antibody is said to "specifically bind" to S-HBs. In certain embodiments, an anti-S-HBs antibody binds to an epitope of S-HBs that is conserved among S-HBs derived from different HBV genotypes.

[0010] The term "antibody" as used herein is used in the broadest sense and encompasses various antibody structures including, but not limited to, monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), other antibody formats (e.g., in a format different from normal IgG and including a VH domain, a VL domain and optionally an Fc domain) and antibody fragments, as long as they exhibit the desired antigen-binding activity.

[0011] ​​An "antibody fragment" is a molecule other than an intact antibody, containing a portion of an intact antibody that binds to the antigen to which the intact antibody binds. Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab')2; diabodies; linear antibodies; single-chain antibody molecules (e.g., scFv and scFab); single-domain antibodies (dAb); and multispecific antibodies formed from antibody fragments. For a review of specific antibody fragments, see Holliger and Hudson, Nature Biotechnology 23:1126-1136 (2005).

[0012] The term "epitope" refers to a site on an antigen, either proteinaceous or non-proteinaceous, to which an anti-S-HBs antibody binds. Epitopes can be formed from continuous amino acid stretch sites (linear epitopes) or from discontinuous amino acids (concrete epitopes), and are formed spatially close together, for example, due to antigen folding (i.e., by tertiary folding of proteinaceous antigens). Linear epitopes generally remain bound to anti-S-HBs antibodies even after the proteinaceous antigen has been exposed to a denaturing agent, while concrete epitopes are generally destroyed upon treatment with a denaturing agent. Epitopes contain at least 3, at least 4, at least 5, at least 6, at least 7, or 8-10 amino acids in a unique spatial structure.

[0013] Screening for antibodies that bind to a specific epitope (i.e., antibodies that bind to the same epitope) may be performed using methods commonly used in the art, such as, but not limited to, alanine scanning, peptide blotting (Meth.Mol.Biol.248(2004)443-463), peptide cleavage analysis, epitope excision, epitope extraction, chemical modification of antigens (see Prot.Sci.9(2000)487-496), and cross-blocking (see "Antibodies", Harlow and Lane, Cold Spring Harbor Press, Cold Spring Harb., NY).

[0014] Antigen structure-based antibody profiling (ASAP), also known as modification-assisted profiling (MAP), allows for the classification of numerous monoclonal antibodies that specifically bind to S-HBs based on their respective binding profiles to chemically or enzymatically modified antigen surfaces (see, for example, US 2004 / 0101920). Each classified antibody binds to the same epitope, which may be distinctly different from or partially overlapping epitopes represented by other classifications.

[0015] Furthermore, competitive binding can be used to easily determine whether an antibody binds to the same S-HBs epitope as the reference antibody, or whether it competes for binding with the reference anti-S-HBs antibody. For example, an antigen that "binds to the same epitope" as the reference anti-S-HBs antibody refers to an antibody that blocks the binding of the reference anti-S-HBs antibody to that antigen by 50% or more in a competitive assay, and conversely, the reference antibody blocks the binding of the antibody to that antigen by 50% or more in a competitive assay. Alternatively, for example, to determine whether an antibody binds to the same epitope as the reference anti-S-HBs antibody, the reference antibody can be bound to S-HBs in a saturated state. After removing excess reference anti-S-HBs antibody, the ability of the anti-S-HBs antibody to bind to S-HBs is evaluated. If the anti-S-HBs antibody can bind to S-HBs after saturated binding of the reference anti-S-HBs antibody, it can be concluded that this anti-S-HBs antibody binds to a different epitope than the reference anti-S-HBs antibody. However, if an anti-S-HBs antibody cannot bind to S-HBs after saturated binding of a reference anti-S-HBs antibody, it is possible that this anti-S-HBs antibody is binding to the same epitope to which the reference anti-S-HBs antibody binds. Conventional experiments can be used to determine whether the antibody in question is binding to the same epitope or whether binding is simply being hindered for steric reasons (e.g., peptide mutation analysis or binding analysis using ELISA, RIA, surface plasmon resonance, flow cytometry, or other quantitative or qualitative antibody binding assays available in the art). This assay should be performed in two setups, i.e., with both antibodies saturated. If, in both setups, only the first (saturated) antibody is able to bind to S-HBs, it can be concluded that this anti-S-HBs antibody and the reference anti-S-HBs antibody are competing for binding to S-HBs.

[0016] In some embodiments, if a competitive binding assay measures that a 1, 5, 10, 20, or 100-fold excess of one antibody inhibits the binding of the other by at least 50%, at least 75%, at least 90%, or even more than 99%, then the two antibodies are considered to bind to the same or overlapping epitopes. (See, for example, Junghans et al., Cancer Res. 50(1990) 1495-1502).

[0017] In some embodiments, two antibodies are considered to bind to the same epitope if substantially all of the amino acid mutations of an antigen that reduce or eliminate the binding of one antibody also reduce or eliminate the binding of the other antibody. Two antibodies are considered to have a “duplicate epitope” if only a subset of amino acid mutations that reduce or eliminate the binding of one antibody also reduces or eliminates the binding of the other antibody.

[0018] The term "chimeric" antibody refers to an antibody in which part of the heavy chain and / or light chain originates from a specific source or species, while the remainder of the heavy chain and / or light chain originates from a different source or species.

[0019] The "class" of an antibody refers to the type of constant domain or constant region it possesses in its heavy chain. Antibodies have five main classes: IgA, IgD, IgE, IgG, and IgM, some of which can be further divided into subclasses (isotypes), such as IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. In certain embodiments, the antibody is the IgG1 isotype. In certain embodiments, the antibody is the IgG1 isotype with P329G, L234A, and L235A mutations to reduce the effector function of the Fc region. In other embodiments, the antibody is the IgG2 isotype. In certain embodiments, the antibody is the IgG4 isotype with an S228P mutation in the hinge region to improve the stability of the IgG4 antibody. The heavy chain constant domains corresponding to different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively. The light chain of an antibody can be assigned to one of two types, called kappa (κ) or lambda (λ), based on the amino acid sequence of its constant domain.

[0020] As used in this application, the terms “human-derived constant region” or “human constant region” refer to the constant heavy chain region and / or constant light chain kappa or lambda region of a human antibody of subclass IgG1, IgG2, IgG3, or IgG4. Such constant regions are known in the art and are described, for example, in Kabat, EA, et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD (1991) (see also, for example, Johnson, G., and Wu, TT, Nucleic Acids Res. 28 (2000) 214-218; Kabat, EA, et al., Proc. Natl. Acad. Sci. USA 72 (1975) 2785-2788). Unless otherwise specified herein, the numbering of amino acid residues in the constant region follows the EU numbering system (also known as the Kabat EU index), as described in Kabat, EA et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD (1991), NIH Publication 91-3242.

[0021] "Effector function" refers to the biological activity resulting from the Fc region of an antibody, and it varies depending on the antibody isotype. Examples of antibody effector functions include: C1q binding and complement-dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; downregulation of cell surface receptors (e.g., B cell receptors); and B cell activation.

[0022] The “effective amount” of a drug, such as a pharmaceutical composition, refers to the amount that is effective in the dosage and duration required to achieve the desired therapeutic or preventive outcome.

[0023] The term “Fc region” is used herein to define the C-terminal region of an immunoglobulin heavy chain that includes at least a portion of the constant region. This term includes both the native sequence Fc region and variant Fc regions. In one embodiment, the human IgG heavy chain Fc region extends from Cys226 or Pro230 to the carboxyl terminus of the heavy chain. However, antibodies produced by host cells may undergo post-translational cleavage of one or more amino acids, particularly one or two, from the C-terminus of the heavy chain. Thus, by expression of a particular nucleic acid molecule encoding a full-length heavy chain, antibodies produced by host cells may contain the full-length heavy chain or a cleaved variant of the full-length heavy chain. This may be the case when the final two C-terminal amino acids of the heavy chain are glycine (G446) and lysine (K447, EU numbering system). Thus, the Fc region may or may not contain C-terminal lysine (Lys447), or C-terminal glycine (Gly446) and lysine (Lys447). The amino acid sequence of the heavy chain containing the Fc region is shown herein together with the C-terminal glycine-lysine dipeptide unless otherwise indicated. In one embodiment, the heavy chain containing the Fc region specified herein, as contained in the antibody according to the present invention, lacks the C-terminal glycine-lysine dipeptide (G446 and K447, EU numbering system). In one embodiment, the heavy chain containing the Fc region specified herein, as contained in the antibody according to the present invention, lacks the C-terminal lysine residue (K447, numbering according to the EU index). Unless otherwise specified herein, the numbering of amino acid residues in the Fc region or constant region follows the EU numbering system, also known as the EU index, as described in Kabat et al., "Sequences of Proteins of Immunological Interest," 5th edition, Public Health Service, National Institutes of Health, Bethesda, Maryland (1991).

[0024] "Framework" or "FR" refers to variable domain residues other than the complementarity-determining region (CDR). The variable domain FR generally consists of four FR domains: FR1, FR2, FR3, and FR4. Therefore, the CDR and FR sequences generally appear in VH (or VL) in the following sequence: FR1-CDR-H1(CDR-L1)-FR2-CDR-H2(CDR-L2)-FR3-CDR-H3(CDR-L3)-FR4.

[0025] The terms “full-length antibody,” “intact antibody,” and “whole antibody” are used herein synonymously to refer to antibodies having a structure substantially similar to that of a natural antibody or having a heavy chain containing an Fc region as defined herein.

[0026] The terms “host cell,” “host cell line,” and “host cell culture” are used synonymously and refer to cells into which exogenous nucleic acids have been introduced, including the progeny of such cells. Host cells include “transformers” and “transformed cells,” which, regardless of passage number, include primary transformed cells and their offspring. The offspring may not have the exact same nucleic acid content as the parent cells, but may include mutations. Mutant progeny having the same function or biological activity as those screened or selected for the original transformed cells are included in this invention.

[0027] A "human antibody" is defined as an antibody produced by a human or human cell, or an antibody having an amino acid sequence corresponding to a non-human antibody that utilizes a sequence encoding the human antibody repertoire or other human antibodies. This definition of a human antibody specifically excludes humanized antibodies that contain non-human antigen-binding residues.

[0028] The "Human Consensus Framework" is a framework representing the most commonly occurring amino acid residues in the selection of human immunoglobulin VL or VH framework sequences. Generally, the selection of human immunoglobulin VL or VH sequences is from subgroups of variable domain sequences. Generally, the sequence subgroups are those described in Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, NIH Publication 91-3242, Bethesda MD (1991), vols. 1-3. In one embodiment, for VL, the subgroup is subgroup Kappa I, as described in Kabat et al. above. In another embodiment, for VH, the subgroup is subgroup Kappa III, as described in Kabat et al. above.

[0029] A "humanized" antibody refers to a chimeric antibody containing amino acid residues derived from non-human CDRs and amino acid residues derived from human FRs. In certain embodiments, a humanized antibody substantially contains all of at least one, typically two, variable domains, in which all or substantially all of the CDRs correspond to the CDRs of a non-human antibody and all or substantially all of the FRs correspond to the FRs of a human antibody. A humanized antibody may optionally contain at least a portion of the antibody constant region derived from a human antibody. The "humanized form" of an antibody, for example, a non-human antibody, refers to an antibody that has undergone humanization.

[0030] As used herein, the terms “hypervariable region” or “HVR” mean each of the regions of an antibody variable domain that are hypervariable within a sequence and determine antigen-binding specificity, such as “complementarity-determining regions” (“CDR”).

[0031] Generally, an antibody contains six CDRs, three located in the VH (CDR-H1, CDR-H2, CDR-H3) and three located in the VL (CDR-L1, CDR-L2, CDR-L3). Illustrative CDRs as used herein include: (a) Hypervariable loops formed at amino acid residues 26-32 (L1), 50-52 (L2), 91-96 (L3), 26-32 (H1), 53-55 (H2), and 96-101 (H3) (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)), (b) CDRs present in amino acid residues 24-34 (L1), 50-56 (L2), 89-97 (L3), 31-35b (H1), 50-65 (H2), and 95-102 (H3) (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991)); and (c) Antigen contact occurring at amino acid residues 27c-36 (L1), 46-55 (L2), 89-96 (L3), 30-35b (H1), 47-58 (H2), and 93-101 (H3) is an example (MacCallum et al. J. Mol. Biol. 262:732-745 (1996)).

[0032] Unless otherwise specified, the CDR is determined in accordance with Kabat et al. above. Those skilled in the art will understand that the notation of the CDR may be determined in accordance with Chothia above, McCallum above, or any other scientifically recognized nomenclature system.

[0033] An "immunoconjugate" is an antibody that is conjugated to one or more heterologous molecules, including, but not limited to, cytotoxic drugs.

[0034] The “individual” or “subject” is a mammal. Mammals include, but are not limited to, domesticated animals (e.g., cattle, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates, e.g., monkeys), rabbits, and rodents (e.g., mice and rats). In certain aspects, the individual or subject is a human.

[0035] An “isolated” antibody is an antibody that has been separated from its natural environment. In some embodiments, antibodies are purified to a purity higher than 95% or 99%, as determined by methods such as electrophoresis (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatography (e.g., ion exchange or reverse-phase HPLC). For a review of methods for evaluating antibody purity, see, for example, Flatman et al., J. Chromatogr. B 848:79-87 (2007). Any of the antibodies described herein may be isolated antibodies.

[0036] The terms “nucleic acid molecule” or “polynucleotide” include any compound and / or substance containing a polymer of nucleotides. Each nucleotide is composed of a base, specifically a purine or pyrimidine base (i.e., cytosine (C), guanine (G), adenine (A), thymine (T), or uracil (U)), a sugar (i.e., deoxyribose or ribose), and a phosphate group. Often, nucleic acid molecules are described by a base sequence, where the bases represent the primary structure (linear structure) of the nucleic acid molecule. The base sequence is typically represented 5' to 3'. In this specification, the term nucleic acid molecule includes deoxyribonucleic acid (DNA), e.g., complementary DNA (cDNA) and genomic DNA, ribonucleic acid (RNA), in particular messenger RNA (mRNA), synthetic forms of DNA or RNA, and mixed polymers containing two or more of these molecules. Nucleic acid molecules may be linear or cyclic. In addition, the term nucleic acid molecule includes both sense strands and antisense strands, as well as both single-stranded and double-stranded forms. Furthermore, nucleic acid molecules described herein may include naturally occurring or non-naturally occurring nucleotides. Examples of non-naturally occurring nucleotides include modified nucleotide bases or chemically modified residues having derivatized sugar or phosphate backbone bonds. Nucleic acid molecules also include DNA and RNA molecules suitable as vectors for the direct expression of the antibodies of the present invention in vitro and / or in vivo in a host or patient, for example. Such DNA (e.g., cDNA) or RNA (e.g., mRNA) vectors may or may not be modified. For example, mRNA may be chemically modified to enhance the stability of the RNA vector and / or the expression of the encoded molecule so that mRNA can be injected into a target in vivo to produce an antibody. (For example, see Stadler et al, Nature Medicine 2017, published online 12 June 2017, doi:10.1038 / nm.4356 or EP 2 101 823 B1).

[0037] "Isolated" nucleic acids refer to nucleic acid molecules that have been separated from their natural environment. Isolated nucleic acids include nucleic acid molecules that are normally found inside cells, but these nucleic acid molecules are located outside of chromosomes or in chromosomal locations different from their natural chromosomal locations.

[0038] "Isolated nucleic acid encoding an anti-S-HBs antibody" means one or more nucleic acid molecules encoding the heavy and light chains (or fragments thereof) of an S-HBs antibody, including such nucleic acid molecules(s) in a single vector or separate vectors, and such nucleic acid molecules(s) are located at one or more locations within a host cell.

[0039] As used herein, the term “monoclonal antibody” refers to an antibody obtained from a substantially homogeneous population of antibodies, i.e., the individual antibodies constituting that population are identical and / or bind to the same epitope, with the exception of possible variant antibodies, such as those containing spontaneous mutations or arising during the production of a monoclonal antibody preparation, which are generally present in small amounts. In contrast to polyclonal antibody preparations, which typically contain different antibodies directed toward different determinants (epitopes), each monoclonal antibody in a monoclonal antibody preparation is directed toward a single determinant on one antigen. Therefore, the modified term “monoclonal” indicates the characteristic of an antibody obtained from a substantially homogeneous collection of antibodies and should not be interpreted as requiring the production of the antibody by any particular method. For example, monoclonal antibodies according to the present invention can be produced by a variety of techniques, including but not limited to hybridoma methods, recombinant DNA methods, phage display methods, and methods utilizing transgenic animals containing all or part of a human immunoglobulin locus, including but not limited to such methods and other exemplary methods for producing monoclonal antibodies described herein.

[0040] A "naked antibody" refers to an antibody that is not bound to a heterogeneous site (e.g., a cytotoxic site) or a radioactive label. Naked antibodies may be present in a pharmaceutical composition.

[0041] "Natural antibodies" refer to naturally occurring immunoglobulin molecules with various structures. For example, a natural IgG antibody is a heterotetrameric glycoprotein with approximately 150,000 daltons, containing two identical light chains and two identical heavy chains linked by disulfide bonds. From the N-terminus to the C-terminus, each heavy chain has a variable domain (VH), also called a variable heavy domain or heavy chain variable region, followed by three constant heavy domains (CH1, CH2, and CH3). Similarly, from the N-terminus to the C-terminus, each light chain has a variable domain (VL), also called a variable light domain or light chain variable region, followed by a constant light (CL) domain.

[0042] The term “package insert” is used to refer to the instructions typically included on the market packaging of a therapeutic product, including information relating to indications, use, dosage, administration, combination therapy, contraindications, and / or warnings for such therapeutic product.

[0043] The "amino acid sequence identity percentage (%)" relative to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical to those in the reference polypeptide sequence, after aligning the sequences for alignment purposes and introducing gaps if necessary to achieve the maximum sequence identity, without considering any conservative substitutions as part of the sequence identity. Alignment for determining the amino acid sequence identity percentage can be achieved in various ways within the scope of the art, for example, using publicly available computer software such as BLAST, BLAST-2, Clustal W, Megalign (DNASTAR) software, or FASTA program packages. Those skilled in the art can determine appropriate parameters for sequence alignment, including any algorithm necessary to achieve the maximum alignment over the entire length of the sequences being compared. Alternatively, the identity percentage value can be generated using the sequence comparison computer program ALIGN-2. The ALIGN-2 sequence comparison computer program was created by Genentech, Inc., and its source code is filed in the user documentation of the US Copyright Office (Washington DC, 20559), registered under US Copyright Registration No. TXU510087, and published in International Publication No. 2001 / 007611.

[0044] Unless otherwise noted, for the purposes of this specification, amino acid sequence identity percentage values ​​are generated using the ggsearch program in FASTA package version 36.3.8c, or subsequently using the BLOSUM50 comparison matrix. The FASTA program package is described by WRPearson and DJLipman (1988), "Improved Tools for Biological Sequence Analysis," PNAS 85:2444-2448; WRPearson (1996), "Effective protein sequence comparison," Meth.Enzymol.266:227-258; and Pearson et al. (1997), Genomics 46:24-36, and is publicly available at www.fasta.bioch.virginia.edu / fasta_www2 / fasta_down.shtml or www.ebi.ac.uk / Tools / sss / fasta. Alternatively, you can use the ggsearch(global protein:protein) program with default options (BLOSUM50;open:-10;ext:-2;Ktup=2) to compare sequences using a public server accessible at fasta.bioch.virginia.edu / fasta_www2 / index.cgi, ensuring that a global rather than local alignment is performed. The amino acid identity percentage is given in the output alignment header.

[0045] The terms "pharmaceutical composition" or "pharmaceutical preparation" refer to a preparation in which the active ingredient contained therein is in a form that is effective in terms of its biological activity, and which does not contain any additional ingredients that are unacceptably toxic to the subject to which the pharmaceutical composition is to be administered.

[0046] "Pharmacologically acceptable carriers" refer to components in a pharmaceutical composition or preparation other than the active ingredient that are non-toxic to the target. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives.

[0047] The terms “S-HBs” or “S-HBsAg” (referring to small hepatitis B surface antigens) as used interchangeably herein encompass “full-length” untreated S-HBs and any form of S-HBs resulting from intracellular processing. This term also encompasses naturally occurring variants of S-HBs, such as splice variants or allele variants. The amino acid sequence of an exemplary S-HBs is shown in SEQ ID NO: 253. The antibodies of the present invention can bind to at least the S-HBs of SEQ ID NO: 253 with, for example, the affinity or binding activity discussed herein. Optionally, the antibodies of the present invention may bind to, in addition to or instead of, one or more proteins containing or consisting of consensus sequences selected from SEQ ID NOs: 254-262, for example, the protein of SEQ ID NO: 257.

[0048] As used herein, “treatment” (and its grammatical variations, e.g., “to treat” or “treating”) refers to a clinical intervention in an attempt to alter the natural course of a disease in the treated individual, and may be performed for preventive purposes or during the course of a clinicopathological disease. Desired effects of treatment include, but are not limited to, prevention of disease onset or recurrence, alleviation of symptoms, reduction of any direct or indirect pathological consequences of the disease, reduction of the rate of disease progression, recovery or remission of the condition, and remission or improvement of prognosis. In some embodiments, the antibodies of the present invention are used to delay the onset of a disease or to slow the progression of a disease.

[0049] Hepatitis B can be chronic or acute, and the antibodies of the present invention may be used to treat either condition. Acute hepatitis generally refers to an infection within the first six months after exposure to the virus. Chronic hepatitis generally refers to an infection that progresses after six months. In some embodiments, treatment of hepatitis may refer to a reduction in HBV virus, elimination of HBV virus, reduction of symptoms caused by HBV infection, prevention or reduction of progression of hepatitis to liver diseases such as cirrhosis, hepatic fibrosis, hepatic failure and / or liver cancer, a reduction in detectable HBV surface antigen (HBsAg) in serum, and / or seroconversion of antibodies to HBV surface antigen (HBsAg), i.e., the absence of detectable HBsAg in serum. Detection of HBsAg may be performed by any well-established screening assay in the art, such as Elecsys HBsAg II (Roche Diagnostics), Auszyme Monoclonal [overnight incubation] version B, IMx HBsAg (Abbott), or Monolisa S-HBsAg ULTRA (Bio-Rad, France) ELISA.

[0050] A "variable region" or "variable domain" is a domain in the heavy or light chain of an antibody that is involved in the binding of the antibody to the antigen. The variable domains of the heavy and light chains of natural antibodies (VH and VL, respectively) generally have similar structures, and each domain contains four conserved framework regions (FRs) and three complementarity-determining regions (CDRs) (e.g., Kindt et al., Kuby Immunology, 6). th See ed., WH Freeman and Co., page 91 (2007). A single VH or VL domain may be sufficient to confer antigen-binding specificity. Furthermore, antibodies that bind to a specific antigen may be isolated by screening a library of complementary VL or VH domains using the VH or VL domain of the antibody that binds to the antigen, respectively. See, for example, Portolano et al., J. Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991).

[0051] As used herein, the term “vector” refers to a nucleic acid molecule capable of replicating another nucleic acid it is linked to. This term includes vectors as self-replicating nucleic acid structures, and vectors incorporated into the genome of a host cell into which they are introduced. Certain vectors can direct the expression of a operably linked nucleic acid. Such vectors are referred to herein as “expression vectors.”

[0052] II. Compositions and Methods In one embodiment, the present invention is based in part on the inventors' identification of antibodies from individuals who have spontaneously cleared chronic hepatitis B virus (HBV) infection and obtained protection from reinfection ("controllers") and individuals who have been vaccinated against HBV ("vaccinees"). The inventors have determined that such antibodies may have advantageous properties such as high affinity or binding activity to S-HBs antigen, potent neutralizing activity and / or cross-genotypic reactivity. In certain embodiments, antibodies that bind to S-HBs are provided. Antibodies of the present invention are useful, for example, in the diagnosis or treatment of hepatitis B.

[0053] A. Exemplary anti-S-HBs antibody In one embodiment, the present invention provides an antibody that binds to S-HBs. In one embodiment, an isolated antibody that binds to S-HBs is provided. In one embodiment, the present invention provides an antibody that specifically binds to S-HBs. In a particular embodiment, the anti-S-HBs antibody has one or more of the following characteristics:

[0054] ● Binds to S-HBs (e.g., SEQ ID NO: 253); and / or ● To bind to one or more S-HBs proteins having SEQ ID NOs. 254-262 (e.g., at least SEQ ID NOs. 257), optionally to two or more of the proteins (e.g., at least SEQ ID NOs. 257 and 258), optionally to three, four, five, six, seven, eight or more of the proteins, and optionally to all of the proteins; and / or ● Binds to S-HBs of subtype adw and / or ayw, for example, genotype D, preferably both adw and ayw subtypes; ● Avoid significant cross-reactivity to autoantigens such as galectin-3 / -8 and E3 ubiquitin-protein ligase UBR2; and / or ● (For example, measured in vitro or in vivo) possesses neutralizing activity against HBV genotype D; ● (For example, measured in vitro or in vivo) possessing neutralizing activity against each of the HBV genotypes A-D; and / or ● Viremia can be suppressed in vivo.

[0055] For example, in some embodiments, the antibody may have a neutralization IC50 value against HBV genome D that is ≤1 ng / ml when measured in vitro.

[0056] In other exemplary embodiments, the antibody may have the following properties: ● Cross-reactive with each of the proteins of sequence numbers 254-262; and ● (For example, measured in vitro or in vivo) It has neutralizing activity against HBV genotype D.

[0057] The exemplary antibodies described above may also preferably avoid significant cross-reactivity to autoantigens such as galectin-3 / -8 and E3 ubiquitin-protein ligase UBR2.

[0058] The antibody is K, which is discussed herein. D For example, the antibody can bind to S-HBs and / or one or more S-HBs proteins having SEQ ID NOs. 254-262 at concentrations of ≤1 μM, ≤100 nM, ≤10 nM, ≤1 nM, ≤0.1 nM, ≤0.01 nM, or ≤0.001 nM. In some embodiments, the antibody is a reference antibody against the same antigen. D A value that is 50, 10, 9, 8, 7, 6, 5, 4, 3, or 2 times higher than the reference antibody, or the K of the reference antibody. D K is as follows: DThe reference antibody is selected from the group consisting of Bc1.187, Bv4.115, Bc8.159, Bv6.172, Bc1.229, Bc8.111, Bc1.128, Bc3.106, Bc1.180, Bv4.104, Bc8.104, Bc4.204, Bc1.263, and Bv4.105, and is capable of binding to S-HBs and / or one or more S-HBs proteins having sequence numbers 254-262.

[0059] Alternatively, the antibody may exhibit binding activity to S-HBs and / or one or more S-HBs proteins having sequence numbers 254-262, which is at least 25%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the binding activity of the reference antibody against the same antigen (as evaluated by the same assay, e.g., ELISA assay or flow cytometry assay), and the reference antibody is selected from the group consisting of Bc1.187, Bv4.115, Bc8.159, Bv6.172, Bc1.229, Bc8.111, Bc1.128, Bc3.106, Bc1.180, Bv4.104, Bc8.104, Bc4.204, Bc1.263, and Bv4.105. In some embodiments, the activity may preferably be at least 50% of the activity of the reference antibody. Optionally, the reference antibody may be Bc1.187, meaning that the antibody, when evaluated in the same assay, may exhibit at least 25%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the binding activity of Bc1.187 to the reference antigen.

[0060] In other embodiments, the antibody may bind to S-HBs / or one or more S-HBs proteins having sequence numbers 254-262 at an EC50 of 50, 10, 9, 8, 7, 6, 5, 4, 3, or 2 times or less of the EC50 of the reference antibody, the EC50 of which is measured by ELISA or flow cytometry, and the reference antibody is selected from the group consisting of Bc1.187, Bv4.115, Bc8.159, Bv6.172, Bc1.229, Bc8.111, Bc1.128, Bc3.106, Bc1.180, Bv4.104, Bc8.104, Bc4.204, Bc1.263 and Bv4.105. "Avoiding significant cross-reactivity with" means, for example, in the assay described herein, that the antibody does not show significant binding to the reference protein, for example, K with a M content greater than 1 μM. D This means having or not having detectable bonds.

[0061] In some embodiments, the antibody according to the present invention, neutralized against an HBV genotype, for example genotype D, may have an IC50 value for in vitro viral infectivity of, for example, 50 ng / ml or less or 10 ng / ml or less. It may be preferable for the antibody to have an IC50 of ≤1 ng / ml, ≤500 pg / ml, or, in some embodiments, ≤100 pg / ml, ≤50 pg / ml, or ≤10 pg / ml. In some embodiments, the neutralizing antibody may have an IC50 value of ≤1 pg / ml, optionally ≤0.1 pg / ml. Optionally, the IC50 value may be greater than 0.01 pg / ml or 0.005 pg / ml. In another embodiment, an antibody neutralizing a specific HBV genotype, for example genotype D, may have an IC50 value of 50, 10, 9, 8, 7, 6, 5, 4, 3, or 2 times or less the IC50 value of a reference antibody against the same genotype (evaluated in the same assay), and the reference antibody is selected from the group consisting of Bc1.187, Bv4.115, Bc8.159, Bv6.172, Bc1.229, Bc8.111, Bc1.128, Bc3.106, Bc1.180, Bv4.104, Bc8.104, Bc4.204, Bc1.263, and Bv4.105.

