WO2023066171A1 - 特异性结合乙型肝炎病毒表面抗原pre-S1的抗体及其应用 - Google Patents

特异性结合乙型肝炎病毒表面抗原pre-S1的抗体及其应用 Download PDF

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WO2023066171A1
WO2023066171A1 PCT/CN2022/125558 CN2022125558W WO2023066171A1 WO 2023066171 A1 WO2023066171 A1 WO 2023066171A1 CN 2022125558 W CN2022125558 W CN 2022125558W WO 2023066171 A1 WO2023066171 A1 WO 2023066171A1
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amino acid
seq
acid sequence
cdr2
cdr1
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PCT/CN2022/125558
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English (en)
French (fr)
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唐巧朋
李忠
李平
牛玉强
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北京三诺佳邑生物技术有限责任公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans

Definitions

  • the present application relates to an antibody or an antigen-binding fragment specifically binding to the surface antigen pre-S1 of hepatitis B virus, and a preparation method and use thereof.
  • HBV hepatitis B virus
  • the HBV genome is about 3.2 kb in length, partially double-stranded, relaxed circular DNA (rcDNA), which consists of a complete coding negative strand (-) and an incomplete non-coding positive strand (+) (Lamontagne , R Jason et al. Hepatoma research vol.2(2016):163-186.; Glebe, Dieter, and Corinna M Bremer. Seminars in liver disease vol.33,2(2013):103-12.).
  • the coding minus strand contains four overlapping open reading frames (ORFs) (preC/C, P, preS/S and X), where the preS/S ORFs encode large (L), medium (M) and small (S) envelope protein.
  • the L protein contains pre-S1, pre-S2 and S domains, the M protein contains pre-S2 and S domains, and the S protein contains only the S domain (Sheu, S Y, and S J Lo. Virology vol.188,1 (1992):353-7.). These three surface antigens are known to stimulate the production of HBV virus neutralizing antibodies.
  • the pre-S1 domain of the L protein is considered a key determinant of HBV invasion and mediates the interaction between the virus and receptors on hepatocytes (Gripon, P et al. Virology vol. 213, 2 (1995) :292-9.; Le Seyec, J et al.
  • NTCP sodium taurocholate cotransporting polypeptide
  • HBV pre-S1 antibodies against HBV pre-S1, such as the anti-HBV pre-S1 antibody 2H5-A14 and its transformed variants A14-20m1 and A14-8 disclosed in the patent CN107614525B (as a control in the example part of this application Antibody);
  • Patent application CN108064238A discloses a humanized antibody specifically binding to KR127 of HBV pre-S1 and its use.
  • anti-HBV pre-S1 antibodies with high affinity, high neutralizing activity, and/or high ADCC activity in the existing therapeutic field are examples of anti-HBV pre-S1 antibodies with high affinity, high neutralizing activity, and/or high ADCC activity in the existing therapeutic field.
  • an isolated antibody specifically binding to the HBV surface antigen pre-S1 domain comprising: a heavy chain variable domain (V H ), said V H comprising: a heavy chain complementarity determining region (HC-CDR) 1, which comprises TYGIT (SEQ ID NO: 18); HC-CDR2, which comprises SRIPIX 1 GAALYAQKFQG (SEQ ID NO: 115), wherein X 1 is F or L; and HC-CDR3, which comprises NX 1 RGGFAAY (SEQ ID NO: 116), wherein X 1 is D or T; and a light chain variable domain (V L ), said V L comprising: LC-CDR1 comprising RSSQSLX 1 HSNX 2 YNYLD (SEQ ID NO: 117), wherein X 1 is L or T, X 2 is A or G; LC-CDR2, which comprises LGX 1 X 2 RAS (SEQ ID NO: 118), wherein X 1 is H or S, and
  • an isolated antibody specifically binding to the HBV surface antigen pre-S1 domain comprises: V H , and the V H comprises: HC-CDR1, which comprises SEQ ID NO: 18
  • the amino acid sequence of amino acid sequence or its variant, and described variant comprises the substitution of about 3 amino acids at most; HC-CDR2, it comprises the amino acid sequence or its variant shown in any one of SEQ ID NOs:37-38, and described variant
  • the body comprises a substitution of at most about 3 amino acids; and HC-CDR3, which comprises the amino acid sequence shown in any one of SEQ ID NOs: 56-57 or a variant thereof, said variant comprising a substitution of at most about 3 amino acids;
  • V L said V L comprises: LC-CDR1, which comprises SEQ ID NOs: 59, and the amino acid sequence shown in any one of 76-77 or its variant, said variant comprising at most about 3 amino acids Substitution; LC-CDR2, which comprises the amino acid sequence shown in any one of SEQ ID NOs:79
  • an isolated antibody specifically binding to the HBV surface antigen pre-S1 domain comprising: V H , said V H comprising an amino acid sequence as represented by any one of SEQ ID NOs: 146-150 HC-CDR1, HC- CDR2 and HC-CDR3 contained in V H shown, and V L comprising LC-CDR1 contained in V L as shown in any amino acid sequence of SEQ ID NOs: 176-183 , LC-CDR2 and LC-CDR3.
  • an isolated antibody specifically binding to the HBV surface antigen pre-S1 domain comprises: (i) V H , which comprises the V H as shown in the amino acid sequence of SEQ ID NO: 146 HC-CDR1, HC-CDR2 and HC-CDR3; and V L , which comprises LC-CDR1, LC-CDR2 and LC-CDR3 contained in V L as shown in the amino acid sequence SEQ ID NO: 176; (ii) V H , which comprises HC-CDR1, HC-CDR2 and HC-CDR3 contained in V H as shown in amino acid sequence SEQ ID NO:147; and V L , which comprises V L as shown in amino acid sequence SEQ ID NO:177 LC-CDR1, LC-CDR2 and LC-CDR3 comprising; (iii) VH comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprising VH as shown in the amino acid sequence of SEQ ID NO:
  • an isolated antibody specifically binding to the HBV surface antigen pre-S1 domain comprising: (i) V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, HC-CDR2, which comprises the amino acid sequence of SEQ ID NO: 37, and HC-CDR3, which comprises the amino acid sequence of SEQ ID NO: 56, or a variant of said VH , comprising at most about A substitution of 5 amino acids; and a V L comprising: LC- CDR1 comprising the amino acid sequence of SEQ ID NO:59, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:79, and LC-CDR3 comprising Comprising the amino acid sequence of SEQ ID NO: 111, or variants of said V L comprising up to about 5 amino acid substitutions in its LC-CDRs; (ii) V H comprising: HC-CDR1 comprising The amino acid sequence of SEQ ID NO: 18, HC-CDR
  • an isolated antibody specifically binding to the HBV surface antigen pre-S1 domain comprising: V H comprising the amino acid sequence shown in any one of SEQ ID NOs: 146-150 or A variant having at least about 80% sequence identity to the amino acid sequence shown in any of SEQ ID NOs: 146-150; and V L comprising any of SEQ ID NOs: 176-183 The amino acid sequence of or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown in any one of SEQ ID NOs: 176-183.
  • an isolated antibody specifically binding to the HBV surface antigen pre-S1 domain comprising: (i) V H comprising the amino acid sequence of SEQ ID NO: 146 or a variant thereof, said A variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 146; and a V L comprising the amino acid sequence of SEQ ID NO: 176 or a variant thereof having the amino acid sequence of SEQ ID NO: 176 at least about 80% sequence identity; (ii) VH comprising the amino acid sequence of SEQ ID NO: 147 or a variant thereof having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 147; and V L comprising the amino acid sequence of SEQ ID NO: 177 or a variant thereof having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 177; (iii) V H comprising the amino acid sequence of SEQ ID NO: 148 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid
  • an isolated antibody specifically binding to the HBV surface antigen pre-S1 domain comprises: (i) V H , which comprises the V H as shown in the amino acid sequence SEQ ID NO: 120 HC-CDR1, HC-CDR2 and HC-CDR3; and V L , which comprises LC-CDR1, LC-CDR2 and LC-CDR3 contained in V L as shown in the amino acid sequence SEQ ID NO: 151; (ii) V H , which comprises HC-CDR1, HC-CDR2 and HC-CDR3 contained in V H as shown in the amino acid sequence of SEQ ID NO:121; and V L , which comprises the V L shown in the amino acid sequence of SEQ ID NO:152 LC-CDR1, LC-CDR2 and LC-CDR3 comprised; (iii) VH comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprised by VH as shown in the amino acid sequence SEQ ID NO:
  • an isolated antibody specifically binding to the HBV surface antigen pre-S1 domain comprising: (i) V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, HC-CDR2, which comprises the amino acid sequence of SEQ ID NO: 19, and HC-CDR3, which comprises the amino acid sequence of SEQ ID NO: 39, or a variant of said VH , comprising at most about A substitution of 5 amino acids; and a VL comprising: LC- CDR1 comprising the amino acid sequence of SEQ ID NO:58, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:79, and LC-CDR3 comprising Comprising the amino acid sequence of SEQ ID NO: 93, or variants of said V L comprising up to about 5 amino acid substitutions in its LC-CDRs; (ii) V H comprising: HC-CDR1 comprising The amino acid sequence of SEQ ID NO:2, HC-CDR2
  • HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 30, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 50, or a variant of said VH comprising at most about 5 of its HC-CDRs amino acid substitutions; and a VL comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO:61, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:81, and LC-CDR3 comprising the amino acid sequence Sequence SEQ ID NO: 105, or variants of said V L comprising up to about 5 amino acid substitutions in its LC-CDRs; (xiv) V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 13, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 30, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 50, or a variant of said VH comprising in its HC-CDRs A substitution of up
  • VH comprising: HC- CDR1 comprising the amino acid sequence of SEQ ID NO: 15, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 34, and HC-CDR3, It comprises the amino acid sequence of SEQ ID NO: 53, or a variant of said VH comprising up to about 5 amino acid substitutions in its HC-CDRs; and a VL comprising: LC-CDR1 comprising amino acid Sequence SEQ ID NO:73, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:81, and LC-CDR3, which comprises the amino acid sequence of SEQ ID NO:109, or variants of said VL , in which LC-CDRs A substitution comprising:
  • any of the above-mentioned isolated antibodies specifically binding to the HBV surface antigen pre-S1 domain comprises: (i) V H comprising the amino acid sequence shown in SEQ ID NO: 120 or A variant thereof, which has at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO: 120; and V L , which comprises the amino acid sequence set forth in SEQ ID NO: 151 or a variant thereof, wherein Said variant has at least about 80% sequence identity to the amino acid sequence shown in SEQ ID NO: 151; (ii) V H comprising the amino acid sequence shown in SEQ ID NO: 121 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO: 121; and V L comprising the amino acid sequence set forth in SEQ ID NO: 152 or a variant thereof that is identical to SEQ ID NO: The amino acid sequence shown in 152 has at least about 80% sequence identity; (iii) V H , which comprises the amino acid sequence shown in
  • any of the isolated antibodies described above binds the HBV pre-S1 antigen with a Kd value of about 1 pM to about 100 nM.
  • an isolated antibody specifically binding to the HBV surface antigen pre-S1 domain is provided, which competes with any of the above-mentioned isolated anti-HBV pre-S1 antibodies for specific binding to hepatitis B virus. In some embodiments, an isolated antibody specifically binding to the HBV surface antigen pre-S1 domain is provided, which specifically binds to the same epitope as any of the above-mentioned isolated anti-HBV pre-S1 antibodies.
  • any one of the isolated antibodies as described above that specifically binds to the pre-S1 domain of an HBV surface antigen comprising an Fc fragment.
  • the isolated antibody specifically binding to the HBV surface antigen pre-S1 domain is a full-length IgG antibody.
  • the isolated antibody specifically binding to the HBV surface antigen pre-S1 domain is a full-length IgG1, IgG2, IgG3 or IgG4 antibody.
  • the isolated antibody that specifically binds the HBV surface antigen pre-S1 domain is chimeric, fully human or humanized.
  • the isolated antibody specifically binding to the HBV surface antigen pre-S1 domain is an antigen-binding fragment selected from Fab, Fab', F(ab)' 2 , Fab'- SH, single-chain Fv (scFv), Fv fragments, dAb, Fd, nanobody, diabody and linear antibody.
  • an isolated nucleic acid molecule encoding an antibody that specifically binds to the pre-S1 domain of an HBV surface antigen as described above.
  • a vector comprising any one of the nucleic acid molecules described above.
  • a host cell comprising any of the above-mentioned antibodies specifically binding to the HBV surface antigen pre-S1 domain, any of the above-mentioned nucleic acid molecules, or any of the above-mentioned a carrier.
  • a method for preparing an antibody specifically binding to the HBV surface antigen pre-S1 domain comprising: a) under conditions capable of effectively expressing an antibody specifically binding to the HBV surface antigen pre-S1 domain culturing any one of the above host cells; and b) obtaining the expressed antibody specifically binding to the HBV surface antigen pre-S1 domain from the host cells.
  • a method for preventing, improving or treating a disease or condition in a desired individual comprising administering to the individual an effective amount of any one of the above-mentioned specific binding HBV surface antigen pre-S1 domains antibodies.
  • use of any antibody specifically binding to the HBV surface antigen pre-S1 domain as described above in the preparation of a pharmaceutical composition for preventing, improving or treating a disease or condition in a desired individual is provided.
  • any one of the antibodies specifically binding to the HBV surface antigen pre-S1 domain as described above or an antibody comprising any of the above-mentioned antibodies specifically binding to the HBV surface antigen pre-S1 domain is provided Use of the pharmaceutical composition in the preparation of medicaments for preventing, improving or treating diseases or conditions.
  • the desired individual includes, but is not limited to, an individual who has been infected with HBV, has been exposed to, is at risk of, or is susceptible to HBV.
  • the disease or condition is or is associated with HBV infection.
  • the disease or condition is selected from, for example, hepatitis B and liver failure associated with HBV infection, liver cirrhosis, and liver cancer.
  • any one of the above-mentioned antibodies specifically binding to the HBV surface antigen pre-S1 domain in the preparation of a pharmaceutical composition for preventing, improving or treating HBV infection or diseases related to HBV infection use is provided.
  • the antibody specifically binding to the HBV surface antigen pre-S1 domain (such as a full-length antibody) or a pharmaceutical composition thereof is combined with a second, third or fourth agent (including, for example, other antiviral agents, Antiallergic agents, antinausea agents (or antiemetic agents), analgesics, cytoprotectants or immunosuppressants) are used in combination to prevent, improve or treat HBV infection or diseases related to HBV infection.
  • a second, third or fourth agent including, for example, other antiviral agents, Antiallergic agents, antinausea agents (or antiemetic agents), analgesics, cytoprotectants or immunosuppressants
  • the other antiviral agents may include, but are not limited to, interferon, nucleoside/nucleotide analogs, anti-HBV monoclonal antibodies, anti-HBV polyclonal antibodies, DNA polymerase inhibitors or therapeutic vaccines.
  • the nucleoside/nucleotide analogs may include, but are not limited to, lamivudine, entecavir, clevudine or adefovir dipivoxil.
  • compositions, kits and production products comprising any one of the above-mentioned antibodies specifically binding to the HBV surface antigen pre-S1 domain are also provided.
  • the results shown in Figures 1A-1E are the neutralizing activity of the anti-HBV pre-S1 antibody.
  • the results shown in Figure 1A are the neutralizing activity of the anti-HBV pre-S1 antibody K31.
  • the results shown in Figure 1B are the neutralizing activity of the anti-HBV pre-S1 antibody K50.
  • the results shown in Figure 1C are the neutralizing activity of the anti-HBV pre-S1 antibody K55.
  • the results shown in Figure 1D are the neutralizing activity of the anti-HBV pre-S1 antibody K80.
  • the results shown in Figure 1E are the neutralizing activity of the anti-HBV pre-S1 antibody K127.
  • the present application provides an antibody specifically binding to the pre-S1 domain of HBV surface antigen (anti-pre-S1 antibody).
  • anti-pre-S1 antibody an antibody specifically binding to the pre-S1 domain of HBV surface antigen.
  • Anti-HBV pre-S1 antibodies provided by the application include, for example, full-length anti-HBV pre-S1 antibodies, anti-HBV pre-S1 single-chain Fv (scFvs), anti-HBV pre-S1 Fc fusion proteins, multispecific (such as bis specific) anti-HBV pre-S1 antibodies, anti-HBV pre-S1 immunoconjugates, and the like.
  • the application provides an anti-HBV pre-S1 antibody, the anti-HBV pre-S1 antibody comprising: heavy chain variable domain ( VH ), said VH comprising: heavy chain complementarity determining region (HC-CDR )1, which comprises TYGIT (SEQ ID NO: 18); HC-CDR2, which comprises SRIPIX 1 GALYAQKFQG (SEQ ID NO: 115), wherein X 1 is F or L; and HC-CDR3, which comprises NX 1 RGGFAAY ( SEQ ID NO: 116), wherein X 1 is D or T; and a light chain variable domain (V L ), said V L comprising: light chain complementarity determining region (LC-CDR) 1 comprising RSSQSLX 1 HSNX 2 YNYLD (SEQ ID NO: 117), wherein X 1 is L or T, X 2 is A or G; LC-CDR2, which comprises LGX 1 X 2 RAS (SEQ ID NO: 118), wherein X
  • the present application provides an anti-HBV pre-S1 antibody, the anti-HBV pre-S1 antibody comprising: (i) V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO:1, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 19, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 39, or variants of said VH comprising up to about 5 amino acids in the HC-CDRs Substitution; and V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO:58, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:79, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO:79 ID NO: 93, or a variant of said VL , comprising a substitution of up to about 5 amino acids in its LC-CDRs; (ii) VH , said VH comprising: HC-CDR1 comprising: HC
  • HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 30, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 50, or a variant of said VH comprising at most about 5 of its HC-CDRs amino acid substitutions; and a VL comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO:69, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:81, and LC-CDR3 comprising the amino acid sequence Sequence SEQ ID NO: 103, or variants of said V L comprising up to about 5 amino acid substitutions in its LC-CDRs; (xv) V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 9, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 31, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 51, or a variant of said VH comprising in its HC-CDRs A substitution of up to
  • nucleic acids encoding anti-HBV pre-S1 antibodies are also provided.
  • compositions comprising anti-HBV pre-S1 antibodies are also provided.
  • treatment is a method of obtaining a beneficial or desired result, including a clinical result.
  • the beneficial or desired clinical result Including, but not limited to, one or more of the following: alleviating one or more symptoms caused by the disease, reducing the extent of the disease, stabilizing the disease (e.g., preventing or delaying disease progression), preventing or delaying the spread of the disease (e.g., viral spread), preventing or delaying disease recurrence, delaying or slowing disease progression, improving disease state, remission of disease (partial or total), reducing dose of one or more other drugs needed to treat disease, delaying disease progression, improving or enhancing Quality of life, increasing body weight, and/or prolonging survival.
  • treatment also includes the reduction of disease pathological outcome (for example, for HBV virus infection, viral load, liver injury degree). The method of the present application considers Any one or more aspects of these treatments.
  • prevention is meant to include preventive measures to prevent a disease or preventive measures to reduce the risk of a disease.
  • antibody includes full-length antibodies and antigen-binding fragments thereof.
  • Full-length antibodies include two heavy chains and two light chains.
  • the variable regions of the light and heavy chains are responsible for antigen binding.
  • the variable regions in both chains usually include 3 hypervariable loops called complementarity determining regions (CDRs) (light chain (LC) CDRs include LC-CDR1, LC-CDR2 and LC-CDR3, heavy chain (HC ) CDRs include HC-CDR1, HC-CDR2 and HC-CDR3).