[0062] In another embodiment, an antibody neutralizing a particular HBV genotype may, by evaluation using the same assay (e.g., the assay described herein), possess or retain at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the in vivo neutralizing activity or viremia-suppressing activity of a reference antibody against the same genotype, for example, a reference antibody selected from the group consisting of Bc1.187, Bv4.115, Bc8.159, Bv6.172, Bc1.229, Bc8.111, Bc1.128, Bc3.106, Bc1.180, Bv4.104, Bc8.104, Bc4.204, Bc1.263, and Bv4.105.

[0063] In some embodiments, the antibody may be cross-reactive with each of the proteins of SEQ ID NOs. 254-262 (for example, having binding activity to each as described above), and the IC50 for in vitro neutralization of HBV genotype D may be ≤100 pg / ml. Optionally, IC 50 The value may be ≤50 pg / ml or ≤10 pg / ml. In some embodiments, the IC50 value may be ≤1 pg / ml, and optionally ≤0.1 pg / ml.

[0064] Various embodiments of the specific antibody according to the present invention are shown in the following sections A to N.

[0065] A In one embodiment, the present invention provides an antibody comprising a VH domain comprising at least one, at least two, or all three VH CDR sequences selected from (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 2, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 3. In another embodiment, the antibody comprises a VH domain comprising the following CDR(a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 2; and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 3; or a variant thereof in which one, two, or three amino acids in one or more of CDR-H1, CDR-H2, or CDR-H3 are replaced with other amino acids.

[0066] In one embodiment, the VH domain is (a) the heavy chain framework region 1 (HC-FR1) of SEQ ID NO: 7, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; (b) the heavy chain framework region 2 (HC-FR2) of SEQ ID NO: 8, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; (c) the heavy chain of SEQ ID NO: 9 (d) The VH domain may further include one or more heavy chain framework sequences selected from (a) to (d) the heavy chain framework region 3 (HC-FR3) or variants having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and (d) the heavy chain framework region 4 (HC-FR4) of SEQ ID NO: 10 or variants having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. Optionally, the VH domain contains each of the heavy chain framework sequences defined in (a) to (d). Optionally, the sequence identity percentage is 95%. Optionally, the sequence identity percentage is 98%.

[0067] In another embodiment, the anti-S-HBs antibody contains a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 16. In one embodiment, the anti-S-HBs antibody contains a heavy chain variable domain (VH) sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 16. In a particular embodiment, the VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but the anti-S-HBs antibody containing that sequence retains the ability to bind to S-HBs. In a particular embodiment, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 16. In certain embodiments, substitutions, insertions, or deletions occur in the region outside the CDR (i.e., at the FR). Optionally, the anti-S-HBs antibody contains the VH sequence of SEQ ID NO: 16, which includes post-translational modifications of that sequence. In certain embodiments, the VH contains one, two, or three CDRs selected from: (a) CDR-H1 containing the amino acid sequence of SEQ ID NO: 1, (b) CDR-H2 containing the amino acid sequence of SEQ ID NO: 2, and (c) CDR-H3 containing the amino acid sequence of SEQ ID NO: 3.

[0068] In another embodiment, the anti-S-HBs antibody comprises one or more of the VH heavy chain CDR sequences of SEQ ID NO: 16. In one embodiment, the anti-S-HBs antibody comprises one or more (preferably all three) of the VH domain heavy chain CDR amino acid sequences of SEQ ID NO: 16, and a framework of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% sequence identity. Optionally, the sequence identity is 95% or 98%.

[0069] In another embodiment, the present invention provides an antibody comprising a VL domain comprising at least one, at least two, or all three VL CDR sequences selected from (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 4, (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 5, and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 6. In another embodiment, the antibody comprises a VL domain comprising the following CDR(a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 4; (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 6; or a variant thereof in which one, two, or three amino acids in one or more of CDR-L1, CDR-L2, or CDR-L3 are replaced with other amino acids.

[0070] In one embodiment, the anti-S-HBs antibody VL domain is (a) a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with respect to the light chain framework region 1 (LC-FR1) of SEQ ID NO: 11, or at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with respect to the light chain framework region 2 (LC-FR2) of SEQ ID NO: 12, or a variant having1 (LC-FR2) of SEQ ID NO: 12 (d) The light chain framework region 3 (LC-FR3) of sequence number 13, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and (d) the light chain framework region 4 (LC-FR4) of sequence number 14, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. Optionally, the VL domain contains each of the light chain framework sequences defined in (a) to (d). Optionally, the sequence identity percentage is 95%. The sequence identity percentage is arbitrarily 98%.

[0071] In another embodiment, an anti-S-HBs antibody is provided, comprising a light chain variable domain (VL) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with respect to the amino acid sequence of SEQ ID NO: 15. In one embodiment, the anti-S-HBs antibody comprises a light chain variable domain (VL) sequence having at least 95% sequence identity with respect to the amino acid sequence of SEQ ID NO: 15. In a particular embodiment, the VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but the anti-S-HBs antibody containing that sequence retains the ability to bind to S-HBs. In a particular embodiment, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 15. In certain embodiments, substitutions, insertions, or deletions occur in the region outside the CDR (i.e., at the FR). Optionally, the anti-S-HBs antibody contains the VL sequence of SEQ ID NO: 15, which includes post-translational modifications of that sequence. In certain embodiments, the VL contains one, two, or three CDRs selected from: (a) CDR-L1 containing the amino acid sequence of SEQ ID NO: 4, (b) CDR-L2 containing the amino acid sequence of SEQ ID NO: 5, and (c) CDR-L3 containing the amino acid sequence of SEQ ID NO: 6.

[0072] In another embodiment, the anti-S-HBs antibody comprises one or more of the VL CDR sequences of SEQ ID NO: 15. In one embodiment, the anti-S-HBs antibody comprises one or more (preferably all three) of the light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 15, and a framework of sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%. Optionally, the sequence identity is 95% or 98%.

[0073] In another embodiment, an anti-S-HBs antibody is provided, comprising a VH sequence of any of the embodiments provided above and a VL sequence of any of the embodiments provided above.

[0074] For example, in one exemplary embodiment, the antibody comprises a VH domain containing CDR-H3 of SEQ ID NO: 3; and a VL domain containing CDR-L3 of SEQ ID NO: 6. Optionally, the VH domain further comprises CDR-H2 of SEQ ID NO: 2.

[0075] In another exemplary embodiment, the antibody includes: i) VH domains including the following CDR(a) CDR-H1 containing the amino acid sequence of SEQ ID NO: 1; (b) CDR-H2 containing the amino acid sequence of SEQ ID NO: 2; and (c) CDR-H3 containing the amino acid sequence of SEQ ID NO: 3; or variants thereof in which one, two, or three amino acids in one or more of CDR-H1, CDR-H2, or CDR-H3 are replaced by other amino acids; and ii) VL domains including the following CDR(a) CDR-L1 containing the amino acid sequence of SEQ ID NO: 4; (b) CDR-L2 containing the amino acid sequence of SEQ ID NO: 5; and (c) CDR-L3 containing the amino acid sequence of SEQ ID NO: 6; or variants thereof in which one, two, or three amino acids in one or more of CDR-L1, CDR-L2, or CDR-L3 are replaced by other amino acids.

[0076] In another exemplary embodiment, the antibody includes: i) A heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 16; and ii) A light chain variable domain (VL) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acid sequence of Sequence ID No. 15.

[0077] In another exemplary embodiment, the anti-S-HBs antibody comprises (a) CDR-H1 containing the amino acid sequence of SEQ ID NO: 1; (b) CDR-H2 containing the amino acid sequence of SEQ ID NO: 2; (c) CDR-H3 containing the amino acid sequence of SEQ ID NO: 3; (d) CDR-L1 containing the amino acid sequence of SEQ ID NO: 4; (e) CDR-L2 containing the amino acid sequence of SEQ ID NO: 5; and (f) CDR-L3 containing the amino acid sequence of SEQ ID NO: 6, as well as a VH domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with respect to the amino acid sequence of SEQ ID NO: 16, and a VL domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with respect to the amino acid sequence of SEQ ID NO: 15. In one embodiment, the VH domain has at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 16. In another embodiment, the VL domain has at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 15. In one embodiment, the antibody specifically binds to S-HBs. In another embodiment, the antibody binds to S-HBs having a dissociation constant (KD) that is up to 10 times less or up to 10 times more than the dissociation constant (KD) of an antibody containing the VH sequence of SEQ ID NO: 16 and the VL sequence of SEQ ID NO: 15.

[0078] In one embodiment, the antibody comprises the VH and VL sequences of SEQ ID NO: 16 and SEQ ID NO: 15, respectively, and includes post-translational modifications of those sequences.

[0079] In a further embodiment, the antibody may comprise the full-length light chain of SEQ ID NO: 17 and / or the full-length heavy chain of SEQ ID NO: 18 or 263.

[0080] In further embodiments, the present invention provides antibodies that bind to the same epitopes as the anti-S-HBs antibodies provided herein. For example, in certain embodiments, antibodies that bind to the same epitopes as an anti-S-HBs antibody comprising the VH sequence of SEQ ID NO: 16 and the VL sequence of SEQ ID NO: 15 are provided. In certain embodiments, antibodies that bind to the following residues of S-HBs of SEQ ID NO: 253: C137; and optionally one or more of C138, K141, G145, and / or C149 are provided. In some embodiments, the antibodies may further bind to one or more of I152, N146, C147, and / or T148; and optionally W156. The antibodies may comprise any of the sequences defined above.

[0081] In a further embodiment, the present invention provides antibodies that compete with the anti-S-HBs antibodies provided herein for binding to S-HBs.

[0082] In some embodiments, the antibodies described in this section may, when evaluated by the same assay, e.g., ELISA assay or flow cytometry assay, have or retain at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the binding activity of the reference antibody Bc1.187 to S-HBs (e.g., SEQ ID NO: 253). In addition to or instead of the above, the antibodies described in this section may, when evaluated by the same assay, e.g., ELISA assay or flow cytometry assay, have or retain at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the binding activity of the reference antibody Bc1.187 to each of the proteins of SEQ ID NO: 254-262 (e.g., at least SEQ ID NO: 257), when evaluated by the same assay, e.g., ELISA assay or flow cytometry assay.

[0083] The reference antibody Bc1.187 is an anti-S-HBs antibody containing the VH sequence of SEQ ID NO: 16 and the VL sequence of SEQ ID NO: 15. It has a full-length heavy chain of SEQ ID NO: 18 or 263 and a full-length light chain of SEQ ID NO: 17. SEQ ID NO: 263 contains the IgG1 constant region expressed by vector LT615368.1, as used in the examples.

[0084] In some embodiments, the antibodies described in this section are evaluated in the same assay as the reference antibody Bc1.187 against the same antigen. D K is 50, 10, 9, 8, 7, 6, 5, 4, 3 or less than or equal to 2 times the value, or less than or equal to that value. D It can bind to S-HBs by value (for example, sequence number 253).

[0085] In addition to or instead of the above, the antibodies described in this section shall be evaluated in the same assay as the reference antibody Bc1.187 against the same antigen. D K is 50, 10, 9, 8, 7, 6, 5, 4, 3 or less than or equal to 2 times the value, or less than or equal to that value. D The value may bind to one or more of the sequences 254-262 (e.g., at least sequence 257), or optionally to each of the proteins in sequences 254-262.

[0086] In some embodiments, the antibodies described in this section may bind to S-HBs (e.g., SEQ ID NO: 253) at an EC50 of 50, 10, 9, 8, 7, 6, 5, 4, 3, or 2 times or less the EC50 of the reference antibody Bc1.187, as measured by ELISA or flow cytometry. Alternatively, or in addition to the above, the antibodies may bind to one or more of SEQ ID NOs: 254-262 (e.g., at least SEQ ID NO: 257), optionally, to each of the proteins of SEQ ID NOs: 254-262, at an EC50 of 50, 10, 9, 8, 7, 6, 5, 4, 3, or 2 times or less the EC50 of the reference antibody Bc1.187, as measured by ELISA or flow cytometry.

[0087] In some embodiments, the antibodies described in this section may have or retain in vitro neutralizing activity against HBV genotypes A, B, C, and / or D, or optionally all of A, B, C, and D. For example, the antibodies described in this section may have or retain in vitro neutralizing activity against HBV genotype D, and their IC50 values ​​may be ≤1 pg / ml, optionally ≤0.1 pg / ml.

[0088] In another embodiment, the antibody may have an IC50 value of 50, 10, 9, 8, 7, 6, 5, 4, 3, or 2 times or less the IC50 value of the reference antibody Bc1.187 for the same genotype, when evaluated using the same assay (e.g., the in vitro neutralization assay described herein) for neutralization of HBV genotypes A, B, C and / or D, optionally at least D, optionally A, B, C and D.

[0089] In another embodiment, the antibody may, when evaluated using the same assay (e.g., the assay described herein), have or retain at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the in vivo neutralizing activity of the reference antibody Bc1.187 against HBV genotypes A, B, C, and / or D, optionally at least D, or optionally all of A, B, C, and D.

[0090] Optionally, the antibody can suppress viremia in vivo in individuals infected with, for example, HBV genotype A, B, C, or D, optionally D. Optionally, the antibody may, when evaluated using the same assay (e.g., the assay described herein), possess or retain at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the in vivo viremia-suppressing activity of the reference antibody Bc1.187 against HBV genotypes A, B, C, and / or D, optionally at least D, or optionally all of A, B, C, and D.

[0091] B In one embodiment, the present invention provides an antibody comprising a VH domain comprising at least one, at least two, or all three VH CDR sequences selected from (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 19, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 20, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 21. In another embodiment, the antibody comprises a VH domain comprising the following CDR(a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 19; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 20; and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 21; or a variant thereof in which one, two, or three amino acids in one or more of CDR-H1, CDR-H2, or CDR-H3 are replaced with other amino acids.

[0092] In one embodiment, the VH domain is (a) the heavy chain framework region 1 (HC-FR1) of SEQ ID NO: 25, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; (b) the heavy chain framework region 2 (HC-FR2) of SEQ ID NO: 26, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; (c) the heavy chain framework region 1 (HC-FR2) of SEQ ID NO: 26 (d) The VH domain may further include one or more heavy chain framework sequences selected from (a) to (d) heavy chain framework region 3 (HC-FR3) or variants having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and (d) heavy chain framework region 4 (HC-FR4) of SEQ ID NO: 28 or variants having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. Optionally, the VH domain contains each of the heavy chain framework sequences defined in (a) to (d). Optionally, the sequence identity percentage is 95%. Optionally, the sequence identity percentage is 98%.

[0093] In another embodiment, the anti-S-HBs antibody contains a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 34. In one embodiment, the anti-S-HBs antibody contains a heavy chain variable domain (VH) sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 34. In a particular embodiment, the VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but the anti-S-HBs antibody containing that sequence retains the ability to bind to S-HBs. In a particular embodiment, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 34. In certain embodiments, substitutions, insertions, or deletions occur in the region outside the CDR (i.e., at the FR). Optionally, the anti-S-HBs antibody contains the VH sequence of SEQ ID NO: 34, which includes post-translational modifications of that sequence. In certain embodiments, the VH contains one, two, or three CDRs selected from: (a) CDR-H1 containing the amino acid sequence of SEQ ID NO: 19, (b) CDR-H2 containing the amino acid sequence of SEQ ID NO: 20, and (c) CDR-H3 containing the amino acid sequence of SEQ ID NO: 21.

[0094] In another embodiment, the anti-S-HBs antibody comprises one or more of the VH heavy chain CDR sequences of SEQ ID NO: 34. In one embodiment, the anti-S-HBs antibody comprises one or more (preferably all three) of the VH domain heavy chain CDR amino acid sequences of SEQ ID NO: 34 and a framework of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% sequence identity. Optionally, the sequence identity is 95% or 98%.

[0095] In another embodiment, the present invention provides an antibody comprising a VL domain comprising at least one, at least two, or all three VL CDR sequences selected from (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 22, (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 23, and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 24. In another embodiment, the antibody comprises a VL domain comprising the following CDR(a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 22; (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 23; and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 24; or a variant thereof in which one, two, or three amino acids in one or more of CDR-L1, CDR-L2, or CDR-L3 are replaced with other amino acids.

[0096] In one embodiment, the anti-S-HBs antibody VL domain is (a) a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with respect to the light chain framework region 1 (LC-FR1) of SEQ ID NO: 29, or at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with respect to the light chain framework region 2 (LC-FR2) of SEQ ID NO: 30, or a variant having1 (LC-FR1) of SEQ ID NO: 29, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with respect to the light chain framework region 1 (LC-FR1) of SEQ ID NO: 29, or a variant having at least 85%, 86%, 87 (d) The light chain framework region 3 (LC-FR3) of sequence number 31, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and (d) the light chain framework region 4 (LC-FR4) of sequence number 32, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. Optionally, the VL domain contains each of the light chain framework sequences defined in (a) to (d). Optionally, the sequence identity percentage is 95%. The sequence identity percentage is arbitrarily 98%.

[0097] In another embodiment, an anti-S-HBs antibody is provided, comprising a light chain variable domain (VL) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with respect to the amino acid sequence of SEQ ID NO: 33. In one embodiment, the anti-S-HBs antibody comprises a light chain variable domain (VL) sequence having at least 95% sequence identity with respect to the amino acid sequence of SEQ ID NO: 33. In a particular embodiment, the VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but the anti-S-HBs antibody containing that sequence retains the ability to bind to S-HBs. In a particular embodiment, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 33. In certain embodiments, substitutions, insertions, or deletions occur in the region outside the CDR (i.e., at the FR). Optionally, the anti-S-HBs antibody contains the VL sequence of SEQ ID NO: 33, which includes post-translational modifications of that sequence. In certain embodiments, the VL contains one, two, or three CDRs selected from: (a) CDR-L1 containing the amino acid sequence of SEQ ID NO: 22, (b) CDR-L2 containing the amino acid sequence of SEQ ID NO: 23, and (c) CDR-L3 containing the amino acid sequence of SEQ ID NO: 24.

[0098] In another embodiment, the anti-S-HBs antibody comprises one or more of the VL CDR sequences of SEQ ID NO: 33. In one embodiment, the anti-S-HBs antibody comprises one or more (preferably all three) of the light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 33, and a framework of sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%. Optionally, the sequence identity is 95% or 98%.

[0099] In another embodiment, an anti-S-HBs antibody is provided, comprising a VH sequence of any of the embodiments provided above and a VL sequence of any of the embodiments provided above.

[0100] For example, in one exemplary embodiment, the antibody comprises a VH domain containing CDR-H3 of SEQ ID NO: 21; and a VL domain containing CDR-L3 of SEQ ID NO: 24. Optionally, the VH domain further comprises CDR-H2 of SEQ ID NO: 20.

[0101] In another exemplary embodiment, the antibody includes: i) VH domains including the following CDR(a) CDR-H1 containing the amino acid sequence of SEQ ID NO: 19; (b) CDR-H2 containing the amino acid sequence of SEQ ID NO: 20; and (c) CDR-H3 containing the amino acid sequence of SEQ ID NO: 21; or variants thereof in which one, two, or three amino acids in one or more of CDR-H1, CDR-H2, or CDR-H3 are replaced by other amino acids; and ii) VL domains including the following CDR(a) CDR-L1 containing the amino acid sequence of SEQ ID NO: 22; (b) CDR-L2 containing the amino acid sequence of SEQ ID NO: 23; and (c) CDR-L3 containing the amino acid sequence of SEQ ID NO: 24; or variants thereof in which one, two, or three amino acids in one or more of CDR-L1, CDR-L2, or CDR-L3 are replaced by other amino acids.

[0102] In another exemplary embodiment, the antibody includes: i) A heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 34; and ii) A light chain variable domain (VL) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acid sequence of Sequence ID No. 33.

[0103] In another exemplary embodiment, the anti-S-HBs antibody comprises (a) CDR-H1 containing the amino acid sequence of SEQ ID NO: 19; (b) CDR-H2 containing the amino acid sequence of SEQ ID NO: 20; (c) CDR-H3 containing the amino acid sequence of SEQ ID NO: 21; (d) CDR-L1 containing the amino acid sequence of SEQ ID NO: 22; (e) CDR-L2 containing the amino acid sequence of SEQ ID NO: 23; and (f) CDR-L3 containing the amino acid sequence of SEQ ID NO: 24, as well as a VH domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with respect to the amino acid sequence of SEQ ID NO: 34, and a VL domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with respect to the amino acid sequence of SEQ ID NO: 33. In one embodiment, the VH domain has at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 34. In another embodiment, the VL domain has at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 33. In one embodiment, the antibody specifically binds to S-HBs. In another embodiment, the antibody binds to S-HBs having a dissociation constant (KD) that is up to 10 times lower or up to 10 times higher than the dissociation constant (KD) of an antibody containing the VH sequence of SEQ ID NO: 34 and the VL sequence of SEQ ID NO: 33.

[0104] In one embodiment, the antibody comprises the VH and VL sequences of SEQ ID NO: 34 and SEQ ID NO: 33, respectively, including post-translational modifications of those sequences.

[0105] In a further embodiment, the antibody may comprise the full-length light chain of SEQ ID NO: 35 and / or the full-length heavy chain of SEQ ID NO: 36 or 264.

[0106] In further embodiments, the present invention provides antibodies that bind to the same epitopes as the anti-S-HBs antibodies provided herein. For example, in certain embodiments, an antibody is provided that binds to the same epitopes as an anti-S-HBs antibody comprising the VH sequence of SEQ ID NO: 34 and the VL sequence of SEQ ID NO: 33. In certain embodiments, an antibody is provided that binds to one or more of the following residues of S-HBs in SEQ ID NO: 253: C138, C139 and / or C149, and optionally R169. Optionally, the antibody may further bind to one or more of L109, R122, C147, T148, I152, W156, F161, and / or W165. The antibody may contain any of the sequences defined above.

[0107] In a further embodiment, the present invention provides antibodies that compete with the anti-S-HBs antibodies provided herein for binding to S-HBs.

[0108] In some embodiments, the antibodies described in this section may have, or retain, at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the binding activity of the reference antibody Bc1.180 against S-HBs (e.g., SEQ ID NO: 253) when evaluated by the same assay, e.g., an ELISA assay or a flow cytometry assay.

[0109] In addition to or instead of the above, the antibodies described in this section may, when evaluated by the same assay, e.g., ELISA assay or flow cytometry assay, have or retain at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the binding activity of reference antibody Bc1.180 to each of the proteins of SEQ ID NOs. 254-262, optionally, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

[0110] The reference antibody Bc1.180 has the VH sequence of SEQ ID NO: 34 and the VL sequence of SEQ ID NO: 33. It has the full-length heavy chain of SEQ ID NO: 36 or 264 and the full-length light chain of SEQ ID NO: 35. SEQ ID NO: 264 contains the IgG1 constant region expressed by vector LT615368.1, as used in the examples.

[0111] In some embodiments, the antibodies described in this section are evaluated in the same assay as the reference antibody Bc1.180 against the same antigen. D K is 50, 10, 9, 8, 7, 6, 5, 4, 3 or less than or equal to 2 times the value, or less than or equal to that value. D It can bind to S-HBs by value (for example, sequence number 253).

[0112] In addition to or instead of the above, the antibodies described in this section shall be evaluated in the same assay as the reference antibody Bc1.180 against the same antigen. D K is 50, 10, 9, 8, 7, 6, 5, 4, 3 or less than or equal to 2 times the value, or less than or equal to that value. D The value may bind to one or more of the sequences 254-262 (e.g., at least sequence 257), or optionally to each of the proteins in sequences 254-262.

[0113] In some embodiments, the antibodies described in this section may bind to S-HBs (e.g., SEQ ID NO: 253) at an EC50 of 50, 10, 9, 8, 7, 6, 5, 4, 3, or 2 times or less the EC50 of reference antibody Bc1.180, as measured by ELISA or flow cytometry. Alternatively, or in addition to the above, the antibodies may bind to one or more of SEQ ID NOs: 254-262 (e.g., at least SEQ ID NO: 257), optionally, to each of the proteins of SEQ ID NOs: 254-262, at an EC50 of 50, 10, 9, 8, 7, 6, 5, 4, 3, or 2 times or less the EC50 of reference antibody Bc1.180, as measured by ELISA or flow cytometry. In some embodiments, the antibodies described in this section may have or retain in vitro neutralizing activity against HBV genotypes A, B, C and / or D, optionally all of A, B, C and D. For example, the antibodies described in this section may have or retain in vitro neutralizing activity against HBV genotype D, and for instance, their IC50 values ​​may be ≤1 pg / ml, and optionally ≤0.1 pg / ml.

[0114] In another embodiment, the antibody is evaluated using the same assay (e.g., the assay described herein) for neutralization of HBV genotypes A, B, C and / or D, optionally at least D, optionally A, B, C and D, and has an IC50 value of 50, 10, 9, 8, 7, 6, 5, 4, 3, or 2 times or less of the IC50 value of the reference antibody Bc1.180 for the same genotype, or an IC50 value less than or equal to that value. 50 It may have a value.

[0115] In another embodiment, the antibody may, when evaluated using the same assay (e.g., the assay described herein), have or retain at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the in vivo neutralizing activity of the reference antibody Bc1.180 against HBV genotypes A, B, C, and / or D, optionally at least D, or optionally all of A, B, C, and D.

[0116] Optionally, the antibody can suppress viremia in vivo in individuals infected with, for example, HBV genotype A, B, C, or D, optionally D. Optionally, the antibody may have, or retain, at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the in vivo viremia-suppressing activity of the reference antibody Bc1.180 against HBV genotypes A, B, C, and / or D, optionally at least D, or optionally all of A, B, C, and D, as evaluated using the same assay (e.g., the assay described herein).

[0117] C. In one embodiment, the present invention provides an antibody comprising a VH domain comprising at least one, at least two, or all three VH CDR sequences selected from (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 37, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 38, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 39. In another embodiment, the antibody comprises a VH domain comprising the following CDR(a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 37; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 38; and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 39; or a variant thereof in which one, two, or three amino acids in one or more of CDR-H1, CDR-H2, or CDR-H3 are replaced with other amino acids.

[0118] In one embodiment, the VH domain is (a) the heavy chain framework region 1 (HC-FR1) of SEQ ID NO: 43, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; (b) the heavy chain framework region 2 (HC-FR2) of SEQ ID NO: 44, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; (c) the heavy chain framework region 1 (HC-FR2) of SEQ ID NO: 45 (d) The VH domain may further include one or more heavy chain framework sequences selected from (a) to (d) heavy chain framework region 3 (HC-FR3) or variants having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and (d) heavy chain framework region 4 (HC-FR4) of SEQ ID NO: 46 or variants having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. Optionally, the VH domain contains each of the heavy chain framework sequences defined in (a) to (d). Optionally, the sequence identity percentage is 95%. Optionally, the sequence identity percentage is 98%.

[0119] In another embodiment, the anti-S-HBs antibody contains a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 52. In one embodiment, the anti-S-HBs antibody contains a heavy chain variable domain (VH) sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 52. In a particular embodiment, the VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but the anti-S-HBs antibody containing that sequence retains the ability to bind to S-HBs. In a particular embodiment, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 52. In certain embodiments, substitutions, insertions, or deletions occur in the region outside the CDR (i.e., at the FR). Optionally, the anti-S-HBs antibody contains the VH sequence of SEQ ID NO: 52, which includes post-translational modifications of that sequence. In certain embodiments, the VH contains one, two, or three CDRs selected from: (a) CDR-H1 containing the amino acid sequence of SEQ ID NO: 37, (b) CDR-H2 containing the amino acid sequence of SEQ ID NO: 38, and (c) CDR-H3 containing the amino acid sequence of SEQ ID NO: 39.

[0120] In another embodiment, the anti-S-HBs antibody comprises one or more of the VH heavy chain CDR sequences of SEQ ID NO: 52. In one embodiment, the anti-S-HBs antibody comprises one or more (preferably all three) of the VH domain heavy chain CDR amino acid sequences of SEQ ID NO: 52, and a framework of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% sequence identity. Optionally, the sequence identity is 95% or 98%.

[0121] In another embodiment, the present invention provides an antibody comprising a VL domain comprising at least one, at least two, or all three VL CDR sequences selected from (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 40, (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 41, and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 42. In another embodiment, the antibody comprises a VL domain comprising the following CDR(a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 40; (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 41; and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 42; or a variant thereof in which one, two, or three amino acids in one or more of CDR-L1, CDR-L2, or CDR-L3 are replaced with other amino acids.

[0122] In one embodiment, the anti-S-HBs antibody VL domain is (a) a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with respect to the light chain framework region 1 (LC-FR1) of SEQ ID NO: 47, (b) a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with respect to the light chain framework region 2 (LC-FR2) of SEQ ID NO: 48, (c) sequence number (d) The light chain framework region 3 (LC-FR3) of sequence number 49, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and (d) the light chain framework region 4 (LC-FR4) of sequence number 50, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. Optionally, the VL domain contains each of the light chain framework sequences defined in (a) to (d). Optionally, the sequence identity percentage is 95%. The sequence identity percentage is arbitrarily 98%.

[0123] In another embodiment, an anti-S-HBs antibody is provided, comprising a light chain variable domain (VL) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with respect to the amino acid sequence of SEQ ID NO: 51. In one embodiment, the anti-S-HBs antibody comprises a light chain variable domain (VL) sequence having at least 95% sequence identity with respect to the amino acid sequence of SEQ ID NO: 51. In a particular embodiment, the VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but the anti-S-HBs antibody containing that sequence retains the ability to bind to S-HBs. In a particular embodiment, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 51. In certain embodiments, substitutions, insertions, or deletions occur in the region outside the CDR (i.e., at the FR). Optionally, the anti-S-HBs antibody contains the VL sequence of SEQ ID NO: 51, which includes post-translational modifications of that sequence. In certain embodiments, the VL contains one, two, or three CDRs selected from: (a) CDR-L1 containing the amino acid sequence of SEQ ID NO: 40, (b) CDR-L2 containing the amino acid sequence of SEQ ID NO: 41, and (c) CDR-L3 containing the amino acid sequence of SEQ ID NO: 42.

[0124] In another embodiment, the anti-S-HBs antibody comprises one or more of the VL CDR sequences of SEQ ID NO: 51. In one embodiment, the anti-S-HBs antibody comprises one or more (preferably all three) of the VL domain light chain CDR amino acid sequences of SEQ ID NO: 51, and a framework of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% sequence identity. Optionally, the sequence identity is 95% or 98%.

[0125] In another embodiment, an anti-S-HBs antibody is provided, comprising a VH sequence of any of the embodiments provided above and a VL sequence of any of the embodiments provided above.

[0126] For example, in one exemplary embodiment, the antibody comprises a VH domain containing CDR-H3 of SEQ ID NO: 39; and a VL domain containing CDR-L3 of SEQ ID NO: 42. Optionally, the VH domain further comprises CDR-H2 of SEQ ID NO: 38.

[0127] In another exemplary embodiment, the antibody includes: i) VH domains including the following CDR(a) CDR-H1 containing the amino acid sequence of SEQ ID NO: 37; (b) CDR-H2 containing the amino acid sequence of SEQ ID NO: 38; and (c) CDR-H3 containing the amino acid sequence of SEQ ID NO: 39; or variants thereof in which one, two, or three amino acids in one or more of CDR-H1, CDR-H2, or CDR-H3 are replaced by other amino acids; and ii) VL domains including the following CDR(a) CDR-L1 containing the amino acid sequence of SEQ ID NO: 40; (b) CDR-L2 containing the amino acid sequence of SEQ ID NO: 41; and (c) CDR-L3 containing the amino acid sequence of SEQ ID NO: 42; or variants thereof in which one, two, or three amino acids in one or more of CDR-L1, CDR-L2, or CDR-L3 are replaced by other amino acids.

[0128] In another exemplary embodiment, the antibody includes: i) A heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 52; and ii) A light chain variable domain (VL) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acid sequence of Sequence ID No. 51.

[0129] In another exemplary embodiment, the anti-S-HBs antibody comprises (a) CDR-H1 containing the amino acid sequence of SEQ ID NO: 37; (b) CDR-H2 containing the amino acid sequence of SEQ ID NO: 38; (c) CDR-H3 containing the amino acid sequence of SEQ ID NO: 39; (d) CDR-L1 containing the amino acid sequence of SEQ ID NO: 40; (e) CDR-L2 containing the amino acid sequence of SEQ ID NO: 41; and (f) CDR-L3 containing the amino acid sequence of SEQ ID NO: 42, as well as a VH domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with respect to the amino acid sequence of SEQ ID NO: 52, and a VL domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with respect to the amino acid sequence of SEQ ID NO: 51. In one embodiment, the VH domain has at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 52. In another embodiment, the VL domain has at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 51. In one embodiment, the antibody specifically binds to S-HBs. In another embodiment, the antibody binds to S-HBs having a dissociation constant (KD) that is up to 10 times lower or up to 10 times higher than the dissociation constant (KD) of an antibody containing the VH sequence of SEQ ID NO: 52 and the VL sequence of SEQ ID NO: 51.

[0130] In one embodiment, the antibody comprises the VH and VL sequences of SEQ ID NO: 52 and SEQ ID NO: 51, respectively, and includes post-translational modifications of those sequences.

[0131] In a further embodiment, the antibody may comprise the full-length light chain of SEQ ID NO: 53 and / or the full-length heavy chain of SEQ ID NO: 54 or 265.

[0132] In further embodiments, the present invention provides antibodies that bind to the same epitopes as the anti-S-HBs antibodies provided herein. For example, in certain embodiments, antibodies that bind to the same epitopes as an anti-S-HBs antibody comprising the VH sequence of SEQ ID NO: 52 and the VL sequence of SEQ ID NO: 51 are provided. In certain embodiments, antibodies that bind to one or more of the following residues of S-HBs in SEQ ID NO: 253: L109, C138, I152, W156, and / or R169 are provided. Optionally, the antibody further binds to P111 and / or F161. The antibody may contain any of the sequences defined above.

[0133] In a further embodiment, the present invention provides antibodies that compete with the anti-S-HBs antibodies provided herein for binding to S-HBs.

[0134] In some embodiments, the antibodies described in this section may have, or retain, at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the binding activity of the reference antibody Bc3.106 against S-HBs (e.g., SEQ ID NO: 253) when evaluated by the same assay, e.g., an ELISA assay or a flow cytometry assay.

[0135] In addition to or instead of the above, the antibodies described in this section may, when evaluated by the same assay, e.g., ELISA assay or flow cytometry assay, have or retain at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the binding activity of the reference antibody Bc3.106 to each of the proteins of SEQ ID NOs. 254–262, optionally, to one or more of the proteins of SEQ ID NOs. 254–262.

[0136] The reference antibody Bc3.106 has the VH sequence of SEQ ID NO: 52 and the VL sequence of SEQ ID NO: 51. It has the full-length heavy chain of SEQ ID NO: 54 or 265 and the full-length light chain of SEQ ID NO: 53. SEQ ID NO: 265 contains the IgG1 constant region expressed by vector LT615368.1, as used in the examples.

[0137] In some embodiments, the antibodies described in this section are evaluated in the same assay as the reference antibody Bc3.106 against the same antigen. D K is 50, 10, 9, 8, 7, 6, 5, 4, 3 or less than or equal to 2 times the value, or less than or equal to that value. D It can bind to S-HBs by value (for example, sequence number 253).

[0138] In addition to this, or instead, the antibody is evaluated in the same assay as the reference antibody Bc3.106 against the same antigen. D K is 50, 10, 9, 8, 7, 6, 5, 4, 3 or less than or equal to 2 times the value, or less than or equal to that value. D The value may bind to one or more of the sequences 254-262 (e.g., at least sequence 257), or optionally to each of the proteins in sequences 254-262.

[0139] In some embodiments, the antibodies described in this section may bind to S-HBs (e.g., SEQ ID NO: 253) with an EC50 of 50, 10, 9, 8, 7, 6, 5, 4, 3, or 2 times or less the EC50 of the reference antibody Bc3.106, as measured by ELISA or flow cytometry. Alternatively, or in addition to the above, the antibodies may bind to one or more of SEQ ID NOs: 254-262 (e.g., at least SEQ ID NO: 257), optionally, to each of the proteins of SEQ ID NOs: 254-262, with an EC50 of 50, 10, 9, 8, 7, 6, 5, 4, 3, or 2 times or less the EC50 of the reference antibody Bc3.106, as measured by ELISA or flow cytometry.

[0140] In some embodiments, the antibodies described in this section may have or retain in vitro neutralizing activity against HBV genotypes A, B, C, and / or D, or optionally all of A, B, C, and D. For example, the antibodies described in this section may have or retain in vitro neutralizing activity against HBV genotype D, and for example, the IC50 value may be ≤10 pg / ml, or optionally ≤1 pg / ml.

[0141] In another embodiment, the antibody is evaluated using the same assay (e.g., the assay described herein) for neutralization of HBV genotypes A, B, C and / or D, optionally at least D, and optionally all of A, B, C and D, to obtain the IC of reference antibody Bc3.106 against the same genotype. 50 IC values ​​that are 50, 10, 9, 8, 7, 6, 5, 4, 3 or less than or twice the value, or less than or equal to that value. 50 It may have a value.

[0142] In another embodiment, the antibody may, when evaluated using the same assay (e.g., the assay described herein), have or retain at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the in vivo neutralizing activity of the reference antibody Bc3.106 against HBV genotypes A, B, C, and / or D, optionally at least D, or optionally all of A, B, C, and D.

[0143] Optionally, the antibody can suppress viremia in vivo in individuals infected with, for example, HBV genotype A, B, C, or D, optionally D. Optionally, the antibody may have, or retain, at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the in vivo viremia-suppressing activity of the reference antibody Bc3.106 against HBV genotypes A, B, C, and / or D, optionally at least D, or optionally all of A, B, C, and D, as evaluated using the same assay (e.g., the assay described herein).

[0144] D. In one embodiment, the present invention provides an antibody comprising a VH domain comprising at least one, at least two, or all three VH CDR sequences selected from (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 55, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 56, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 57. In another embodiment, the antibody comprises a VH domain comprising the following CDR(a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 55; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 56; and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 57; or a variant thereof in which one, two, or three amino acids in one or more of CDR-H1, CDR-H2, or CDR-H3 are replaced with other amino acids.

[0145] In one embodiment, the VH domain is (a) the heavy chain framework region 1 (HC-FR1) of SEQ ID NO: 61, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; (b) the heavy chain framework region 2 (HC-FR2) of SEQ ID NO: 62, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; (c) the heavy chain framework region 1 (HC-FR2) of SEQ ID NO: 63 (d) The VH domain may further include one or more heavy chain framework sequences selected from (a) to (d) the heavy chain framework region 3 (HC-FR3), or variants having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and (d) the heavy chain framework region 4 (HC-FR4) of SEQ ID NO: 64, or variants having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. Optionally, the VH domain contains each of the heavy chain framework sequences defined in (a) to (d). Optionally, the sequence identity percentage is 95%. Optionally, the sequence identity percentage is 98%.

[0146] In another embodiment, the anti-S-HBs antibody contains a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 70. In one embodiment, the anti-S-HBs antibody contains a heavy chain variable domain (VH) sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 70. In a particular embodiment, the VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but the anti-S-HBs antibody containing that sequence retains the ability to bind to S-HBs. In a particular embodiment, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 70. In certain embodiments, substitutions, insertions, or deletions occur in the region outside the CDR (i.e., at the FR). Optionally, the anti-S-HBs antibody contains the VH sequence of SEQ ID NO: 70, which includes post-translational modifications of that sequence. In certain embodiments, the VH contains one, two, or three CDRs selected from: (a) CDR-H1 containing the amino acid sequence of SEQ ID NO: 55, (b) CDR-H2 containing the amino acid sequence of SEQ ID NO: 56, and (c) CDR-H3 containing the amino acid sequence of SEQ ID NO: 57.

[0147] In another embodiment, the anti-S-HBs antibody comprises one or more of the VH heavy chain CDR sequences of SEQ ID NO: 70. In one embodiment, the anti-S-HBs antibody comprises one or more (preferably all three) of the VH domain heavy chain CDR amino acid sequences of SEQ ID NO: 70 and a framework of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% sequence identity. Optionally, the sequence identity is 95% or 98%.

[0148] In another embodiment, the present invention provides an antibody comprising a VL domain comprising at least one, at least two, or all three VL CDR sequences selected from (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 58, (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 59, and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 60. In another embodiment, the antibody comprises a VL domain comprising the following CDR(a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 58; (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 59; and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 60; or a variant thereof in which one, two, or three amino acids in one or more of CDR-L1, CDR-L2, or CDR-L3 are replaced with other amino acids.

[0149] In one embodiment, the anti-S-HBs antibody VL domain is (a) a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with respect to the light chain framework region 1 (LC-FR1) of SEQ ID NO: 65, (b) a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with respect to the light chain framework region 2 (LC-FR2) of SEQ ID NO: 66, (c) sequence number (d) The light chain framework region 3 (LC-FR3) of sequence number 67, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and (d) the light chain framework region 4 (LC-FR4) of sequence number 68, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. Optionally, the VL domain contains each of the light chain framework sequences defined in (a) to (d). Optionally, the sequence identity percentage is 95%. The sequence identity percentage is arbitrarily 98%.

[0150] In another embodiment, an anti-S-HBs antibody is provided, comprising a light chain variable domain (VL) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with respect to the amino acid sequence of SEQ ID NO: 69. In one embodiment, the anti-S-HBs antibody comprises a light chain variable domain (VL) sequence having at least 95% sequence identity with respect to the amino acid sequence of SEQ ID NO: 69. In a particular embodiment, the VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but the anti-S-HBs antibody containing that sequence retains the ability to bind to S-HBs. In a particular embodiment, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 69. In certain embodiments, substitutions, insertions, or deletions occur in the region outside the CDR (i.e., at the FR). Optionally, the anti-S-HBs antibody contains the VL sequence of SEQ ID NO: 69, which includes post-translational modifications of that sequence. In certain embodiments, the VL contains one, two, or three CDRs selected from: (a) CDR-L1 containing the amino acid sequence of SEQ ID NO: 58, (b) CDR-L2 containing the amino acid sequence of SEQ ID NO: 59, and (c) CDR-L3 containing the amino acid sequence of SEQ ID NO: 60.

[0151] In another embodiment, the anti-S-HBs antibody comprises one or more of the VL CDR sequences of SEQ ID NO: 69. In one embodiment, the anti-S-HBs antibody comprises one or more (preferably all three) of the light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 69, and a framework of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% sequence identity. Optionally, the sequence identity is 95% or 98%.

[0152] In another embodiment, an anti-S-HBs antibody is provided, comprising a VH sequence of any of the embodiments provided above and a VL sequence of any of the embodiments provided above.

[0153] For example, in one exemplary embodiment, the antibody comprises a VH domain containing CDR-H3 of SEQ ID NO: 57; and a VL domain containing CDR-L3 of SEQ ID NO: 60. Optionally, the VH domain further comprises CDR-H2 of SEQ ID NO: 56.

[0154] In another exemplary embodiment, the antibody includes: i) VH domains including the following CDR(a) CDR-H1 containing the amino acid sequence of SEQ ID NO: 55; (b) CDR-H2 containing the amino acid sequence of SEQ ID NO: 56; and (c) CDR-H3 containing the amino acid sequence of SEQ ID NO: 57; or variants thereof in which one, two, or three amino acids in one or more of CDR-H1, CDR-H2, or CDR-H3 are replaced by other amino acids; and ii) VL domains including the following CDR(a) CDR-L1 containing the amino acid sequence of SEQ ID NO: 58; (b) CDR-L2 containing the amino acid sequence of SEQ ID NO: 59; and (c) CDR-L3 containing the amino acid sequence of SEQ ID NO: 60; or variants thereof in which one, two, or three amino acids in one or more of CDR-L1, CDR-L2, or CDR-L3 are replaced by other amino acids.

[0155] In another exemplary embodiment, the antibody includes: i) A heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 70; and ii) A light chain variable domain (VL) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acid sequence of Sequence ID No. 69.

[0156] In another exemplary embodiment, the anti-S-HBs antibody comprises (a) CDR-H1 containing the amino acid sequence of SEQ ID NO: 55; (b) CDR-H2 containing the amino acid sequence of SEQ ID NO: 56; (c) CDR-H3 containing the amino acid sequence of SEQ ID NO: 57; (d) CDR-L1 containing the amino acid sequence of SEQ ID NO: 58; (e) CDR-L2 containing the amino acid sequence of SEQ ID NO: 59; and (f) CDR-L3 containing the amino acid sequence of SEQ ID NO: 60, as well as a VH domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with respect to the amino acid sequence of SEQ ID NO: 70, and a VL domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with respect to the amino acid sequence of SEQ ID NO: 69. In one embodiment, the VH domain has at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 70. In another embodiment, the VL domain has at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 69. In one embodiment, the antibody specifically binds to S-HBs. In another embodiment, the antibody binds to S-HBs having a dissociation constant (KD) that is up to 10 times lower or up to 10 times higher than the dissociation constant (KD) of an antibody containing the VH sequence of SEQ ID NO: 70 and the VL sequence of SEQ ID NO: 69.

[0157] In one embodiment, the antibody comprises the VH and VL sequences of SEQ ID NO: 70 and SEQ ID NO: 69, respectively, including post-translational modifications of those sequences.

[0158] In a further embodiment, the antibody may comprise the full-length light chain of SEQ ID NO: 71 and / or the full-length heavy chain of SEQ ID NO: 72 or 266.

[0159] In further embodiments, the present invention provides antibodies that bind to the same epitopes as the anti-S-HBs antibodies provided herein. For example, in certain embodiments, an antibody is provided that binds to the same epitopes as an anti-S-HBs antibody comprising the VH sequence of SEQ ID NO: 70 and the VL sequence of SEQ ID NO: 69. In certain embodiments, an antibody is provided that binds to one or more of the following residues of S-HBs in SEQ ID NO: 253: C121, R122, C124, C137, C139, K141, N146, C147 and / or C149. In some embodiments, the antibody may also bind to one or more of I110, T118, P120, C138, P142, D144, T148 and / or I152. The antibody may contain any of the sequences defined above.

[0160] In a further embodiment, the present invention provides antibodies that compete with the anti-S-HBs antibodies provided herein for binding to S-HBs.

[0161] In some embodiments, the antibodies described in this section may have, or retain, at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the binding activity of the reference antibody Bv4.104 against S-HBs (e.g., SEQ ID NO: 253) when evaluated in the same assay, e.g., an ELISA assay or a flow cytometry assay.

[0162] In addition to or instead of the above, the antibodies described in this section may, when evaluated by the same assay, e.g., ELISA assay or flow cytometry assay, have or retain at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the binding activity of reference antibody Bv4.104 to one or more of the proteins of SEQ ID NOs. 257 and 258, or to each of them, optionally to at least the protein of SEQ ID NO. 257.

[0163] Reference antibody Bv4.104 has the VH sequence of SEQ ID NO: 70 and the VL sequence of SEQ ID NO: 69. It has the full-length heavy chain of SEQ ID NO: 72 or 266 and the full-length light chain of SEQ ID NO: 71. SEQ ID NO: 266 contains the IgG1 constant region expressed by vector LT615368.1, as used in the examples.

[0164] In some embodiments, the antibodies described in this section are evaluated in the same assay as the reference antibody Bv4.104 against the same antigen. D K is 50, 10, 9, 8, 7, 6, 5, 4, 3 or less than or equal to 2 times the value, or less than or equal to that value. D It can bind to S-HBs by value (for example, sequence number 253).

[0165] In addition to this, or instead, the antibody is evaluated in the same assay as the reference antibody Bv4.104 against the same antigen. D K is 50, 10, 9, 8, 7, 6, 5, 4, 3 or less than or equal to 2 times the value, or less than or equal to that value. D The value indicates that it may optionally bind to one or more of the proteins of sequence numbers 257 and 258, or to each of them, at least to the protein of sequence number 257.

[0166] In some embodiments, the antibodies described in this section may bind to S-HBs (e.g., SEQ ID NO: 253) at an EC50 of 50, 10, 9, 8, 7, 6, 5, 4, 3, or 2 times or less the EC50 of reference antibody Bv4.104, as measured by ELISA or flow cytometry. Alternatively, or in addition to the above, the antibodies may bind to one or more of the proteins of SEQ ID NOs: 257 and 258, or each of them, optionally to at least the protein of SEQ ID NO: 257, at an EC50 of 50, 10, 9, 8, 7, 6, 5, 4, 3, or 2 times or less the EC50 of reference antibody Bv4.104, as measured by ELISA or flow cytometry.

[0167] In some embodiments, the antibodies described in this section may have or retain in vitro neutralizing activity against HBV genotype D, for example, an IC50 value of ≤100 pg / ml, optionally ≤10 pg / ml.

[0168] In another embodiment, the antibody is evaluated for neutralization of HBV genotype D using the same assay (e.g., the in vitro neutralization assay described herein) to obtain the IC of reference antibody Bv4.104 against the same genotype. 50 IC values ​​that are 50, 10, 9, 8, 7, 6, 5, 4, 3 or less than or twice the value, or less than or equal to that value. 50 It may have a value.

[0169] In another embodiment, the antibody may have, or retain, at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the in vivo neutralizing activity of the reference antibody Bv4.104 against HBV genotype D, as evaluated using the same assay (e.g., the assay described herein).

[0170] Optionally, the antibody can suppress viremia in vivo in individuals infected with, for example, HBV genotype D. Optionally, the antibody may have, or retain, at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the in vivo viremia-suppressing activity of the reference antibody Bv4.104 against HBV genotype D, as evaluated using the same assay (e.g., the assay described herein).

[0171] E. In one embodiment, the present invention provides an antibody comprising a VH domain comprising at least one, at least two, or all three VH CDR sequences selected from (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 73, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 74, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 75. In another embodiment, the antibody comprises a VH domain comprising the following CDR(a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 73; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 74; and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 75; or a variant thereof in which one, two, or three amino acids in one or more of CDR-H1, CDR-H2, or CDR-H3 are replaced with other amino acids.

[0172] In one embodiment, the VH domain is (a) the heavy chain framework region 1 (HC-FR1) of SEQ ID NO: 79, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; (b) the heavy chain framework region 2 (HC-FR2) of SEQ ID NO: 80, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; (c) the heavy chain framework region 81 (d) The VH domain may further include one or more heavy chain framework sequences selected from (a) to (d) heavy chain framework region 3 (HC-FR3) or variants having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and (d) heavy chain framework region 4 (HC-FR4) of SEQ ID NO: 82 or variants having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. Optionally, the VH domain contains each of the heavy chain framework sequences defined in (a) to (d). Optionally, the sequence identity percentage is 95%. Optionally, the sequence identity percentage is 98%.

[0173] In another embodiment, the anti-S-HBs antibody contains a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 88. In one embodiment, the anti-S-HBs antibody contains a heavy chain variable domain (VH) sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 88. In a particular embodiment, the VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but the anti-S-HBs antibody containing that sequence retains the ability to bind to S-HBs. In a particular embodiment, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 88. In certain embodiments, substitutions, insertions, or deletions occur in the region outside the CDR (i.e., at the FR). Optionally, the anti-S-HBs antibody contains the VH sequence of SEQ ID NO: 88, which includes post-translational modifications of that sequence. In certain embodiments, the VH contains one, two, or three CDRs selected from: (a) CDR-H1 containing the amino acid sequence of SEQ ID NO: 73, (b) CDR-H2 containing the amino acid sequence of SEQ ID NO: 74, and (c) CDR-H3 containing the amino acid sequence of SEQ ID NO: 75.

[0174] In another embodiment, the anti-S-HBs antibody comprises one or more of the VH heavy chain CDR sequences of SEQ ID NO: 88. In one embodiment, the anti-S-HBs antibody comprises one or more (preferably all three) of the VH domain heavy chain CDR amino acid sequences of SEQ ID NO: 88, and a framework of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% sequence identity. Optionally, the sequence identity is 95% or 98%.

[0175] In another embodiment, the present invention provides an antibody comprising a VL domain comprising at least one, at least two, or all three VL CDR sequences selected from (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 76, (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 77, and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 78. In another embodiment, the antibody comprises a VL domain comprising the following CDR(a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 76; (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 77; and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 78; or a variant thereof in which one, two, or three amino acids in one or more of CDR-L1, CDR-L2, or CDR-L3 are replaced with other amino acids.

[0176] In one embodiment, the anti-S-HBs antibody VL domain is (a) a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with respect to the light chain framework region 1 (LC-FR1) of SEQ ID NO: 83, or at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with respect to the light chain framework region 2 (LC-FR2) of SEQ ID NO: 841 (LC-FR1) of SEQ ID NO: 84, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with respect to the light chain framework region 1 (LC-FR1) of SEQ ID NO: 84, or at least 85%, 86%, 87%, 88%, 89%, (d) The light chain framework region 3 (LC-FR3) of sequence number 85, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and (d) the light chain framework region 4 (LC-FR4) of sequence number 86, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. Optionally, the VL domain contains each of the light chain framework sequences defined in (a) to (d). Optionally, the sequence identity percentage is 95%. The sequence identity percentage is arbitrarily 98%.

[0177] In another embodiment, an anti-S-HBs antibody is provided, comprising a light chain variable domain (VL) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with respect to the amino acid sequence of SEQ ID NO: 87. In one embodiment, the anti-S-HBs antibody comprises a light chain variable domain (VL) sequence having at least 95% sequence identity with respect to the amino acid sequence of SEQ ID NO: 87. In a particular embodiment, the VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but the anti-S-HBs antibody containing that sequence retains the ability to bind to S-HBs. In a particular embodiment, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 87. In certain embodiments, substitutions, insertions, or deletions occur in the region outside the CDR (i.e., at the FR). Optionally, the anti-S-HBs antibody contains the VL sequence of SEQ ID NO: 87, which includes post-translational modifications of that sequence. In certain embodiments, the VL contains one, two, or three CDRs selected from: (a) CDR-L1 containing the amino acid sequence of SEQ ID NO: 76, (b) CDR-L2 containing the amino acid sequence of SEQ ID NO: 77, and (c) CDR-L3 containing the amino acid sequence of SEQ ID NO: 78.

[0178] In another embodiment, the anti-S-HBs antibody comprises one or more of the VL CDR sequences of SEQ ID NO: 87. In one embodiment, the anti-S-HBs antibody comprises one or more (preferably all three) of the light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 87, and a framework of sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%. Optionally, the sequence identity is 95% or 98%.

[0179] In another embodiment, an anti-S-HBs antibody is provided, comprising a VH sequence of any of the embodiments provided above and a VL sequence of any of the embodiments provided above.

[0180] For example, in one exemplary embodiment, the antibody comprises a VH domain containing CDR-H3 of SEQ ID NO: 75; and a VL domain containing CDR-L3 of SEQ ID NO: 78. Optionally, the VH domain further comprises CDR-H2 of SEQ ID NO: 74.

[0181] In another exemplary embodiment, the antibody includes: i) VH domains including the following CDR(a) CDR-H1 containing the amino acid sequence of SEQ ID NO: 73; (b) CDR-H2 containing the amino acid sequence of SEQ ID NO: 74; and (c) CDR-H3 containing the amino acid sequence of SEQ ID NO: 75; or variants thereof in which one, two, or three amino acids in one or more of CDR-H1, CDR-H2, or CDR-H3 are replaced by other amino acids; and ii) VL domains including the following CDR(a) CDR-L1 containing the amino acid sequence of SEQ ID NO: 76; (b) CDR-L2 containing the amino acid sequence of SEQ ID NO: 77; and (c) CDR-L3 containing the amino acid sequence of SEQ ID NO: 78; or variants thereof in which one, two, or three amino acids in one or more of CDR-L1, CDR-L2, or CDR-L3 are replaced by other amino acids.

[0182] In another exemplary embodiment, the antibody includes: i) A heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 88; and ii) A light chain variable domain (VL) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acid sequence of Sequence ID No. 87.

[0183] In another exemplary embodiment, the anti-S-HBs antibody comprises (a) CDR-H1 containing the amino acid sequence of SEQ ID NO: 73; (b) CDR-H2 containing the amino acid sequence of SEQ ID NO: 74; (c) CDR-H3 containing the amino acid sequence of SEQ ID NO: 75; (d) CDR-L1 containing the amino acid sequence of SEQ ID NO: 76; (e) CDR-L2 containing the amino acid sequence of SEQ ID NO: 77; and (f) CDR-L3 containing the amino acid sequence of SEQ ID NO: 78, as well as a VH domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with respect to the amino acid sequence of SEQ ID NO: 88, and a VL domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with respect to the amino acid sequence of SEQ ID NO: 87. In one embodiment, the VH domain has at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 88. In another embodiment, the VL domain has at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 87. In one embodiment, the antibody specifically binds to S-HBs. In another embodiment, the antibody binds to S-HBs having a dissociation constant (KD) that is up to 10 times less or up to 10 times more than the dissociation constant (KD) of an antibody containing the VH sequence of SEQ ID NO: 88 and the VL sequence of SEQ ID NO: 87.

[0184] In one embodiment, the antibody comprises the VH and VL sequences of SEQ ID NO: 88 and SEQ ID NO: 87, respectively, and includes post-translational modifications of those sequences.

[0185] In a further embodiment, the antibody may comprise the full-length light chain of SEQ ID NO: 89 and / or the full-length heavy chain of SEQ ID NO: 90 or 267.

[0186] In further embodiments, the present invention provides antibodies that bind to the same epitopes as the anti-S-HBs antibodies provided herein. For example, in certain embodiments, antibodies that bind to the same epitopes as an anti-S-HBs antibody comprising the VH sequence of SEQ ID NO: 88 and the VL sequence of SEQ ID NO: 87 are provided. In certain embodiments, antibodies are provided that bind to the following residues of S-HBs of SEQ ID NO: 253: C121, and / or one or more of I110, P120, C124, C137, C139, C147, T148, and / or C149. Optionally, the antibody may further bind to one or more of C138, K141, P142, D144, G145, P150, I152, and / or W156. The antibody may contain any of the sequences defined above.

[0187] In a further embodiment, the present invention provides antibodies that compete with the anti-S-HBs antibodies provided herein for binding to S-HBs.

[0188] In some embodiments, the antibodies described in this section may have, or retain, at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the binding activity of the reference antibody Bc8.111 against S-HBs (e.g., SEQ ID NO: 253) when evaluated by the same assay, e.g., an ELISA assay or a flow cytometry assay.