  • CDRs complementarity determining regions
  • the CDR boundaries of the antibodies or antigen-binding fragments disclosed herein can be defined or identified by the Kabat, Chothia or Al-Lazikani conventions (Al-Lazikani 1997; Chothia 1985; Chothia 1987; Chothia 1989; Kabat 1987; Kabat 1991).
  • the three CDR regions of the heavy or light chain are inserted between flanking segments called framework regions (FRs), which are more conserved than the CDR regions and form a scaffold to support the hypervariable loops.
  • FRs flanking segments
  • the constant regions of the heavy and light chains are not involved in antigen binding, but exhibit various effector functions.
  • Antibodies are classified based on the amino acid sequence of the constant region of their heavy chains.
  • the five major classes or isotypes of antibodies are IgA, IgD, IgE, IgG and IgM, characterized by heavy chains of the alpha, delta, epsilon, gamma and mu types, respectively.
  • major antibody classes are divided into subclasses such as IgG1 ( ⁇ 1 heavy chain), IgG2 ( ⁇ 2 heavy chain), IgG3 ( ⁇ 3 heavy chain), IgG4 ( ⁇ 4 heavy chain), IgA1 ( ⁇ 1 heavy chain) or IgA2 ( ⁇ 2 heavy chain).
  • antigen-binding fragment includes antibody fragments, for example, diabodies, Fab, Fab', F(ab') 2 , Fv fragments, disulfide bond-stabilized Fv fragments (dsFv), (dsFv) 2 , bispecific dsFv (dsFv-dsFv'), disulfide bond stabilized diabody (ds diabody), single chain Fv (scFv), scFv dimer (divalent diabody), Multispecific antibody, single domain antibody, nanobody (nanobady), domain antibody, bivalent domain antibody, or any other antibody fragment that is capable of binding to an antigen but does not contain a complete antibody structure, consisting of antibody fragments containing one or more CDRs .
  • an antigen-binding fragment is capable of binding the same antigen as a parent antibody or a fragment of a parent antibody (eg, a parent scFv).
  • Antigen-binding fragments also include fusion proteins comprising the antibody fragments described above.
  • an antigen-binding fragment may comprise one or more CDRs from a particular human antibody grafted into framework regions from one or more different human antibodies.
  • epitope refers to a specific atom or group of amino acids on an antigen to which an antibody or antibody portion binds. If two antibodies or antibody portions appear to compete for binding to an antigen, they likely bind the same epitope on the antigen.
  • the primary antibody when the first antibody inhibits the binding of the second antibody to the HBV pre-S1 target by at least 50% (e.g., at least 55%, 60%, 65%, 70%, 75%, 80%, 85%) at an equimolar concentration , 90%, 95%, 98%, or 99%), the primary antibody "competes" with the secondary antibody for binding to the HBV pre-S1 target, and vice versa.
  • PCT publication WO 03/48731 describes a cross-competition-based high-throughput antibody "epitope-sorting" method.
  • the term “specifically binds”, “specifically recognizes” or “is specific for” refers to a measurable and reproducible interaction, for example binding of an antibody to a target can The presence of the target is determined in a heterogeneous population of molecules, including biomolecules.
  • the ability of an antibody to specifically recognize a certain target means that the antibody binds to the target with higher affinity, avidity, easier and/or longer duration than other targets.
  • an antibody that specifically recognizes an antigen reacts with one or more epitopes of the antigen with a binding affinity at least 10 times greater than its binding affinity for other targets.
  • an "isolated" anti-HBV pre-S1 antibody is an anti-HBV pre-S1 antibody that is (1) not related to the naturally occurring protein, (2) free of other proteins of the same origin, (3) expressed by cells of different species, or (4) not present in nature.
  • isolated nucleic acid refers to nucleic acid of genomic, cDNA or synthetic origin or combinations thereof. According to its source, the "isolated nucleic acid” refers to (1) not related to all or part of the polynucleotide in the "isolated nucleic acid” found in nature, (2) may be associated with polynucleotides that are not associated with it in nature. The nucleotides are operably linked, or (3) do not occur in nature as part of a longer sequence.
  • CDR or "complementarity determining region” means the non-contiguous antigen binding sites found within the variable domains of heavy and light chain polypeptides.
  • CDR or "complementarity determining region” means the non-contiguous antigen binding sites found within the variable domains of heavy and light chain polypeptides.
  • Kabat et al. J.Biol.Chem.252:6609-6616 (1977); Kabat et al., U.S. Dept. of Health and Human Services, "Sequences of proteins of immunological interest” (1991); Chothia et al. al., J. Mol. Biol. 196:901-917 (1987); Al-Lazikani B. et al., J. Mol. Biol., 273: 927-948 (1997); MacCallum et al., J.
  • chimeric antibody means that a part of the heavy chain and/or light chain is identical or homologous to the corresponding sequence in an antibody from a specific species or belonging to a specific antibody class or subclass, and this (s) chain The remaining part is identical or homologous to the corresponding sequence in antibodies from another genus or belonging to other antibody classes or subclasses, and fragments of such antibodies, as long as they have the biological activity in this application ( See U.S. Patent No. 4,816,567; and Morrison et al., Proc. Natl. Acad. Sci. USA, 81:6851-6855 (1984)).
  • Fv is the smallest antibody fragment that contains the complete antigen recognition and binding site. This fragment is a dimer formed by tight non-covalent linkage of one heavy chain variable domain and one light chain variable domain. Six hypervariable loops (3 loops each in the light and heavy chains) are derived from the folding of these two domains, which provide the antibody with amino acid residues for binding to the antigen and endow the antibody with the antigen binding specificity. However, even a single variable domain (or half of an Fv fragment, which contains only the 3 CDRs specific for an antigen) has the ability to recognize and bind antigen, albeit with a lower affinity than the full binding site.
  • Single-chain Fv also abbreviated “sFv” or “scFv”
  • sFv is an antibody fragment comprising the VH and VL antibody domains linked into a single polypeptide chain.
  • the scFv polypeptide further includes a linking polypeptide between the VH and VL domains , which allows the scFv to form a desired structure for antigen binding.
  • diabody is a small antibody fragment prepared by constructing a scFv fragment (see the above paragraph) using a short linker (for example, 5-10 residues) between the VH and VL domains. This allows for interchain rather than intrachain pairing of the variable domains, resulting in a bivalent fragment, ie, a fragment with two antigen-binding sites.
  • Bispecific diabodies are heterodimers of two "crossover" scFv fragments in which the VH and VL domains of the two antibodies are located on different polypeptide chains.
  • Diabodies are fully described in EP 404,097; WO 93/11161; Hollinger et al., Proc. Natl. Acad. Sci. USA, 90:6444-6448 (1993).
  • Humanized forms of non-human (eg, rodent) antibodies are chimeric antibodies, which include minimal sequence derived from the non-human antibody.
  • humanized antibodies are human immunoglobulins (recipient antibodies) in which the hypervariable region (HVR) residues of the recipient antibody are derived from a non-human species such as mouse, rat, rabbit or Non-human mammalian hypervariable region residues with desired antibody specificity, affinity and performance are substituted (donor antibody).
  • HVR hypervariable region residues of the recipient antibody
  • donor antibody Non-human mammalian hypervariable region residues with desired antibody specificity, affinity and performance are substituted (donor antibody).
  • residues in the framework regions of the human immunoglobulin are replaced by corresponding non-human residues.
  • humanized antibodies can include residues that are found neither in the recipient antibody nor in the donor antibody. These modifications can further improve antibody performance.
  • a humanized antibody will comprise substantially all, at least one, and usually two variable domains in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin, and all or Essentially all framework regions are human immunoglobulin sequences.
  • the human antibody optionally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin.
  • Fc immunoglobulin constant region
  • Percent amino acid sequence identity or “homology” of the polypeptide and antibody sequences identified herein is defined: a sequence comparison is made where conservative substitutions are considered to be part of the sequence identity, and the candidate sequence is Compare the percentage of identical amino acid residues in polypeptide sequences. Percent amino acid sequence identities can be determined by various alignment methods that are within the skill in the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN, Megalign (DNASTAR), or MUSCLE software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared.
  • percent amino acid sequence identity values are calculated using the sequence alignment computer program MUSCLE (Edgar, R.C., Nucleic Acids Research 32(5):1792-1797, 2004; Edgar, R.C., BMC Bioinformatics 5(1) :113,2004) generated.
  • Fc receptor or "FcR” is used to describe a receptor that binds the Fc region of an antibody.
  • the FcR described herein is an FcR that binds an IgG antibody (a gamma receptor), including receptors of the Fc ⁇ RI, Fc ⁇ RII, and Fc ⁇ RIII subclasses, including allelic variants of these receptors and available into spliced form.
  • FcyRII receptors include FcyRIIA ("activating receptor") and FcyRIIB ("inhibiting receptor”), which have similar amino acid sequences and differ mainly in the cytoplasmic domain.
  • the cytoplasmic domain of the activating receptor Fc ⁇ RIIA contains an immunoreceptor tyrosine activation motif (ITAM).
  • the cytoplasmic domain of the inhibitory receptor Fc ⁇ RIIB contains an immunoreceptor tyrosine inhibition motif (ITIM) (see M.in Annu. Rev. Immunol. 15:203-234 (1997)).
  • ITAM immunoreceptor tyrosine activation motif
  • ITIM immunoreceptor tyrosine inhibition motif
  • FcR in this application encompasses other types of FcRs, including FcRs identified in the future.
  • FcR also includes the neonatal receptor FcRn, which is responsible for the transfer of maternal IgGs to the neonate (Guyer et al., J. Immunol. 117:587 (1976) and Kim et al., J. Immunol. 24:249 (1994 )).
  • FcRn refers to the neonatal Fc receptor (FcRn).
  • FcRn is structurally similar to the major histocompatibility complex (MHC) and consists of an alpha chain non-covalently bound to beta2 microglobulin.
  • MHC major histocompatibility complex
  • FcRn plays an important role in the passive transport of immunoglobulin IgGs from mother to neonate and in the regulation of serum IgG levels.
  • FcRn acts as a salvage receptor that binds and transports endocytosed IgG in intact form within and between cells and saves them from undergoing the default degradation pathway.
  • the "CH1 domain" of the human IgG heavy chain constant region typically extends from amino acid 118 to amino acid 215 (EU numbering system).
  • a "hinge region” is generally defined as extending from Glu 216 to Pro 230 of human IgGl (Burton, Molec. Immunol. 22:161-206 (1985)). Hinge regions of other IgG isotypes can be aligned with the IgGl sequence by placing the first and last cysteine residues that form inter-heavy chain disulfide bonds in the same position as IgGl.
  • the "CH2 domain" of the human IgG Fc region typically extends from amino acid 231 to amino acid 340.
  • the CH2 domain is unique in that it is not tightly paired with another region, but instead has two N-terminally linked branched sugar chains inserted between the two CH2 domains of the intact native IgG molecule. It has been speculated that sugars may act as a surrogate for domain-to-domain pairing, helping to keep the CH2 domain stable. Burton, Molec. Immunol. 22:161-206 (1985).
  • a "CH3" domain includes a stretch within the Fc region from the C-terminal residue to the CH2 domain (from amino acid 341 to the C-terminus of the antibody sequence, usually amino acid residue 446 or 447 of IgG).
  • a “functional Fc fragment” has the "effector function” that a native Fc region sequence has.
  • effector functions include Clq binding; complement-dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); antibody-dependent cell-mediated phagocytosis ( ADCP); phagocytosis; downregulation of cell surface receptors (eg, B cell receptor; BCR), etc.
  • Such effector functions typically require binding of the Fc region to a binding domain (eg, antibody variable region) and can be assessed using a variety of assays well known in the art.
  • Antibodies of IgG Fc variants having "altered" FcR binding affinity or ADCC activity have increased or decreased FcR binding activity and/or ADCC activity compared to a parent polypeptide or a polypeptide comprising a native Fc sequence.
  • An Fc variant exhibiting "enhanced binding" to an FcR has a higher binding affinity for at least one FcR (e.g., a lower apparent Kd or IC50 value) than the parental polypeptide or a polypeptide comprising a native IgG Fc sequence. ).
  • the binding ability is increased by 3 times, such as 5, 10, 25, 50, 60, 100, 150, 200, even up to 500 times or the binding ability is increased by 25% to 1000%, compared to the parental polypeptide.
  • An Fc variant that exhibits "reduced binding" to an FcR has a lower affinity for at least one FcR (eg, a higher apparent Kd or IC50 value) than a parental polypeptide.
  • the binding capacity is reduced by 40% or more compared to the parental polypeptide.
  • ADCC antibody-dependent cell-mediated cytotoxicity
  • cytotoxic cells such as natural killer cells (NK), neutrophils
  • FcRs Fc receptors
  • NK cells only express Fc ⁇ RIII
  • monocytes express Fc ⁇ RI, Fc ⁇ RII, and Fc ⁇ RIII.
  • FcR expression on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol 9:457-92 (1991).
  • an in vitro ADCC assay can be performed, as described in US Patent No. 5,500,362 or 5,821,337. Suitable effector cells for such experiments include peripheral blood mononuclear cells (PBMC) and natural killer cells (NK).
  • PBMC peripheral blood mononuclear cells
  • NK natural killer cells
  • the ADCC activity of a molecule of interest can also be assessed in vivo, for example as described in animal models as disclosed in Clynes et al. PNAS (USA) 95:652-656 (1998).
  • the polypeptide of the antibody is substantially the same in number as the wild-type IgG Fc polypeptide (or parental polypeptide) in the experiment, it can mediate ADCC more effectively in vitro or in vivo.
  • Such variants are typically identified using any in vitro ADCC assay known in the art, eg, assays or methods for identifying ADCC activity, eg, in animal models and the like. In some embodiments, such variants mediate ADCC 5 to 100 fold more efficiently, eg 25 to 50 fold, compared to wild type Fc (or parental polypeptide).
  • Antibody-dependent cell-mediated phagocytosis or “ADCP” refers to a cell-mediated response in which non-specific cytotoxic cells expressing Fc ⁇ Rs recognize antibodies bound to target cells and subsequently cause phagocytosis of the target cells .
  • “Complement-dependent cytotoxicity” or “CDC” refers to the lysis of target cells in the presence of complement. Activation of the classical complement pathway is initiated by the binding of the first component of the complement system (Clq) to antibodies (subclasses of appropriate structure) that bind cognate antigens.
  • Clq first component of the complement system
  • a CDC assay can be performed as described in Gazzano-Santoro et al., J. Immunol. Methods 202:163 (1996).
  • Polypeptide variants with altered Fc region amino acid sequences and increased or decreased C1q binding ability are described in US Patent No. 6,194,551B1 and WO99/51642. The contents of these patent publications are expressly incorporated herein by reference. See also Idusogie et al. J. Immunol. 164:4178-4184 (2000).
  • Neutralization means inhibition of virus infection of a host cell. Without relying on any one theory, the neutralization mechanism of a particular antibody may include blocking the interaction of viral capsid proteins with cell surface receptors, or disrupting entry and trafficking prior to delivery of the viral genome to the nucleus of the host cell any stage in the process.
  • nucleotide sequence encoding an amino acid sequence includes all nucleotide sequences that are mutually degenerate forms and encode the same amino acid sequence.
  • a nucleotide sequence encoding a protein or RNA may also include introns, eg, a nucleotide sequence encoding a protein may, in some forms, include introns.
  • operably linked refers to a functional linkage between a regulatory sequence and a heterologous nucleotide sequence such that the latter is expressed.
  • a first nucleotide sequence is operably linked to a second nucleotide sequence when the first nucleotide sequence is in a functional relationship with the second nucleotide sequence.
  • a promoter is operably linked to a coding sequence if the promoter affects the transcription or expression of the coding sequence.
  • operably linked DNA sequences are contiguous and, when necessary, join two protein coding regions in the same reading frame.
  • “Homologous” refers to sequence similarity or sequence identity between two polypeptides or between two nucleic acid molecules. If the same position in the two compared sequences is the same base or amino acid monomer subunit, for example, the same position in the two DNA molecules is adenine, then the two DNA molecules are homologous at this position.
  • the percent homology between two sequences is a function of the ratio of the number of matching or homologous positions shared by the two sequences to the total number of positions multiplied by 100. For example, if 6 out of 10 positions in two sequences are matched or homologous, then the homology of the two sequences is 60%. For example, the DNA sequences ATTGCC and TATGGC share 50% homology. Generally speaking, when comparing two sequences, the comparison is performed with the aim of obtaining the maximum homology.
  • the "effective amount” of the anti-HBV pre-S1 antibody or composition disclosed herein refers to the amount sufficient to achieve a specific purpose.
  • An “effective amount” can be determined empirically and by methods known in relation to the purpose.
  • a therapeutically effective amount refers to the amount of the anti-HBV pre-S1 antibody or its composition disclosed herein that can effectively treat the individual's disease or symptom.
  • the therapeutically effective amount of anti-HBV pre-S1 antibody or its composition refers to the amount of binding molecules that can effectively prevent or treat the condition caused by HBV infection.
  • Anti-HBV pre-S1 antibodies or compositions thereof disclosed herein are capable of preventing and/or killing existing HBV-infected cells to some extent, which may be cytostatic or cytotoxic.
  • a therapeutically effective amount refers to an amount that can prolong the survival of a patient.
  • a therapeutically effective amount refers to an amount that can improve the progression-free survival of a patient.
  • pharmaceutically acceptable refers to a material that has no biological activity or other undesired properties, for example, the material can be added to a pharmaceutical composition administered to a patient, and Does not cause significant adverse biological reactions, or interact in a deleterious manner with any other components contained in the composition.
  • Pharmaceutically acceptable carriers or excipients preferably meet the required criteria for toxicology or manufacturing testing and/or are included in the inactive ingredient guidelines prepared by the US Food and Drug Administration.
  • Embodiments of the application described herein are to be understood to include “consisting of” and/or “consisting essentially of” embodiments.
  • reference to "not" a value or parameter generally means and describes "other than” a value or parameter.
  • the method cannot be used to treat type X cancer, meaning that the method is usually used to treat other types of cancer than type X cancer.
  • the present application provides an anti-HBV pre-S1 antibody specifically binding to the HBV surface antigen pre-S1 domain.
  • the anti-HBV pre-S1 antibodies include, but are not limited to, humanized antibodies, chimeric antibodies, mouse antibodies, human antibodies, and antibody molecules comprising heavy chain and/or light chain CDRs described herein.
  • the application provides an isolated antibody that binds to an HBV pre-S1 antigen.
  • Contemplated anti-HBV pre-S1 antibodies include, for example, full-length anti-HBV pre-S1 antibodies (such as full-length IgG1 or IgG4), anti-HBV pre-S1 single-chain Fv, anti-HBV pre-S1 Fc fusion proteins, multispecific (such as bispecific) anti-HBV pre-S1 antibodies, anti-HBV pre-S1 immunoconjugates, and the like.
  • the anti-HBV pre-S1 antibody is a full-length antibody (eg, full-length IgG1 or IgG4) or an antigen-binding fragment thereof that specifically binds to the HBV pre-S1 domain.
  • the anti-HBV pre-S1 antibody is Fab, Fab', F(ab)' 2 , Fab'-SH, single chain Fv (scFv), Fv fragment, dAb, Fd, nanobody, Diabodies or linear antibodies.
  • the antibody that specifically binds to the HBV pre-S1 domain refers to that the binding affinity of the antibody to the HBV pre-S1 antigen is at least 10 times that of the non-target binding affinity (including, for example, 10, 10 2 , 10 3 , 10 4 , 10 5 , 10 6 , or 10 7 times).
  • non-target refers to an antigen that is not HBV pre-S1.
  • Binding affinity can be determined by methods known in the art, such as ELISA, fluorescence activated cell sorting (FACS) analysis or radioimmunoprecipitation analysis (RIA).
  • Kd values can be determined by methods known in the art, such as surface plasmon resonance (SPR) techniques or biolayer interferometry (BLI).
  • anti-HBV pre-S1 antibodies comprising human sequences (e.g., human heavy and light chain variable domains comprising human CDR sequences) are broadly discussed herein, nonhuman anti-HBV pre-S1 antibodies are also contemplated.
  • the non-human anti-HBV pre-S1 antibody comprises the human CDR sequences and non-human framework region sequences of the anti-HBV pre-S1 antibodies described herein, and in some embodiments, the non-human framework region sequences comprise any Sequences for generating heavy and/or light chain variable domains using one or more human CDR sequences as described herein, including, for example, mammalian, e.g., mouse, rat, rabbit, pig, bovine (e.g.
  • a non-human anti-HBV pre-S1 antibody comprises an anti-HBV pre-S1 antibody produced by grafting one or more of the human CDR sequences described herein into a non-human framework region (e.g., a mouse or chicken framework region sequence). HBV pre-S1 antibody.
  • the complete amino acid sequence of the exemplary HBV B genotype pre-S1 antigen comprises or consists of the amino acid sequence shown in SEQ ID NO: 190.
  • the complete amino acid sequence of the exemplary HBV C genotype pre-S1 antigen comprises or consists of the amino acid sequence shown in SEQ ID NO: 191.
  • the anti-HBV pre-S1 antibodies described herein specifically recognize an epitope in the HBV pre-S1 domain.
  • the anti-HBV pre-S1 antibody can bind to pre-S1 antigens of various HBV genotypes, and its binding to HBV has a broad spectrum.
  • any anti-HBV pre-S1 antibody as described herein said anti-HBV pre-S1 antibody comprises an antibody heavy chain constant region and an antibody light chain constant region.
  • the anti-HBV pre-S1 antibody comprises an IgG1 heavy chain constant region.
  • the anti-HBV pre-S1 antibody comprises an IgG2 type heavy chain constant region.
  • the anti-HBV pre-S1 antibody comprises an IgG3 type heavy chain constant region.
  • the anti-HBV pre-S1 antibody comprises an IgG4 type heavy chain constant region.
  • the heavy chain constant region comprises (including consists of or consists essentially of) the amino acid sequence of SEQ ID NO: 186.
  • the heavy chain constant region comprises (including consists of or consists essentially of) the amino acid sequence of SEQ ID NO: 187.
  • the anti-HBV pre-S1 antibody comprises a kappa light chain constant region.
  • the light chain constant region comprises (including consists of or consists essentially of) the amino acid sequence of SEQ ID NO: 188.
  • the anti-HBV pre-S1 antibody comprises a lambda light chain constant region.
  • the light chain constant region comprises (including consists of or consists essentially of) the amino acid sequence of SEQ ID NO: 189.
  • the anti-HBV pre-S1 antibody comprises an antibody heavy chain variable domain and an antibody light chain variable domain.
  • the anti-HBV pre-S1 antibody comprises VH , and the VH comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 19.
  • HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 39, or a variant of said VH comprising up to about 5 amino acid substitutions in its HC-CDRs; and VL comprising: LC - CDR1 comprising the amino acid sequence of SEQ ID NO:58, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:79, LC-CDR3 comprising the amino acid sequence of SEQ ID NO:93, or a variant of said VL , It contains up to about 5 amino acid substitutions in its LC-CDRs.
  • the anti-HBV pre-S1 antibody comprises VH
  • the VH comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 19, and HC-CDR3, which comprises the amino acid sequence of SEQ ID NO: 39; and V L , which comprises: LC- CDR1 , which comprises the amino acid sequence of SEQ ID NO: 58, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO: 58; ID NO:79, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO:93.
  • the anti-HBV pre-S1 antibody comprises VH comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprised by VH as shown in the amino acid sequence of SEQ ID NO: 120; and VL , which comprises LC-CDR1, LC-CDR2 and LC-CDR3 contained in the V L shown in the amino acid sequence of SEQ ID NO: 151.
  • the anti-HBV pre-S1 antibody comprises: VH , the VH comprising the amino acid sequence of SEQ ID NO: 120 or a variant thereof, the variant having at least the same amino acid sequence of SEQ ID NO: 120 about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and a VL comprising the amino acid sequence of SEQ ID NO: 151 Or a variant thereof having at least about 80% (eg at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence with the amino acid sequence of SEQ ID NO: 151 identity.
  • the anti-HBV pre-S1 antibody comprises a VH comprising the amino acid sequence of SEQ ID NO:120, and a VL comprising the amino acid sequence of SEQ ID NO:151.
  • the anti-HBV pre-S1 antibody comprises VH , and the VH comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO:2, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 20.
  • HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 40, or a variant of said VH comprising up to about 5 amino acid substitutions in its HC-CDRs; and VL comprising: LC - CDR1 comprising the amino acid sequence of SEQ ID NO:59, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:79, LC-CDR3 comprising the amino acid sequence of SEQ ID NO:94, or a variant of said VL , It contains up to about 5 amino acid substitutions in its LC-CDRs.
  • the anti-HBV pre-S1 antibody comprises VH
  • the VH comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO:2, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 20, and HC-CDR3, which comprises the amino acid sequence of SEQ ID NO:40; and VL , which comprises: LC-CDR1, which comprises the amino acid sequence of SEQ ID NO:59, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:59 ; ID NO:79, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO:94.
  • the anti-HBV pre-S1 antibody comprises a VH comprising HC-CDR1, HC-CDR2 and HC-CDR3 contained in the VH as shown in the amino acid sequence of SEQ ID NO: 121; and VL , which comprises LC-CDR1, LC-CDR2 and LC-CDR3 contained in the V L as shown in the amino acid sequence of SEQ ID NO: 152.
  • the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 121 or a variant thereof having at least the same amino acid sequence as SEQ ID NO: 121 about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and a VL comprising the amino acid sequence of SEQ ID NO: 152 Or a variant thereof having at least about 80% (eg at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence with the amino acid sequence of SEQ ID NO: 152 identity.
  • the anti-HBV pre-S1 antibody comprises a VH comprising the amino acid sequence of SEQ ID NO:121, and a VL comprising the amino acid sequence of SEQ ID NO:152.
  • the anti-HBV pre-S1 antibody comprises VH , and the VH comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 3, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 21.
  • HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 41, or a variant of said VH comprising up to about 5 amino acid substitutions in its HC-CDRs; and VL comprising: LC - CDR1 comprising the amino acid sequence of SEQ ID NO:60, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:80, LC-CDR3 comprising the amino acid sequence of SEQ ID NO:95, or a variant of said VL , It contains up to about 5 amino acid substitutions in its LC-CDRs.
  • the anti-HBV pre-S1 antibody comprises VH
  • the VH comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 3, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 21, and HC-CDR3, which comprises the amino acid sequence of SEQ ID NO:41; and VL , which comprises: LC-CDR1, which comprises the amino acid sequence of SEQ ID NO:60, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:80, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO:95.
  • the anti-HBV pre-S1 antibody comprises VH comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprised by VH as shown in the amino acid sequence of SEQ ID NO: 122; and VL , which comprises LC-CDR1, LC-CDR2 and LC-CDR3 contained in the V L as shown in the amino acid sequence of SEQ ID NO: 153.
  • the anti-HBV pre-S1 antibody comprises: VH , the VH comprising the amino acid sequence of SEQ ID NO: 122 or a variant thereof, the variant having at least the same amino acid sequence of SEQ ID NO: 122 about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and a VL comprising the amino acid sequence of SEQ ID NO: 153 Or a variant thereof having at least about 80% (eg at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence with the amino acid sequence of SEQ ID NO: 153 identity.
  • the anti-HBV pre-S1 antibody comprises a VH comprising the amino acid sequence of SEQ ID NO: 122, and a VL comprising the amino acid sequence of SEQ ID NO: 153.
  • the anti-HBV pre-S1 antibody comprises VH , and the VH comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 4, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 22.
  • HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 42, or a variant of said VH comprising up to about 5 amino acid substitutions in its HC-CDRs
  • VL comprising: LC - CDR1 comprising the amino acid sequence of SEQ ID NO:61, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:81, LC-CDR3 comprising the amino acid sequence of SEQ ID NO:96, or a variant of said VL , It contains up to about 5 amino acid substitutions in its LC-CDRs.
  • the anti-HBV pre-S1 antibody comprises VH
  • the VH comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO:4, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 22, and HC-CDR3, which comprises the amino acid sequence of SEQ ID NO:42; and VL , which comprises: LC-CDR1, which comprises the amino acid sequence of SEQ ID NO:61, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:81, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO:96.
  • the anti-HBV pre-S1 antibody comprises a VH comprising HC-CDR1, HC-CDR2 and HC-CDR3 contained in the VH as shown in the amino acid sequence of SEQ ID NO: 123; and VL , which comprises LC-CDR1, LC-CDR2 and LC-CDR3 contained in the V L as shown in the amino acid sequence SEQ ID NO: 154.
  • the anti-HBV pre-S1 antibody comprises: V H , the V H comprising the amino acid sequence of SEQ ID NO: 123 or a variant thereof having at least the same amino acid sequence of SEQ ID NO: 123 about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and a VL comprising the amino acid sequence of SEQ ID NO: 154 Or a variant thereof having at least about 80% (eg at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence with the amino acid sequence of SEQ ID NO: 154 identity.
  • the anti-HBV pre-S1 antibody comprises a VH comprising the amino acid sequence of SEQ ID NO:123, and a VL comprising the amino acid sequence of SEQ ID NO:154.
  • the anti-HBV pre-S1 antibody comprises VH , and the VH comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO:5, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 23.
  • HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 43, or a variant of said VH comprising up to about 5 amino acid substitutions in its HC-CDRs
  • VL comprising: LC - CDR1 comprising the amino acid sequence of SEQ ID NO:61, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:82, LC-CDR3 comprising the amino acid sequence of SEQ ID NO:97, or a variant of said VL , It contains up to about 5 amino acid substitutions in its LC-CDRs.
  • the anti-HBV pre-S1 antibody comprises VH
  • the VH comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO:5, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 23, and HC-CDR3, which comprises the amino acid sequence of SEQ ID NO:43; and V L , which comprises: LC- CDR1 , which comprises the amino acid sequence of SEQ ID NO:61, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:82, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO:97.
  • the anti-HBV pre-S1 antibody comprises VH comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprised by VH as shown in the amino acid sequence of SEQ ID NO: 124; and VL , which comprises LC-CDR1, LC-CDR2 and LC-CDR3 contained in the V L as shown in the amino acid sequence of SEQ ID NO: 155.
  • the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 124 or a variant thereof having at least the same amino acid sequence of SEQ ID NO: 124 about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and a VL comprising the amino acid sequence of SEQ ID NO: 155 Or a variant thereof having at least about 80% (eg at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence with the amino acid sequence of SEQ ID NO: 155 identity.
  • the anti-HBV pre-S1 antibody comprises a VH comprising the amino acid sequence of SEQ ID NO: 124, and a VL comprising the amino acid sequence of SEQ ID NO: 155.
  • the anti-HBV pre-S1 antibody comprises VH , and the VH comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO:7, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 25.
  • HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 45, or a variant of said VH comprising up to about 5 amino acid substitutions in its HC-CDRs
  • VL comprising: LC - CDR1 comprising the amino acid sequence of SEQ ID NO:63, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:84, LC-CDR3 comprising the amino acid sequence of SEQ ID NO:99, or a variant of said VL , It contains up to about 5 amino acid substitutions in its LC-CDRs.
  • the anti-HBV pre-S1 antibody comprises VH
  • the VH comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO:7, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 25, and HC-CDR3, which comprises the amino acid sequence of SEQ ID NO:45; and VL , which comprises: LC-CDR1, which comprises the amino acid sequence of SEQ ID NO:63, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:63 ; ID NO:84, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO:99.
  • the anti-HBV pre-S1 antibody comprises VH comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprised by VH as shown in the amino acid sequence of SEQ ID NO: 126; and VL , which comprises LC-CDR1, LC-CDR2 and LC-CDR3 contained in the V L as shown in the amino acid sequence of SEQ ID NO: 157.
  • the anti-HBV pre-S1 antibody comprises: V H , the V H comprising the amino acid sequence of SEQ ID NO: 126 or a variant thereof having at least the same amino acid sequence of SEQ ID NO: 126 about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and a VL comprising the amino acid sequence of SEQ ID NO: 157 Or a variant thereof having at least about 80% (eg at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence with the amino acid sequence of SEQ ID NO: 157 identity.
  • the anti-HBV pre-S1 antibody comprises a VH comprising the amino acid sequence of SEQ ID NO: 126, and a VL comprising the amino acid sequence of SEQ ID NO: 157.
  • the anti-HBV pre-S1 antibody comprises VH , and the VH comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO:7, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 26.
  • HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 46, or a variant of said VH comprising up to about 5 amino acid substitutions in its HC-CDRs
  • VL comprising: LC - CDR1 comprising the amino acid sequence of SEQ ID NO: 64, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 79, LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 100, or a variant of said VL , It contains up to about 5 amino acid substitutions in its LC-CDRs.
  • the anti-HBV pre-S1 antibody comprises VH
  • the VH comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 7, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and HC-CDR3, which comprises the amino acid sequence of SEQ ID NO:46; and V L , which comprises: LC- CDR1 , which comprises the amino acid sequence of SEQ ID NO:64, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:64; ID NO:79, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO:100.
  • the anti-HBV pre-S1 antibody comprises VH comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprised by VH as shown in the amino acid sequence of SEQ ID NO: 128; and VL , which comprises LC-CDR1, LC-CDR2 and LC-CDR3 contained in the V L as shown in the amino acid sequence of SEQ ID NO: 158.
  • the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 128 or a variant thereof having at least the same amino acid sequence of SEQ ID NO: 128 about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and a VL comprising the amino acid sequence of SEQ ID NO: 158 Or a variant thereof having at least about 80% (eg at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence with the amino acid sequence of SEQ ID NO: 158 identity.
  • the anti-HBV pre-S1 antibody comprises a VH comprising the amino acid sequence of SEQ ID NO: 128, and a VL comprising the amino acid sequence of SEQ ID NO: 158.
  • the anti-HBV pre-S1 antibody comprises VH , and the VH comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 8, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 27.
  • HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 47, or a variant of said VH comprising up to about 5 amino acid substitutions in its HC-CDRs
  • VL comprising: LC - CDR1 comprising the amino acid sequence of SEQ ID NO: 65, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 85, LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 101, or a variant of said VL , It contains up to about 5 amino acid substitutions in its LC-CDRs.
  • the anti-HBV pre-S1 antibody comprises VH
  • the VH comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 8, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 27, and HC-CDR3, which comprises the amino acid sequence of SEQ ID NO:47; and V L , which comprises: LC- CDR1 , which comprises the amino acid sequence of SEQ ID NO:65, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:65; ID NO:85, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO:101.
  • the anti-HBV pre-S1 antibody comprises VH comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprised by VH as shown in the amino acid sequence of SEQ ID NO: 130; and VL , which comprises LC-CDR1, LC-CDR2 and LC-CDR3 contained in the V L as shown in the amino acid sequence of SEQ ID NO: 159.
  • the anti-HBV pre-S1 antibody comprises: VH , the VH comprising the amino acid sequence of SEQ ID NO: 130 or a variant thereof, the variant having at least the same amino acid sequence of SEQ ID NO: 130 about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and a VL comprising the amino acid sequence of SEQ ID NO: 159 Or a variant thereof having at least about 80% (eg at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence with the amino acid sequence of SEQ ID NO: 159 identity.
  • the anti-HBV pre-S1 antibody comprises a VH comprising the amino acid sequence of SEQ ID NO:130, and a VL comprising the amino acid sequence of SEQ ID NO:159.
  • the anti-HBV pre-S1 antibody comprises VH , and the VH comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 9, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 28.
  • HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 48, or a variant of said VH comprising up to about 5 amino acid substitutions in its HC-CDRs; and VL comprising: LC - CDR1 comprising the amino acid sequence of SEQ ID NO: 66, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 86, LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 102, or a variant of said VL , It contains up to about 5 amino acid substitutions in its LC-CDRs.
  • the anti-HBV pre-S1 antibody comprises VH
  • the VH comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 9, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 28, and HC-CDR3, which comprises the amino acid sequence of SEQ ID NO:48; and V L , which comprises: LC- CDR1 , which comprises the amino acid sequence of SEQ ID NO:66, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:66; ID NO:86, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO:102.
  • the anti-HBV pre-S1 antibody comprises VH comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprised by VH as shown in the amino acid sequence of SEQ ID NO: 131; and VL , which comprises LC-CDR1, LC-CDR2 and LC-CDR3 contained in the V L shown in the amino acid sequence of SEQ ID NO: 160.
  • the anti-HBV pre-S1 antibody comprises: VH , the VH comprising the amino acid sequence of SEQ ID NO: 131 or a variant thereof having at least the same amino acid sequence as SEQ ID NO: 131 about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and a VL comprising the amino acid sequence of SEQ ID NO: 160 Or a variant thereof having at least about 80% (eg at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence with the amino acid sequence of SEQ ID NO: 160 identity.
  • the anti-HBV pre-S1 antibody comprises a VH comprising the amino acid sequence of SEQ ID NO:131, and a VL comprising the amino acid sequence of SEQ ID NO:160.
  • the anti-HBV pre-S1 antibody comprises VH , and the VH comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 6, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 24.
  • HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 44, or a variant of said VH comprising up to about 5 amino acid substitutions in its HC-CDRs
  • VL comprising: LC - CDR1 comprising the amino acid sequence of SEQ ID NO:62, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:83, LC-CDR3 comprising the amino acid sequence of SEQ ID NO:98, or a variant of said VL , It contains up to about 5 amino acid substitutions in its LC-CDRs.
  • the anti-HBV pre-S1 antibody comprises VH
  • the VH comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 6, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 24, and HC-CDR3, which comprises the amino acid sequence of SEQ ID NO:44; and VL , which comprises: LC-CDR1, which comprises the amino acid sequence of SEQ ID NO:62, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:83, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO:98.
  • the anti-HBV pre-S1 antibody comprises VH comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprised by VH as shown in the amino acid sequence of SEQ ID NO: 132; and VL , which comprises LC-CDR1, LC-CDR2 and LC-CDR3 contained in the V L as shown in the amino acid sequence of SEQ ID NO: 161.
  • the anti-HBV pre-S1 antibody comprises: VH , the VH comprising the amino acid sequence of SEQ ID NO: 132 or a variant thereof, the variant having at least the same amino acid sequence of SEQ ID NO: 132 about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and a VL comprising the amino acid sequence of SEQ ID NO: 161 Or a variant thereof having at least about 80% (eg at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence with the amino acid sequence of SEQ ID NO: 161 identity.
  • the anti-HBV pre-S1 antibody comprises a VH comprising the amino acid sequence of SEQ ID NO:132, and a VL comprising the amino acid sequence of SEQ ID NO:161.
  • the anti-HBV pre-S1 antibody comprises VH , and the VH comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 10, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 29.
  • HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 49, or a variant of said VH comprising up to about 5 amino acid substitutions in its HC-CDRs; and VL comprising: LC - CDR1 comprising the amino acid sequence of SEQ ID NO: 67, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 87, LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 103, or a variant of said VL , It contains up to about 5 amino acid substitutions in its LC-CDRs.
  • the anti-HBV pre-S1 antibody comprises VH
  • the VH comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 10, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 29, and HC-CDR3, which comprises the amino acid sequence of SEQ ID NO:49; and V L , which comprises: LC- CDR1 , which comprises the amino acid sequence of SEQ ID NO:67, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:67; ID NO:87, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO:103.