[0189] In addition to or instead of the above, the antibodies described in this section may, when evaluated by the same assay, e.g., ELISA assay or flow cytometry assay, have or retain at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the binding activity of the reference antibody Bc8.111 to each of the proteins of SEQ ID NOs. 254–262, optionally, to one or more of the proteins of SEQ ID NOs. 254–262.

[0190] The reference antibody Bc8.111 has the VH sequence of SEQ ID NO: 88 and the VL sequence of SEQ ID NO: 87. It has the full-length heavy chain of SEQ ID NO: 90 or 267 and the full-length light chain of SEQ ID NO: 89. SEQ ID NO: 267 contains the IgG1 constant region expressed by vector LT615368.1, as used in the examples. In some embodiments, the antibodies described in this section are evaluated in the same assay as the K of the reference antibody Bc8.111 against the same antigen. D K is 50, 10, 9, 8, 7, 6, 5, 4, 3 or less than or equal to 2 times the value, or less than or equal to that value. D It can bind to S-HBs by value (for example, sequence number 253).

[0191] In addition to this, or instead, the antibody is evaluated in the same assay as the reference antibody Bc8.111 against the same antigen. D K is 50, 10, 9, 8, 7, 6, 5, 4, 3 or less than or equal to 2 times the value, or less than or equal to that value. D The value may bind to one or more of the sequences 254-262 (e.g., at least sequence 257), or optionally to each of the proteins in sequences 254-262.

[0192] In some embodiments, the antibodies described in this section may bind to S-HBs (e.g., SEQ ID NO: 253) at an EC50 of 50, 10, 9, 8, 7, 6, 5, 4, 3, or 2 times or less the EC50 of the reference antibody Bc8.111, as measured by ELISA or flow cytometry. Alternatively, or in addition to the above, the antibodies may bind to one or more of the proteins SEQ ID NOs: 254-262, or each of them, optionally to at least the protein SEQ ID NO: 257, at an EC50 of 50, 10, 9, 8, 7, 6, 5, 4, 3, or 2 times or less the EC50 of the reference antibody Bc8.111, as measured by ELISA or flow cytometry.

[0193] In some embodiments, the antibodies described in this section may have or retain in vitro neutralizing activity against HBV genotypes A, B, C, and / or D, or optionally all of A, B, C, and D. For example, the antibodies described in this section may have or retain in vitro neutralizing activity against HBV genotype D, for example, IC 50 The value can be ≤100 pg / ml, and arbitrarily ≤10 pg / ml.

[0194] In another embodiment, the antibody is evaluated using the same assay (e.g., the in vitro neutralization assay described herein) for neutralization of HBV genotypes A, B, C and / or D, optionally at least D, optionally A, B, C and D, and has an IC50 value of 50, 10, 9, 8, 7, 6, 5, 4, 3, or 2 times or less of the IC50 value of the reference antibody Bc8.111 for the same genotype, or less than or equal to such value. 50 It may have a value.

[0195] In another embodiment, the antibody may have, or retain, at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the in vivo neutralizing activity of the reference antibody Bc8.111 against HBV genotypes A, B, C, and / or D, as evaluated using the same assay (e.g., the assay described herein).

[0196] Optionally, the antibody can suppress viremia in vivo in individuals infected with, for example, HBV genotype A, B, C, or D, optionally D. Optionally, the antibody may have, or retain, at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the in vivo viremia-suppressing activity of the reference antibody Bc8.111 against HBV genotypes A, B, C, and / or D, as evaluated using the same assay (e.g., the assay described herein).

[0197] F. In one embodiment, the present invention provides an antibody comprising a VH domain comprising at least one, at least two, or all three VH CDR sequences selected from (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 91, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 92, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 93. In another embodiment, the antibody comprises a VH domain comprising the following CDR(a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 91; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 92; and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 93; or a variant thereof in which one, two, or three amino acids in one or more of CDR-H1, CDR-H2, or CDR-H3 are replaced with other amino acids.

[0198] In one embodiment, the VH domain is (a) the heavy chain framework region 1 (HC-FR1) of SEQ ID NO: 97, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; (b) the heavy chain framework region 2 (HC-FR2) of SEQ ID NO: 98, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; (c) the heavy chain framework region of SEQ ID NO: 99 (d) The VH domain may further include one or more heavy chain framework sequences selected from (a) to (d) the heavy chain framework region 3 (HC-FR3) or variants having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and (d) the heavy chain framework region 4 (HC-FR4) of SEQ ID NO: 100 or variants having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. Optionally, the VH domain contains each of the heavy chain framework sequences defined in (a) to (d). Optionally, the sequence identity percentage is 95%. Optionally, the sequence identity percentage is 98%.

[0199] In another embodiment, the anti-S-HBs antibody contains a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 106. In one embodiment, the anti-S-HBs antibody contains a heavy chain variable domain (VH) sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 106. In a particular embodiment, the VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but the anti-S-HBs antibody containing that sequence retains the ability to bind to S-HBs. In a particular embodiment, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 106. In certain embodiments, substitutions, insertions, or deletions occur in the region outside the CDR (i.e., at the FR). Optionally, the anti-S-HBs antibody contains the VH sequence of SEQ ID NO: 106, which includes post-translational modifications of that sequence. In certain embodiments, the VH contains one, two, or three CDRs selected from: (a) CDR-H1 containing the amino acid sequence of SEQ ID NO: 91, (b) CDR-H2 containing the amino acid sequence of SEQ ID NO: 92, and (c) CDR-H3 containing the amino acid sequence of SEQ ID NO: 93.

[0200] In another embodiment, the anti-S-HBs antibody comprises one or more of the VH heavy chain CDR sequences of SEQ ID NO: 106. In one embodiment, the anti-S-HBs antibody comprises one or more (preferably all three) of the VH domain heavy chain CDR amino acid sequences of SEQ ID NO: 106, and a framework of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% sequence identity. Optionally, the sequence identity is 95% or 98%.

[0201] In another embodiment, the present invention provides an antibody comprising a VL domain comprising at least one, at least two, or all three VL CDR sequences selected from (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 94, (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 95, and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 96. In another embodiment, the antibody comprises a VL domain comprising the following CDR(a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 94; (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 95; and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 96; or a variant thereof in which one, two, or three amino acids in one or more of CDR-L1, CDR-L2, or CDR-L3 are replaced with other amino acids.

[0202] In one embodiment, the anti-S-HBs antibody VL domain is (a) a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with respect to the light chain framework region 1 (LC-FR1) of SEQ ID NO: 101, or at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with respect to the light chain framework region 2 (LC-FR2) of SEQ ID NO: 102, or a variant having1 (LC-FR2) of SEQ ID NO: 102, or at least 85%, 86%, 87%, 88%, 89%, 90%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with respect to the light chain framework region 1 (LC-FR1) of SEQ ID NO: 102, or at least 85%, 86%, 87%, (d) The light chain framework region 3 (LC-FR3) of sequence number 103, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and (d) the light chain framework region 4 (LC-FR4) of sequence number 104, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. Optionally, the VL domain contains each of the light chain framework sequences defined in (a) to (d). Optionally, the sequence identity percentage is 95%. The sequence identity percentage is arbitrarily 98%.

[0203] In another embodiment, an anti-S-HBs antibody is provided, comprising a light chain variable domain (VL) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with respect to the amino acid sequence of SEQ ID NO: 105. In one embodiment, the anti-S-HBs antibody comprises a light chain variable domain (VL) sequence having at least 95% sequence identity with respect to the amino acid sequence of SEQ ID NO: 105. In a particular embodiment, the VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but the anti-S-HBs antibody containing that sequence retains the ability to bind to S-HBs. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 105. In certain embodiments, the substitutions, insertions, or deletions occur in the region outside the CDR (i.e., in the FR). Optionally, the anti-S-HBs antibody contains the VL sequence of SEQ ID NO: 105, which includes post-translational modifications of that sequence. In certain embodiments, the VL contains one, two, or three CDRs selected from: (a) CDR-L1 containing the amino acid sequence of SEQ ID NO: 94, (b) CDR-L2 containing the amino acid sequence of SEQ ID NO: 95, and (c) CDR-L3 containing the amino acid sequence of SEQ ID NO: 96.

[0204] In another embodiment, the anti-S-HBs antibody comprises one or more of the VL CDR sequences of SEQ ID NO: 105. In one embodiment, the anti-S-HBs antibody comprises one or more (preferably all three) of the VL domain light chain CDR amino acid sequences of SEQ ID NO: 105, and a framework of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% sequence identity. Optionally, the sequence identity is 95% or 98%.

[0205] In another embodiment, an anti-S-HBs antibody is provided, comprising a VH sequence of any of the embodiments provided above and a VL sequence of any of the embodiments provided above.

[0206] For example, in one exemplary embodiment, the antibody comprises a VH domain containing CDR-H3 of SEQ ID NO: 93; and a VL domain containing CDR-L3 of SEQ ID NO: 96. Optionally, the VH domain further comprises CDR-H2 of SEQ ID NO: 92.

[0207] In another exemplary embodiment, the antibody includes: i) VH domains including the following CDR(a) CDR-H1 containing the amino acid sequence of SEQ ID NO: 91; (b) CDR-H2 containing the amino acid sequence of SEQ ID NO: 92; and (c) CDR-H3 containing the amino acid sequence of SEQ ID NO: 93; or variants thereof in which one, two, or three amino acids in one or more of CDR-H1, CDR-H2, or CDR-H3 are replaced by other amino acids; and ii) VL domains including the following CDR(a) CDR-L1 containing the amino acid sequence of SEQ ID NO: 94; (b) CDR-L2 containing the amino acid sequence of SEQ ID NO: 95; and (c) CDR-L3 containing the amino acid sequence of SEQ ID NO: 96; or variants thereof in which one, two, or three amino acids in one or more of CDR-L1, CDR-L2, or CDR-L3 are replaced by other amino acids.

[0208] In another exemplary embodiment, the antibody includes: i) A heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 106; and ii) A light chain variable domain (VL) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 105.

[0209] In another exemplary embodiment, the anti-S-HBs antibody comprises (a) CDR-H1 containing the amino acid sequence of SEQ ID NO: 91; (b) CDR-H2 containing the amino acid sequence of SEQ ID NO: 92; (c) CDR-H3 containing the amino acid sequence of SEQ ID NO: 93; (d) CDR-L1 containing the amino acid sequence of SEQ ID NO: 94; (e) CDR-L2 containing the amino acid sequence of SEQ ID NO: 95; and (f) CDR-L3 containing the amino acid sequence of SEQ ID NO: 96, as well as a VH domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with respect to the amino acid sequence of SEQ ID NO: 106, and a VL domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with respect to the amino acid sequence of SEQ ID NO: 105. In one embodiment, the VH domain has at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 106. In another embodiment, the VL domain has at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 105. In one embodiment, the antibody specifically binds to S-HBs. In another embodiment, the antibody binds to S-HBs having a dissociation constant (KD) that is up to 10 times less or up to 10 times more than the dissociation constant (KD) of an antibody containing the VH sequence of SEQ ID NO: 106 and the VL sequence of SEQ ID NO: 105.

[0210] In one embodiment, the antibody comprises the VH and VL sequences of SEQ ID NO: 106 and SEQ ID NO: 105, respectively, including post-translational modifications of those sequences.

[0211] In a further embodiment, the antibody may comprise the full-length light chain of SEQ ID NO: 107 and / or the full-length heavy chain of SEQ ID NO: 108 or 268.

[0212] In further embodiments, the present invention provides antibodies that bind to the same epitopes as the anti-S-HBs antibodies provided herein. For example, in certain embodiments, antibodies that bind to the same epitopes as an anti-S-HBs antibody comprising the VH sequence of SEQ ID NO: 106 and the VL sequence of SEQ ID NO: 105 are provided. In certain embodiments, antibodies that bind to one or more of the following residues of S-HBs in SEQ ID NO: 253: W156 and / or R169 are provided. Optionally, the antibody may further bind to one or more of I152 and / or C138. The antibody may contain any of the sequences defined above.

[0213] In a further embodiment, the present invention provides antibodies that compete with the anti-S-HBs antibodies provided herein for binding to S-HBs.

[0214] In some embodiments, the antibodies described in this section may have, or retain, at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the binding activity of the reference antibody Bc8.104 against S-HBs (e.g., SEQ ID NO: 253) when evaluated by the same assay, e.g., an ELISA assay or a flow cytometry assay.

[0215] In addition to or instead of the above, the antibodies described in this section may, when evaluated by the same assay, e.g., ELISA assay or flow cytometry assay, have or retain at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the binding activity of the reference antibody Bc8.104 to each of the proteins of SEQ ID NOs. 254–262, optionally, to one or more of the proteins of SEQ ID NOs. 254–262.

[0216] The reference antibody Bc8.104 has the VH sequence of SEQ ID NO: 106 and the VL sequence of SEQ ID NO: 105. It has the full-length heavy chain of SEQ ID NO: 108 or 268 and the full-length light chain of SEQ ID NO: 107. SEQ ID NO: 268 contains the IgG1 constant region expressed by the vector LT615368.1 as used in the examples.

[0217] In some embodiments, the antibodies described in this section are evaluated in the same assay and have a K D value that is 50, 10, 9, 8, 7, 6, 5, 4, 3, or 2-fold or less, or less than that value, of the K D value of the reference antibody Bc8.104 against the same antigen and can bind to S-HBs (e.g., of SEQ ID NO: 253).

[0218] In addition to, or instead of, this, the antibodies described in this section are evaluated in the same assay and have a K D value that is 50, 10, 9, 8, 7, 6, 5, 4, 3, or 2-fold or less, or less than that value, of the K D value and can bind to one or more (e.g., at least SEQ ID NO: 257) of SEQ ID NOs: 254 - 262, optionally to each of the proteins of SEQ ID NOs: 254 - 262.

[0219] In some embodiments, the antibodies described in this section are measured by ELISA or flow cytometry and have an EC50 that is 50, 10, 9, 8, 7, 6, 5, 4, 3, or 2-fold or less, or less than that value, of the EC50 of the reference antibody Bc8.104 and can bind to S-HBs (e.g., of SEQ ID NO: 253). Instead of, or in addition to, this, the antibodies can be measured by ELISA or flow cytometry and have an EC50 that is 50, 10, 9, 8, 7, 6, 5, 4, 3, or 2-fold or less, or less than that value, of the EC50 of the reference antibody Bc8.104 and can bind to one or more, or each, of the proteins of SEQ ID NOs: 254 - 262, optionally at least to the protein of SEQ ID NO: 257.

[0220] In some embodiments, the antibodies described in this section may have or retain in vitro neutralizing activity against HBV genotypes A, B, C, and / or D, or optionally all of A, B, C, and D. For example, the antibodies described in this section may have or retain in vitro neutralizing activity against HBV genotype D, for example, an IC50 value of ≤100 pg / ml, optionally ≤10 pg / ml.

[0221] In another embodiment, the antibody may have an IC50 value of 50, 10, 9, 8, 7, 6, 5, 4, 3, or 2 times or less the IC50 value of the reference antibody Bc8.104 against the same genotype, when evaluated using the same assay (e.g., the in vitro neutralization assay described herein) for neutralization of HBV genotypes A, B, C and / or D, optionally at least D, optionally A, B, C and D.

[0222] In another embodiment, the antibody may, when evaluated using the same assay (e.g., the assay described herein), have or retain at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the neutralizing activity of the reference antibody Bc8.104 against HBV genotypes A, B, C, and / or D, optionally at least D, or optionally all of A, B, C, and D.

[0223] Optionally, the antibody can suppress viremia in vivo in individuals infected with, for example, HBV genotype A, B, C, or D, optionally D. Optionally, the antibody may have, or retain, at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the in vivo viremia-suppressing activity of the reference antibody Bc8.104 against HBV genotypes A, B, C, and / or D, optionally at least D, or optionally all of A, B, C, and D, as evaluated using the same assay (e.g., the assay described herein).

[0224] G. In one embodiment, the present invention provides an antibody comprising a VH domain comprising at least one, at least two, or all three VH CDR sequences selected from (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 109, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 110, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 111. In another embodiment, the antibody comprises a VH domain comprising the following CDR(a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 109; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 110; and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 111; or a variant thereof in which one, two, or three amino acids in one or more of CDR-H1, CDR-H2, or CDR-H3 are replaced with other amino acids.

[0225] In one embodiment, the VH domain is (a) the heavy chain framework region 1 (HC-FR1) of SEQ ID NO: 115, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; (b) the heavy chain framework region 2 (HC-FR2) of SEQ ID NO: 116, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; (c) SEQ ID NO: 117 (d) The heavy chain framework region 3 (HC-FR3) of (a) or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and (d) the heavy chain framework region 4 (HC-FR4) of SEQ ID NO: 118 or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. Optionally, the VH domain contains each of the heavy chain framework sequences defined in (a) to (d). Optionally, the sequence identity percentage is 95%. Optionally, the sequence identity percentage is 98%.

[0226] In another embodiment, the anti-S-HBs antibody contains a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 124. In one embodiment, the anti-S-HBs antibody contains a heavy chain variable domain (VH) sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 124. In a particular embodiment, the VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but the anti-S-HBs antibody containing that sequence retains the ability to bind to S-HBs. In a particular embodiment, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 124. In certain embodiments, substitutions, insertions, or deletions occur in the region outside the CDR (i.e., at the FR). Optionally, the anti-S-HBs antibody contains the VH sequence of SEQ ID NO: 124, which includes post-translational modifications of that sequence. In certain embodiments, the VH contains one, two, or three CDRs selected from: (a) CDR-H1 containing the amino acid sequence of SEQ ID NO: 109, (b) CDR-H2 containing the amino acid sequence of SEQ ID NO: 110, and (c) CDR-H3 containing the amino acid sequence of SEQ ID NO: 111.

[0227] In another embodiment, the anti-S-HBs antibody comprises one or more of the VH heavy chain CDR sequences of SEQ ID NO: 124. In one embodiment, the anti-S-HBs antibody comprises one or more (preferably all three) of the VH domain heavy chain CDR amino acid sequences of SEQ ID NO: 124 and a framework of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% sequence identity. Optionally, the sequence identity is 95% or 98%.

[0228] In another embodiment, the present invention provides an antibody comprising a VL domain comprising at least one, at least two, or all three VL CDR sequences selected from (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 112, (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 113, and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 114. In another embodiment, the antibody comprises a VL domain comprising the following CDR(a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 112; (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 113; and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 114; or a variant thereof in which one, two, or three amino acids in one or more of CDR-L1, CDR-L2, or CDR-L3 are replaced with other amino acids.

[0229] In one embodiment, the anti-S-HBs antibody VL domain is (a) a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with respect to the light chain framework region 1 (LC-FR1) of SEQ ID NO: 119, or at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with respect to the light chain framework region 2 (LC-FR2) of SEQ ID NO: 120, or a variant having1 (LC-FR2) of SEQ ID NO: 120, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with respect to the light chain framework region 1 (LC-FR1) of SEQ ID NO: 120, or a variant having at least 85%, 8 (d) The light chain framework region 3 (LC-FR3) of sequence number 121, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and (d) the light chain framework region 4 (LC-FR4) of sequence number 122, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. Optionally, the VL domain contains each of the light chain framework sequences defined in (a) to (d). Optionally, the sequence identity percentage is 95%. The sequence identity percentage is arbitrarily 98%.

[0230] In another embodiment, an anti-S-HBs antibody is provided, comprising a light chain variable domain (VL) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with respect to the amino acid sequence of SEQ ID NO: 123. In one embodiment, the anti-S-HBs antibody comprises a light chain variable domain (VL) sequence having at least 95% sequence identity with respect to the amino acid sequence of SEQ ID NO: 123. In a particular embodiment, the VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but the anti-S-HBs antibody containing that sequence retains the ability to bind to S-HBs. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 123. In certain embodiments, the substitutions, insertions, or deletions occur in the region outside the CDR (i.e., in the FR). Optionally, the anti-S-HBs antibody contains the VL sequence of SEQ ID NO: 123, which includes post-translational modifications of that sequence. In certain embodiments, the VL contains one, two, or three CDRs selected from: (a) CDR-L1 containing the amino acid sequence of SEQ ID NO: 112, (b) CDR-L2 containing the amino acid sequence of SEQ ID NO: 113, and (c) CDR-L3 containing the amino acid sequence of SEQ ID NO: 114.

[0231] In another embodiment, the anti-S-HBs antibody comprises one or more of the VL CDR sequences of SEQ ID NO: 123. In one embodiment, the anti-S-HBs antibody comprises one or more (preferably all three) of the VL domain light chain CDR amino acid sequences of SEQ ID NO: 123 and a framework amino acid sequence of the VL domain of SEQ ID NO: 123 with at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% sequence identity. Optionally, the sequence identity is 95% or 98%.

[0232] In another embodiment, an anti-S-HBs antibody is provided, comprising a VH sequence of any of the embodiments provided above and a VL sequence of any of the embodiments provided above.

[0233] For example, in one exemplary embodiment, the antibody comprises a VH domain containing CDR-H3 of SEQ ID NO: 111; and a VL domain containing CDR-L3 of SEQ ID NO: 114. Optionally, the VH domain further comprises CDR-H2 of SEQ ID NO: 110.

[0234] In another exemplary embodiment, the antibody includes: i) VH domains including the following CDR(a) CDR-H1 containing the amino acid sequence of SEQ ID NO: 109; (b) CDR-H2 containing the amino acid sequence of SEQ ID NO: 110; and (c) CDR-H3 containing the amino acid sequence of SEQ ID NO: 111; or variants thereof in which one, two, or three amino acids in one or more of CDR-H1, CDR-H2, or CDR-H3 are replaced by other amino acids; and ii) VL domains including the following CDR(a) CDR-L1 containing the amino acid sequence of SEQ ID NO: 112; (b) CDR-L2 containing the amino acid sequence of SEQ ID NO: 113; and (c) CDR-L3 containing the amino acid sequence of SEQ ID NO: 114; or variants thereof in which one, two, or three amino acids in one or more of CDR-L1, CDR-L2, or CDR-L3 are replaced by other amino acids.

[0235] In another exemplary embodiment, the antibody includes: i) A heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 124; and ii) A light chain variable domain (VL) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acid sequence of sequence number 123.

[0236] In another exemplary embodiment, the anti-S-HBs antibody comprises (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 109; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 110; (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 111; (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 112; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 113; and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 114, and a VH domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 124, and a VL domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 123. In one aspect, the VH domain has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 124. In one aspect, the VL domain has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 123. In one embodiment, the antibody specifically binds to S-HBs. In another embodiment, the antibody binds to S-HBs having a dissociation constant (KD) that is decreased by up to 10-fold or increased by up to 10-fold compared to the dissociation constant (KD) of an antibody comprising the VH sequence of SEQ ID NO: 124 and the VL sequence of SEQ ID NO: 123.

[0237] In one aspect, the antibody comprises the VH and VL sequences of SEQ ID NO: 124 and SEQ ID NO: 123, respectively, including post-translational modifications of those sequences.

[0238] In a further aspect, the antibody may comprise the full-length light chain of SEQ ID NO: 125 and / or the full-length heavy chain of SEQ ID NO: 126 or 269.

[0239] In further embodiments, the present invention provides antibodies that bind to the same epitopes as the anti-S-HBs antibodies provided herein. For example, in certain embodiments, antibodies that bind to the same epitopes as an anti-S-HBs antibody comprising the VH sequence of SEQ ID NO: 124 and the VL sequence of SEQ ID NO: 123 are provided. In certain embodiments, antibodies that bind to one or more of the following residues of S-HBs in SEQ ID NO: 253: C137, C138 and / or D144 are provided. Optionally, the antibody may further bind to one or more of P142, N146, T148, C149, I152 and / or W156. The antibody may contain any of the sequences defined above.

[0240] In a further embodiment, the present invention provides antibodies that compete with the anti-S-HBs antibodies provided herein for binding to S-HBs.

[0241] In some embodiments, the antibodies described in this section may have, or retain, at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the binding activity of the reference antibody Bv6.172 against S-HBs (e.g., SEQ ID NO: 253) when evaluated in the same assay, e.g., an ELISA assay or a flow cytometry assay.

[0242] In addition to or instead of the above, the antibodies described in this section may, when evaluated by the same assay, e.g., ELISA assay or flow cytometry assay, have or retain at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the binding activity of reference antibody Bv6.172 to each of the proteins of SEQ ID NOs. 254–262, optionally, to one or more of the proteins of SEQ ID NOs. 254–262.

[0243] Reference antibody Bv6.172 has the VH sequence of SEQ ID NO: 124 and the VL sequence of SEQ ID NO: 123. It has the full-length heavy chain of SEQ ID NO: 126 or 269 and the full-length light chain of SEQ ID NO: 125. SEQ ID NO: 269 contains the IgG1 constant region expressed by vector LT615368.1, as used in the examples.

[0244] In some embodiments, the antibodies described in this section are evaluated in the same assay as the reference antibody Bv6.172 against the same antigen. D K is 50, 10, 9, 8, 7, 6, 5, 4, 3 or less than or equal to 2 times the value, or less than or equal to that value. D It can bind to S-HBs by value (for example, sequence number 253).

[0245] In addition to this, or instead, the antibody is evaluated in the same assay as the reference antibody Bv6.172 against the same antigen. D K is 50, 10, 9, 8, 7, 6, 5, 4, 3 or less than or equal to 2 times the value, or less than or equal to that value. D The value may bind to one or more of the sequences 254-262 (e.g., at least sequence 257), or optionally to each of the proteins in sequences 254-262.

[0246] In some embodiments, the antibodies described in this section may bind to S-HBs (e.g., SEQ ID NO: 253) at an EC50 of 50, 10, 9, 8, 7, 6, 5, 4, 3, or 2 times or less the EC50 of reference antibody Bv6.172, as measured by ELISA or flow cytometry. Alternatively, or in addition to the above, the antibodies may bind to one or more of the proteins SEQ ID NOs: 254-262, or each of them, optionally to at least the protein SEQ ID NO: 257, at an EC50 of 50, 10, 9, 8, 7, 6, 5, 4, 3, or 2 times or less the EC50 of reference antibody Bv6.172, as measured by ELISA or flow cytometry.

[0247] In some embodiments, the antibodies described in this section may have or retain in vitro neutralizing activity against HBV genotype D, for example, IC 50 The value can be ≤100 pg / ml, and arbitrarily ≤10 pg / ml.

[0248] In another embodiment, the antibody is evaluated for neutralization of HBV genotypes A, B, C, and / or D using the same assay (e.g., the in vitro neutralization assay described herein) to obtain the IC of reference antibody Bv6.172 against the same genotype. 50 IC values ​​that are 50, 10, 9, 8, 7, 6, 5, 4, 3 or less than or twice the value, or less than or equal to that value. 50 It may have a value.

[0249] In another embodiment, the antibody may, when evaluated using the same assay (e.g., the assay described herein), have or retain at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the in vivo neutralizing activity of the reference antibody Bv6.172 against HBV genotypes A, B, C, and / or D, optionally at least D, or optionally all of A, B, C, and D.

[0250] Optionally, the antibody can suppress viremia in vivo in individuals infected with, for example, HBV genotype A, B, C, or D, optionally D. Optionally, the antibody may have, or retain, at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the in vivo viremia-suppressing activity of the reference antibody Bv6.172 against HBV genotypes A, B, C, and / or D, optionally at least D, or optionally all of A, B, C, and D, as evaluated using the same assay (e.g., the assay described herein).

[0251] H. In one embodiment, the present invention provides an antibody comprising a VH domain comprising at least one, at least two, or all three VH CDR sequences selected from (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 127, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 128, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 129. In another embodiment, the antibody comprises a VH domain comprising the following CDR(a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 127; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 128; and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 129; or a variant thereof in which one, two, or three amino acids in one or more of CDR-H1, CDR-H2, or CDR-H3 are replaced with other amino acids.

[0252] In one embodiment, the VH domain is (a) the heavy chain framework region 1 (HC-FR1) of SEQ ID NO: 133, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; (b) the heavy chain framework region 2 (HC-FR2) of SEQ ID NO: 134, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; (c) SEQ ID NO: 135 (d) The heavy chain framework region 3 (HC-FR3) of (a) or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and (d) the heavy chain framework region 4 (HC-FR4) of SEQ ID NO: 136 or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. Optionally, the VH domain contains each of the heavy chain framework sequences defined in (a) to (d). Optionally, the sequence identity percentage is 95%. Optionally, the sequence identity percentage is 98%.

[0253] In another embodiment, the anti-S-HBs antibody contains a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 142. In one embodiment, the anti-S-HBs antibody contains a heavy chain variable domain (VH) sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 142. In a particular embodiment, the VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but the anti-S-HBs antibody containing that sequence retains the ability to bind to S-HBs. In a particular embodiment, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 142. In certain embodiments, substitutions, insertions, or deletions occur in the region outside the CDR (i.e., at the FR). Optionally, the anti-S-HBs antibody contains the VH sequence of SEQ ID NO: 142, which includes post-translational modifications of that sequence. In certain embodiments, the VH contains one, two, or three CDRs selected from: (a) CDR-H1 containing the amino acid sequence of SEQ ID NO: 127, (b) CDR-H2 containing the amino acid sequence of SEQ ID NO: 128, and (c) CDR-H3 containing the amino acid sequence of SEQ ID NO: 129.

[0254] In another embodiment, the anti-S-HBs antibody comprises one or more of the VH heavy chain CDR sequences of SEQ ID NO: 142. In one embodiment, the anti-S-HBs antibody comprises one or more (preferably all three) of the VH domain heavy chain CDR amino acid sequences of SEQ ID NO: 142, and a framework of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% sequence identity. Optionally, the sequence identity is 95% or 98%.

[0255] In another embodiment, the present invention provides an antibody comprising a VL domain comprising at least one, at least two, or all three VL CDR sequences selected from (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 130, (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 131, and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 132. In another embodiment, the antibody comprises a VL domain comprising the following CDR(a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 130; (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 131; and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 132; or a variant thereof in which one, two, or three amino acids in one or more of CDR-L1, CDR-L2, or CDR-L3 are replaced with other amino acids.

[0256] In one embodiment, the anti-S-HBs antibody VL domain is (a) a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with respect to the light chain framework region 1 (LC-FR1) of SEQ ID NO: 137, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with respect to the light chain framework region 2 (LC-FR2) of SEQ ID NO: 1381 (LC-FR1) of SEQ ID NO: 137, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with respect to the light chain framework region 1 (LC-FR1) of SEQ ID NO: 137, or a variant having at least 85 (d) The light chain framework region 3 (LC-FR3) of sequence number 139, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and (d) the light chain framework region 4 (LC-FR4) of sequence number 140, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. Optionally, the VL domain contains each of the light chain framework sequences defined in (a) to (d). Optionally, the sequence identity percentage is 95%. The sequence identity percentage is arbitrarily 98%.

[0257] In another embodiment, an anti-S-HBs antibody is provided, comprising a light chain variable domain (VL) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with respect to the amino acid sequence of SEQ ID NO: 141. In one embodiment, the anti-S-HBs antibody comprises a light chain variable domain (VL) sequence having at least 95% sequence identity with respect to the amino acid sequence of SEQ ID NO: 141. In a particular embodiment, the VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but the anti-S-HBs antibody containing that sequence retains the ability to bind to S-HBs. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 141. In certain embodiments, the substitutions, insertions, or deletions occur in the region outside the CDR (i.e., in the FR). Optionally, the anti-S-HBs antibody contains the VL sequence of SEQ ID NO: 141, which includes post-translational modifications of that sequence. In certain embodiments, the VL contains one, two, or three CDRs selected from: (a) CDR-L1 containing the amino acid sequence of SEQ ID NO: 130, (b) CDR-L2 containing the amino acid sequence of SEQ ID NO: 131, and (c) CDR-L3 containing the amino acid sequence of SEQ ID NO: 132.

[0258] In another embodiment, the anti-S-HBs antibody comprises one or more of the VL CDR sequences of SEQ ID NO: 141. In one embodiment, the anti-S-HBs antibody comprises one or more (preferably all three) of the VL domain light chain CDR amino acid sequences of SEQ ID NO: 141 and a framework amino acid sequence of the VL domain of SEQ ID NO: 141 with at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% sequence identity. Optionally, the sequence identity is 95% or 98%.

[0259] In another embodiment, an anti-S-HBs antibody is provided, comprising a VH sequence of any of the embodiments provided above and a VL sequence of any of the embodiments provided above.

[0260] For example, in one exemplary embodiment, the antibody comprises a VH domain containing CDR-H3 of SEQ ID NO: 129; and a VL domain containing CDR-L3 of SEQ ID NO: 132. Optionally, the VH domain further comprises CDR-H2 of SEQ ID NO: 128.

[0261] In another exemplary embodiment, the antibody includes: i) VH domains including the following CDR(a) CDR-H1 containing the amino acid sequence of SEQ ID NO: 127; (b) CDR-H2 containing the amino acid sequence of SEQ ID NO: 128; and (c) CDR-H3 containing the amino acid sequence of SEQ ID NO: 129; or variants thereof in which one, two, or three amino acids in one or more of CDR-H1, CDR-H2, or CDR-H3 are replaced by other amino acids; and ii) VL domains including the following CDR(a) CDR-L1 containing the amino acid sequence of SEQ ID NO: 130; (b) CDR-L2 containing the amino acid sequence of SEQ ID NO: 131; and (c) CDR-L3 containing the amino acid sequence of SEQ ID NO: 132; or variants thereof in which one, two, or three amino acids in one or more of CDR-L1, CDR-L2, or CDR-L3 are replaced by other amino acids.

[0262] In another exemplary embodiment, the antibody includes: i) A heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 142; and ii) A light chain variable domain (VL) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acid sequence of Sequence ID No. 141.

[0263] In another exemplary embodiment, the anti-S-HBs antibody comprises (a) CDR-H1 containing the amino acid sequence of SEQ ID NO: 127; (b) CDR-H2 containing the amino acid sequence of SEQ ID NO: 128; (c) CDR-H3 containing the amino acid sequence of SEQ ID NO: 129; (d) CDR-L1 containing the amino acid sequence of SEQ ID NO: 130; (e) CDR-L2 containing the amino acid sequence of SEQ ID NO: 131; and (f) CDR-L3 containing the amino acid sequence of SEQ ID NO: 132, as well as a VH domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with respect to the amino acid sequence of SEQ ID NO: 142, and a VL domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with respect to the amino acid sequence of SEQ ID NO: 141. In one embodiment, the VH domain has at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 142. In another embodiment, the VL domain has at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 141. In one embodiment, the antibody specifically binds to S-HBs. In another embodiment, the antibody binds to S-HBs having a dissociation constant (KD) that is up to 10 times lower or up to 10 times higher than the dissociation constant (KD) of an antibody containing the VH sequence of SEQ ID NO: 142 and the VL sequence of SEQ ID NO: 141.

[0264] In one embodiment, the antibody comprises the VH and VL sequences of SEQ ID NO: 142 and SEQ ID NO: 141, respectively, and includes post-translational modifications of those sequences.

[0265] In a further embodiment, the antibody may comprise the full-length light chain of SEQ ID NO: 143 and / or the full-length heavy chain of SEQ ID NO: 144 or 270.

[0266] In further embodiments, the present invention provides antibodies that bind to the same epitopes as the anti-S-HBs antibodies provided herein. For example, in certain embodiments, antibodies that bind to the same epitopes as an anti-S-HBs antibody comprising the VH sequence of SEQ ID NO: 142 and the VL sequence of SEQ ID NO: 141 are provided. In certain embodiments, antibodies that bind to one or more of the following residues of S-HBs in SEQ ID NO: 253: C137, C138 and / or C139 are provided. Optionally, the antibody also binds to C124, optionally further to W156, and optionally to one or more of N146, T148 and / or I152. The antibody may contain any of the sequences defined above.

[0267] In a further embodiment, the present invention provides antibodies that compete with the anti-S-HBs antibodies provided herein for binding to S-HBs.

[0268] In some embodiments, the antibodies described in this section may have, or retain, at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the binding activity of the reference antibody Bv4.115 against S-HBs (e.g., SEQ ID NO: 253) when evaluated by the same assay, e.g., ELISA or flow cytometry assay.

[0269] In addition to or instead of the above, the antibodies described in this section may, when evaluated by the same assay, e.g., ELISA or flow cytometry assay, have or retain at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the binding activity of reference antibody Bv4.115 to each of the proteins of SEQ ID NOs. 254–262, optionally, to one or more of the proteins of SEQ ID NOs. 254–262.

[0270] Reference antibody Bv4.115 has the VH sequence of SEQ ID NO: 142 and the VL sequence of SEQ ID NO: 141. It has the full-length heavy chain of SEQ ID NO: 144 or 270 and the full-length light chain of SEQ ID NO: 143. SEQ ID NO: 270 contains the IgG1 constant region expressed by vector LT615368.1, as used in the examples.

[0271] In some embodiments, the antibodies described in this section are evaluated in the same assay as the reference antibody Bv4.115 against the same antigen. D K is 50, 10, 9, 8, 7, 6, 5, 4, 3 or less than or equal to 2 times the value, or less than or equal to that value. D It can bind to S-HBs by value (for example, sequence number 253).

[0272] In addition to this, or instead, the antibody is evaluated in the same assay as the reference antibody Bv4.115 against the same antigen. D K is 50, 10, 9, 8, 7, 6, 5, 4, 3 or less than or equal to 2 times the value, or less than or equal to that value. D The value may bind to one or more of the sequences 254-262 (e.g., at least sequence 257), or optionally to each of the proteins in sequences 254-262.

[0273] In some embodiments, the antibodies described in this section may bind to S-HBs (e.g., SEQ ID NO: 253) at an EC50 of 50, 10, 9, 8, 7, 6, 5, 4, 3, or 2 times or less the EC50 of reference antibody Bv4.115, as measured by ELISA or flow cytometry. Alternatively, or in addition to the above, the antibodies may bind to one or more of the proteins SEQ ID NOs: 254-262, or each of them, optionally to at least the protein SEQ ID NO: 257, at an EC50 of 50, 10, 9, 8, 7, 6, 5, 4, 3, or 2 times or less the EC50 of reference antibody Bv4.115, as measured by ELISA or flow cytometry.

[0274] In some embodiments, the antibodies described in this section may have or retain in vitro neutralizing activity against HBV genotypes A, B, C, and / or D, or optionally all of A, B, C, and D. For example, the antibodies described in this section may have or retain in vitro neutralizing activity against HBV genotype D, for example, an IC50 value of ≤100 pg / ml, optionally ≤10 pg / ml.

[0275] In another embodiment, the antibody may have an IC50 value of 50, 10, 9, 8, 7, 6, 5, 4, 3, or 2 times or less the IC50 value of the reference antibody Bv4.115 for the same genotype, when evaluated using the same assay (e.g., the in vitro neutralization assay described herein) for neutralization of HBV genotypes A, B, C and / or D, optionally at least D, optionally A, B, C and D.

[0276] In another embodiment, the antibody may, when evaluated using the same assay (e.g., the assay described herein), have or retain at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the in vivo neutralizing activity of the reference antibody Bv4.115 against HBV genotypes A, B, C, and / or D, optionally at least D, or optionally all of A, B, C, and D.

[0277] Optionally, the antibody can suppress viremia in vivo in individuals infected with, for example, HBV genotype A, B, C, or D, optionally D. Optionally, the antibody may have, or retain, at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the in vivo viremia-suppressing activity of the reference antibody Bv4.115 against HBV genotypes A, B, C, and / or D, optionally at least D, or optionally all of A, B, C, and D, as evaluated using the same assay (e.g., the assay described herein).

[0278] I. In one embodiment, the present invention provides an antibody comprising a VH domain comprising at least one, at least two, or all three VH CDR sequences selected from (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 145, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 146, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 147. In another embodiment, the antibody comprises a VH domain comprising the following CDR(a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 145; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 146; and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 147; or a variant thereof in which one, two, or three amino acids in one or more of CDR-H1, CDR-H2, or CDR-H3 are replaced with other amino acids.

[0279] In one embodiment, the VH domain is (a) the heavy chain framework region 1 (HC-FR1) of SEQ ID NO: 151, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; (b) the heavy chain framework region 2 (HC-FR2) of SEQ ID NO: 152, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; (c) SEQ ID NO: 153 (d) The heavy chain framework region 3 (HC-FR3) of (a) or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and (d) the heavy chain framework region 4 (HC-FR4) of SEQ ID NO: 154 or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. Optionally, the VH domain contains each of the heavy chain framework sequences defined in (a) to (d). Optionally, the sequence identity percentage is 95%. Optionally, the sequence identity percentage is 98%.

[0280] In another embodiment, the anti-S-HBs antibody contains a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 160. In one embodiment, the anti-S-HBs antibody contains a heavy chain variable domain (VH) sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 160. In a particular embodiment, the VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but the anti-S-HBs antibody containing that sequence retains the ability to bind to S-HBs. In a particular embodiment, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 160. In certain embodiments, substitutions, insertions, or deletions occur in the region outside the CDR (i.e., at the FR). Optionally, the anti-S-HBs antibody contains the VH sequence of SEQ ID NO: 160, which includes post-translational modifications of that sequence. In certain embodiments, the VH contains one, two, or three CDRs selected from: (a) CDR-H1 containing the amino acid sequence of SEQ ID NO: 145, (b) CDR-H2 containing the amino acid sequence of SEQ ID NO: 146, and (c) CDR-H3 containing the amino acid sequence of SEQ ID NO: 147.

[0281] In another embodiment, the anti-S-HBs antibody comprises one or more of the VH heavy chain CDR sequences of SEQ ID NO: 160. In one embodiment, the anti-S-HBs antibody comprises one or more (preferably all three) of the VH domain heavy chain CDR amino acid sequences of SEQ ID NO: 160 and a framework of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% sequence identity. Optionally, the sequence identity is 95% or 98%.

[0282] In another embodiment, the present invention provides an antibody comprising a VL domain comprising at least one, at least two, or all three VL CDR sequences selected from (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 148, (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 149, and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 150. In another embodiment, the antibody comprises a VL domain comprising the following CDR(a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 148; (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 149; and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 150; or a variant thereof in which one, two, or three amino acids in one or more of CDR-L1, CDR-L2, or CDR-L3 are replaced with other amino acids.

[0283] In one embodiment, the anti-S-HBs antibody VL domain is (a) a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with respect to the light chain framework region 1 (LC-FR1) of SEQ ID NO: 155, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with respect to the light chain framework region 2 (LC-FR2) of SEQ ID NO: 1561 (LC-FR2) of SEQ ID NO: 155, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with respect to the light chain framework region 1 (LC-FR1) of SEQ ID NO: 155, or a variant having at least 85 (d) The light chain framework region 3 (LC-FR3) of sequence number 157, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and (d) the light chain framework region 4 (LC-FR4) of sequence number 158, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. Optionally, the VL domain contains each of the light chain framework sequences defined in (a) to (d). Optionally, the sequence identity percentage is 95%. The sequence identity percentage is arbitrarily 98%.

[0284] In another embodiment, an anti-S-HBs antibody is provided, comprising a light chain variable domain (VL) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with respect to the amino acid sequence of SEQ ID NO: 159. In one embodiment, the anti-S-HBs antibody comprises a light chain variable domain (VL) sequence having at least 95% sequence identity with respect to the amino acid sequence of SEQ ID NO: 159. In a particular embodiment, the VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but the anti-S-HBs antibody containing that sequence retains the ability to bind to S-HBs. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 159. In certain embodiments, the substitutions, insertions, or deletions occur in the region outside the CDR (i.e., in the FR). Optionally, the anti-S-HBs antibody contains the VL sequence of SEQ ID NO: 159, which includes post-translational modifications of that sequence. In certain embodiments, the VL contains one, two, or three CDRs selected from: (a) CDR-L1 containing the amino acid sequence of SEQ ID NO: 148, (b) CDR-L2 containing the amino acid sequence of SEQ ID NO: 149, and (c) CDR-L3 containing the amino acid sequence of SEQ ID NO: 150.

[0285] In another embodiment, the anti-S-HBs antibody comprises one or more of the VL CDR sequences of SEQ ID NO: 159. In one embodiment, the anti-S-HBs antibody comprises one or more (preferably all three) of the VL domain light chain CDR amino acid sequences of SEQ ID NO: 159 and a framework amino acid sequence of the VL domain of SEQ ID NO: 159 with a sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%. Optionally, the sequence identity is 95% or 98%.

[0286] In another embodiment, an anti-S-HBs antibody is provided, comprising a VH sequence of any of the embodiments provided above and a VL sequence of any of the embodiments provided above.

[0287] For example, in one exemplary embodiment, the antibody comprises a VH domain containing CDR-H3 of SEQ ID NO: 147; and a VL domain containing CDR-L3 of SEQ ID NO: 150. Optionally, the VH domain further comprises CDR-H2 of SEQ ID NO: 146.

[0288] In another exemplary embodiment, the antibody includes: i) VH domains including the following CDR(a) CDR-H1 containing the amino acid sequence of SEQ ID NO: 145; (b) CDR-H2 containing the amino acid sequence of SEQ ID NO: 146; and (c) CDR-H3 containing the amino acid sequence of SEQ ID NO: 147; or variants thereof in which one, two, or three amino acids in one or more of CDR-H1, CDR-H2, or CDR-H3 are replaced by other amino acids; and ii) VL domains including the following CDR(a) CDR-L1 containing the amino acid sequence of SEQ ID NO: 148; (b) CDR-L2 containing the amino acid sequence of SEQ ID NO: 149; and (c) CDR-L3 containing the amino acid sequence of SEQ ID NO: 150; or variants thereof in which one, two, or three amino acids in one or more of CDR-L1, CDR-L2, or CDR-L3 are replaced by other amino acids.

[0289] In another exemplary embodiment, the antibody includes: i) A heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 160; and ii) A light chain variable domain (VL) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acid sequence of sequence number 159.

[0290] In another exemplary embodiment, the anti-S-HBs antibody comprises (a) CDR-H1 containing the amino acid sequence of SEQ ID NO: 145; (b) CDR-H2 containing the amino acid sequence of SEQ ID NO: 146; (c) CDR-H3 containing the amino acid sequence of SEQ ID NO: 147; (d) CDR-L1 containing the amino acid sequence of SEQ ID NO: 148; (e) CDR-L2 containing the amino acid sequence of SEQ ID NO: 149; and (f) CDR-L3 containing the amino acid sequence of SEQ ID NO: 150, as well as a VH domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with respect to the amino acid sequence of SEQ ID NO: 160, and a VL domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with respect to the amino acid sequence of SEQ ID NO: 159. In one embodiment, the VH domain has at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 160. In another embodiment, the VL domain has at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 159. In one embodiment, the antibody specifically binds to S-HBs. In another embodiment, the antibody binds to S-HBs having a dissociation constant (KD) that is up to 10 times lower or up to 10 times higher than the dissociation constant (KD) of an antibody containing the VH sequence of SEQ ID NO: 160 and the VL sequence of SEQ ID NO: 159.

[0291] In one embodiment, the antibody comprises the VH and VL sequences of SEQ ID NO: 160 and SEQ ID NO: 159, respectively, including post-translational modifications of those sequences.

[0292] In a further embodiment, the antibody may comprise the full-length light chain of SEQ ID NO: 161 and / or the full-length heavy chain of SEQ ID NO: 162 or 271.

[0293] In further embodiments, the present invention provides antibodies that bind to the same epitopes as the anti-S-HBs antibodies provided herein. For example, in certain embodiments, antibodies that bind to the same epitopes as an anti-S-HBs antibody comprising the VH sequence of SEQ ID NO: 160 and the VL sequence of SEQ ID NO: 159 are provided. In certain embodiments, antibodies that bind to one or more of the following residues of S-HBs in SEQ ID NO: 253: C121, K141, D144, and / or G145 are provided. Optionally, the antibody may further bind to one or more of C139, C147, C149, I152, and / or W156. The antibody may contain any of the sequences defined above.

[0294] In a further embodiment, the present invention provides antibodies that compete with the anti-S-HBs antibodies provided herein for binding to S-HBs.

[0295] In some embodiments, the antibodies described in this section may have, or retain, at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the binding activity of the reference antibody Bc1.229 against S-HBs (e.g., SEQ ID NO: 253) when evaluated by the same assay, e.g., ELISA or flow cytometry assay.

[0296] In addition to or instead of the above, the antibodies described in this section may, when evaluated by the same assay, e.g., ELISA or flow cytometry assay, have or retain at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the binding activity of the reference antibody Bc1.229 to each of the proteins of SEQ ID NOs. 254–262, optionally, to one or more of the proteins of SEQ ID NOs. 254–262.

[0297] The reference antibody Bc1.229 has the VH sequence of SEQ ID NO: 160 and the VL sequence of SEQ ID NO: 159. It has the full-length heavy chain of SEQ ID NO: 162 or 271 and the full-length light chain of SEQ ID NO: 161. SEQ ID NO: 271 contains the IgG1 constant region expressed by vector LT615368.1, as used in the examples.

[0298] In some embodiments, the antibodies described in this section are evaluated in the same assay as the reference antibody Bc1.229 against the same antigen. D K is 50, 10, 9, 8, 7, 6, 5, 4, 3 or less than or equal to 2 times the value, or less than or equal to that value. D It can bind to S-HBs by value (for example, sequence number 253).

[0299] In addition to this, or instead, the antibody is evaluated in the same assay as the reference antibody Bc1.229 against the same antigen. D K is 50, 10, 9, 8, 7, 6, 5, 4, 3 or less than or equal to 2 times the value, or less than or equal to that value. D The value may bind to one or more of the sequences 254-262 (e.g., at least sequence 257), or optionally to each of the proteins in sequences 254-262.

[0300] In some embodiments, the antibodies described in this section may bind to S-HBs (e.g., SEQ ID NO: 253) at an EC50 of 50, 10, 9, 8, 7, 6, 5, 4, 3, or 2 times or less the EC50 of reference antibody Bc1.229, as measured by ELISA or flow cytometry. Alternatively, or in addition to the above, the antibodies may bind to one or more of the proteins SEQ ID NOs: 254-262, or each of them, and optionally to at least the protein SEQ ID NO: 257, at an EC50 of 50, 10, 9, 8, 7, 6, 5, 4, 3, or 2 times or less the EC50 of reference antibody Bc1.229, as measured by ELISA or flow cytometry.

[0301] In some embodiments, the antibodies described in this section may have or retain in vitro neutralizing activity against HBV genotypes A, B, C, and / or D, or optionally all of A, B, C, and D. For example, the antibodies described in this section may have or retain in vitro neutralizing activity against HBV genotype D, and for example, the IC50 value may be ≤1 ng / ml, optionally ≤100 pg / ml.

[0302] In another embodiment, the antibody is evaluated using the same assay (e.g., the in vitro neutralization assay described herein) for neutralization of HBV genotypes A, B, C and / or D, optionally at least D, and optionally all of A, B, C and D, to obtain the IC of the reference antibody Bc1.229 against the same genotype. 50 IC values ​​that are 50, 10, 9, 8, 7, 6, 5, 4, 3 or less than or twice the value, or less than or equal to that value. 50 It may have a value.

[0303] In another embodiment, the antibody may, when evaluated using the same assay (e.g., the assay described herein), have or retain at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the in vivo neutralizing activity of the reference antibody Bc1.229 against HBV genotypes A, B, C, and / or D, optionally at least D, or optionally all of A, B, C, and D.

[0304] Optionally, the antibody can suppress viremia in vivo in individuals infected with, for example, HBV genotype A, B, C, or D, optionally D. Optionally, the antibody may have, or retain, at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the in vivo viremia-suppressing activity of the reference antibody Bc1.229 against HBV genotypes A, B, C, and / or D, optionally at least D, or optionally all of A, B, C, and D, as evaluated using the same assay (e.g., the assay described herein).

[0305] J. In one embodiment, the present invention provides an antibody comprising a VH domain comprising at least one, at least two, or all three VH CDR sequences selected from (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 163, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 164, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 165. In another embodiment, the antibody comprises a VH domain comprising the following CDR(a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 163; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 164; and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 165; or a variant thereof in which one, two, or three amino acids in one or more of CDR-H1, CDR-H2, or CDR-H3 are replaced with other amino acids.

[0306] In one embodiment, the VH domain is (a) the heavy chain framework region 1 (HC-FR1) of SEQ ID NO: 169, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; (b) the heavy chain framework region 2 (HC-FR2) of SEQ ID NO: 170, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; (c) SEQ ID NO: 171 (d) The heavy chain framework region 3 (HC-FR3) of (a) or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and (d) the heavy chain framework region 4 (HC-FR4) of SEQ ID NO: 172 or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. Optionally, the VH domain contains each of the heavy chain framework sequences defined in (a) to (d). Optionally, the sequence identity percentage is 95%. Optionally, the sequence identity percentage is 98%.

[0307] In another embodiment, the anti-S-HBs antibody contains a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 178. In one embodiment, the anti-S-HBs antibody contains a heavy chain variable domain (VH) sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 178. In a particular embodiment, the VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but the anti-S-HBs antibody containing that sequence retains the ability to bind to S-HBs. In a particular embodiment, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 178. In certain embodiments, substitutions, insertions, or deletions occur in the region outside the CDR (i.e., at the FR). Optionally, the anti-S-HBs antibody contains the VH sequence of SEQ ID NO: 178, which includes post-translational modifications of that sequence. In certain embodiments, the VH contains one, two, or three CDRs selected from: (a) CDR-H1 containing the amino acid sequence of SEQ ID NO: 163, (b) CDR-H2 containing the amino acid sequence of SEQ ID NO: 164, and (c) CDR-H3 containing the amino acid sequence of SEQ ID NO: 165.

[0308] In another embodiment, the anti-S-HBs antibody comprises one or more of the VH heavy chain CDR sequences of SEQ ID NO: 178. In one embodiment, the anti-S-HBs antibody comprises one or more (preferably all three) of the VH domain heavy chain CDR amino acid sequences of SEQ ID NO: 178, and a framework of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% sequence identity. Optionally, the sequence identity is 95% or 98%.

[0309] In another embodiment, the present invention provides an antibody comprising a VL domain comprising at least one, at least two, or all three VL CDR sequences selected from (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 166, (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 167, and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 168. In another embodiment, the antibody comprises a VL domain comprising the following CDR(a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 168; or a variant thereof in which one, two, or three amino acids in one or more of CDR-L1, CDR-L2, or CDR-L3 are replaced with other amino acids.

[0310] In one embodiment, the anti-S-HBs antibody VL domain is (a) a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with respect to the light chain framework region 1 (LC-FR1) of SEQ ID NO: 173, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with respect to the light chain framework region 2 (LC-FR2) of SEQ ID NO: 1741 (LC-FR2) of SEQ ID NO: 174, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with respect to the light chain framework region 1 (LC-FR1) of SEQ ID NO: 174, or a variant having at least 85 (d) The light chain framework region 3 (LC-FR3) of sequence number 175, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and (d) the light chain framework region 4 (LC-FR4) of sequence number 176, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. Optionally, the VL domain contains each of the light chain framework sequences defined in (a) to (d). Optionally, the sequence identity percentage is 95%. The sequence identity percentage is arbitrarily 98%.

[0311] In another embodiment, an anti-S-HBs antibody is provided, comprising a light chain variable domain (VL) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with respect to the amino acid sequence of SEQ ID NO: 177. In one embodiment, the anti-S-HBs antibody comprises a light chain variable domain (VL) sequence having at least 95% sequence identity with respect to the amino acid sequence of SEQ ID NO: 177. In a particular embodiment, the VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but the anti-S-HBs antibody containing that sequence retains the ability to bind to S-HBs. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 177. In certain embodiments, the substitutions, insertions, or deletions occur in the region outside the CDR (i.e., in the FR). Optionally, the anti-S-HBs antibody contains the VL sequence of SEQ ID NO: 177, which includes post-translational modifications of that sequence. In certain embodiments, the VL contains one, two, or three CDRs selected from: (a) CDR-L1 containing the amino acid sequence of SEQ ID NO: 166, (b) CDR-L2 containing the amino acid sequence of SEQ ID NO: 167, and (c) CDR-L3 containing the amino acid sequence of SEQ ID NO: 168.

[0312] In another embodiment, the anti-S-HBs antibody comprises one or more of the VL CDR sequences of SEQ ID NO: 177. In one embodiment, the anti-S-HBs antibody comprises one or more (preferably all three) of the VL domain light chain CDR amino acid sequences of SEQ ID NO: 177, and a framework of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% sequence identity. Optionally, the sequence identity is 95% or 98%.

[0313] In another embodiment, an anti-S-HBs antibody is provided, comprising a VH sequence of any of the embodiments provided above and a VL sequence of any of the embodiments provided above.

[0314] For example, in one exemplary embodiment, the antibody comprises a VH domain containing CDR-H3 of SEQ ID NO: 165; and a VL domain containing CDR-L3 of SEQ ID NO: 168. Optionally, the VH domain further comprises CDR-H2 of SEQ ID NO: 164.

[0315] In another exemplary embodiment, the antibody includes: i) VH domains including the following CDR(a) CDR-H1 containing the amino acid sequence of SEQ ID NO: 163; (b) CDR-H2 containing the amino acid sequence of SEQ ID NO: 164; and (c) CDR-H3 containing the amino acid sequence of SEQ ID NO: 165; or variants thereof in which one, two, or three amino acids in one or more of CDR-H1, CDR-H2, or CDR-H3 are replaced by other amino acids; and ii) VL domains including the following CDR(a) CDR-L1 containing the amino acid sequence of SEQ ID NO: 166; (b) CDR-L2 containing the amino acid sequence of SEQ ID NO: 167; and (c) CDR-L3 containing the amino acid sequence of SEQ ID NO: 168; or variants thereof in which one, two, or three amino acids in one or more of CDR-L1, CDR-L2, or CDR-L3 are replaced by other amino acids.

[0316] In another exemplary embodiment, the antibody includes: i) A heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 178; and ii) A light chain variable domain (VL) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acid sequence of Sequence ID No. 177.