  • the anti-HBV pre-S1 antibody comprises a VH comprising HC-CDR1, HC-CDR2 and HC-CDR3 contained in the VH as shown in the amino acid sequence of SEQ ID NO: 133; and VL , which comprises LC-CDR1, LC-CDR2 and LC-CDR3 contained in the V L as shown in the amino acid sequence of SEQ ID NO: 162.
  • the anti-HBV pre-S1 antibody comprises: VH , the VH comprising the amino acid sequence of SEQ ID NO: 133 or a variant thereof having at least the same amino acid sequence of SEQ ID NO: 133 about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and a VL comprising the amino acid sequence of SEQ ID NO: 162 Or a variant thereof having at least about 80% (eg at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence with the amino acid sequence of SEQ ID NO: 162 identity.
  • the anti-HBV pre-S1 antibody comprises a VH comprising the amino acid sequence of SEQ ID NO:133, and a VL comprising the amino acid sequence of SEQ ID NO:162.
  • the anti-HBV pre-S1 antibody comprises VH , and the VH comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 11, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 30.
  • HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 50, or a variant of said VH comprising up to about 5 amino acid substitutions in its HC-CDRs
  • VL comprising: LC - CDR1 comprising the amino acid sequence of SEQ ID NO:68, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:81, LC-CDR3 comprising the amino acid sequence of SEQ ID NO:104, or a variant of said VL , It contains up to about 5 amino acid substitutions in its LC-CDRs.
  • the anti-HBV pre-S1 antibody comprises VH
  • the VH comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 11, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 30, and HC-CDR3, which comprises the amino acid sequence of SEQ ID NO:50
  • V L which comprises: LC- CDR1 , which comprises the amino acid sequence of SEQ ID NO:68, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:68; ID NO:81, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO:104.
  • the anti-HBV pre-S1 antibody comprises VH comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprised by VH as shown in the amino acid sequence of SEQ ID NO: 134; and VL , which comprises LC-CDR1, LC-CDR2 and LC-CDR3 contained in the V L as shown in the amino acid sequence of SEQ ID NO: 163.
  • the anti-HBV pre-S1 antibody comprises: VH , the VH comprising the amino acid sequence of SEQ ID NO: 134 or a variant thereof, the variant having at least the same amino acid sequence of SEQ ID NO: 134 about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and a VL comprising the amino acid sequence of SEQ ID NO: 163 Or a variant thereof having at least about 80% (eg at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence with the amino acid sequence of SEQ ID NO: 163 identity.
  • the anti-HBV pre-S1 antibody comprises a VH comprising the amino acid sequence of SEQ ID NO:134, and a VL comprising the amino acid sequence of SEQ ID NO:163.
  • the anti-HBV pre-S1 antibody comprises a VH comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 12, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 30.
  • HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 50, or a variant of said VH comprising up to about 5 amino acid substitutions in its HC-CDRs;
  • VL comprising: LC - CDR1 comprising the amino acid sequence of SEQ ID NO: 61, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 81, LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 105, or a variant of said VL , It contains up to about 5 amino acid substitutions in its LC-CDRs.
  • the anti-HBV pre-S1 antibody comprises VH
  • the VH comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 12, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 30, and HC-CDR3, which comprises the amino acid sequence of SEQ ID NO:50; and VL , which comprises: LC-CDR1, which comprises the amino acid sequence of SEQ ID NO:61, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:81, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO:105.
  • the anti-HBV pre-S1 antibody comprises a VH comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprised by the VH as shown in the amino acid sequence of SEQ ID NO: 135; and VL , which comprises LC-CDR1, LC-CDR2 and LC-CDR3 contained in the V L as shown in the amino acid sequence SEQ ID NO: 164.
  • the anti-HBV pre-S1 antibody comprises: VH , the VH comprising the amino acid sequence of SEQ ID NO: 135 or a variant thereof having at least the same amino acid sequence of SEQ ID NO: 135 about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and a VL comprising the amino acid sequence of SEQ ID NO: 164 Or a variant thereof having at least about 80% (eg at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence with the amino acid sequence of SEQ ID NO: 164 identity.
  • the anti-HBV pre-S1 antibody comprises a VH comprising the amino acid sequence of SEQ ID NO:135, and a VL comprising the amino acid sequence of SEQ ID NO:164.
  • the anti-HBV pre-S1 antibody comprises VH , and the VH comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 13, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 30.
  • HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 50, or a variant of said VH comprising up to about 5 amino acid substitutions in its HC-CDRs
  • VL comprising: LC - CDR1 comprising the amino acid sequence of SEQ ID NO:69, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:81, LC-CDR3 comprising the amino acid sequence of SEQ ID NO:103, or a variant of said VL , It contains up to about 5 amino acid substitutions in its LC-CDRs.
  • the anti-HBV pre-S1 antibody comprises VH
  • the VH comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 13, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 30, and HC-CDR3, which comprises the amino acid sequence of SEQ ID NO:50; and V L , which comprises: LC- CDR1 , which comprises the amino acid sequence of SEQ ID NO:69, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:69; ID NO:81, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO:103.
  • the anti-HBV pre-S1 antibody comprises VH comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprised by VH as shown in the amino acid sequence of SEQ ID NO: 136; and VL , which comprises LC-CDR1, LC-CDR2 and LC-CDR3 contained in the V L as shown in the amino acid sequence of SEQ ID NO: 165.
  • the anti-HBV pre-S1 antibody comprises: VH , the VH comprising the amino acid sequence of SEQ ID NO: 136 or a variant thereof having at least the same amino acid sequence of SEQ ID NO: 136 about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and a VL comprising the amino acid sequence of SEQ ID NO: 165 Or a variant thereof having at least about 80% (eg at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence with the amino acid sequence of SEQ ID NO: 165 identity.
  • the anti-HBV pre-S1 antibody comprises a VH comprising the amino acid sequence of SEQ ID NO: 136, and a VL comprising the amino acid sequence of SEQ ID NO: 165.
  • the anti-HBV pre-S1 antibody comprises VH , and the VH comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 9, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 31.
  • HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 51, or a variant of said VH comprising up to about 5 amino acid substitutions in its HC-CDRs
  • VL comprising: LC - CDR1 comprising the amino acid sequence of SEQ ID NO:70, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:83, LC-CDR3 comprising the amino acid sequence of SEQ ID NO:106, or a variant of said VL , It contains up to about 5 amino acid substitutions in its LC-CDRs.
  • the anti-HBV pre-S1 antibody comprises VH
  • the VH comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 9, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 31, and HC-CDR3, which comprises the amino acid sequence of SEQ ID NO:51; and VL , which comprises: LC-CDR1, which comprises the amino acid sequence of SEQ ID NO:70, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:83, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO:106.
  • the anti-HBV pre-S1 antibody comprises VH comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprised by VH as shown in the amino acid sequence of SEQ ID NO: 137; and VL , which comprises LC-CDR1, LC-CDR2 and LC-CDR3 contained in the V L as shown in the amino acid sequence of SEQ ID NO: 167.
  • the anti-HBV pre-S1 antibody comprises: V H , the V H comprising the amino acid sequence of SEQ ID NO: 137 or a variant thereof having at least the same amino acid sequence of SEQ ID NO: 137 about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and a VL comprising the amino acid sequence of SEQ ID NO: 167 Or a variant thereof having at least about 80% (eg at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence with the amino acid sequence of SEQ ID NO: 167 identity.
  • the anti-HBV pre-S1 antibody comprises a VH comprising the amino acid sequence of SEQ ID NO: 137, and a VL comprising the amino acid sequence of SEQ ID NO: 167.
  • the anti-HBV pre-S1 antibody comprises VH , and the VH comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 14, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 32.
  • HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 51, or a variant of said VH comprising up to about 5 amino acid substitutions in its HC-CDRs
  • VL comprising: LC - CDR1 comprising the amino acid sequence of SEQ ID NO: 71, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 86, LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 107, or a variant of said VL , It contains up to about 5 amino acid substitutions in its LC-CDRs.
  • the anti-HBV pre-S1 antibody comprises a VH comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 14, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 32, and HC-CDR3, which comprises the amino acid sequence of SEQ ID NO:51; and V L , which comprises: LC- CDR1 , which comprises the amino acid sequence of SEQ ID NO:71, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:71; ID NO:86, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO:107.
  • the anti-HBV pre-S1 antibody comprises a VH comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprised by the VH as shown in the amino acid sequence of SEQ ID NO: 139; and VL , which comprises LC-CDR1, LC-CDR2 and LC-CDR3 contained in the V L as shown in the amino acid sequence SEQ ID NO: 169.
  • the anti-HBV pre-S1 antibody comprises: VH , the VH comprising the amino acid sequence of SEQ ID NO: 139 or a variant thereof having at least the same amino acid sequence of SEQ ID NO: 139 about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and a VL comprising the amino acid sequence of SEQ ID NO: 169 Or a variant thereof having at least about 80% (eg at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence with the amino acid sequence of SEQ ID NO: 169 identity.
  • the anti-HBV pre-S1 antibody comprises a VH comprising the amino acid sequence of SEQ ID NO: 139, and a VL comprising the amino acid sequence of SEQ ID NO: 169.
  • the anti-HBV pre-S1 antibody comprises VH , and the VH comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 11, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 30.
  • HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 50, or a variant of said VH comprising up to about 5 amino acid substitutions in its HC-CDRs
  • VL comprising: LC - CDR1 comprising the amino acid sequence of SEQ ID NO:72, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:81, LC-CDR3 comprising the amino acid sequence of SEQ ID NO:108, or a variant of said VL , It contains up to about 5 amino acid substitutions in its LC-CDRs.
  • the anti-HBV pre-S1 antibody comprises VH
  • the VH comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 11, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 30, and HC-CDR3, which comprises the amino acid sequence of SEQ ID NO:50
  • V L which comprises: LC- CDR1 , which comprises the amino acid sequence of SEQ ID NO:72, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:72; ID NO:81, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO:108.
  • the anti-HBV pre-S1 antibody comprises VH comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprised by VH as shown in the amino acid sequence of SEQ ID NO: 140; and VL , which comprises LC-CDR1, LC-CDR2 and LC-CDR3 contained in the V L as shown in the amino acid sequence of SEQ ID NO: 170.
  • the anti-HBV pre-S1 antibody comprises: VH , the VH comprising the amino acid sequence of SEQ ID NO: 140 or a variant thereof, the variant having at least the same amino acid sequence of SEQ ID NO: 140 about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and a VL comprising the amino acid sequence of SEQ ID NO: 170 Or a variant thereof having at least about 80% (eg at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence with the amino acid sequence of SEQ ID NO: 170 identity.
  • the anti-HBV pre-S1 antibody comprises a VH comprising the amino acid sequence of SEQ ID NO: 140, and a VL comprising the amino acid sequence of SEQ ID NO: 170.
  • the anti-HBV pre-S1 antibody comprises VH , and the VH comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 13, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 33.
  • HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 52, or a variant of said VH comprising up to about 5 amino acid substitutions in its HC-CDRs
  • VL comprising: LC - CDR1 comprising the amino acid sequence of SEQ ID NO:61, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:81, LC-CDR3 comprising the amino acid sequence of SEQ ID NO:97, or a variant of said VL , It contains up to about 5 amino acid substitutions in its LC-CDRs.
  • the anti-HBV pre-S1 antibody comprises VH
  • the VH comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 13, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 33, and HC-CDR3, which comprises the amino acid sequence of SEQ ID NO:52; and VL , which comprises: LC-CDR1, which comprises the amino acid sequence of SEQ ID NO:61, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:81, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO:97.
  • the anti-HBV pre-S1 antibody comprises VH comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprised by VH as shown in the amino acid sequence of SEQ ID NO: 141; and VL , which comprises LC-CDR1, LC-CDR2 and LC-CDR3 contained in the V L as shown in the amino acid sequence of SEQ ID NO: 171.
  • the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 141 or a variant thereof having at least the same amino acid sequence of SEQ ID NO: 141 about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and a VL comprising the amino acid sequence of SEQ ID NO: 171 Or a variant thereof having at least about 80% (eg at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence with the amino acid sequence of SEQ ID NO: 171 identity.
  • the anti-HBV pre-S1 antibody comprises a VH comprising the amino acid sequence of SEQ ID NO: 141, and a VL comprising the amino acid sequence of SEQ ID NO: 171.
  • the anti-HBV pre-S1 antibody comprises VH , and the VH comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 10, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 30.
  • HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 50, or a variant of said VH comprising up to about 5 amino acid substitutions in its HC-CDRs; and VL comprising: LC - CDR1 comprising the amino acid sequence of SEQ ID NO: 61, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 81, LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 103, or a variant of said VL , It contains up to about 5 amino acid substitutions in its LC-CDRs.
  • the anti-HBV pre-S1 antibody comprises VH
  • the VH comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 10, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 30, and HC-CDR3, which comprises the amino acid sequence of SEQ ID NO:50; and V L , which comprises: LC- CDR1 , which comprises the amino acid sequence of SEQ ID NO:61, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:81, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO:103.
  • the anti-HBV pre-S1 antibody comprises VH comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprised by VH as shown in the amino acid sequence of SEQ ID NO: 142; and VL , which comprises LC-CDR1, LC-CDR2 and LC-CDR3 contained in the V L as shown in the amino acid sequence of SEQ ID NO: 172.
  • the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 142 or a variant thereof having at least the same amino acid sequence of SEQ ID NO: 142 about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and a VL comprising the amino acid sequence of SEQ ID NO: 172 Or a variant thereof having at least about 80% (eg at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence with the amino acid sequence of SEQ ID NO: 172 identity.
  • the anti-HBV pre-S1 antibody comprises a VH comprising the amino acid sequence of SEQ ID NO: 142, and a VL comprising the amino acid sequence of SEQ ID NO: 172.
  • the anti-HBV pre-S1 antibody comprises VH , and the VH comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 15, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 34.
  • HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 53, or a variant of said VH comprising up to about 5 amino acid substitutions in its HC-CDRs
  • VL comprising: LC - CDR1 comprising the amino acid sequence of SEQ ID NO:73, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:81, LC-CDR3 comprising the amino acid sequence of SEQ ID NO:109, or a variant of said VL , It contains up to about 5 amino acid substitutions in its LC-CDRs.
  • the anti-HBV pre-S1 antibody comprises VH
  • the VH comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 15, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 34, and HC-CDR3, which comprises the amino acid sequence of SEQ ID NO:53; and V L , which comprises: LC- CDR1 , which comprises the amino acid sequence of SEQ ID NO:73, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:73; ID NO:81, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO:109.
  • the anti-HBV pre-S1 antibody comprises VH comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprised by VH as shown in the amino acid sequence of SEQ ID NO: 143; and VL , which comprises LC-CDR1, LC-CDR2 and LC-CDR3 contained in the V L as shown in the amino acid sequence of SEQ ID NO: 173.
  • the anti-HBV pre-S1 antibody comprises: V H , the V H comprising the amino acid sequence of SEQ ID NO: 143 or a variant thereof having at least the same amino acid sequence of SEQ ID NO: 143 about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and a VL comprising the amino acid sequence of SEQ ID NO: 173 Or a variant thereof having at least about 80% (eg at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence with the amino acid sequence of SEQ ID NO: 173 identity.
  • the anti-HBV pre-S1 antibody comprises a VH comprising the amino acid sequence of SEQ ID NO: 143, and a VL comprising the amino acid sequence of SEQ ID NO: 173.
  • the anti-HBV pre-S1 antibody comprises VH , and the VH comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 16, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 35.
  • HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 54, or a variant of said VH comprising up to about 5 amino acid substitutions in its HC-CDRs; and VL comprising: LC - CDR1 comprising the amino acid sequence of SEQ ID NO:74, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:88, LC-CDR3 comprising the amino acid sequence of SEQ ID NO:110, or a variant of said VL , It contains up to about 5 amino acid substitutions in its LC-CDRs.
  • the anti-HBV pre-S1 antibody comprises VH
  • the VH comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 16, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 35, and HC-CDR3, which comprises the amino acid sequence of SEQ ID NO: 54; and V L , which comprises: LC- CDR1 , which comprises the amino acid sequence of SEQ ID NO: 74, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO: 74; ID NO:88, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO:110.
  • the anti-HBV pre-S1 antibody comprises VH comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprised by VH as shown in the amino acid sequence of SEQ ID NO: 144; and VL , which comprises LC-CDR1, LC-CDR2 and LC-CDR3 contained in the V L as shown in the amino acid sequence SEQ ID NO: 174.
  • the anti-HBV pre-S1 antibody comprises: V H , the V H comprising the amino acid sequence of SEQ ID NO: 144 or a variant thereof having at least the same amino acid sequence of SEQ ID NO: 144 about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and a VL comprising the amino acid sequence of SEQ ID NO: 174 Or a variant thereof having at least about 80% (eg at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence with the amino acid sequence of SEQ ID NO: 174 identity.
  • the anti-HBV pre-S1 antibody comprises a VH comprising the amino acid sequence of SEQ ID NO: 144, and a VL comprising the amino acid sequence of SEQ ID NO: 174.
  • the anti-HBV pre-S1 antibody comprises VH , and the VH comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 17, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 36.
  • HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 55, or a variant of said VH comprising up to about 5 amino acid substitutions in its HC-CDRs; and VL comprising: LC - CDR1 comprising the amino acid sequence of SEQ ID NO:75, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:81, LC-CDR3 comprising the amino acid sequence of SEQ ID NO:97, or a variant of said VL , It contains up to about 5 amino acid substitutions in its LC-CDRs.
  • the anti-HBV pre-S1 antibody comprises VH
  • the VH comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 17, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 36, and HC-CDR3, which comprises the amino acid sequence of SEQ ID NO:55; and V L , which comprises: LC- CDR1 , which comprises the amino acid sequence of SEQ ID NO:75, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:75; ID NO:81, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO:97.
  • the anti-HBV pre-S1 antibody comprises a VH comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprised by the VH as shown in the amino acid sequence of SEQ ID NO: 145; and VL , which comprises LC-CDR1, LC-CDR2 and LC-CDR3 contained in the V L as shown in the amino acid sequence of SEQ ID NO: 175.
  • the anti-HBV pre-S1 antibody comprises: V H , the V H comprising the amino acid sequence of SEQ ID NO: 145 or a variant thereof having at least the same amino acid sequence of SEQ ID NO: 145 about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and a VL comprising the amino acid sequence of SEQ ID NO: 175 Or a variant thereof having at least about 80% (eg at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence with the amino acid sequence of SEQ ID NO: 175 identity.
  • the anti-HBV pre-S1 antibody comprises a VH comprising the amino acid sequence of SEQ ID NO: 145, and a VL comprising the amino acid sequence of SEQ ID NO: 175.
  • the anti-HBV pre-S1 antibody comprises a heavy chain variable domain (V H ), and the V H comprises: a heavy chain complementarity determining region (HC-CDR) 1 comprising TYGIT (SEQ ID NO:18); HC-CDR2, it comprises SRIPIX 1 GAALYAQKFQG (SEQ ID NO:115), wherein X 1 is F or L; And HC-CDR3, it comprises NX 1 RGGFAAY (SEQ ID NO:116), wherein X 1 is D or T; and a light chain variable domain (V L ), said V L comprising: a light chain complementarity determining region (LC-CDR) 1 comprising RSSQSLX 1 HSNX 2 YNYLD (SEQ ID NO: 117 ), wherein X 1 is L or T, X 2 is A or G; LC-CDR2, which comprises LGX 1 X 2 RAS (SEQ ID NO: 118), wherein X 1 is H or S, and X 2 is
  • the anti-HBV pre-S1 antibody comprises a VH
  • the VH comprises: HC-CDR1 comprising the amino acid sequence shown in SEQID NO: 18 or a variant thereof, the variant comprising at most Substitution of about 3 (eg 1, 2 or 3) amino acids; HC-CDR2 comprising the amino acid sequence shown in any of SEQ ID NOs: 37-38 or a variant thereof comprising up to about 3 (eg 1, 2 or 3) amino acid substitutions; and HC-CDR3 comprising the amino acid sequence shown in any of SEQ ID NOs: 56-57 or a variant thereof comprising up to about 3 (eg 1, 2 or 3) amino acid substitutions.