[0317] In another exemplary embodiment, the anti-S-HBs antibody comprises (a) CDR-H1 containing the amino acid sequence of SEQ ID NO: 163; (b) CDR-H2 containing the amino acid sequence of SEQ ID NO: 164; (c) CDR-H3 containing the amino acid sequence of SEQ ID NO: 165; (d) CDR-L1 containing the amino acid sequence of SEQ ID NO: 166; (e) CDR-L2 containing the amino acid sequence of SEQ ID NO: 167; and (f) CDR-L3 containing the amino acid sequence of SEQ ID NO: 168, as well as a VH domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with respect to the amino acid sequence of SEQ ID NO: 178, and a VL domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with respect to the amino acid sequence of SEQ ID NO: 177. In one embodiment, the VH domain has at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 178. In another embodiment, the VL domain has at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 177. In one embodiment, the antibody specifically binds to S-HBs. In another embodiment, the antibody binds to S-HBs having a dissociation constant (KD) that is up to 10 times lower or up to 10 times higher than the dissociation constant (KD) of an antibody containing the VH sequence of SEQ ID NO: 178 and the VL sequence of SEQ ID NO: 177.

[0318] In one embodiment, the antibody comprises the VH and VL sequences of SEQ ID NO: 178 and SEQ ID NO: 177, respectively, including post-translational modifications of those sequences.

[0319] In a further embodiment, the antibody may comprise the full-length light chain of SEQ ID NO: 179 and / or the full-length heavy chain of SEQ ID NO: 180 or 272.

[0320] In further embodiments, the present invention provides antibodies that bind to the same epitopes as the anti-S-HBs antibodies provided herein. For example, in certain embodiments, antibodies that bind to the same epitopes as an anti-S-HBs antibody comprising the VH sequence of SEQ ID NO: 178 and the VL sequence of SEQ ID NO: 177 are provided. In certain embodiments, antibodies that bind to the following residues of S-HBs of SEQ ID NO: 253 are provided: C121, C138, C139, C147 and / or C149. Optionally, the antibody may further bind to one or more of L109, R122, T123, C124, M133, Y134, S136, K141 and / or I152. The antibody may contain any of the sequences defined above.

[0321] In a further embodiment, the present invention provides antibodies that compete with the anti-S-HBs antibodies provided herein for binding to S-HBs.

[0322] In some embodiments, the antibodies described in this section may have, or retain, at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the binding activity of the reference antibody Bc8.159 against S-HBs (e.g., SEQ ID NO: 253) when evaluated by the same assay, e.g., an ELISA assay or a flow cytometry assay.

[0323] In addition to or instead of the above, the antibodies described in this section may, when evaluated by the same assay, e.g., ELISA assay or flow cytometry assay, have or retain at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the binding activity of the reference antibody Bc8.159 to each of the proteins of SEQ ID NOs. 254–262, optionally, to one or more of the proteins of SEQ ID NOs. 254–262.

[0324] The reference antibody Bc8.159 has the VH sequence of SEQ ID NO: 178 and the VL sequence of SEQ ID NO: 177. It has the full-length heavy chain of SEQ ID NO: 180 or 272 and the full-length light chain of SEQ ID NO: 179. SEQ ID NO: 272 contains the IgG1 constant region expressed by vector LT615368.1, as used in the examples.

[0325] In some embodiments, the antibodies described in this section are evaluated in the same assay as the reference antibody Bc8.159 against the same antigen. D K is 50, 10, 9, 8, 7, 6, 5, 4, 3 or less than or equal to 2 times the value, or less than or equal to that value. D It can bind to S-HBs by value (for example, sequence number 253).

[0326] In addition to this, or instead, the antibody is evaluated in the same assay as the reference antibody Bc8.159 against the same antigen. D K is 50, 10, 9, 8, 7, 6, 5, 4, 3 or less than or equal to 2 times the value, or less than or equal to that value. D The value may bind to one or more of the sequences 254-262 (e.g., at least sequence 257), or optionally to each of the proteins in sequences 254-262.

[0327] In some embodiments, the antibodies described in this section may bind to S-HBs (e.g., SEQ ID NO: 253) at an EC50 of 50, 10, 9, 8, 7, 6, 5, 4, 3, or 2 times or less the EC50 of reference antibody Bc8.159, as measured by ELISA or flow cytometry. Alternatively, or in addition to the above, the antibodies may bind to one or more of the proteins SEQ ID NOs: 254-262, or each of them, optionally to at least the protein SEQ ID NO: 257, at an EC50 of 50, 10, 9, 8, 7, 6, 5, 4, 3, or 2 times or less the EC50 of reference antibody Bc8.159, as measured by ELISA or flow cytometry.

[0328] In some embodiments, the antibodies described in this section may have or retain in vitro neutralizing activity against HBV genotypes A, B, C, and / or D, or optionally all of A, B, C, and D. For example, the antibodies described in this section may have or retain in vitro neutralizing activity against HBV genotype D, for example, an IC50 value of ≤1 ng / ml, optionally ≤100 pg / ml.

[0329] In another embodiment, the antibody may have an IC50 value of 50, 10, 9, 8, 7, 6, 5, 4, 3, or 2 times or less the IC50 value of the reference antibody Bc8.159 for the same genotype, when evaluated using the same assay (e.g., the in vitro neutralization assay described herein) for neutralization of HBV genotypes A, B, C and / or D, optionally at least D, optionally A, B, C and D.

[0330] In another embodiment, the antibody may, when evaluated using the same assay (e.g., the assay described herein), have or retain at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the in vivo neutralizing activity of the reference antibody Bc8.159 against HBV genotypes A, B, C, and / or D, optionally at least D, or optionally all of A, B, C, and D.

[0331] Optionally, the antibody can suppress viremia in vivo in individuals infected with, for example, HBV genotype A, B, C, or D, optionally D. Optionally, the antibody may have, or retain, at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the in vivo viremia-suppressing activity of the reference antibody Bc8.159 against HBV genotypes A, B, C, and / or D, optionally at least D, or optionally all of A, B, C, and D, as evaluated using the same assay (e.g., the assay described herein).

[0332] K. In one embodiment, the present invention provides an antibody comprising a VH domain comprising at least one, at least two, or all three VH CDR sequences selected from (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 181, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 182, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 183. In another embodiment, the antibody comprises a VH domain comprising the following CDR(a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 181; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 182; and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 183; or a variant thereof in which one, two, or three amino acids in one or more of CDR-H1, CDR-H2, or CDR-H3 are replaced with other amino acids.

[0333] In one embodiment, the VH domain is (a) the heavy chain framework region 1 (HC-FR1) of SEQ ID NO: 187, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; (b) the heavy chain framework region 2 (HC-FR2) of SEQ ID NO: 188, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; (c) SEQ ID NO: 189 (d) The heavy chain framework region 3 (HC-FR3) of (a) or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and (d) the heavy chain framework region 4 (HC-FR4) of SEQ ID NO: 190 or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. Optionally, the VH domain contains each of the heavy chain framework sequences defined in (a) to (d). Optionally, the sequence identity percentage is 95%. Optionally, the sequence identity percentage is 98%.

[0334] In another embodiment, the anti-S-HBs antibody contains a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 196. In one embodiment, the anti-S-HBs antibody contains a heavy chain variable domain (VH) sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 196. In a particular embodiment, the VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but the anti-S-HBs antibody containing that sequence retains the ability to bind to S-HBs. In a particular embodiment, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 196. In certain embodiments, substitutions, insertions, or deletions occur in the region outside the CDR (i.e., at the FR). Optionally, the anti-S-HBs antibody contains the VH sequence of SEQ ID NO: 196, which includes post-translational modifications of that sequence. In certain embodiments, the VH contains one, two, or three CDRs selected from: (a) CDR-H1 containing the amino acid sequence of SEQ ID NO: 181, (b) CDR-H2 containing the amino acid sequence of SEQ ID NO: 182, and (c) CDR-H3 containing the amino acid sequence of SEQ ID NO: 183.

[0335] In another embodiment, the anti-S-HBs antibody comprises one or more of the VH heavy chain CDR sequences of SEQ ID NO: 196. In one embodiment, the anti-S-HBs antibody comprises one or more (preferably all three) of the VH domain heavy chain CDR amino acid sequences of SEQ ID NO: 196, and a framework of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% sequence identity. Optionally, the sequence identity is 95% or 98%.

[0336] In another embodiment, the present invention provides an antibody comprising a VL domain comprising at least one, at least two, or all three VL CDR sequences selected from (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 184, (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 185, and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 186. In another embodiment, the antibody comprises a VL domain comprising the following CDR(a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 184; (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 185; and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 186; or a variant thereof in which one, two, or three amino acids in one or more of CDR-L1, CDR-L2, or CDR-L3 are replaced with other amino acids.

[0337] In one embodiment, the anti-S-HBs antibody VL domain is (a) a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with respect to the light chain framework region 1 (LC-FR1) of SEQ ID NO: 191, or at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with respect to the light chain framework region 2 (LC-FR2) of SEQ ID NO: 192, or a variant having1 (LC-FR2) of SEQ ID NO: 192, or at least 85%, 86%, 87%, 88%, 89%, 90%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with respect to the light chain framework region 1 (LC-FR1) of SEQ ID NO: 192, or at least 85%, 86%, 87%, (d) The light chain framework region 3 (LC-FR3) of sequence number 193, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and (d) the light chain framework region 4 (LC-FR4) of sequence number 194, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. Optionally, the VL domain contains each of the light chain framework sequences defined in (a) to (d). Optionally, the sequence identity percentage is 95%. The sequence identity percentage is arbitrarily 98%.

[0338] In another embodiment, an anti-S-HBs antibody is provided, comprising a light chain variable domain (VL) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with respect to the amino acid sequence of SEQ ID NO: 195. In one embodiment, the anti-S-HBs antibody comprises a light chain variable domain (VL) sequence having at least 95% sequence identity with respect to the amino acid sequence of SEQ ID NO: 195. In a particular embodiment, the VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but the anti-S-HBs antibody containing that sequence retains the ability to bind to S-HBs. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 195. In certain embodiments, the substitutions, insertions, or deletions occur in the region outside the CDR (i.e., in the FR). Optionally, the anti-S-HBs antibody contains the VL sequence of SEQ ID NO: 195, which includes post-translational modifications of that sequence. In certain embodiments, the VL contains one, two, or three CDRs selected from: (a) CDR-L1 containing the amino acid sequence of SEQ ID NO: 184, (b) CDR-L2 containing the amino acid sequence of SEQ ID NO: 185, and (c) CDR-L3 containing the amino acid sequence of SEQ ID NO: 186.

[0339] In another embodiment, the anti-S-HBs antibody comprises one or more of the VL CDR sequences of SEQ ID NO: 195. In one embodiment, the anti-S-HBs antibody comprises one or more (preferably all three) of the VL domain light chain CDR amino acid sequences of SEQ ID NO: 195, and a framework of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% sequence identity. Optionally, the sequence identity is 95% or 98%.

[0340] In another embodiment, an anti-S-HBs antibody is provided, comprising a VH sequence of any of the embodiments provided above and a VL sequence of any of the embodiments provided above.

[0341] For example, in one exemplary embodiment, the antibody comprises a VH domain containing CDR-H3 of SEQ ID NO: 183; and a VL domain containing CDR-L3 of SEQ ID NO: 186. Optionally, the VH domain further comprises CDR-H2 of SEQ ID NO: 182.

[0342] In another exemplary embodiment, the antibody includes: i) VH domains including the following CDR(a) CDR-H1 containing the amino acid sequence of SEQ ID NO: 181; (b) CDR-H2 containing the amino acid sequence of SEQ ID NO: 182; and (c) CDR-H3 containing the amino acid sequence of SEQ ID NO: 183; or variants thereof in which one, two, or three amino acids in one or more of CDR-H1, CDR-H2, or CDR-H3 are replaced by other amino acids; and ii) VL domains including the following CDR(a) CDR-L1 containing the amino acid sequence of SEQ ID NO: 184; (b) CDR-L2 containing the amino acid sequence of SEQ ID NO: 185; and (c) CDR-L3 containing the amino acid sequence of SEQ ID NO: 186; or variants thereof in which one, two, or three amino acids in one or more of CDR-L1, CDR-L2, or CDR-L3 are replaced by other amino acids.

[0343] In another exemplary embodiment, the antibody includes: i) A heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 196; and ii) A light chain variable domain (VL) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 195.

[0344] In another exemplary embodiment, the anti-S-HBs antibody comprises (a) CDR-H1 containing the amino acid sequence of SEQ ID NO: 181; (b) CDR-H2 containing the amino acid sequence of SEQ ID NO: 182; (c) CDR-H3 containing the amino acid sequence of SEQ ID NO: 183; (d) CDR-L1 containing the amino acid sequence of SEQ ID NO: 184; (e) CDR-L2 containing the amino acid sequence of SEQ ID NO: 185; and (f) CDR-L3 containing the amino acid sequence of SEQ ID NO: 186, as well as a VH domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with respect to the amino acid sequence of SEQ ID NO: 196, and a VL domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with respect to the amino acid sequence of SEQ ID NO: 195. In one embodiment, the VH domain has at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 196. In another embodiment, the VL domain has at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 195. In one embodiment, the antibody specifically binds to S-HBs. In another embodiment, the antibody binds to S-HBs having a dissociation constant (KD) that is up to 10 times lower or up to 10 times higher than the dissociation constant (KD) of an antibody containing the VH sequence of SEQ ID NO: 196 and the VL sequence of SEQ ID NO: 195.

[0345] In one embodiment, the antibody comprises the VH and VL sequences of SEQ ID NO: 196 and SEQ ID NO: 195, respectively, including post-translational modifications of those sequences.

[0346] In a further embodiment, the antibody may comprise the full-length light chain of SEQ ID NO: 197 and / or the full-length heavy chain of SEQ ID NO: 198 or 273.

[0347] In further embodiments, the present invention provides antibodies that bind to the same epitopes as the anti-S-HBs antibodies provided herein. For example, in certain embodiments, an antibody is provided that binds to the same epitopes as an anti-S-HBs antibody comprising the VH sequence of SEQ ID NO: 196 and the VL sequence of SEQ ID NO: 195. In certain embodiments, the following residues of S-HBs in SEQ ID NO: 253: C121, C124, C137, C138, C139, C147 and / or C149, optionally also including I152. Optionally, the antibody further binds to one or more of V106, P108, W156 and / or F161. The antibody may contain any of the sequences defined above.

[0348] In a further embodiment, the present invention provides antibodies that compete with the anti-S-HBs antibodies provided herein for binding to S-HBs.

[0349] In some embodiments, the antibodies described in this section may have, or retain, at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the binding activity of the reference antibody Bc1.128 against S-HBs (e.g., SEQ ID NO: 253) when evaluated by the same assay, e.g., an ELISA assay or a flow cytometry assay.

[0350] In addition to or instead of the above, the antibodies described in this section may, when evaluated by the same assay, e.g., ELISA assay or flow cytometry assay, have or retain at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the binding activity of the reference antibody Bc1.128 to each of the proteins of SEQ ID NOs. 254–262, optionally, to one or more of the proteins of SEQ ID NOs. 254–262 (e.g., at least SEQ ID NOs. 257).

[0351] The reference antibody Bc1.128 has the VH sequence of SEQ ID NO: 196 and the VL sequence of SEQ ID NO: 195. It has the full-length heavy chain of SEQ ID NO: 198 or 273 and the full-length light chain of SEQ ID NO: 197. SEQ ID NO: 273 contains the IgG1 constant region expressed by vector LT615368.1, as used in the examples.

[0352] In some embodiments, the antibodies described in this section are evaluated in the same assay as the reference antibody Bc1.128 against the same antigen. D K is 50, 10, 9, 8, 7, 6, 5, 4, 3 or less than or equal to 2 times the value, or less than or equal to that value. D It can bind to S-HBs by value (for example, sequence number 253).

[0353] In addition to this, or instead, the antibody is evaluated in the same assay as the reference antibody Bc1.128 against the same antigen. D K is 50, 10, 9, 8, 7, 6, 5, 4, 3 or less than or equal to 2 times the value, or less than or equal to that value. D The value may bind to one or more of the sequences 254-262 (e.g., at least sequence 257), or optionally to each of the proteins in sequences 254-262.

[0354] In some embodiments, the antibodies described in this section may bind to S-HBs (e.g., SEQ ID NO: 253) at an EC50 of 50, 10, 9, 8, 7, 6, 5, 4, 3, or 2 times or less the EC50 of reference antibody Bc1.128, as measured by ELISA or flow cytometry. Alternatively, or in addition to the above, the antibodies may bind to one or more of the proteins SEQ ID NOs: 254-262, or each of them, optionally to at least the protein SEQ ID NO: 257, at an EC50 of 50, 10, 9, 8, 7, 6, 5, 4, 3, or 2 times or less the EC50 of reference antibody Bc1.128, as measured by ELISA or flow cytometry.

[0355] In some embodiments, the antibodies described in this section may have or retain in vitro neutralizing activity against HBV genotypes A, B, C, and / or D, or optionally all of A, B, C, and D. For example, the antibodies described in this section may have or retain in vitro neutralizing activity against HBV genotype D, and for example, the IC50 value may be ≤10 ng / ml, or optionally ≤1 ng / ml.

[0356] In another embodiment, the antibody is evaluated using the same assay (e.g., the in vitro neutralization assay described herein) for neutralization of HBV genotypes A, B, C and / or D, optionally at least D, and optionally all of A, B, C and D, to obtain the IC of the reference antibody Bc1.128 against the same genotype. 50 IC values ​​that are 50, 10, 9, 8, 7, 6, 5, 4, 3 or less than or twice the value, or less than or equal to that value. 50 It may have a value.

[0357] In another embodiment, the antibody may, when evaluated using the same assay (e.g., the assay described herein), have or retain at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the in vivo neutralizing activity of the reference antibody Bc1.128 against HBV genotypes A, B, C, and / or D, optionally at least D, or optionally all of A, B, C, and D.

[0358] Optionally, the antibody can suppress viremia in vivo in individuals infected with, for example, HBV genotype A, B, C, or D, optionally D. Optionally, the antibody may have, or retain, at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the in vivo viremia-suppressing activity of the reference antibody Bc1.128 against HBV genotypes A, B, C, and / or D, optionally at least D, or optionally all of A, B, C, and D, as evaluated using the same assay (e.g., the assay described herein).

[0359] L. In one embodiment, the present invention provides an antibody comprising a VH domain comprising at least one, at least two, or all three VH CDR sequences selected from (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 199, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 200, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 201. In another embodiment, the antibody comprises a VH domain comprising the following CDR(a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 199; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 200; and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 201; or a variant thereof in which one, two, or three amino acids in one or more of CDR-H1, CDR-H2, or CDR-H3 are replaced with other amino acids.

[0360] In one embodiment, the VH domain is (a) the heavy chain framework region 1 (HC-FR1) of SEQ ID NO: 205, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; (b) the heavy chain framework region 2 (HC-FR2) of SEQ ID NO: 206, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; (c) SEQ ID NO: 207 (d) The heavy chain framework region 3 (HC-FR3) of (a) or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and (d) the heavy chain framework region 4 (HC-FR4) of SEQ ID NO: 208 or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. Optionally, the VH domain contains each of the heavy chain framework sequences defined in (a) to (d). Optionally, the sequence identity percentage is 95%. Optionally, the sequence identity percentage is 98%.

[0361] In another embodiment, the anti-S-HBs antibody contains a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 214. In one embodiment, the anti-S-HBs antibody contains a heavy chain variable domain (VH) sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 214. In a particular embodiment, the VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but the anti-S-HBs antibody containing that sequence retains the ability to bind to S-HBs. In a particular embodiment, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 214. In certain embodiments, substitutions, insertions, or deletions occur in the region outside the CDR (i.e., at the FR). Optionally, the anti-S-HBs antibody contains the VH sequence of SEQ ID NO: 214, which includes post-translational modifications of that sequence. In certain embodiments, the VH contains one, two, or three CDRs selected from: (a) CDR-H1 containing the amino acid sequence of SEQ ID NO: 199, (b) CDR-H2 containing the amino acid sequence of SEQ ID NO: 200, and (c) CDR-H3 containing the amino acid sequence of SEQ ID NO: 201.

[0362] In another embodiment, the anti-S-HBs antibody comprises one or more of the VH heavy chain CDR sequences of SEQ ID NO: 214. In one embodiment, the anti-S-HBs antibody comprises one or more (preferably all three) of the VH domain heavy chain CDR amino acid sequences of SEQ ID NO: 214 and a framework of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% sequence identity. Optionally, the sequence identity is 95% or 98%.

[0363] In another embodiment, the present invention provides an antibody comprising a VL domain comprising at least one, at least two, or all three VL CDR sequences selected from (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 202, (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 203, and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 204. In another embodiment, the antibody comprises a VL domain comprising the following CDR(a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 202; (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 203; and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 204; or a variant thereof in which one, two, or three amino acids in one or more of CDR-L1, CDR-L2, or CDR-L3 are replaced with other amino acids.

[0364] In one embodiment, the anti-S-HBs antibody VL domain is (a) a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with respect to the light chain framework region 1 (LC-FR1) of SEQ ID NO: 209, or at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with respect to the light chain framework region 2 (LC-FR2) of SEQ ID NO: 210, or a variant having1 (LC-FR1) of SEQ ID NO: 210, or at least 85%, 86%, 87%, 88%, 89%, 90%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with respect to the light chain framework region 1 (LC-FR1) of SEQ ID NO: 210, or at least 85%, 86%, 87%, (d) The light chain framework region 3 (LC-FR3) of sequence number 211, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and (d) the light chain framework region 4 (LC-FR4) of sequence number 212, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. Optionally, the VL domain contains each of the light chain framework sequences defined in (a) to (d). Optionally, the sequence identity percentage is 95%. The sequence identity percentage is arbitrarily 98%.

[0365] In another embodiment, an anti-S-HBs antibody is provided, comprising a light chain variable domain (VL) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with respect to the amino acid sequence of SEQ ID NO: 213. In one embodiment, the anti-S-HBs antibody comprises a light chain variable domain (VL) sequence having at least 95% sequence identity with respect to the amino acid sequence of SEQ ID NO: 213. In a particular embodiment, the VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but the anti-S-HBs antibody containing that sequence retains the ability to bind to S-HBs. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 213. In certain embodiments, the substitutions, insertions, or deletions occur in the region outside the CDR (i.e., in the FR). Optionally, the anti-S-HBs antibody contains the VL sequence of SEQ ID NO: 213, which includes post-translational modifications of that sequence. In certain embodiments, the VL contains one, two, or three CDRs selected from: (a) CDR-L1 containing the amino acid sequence of SEQ ID NO: 202, (b) CDR-L2 containing the amino acid sequence of SEQ ID NO: 203, and (c) CDR-L3 containing the amino acid sequence of SEQ ID NO: 204.

[0366] In another embodiment, the anti-S-HBs antibody comprises one or more of the VL CDR sequences of SEQ ID NO: 213. In one embodiment, the anti-S-HBs antibody comprises one or more (preferably all three) of the VL domain light chain CDR amino acid sequences of SEQ ID NO: 213 and a framework amino acid sequence of the VL domain of SEQ ID NO: 213 with at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% sequence identity. Optionally, the sequence identity is 95% or 98%.

[0367] In another embodiment, an anti-S-HBs antibody is provided, comprising a VH sequence of any of the embodiments provided above and a VL sequence of any of the embodiments provided above.

[0368] For example, in one exemplary embodiment, the antibody comprises a VH domain containing CDR-H3 of SEQ ID NO: 201; and a VL domain containing CDR-L3 of SEQ ID NO: 204. Optionally, the VH domain further comprises CDR-H2 of SEQ ID NO: 200.

[0369] In another exemplary embodiment, the antibody includes: i) VH domains including the following CDR(a) CDR-H1 containing the amino acid sequence of SEQ ID NO: 199; (b) CDR-H2 containing the amino acid sequence of SEQ ID NO: 200; and (c) CDR-H3 containing the amino acid sequence of SEQ ID NO: 201; or variants thereof in which one, two, or three amino acids in one or more of CDR-H1, CDR-H2, or CDR-H3 are replaced by other amino acids; and ii) VL domains including the following CDR(a) CDR-L1 containing the amino acid sequence of SEQ ID NO: 202; (b) CDR-L2 containing the amino acid sequence of SEQ ID NO: 203; and (c) CDR-L3 containing the amino acid sequence of SEQ ID NO: 204; or variants thereof in which one, two, or three amino acids in one or more of CDR-L1, CDR-L2, or CDR-L3 are replaced by other amino acids.

[0370] In another exemplary embodiment, the antibody includes: i) A heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 214; and ii) A light chain variable domain (VL) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acid sequence of Sequence ID No. 213.

[0371] In another exemplary embodiment, the anti-S-HBs antibody comprises (a) CDR-H1 containing the amino acid sequence of SEQ ID NO: 199; (b) CDR-H2 containing the amino acid sequence of SEQ ID NO: 200; (c) CDR-H3 containing the amino acid sequence of SEQ ID NO: 201; (d) CDR-L1 containing the amino acid sequence of SEQ ID NO: 202; (e) CDR-L2 containing the amino acid sequence of SEQ ID NO: 203; and (f) CDR-L3 containing the amino acid sequence of SEQ ID NO: 204, as well as a VH domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with respect to the amino acid sequence of SEQ ID NO: 214, and a VL domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with respect to the amino acid sequence of SEQ ID NO: 213. In one embodiment, the VH domain has at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 214. In another embodiment, the VL domain has at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 213. In one embodiment, the antibody specifically binds to S-HBs. In another embodiment, the antibody binds to S-HBs having a dissociation constant (KD) that is up to 10 times less or up to 10 times more than the dissociation constant (KD) of an antibody containing the VH sequence of SEQ ID NO: 214 and the VL sequence of SEQ ID NO: 213.

[0372] In one embodiment, the antibody comprises the VH and VL sequences of SEQ ID NO: 214 and SEQ ID NO: 213, respectively, including post-translational modifications of those sequences.

[0373] In a further embodiment, the antibody may comprise the full-length light chain of SEQ ID NO: 215 and / or the full-length heavy chain of SEQ ID NO: 216 or 274.

[0374] In further embodiments, the present invention provides antibodies that bind to the same epitopes as the anti-S-HBs antibodies provided herein. For example, in certain embodiments, an antibody is provided that binds to the same epitope as an anti-S-HBs antibody comprising the VH sequence of SEQ ID NO: 214 and the VL sequence of SEQ ID NO: 213. In certain embodiments, an antibody is provided that binds to residue F179 of S-HBs as of SEQ ID NO: 253. The antibody may contain any of the sequences defined above.

[0375] In a further embodiment, the present invention provides antibodies that compete with the anti-S-HBs antibodies provided herein for binding to S-HBs.

[0376] In some embodiments, the antibodies described in this section may, when evaluated by the same assay, e.g., ELISA assay or flow cytometry assay, have or retain at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the binding activity of the reference antibody Bc4.204 to S-HBs (e.g., SEQ ID NO: 253). In addition to or instead of the above, the antibodies described in this section may, when evaluated by the same assay, e.g., ELISA assay or flow cytometry assay, have or retain at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the binding activity of the reference antibody Bc4.204 to proteins having the sequences of SEQ ID NO: 254, 255, 256, 257, 258, 260, and / or 262 (optionally at least SEQ ID NO: 257).

[0377] The reference antibody Bc4.204 has the VH sequence of SEQ ID NO: 214 and the VL sequence of SEQ ID NO: 213. It has the full-length heavy chain of SEQ ID NO: 216 or 274 and the full-length light chain of SEQ ID NO: 215. SEQ ID NO: 274 contains the IgG1 constant region expressed by vector LT615368.1, as used in the examples.

[0378] In some embodiments, the antibodies described in this section are evaluated in the same assay as the reference antibody Bc4.204 against the same antigen.D K is 50, 10, 9, 8, 7, 6, 5, 4, 3 or less than or equal to 2 times the value, or less than or equal to that value. D It can bind to S-HBs (e.g., SEQ ID NO: 253) at a certain value. In addition to this, or instead, the antibody can be evaluated in the same assay as the reference antibody Bc4.204 against the same antigen. D K is 50, 10, 9, 8, 7, 6, 5, 4, 3 or less than or equal to 2 times the value, or less than or equal to that value. D The value can bind to one or more of the sequence numbers 254, 255, 256, 257, 258, 260, and / or 262 (e.g., at least sequence number 257), and optionally to each of the proteins of sequence numbers 254-262.

[0379] In some embodiments, the antibodies described in this section may bind to S-HBs (e.g., SEQ ID NO: 253) at an EC50 of 50, 10, 9, 8, 7, 6, 5, 4, 3, or 2 times or less the EC50 of the reference antibody Bc4.204, as measured by ELISA or flow cytometry. Alternatively, or in addition to the above, the antibodies may bind to one or more proteins having the sequences of SEQ ID NOs: 254, 255, 256, 257, 258, 260 and / or 262, or each of them, optionally to at least the protein of SEQ ID NO: 257, at an EC50 of 50, 10, 9, 8, 7, 6, 5, 4, 3, or 2 times or less the EC50 of the reference antibody Bc4.204, as measured by ELISA or flow cytometry.

[0380] In some embodiments, the antibodies described in this section may have or retain in vitro neutralizing activity against HBV genotypes A, B, C, and / or D, or optionally all of A, B, C, and D. For example, the antibodies described in this section may have or retain in vitro neutralizing activity against HBV genotype D, and for example, the IC50 value may be ≤10 ng / ml, or optionally ≤1 ng / ml.

[0381] In another embodiment, the antibody may have an IC50 value of 50, 10, 9, 8, 7, 6, 5, 4, 3, or 2 times or less the IC50 value of the reference antibody Bc4.204 against the same genotype, when evaluated using the same assay (e.g., the in vitro neutralization assay described herein) for neutralization of HBV genotypes A, B, C and / or D, optionally at least D, optionally A, B, C and D.

[0382] In another embodiment, the antibody may, when evaluated using the same assay (e.g., the assay described herein), have or retain at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the in vivo neutralizing activity of the reference antibody Bc4.204 against HBV genotypes A, B, C, and / or D, optionally at least D, or optionally all of A, B, C, and D.

[0383] Optionally, the antibody can suppress viremia in vivo in individuals infected with, for example, HBV genotype A, B, C, or D, optionally D. Optionally, the antibody may, when evaluated using the same assay (e.g., the assay described herein), possess or retain at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the in vivo viremia-suppressing activity of the reference antibody Bc4.204 against HBV genotypes A, B, C, and / or D, optionally at least D, or optionally all of A, B, C, and D.

[0384] M. In one embodiment, the present invention provides an antibody comprising a VH domain comprising at least one, at least two, or all three VH CDR sequences selected from (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 217, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 218, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 219. In another embodiment, the antibody comprises a VH domain comprising the following CDR(a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 217; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 218; and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 219; or a variant thereof in which one, two, or three amino acids in one or more of CDR-H1, CDR-H2, or CDR-H3 are replaced with other amino acids.

[0385] In one embodiment, the VH domain is (a) the heavy chain framework region 1 (HC-FR1) of SEQ ID NO: 223, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; (b) the heavy chain framework region 2 (HC-FR2) of SEQ ID NO: 224, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; (c) SEQ ID NO: 225 (d) The heavy chain framework region 3 (HC-FR3) of (a) or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and (d) the heavy chain framework region 4 (HC-FR4) of SEQ ID NO: 226 or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. Optionally, the VH domain contains each of the heavy chain framework sequences defined in (a) to (d). Optionally, the sequence identity percentage is 95%. Optionally, the sequence identity percentage is 98%.

[0386] In another embodiment, the anti-S-HBs antibody contains a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 232. In one embodiment, the anti-S-HBs antibody contains a heavy chain variable domain (VH) sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 232. In a particular embodiment, the VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but the anti-S-HBs antibody containing that sequence retains the ability to bind to S-HBs. In a particular embodiment, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 232. In certain embodiments, substitutions, insertions, or deletions occur in the region outside the CDR (i.e., at the FR). Optionally, the anti-S-HBs antibody contains the VH sequence of SEQ ID NO: 232, which includes post-translational modifications of that sequence. In certain embodiments, the VH contains one, two, or three CDRs selected from: (a) CDR-H1 containing the amino acid sequence of SEQ ID NO: 217, (b) CDR-H2 containing the amino acid sequence of SEQ ID NO: 218, and (c) CDR-H3 containing the amino acid sequence of SEQ ID NO: 219.

[0387] In another embodiment, the anti-S-HBs antibody comprises one or more of the VH heavy chain CDR sequences of SEQ ID NO: 232. In one embodiment, the anti-S-HBs antibody comprises one or more (preferably all three) of the VH domain heavy chain CDR amino acid sequences of SEQ ID NO: 232, and a framework of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% sequence identity. Optionally, the sequence identity is 95% or 98%.

[0388] In another embodiment, the present invention provides an antibody comprising a VL domain comprising at least one, at least two, or all three VL CDR sequences selected from (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 220, (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 221, and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 222. In another embodiment, the antibody comprises a VL domain comprising the following CDR(a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 220; (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 221; and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 222; or a variant thereof in which one, two, or three amino acids in one or more of CDR-L1, CDR-L2, or CDR-L3 are replaced with other amino acids.

[0389] In one embodiment, the anti-S-HBs antibody VL domain is (a) a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with respect to the light chain framework region 1 (LC-FR1) of SEQ ID NO: 227, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with respect to the light chain framework region 2 (LC-FR2) of SEQ ID NO: 2281 (LC-FR1) of SEQ ID NO: 227, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with respect to the light chain framework region 1 (LC-FR1) of SEQ ID NO: 227, or a variant having at least 85 (d) The light chain framework region 3 (LC-FR3) of sequence number 229, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and (d) the light chain framework region 4 (LC-FR4) of sequence number 230, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. Optionally, the VL domain contains each of the light chain framework sequences defined in (a) to (d). Optionally, the sequence identity percentage is 95%. The sequence identity percentage is arbitrarily 98%.

[0390] In another embodiment, an anti-S-HBs antibody is provided, comprising a light chain variable domain (VL) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with respect to the amino acid sequence of SEQ ID NO: 231. In one embodiment, the anti-S-HBs antibody comprises a light chain variable domain (VL) sequence having at least 95% sequence identity with respect to the amino acid sequence of SEQ ID NO: 231. In a particular embodiment, the VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but the anti-S-HBs antibody containing that sequence retains the ability to bind to S-HBs. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 231. In certain embodiments, the substitutions, insertions, or deletions occur in the region outside the CDR (i.e., in the FR). Optionally, the anti-S-HBs antibody contains the VL sequence of SEQ ID NO: 231, which includes post-translational modifications of that sequence. In certain embodiments, the VL contains one, two, or three CDRs selected from: (a) CDR-L1 containing the amino acid sequence of SEQ ID NO: 220, (b) CDR-L2 containing the amino acid sequence of SEQ ID NO: 221, and (c) CDR-L3 containing the amino acid sequence of SEQ ID NO: 222.

[0391] In another embodiment, the anti-S-HBs antibody comprises one or more of the VL CDR sequences of SEQ ID NO: 231. In one embodiment, the anti-S-HBs antibody comprises one or more (preferably all three) of the VL domain light chain CDR amino acid sequences of SEQ ID NO: 231, and a framework of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% sequence identity. Optionally, the sequence identity is 95% or 98%.

[0392] In another embodiment, an anti-S-HBs antibody is provided, comprising a VH sequence of any of the embodiments provided above and a VL sequence of any of the embodiments provided above.

[0393] For example, in one exemplary embodiment, the antibody comprises a VH domain containing CDR-H3 of SEQ ID NO: 219; and a VL domain containing CDR-L3 of SEQ ID NO: 222. Optionally, the VH domain further comprises CDR-H2 of SEQ ID NO: 218.

[0394] In another exemplary embodiment, the antibody includes: i) VH domains including the following CDR(a) CDR-H1 containing the amino acid sequence of SEQ ID NO: 217; (b) CDR-H2 containing the amino acid sequence of SEQ ID NO: 218; and (c) CDR-H3 containing the amino acid sequence of SEQ ID NO: 219; or variants thereof in which one, two, or three amino acids in one or more of CDR-H1, CDR-H2, or CDR-H3 are replaced by other amino acids; and ii) VL domains including the following CDR(a) CDR-L1 containing the amino acid sequence of SEQ ID NO: 220; (b) CDR-L2 containing the amino acid sequence of SEQ ID NO: 221; and (c) CDR-L3 containing the amino acid sequence of SEQ ID NO: 222; or variants thereof in which one, two, or three amino acids in one or more of CDR-L1, CDR-L2, or CDR-L3 are replaced by other amino acids.

[0395] In another exemplary embodiment, the antibody includes: i) A heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 232; and ii) A light chain variable domain (VL) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acid sequence of Sequence ID No. 231.

[0396] In another exemplary embodiment, the anti-S-HBs antibody comprises (a) CDR-H1 containing the amino acid sequence of SEQ ID NO: 217; (b) CDR-H2 containing the amino acid sequence of SEQ ID NO: 218; (c) CDR-H3 containing the amino acid sequence of SEQ ID NO: 219; (d) CDR-L1 containing the amino acid sequence of SEQ ID NO: 220; (e) CDR-L2 containing the amino acid sequence of SEQ ID NO: 221; and (f) CDR-L3 containing the amino acid sequence of SEQ ID NO: 222, as well as a VH domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with respect to the amino acid sequence of SEQ ID NO: 232, and a VL domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with respect to the amino acid sequence of SEQ ID NO: 231. In one embodiment, the VH domain has at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 232. In another embodiment, the VL domain has at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 231. In one embodiment, the antibody specifically binds to S-HBs. In another embodiment, the antibody binds to S-HBs having a dissociation constant (KD) that is up to 10 times lower or up to 10 times higher than the dissociation constant (KD) of an antibody containing the VH sequence of SEQ ID NO: 232 and the VL sequence of SEQ ID NO: 231.

[0397] In one embodiment, the antibody comprises the VH and VL sequences of SEQ ID NO: 232 and SEQ ID NO: 231, respectively, including post-translational modifications of those sequences.

[0398] In a further embodiment, the antibody may comprise the full-length light chain of SEQ ID NO: 233 and / or the full-length heavy chain of SEQ ID NO: 234 or 275.

[0399] In further embodiments, the present invention provides antibodies that bind to the same epitopes as the anti-S-HBs antibodies provided herein. For example, in certain embodiments, antibodies that bind to the same epitopes as an anti-S-HBs antibody comprising the VH sequence of SEQ ID NO: 232 and the VL sequence of SEQ ID NO: 231 are provided. In certain embodiments, antibodies that bind to the following residues of S-HBs in SEQ ID NO: 253: W165 and / or R169, and optionally M103, are provided. The antibodies may comprise any of the sequences defined above.

[0400] In a further embodiment, the present invention provides antibodies that compete with the anti-S-HBs antibodies provided herein for binding to S-HBs.

[0401] In some embodiments, the antibodies described in this section may have, or retain, at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the binding activity of the reference antibody Bc1.263 to S-HBs (e.g., SEQ ID NO: 253) when evaluated in the same assay, e.g., an ELISA assay or a flow cytometry assay.

[0402] In addition to or instead of the above, the antibodies described in this section may, when evaluated by the same assay, e.g., ELISA assay or flow cytometry assay, have or retain at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the binding activity of the reference antibody Bc1.263 to each of the proteins of SEQ ID NOs. 254–262, optionally, to one or more of the proteins of SEQ ID NOs. 254–262.

[0403] The reference antibody Bc1.263 has the VH sequence of SEQ ID NO: 232 and the VL sequence of SEQ ID NO: 231. It has the full-length heavy chain of SEQ ID NO: 234 or 275 and the full-length light chain of SEQ ID NO: 233. SEQ ID NO: 275 contains the IgG1 constant region expressed by vector LT615368.1, as used in the examples.

[0404] In some embodiments, the antibodies described in this section are evaluated in the same assay as the reference antibody Bc1.263 against the same antigen. D K is 50, 10, 9, 8, 7, 6, 5, 4, 3 or less than or equal to 2 times the value, or less than or equal to that value. D It can bind to S-HBs by value (for example, sequence number 253).

[0405] In addition to this, or instead, the antibody is evaluated in the same assay as the reference antibody Bc1.263 against the same antigen. D K is 50, 10, 9, 8, 7, 6, 5, 4, 3 or less than or equal to 2 times the value, or less than or equal to that value. D The value may bind to one or more of the sequences 254-262 (e.g., at least sequence 257), or optionally to each of the proteins in sequences 254-262.

[0406] In some embodiments, the antibodies described in this section may bind to S-HBs (e.g., SEQ ID NO: 253) at an EC50 of 50, 10, 9, 8, 7, 6, 5, 4, 3, or 2 times or less the EC50 of reference antibody Bc1.263, as measured by ELISA or flow cytometry. Alternatively, or in addition to the above, the antibodies may bind to one or more of the proteins SEQ ID NOs: 254-262, or each of them, optionally to at least the protein SEQ ID NO: 257, at an EC50 of 50, 10, 9, 8, 7, 6, 5, 4, 3, or 2 times or less the EC50 of reference antibody Bc1.263, as measured by ELISA or flow cytometry.

[0407] In some embodiments, the antibodies described in this section may have or retain in vitro neutralizing activity against HBV genotypes A, B, C, and / or D, or optionally all of A, B, C, and D. For example, the antibodies described in this section may have or retain in vitro neutralizing activity against HBV genotype D, for example, an IC50 value of ≤100 pg / ml, optionally ≤10 pg / ml.

[0408] In another embodiment, the antibody is evaluated using the same assay (e.g., the in vitro neutralization assay described herein) for neutralization of HBV genotypes A, B, C and / or D, optionally at least D, and optionally all of A, B, C and D, to obtain the IC of reference antibody Bc1.263 against the same genotype. 50 IC values ​​that are 50, 10, 9, 8, 7, 6, 5, 4, 3 or less than or twice the value, or less than or equal to that value. 50 It may have a value.

[0409] In another embodiment, the antibody may, when evaluated using the same assay (e.g., the assay described herein), have or retain at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the neutralizing activity of the reference antibody Bc1.263 against HBV genotypes A, B, C, and / or D, optionally at least D, or optionally all of A, B, C, and D.

[0410] Optionally, the antibody can suppress viremia in vivo in individuals infected with, for example, HBV genotype A, B, C, or D, optionally D. Optionally, the antibody may have, or retain, at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the in vivo viremia-suppressing activity of the reference antibody Bc1.263 against HBV genotypes A, B, C, and / or D, optionally at least D, or optionally all of A, B, C, and D, as evaluated using the same assay (e.g., the assay described herein).

[0411] N. In one embodiment, the present invention provides an antibody comprising a VH domain comprising at least one, at least two, or all three VH CDR sequences selected from (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 235, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 236, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 237. In another embodiment, the antibody comprises a VH domain comprising the following CDR(a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 235; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 236; and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 237; or a variant thereof in which one, two, or three amino acids in one or more of CDR-H1, CDR-H2, or CDR-H3 are replaced with other amino acids.

[0412] In one embodiment, the VH domain is (a) the heavy chain framework region 1 (HC-FR1) of SEQ ID NO: 241, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; (b) the heavy chain framework region 2 (HC-FR2) of SEQ ID NO: 242, or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; (c) SEQ ID NO: 243 (d) The heavy chain framework region 3 (HC-FR3) of (a) or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and (d) the heavy chain framework region 4 (HC-FR4) of SEQ ID NO: 244 or a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. Optionally, the VH domain contains each of the heavy chain framework sequences defined in (a) to (d). Optionally, the sequence identity percentage is 95%. Optionally, the sequence identity percentage is 98%.

[0413] In another embodiment, the anti-S-HBs antibody contains a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 250. In one embodiment, the anti-S-HBs antibody contains a heavy chain variable domain (VH) sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 250. In a particular embodiment, the VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but the anti-S-HBs antibody containing that sequence retains the ability to bind to S-HBs. In a particular embodiment, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 250. In certain embodiments, substitutions, insertions, or deletions occur in the region outside the CDR (i.e., at the FR). Optionally, the anti-S-HBs antibody contains the VH sequence of SEQ ID NO: 250, which includes post-translational modifications of that sequence. In certain embodiments, the VH contains one, two, or three CDRs selected from: (a) CDR-H1 containing the amino acid sequence of SEQ ID NO: 235, (b) CDR-H2 containing the amino acid sequence of SEQ ID NO: 236, and (c) CDR-H3 containing the amino acid sequence of SEQ ID NO: 237.

[0414] In another embodiment, the anti-S-HBs antibody comprises one or more of the VH heavy chain CDR sequences of SEQ ID NO: 250. In one embodiment, the anti-S-HBs antibody comprises one or more (preferably all three) of the VH domain heavy chain CDR amino acid sequences of SEQ ID NO: 250 and a framework of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% sequence identity. Optionally, the sequence identity is 95% or 98%.

[0415] In another embodiment, the present invention provides an antibody comprising a VL domain comprising at least one, at least two, or all three VL CDR sequences selected from (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 238, (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 239, and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 240. In another embodiment, the antibody comprises a VL domain comprising the following CDR(a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 238; (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 239; and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 240; or a variant thereof in which one, two, or three amino acids in one or more of CDR-L1, CDR-L2, or CDR-L3 are replaced with other amino acids.

[0416] In one embodiment, the anti-S-HBs antibody VL domain is (a) a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with respect to the light chain framework region 1 (LC-FR1) of SEQ ID NO: 245, (b) a variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with respect to the light chain framework region 2 (LC-FR2) of SEQ ID NO: 246, (c) sequence number (d) The VL domain may further include one or more light chain framework sequences selected from (a) to (d) the light chain framework region 3 (LC-FR3) of sequence number 247, or variants having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and (d) the light chain framework region 4 (LC-FR4) of sequence number 248, or variants having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. Optionally, the VL domain contains each of the light chain framework sequences defined in (a) to (d). Optionally, the sequence identity percentage is 95%. The sequence identity percentage is arbitrarily 98%.

[0417] In another embodiment, an anti-S-HBs antibody is provided, comprising a light chain variable domain (VL) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with respect to the amino acid sequence of SEQ ID NO: 249. In one embodiment, the anti-S-HBs antibody comprises a light chain variable domain (VL) sequence having at least 95% sequence identity with respect to the amino acid sequence of SEQ ID NO: 249. In a particular embodiment, the VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but the anti-S-HBs antibody containing that sequence retains the ability to bind to S-HBs. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 249. In certain embodiments, the substitutions, insertions, or deletions occur in the region outside the CDR (i.e., in the FR). Optionally, the anti-S-HBs antibody contains the VL sequence of SEQ ID NO: 249, which includes post-translational modifications of that sequence. In certain embodiments, the VL contains one, two, or three CDRs selected from (a) CDR-L1 containing the amino acid sequence of SEQ ID NO: 238, (b) CDR-L2 containing the amino acid sequence of SEQ ID NO: 239, and (c) CDR-L3 containing the amino acid sequence of SEQ ID NO: 240.

[0418] In another embodiment, the anti-S-HBs antibody comprises one or more of the VL CDR sequences of SEQ ID NO: 249. In one embodiment, the anti-S-HBs antibody comprises one or more (preferably all three) of the VL domain light chain CDR amino acid sequences of SEQ ID NO: 249 and a framework amino acid sequence of the VL domain of SEQ ID NO: 249 with at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% sequence identity. Optionally, the sequence identity is 95% or 98%.

[0419] In another embodiment, an anti-MerTK antibody is provided, wherein the antibody comprises VH as in any of the embodiments provided above, and VL as in any of the embodiments provided above.

[0420] For example, in one exemplary embodiment, the antibody comprises a VH domain containing CDR-H3 of SEQ ID NO: 237; and a VL domain containing CDR-L3 of SEQ ID NO: 240. Optionally, the VH domain further comprises CDR-H2 of SEQ ID NO: 236.

[0421] In another exemplary embodiment, the antibody includes: i) VH domains including the following CDR(a) CDR-H1 containing the amino acid sequence of SEQ ID NO: 235; (b) CDR-H2 containing the amino acid sequence of SEQ ID NO: 236; and (c) CDR-H3 containing the amino acid sequence of SEQ ID NO: 237; or variants thereof in which one, two, or three amino acids in one or more of CDR-H1, CDR-H2, or CDR-H3 are replaced by other amino acids; and ii) VL domains including the following CDR(a) CDR-L1 containing the amino acid sequence of SEQ ID NO: 238; (b) CDR-L2 containing the amino acid sequence of SEQ ID NO: 239; and (c) CDR-L3 containing the amino acid sequence of SEQ ID NO: 240; or variants thereof in which one, two, or three amino acids in one or more of CDR-L1, CDR-L2, or CDR-L3 are replaced by other amino acids.

[0422] In another exemplary embodiment, the antibody includes: i) A heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 250; and ii) A light chain variable domain (VL) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acid sequence of Sequence ID No. 249.

[0423] In another exemplary embodiment, the anti-S-HBs antibody comprises (a) CDR-H1 containing the amino acid sequence of SEQ ID NO: 235; (b) CDR-H2 containing the amino acid sequence of SEQ ID NO: 236; (c) CDR-H3 containing the amino acid sequence of SEQ ID NO: 237; (d) CDR-L1 containing the amino acid sequence of SEQ ID NO: 238; (e) CDR-L2 containing the amino acid sequence of SEQ ID NO: 239; and (f) CDR-L3 containing the amino acid sequence of SEQ ID NO: 240, as well as a VH domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with respect to the amino acid sequence of SEQ ID NO: 250, and a VL domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with respect to the amino acid sequence of SEQ ID NO: 249. In one embodiment, the VH domain has at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 250. In another embodiment, the VL domain has at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 249. In one embodiment, the antibody specifically binds to S-HBs. In another embodiment, the antibody binds to S-HBs having a dissociation constant (KD) that is up to 10 times lower or up to 10 times higher than the dissociation constant (KD) of an antibody containing the VH sequence of SEQ ID NO: 250 and the VL sequence of SEQ ID NO: 249.

[0424] In one embodiment, the antibody comprises the VH and VL sequences of SEQ ID NO: 250 and SEQ ID NO: 249, respectively, including post-translational modifications of those sequences.

[0425] In a further embodiment, the antibody may comprise the full-length light chain of SEQ ID NO: 251 and / or the full-length heavy chain of SEQ ID NO: 252 or 276.

[0426] In further embodiments, the present invention provides antibodies that bind to the same epitopes as the anti-S-HBs antibodies provided herein. For example, in certain embodiments, antibodies that bind to the same epitopes as an anti-S-HBs antibody comprising the VH sequence of SEQ ID NO: 250 and the VL sequence of SEQ ID NO: 249 are provided. In certain embodiments, antibodies that bind to the following residues of S-HB of SEQ ID NO: 253 are provided: C124, C137, C138 and / or C139, optionally R122, C149 and / or I152; and optionally W156. The antibodies may contain any of the sequences defined above.

[0427] In a further embodiment, the present invention provides antibodies that compete with the anti-MerTK reference antibody provided herein for binding to MerTK.

[0428] In some embodiments, the antibodies described in this section may have, or retain, at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the binding activity of the reference antibody Bv4.105 to S-HBs (e.g., SEQ ID NO: 253) when evaluated in the same assay, e.g., an ELISA assay or a flow cytometry assay.

[0429] In addition to or instead of the above, the antibodies described in this section may, when evaluated in the same assay, e.g., ELISA assay or flow cytometry assay, have or retain at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the binding activity of reference antibody Bv4.105 to one or more proteins of SEQ ID NOs. 257, 258, 259, 260, and / or 261, optionally to each of them, optionally to at least SEQ ID NO. 257.

[0430] The reference antibody Bv4.105 has the VH sequence of SEQ ID NO: 250 and the VL sequence of SEQ ID NO: 249. It has the full-length heavy chain of SEQ ID NO: 252 or 276 and the full-length light chain of SEQ ID NO: 251. SEQ ID NO: 276 contains the IgG1 constant region expressed by vector LT615368.1, as used in the examples.

[0431] In some embodiments, the antibodies described in this section are evaluated in the same assay and have a K D value that is 50, 10, 9, 8, 7, 6, 5, 4, 3, or 2 times or less, or less than that value, of the K D value of the reference antibody Bv4.105 against the same antigen and can bind to S-HBs (e.g., of SEQ ID NO: 253).

[0432] In addition to, or alternatively to, this, the antibodies are evaluated in the same assay and have a K D value that is 50, 10, 9, 8, 7, 6, 5, 4, 3, or 2 times or less, or less than that value, of the K D value and can optionally bind to at least SEQ ID NO: 257, and optionally to one or more of the proteins of SEQ ID NOs: 257, 258, 259, 260, and / or 261, respectively, each optionally.

[0433] In some embodiments, the antibodies described in this section are measured by ELISA or flow cytometry and have an EC50 that is 50, 10, 9, 8, 7, 6, 5, 4, 3, or 2 times or less, or less than that value, of the EC50 of the reference antibody Bv4.105 and can bind to S-HBs (e.g., of SEQ ID NO: 253). Alternatively to, or in addition to, this, the antibodies are measured by ELISA or flow cytometry and have an EC50 that is 50, 10, 9, 8, 7, 6, 5, 4, 3, or 2 times or less, or less than that value, of the EC50 of the reference antibody Bv4.105 and can optionally bind to at least SEQ ID NO: 257, and optionally to one or more of the proteins of SEQ ID NOs: 257, 258, 259, 260, and / or 261, respectively, each optionally.

[0434] In some embodiments, the antibodies described in this section may have or retain in vitro neutralizing activity against HBV genotypes D, E, F, and / or H, optionally all of genotypes D, E, F, and H. For example, the antibodies described in this section may have or retain in vitro neutralizing activity against HBV genotype D, for example, an IC50 value of ≤100 pg / ml, optionally ≤10 pg / ml.

[0435] In another embodiment, the antibody is evaluated using the same assay (e.g., the in vitro neutralization assay described herein) for neutralization of all HBV genotypes D, E, F, G, and / or H, optionally at least D, and optionally D, E, F, G, and / or H, to obtain the IC of reference antibody Bv4.105 against the same genotype. 50 It may have an IC50 value that is 50, 10, 9, 8, 7, 6, 5, 4, 3, or twice or less of that value.

[0436] In another embodiment, the antibody may, when evaluated using the same assay (e.g., the assay described herein), have or retain at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the neutralizing activity of the reference antibody Bv4.105 against HBV genotypes D, E, F, G, and / or H, optionally at least D, and optionally all of D, E, F, G, and H.

[0437] Optionally, the antibody can suppress viremia in vivo in individuals infected with, for example, HBV genotypes D, E, F, G, or H, optionally D. Optionally, the antibody may have, or retain, at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the in vivo viremia-suppressing activity of the reference antibody Bv4.105 against HBV genotypes D, E, F, G, and / or H, optionally at least D, optionally all of D, E, F, G, and H, as evaluated using the same assay (e.g., the assay described herein).

[0438] Generally, an anti-S-HBs antibody according to any aspect of the present invention (including any of A to N above) can be a monoclonal antibody including a chimeric antibody, a humanized antibody or a human antibody. In one aspect, the anti-S-HBs antibody is an antibody fragment, such as Fv, Fab, Fab’, scFv, diabody, or F(ab’)2 fragment.

[0439] In another general aspect, the antibody can be a full-length antibody, such as an intact IgG1, IgG2, IgG3 antibody, or other antibody class or isotype defined herein.

[0440] The C-terminal lysine (Lys447) of the full-length antibody may or may not be present. In another aspect, the C-terminal glycine (Gly446) and C-terminal lysine (Lys447) may or may not be present.

[0441] In a further aspect, an anti-S-HBs antibody according to any of the above aspects may incorporate any of the features described in Sections 1 to 7 below, alone or in combination:

[0442] 1. Antibody affinity

[0443] In certain aspects, the antibodies provided herein have a dissociation constant (K D ) for the target protein of ≦1 μM, ≦100 nM, ≦10 nM, ≦1 nM, ≦0.1 nM, ≦0.01 nM or ≦0.001 nM (e.g., 10 -8 M or less, e.g., 10 -8 M to 10 -13 M, e.g., 10 -9 M to 10 -13 M).

[0444] In other aspects, the antibodies provided herein, when evaluated in the same assay, have a K D value that is 50, 10, 9, 8, 7, 6, 5, 4, 3, or 2-fold or less, or less than that value, of the K DThe antibody possesses or retains the following, and the reference antibody is selected from the group consisting of Bc1.187, Bv4.115, Bc8.159, Bv6.172, Bc1.229, Bc8.111, Bc1.128, Bc3.106, Bc1.180, Bv4.104, Bc8.104, Bc4.204, Bc1.263, and Bv4.105.

[0445] In one aspect, K D This is measured using the BIACORE® surface plasmon resonance assay. For example, assays using BIACORE®-2000 or BIACORE®-3000 (BIAcore, Inc., Piscataway, NJ) are performed at 25°C for approximately 10 response units (RUs) using an immobilized antigen CM5 chip. In one embodiment, a carboxymethylated dextran biosensor chip (CM5, BIACORE, Inc.) is activated with N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) according to the supplier's instructions. The antigen is diluted to 5 μg / ml (approximately 0.2 μM) with 10 mM sodium acetate at pH 4.8, and then injected at a flow rate of 5 μl / min to achieve approximately 10 response units (RUs) of the coupled protein. After antigen injection, 1M ethanolamine is injected to block unreacted groups. For kinetic analysis, 2-fold serial dilutions of Fab (0.78 nM to 500 nM) are injected at a flow rate of approximately 25 μL / min into PBS containing 0.05% polysorbate 20 (TWEEN-20®) surfactant (PBST) at 25°C. The association rate (k on ) and dissociation rate (k off The equilibrium dissociation constant (K) is calculated using a simple one-to-one Langmuir coupled model (BIACORE® Evaluation Software version 3.2) by simultaneously fitting the association sensorgram and dissociation sensorgram. D ) is k off / k onIt is calculated as a ratio. For example, see Chen et al. J.Mol.Biol.293:865-881(1999). The ON velocity is 10 by the above surface plasmon resonance assay. 6 M -1 s -1 If it exceeds this value, this ON rate can be determined by using a fluorescence quenching technique, which measures the increase or decrease in fluorescence emission intensity (excitation = 295 nm, emission = 340 nm, 16 nm band-passing) of a 20 nM anti-antigen antibody (Fab type) in PBS (pH 7.2) at 25°C in the presence of gradually increasing concentrations of antigen, measured with a spectrometer such as an Aviv Instruments stop-flow spectrophotometer equipped with a stirred cuvette or an 8000 series SLM-AMINCO™ spectrophotometer (ThermoSpectronic).

[0446] In another embodiment, as described, for example, in Friguet et al J Immunol.Methods(1985)77(2):305-19, ELISA is used to obtain K D It is possible to calculate this.