  • the anti-HBV pre-S1 antibody comprises VH
  • the VH comprises: HC-CDR1 comprising the amino acid sequence shown in SEQ ID NO: 18, HC-CDR2 comprising SEQ ID NOs The amino acid sequence shown in any of SEQ ID NOs: 37-38, HC-CDR3, which comprises the amino acid sequence shown in any of SEQ ID NOs: 56-57.
  • the anti-HBV pre-S1 antibody comprises a V L comprising: LC- CDR1 comprising the amino acid sequence shown in any one of SEQ ID NOs: 59, and 76-77, or Variant, described variant comprises the substitution of at most about 3 (such as 1,2 or 3) amino acids; LC-CDR2, it comprises SEQ ID NOs:79, and the aminoacid sequence shown in any one of 89-91 or A variant thereof comprising at most about 3 (eg 1, 2 or 3) amino acid substitutions; and LC-CDR3 comprising the amino acid sequence shown in any of SEQ ID NOs: 111-114 or its A variant comprising up to about 3 (eg 1, 2 or 3) amino acid substitutions.
  • the anti-HBV pre-S1 antibody comprises a V L comprising: LC- CDR1 comprising the amino acid sequence shown in any one of SEQ ID NOs: 59 and 76-77, LC - CDR2 comprising the amino acid sequence shown in any of SEQ ID NOs: 79 and 89-91, LC-CDR3 comprising the amino acid sequence shown in any of SEQ ID NOs: 111-114.
  • the anti-HBV pre-S1 antibody comprises a VH
  • the VH comprises: HC-CDR1 comprising the amino acid sequence shown in SEQ ID NO: 18 or a variant thereof, the variant comprising Substitution of at most about 3 (eg 1, 2 or 3) amino acids; HC-CDR2 comprising the amino acid sequence shown in any of SEQ ID NOs: 37-38 or a variant thereof comprising at most about 3 (eg 1, 2 or 3) amino acid substitutions; and HC-CDR3 comprising the amino acid sequence shown in any of SEQ ID NOs: 56-57 or a variant thereof comprising up to about 3 (for example 1, 2 or 3) amino acid substitutions; and VL , said VL comprising: LC-CDR1, which comprises SEQ ID NOs:59, and the amino acid sequence shown in any one of 76-77 or its Variant, described variant comprises the substitution of at most about 3 (such as 1,2 or 3) amino acids; LC-CDR2, it comprises SEQ ID NOs
  • the anti-HBV pre-S1 antibody comprises VH
  • the VH comprises: HC-CDR1 comprising the amino acid sequence shown in SEQ ID NO: 18, HC-CDR2 comprising SEQ ID NOs : the amino acid sequence shown in any of SEQ ID NOs: 37-38, and HC-CDR3, which comprises the amino acid sequence shown in any of SEQ ID NOs: 56-57; and V L , said V L comprising: LC-CDR1, It comprises the amino acid sequence shown in any of SEQ ID NOs:59 and 76-77, LC-CDR2, which comprises the amino acid sequence shown in any of SEQ ID NOs:79 and 89-91, and LC-CDR3 , which comprises the amino acid sequence shown in any one of SEQ ID NOs: 111-114.
  • the anti-HBV pre-S1 antibody comprises VH , and the VH comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 37.
  • HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 56, or a variant of said VH comprising up to about 5 amino acid substitutions in its HC-CDRs
  • VL comprising: LC - CDR1 comprising the amino acid sequence of SEQ ID NO:59, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:79, LC-CDR3 comprising the amino acid sequence of SEQ ID NO:111, or a variant of said VL , It contains up to about 5 amino acid substitutions in its LC-CDRs.
  • the anti-HBV pre-S1 antibody comprises a VH comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 37, and HC-CDR3, which comprises the amino acid sequence of SEQ ID NO:56; and VL , which comprises: LC-CDR1, which comprises the amino acid sequence of SEQ ID NO:59, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:59 ; ID NO:79, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO:111.
  • the anti-HBV pre-S1 antibody comprises VH , and the VH comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 38.
  • HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 57, or a variant of said VH comprising up to about 5 amino acid substitutions in its HC-CDRs; and VL comprising: LC - CDR1 comprising the amino acid sequence of SEQ ID NO: 76, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 79, LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 112, or a variant of said VL , It contains up to about 5 amino acid substitutions in its LC-CDRs.
  • the anti-HBV pre-S1 antibody comprises a VH comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 38, and HC-CDR3, which comprises the amino acid sequence of SEQ ID NO:57; and V L , which comprises: LC- CDR1 , which comprises the amino acid sequence of SEQ ID NO:76, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:76; ID NO:79, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO:112.
  • the anti-HBV pre-S1 antibody comprises VH , and the VH comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 37.
  • HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 57, or a variant of said VH comprising up to about 5 amino acid substitutions in its HC-CDRs; and VL comprising: LC - CDR1 comprising the amino acid sequence of SEQ ID NO: 77, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 89, LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 111, or a variant of said VL , It contains up to about 5 amino acid substitutions in its LC-CDRs.
  • the anti-HBV pre-S1 antibody comprises a VH comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 37, and HC-CDR3, which comprises the amino acid sequence of SEQ ID NO:57; and VL , which comprises: LC-CDR1, which comprises the amino acid sequence of SEQ ID NO:77, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:77 ; ID NO:89, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO:111.
  • the anti-HBV pre-S1 antibody comprises VH , and the VH comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 37.
  • HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 57, or a variant of said VH comprising up to about 5 amino acid substitutions in its HC-CDRs; and VL comprising: LC - CDR1 comprising the amino acid sequence of SEQ ID NO:77, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:90, LC-CDR3 comprising the amino acid sequence of SEQ ID NO:111, or a variant of said VL , It contains up to about 5 amino acid substitutions in its LC-CDRs.
  • the anti-HBV pre-S1 antibody comprises VH
  • the VH comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 37, and HC-CDR3, which comprises the amino acid sequence of SEQ ID NO:57
  • VL which comprises: LC-CDR1, which comprises the amino acid sequence of SEQ ID NO:77, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:77 ; ID NO:90, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO:111.
  • the anti-HBV pre-S1 antibody comprises a VH comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 38.
  • HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 57, or a variant of said VH comprising up to about 5 amino acid substitutions in its HC-CDRs;
  • VL comprising: LC - CDR1 comprising the amino acid sequence of SEQ ID NO: 76, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 79, LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 111, or a variant of said VL , It contains up to about 5 amino acid substitutions in its LC-CDRs.
  • the anti-HBV pre-S1 antibody comprises VH
  • the VH comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 38, and HC-CDR3, which comprises the amino acid sequence of SEQ ID NO:57; and V L , which comprises: LC- CDR1 , which comprises the amino acid sequence of SEQ ID NO:76, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:76; ID NO:79, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO:111.
  • the anti-HBV pre-S1 antibody comprises VH , and the VH comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 38.
  • HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 57, or a variant of said VH comprising up to about 5 amino acid substitutions in its HC-CDRs; and VL comprising: LC - CDR1 comprising the amino acid sequence of SEQ ID NO: 77, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 79, LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 113, or a variant of said VL , It contains up to about 5 amino acid substitutions in its LC-CDRs.
  • the anti-HBV pre-S1 antibody comprises a VH comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 38, and HC-CDR3, which comprises the amino acid sequence of SEQ ID NO:57; and V L , which comprises: LC- CDR1 , which comprises the amino acid sequence of SEQ ID NO:77, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:77; ID NO:79, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO:113.
  • the anti-HBV pre-S1 antibody comprises a VH comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 37.
  • HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 57, or a variant of said VH comprising up to about 5 amino acid substitutions in its HC-CDRs;
  • VL comprising: LC - CDR1 comprising the amino acid sequence of SEQ ID NO:77, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:89, LC-CDR3 comprising the amino acid sequence of SEQ ID NO:114, or a variant of said VL , It contains up to about 5 amino acid substitutions in its LC-CDRs.
  • the anti-HBV pre-S1 antibody comprises VH
  • the VH comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 37, and HC-CDR3, which comprises the amino acid sequence of SEQ ID NO:57
  • VL which comprises: LC-CDR1, which comprises the amino acid sequence of SEQ ID NO:77, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:77 ; ID NO:89, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO:114.
  • the anti-HBV pre-S1 antibody comprises VH , and the VH comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 37.
  • HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 57, or a variant of said VH comprising up to about 5 amino acid substitutions in its HC-CDRs; and VL comprising: LC - CDR1 comprising the amino acid sequence of SEQ ID NO:77, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:91, LC-CDR3 comprising the amino acid sequence of SEQ ID NO:113, or a variant of said VL , It contains up to about 5 amino acid substitutions in its LC-CDRs.
  • the anti-HBV pre-S1 antibody comprises VH
  • the VH comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 37, and HC-CDR3, which comprises the amino acid sequence of SEQ ID NO:57
  • VL which comprises: LC-CDR1, which comprises the amino acid sequence of SEQ ID NO:77, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:77 ; ID NO:91, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO:113.
  • the anti-HBV pre-S1 antibody comprises VH , and the VH comprises HC-CDR1 and HC-CDR2 contained in VH as shown in any amino acid sequence of SEQ ID NOs: 146-150 and HC-CDR3; and VL , said VL comprising LC-CDR1, LC-CDR2 and LC-CDR3 contained in VL as shown in any one of the amino acid sequences of SEQ ID NOs: 176-183.
  • the anti-HBV pre-S1 antibody comprises VH comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprised by VH as shown in the amino acid sequence of SEQ ID NO: 146; and VL , which comprises LC-CDR1, LC-CDR2 and LC-CDR3 contained in the V L as shown in the amino acid sequence of SEQ ID NO: 176.
  • the anti-HBV pre-S1 antibody comprises VH comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprised by VH as shown in the amino acid sequence of SEQ ID NO: 147; and VL , which comprises LC-CDR1, LC-CDR2 and LC-CDR3 contained in the V L as shown in the amino acid sequence SEQ ID NO: 177.
  • the anti-HBV pre-S1 antibody comprises VH comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprised by VH as shown in the amino acid sequence of SEQ ID NO: 148; and VL , which comprises LC-CDR1, LC-CDR2 and LC-CDR3 contained in the V L as shown in the amino acid sequence of SEQ ID NO: 178.
  • the anti-HBV pre-S1 antibody comprises VH comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprised by VH as shown in the amino acid sequence of SEQ ID NO: 149; and VL , which comprises LC-CDR1, LC-CDR2 and LC-CDR3 contained in the V L as shown in the amino acid sequence of SEQ ID NO: 179.
  • the anti-HBV pre-S1 antibody comprises VH comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprised by VH as shown in the amino acid sequence of SEQ ID NO: 147; and VL , which comprises LC-CDR1, LC-CDR2 and LC-CDR3 contained in the V L as shown in the amino acid sequence of SEQ ID NO: 180.
  • the anti-HBV pre-S1 antibody comprises VH comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprised by VH as shown in the amino acid sequence of SEQ ID NO: 147; and VL , which comprises LC-CDR1, LC-CDR2 and LC-CDR3 contained in the V L as shown in the amino acid sequence of SEQ ID NO: 181.
  • the anti-HBV pre-S1 antibody comprises VH comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprised by VH as shown in the amino acid sequence of SEQ ID NO: 148; and VL , which comprises LC-CDR1, LC-CDR2 and LC-CDR3 contained in the V L as shown in the amino acid sequence of SEQ ID NO: 182.
  • the anti-HBV pre-S1 antibody comprises VH comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprised by VH as shown in the amino acid sequence of SEQ ID NO: 150; and VL , which comprises LC-CDR1, LC-CDR2 and LC-CDR3 contained in the V L as shown in the amino acid sequence of SEQ ID NO: 183.
  • the anti-HBV pre-S1 antibody comprises: V H , the V H comprising the amino acid sequence shown in any one of SEQ ID NOs: 146-150 or a variant thereof, and the variant is identical to SEQ ID NOs: 146-150
  • the amino acid sequences shown in any of ID NOs: 146-150 have at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity
  • V L said V L comprises the amino acid sequence shown in any one of SEQ ID NOs:176-183 or its variant, and said variant has the amino acid sequence shown in any one of SEQ ID NOs:176-183 At least about 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.
  • the anti-HBV pre-S1 antibody comprises a V H comprising the amino acid sequence shown in any one of SEQ ID NOs: 146-150, and a V L comprising SEQ ID The amino acid sequence shown in any one of NOs:176-183.
  • the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 146 or a variant thereof having at least the same amino acid sequence of SEQ ID NO: 146 about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and a VL comprising the amino acid sequence of SEQ ID NO: 176 Or a variant thereof having at least about 80% (eg at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence with the amino acid sequence of SEQ ID NO: 176 identity.
  • the anti-HBV pre-S1 antibody comprises a VH comprising the amino acid sequence of SEQ ID NO: 146, and a VL comprising the amino acid sequence of SEQ ID NO: 176.
  • the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 147 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and a VL comprising the amino acid sequence of SEQ ID NO: 177 Or a variant thereof having at least about 80% (eg at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence with the amino acid sequence of SEQ ID NO: 177 identity.
  • the anti-HBV pre-S1 antibody comprises a VH comprising the amino acid sequence of SEQ ID NO: 147, and a VL comprising the amino acid sequence of SEQ ID NO: 177.
  • the anti-HBV pre-S1 antibody comprises: V H , the V H comprising the amino acid sequence of SEQ ID NO: 148 or a variant thereof having at least the same amino acid sequence of SEQ ID NO: 148 about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and a VL comprising the amino acid sequence of SEQ ID NO: 178 Or a variant thereof having at least about 80% (eg at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence with the amino acid sequence of SEQ ID NO: 178 identity.
  • the anti-HBV pre-S1 antibody comprises a VH comprising the amino acid sequence of SEQ ID NO: 148, and a VL comprising the amino acid sequence of SEQ ID NO: 178.
  • the anti-HBV pre-S1 antibody comprises: V H , the V H comprising the amino acid sequence of SEQ ID NO: 149 or a variant thereof having at least the same amino acid sequence as SEQ ID NO: 149 about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and a VL comprising the amino acid sequence of SEQ ID NO: 179 Or a variant thereof having at least about 80% (eg at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence with the amino acid sequence of SEQ ID NO: 179 identity.
  • the anti-HBV pre-S1 antibody comprises a VH comprising the amino acid sequence of SEQ ID NO: 149, and a VL comprising the amino acid sequence of SEQ ID NO: 179.
  • the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 147 or a variant thereof having at least the same amino acid sequence of SEQ ID NO: 147 about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and a VL comprising the amino acid sequence of SEQ ID NO: 180 Or a variant thereof having at least about 80% (eg at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence with the amino acid sequence of SEQ ID NO: 180 identity.
  • the anti-HBV pre-S1 antibody comprises a VH comprising the amino acid sequence of SEQ ID NO: 147, and a VL comprising the amino acid sequence of SEQ ID NO: 180.
  • the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 147 or a variant thereof having at least the same amino acid sequence of SEQ ID NO: 147 about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and a VL comprising the amino acid sequence of SEQ ID NO: 181 Or a variant thereof having at least about 80% (eg at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence with the amino acid sequence of SEQ ID NO: 181 identity.
  • the anti-HBV pre-S1 antibody comprises a VH comprising the amino acid sequence of SEQ ID NO:147, and a VL comprising the amino acid sequence of SEQ ID NO:181.
  • the anti-HBV pre-S1 antibody comprises: V H , the V H comprising the amino acid sequence of SEQ ID NO: 148 or a variant thereof having at least the same amino acid sequence of SEQ ID NO: 148 about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and a VL comprising the amino acid sequence of SEQ ID NO: 182 Or a variant thereof having at least about 80% (eg at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence with the amino acid sequence of SEQ ID NO: 182 identity.
  • the anti-HBV pre-S1 antibody comprises a VH comprising the amino acid sequence of SEQ ID NO: 148, and a VL comprising the amino acid sequence of SEQ ID NO: 182.
  • the anti-HBV pre-S1 antibody comprises: VH , the VH comprising the amino acid sequence of SEQ ID NO: 150 or a variant thereof, the variant having at least the same amino acid sequence of SEQ ID NO: 150 about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and a VL comprising the amino acid sequence of SEQ ID NO: 183 Or a variant thereof having at least about 80% (eg at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence with the amino acid sequence of SEQ ID NO: 183 identity.
  • the anti-HBV pre-S1 antibody comprises a VH comprising the amino acid sequence of SEQ ID NO:150, and a VL comprising the amino acid sequence of SEQ ID NO:183.
  • the anti-HBV pre-S1 antibody comprises VH , and the VH comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 37.
  • HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 56, or a variant of said VH comprising up to about 5 amino acid substitutions in its HC-CDRs
  • VL comprising: LC - CDR1 comprising the amino acid sequence of SEQ ID NO:78, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:92, LC-CDR3 comprising the amino acid sequence of SEQ ID NO:93, or a variant of said VL , It contains up to about 5 amino acid substitutions in its LC-CDRs.
  • the anti-HBV pre-S1 antibody comprises VH
  • the VH comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 37, and HC-CDR3, which comprises the amino acid sequence of SEQ ID NO:56; and VL , which comprises: LC-CDR1, which comprises the amino acid sequence of SEQ ID NO:78, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:78 ; ID NO:92, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO:93.
  • the anti-HBV pre-S1 antibody comprises VH comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprised by VH as shown in the amino acid sequence of SEQ ID NO: 146; and VL , which comprises LC-CDR1, LC-CDR2 and LC-CDR3 contained in the V L as shown in the amino acid sequence SEQ ID NO: 184.
  • the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 146 or a variant thereof having at least the same amino acid sequence of SEQ ID NO: 146 about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and a VL comprising the amino acid sequence of SEQ ID NO: 184 Or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence with the amino acid sequence of SEQ ID NO: 184 identity.
  • the anti-HBV pre-S1 antibody comprises a VH comprising the amino acid sequence of SEQ ID NO:146, and a VL comprising the amino acid sequence of SEQ ID NO:184.
  • amino acid substitutions described above are limited to the "exemplary substitutions” shown in Table 4 herein. In some embodiments, amino acid substitutions are limited to the "preferred substitutions” shown in Table 4 herein.
  • functional epitopes can be resolved by combined alanine scanning methods. During this process, the combinatorial alanine scanning technique can be used to identify amino acids in the HBV pre-S1 protein that are essential for the interaction with anti-HBV pre-S1 antibodies.
  • the epitope is conformational, and the epitope can be identified using the crystal structure of an anti-HBV pre-S1 antibody bound to the HBV pre-S1 protein.
  • the application provides antibodies that compete with any of the anti-HBV pre-S1 antibodies described herein for binding to an HBV pre-S1 antigen.
  • antibodies are provided that compete with any of the anti-HBV pre-S1 antibodies described herein for binding to an epitope on an HBV pre-S1 antigen.
  • an anti-HBV pre-S1 antibody is provided that binds to the same epitope as an anti-HBV pre-S1 antibody molecule comprising VH and VL , wherein the VH comprises SEQ ID NOs: 120-150 Any of the amino acid sequences shown, and the V L comprises any of the amino acid sequences shown in SEQ ID NOs: 151-185.
  • anti-HBV pre-S1 antibodies are provided that compete for binding to HBV pre-S1 with anti-HBV pre-S1 antibodies comprising VH and VL , wherein said VH comprises SEQ ID NOs: 120- The amino acid sequence shown in any one of 150, and the V L comprises the amino acid sequence shown in any one of SEQ ID NOs: 151-185.
  • competition assays can be used to identify monoclonal antibodies that compete with the anti-HBV pre-S1 antibodies described herein for binding to HBV pre-S1. Competition experiments can determine whether two antibodies bind to the same epitope by recognizing identical or spatially overlapping epitopes or by one antibody competitively inhibiting binding of the other antibody to the antigen. In certain embodiments, such competing antibodies bind to the same epitope as the antibodies described herein.
  • Some exemplary competition assays include, but are not limited to, conventional assays as mentioned in Harlow and Lane (1988) Antibodies: A Laboratory Manual ch. 14 (Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y.).
  • each antibody is said to bind the same epitope if it blocks 50% or more of the binding of the other antibody.
  • the antibody that competes with the anti-HBV pre-S1 antibody described herein is a chimeric antibody, a humanized antibody, or a fully human antibody.
  • Exemplary anti-HBV pre-S1 antibody sequences are shown in Table 2 and Table 3, wherein the CDR numbering is performed according to the Kabat definition. Those skilled in the art will recognize that there are a variety of known algorithms for predicting the location of CDRs and defining antibody light and heavy chain variable regions. Also within the scope of this application are antibodies comprising the CDRs, VH and/or VL sequences of antibodies as described herein, but based on prediction algorithms other than those exemplified in the table below.
  • the anti-HBV pre-S1 antibody is a full-length anti-HBV pre-S1 antibody.
  • the full length anti-HBV pre-S1 antibody is IgA, IgD, IgE, IgG or IgM.
  • the full-length anti-HBV pre-S1 antibody comprises an IgG constant region, such as the constant region of IgG1, IgG2, IgG3, IgG4, or variants thereof.
  • the full-length anti-HBV pre-S1 antibody comprises a lambda light chain constant region.
  • the full-length anti-HBV pre-S1 antibody comprises a kappa light chain constant region.
  • the full-length anti-HBV pre-S1 antibody is a full-length human anti-HBV pre-S1 antibody.
  • the full-length anti-HBV pre-S1 antibody comprises a mouse immunoglobulin Fc sequence.
  • the full-length anti-HBV pre-S1 antibody comprises an altered or otherwise altered Fc sequence such that it has enhanced antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent Effector functions of sex cell-mediated phagocytosis (ADCP) or complement-dependent cytotoxicity (CDC).
  • ADCC antibody-dependent cell-mediated cytotoxicity
  • ADCP antibody-dependent Effector functions of sex cell-mediated phagocytosis
  • CDC complement-dependent cytotoxicity
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region that specifically binds to an HBV pre-S1 antigen.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG2 constant region is provided, and the anti-HBV pre-S1 antibody specifically binds to HBV pre-S1.
  • the IgG2 is human IgG2.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG3 constant region is provided, and the anti-HBV pre-S1 antibody specifically binds to HBV pre-S1.
  • the IgG3 is human IgG3.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region is provided, and the anti-HBV pre-S1 antibody specifically binds to HBV pre-S1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure
  • the domain comprises: HC-CDR1 comprising the amino acid sequence shown in any one of SEQ ID NOs: 1-18 or a variant thereof comprising a substitution of up to about 3 (e.g.
  • HC-CDR2 comprising the amino acid sequence shown in any of SEQ ID NOs: 19-38 or a variant thereof comprising at most about 3 (eg 1, 2 or 3) amino acid substitutions
  • HC-CDR3 comprising the amino acid sequence shown in any of SEQ ID NOs: 39-57 or a variant thereof comprising at most about 3 (eg 1, 2 or 3) amino acid substitutions
  • b ) light chain variable domain said light chain variable domain comprises: LC-CDR1, it comprises the aminoacid sequence shown in any one of SEQ ID NOs:58-78 or its variant, and said variant comprises at most A substitution of about 3 (eg 1, 2 or 3) amino acids
  • LC-CDR2 comprising the amino acid sequence shown in any of SEQ ID NOs: 79-92 or a variant thereof comprising up to about 3 (for example 1, 2 or 3) amino acid substitutions
  • With LC-CDR3 it comprises the amino acid sequence shown in any one of SEQ ID NOs:93-114 or its
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG2 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure
  • the domain comprises: HC-CDR1 comprising the amino acid sequence shown in any one of SEQ ID NOs: 1-18 or a variant thereof comprising a substitution of up to about 3 (e.g.
  • HC-CDR2 comprising the amino acid sequence shown in any of SEQ ID NOs: 19-38 or a variant thereof comprising at most about 3 (eg 1, 2 or 3) amino acid substitutions
  • HC-CDR3 comprising the amino acid sequence shown in any of SEQ ID NOs: 39-57 or a variant thereof comprising at most about 3 (eg 1, 2 or 3) amino acid substitutions
  • b ) light chain variable domain said light chain variable domain comprises: LC-CDR1, it comprises the aminoacid sequence shown in any one of SEQ ID NOs:58-78 or its variant, and said variant comprises at most Substitution of about 3 (eg 1, 2 or 3) amino acids; LC-CDR2 comprising the amino acid sequence shown in any of SEQ ID NOs: 79-92 or a variant thereof comprising up to about 3 (for example 1, 2 or 3) amino acid substitutions; With LC-CDR3, it comprises the amino acid sequence shown in any one of SEQ ID NOs:93-114 or its
  • the IgG2 is human IgG2.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG3 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure
  • the domain comprises: HC-CDR1 comprising the amino acid sequence shown in any one of SEQ ID NOs: 1-18 or a variant thereof comprising a substitution of up to about 3 (e.g.
  • HC-CDR2 comprising the amino acid sequence shown in any one of SEQ ID NOs: 19-38 or a variant thereof comprising at most about 3 (eg 1, 2 or 3) amino acid substitutions
  • HC-CDR3 comprising the amino acid sequence shown in any of SEQ ID NOs: 39-57 or a variant thereof comprising at most about 3 (eg 1, 2 or 3) amino acid substitutions
  • said light chain variable domain comprises: LC-CDR1, it comprises the aminoacid sequence shown in any one of SEQ ID NOs:58-78 or its variant, and said variant comprises at most Substitution of about 3 (eg 1, 2 or 3) amino acids
  • LC-CDR2 comprising the amino acid sequence shown in any of SEQ ID NOs: 79-92 or a variant thereof comprising up to about 3 (for example 1, 2 or 3) amino acid substitutions
  • With LC-CDR3 it comprises the amino acid sequence shown in any one of SEQ ID NOs:93-
  • the IgG3 is human IgG3.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure
  • the domain comprises: HC-CDR1 comprising the amino acid sequence shown in any one of SEQ ID NOs: 1-18 or a variant thereof comprising a substitution of up to about 3 (e.g.
  • HC-CDR2 comprising the amino acid sequence shown in any of SEQ ID NOs: 19-38 or a variant thereof comprising at most about 3 (eg 1, 2 or 3) amino acid substitutions
  • HC-CDR3 comprising the amino acid sequence shown in any of SEQ ID NOs: 39-57 or a variant thereof comprising at most about 3 (eg 1, 2 or 3) amino acid substitutions
  • said light chain variable domain comprises: LC-CDR1, it comprises the aminoacid sequence shown in any one of SEQ ID NOs:58-78 or its variant, and said variant comprises at most A substitution of about 3 (eg 1, 2 or 3) amino acids
  • LC-CDR2 comprising the amino acid sequence shown in any of SEQ ID NOs: 79-92 or a variant thereof comprising up to about 3 (e.g.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure
  • the domain comprises: HC-CDR1, which comprises the amino acid sequence shown in any of SEQ ID NOs: 1-18, HC-CDR2, which comprises the amino acid sequence shown in any of SEQ ID NOs: 19-38, and HC- CDR3 comprising the amino acid sequence shown in any of SEQ ID NOs: 39-57, or a variant of the heavy chain variable domain comprising up to about 5 (eg 1, 2, 3, 4 or 5) amino acid substitutions; and b) a light chain variable domain comprising: LC-CDR1 comprising any of SEQ ID NOs: 58-78 Amino acid sequence, LC-CDR2, which comprises the amino acid sequence shown in any of SEQ ID NOs:79-92, and LC-CDR3, which comprises the amino acid sequence shown in any
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region
  • said anti-HBV pre-S1 antibody comprises a) a heavy chain variable domain, said heavy chain variable domain Comprising: HC-CDR1, which comprises the amino acid sequence shown in any one of SEQ ID NOs:1-18, HC-CDR2, which comprises the amino acid sequence shown in any one of SEQ ID NOs:19-38, and HC-CDR3 , which comprises the amino acid sequence shown in any one of SEQ ID NOs: 39-57, or a variant of the heavy chain variable domain comprising up to about 5 (eg 1, 2, 3) in its HC-CDR sequence , 4 or 5) amino acid substitutions; and b) a light chain variable domain comprising: LC-CDR1 comprising any of the amino acids shown in SEQ ID NOs:58-78
  • the sequence, LC-CDR2 comprises the amino acid sequence shown in any of SEQ ID NOs:79-92, and
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure
  • the domain comprises: HC-CDR1, which comprises the amino acid sequence shown in any of SEQ ID NOs: 1-18, HC-CDR2, which comprises the amino acid sequence shown in any of SEQ ID NOs: 19-38, and HC- CDR3 comprising the amino acid sequence shown in any of SEQ ID NOs:39-57; and b) a light chain variable domain comprising: LC-CDR1 comprising SEQ ID NOs:
  • the amino acid sequence shown in any of 58-78, LC-CDR2 it comprises the amino acid sequence shown in any of SEQ ID NOs:79-92, and LC-CDR3, it comprises any of SEQ ID NOs:93-114
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure
  • the domain comprises: HC-CDR1, which comprises the amino acid sequence shown in any of SEQ ID NOs: 1-18, HC-CDR2, which comprises the amino acid sequence shown in any of SEQ ID NOs: 19-38, and HC- CDR3 comprising the amino acid sequence shown in any of SEQ ID NOs:39-57; and b) a light chain variable domain comprising: LC-CDR1 comprising SEQ ID NOs:
  • the amino acid sequence shown in any of 58-78, LC-CDR2 it comprises the amino acid sequence shown in any of SEQ ID NOs:79-92, and LC-CDR3, it comprises any of SEQ ID NOs:93-114
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure The domain comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO:1, HC-CDR2 comprising the amino acid sequence of SEQ ID NO:19, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO:39; and b) light Chain variable domains, said light chain variable domains comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 58, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 79, and LC-CDR3 comprising Comprising the amino acid sequence of SEQ ID NO:93.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure The domain comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO:2, HC-CDR2 comprising the amino acid sequence of SEQ ID NO:20, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO:40; and b) light Chain variable domains, said light chain variable domains comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 59, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 79, and LC-CDR3 comprising Comprising the amino acid sequence of SEQ ID NO:94.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure The domain comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO:3, HC-CDR2 comprising the amino acid sequence of SEQ ID NO:21, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO:41; and b) light Chain variable domains, said light chain variable domains comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 60, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 80, and LC-CDR3 comprising Comprising the amino acid sequence of SEQ ID NO:95.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure The domain comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO:4, HC-CDR2 comprising the amino acid sequence of SEQ ID NO:22, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO:42; and b) light Chain variable domains, said light chain variable domains comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 61, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 81, and LC-CDR3 comprising Comprising the amino acid sequence of SEQ ID NO:96.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure The domain comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO:5, HC-CDR2 comprising the amino acid sequence of SEQ ID NO:23, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO:43; and b) light Chain variable domains, said light chain variable domains comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 61, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 82, and LC-CDR3 comprising Comprising the amino acid sequence of SEQ ID NO:97.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure The domain comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO:7, HC-CDR2 comprising the amino acid sequence of SEQ ID NO:25, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO:45; and b) light Chain variable domains, said light chain variable domains comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 63, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 84, and LC-CDR3 comprising Comprising the amino acid sequence of SEQ ID NO:99.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure The domain comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO:7, HC-CDR2 comprising the amino acid sequence of SEQ ID NO:26, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO:46; and b) light Chain variable domains, said light chain variable domains comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 64, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 79, and LC-CDR3 comprising Contains the amino acid sequence SEQ ID NO:100.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure The domain comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO:8, HC-CDR2 comprising the amino acid sequence of SEQ ID NO:27, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO:47; and b) light Chain variable domains, said light chain variable domains comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 65, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 85, and LC-CDR3 comprising Comprising the amino acid sequence of SEQ ID NO: 101.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure The domain comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO:9, HC-CDR2 comprising the amino acid sequence of SEQ ID NO:28, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO:48; and b) light Chain variable domains, said light chain variable domains comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 66, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 86, and LC-CDR3 comprising Comprising the amino acid sequence of SEQ ID NO: 102.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure The domain comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO:6, HC-CDR2 comprising the amino acid sequence of SEQ ID NO:24, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO:44; and b) light Chain variable domains, said light chain variable domains comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 62, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 83, and LC-CDR3 comprising Comprising the amino acid sequence of SEQ ID NO:98.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure The domain comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 10, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 29, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 49; and b) light Chain variable domains, said light chain variable domains comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 67, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 87, and LC-CDR3 comprising Comprising the amino acid sequence of SEQ ID NO: 103.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure The domain comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 11, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 30, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 50; and b) light Chain variable domains, said light chain variable domains comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 68, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 81, and LC-CDR3 comprising Comprising the amino acid sequence of SEQ ID NO: 104.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure The domain comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 12, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 30, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 50; and b) light Chain variable domains, said light chain variable domains comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 61, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 81, and LC-CDR3 comprising Comprising the amino acid sequence of SEQ ID NO: 105.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure The domain comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 13, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 30, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 50; and b) light Chain variable domains, said light chain variable domains comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 69, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 81, and LC-CDR3 comprising Comprising the amino acid sequence of SEQ ID NO: 103.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure The domain comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO:9, HC-CDR2 comprising the amino acid sequence of SEQ ID NO:31, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO:51; and b) light Chain variable domains, said light chain variable domains comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 70, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 83, and LC-CDR3 comprising Comprising the amino acid sequence of SEQ ID NO: 106.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure The domain comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 14, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 32, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 51; and b) light Chain variable domains, said light chain variable domains comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 71, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 86, and LC-CDR3 comprising Comprising the amino acid sequence of SEQ ID NO: 107.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure The domain comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 11, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 30, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 50; and b) light Chain variable domains, said light chain variable domains comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 72, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 81, and LC-CDR3 comprising Comprising the amino acid sequence of SEQ ID NO: 108.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure The domain comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 13, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 33, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 52; and b) light Chain variable domains, said light chain variable domains comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 61, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 81, and LC-CDR3 comprising Comprising the amino acid sequence of SEQ ID NO:97.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure The domain comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 10, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 30, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 50; and b) light Chain variable domains, said light chain variable domains comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 61, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 81, and LC-CDR3 comprising Comprising the amino acid sequence of SEQ ID NO: 103.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure The domain comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 15, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 34, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 53; and b) light Chain variable domains, said light chain variable domains comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 73, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 81, and LC-CDR3 comprising Comprising the amino acid sequence of SEQ ID NO: 109.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure The domain comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 16, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 35, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 54; and b) light Chain variable domains, said light chain variable domains comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 74, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 88, and LC-CDR3 comprising Comprising the amino acid sequence of SEQ ID NO: 110.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure The domain comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 17, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 36, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 55; and b) light Chain variable domains, said light chain variable domains comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 75, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 81, and LC-CDR3 comprising Comprising the amino acid sequence of SEQ ID NO:97.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure The domain comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 37, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 56; and b) light Chain variable domains, said light chain variable domains comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 59, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 79, and LC-CDR3 comprising Comprising the amino acid sequence of SEQ ID NO: 111.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure The domain comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 38, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 57; and b) light Chain variable domains, said light chain variable domains comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 76, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 79, and LC-CDR3 comprising Comprising the amino acid sequence of SEQ ID NO: 112.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure The domain comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 37, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 57; and b) light Chain variable domains, said light chain variable domains comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 77, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 89, and LC-CDR3 comprising Comprising the amino acid sequence of SEQ ID NO: 111.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure The domain comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 37, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 57; and b) light Chain variable domains, said light chain variable domains comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 77, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 90, and LC-CDR3 comprising Comprising the amino acid sequence of SEQ ID NO: 111.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure The domain comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 38, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 57; and b) light Chain variable domains, said light chain variable domains comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 76, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 79, and LC-CDR3 comprising Comprising the amino acid sequence of SEQ ID NO: 111.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure The domain comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 38, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 57; and b) light Chain variable domains, said light chain variable domains comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 77, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 79, and LC-CDR3 comprising Comprising the amino acid sequence of SEQ ID NO: 113.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure The domain comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 37, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 57; and b) light Chain variable domains, said light chain variable domains comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 77, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 89, and LC-CDR3 comprising Comprising the amino acid sequence of SEQ ID NO: 114.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure The domain comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 37, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 57; and b) light Chain variable domains, said light chain variable domains comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 77, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 91, and LC-CDR3 comprising Comprising the amino acid sequence of SEQ ID NO: 113.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure The domain comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 37, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 56; and b) light Chain variable domains, said light chain variable domains comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 78, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 92, and LC-CDR3 comprising Comprising the amino acid sequence of SEQ ID NO:93.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure The domain comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO:1, HC-CDR2 comprising the amino acid sequence of SEQ ID NO:19, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO:39; and b) light Chain variable domains, said light chain variable domains comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 58, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 79, and LC-CDR3 comprising Comprising the amino acid sequence of SEQ ID NO:93.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure The domain comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO:2, HC-CDR2 comprising the amino acid sequence of SEQ ID NO:20, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO:40; and b) light Chain variable domains, said light chain variable domains comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 59, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 79, and LC-CDR3 comprising Comprising the amino acid sequence of SEQ ID NO:94.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure The domain comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO:3, HC-CDR2 comprising the amino acid sequence of SEQ ID NO:21, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO:41; and b) light Chain variable domains, said light chain variable domains comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 60, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 80, and LC-CDR3 comprising Comprising the amino acid sequence of SEQ ID NO:95.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure The domain comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO:4, HC-CDR2 comprising the amino acid sequence of SEQ ID NO:22, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO:42; and b) light Chain variable domains, said light chain variable domains comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 61, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 81, and LC-CDR3 comprising Comprising the amino acid sequence of SEQ ID NO:96.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure The domain comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO:5, HC-CDR2 comprising the amino acid sequence of SEQ ID NO:23, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO:43; and b) light Chain variable domains, said light chain variable domains comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 61, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 82, and LC-CDR3 comprising Comprising the amino acid sequence of SEQ ID NO:97.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure The domain comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO:7, HC-CDR2 comprising the amino acid sequence of SEQ ID NO:25, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO:45; and b) light Chain variable domains, said light chain variable domains comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 63, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 84, and LC-CDR3 comprising Comprising the amino acid sequence of SEQ ID NO:99.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure The domain comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO:7, HC-CDR2 comprising the amino acid sequence of SEQ ID NO:26, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO:46; and b) light Chain variable domains, said light chain variable domains comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 64, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 79, and LC-CDR3 comprising Contains the amino acid sequence SEQ ID NO:100.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure The domain comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO:8, HC-CDR2 comprising the amino acid sequence of SEQ ID NO:27, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO:47; and b) light Chain variable domains, said light chain variable domains comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 65, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 85, and LC-CDR3 comprising Comprising the amino acid sequence of SEQ ID NO: 101.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure The domain comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO:9, HC-CDR2 comprising the amino acid sequence of SEQ ID NO:28, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO:48; and b) light Chain variable domains, said light chain variable domains comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 66, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 86, and LC-CDR3 comprising Comprising the amino acid sequence of SEQ ID NO: 102.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure The domain comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO:6, HC-CDR2 comprising the amino acid sequence of SEQ ID NO:24, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO:44; and b) light Chain variable domains, said light chain variable domains comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 62, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 83, and LC-CDR3 comprising Comprising the amino acid sequence of SEQ ID NO:98.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure The domain comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 10, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 29, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 49; and b) light Chain variable domains, said light chain variable domains comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 67, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 87, and LC-CDR3 comprising Comprising the amino acid sequence of SEQ ID NO: 103.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure The domain comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 11, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 30, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 50; and b) light Chain variable domains, said light chain variable domains comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 68, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 81, and LC-CDR3 comprising Comprising the amino acid sequence of SEQ ID NO: 104.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure The domain comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 12, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 30, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 50; and b) light Chain variable domains, said light chain variable domains comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 61, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 81, and LC-CDR3 comprising Comprising the amino acid sequence of SEQ ID NO: 105.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure The domain comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 13, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 30, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 50; and b) light Chain variable domains, said light chain variable domains comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 69, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 81, and LC-CDR3 comprising Comprising the amino acid sequence of SEQ ID NO: 103.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure The domain comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO:9, HC-CDR2 comprising the amino acid sequence of SEQ ID NO:31, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO:51; and b) light Chain variable domains, said light chain variable domains comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 70, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 83, and LC-CDR3 comprising Comprising the amino acid sequence of SEQ ID NO: 106.