[0447] 2. Antibody fragments

[0448] In certain embodiments, the antibodies provided herein are antibody fragments.

[0449] In one embodiment, the antibody fragment is a Fab, Fab', Fab'-SH, or F(ab')2 fragment, particularly a Fab fragment. When an intact antibody is digested with papain, two identical antigen-binding fragments (so-called "Fab" fragments) are obtained, each containing the variable domains of the heavy and light chains (VH and VL, respectively), as well as the constant domain (CL) of the light chain and the first constant domain (CH1) of the heavy chain. Therefore, a "Fab fragment" is an antibody fragment having a light chain containing the VL and CL domains, and a heavy chain fragment containing the VH and CH1 domains. A "Fab' fragment" is different from a Fab fragment by adding residues at the carboxyl terminus of the CH1 domain, which contains one or more cysteines, from the antibody hinge region. Fab'-SH is a Fab' fragment in which the cysteine ​​residues (multiple valencies) of the constant domain retain a free thiol group. Pepsin treatment yields an F(ab')2 fragment having two antigen-binding sites (two Fab fragments) and a portion of the Fc region. For a description of the Fab and F(ab')2 fragments, which contain salvage receptor-binding epitope residues and have a longer in vivo half-life, please refer to U.S. Patent No. 5,869,046.

[0450] In another embodiment, the antibody fragment is a diabody, triabody, or tetrabody. A "diabody" is an antibody fragment having two antigen-binding sites that may be bivalent or bispecific. See, for example, European Patent No. 404,097, WO1993 / 01161, Hudson et al., Nat. Med. 9:129-134 (2003), and Hollinger et al., Proc. Natl. Acad. Sci. USA 90:6444-6448 (1993). Triabodies and tetrabodies are also described in Hudson et al., Nat. Med. 9:129-134 (2003).

[0451] In a further embodiment, the antibody fragment is a single-stranded Fab fragment. The "single-stranded Fab fragment" or "scFab" is a polypeptide comprising an antibody heavy chain variable domain (VH), an antibody heavy chain constant domain 1 (CH1), an antibody light chain variable domain (VL), an antibody light chain constant domain (CL), and a linker, wherein the antibody domain and the linker have one of the following orders from the N-terminus to the C-terminus: a) VH-CH1-linker-VL-CL, b) VL-CL-linker-VH-CH1, c) VH-CL-linker-VL-CH1, or d) VL-CH1-linker-VH-CL. In particular, the linker is a polypeptide of at least 30 amino acids, preferably 32 to 50 amino acids. The single-stranded Fab fragment is stabilized by a native disulfide bond between the CL domain and the CH1 domain. In addition, these single-stranded Fab fragments can be further stabilized by the formation of interchain disulfide bonds via the insertion of cysteine ​​residues (for example, at position 44 of the variable heavy chain and position 100 of the variable light chain, according to Kabat numbering).

[0452] In another embodiment, the antibody fragment is a single-stranded variable fragment (scFv). A "single-stranded variable fragment" or "scFv" is a fusion protein of the variable domains of the heavy chain (VH) and light chain (VL) of an antibody, linked by a linker. In particular, the linker is a short polypeptide of 10 to 25 amino acids, usually rich in glycine for flexibility and serine or threonine for solubility, and can be linked at either the N-terminus of VH or the C-terminus of VL. This protein can retain the specificity of the original antibody despite the removal of the constant region and the introduction of a linker. For a review of scFv fragments, see, for example, Pluckthun, The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., (Springer-Verlag, New York), pp. 269-315 (1994). See also International Publication No. 93 / 16185 and U.S. Publications No. 5,571,894 and No. 5,587,458.

[0453] In another embodiment, the antibody fragment is a single-domain antibody. A "single-domain antibody" is an antibody fragment that includes all or part of the heavy chain variable domain or all or part of the light chain variable domain of an antibody. In a particular embodiment, the single-domain antibody is a human single-domain antibody (see Domantis, Inc., Waltham, MA; for example, U.S. Patent No. 6,248,516B1).

[0454] Antibody fragments can be produced by a variety of techniques, including, but not limited to, proteolytic digestion of intact antibodies and recombinant production by recombinant host cells (e.g., Escherichia coli), as described herein.

[0455] 3. Chimeric antibodies and humanized antibodies

[0456] In certain embodiments, the antibodies provided herein are chimeric antibodies. Certain chimeric antibodies are described, for example, in U.S. Patent No. 4,816,567 and in Morrison et al., Proc. Natl. Acad. Sci. USA, 81:6851-6855 (1984). In one example, a chimeric antibody includes a non-human variable region (e.g., a variable region derived from mouse, rat, hamster, rabbit, or non-human primate, e.g., monkey) and a human constant region. In further examples, a chimeric antibody is a “class-switched” antibody in which the class or subclass is changed from those of the parent antibody. A chimeric antibody includes its antigen-binding fragment.

[0457] In certain embodiments, chimeric antibodies are humanized antibodies. Typically, non-human antibodies are humanized to reduce their immunogenicity against humans while retaining the specificity and affinity of the parent non-human antibody. Humanized antibodies typically contain one or more variable domains (CDRs or parts thereof) derived from the non-human antibody, and FRs (or parts thereof) derived from the human antibody sequence. Humanized antibodies also optionally contain at least a portion of the human constant region. In some embodiments, several FR residues in the humanized antibody are replaced with corresponding residues from the non-human antibody (e.g., the antibody from which the CDR residues are derived) to restore or improve antibody specificity or affinity, for example.

[0458] Humanized antibodies and their production methods are reviewed in Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008), and further described below: Riechmann et al., Nature 332:323-329 (1988); Queen et al., Proc. Nat'l Acad. Sci. USA 86:10029-10033 (1989); U.S. Patents No. 5,821,337, No. 7,527,791, No. 6,982,321, and No. 7,087,409; Kashmiri et al., Methods 36:25-34 (2005) (Describes specificity-determining region (SDR) grafts); Padlan, Mol.Immunol.28:489-498 (1991) (Describes resurfacing); Dall'Acqua et al., Methods 36:43-60 (2005) (Describes "FR shuffling"); and Osbourn et al., Methods 36:61-68 (2005) and Klimka et al., Br.J.Cancer,83:252-260 (2000) (Describes the "guided selection approach" to FR shuffling).

[0459] Human framework regions that may be used for humanization include, but are not limited to, the following: framework regions selected using the "best fit" method (see, e.g., Sims et al. J. Immunol. 151:2296 (1993)); framework regions derived from consensus sequences of human antibodies of specific subgroups of light chain or heavy chain variable regions (see, e.g., Carter et al. Proc. Natl. Acad. Sci. USA, 89:4285 (1992); and Presta et al. J. Immunol., 151:2623 (1993)); human maturation (somatic mutation) framework regions or human germ cell framework regions (see, e.g., Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008)); and framework regions derived from screening of FR libraries (see, e.g., Baca et al. See al., J. Biol. Chem. 272:10678-10684 (1997) and Rosok et al., J. Biol. Chem. 271:22611-22618 (1996).

[0460] 4. Human antibodies In certain embodiments, the antibodies provided herein are human antibodies. Human antibodies can be prepared using a variety of techniques known in the art. Human antibodies are generally described in van Dijk and van de Winkel, Curr. Opin. Pharmacol. 5:368-74 (2001) and Lonberg, Curr. Opin. Immunol. 20:450-459 (2008).

[0461] Human antibodies can be prepared by administering immunogens to transgenic animals modified to produce intact human antibodies or intact antibodies with human variable regions in response to antigen challenge. Such animals typically contain, or have extrachromosomal, or randomly integrated human immunoglobulin loci, replacing endogenous immunoglobulin loci. In such transgenic mice, endogenous immunoglobulin loci are generally inactivated. For a review of methods for obtaining human antibodies from transgenic animals, see Lonberg, Nat. Biotech. 23:1117-1125 (2005). See also, for example, U.S. Patent Nos. 6,075,181 and 6,150,584 describing XENOMOUSE® technology; U.S. Patent No. 5,770,429 describing HuMab® technology; U.S. Patent No. 7,041,870 describing KM MOUSE® technology; and U.S. Patent Application Publication 2007 / 0061900 describing VelociMouse® technology. The human variable region from intact antibodies produced by such animal...

Claims

1. An antibody that binds to S-HBs, is cross-reactive to each of the HBV proteins of SEQ ID NOs. 254-262, and / or has a neutralizing IC50 value against HBV genome D ≤ 1 ng / ml as measured in vitro.

2. The antibody according to claim 1, wherein, when measured in vitro, the neutralizing IC50 value against HBV genome D is ≤100 pg / ml.

3. An antibody that binds to S-HBs, A heavy chain variable domain (VH) comprising (a) CDR-H1 containing the amino acid sequence of SEQ ID NO: 1, (b) CDR-H2 containing the amino acid sequence of SEQ ID NO: 2, and (c) CDR-H3 containing the amino acid sequence of SEQ ID NO: 3; and (d) CDR-L1 containing the amino acid sequence of SEQ ID NO: 4, (e) CDR-L2 containing the amino acid sequence of SEQ ID NO: 5, and (f) CDR-L3 containing the amino acid sequence of SEQ ID NO: 6, comprising a light chain variable domain (VL). Antibodies containing antibodies.

4. (a) A VH sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 16; (b) A VL sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 15; and (c) The VH sequence defined in (a) and the VL sequence defined in (b) The antibody according to claim 3, comprising a sequence selected from the group consisting of the following.

5. The antibody according to claim 3 or claim 4, comprising the VH sequence of SEQ ID NO: 16 and the VL sequence of SEQ ID NO:

15.

6. An antibody that binds to S-HBs, A heavy chain variable domain (VH) comprising (a) CDR-H1 containing the amino acid sequence of SEQ ID NO: 19, (b) CDR-H2 containing the amino acid sequence of SEQ ID NO: 20, and (c) CDR-H3 containing the amino acid sequence of SEQ ID NO: 21; and (d) CDR-L1 containing the amino acid sequence of SEQ ID NO: 22, (e) CDR-L2 containing the amino acid sequence of SEQ ID NO: 23, and (f) CDR-L3 containing the amino acid sequence of SEQ ID NO: 24, comprising a light chain variable domain (VL). Antibodies containing antibodies.

7. (a) A VH sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 34; (b) A VL sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 33; and (c) The VH sequence defined in (a) and the VL sequence defined in (b) The antibody according to claim 6, comprising a sequence selected from the group consisting of the following.

8. The antibody according to claim 6 or claim 7, comprising the VH sequence of SEQ ID NO: 34 and the VL sequence of SEQ ID NO:

33.

9. An antibody that binds to S-HBs, A heavy chain variable domain (VH) comprising (a) CDR-H1 containing the amino acid sequence of SEQ ID NO: 37, (b) CDR-H2 containing the amino acid sequence of SEQ ID NO: 38, and (c) CDR-H3 containing the amino acid sequence of SEQ ID NO: 39; and (d) CDR-L1 containing the amino acid sequence of SEQ ID NO: 40, (e) CDR-L2 containing the amino acid sequence of SEQ ID NO: 41, and (f) CDR-L3 containing the amino acid sequence of SEQ ID NO: 42, comprising a light chain variable domain (VL). Antibodies containing antibodies.

10. (a) A VH sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 52; (b) A VL sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 51; and (c) The VH sequence defined in (a) and the VL sequence defined in (b) The antibody according to claim 9, comprising a sequence selected from the group consisting of the following.

11. The antibody according to claim 9 or claim 10, comprising the VH sequence of SEQ ID NO: 52 and the VL sequence of SEQ ID NO:

51.

12. An antibody that binds to S-HBs, A heavy chain variable domain (VH) comprising (a) CDR-H1 containing the amino acid sequence of SEQ ID NO: 55, (b) CDR-H2 containing the amino acid sequence of SEQ ID NO: 56, and (c) CDR-H3 containing the amino acid sequence of SEQ ID NO: 57; and (d) CDR-L1 containing the amino acid sequence of SEQ ID NO: 58, (e) CDR-L2 containing the amino acid sequence of SEQ ID NO: 59, and (f) CDR-L3 containing the amino acid sequence of SEQ ID NO: 60, comprising a light chain variable domain (VL). Antibodies containing antibodies.

13. (a) A VH sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 70; (b) A VL sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 69; and (c) The VH sequence defined in (a) and the VL sequence defined in (b) The antibody according to claim 12, comprising a sequence selected from the group consisting of the following.

14. The antibody according to claim 12 or claim 13, comprising the VH sequence of SEQ ID NO: 70 and the VL sequence of SEQ ID NO:

69.

15. An antibody that binds to S-HBs, A heavy chain variable domain (VH) comprising (a) CDR-H1 containing the amino acid sequence of SEQ ID NO: 73, (b) CDR-H2 containing the amino acid sequence of SEQ ID NO: 74, and (c) CDR-H3 containing the amino acid sequence of SEQ ID NO: 75; and (d) CDR-L1 containing the amino acid sequence of SEQ ID NO: 76, (e) CDR-L2 containing the amino acid sequence of SEQ ID NO: 77, and (f) CDR-L3 containing the amino acid sequence of SEQ ID NO: 78, comprising a light chain variable domain (VL). Antibodies containing antibodies.

16. (a) A VH sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 88; (b) A VL sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 87; and (c) The VH sequence defined in (a) and the VL sequence defined in (b) The antibody according to claim 15, comprising a sequence selected from the group consisting of the following.

17. The antibody according to claim 15 or claim 16, comprising the VH sequence of SEQ ID NO: 88 and the VL sequence of SEQ ID NO:

87.

18. An antibody that binds to S-HBs, A heavy chain variable domain (VH) comprising (a) CDR-H1 containing the amino acid sequence of SEQ ID NO: 91, (b) CDR-H2 containing the amino acid sequence of SEQ ID NO: 92, and (c) CDR-H3 containing the amino acid sequence of SEQ ID NO: 93; and (d) CDR-L1 containing the amino acid sequence of SEQ ID NO: 94, (e) CDR-L2 containing the amino acid sequence of SEQ ID NO: 95, and (f) CDR-L3 containing the amino acid sequence of SEQ ID NO: 96, comprising a light chain variable domain (VL). Antibodies containing antibodies.

19. (a) A VH sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 106; (b) A VL sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 105; and (c) The VH sequence defined in (a) and the VL sequence defined in (b) The antibody according to claim 18, comprising a sequence selected from the group consisting of the following.

20. The antibody according to claim 18 or claim 19, comprising the VH sequence of SEQ ID NO: 106 and the VL sequence of SEQ ID NO:

105.

21. An antibody that binds to S-HBs, A heavy chain variable domain (VH) comprising (a) CDR-H1 containing the amino acid sequence of SEQ ID NO: 109, (b) CDR-H2 containing the amino acid sequence of SEQ ID NO: 110, and (c) CDR-H3 containing the amino acid sequence of SEQ ID NO: 111; and (d) CDR-L1 containing the amino acid sequence of SEQ ID NO: 112, (e) CDR-L2 containing the amino acid sequence of SEQ ID NO: 113, and (f) CDR-L3 containing the amino acid sequence of SEQ ID NO: 114, comprising a light chain variable domain (VL). Antibodies containing antibodies.

22. (a) A VH sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 124; (b) A VL sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 125; and (c) The VH sequence defined in (a) and the VL sequence defined in (b) The antibody according to claim 21, comprising a sequence selected from the group consisting of the following.

23. The antibody according to claim 21 or claim 22, comprising the VH sequence of SEQ ID NO: 124 and the VL sequence of SEQ ID NO:

123.

24. An antibody that binds to S-HBs, A heavy chain variable domain (VH) comprising (a) CDR-H1 containing the amino acid sequence of SEQ ID NO: 127, (b) CDR-H2 containing the amino acid sequence of SEQ ID NO: 128, and (c) CDR-H3 containing the amino acid sequence of SEQ ID NO: 129; and (d) CDR-L1 containing the amino acid sequence of SEQ ID NO: 130, (e) CDR-L2 containing the amino acid sequence of SEQ ID NO: 131, and (f) CDR-L3 containing the amino acid sequence of SEQ ID NO: 132, comprising a light chain variable domain (VL). Antibodies containing antibodies.

25. (a) A VH sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 142; (b) A VL sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 141; and (c) The VH sequence defined in (a) and the VL sequence defined in (b) The antibody according to claim 24, comprising a sequence selected from the group consisting of the following.

26. The antibody according to claim 24 or claim 25, comprising the VH sequence of SEQ ID NO: 142 and the VL sequence of SEQ ID NO:

141.

27. An antibody that binds to S-HBs, A heavy chain variable domain (VH) comprising (a) CDR-H1 containing the amino acid sequence of SEQ ID NO: 145, (b) CDR-H2 containing the amino acid sequence of SEQ ID NO: 146, and (c) CDR-H3 containing the amino acid sequence of SEQ ID NO: 147; and (d) CDR-L1 containing the amino acid sequence of SEQ ID NO: 148, (e) CDR-L2 containing the amino acid sequence of SEQ ID NO: 149, and (f) CDR-L3 containing the amino acid sequence of SEQ ID NO: 150, comprising a light chain variable domain (VL). Antibodies containing antibodies.

28. (a) A VH sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 160; (b) A VL sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 159; and (c) The VH sequence defined in (a) and the VL sequence defined in (b) The antibody according to claim 27, comprising a sequence selected from the group consisting of the following.

29. The antibody according to claim 27 or claim 28, comprising the VH sequence of SEQ ID NO: 160 and the VL sequence of SEQ ID NO:

159.

30. An antibody that binds to S-HBs, A heavy chain variable domain (VH) comprising (a) CDR-H1 containing the amino acid sequence of SEQ ID NO: 163, (b) CDR-H2 containing the amino acid sequence of SEQ ID NO: 164, and (c) CDR-H3 containing the amino acid sequence of SEQ ID NO: 165; and (d) CDR-L1 containing the amino acid sequence of SEQ ID NO: 166, (e) CDR-L2 containing the amino acid sequence of SEQ ID NO: 167, and (f) CDR-L3 containing the amino acid sequence of SEQ ID NO: 168, comprising a light chain variable domain (VL). Antibodies containing antibodies.

31. (a) A VH sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 178; (b) A VL sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 177; and (c) The VH sequence defined in (a) and the VL sequence defined in (b) The antibody according to claim 30, comprising a sequence selected from the group consisting of the following.

32. The antibody according to claim 30 or claim 31, comprising the VH sequence of SEQ ID NO: 178 and the VL sequence of SEQ ID NO:

177.

33. An antibody that binds to S-HBs, A heavy chain variable domain (VH) comprising (a) CDR-H1 containing the amino acid sequence of SEQ ID NO: 181, (b) CDR-H2 containing the amino acid sequence of SEQ ID NO: 182, and (c) CDR-H3 containing the amino acid sequence of SEQ ID NO: 183; and (d) CDR-L1 containing the amino acid sequence of SEQ ID NO: 184, (e) CDR-L2 containing the amino acid sequence of SEQ ID NO: 185, and (f) CDR-L3 containing the amino acid sequence of SEQ ID NO: 186, comprising a light chain variable domain (VL). Antibodies containing antibodies.

34. (a) A VH sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 196; (b) A VL sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 195; and (c) The VH sequence defined in (a) and the VL sequence defined in (b) The antibody according to claim 33, comprising a sequence selected from the group consisting of the following.

35. The antibody according to claim 33 or claim 34, comprising the VH sequence of SEQ ID NO: 196 and the VL sequence of SEQ ID NO:

195.

36. An antibody that binds to S-HBs, comprising a heavy chain variable domain (VH) comprising (a) CDR-H1 containing the amino acid sequence of SEQ ID NO: 199, (b) CDR-H2 containing the amino acid sequence of SEQ ID NO: 200, and (c) CDR-H3 containing the amino acid sequence of SEQ ID NO: 201, and a light chain variable domain (VL) comprising (d) CDR-L1 containing the amino acid sequence of SEQ ID NO: 202, (e) CDR-L2 containing the amino acid sequence of SEQ ID NO: 203, and (f) CDR-L3 containing the amino acid sequence of SEQ ID NO:

204.

37. (a) A VH sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 214; (b) A VL sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 213; and (c) The VH sequence defined in (a) and the VL sequence defined in (b) The antibody according to claim 36, comprising a sequence selected from the group consisting of the following.

38. The antibody according to claim 36 or claim 37, comprising the VH sequence of SEQ ID NO: 214 and the VL sequence of SEQ ID NO:

213.

39. An antibody that binds to S-HBs, comprising a heavy chain variable domain (VH) comprising (a) CDR-H1 containing the amino acid sequence of SEQ ID NO: 217, (b) CDR-H2 containing the amino acid sequence of SEQ ID NO: 218, and (c) CDR-H3 containing the amino acid sequence of SEQ ID NO: 219, and a light chain variable domain (VL) comprising (d) CDR-L1 containing the amino acid sequence of SEQ ID NO: 220, (e) CDR-L2 containing the amino acid sequence of SEQ ID NO: 221, and (f) CDR-L3 containing the amino acid sequence of SEQ ID NO:

222.

40. (a) A VH sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 232; (b) A VL sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 231; and (c) The VH sequence defined in (a) and the VL sequence defined in (b) The antibody according to claim 39, comprising a sequence selected from the group consisting of the following.

41. The antibody according to claim 39 or claim 40, comprising the VH sequence of SEQ ID NO: 232 and the VL sequence of SEQ ID NO:

231.

42. An antibody that binds to S-HBs, comprising a heavy chain variable domain (VH) comprising (a) CDR-H1 containing the amino acid sequence of SEQ ID NO: 235, (b) CDR-H2 containing the amino acid sequence of SEQ ID NO: 236, and (c) CDR-H3 containing the amino acid sequence of SEQ ID NO: 237, and a light chain variable domain (VL) comprising (d) CDR-L1 containing the amino acid sequence of SEQ ID NO: 238, (e) CDR-L2 containing the amino acid sequence of SEQ ID NO: 239, and (f) CDR-L3 containing the amino acid sequence of SEQ ID NO:

240.

43. (a) A VH sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 250; (b) A VL sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 249; and (c) The VH sequence defined in (a) and the VL sequence defined in (b) The antibody according to claim 42, comprising a sequence selected from the group consisting of the following.

44. The antibody according to claim 42 or claim 43, comprising the VH sequence of SEQ ID NO: 250 and the VL sequence of SEQ ID NO:

249.

45. The antibody according to any one of claims 3 to 11, 15 to 35, or 39 to 41, which is cross-reactive to each of the HBV proteins of sequence numbers 254 to 262.

46. An antibody according to any one of claims 3 to 45, having neutralizing activity against genomic D HBV in vivo or in vitro.

47. The antibody according to any one of claims 3 to 46, wherein, when measured in vitro, the neutralizing IC50 value against HBV genome D is ≤1 ng / ml.

48. The antibody according to any one of claims 1 to 47, which is a monoclonal antibody.

49. The antibody according to any one of claims 1 to 48, which is a human antibody or a chimeric antibody.

50. The antibody according to any one of claims 1 to 49, which is an antibody fragment that binds to S-HBs.

51. The antibody according to any one of claims 1 to 49, which is a full-length IgG antibody.

52. The antibody according to any one of claims 3 to 5, comprising the heavy chain of SEQ ID NO: 18 or 263 and the light chain of SEQ ID NO:

17.

53. The antibody according to any one of claims 6 to 8, comprising the heavy chain of SEQ ID NO: 36 or 264 and the light chain of SEQ ID NO:

35.

54. The antibody according to any one of claims 9 to 11, comprising the heavy chain of SEQ ID NO: 54 or 265 and the light chain of SEQ ID NO:

53.

55. The antibody according to any one of claims 12 to 14, comprising the heavy chain of SEQ ID NO: 72 or 266 and the light chain of SEQ ID NO:

71.

56. The antibody according to any one of claims 15 to 17, comprising the heavy chain of SEQ ID NO: 90 or 267 and the light chain of SEQ ID NO:

89.

57. The antibody according to any one of claims 18 to 20, comprising the heavy chain of SEQ ID NO: 108 or 268 and the light chain of SEQ ID NO:

107.

58. The antibody according to any one of claims 21 to 23, comprising the heavy chain of SEQ ID NO: 126 or 269 and the light chain of SEQ ID NO:

125.

59. The antibody according to any one of claims 24 to 26, comprising the heavy chain of SEQ ID NO: 144 or 270 and the light chain of SEQ ID NO:

143.

60. The antibody according to any one of claims 27 to 29, comprising the heavy chain of SEQ ID NO: 162 or 271 and the light chain of SEQ ID NO:

161.

61. The antibody according to any one of claims 30 to 32, comprising the heavy chain of SEQ ID NO: 180 or 272 and the light chain of SEQ ID NO:

179.

62. The antibody according to any one of claims 33 to 35, comprising the heavy chain of SEQ ID NO: 198 or 273 and the light chain of SEQ ID NO:

197.

63. The antibody according to any one of claims 36 to 38, comprising the heavy chain of SEQ ID NO: 216 or 274 and the light chain of SEQ ID NO:

215.

64. The antibody according to any one of claims 39 to 41, comprising the heavy chain of SEQ ID NO: 234 or 275 and the light chain of SEQ ID NO:

233.

65. The antibody according to any one of claims 42 to 44, comprising the heavy chain of SEQ ID NO: 252 or 276 and the light chain of SEQ ID NO:

251.

66. The antibody according to claim 51, comprising an Fc region having one or more substitutions internally that improve the binding of the Fc region to FcRn.

67. The aforementioned substitution is i) M252Y, S254T and T256E; ii) M428L, N434A and Y436T; iii) N434A; and iv) T307H and N434H The antibody according to claim 66, selected from the group consisting of the following.

68. i) M252Y, S254T and T256E; ii) M428L, N434A and Y436T; iii) N434A; and iv) T307H and N434H The antibody according to claim 67, comprising the light chain of SEQ ID NO: 17 and the heavy chain of SEQ ID NO: 18 or 263, modified by substitution selected from the group consisting of the above.

69. i) M252Y, S254T and T256E; ii) M428L, N434A and Y436T; iii) N434A; and iv) T307H and N434H The antibody according to claim 67, comprising a light chain according to any one of claims 53 to 65 and a heavy chain according to any one of claims 53 to 65, modified by a substitution selected from the group consisting of the above.

70. An isolated nucleic acid encoding an antibody according to any one of claims 1 to 69.

71. A host cell comprising the nucleic acid described in claim 70.

72. A method for producing an antibody that binds to S-HBs, comprising culturing the host cell described in claim 71 under conditions suitable for the expression of the antibody.

73. The method according to claim 72, further comprising recovering the antibody from the host cell.

74. An antibody produced by the method described in claim 73.

75. A pharmaceutical composition comprising an antibody according to any one of claims 1 to 69 or claim 74, and a pharmaceutically acceptable carrier.

76. The pharmaceutical composition according to claim 75, further comprising an additional therapeutic agent.

77. The pharmaceutical composition according to claim 76, wherein the additional therapeutic agent is selected from siRNA targeting an HBV sequence; nucleotide analog reverse transcriptase inhibitors or nucleoside analogs, INFα or pegylated INF-α; therapeutic vaccines; TLR agonists; and / or checkpoint inhibitors.

78. An antibody according to any one of claims 1 to 69 or 74, or a pharmaceutical composition according to any one of claims 75 to 77, for use as a pharmaceutical.

79. An antibody according to any one of claims 1 to 69 or 74, or a pharmaceutical composition according to any one of claims 75 to 77, for use in the treatment of hepatitis B.

80. An antibody according to any one of claims 1 to 69 or claim 74, or a pharmaceutical composition according to claim 75, for use in the treatment of hepatitis B, wherein the treatment further comprises administering an additional therapeutic agent.

81. The antibody or pharmaceutical composition for use according to claim 80, wherein the additional therapeutic agent is selected from the group consisting of HCl sequence-targeting siRNA; nucleotide analog reverse transcriptase inhibitors or nucleoside analogs; INFα or pegylated IFN-α; therapeutic vaccines; TLR agonists; and / or checkpoint inhibitors.

82. A therapeutic agent for use in the treatment of hepatitis B, selected from INFα; therapeutic vaccine; TLR agonist; and / or checkpoint inhibitor, wherein the treatment further comprises administering an antibody according to any one of claims 1 to 69 or claim 74 or a pharmaceutical composition according to claim 75.

83. The antibody, pharmaceutical composition, or therapeutic agent according to any one of claims 79 to 82 for use according to any one of claims 79 to 82, wherein the hepatitis B is chronic hepatitis B.

84. Use of an antibody according to any one of claims 1 to 69 or 74, or a pharmaceutical composition according to any one of claims 75 to 77, in the manufacture of a pharmaceutical for treating hepatitis B.

85. The use according to claim 84, wherein the hepatitis B is chronic hepatitis B.

86. A method for treating an individual having hepatitis B, comprising administering to the individual an effective amount of an antibody according to any one of claims 1 to 69 or a pharmaceutical composition according to claim 75.

87. The method according to claim 86, further comprising administering an additional therapeutic agent to the individual.

88. The method according to claim 87, wherein the additional therapeutic agent is selected from the group consisting of siRNA targeting HBV sequences; nucleotide analog reverse transcriptase inhibitors or nucleoside analogs; INFα or pegylated IFN-α; therapeutic vaccines; TLR agonists; and / or checkpoint inhibitors.

89. The method according to any one of claims 86 to 88, wherein the hepatitis B is chronic hepatitis B.

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