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure The domain comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 14, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 32, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 51; and b) light Chain variable domains, said light chain variable domains comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 71, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 86, and LC-CDR3 comprising Comprising the amino acid sequence of SEQ ID NO: 107.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure The domain comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 11, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 30, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 50; and b) light Chain variable domains, said light chain variable domains comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 72, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 81, and LC-CDR3 comprising Comprising the amino acid sequence of SEQ ID NO: 108.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure The domain comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 13, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 33, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 52; and b) light Chain variable domains, said light chain variable domains comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 61, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 81, and LC-CDR3 comprising Comprising the amino acid sequence of SEQ ID NO:97.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure The domain comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 10, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 30, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 50; and b) light Chain variable domains, said light chain variable domains comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 61, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 81, and LC-CDR3 comprising Comprising the amino acid sequence of SEQ ID NO: 103.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure The domain comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 15, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 34, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 53; and b) light Chain variable domains, said light chain variable domains comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 73, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 81, and LC-CDR3 comprising Comprising the amino acid sequence of SEQ ID NO: 109.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure The domain comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 16, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 35, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 54; and b) light Chain variable domains, said light chain variable domains comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 74, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 88, and LC-CDR3 comprising Comprising the amino acid sequence of SEQ ID NO: 110.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure The domain comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 17, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 36, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 55; and b) light Chain variable domains, said light chain variable domains comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 75, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 81, and LC-CDR3 comprising Comprising the amino acid sequence of SEQ ID NO:97.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure The domain comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 37, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 56; and b) light Chain variable domains, said light chain variable domains comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 59, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 79, and LC-CDR3 comprising Comprising the amino acid sequence of SEQ ID NO: 111.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure The domain comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 38, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 57; and b) light Chain variable domains, said light chain variable domains comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 76, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 79, and LC-CDR3 comprising Comprising the amino acid sequence of SEQ ID NO: 112.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure The domain comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 37, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 57; and b) light Chain variable domains, said light chain variable domains comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 77, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 89, and LC-CDR3 comprising Comprising the amino acid sequence of SEQ ID NO: 111.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure The domain comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 37, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 57; and b) light Chain variable domains, said light chain variable domains comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 77, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 90, and LC-CDR3 comprising Comprising the amino acid sequence of SEQ ID NO: 111.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure The domain comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 38, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 57; and b) light Chain variable domains, said light chain variable domains comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 76, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 79, and LC-CDR3 comprising Comprising the amino acid sequence of SEQ ID NO: 111.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure The domain comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 38, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 57; and b) light Chain variable domains, said light chain variable domains comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 77, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 79, and LC-CDR3 comprising Comprising the amino acid sequence of SEQ ID NO: 113.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure The domain comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 37, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 57; and b) light Chain variable domains, said light chain variable domains comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 77, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 89, and LC-CDR3 comprising Comprising the amino acid sequence of SEQ ID NO: 114.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure The domain comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 37, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 57; and b) light Chain variable domains, said light chain variable domains comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 77, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 91, and LC-CDR3 comprising Comprising the amino acid sequence of SEQ ID NO: 113.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region
  • said anti-HBV pre-S1 antibody comprises: a) a heavy chain variable domain, said heavy chain variable structure The domain comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 37, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 56; and b) light Chain variable domains, said light chain variable domains comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 78, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 92, and LC-CDR3 comprising Comprising the amino acid sequence of SEQ ID NO:93.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region wherein the anti-HBV pre-S1 antibody comprises: a heavy chain variable domain ( VH ), said VH comprising SEQ ID
  • VH heavy chain variable domain
  • V L light chain variable domain
  • said V L comprising any of SEQ ID NOs: 151-185 A amino acid sequence or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%) of any of the amino acid sequences shown in SEQ ID NOs: 151-185 , 96%, 97%, 98% or 99%) sequence identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG2 constant region wherein the anti-HBV pre-S1 antibody comprises: a heavy chain variable domain ( VH ), said VH comprising SEQ ID
  • VH heavy chain variable domain
  • V L light chain variable domain
  • said V L comprising any of SEQ ID NOs: 151-185 A amino acid sequence or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%) of any of the amino acid sequences shown in SEQ ID NOs: 151-185 , 96%, 97%, 98% or 99%) sequence identity.
  • the IgG2 is human IgG2.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG3 constant region wherein the anti-HBV pre-S1 antibody comprises: a heavy chain variable domain ( VH ), said VH comprising SEQ ID
  • VH heavy chain variable domain
  • V L light chain variable domain
  • said V L comprising any of SEQ ID NOs: 151-185 A amino acid sequence or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%) of any of the amino acid sequences shown in SEQ ID NOs: 151-185 , 96%, 97%, 98% or 99%) sequence identity.
  • the IgG3 is human IgG3.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region wherein the anti-HBV pre-S1 antibody comprises: a heavy chain variable domain ( VH ), said VH comprising SEQ ID
  • VH heavy chain variable domain
  • V L light chain variable domain
  • said V L comprising any of SEQ ID NOs: 151-185 A amino acid sequence or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%) of any of the amino acid sequences shown in SEQ ID NOs: 151-185 , 96%, 97%, 98% or 99%) sequence identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region wherein the anti-HBV pre-S1 antibody comprises: a heavy chain variable domain ( VH ), said VH comprising SEQ ID The amino acid sequence shown in any of NOs: 120-150, and the light chain variable domain (V L ), said V L comprising the amino acid sequence shown in any of SEQ ID NOs: 151-185.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region wherein the anti-HBV pre-S1 antibody comprises: a heavy chain variable domain ( VH ), said VH comprising SEQ ID The amino acid sequence shown in any of NOs: 120-150, and the light chain variable domain (V L ), said V L comprising the amino acid sequence shown in any of SEQ ID NOs: 151-185.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region comprising an IgG1 constant region
  • the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 120 or a variant thereof, wherein The variant has at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 120; and V L comprising the amino acid sequence of SEQ ID NO: 151 or a variant thereof that is identical to the amino acid sequence of SEQ ID NO: 151 have at least about 80% sequence identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region comprising an IgG1 constant region
  • the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 121 or a variant thereof, wherein Said variant has at least about 80% sequence identity with amino acid sequence SEQ ID NO:121; have at least about 80% sequence identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region comprising an IgG1 constant region
  • the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 122 or a variant thereof, wherein Said variant has at least about 80% sequence identity with amino acid sequence SEQ ID NO:122; have at least about 80% sequence identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region comprising an IgG1 constant region
  • the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 123 or a variant thereof, wherein Said variant has at least about 80% sequence identity with amino acid sequence SEQ ID NO:123; have at least about 80% sequence identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region comprising an IgG1 constant region
  • the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 124 or a variant thereof, wherein Said variant has at least about 80% sequence identity with amino acid sequence SEQ ID NO:124; have at least about 80% sequence identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region wherein the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 126 or a variant thereof, wherein Said variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 126; and V L comprising the amino acid sequence of SEQ ID NO: 157 or a variant thereof, said variant having the amino acid sequence of SEQ ID NO: 157 have at least about 80% sequence identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region comprising an IgG1 constant region
  • the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 128 or a variant thereof, wherein Said variant has at least about 80% sequence identity with amino acid sequence SEQ ID NO: 128; have at least about 80% sequence identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region wherein the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 130 or a variant thereof, wherein Said variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 130; and V L comprising the amino acid sequence of SEQ ID NO: 159 or a variant thereof, said variant having the amino acid sequence of SEQ ID NO: 159 have at least about 80% sequence identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region comprising an IgG1 constant region
  • the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 131 or a variant thereof, wherein Said variant has at least about 80% sequence identity with amino acid sequence SEQ ID NO:131; have at least about 80% sequence identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region wherein the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 132 or a variant thereof, wherein Said variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 132; and V L comprising the amino acid sequence of SEQ ID NO: 161 or a variant thereof, said variant having the amino acid sequence of SEQ ID NO: 161 have at least about 80% sequence identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region comprising an IgG1 constant region
  • the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 133 or a variant thereof, wherein Said variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 133; and V L comprising the amino acid sequence of SEQ ID NO: 162 or a variant thereof, said variant having the amino acid sequence of SEQ ID NO: 162 have at least about 80% sequence identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region wherein the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 134 or a variant thereof, wherein Said variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 134; and V L comprising the amino acid sequence of SEQ ID NO: 163 or a variant thereof, said variant having the amino acid sequence of SEQ ID NO: 163 have at least about 80% sequence identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region comprising an IgG1 constant region
  • the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 135 or a variant thereof, wherein Said variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 135; and V L comprising the amino acid sequence of SEQ ID NO: 164 or a variant thereof, said variant having the same have at least about 80% sequence identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region comprising an IgG1 constant region
  • the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 136 or a variant thereof, wherein Said variant has at least about 80% sequence identity with amino acid sequence SEQ ID NO: 136; have at least about 80% sequence identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region comprising an IgG1 constant region
  • the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 137 or a variant thereof, wherein Said variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 137; and V L comprising the amino acid sequence of SEQ ID NO: 167 or a variant thereof, said variant having the amino acid sequence of SEQ ID NO: 167 have at least about 80% sequence identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region comprising an IgG1 constant region
  • the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 139 or a variant thereof, wherein Said variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 139; and V L comprising the amino acid sequence of SEQ ID NO: 169 or a variant thereof, said variant having the amino acid sequence of SEQ ID NO: 169 have at least about 80% sequence identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region wherein the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 140 or a variant thereof, wherein Said variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 140; and V L comprising the amino acid sequence of SEQ ID NO: 170 or a variant thereof, said variant having the amino acid sequence of SEQ ID NO: 170 have at least about 80% sequence identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region wherein the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 141 or a variant thereof, wherein Said variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 141; and V L comprising the amino acid sequence of SEQ ID NO: 171 or a variant thereof, said variant having the amino acid sequence of SEQ ID NO: 171 have at least about 80% sequence identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region comprising an IgG1 constant region
  • the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 142 or a variant thereof, wherein Said variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 142; and V L comprising the amino acid sequence of SEQ ID NO: 172 or a variant thereof, said variant having the amino acid sequence of SEQ ID NO: 172 have at least about 80% sequence identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region wherein the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 143 or a variant thereof, wherein Said variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 143; and V L comprising the amino acid sequence of SEQ ID NO: 173 or a variant thereof, said variant having the amino acid sequence of SEQ ID NO: 173 have at least about 80% sequence identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region wherein the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 144 or a variant thereof, wherein Said variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 144; and V L comprising the amino acid sequence of SEQ ID NO: 174 or a variant thereof, said variant having the amino acid sequence of SEQ ID NO: 174 have at least about 80% sequence identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region wherein the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 145 or a variant thereof, wherein Said variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 145; and V L comprising the amino acid sequence of SEQ ID NO: 175 or a variant thereof, said variant having the amino acid sequence of SEQ ID NO: 175 have at least about 80% sequence identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region wherein the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 146 or a variant thereof, wherein Said variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 146; and V L comprising the amino acid sequence of SEQ ID NO: 176 or a variant thereof, said variant having the amino acid sequence of SEQ ID NO: 176 have at least about 80% sequence identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region comprising an IgG1 constant region
  • the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 147 or a variant thereof, wherein Said variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 147; and V L comprising the amino acid sequence of SEQ ID NO: 177 or a variant thereof, said variant having the same have at least about 80% sequence identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region comprising an IgG1 constant region
  • the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 148 or a variant thereof, wherein Said variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 148; and V L comprising the amino acid sequence of SEQ ID NO: 178 or a variant thereof, said variant having the amino acid sequence of SEQ ID NO: 178 have at least about 80% sequence identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region comprising an IgG1 constant region
  • the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 149 or a variant thereof, wherein Said variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 149; and V L comprising the amino acid sequence of SEQ ID NO: 179 or a variant thereof, said variant having the amino acid sequence of SEQ ID NO: 179 have at least about 80% sequence identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region wherein the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 147 or a variant thereof, wherein Said variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 147; and V L comprising the amino acid sequence of SEQ ID NO: 180 or a variant thereof, said variant having the amino acid sequence of SEQ ID NO: 180 have at least about 80% sequence identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region wherein the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 147 or a variant thereof, wherein Said variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 147; and V L comprising the amino acid sequence of SEQ ID NO: 181 or a variant thereof, said variant having the amino acid sequence of SEQ ID NO: 181 have at least about 80% sequence identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region comprising an IgG1 constant region
  • the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 148 or a variant thereof, wherein Said variant has at least about 80% sequence identity with amino acid sequence SEQ ID NO:148; have at least about 80% sequence identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region comprising an IgG1 constant region
  • the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 150 or a variant thereof, wherein Said variant has at least about 80% sequence identity with amino acid sequence SEQ ID NO:150; have at least about 80% sequence identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG1 constant region wherein the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 146 or a variant thereof, wherein Said variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 146; and V L comprising the amino acid sequence of SEQ ID NO: 184 or a variant thereof, said variant having the amino acid sequence of SEQ ID NO: 184 have at least about 80% sequence identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:186.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region comprising an IgG4 constant region
  • the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 120 or a variant thereof, wherein Said variant has at least about 80% sequence identity with amino acid sequence SEQ ID NO:120; NO: 151 has at least about 80% sequence identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region comprising an IgG4 constant region
  • the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 121 or a variant thereof, wherein Said variant has at least about 80% sequence identity with amino acid sequence SEQ ID NO: 121; NO: 152 has at least about 80% sequence identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region comprising an IgG4 constant region
  • the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 122 or a variant thereof, wherein Said variant has at least about 80% sequence identity with amino acid sequence SEQ ID NO: 122; NO: 120 has at least about 80% sequence identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region comprising an IgG4 constant region
  • the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 123 or a variant thereof, wherein Said variant has at least about 80% sequence identity with amino acid sequence SEQ ID NO:123; NO: 154 has at least about 80% sequence identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region comprising an IgG4 constant region
  • the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 124 or a variant thereof, wherein Said variant has at least about 80% sequence identity with amino acid sequence SEQ ID NO: 124; NO: 155 has at least about 80% sequence identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region comprising an IgG4 constant region
  • the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 126 or a variant thereof, wherein Said variant has at least about 80% sequence identity with amino acid sequence SEQ ID NO:126; NO: 157 has at least about 80% sequence identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region comprising an IgG4 constant region
  • the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 128 or a variant thereof, wherein Said variant has at least about 80% sequence identity with amino acid sequence SEQ ID NO: 128; NO: 158 has at least about 80% sequence identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region comprising an IgG4 constant region
  • the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 130 or a variant thereof, wherein Said variant has at least about 80% sequence identity with amino acid sequence SEQ ID NO:130; NO: 159 has at least about 80% sequence identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region comprising an IgG4 constant region
  • the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 131 or a variant thereof, wherein Said variant has at least about 80% sequence identity with amino acid sequence SEQ ID NO:131; NO: 160 has at least about 80% sequence identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region comprising an IgG4 constant region
  • the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 132 or a variant thereof, wherein Said variant has at least about 80% sequence identity with amino acid sequence SEQ ID NO: 132; NO: 161 has at least about 80% sequence identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region wherein the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 133 or a variant thereof, wherein Said variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 133; and a V L comprising the amino acid sequence of SEQ ID NO: 162 or a variant thereof , said variant having the amino acid sequence of SEQ ID NO: 162 has at least about 80% sequence identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region comprising an IgG4 constant region
  • the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 134 or a variant thereof, wherein Said variant has at least about 80% sequence identity with amino acid sequence SEQ ID NO:134; NO: 163 has at least about 80% sequence identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region wherein the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 135 or a variant thereof, wherein Said variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 135; and V L , said V L comprising the amino acid sequence of SEQ ID NO: 164 or a variant thereof, said variant having the amino acid sequence of SEQ ID NO: 164 has at least about 80% sequence identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region comprising an IgG4 constant region
  • the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 136 or a variant thereof, wherein Said variant has at least about 80% sequence identity with amino acid sequence SEQ ID NO:136; NO: 165 has at least about 80% sequence identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region wherein the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 137 or a variant thereof, wherein Said variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 137; and V L , said V L comprising the amino acid sequence of SEQ ID NO: 167 or a variant thereof, said variant having the amino acid sequence of SEQ ID NO: 167 has at least about 80% sequence identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region wherein the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 139 or a variant thereof, wherein Said variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 139; and V L , said V L comprising the amino acid sequence of SEQ ID NO: 169 or a variant thereof, said variant having the amino acid sequence of SEQ ID NO: 169 has at least about 80% sequence identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region wherein the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 140 or a variant thereof, wherein Said variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 140; and V L , said V L comprising the amino acid sequence of SEQ ID NO: 170 or a variant thereof, said variant having the amino acid sequence of SEQ ID NO: 170 has at least about 80% sequence identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region comprising an IgG4 constant region
  • the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 141 or a variant thereof, wherein Said variant has at least about 80% sequence identity with amino acid sequence SEQ ID NO: 141; NO: 171 has at least about 80% sequence identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region comprising an IgG4 constant region
  • the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 142 or a variant thereof, wherein Said variant has at least about 80% sequence identity with amino acid sequence SEQ ID NO: 142; NO: 172 has at least about 80% sequence identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region comprising an IgG4 constant region
  • the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 143 or a variant thereof, wherein Said variant has at least about 80% sequence identity with amino acid sequence SEQ ID NO: 143; NO: 173 has at least about 80% sequence identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region comprising an IgG4 constant region
  • the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 144 or a variant thereof, wherein Said variant has at least about 80% sequence identity with amino acid sequence SEQ ID NO: 144; NO: 174 has at least about 80% sequence identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region wherein the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 145 or a variant thereof, wherein Said variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 145; and a V L comprising the amino acid sequence of SEQ ID NO: 175 or a variant thereof , said variant having the amino acid sequence of SEQ ID NO: 175 has at least about 80% sequence identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region comprising an IgG4 constant region
  • the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 146 or a variant thereof, wherein Said variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 146; and a V L comprising the amino acid sequence of SEQ ID NO: 176 or a variant thereof , said variant having the amino acid sequence of SEQ ID NO: 176 has at least about 80% sequence identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region wherein the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 147 or a variant thereof, wherein Said variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 147; and V L , said V L comprising the amino acid sequence of SEQ ID NO: 177 or a variant thereof, said variant having the amino acid sequence of SEQ ID NO: 177 has at least about 80% sequence identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region comprising an IgG4 constant region
  • the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 148 or a variant thereof, wherein Said variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 148; and a V L comprising the amino acid sequence of SEQ ID NO: 178 or a variant thereof , said variant having the amino acid sequence of SEQ ID NO: 178 has at least about 80% sequence identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region comprising an IgG4 constant region
  • the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 149 or a variant thereof, wherein Said variant has at least about 80% sequence identity with amino acid sequence SEQ ID NO:149; NO: 179 has at least about 80% sequence identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region comprising an IgG4 constant region
  • the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 147 or a variant thereof, wherein Said variant has at least about 80% sequence identity with amino acid sequence SEQ ID NO: 147; NO: 180 has at least about 80% sequence identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region wherein the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 147 or a variant thereof, wherein Said variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 147; and a V L comprising the amino acid sequence of SEQ ID NO: 181 or a variant thereof , said variant having the amino acid sequence of SEQ ID NO: 181 has at least about 80% sequence identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region comprising an IgG4 constant region
  • the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 148 or a variant thereof, wherein Said variant has at least about 80% sequence identity with amino acid sequence SEQ ID NO:148; NO: 182 has at least about 80% sequence identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region comprising an IgG4 constant region
  • the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 150 or a variant thereof, wherein Said variant has at least about 80% sequence identity with amino acid sequence SEQ ID NO:150; NO: 183 has at least about 80% sequence identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a full-length anti-HBV pre-S1 antibody comprising an IgG4 constant region comprising an IgG4 constant region
  • the anti-HBV pre-S1 antibody comprises: V H comprising the amino acid sequence of SEQ ID NO: 146 or a variant thereof, wherein Said variant has at least about 80% sequence identity with amino acid sequence SEQ ID NO:146; NO: 184 has at least about 80% sequence identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • Binding affinity is expressed as Kd, Koff, Kon or Ka.
  • Koff refers to the rate constant for dissociation of an antibody from an antigen/antibody complex, as determined by a kinetic selective device.
  • Kon refers to the association rate constant for the binding of an antibody to an antigen to form an antigen/antibody complex.
  • the equilibrium dissociation constant Kd used herein refers to the dissociation constant when a specific antibody-antigen interacts, and refers to the antigen concentration required when the antigen occupies half of all antibody binding sites and reaches equilibrium in the antibody molecule solution, which is equal to Koff /Kon. The determination of Kd assumes that all bound molecules are in solution.
  • the corresponding equilibrium dissociation rate constant is expressed in terms of EC50 , which is a good approximation of Kd.
  • the affinity association constant Ka is the reciprocal of the dissociation constant Kd.
  • the dissociation constant (Kd) can be used as an indicator of the affinity of the antibody moiety for the antigen.
  • simple analysis can be performed by the Scatchard method using antibodies labeled with various markers, and a Biacore instrument (manufactured by Amersham Biosciences), and the interaction between biomolecules can be analyzed by surface plasmon resonance according to the user's manual or the attached kit. . Kd values obtained using these methods are expressed in units of M.
  • An antibody that specifically binds a target may have, for example, ⁇ 10 ⁇ 7 M, ⁇ 10 ⁇ 8 M, ⁇ 10 ⁇ 9 M, ⁇ 10 ⁇ 10 M, ⁇ 10 ⁇ 11 M, ⁇ 10 ⁇ 12 M, or ⁇ 10 ⁇ Kd value of 13M .
  • the binding specificity of an antibody can be determined experimentally by methods known in the art. These methods include, but are not limited to, Western blots, ELISA-, RIA-, ECL-, IRMA-, EIA-, BIAcore tests, and peptide scans, among others.
  • the anti-HBV pre-S1 antibody specifically binds the HBV pre-S1 target with a Kd value of 10 ⁇ 7 M to 10 ⁇ 13 M (for example, 10 ⁇ 7 M to 10 ⁇ 13 M, 10 ⁇ 1 8 M to 10 -13 M, 10 -9 M to 10 -13 M or 10 -10 M to 10 -12 M).
  • the Kd value of the binding between the anti-HBV pre-S1 antibody and HBV pre-S1 is 10 ⁇ 7 M to 10 ⁇ 13 M, 1 ⁇ 10 ⁇ 7 M to 5 ⁇ 10 ⁇ 13 M, 10 -7 M to 10 -12 M, 10 -7 M to 10 -11 M, 10 -7 M to 10 -10 M, 10 -7 M to 10 -9 M, 10 - 8 M to 10 -13 M, 1 ⁇ 10 -8 M to 5 ⁇ 10 -13 M, 10 -8 M to 10 -12 M, 10 -8 M to 10 -11 M, 10 -8 M to 10 -10 M, 10 -8 M to 10 -9 M, 5 ⁇ 10 -9 M to 1 ⁇ 10 -13 M, 5 ⁇ 10 -9 M to 1 ⁇ 10 -12 M, 5 ⁇ 10 -9 M to 1 ⁇ 10 -11 M, 5 ⁇ 10 - 9 M to 1 ⁇ 10 -10 M, 10 -9 M to 10 -13 M, 10 -9 M to 10 -12 M, 10 -9 M to 10 -11 M, 10 -9 M to 10 -11
  • the Kd value of the binding between the anti-HBV pre-S1 antibody and the non-target is higher than the Kd value of the anti-HBV pre-S1 antibody and the target, and in some embodiments cited herein, the anti-HBV pre-S1
  • the binding affinity of the antibody to a target eg, HBV pre-S1 antigen
  • non-target refers to an antigen other than HBV pre-S1.
  • the Kd value of the anti-HBV pre-S1 antibody (for HBV pre-S1) binding to a non-HBV pre-S1 target is at least 10 times different, such as 10-100 times, 100-1000 times, 10 3 - 10 4 times, 10 4 -10 5 times, 10 5 -10 6 times, 10 6 -10 7 times, 10 7 -10 8 times, 10 8 -10 9 times, 10 9 -10 10 times, 10 10 -10 11 times, 10 11 -10 12 times.
  • the non-target binding Kd value of the anti-HBV pre-S1 antibody is 10 -1 M to 10 -6 M (for example, 10 -1 M to 10 -6 M, 10 -1 M to 10 - 5 M, 10 -2 M to 10 -4 M).
  • the non-target refers to an antigen other than HBV pre-S1.
  • the Kd value for the binding between the anti-HBV pre-S1 antibody and the non-HBV pre-S1 target is 10 ⁇ 1 M to 10 ⁇ 6 M, 1 ⁇ 10 ⁇ 1 M to 5 ⁇ 10 ⁇ 6 M, 10 -1 M to 10 -5 M, 1 ⁇ 10 -1 M to 5 ⁇ 10 -5 M, 10 -1 M to 10 -4 M, 1 ⁇ 10 -1 M to 5 ⁇ 10 -4 M, 10 -1 M to 10 -3 M, 1 ⁇ 10 -1 M to 5 ⁇ 10 -3 M, 10 -1 M to 10 -2 M, 10 -2 M to 10 -6 M , 1 ⁇ 10 -2 M to 5 ⁇ 10 -6 M, 10 -2 M to 10 -5 M, 1 ⁇ 10 -2 M to 5 ⁇ 10 -5 M, 10 -2 M to 10 -4 M, 1 ⁇ 10 -2 M to 5 ⁇ 10 -4 M, 10 -2 M to 10 -3 M, 10 -3 M to 10 -6 M, 1 ⁇ 10 -3 M to 5 ⁇ 10 -6 M, 10 -2 M to 10
  • said anti-HBV pre-S1 antibody when referring to an anti-HBV pre-S1 antibody that specifically recognizes an HBV pre-S1 target with high binding affinity and binds a non-target with low binding affinity, said anti-HBV pre-S1 antibody binds to HBV pre -S1 target binding has a Kd value of 10 -7 M to 10 -13 M (for example, 10 -7 M to 10 -13 M, 10 -8 M to 10 -13 M, 10 -9 M to 10 -13 M, 10 -10 M to 10 -12 M), and the Kd value for non-target binding is 10 -1 M to 10 -6 M (for example, 10 -1 M to 10 -6 M, 10 -1 M to 10 -5 M, 10 -2 M to 10 -4 M).
  • the binding affinity of the anti-HBV pre-S1 antibody is compared with that of a control anti-HBV pre-S1 antibody (such as A14-20m1 or A14-8) for comparison of binding affinities.
  • the Kd value of the binding between the control anti-HBV pre-S1 antibody and HBV pre-S1 can be at least the Kd value of the binding between the anti-HBV pre-S1 antibody described in the present application and HBV pre-S1 2 times, such as 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 10-100 times, 100-1000 times, 10 3 -10 4 times.
  • nucleic acid molecules encoding anti-HBV pre-S1 antibodies are also contemplated.
  • a nucleic acid encoding a full-length anti-HBV pre-S1 antibody is provided (or a group), including any full-length anti-HBV pre-S1 antibody described herein.
  • the nucleic acid (or a set of nucleic acids) of the anti-HBV pre-S1 antibody described herein may also include a nucleic acid sequence encoding a polypeptide tag (such as a protein purification tag, His tag, HA tag).
  • isolated host cells comprising anti-HBV pre-S1 antibodies, isolated nucleic acids encoding anti-HBV pre-S1 antibody polypeptide components, or comprising encoding anti-HBV pre-S1 antibody polypeptide components described herein Nucleic acid carrier.
  • variants include nucleotide sequences that hybridize to the nucleic acid sequence encoding the anti-HBV pre-S1 antibody of the application at least under moderately stringent hybridization conditions.
  • the present application also provides a vector into which the nucleic acid sequence of the present application can be inserted.
  • a natural or synthetic nucleic acid encoding an anti-HBV pre-S1 antibody is inserted into a suitable expression vector such that the nucleic acid is operably linked to 5' and 3' regulatory elements, including, for example, promoters (e.g., lymphoid Cell-specific promoter) and 3' untranslated region (UTR), can express anti-HBV pre-S1 antibody (such as full-length anti-HBV pre-S1 antibody).
  • promoters e.g., lymphoid Cell-specific promoter
  • UTR 3' untranslated region
  • the vectors are suitable for replication and integration in eukaryotic host cells.
  • Typical cloning and expression vectors contain transcriptional and translational terminators, initiation sequences and promoters to regulate the expression of the nucleic acid sequence of interest.
  • nucleic acids described herein can also be used in nucleic acid immunization and gene therapy by using standard gene delivery protocols. Methods of nucleic acid delivery are known in the art. See, eg, U.S. Pat. Nos. 5,399,346, 5,580,859, 5,589,466, the entire contents of which are incorporated herein by reference. In some embodiments, the present application also provides gene therapy vectors.
  • Nucleic acids can be cloned into many types of vectors.
  • nucleic acids can be cloned into vectors including, but not limited to, plasmids, phagemids, phage derivatives, animal viruses, and cosmids.
  • Vectors of particular interest include expression vectors, replication vectors, probe generation vectors and sequencing vectors.
  • expression vectors can be provided to cells in the form of viral vectors.
  • Viral vector technology is well known in the art and described, for example, in Green and Sambrook (2013, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, New York), among other virology or molecular biology manuals.
  • Viruses that can be used as vectors include, but are not limited to, retroviruses, adenoviruses, adeno-associated viruses, herpesviruses, and lentiviruses.
  • suitable vectors include an origin of replication functional in at least one organism, a promoter sequence, convenient restriction enzyme sites, and one or more selectable markers (see, e.g., WO 01/96584; WO 01/29058; and U.S. Pat. No. 6,326,193).
  • retroviruses provide a convenient platform for gene delivery systems.
  • the selected gene can be inserted into a vector and packaged in retroviral particles using techniques known in the art.
  • the recombinant virus is then isolated and delivered to cells of the subject either in vivo or in vitro.
  • Many retroviral systems are known in the art.
  • adenoviral vectors are used.
  • Many adenoviral vectors are known in the art.
  • lentiviral vectors are used.
  • Vectors derived from retroviruses are suitable tools for long-term gene transfer because they allow long-term stable integration of the transgene and propagation in progeny cells.
  • Lentiviral vectors have an additional advantage over tumor-derived retroviruses such as murine leukemia virus in that they can transduce non-dividing cells such as hepatocytes. At the same time, it has the added advantage of low immunogenicity.
  • promoter elements such as enhancers, regulate transcription initiation frequency. Typically they are located 30-110 bp upstream of the initiation site, although it has recently been discovered that many promoters also contain functional elements downstream of the initiation site.
  • the spacing between promoter elements is usually flexible so that promoter function is maintained when elements are swapped or moved relative to each other. In the thymidine kinase (tk) promoter, activity begins to decline when the spacing between promoter elements increases to 50 bp.
  • tk thymidine kinase
  • a suitable promoter is the immediate early cytomegalovirus (CMV) promoter sequence.
  • the promoter sequence is a strong constitutive promoter sequence, which can drive high-level expression of any polynucleotide sequence operably linked to it.
  • Another example of a suitable promoter is the elongation factor 1 alpha (EF-1 alpha) promoter.
  • constitutive promoters can also be used, including but not limited to Simian virus 40 (SV40) early promoter, mouse mammary tumor virus (MMTV), human immunodeficiency virus long terminal repeat (HIV-LTR) promoter , MoMuLV promoter, avian leukemia virus promoter, Epstein-Barr virus immediate early promoter, Rous sarcoma virus promoter and human gene promoter, for example including but not limited to actin promoter, myosin promoter, Hemoglobin promoter and creatine kinase promoter.
  • SV40 Simian virus 40
  • MMTV mouse mammary tumor virus
  • HV-LTR human immunodeficiency virus long terminal repeat
  • MoMuLV promoter avian leukemia virus promoter
  • Epstein-Barr virus immediate early promoter Epstein-Barr virus immediate early promoter
  • Rous sarcoma virus promoter Rous sarcoma virus promoter
  • human gene promoter for example including but not limited to actin
  • an inducible promoter provides a molecular switch that turns on expression of a polynucleotide sequence to which it is operably linked when such expression is desired and turns off expression when it is not.
  • Inducible promoters include, but are not limited to, the metallothionein promoter, the glucocorticoid promoter, the progesterone promoter, and the tetracycline promoter.
  • the expression of anti-HBV pre-S1 antibodies is inducible.
  • the nucleic acid sequence encoding the anti-HBV pre-S1 antibody is operably linked to an inducible promoter, including any inducible promoter described herein.
  • an inducible promoter provides a molecular switch that turns on expression of a polynucleotide sequence to which it is operably linked when expression is desired and turns off expression when expression is not desired.
  • exemplary inducible promoters suitable for use in eukaryotic cells include, but are not limited to, hormone regulatory elements (see, e.g., Mader, S. and White, J.H. (1993) Proc. Natl. Acad. Sci. USA 90:5603-5607) , synthetic ligand regulatory elements (seeing Spencer, D.M.et al (1993) Science 262:1019-1024) and ionizing radiation regulatory elements (seeing Manome, Y.et al.
  • the inducible promoter system used to express the anti-HBV pre-S1 antibody is the Tet system. In some embodiments, the inducible promoter system used to express the anti-HBV pre-S1 antibody is the E. coli lac repression system.
  • an exemplary inducible promoter system employed herein is the Tet system.
  • the system is based on the Tet system described by Gossen et al. (1993).
  • the polynucleotide of interest is controlled by a promoter comprising one or more Tet operator (TetO) sites.
  • TetO Tet operator
  • TetR Tet repressor
  • the activated state e.g., in the presence of inducers such as tetracycline (Tc), anhydrotetracycline, doxycycline (Dox) or their active analogs, the inducer releases TetR from TetO, resulting in transcription .
  • inducers such as tetracycline (Tc), anhydrotetracycline, doxycycline (Dox) or their active analogs
  • Doxycycline is a member of the tetracycline antibiotic family with the chemical name 1-dimethylamino-2,4a,5,7-pentahydroxy-11-methyl-4,6-dioxy-1,4a , 11,11a,12,12a-Hexahydrotetraene-3-carboxamide.
  • TetR is codon optimized for expression in mammalian cells, such as mouse or human cells. Due to the degeneracy of the genetic code, most amino acids are encoded by more than one codon, allowing a large number of variations in the sequence of a given nucleic acid without any change in the amino acid sequence it encodes. However, many organisms differ in their codon usage, also known as "codon bias" (ie, the preference for a given amino acid to use a particular codon). Codon bias is often associated with the presence of dominant tRNA species for specific codons, which in turn increases the efficiency of mRNA translation. A coding sequence derived from a particular species (eg, prokaryotes) can thus be tailored by codon optimization to enhance its expression in a different species (eg, eukaryotes).
  • Tet-Off transcription is inactivated in the presence of Tc or Dox.
  • a tetracycline-regulated transcriptional activator consisting of TetR fused to the strong transcriptional activation domain of herpes simplex virus VP16, regulates the expression of target nucleic acids under the transcriptional control of a tetracycline-responsive promoter element (TRE).
  • the TRE element consists of a TetO sequence fused in tandem to a promoter (usually a minimal promoter sequence derived from the human cytomegalovirus immediate early promoter).
  • Tc or Dox binds TRE and activates transcription of target genes.
  • tTA cannot bind TRE and target genes cannot be expressed.
  • rtTA is a fusion protein consisting of the TetR repressor and the VP16 transcriptional activation domain.
  • a change of 4 amino acids in the DNA-binding region of TetR altered the binding properties of rtTA so that it could only recognize the tetO sequence on the target transgenic TRE in the presence of Dox. Therefore, in the Tet-On system, rtTA can activate the transcription of TRE-regulated target genes only in the presence of Dox.
  • lac repressor system of E. coli (see Brown et al., Cell 49:603-612 (1987)).
  • the Lac repressor system functions by regulating the transcription of a polynucleotide of interest operably linked to a promoter comprising the lac operator (lacO).
  • lacO lac operator
  • lacR lac repressor
  • lacR lacR
  • lacR lacR
  • Expression of the polynucleotide of interest is induced by a suitable inducer, for example, isopropyl- ⁇ -Dthiogalactopyranoside (IPTG).
  • IPTG isopropyl- ⁇ -Dthiogalactopyranoside
  • the expression vector to be introduced into the cells may also contain a selectable marker gene or a reporter gene or both to facilitate the identification and selection of expressing cells from a population of cells transfected or infected with the viral vector.
  • selectable markers can be carried on separate DNA fragments and used in co-transfection experiments. Either a selectable marker gene or a reporter gene can be flanked by appropriate regulatory sequences to enable its expression in the host cell.
  • Useful selectable markers include, for example, antibiotic resistance genes such as neo and the like.
  • Reporter genes can be used to identify potentially transfected cells and evaluate the function of regulatory sequences.
  • a reporter gene is a gene not present in or expressed by a recipient organism or tissue that encodes a polypeptide whose expression is manifested by some readily detectable property, such as enzymatic activity. After the DNA is introduced into the recipient cells, the expression of the reporter gene is detected at an appropriate time.
  • Suitable reporter genes may include genes encoding luciferase, ⁇ -galactosidase, chloramphenicol acetyltransferase, secreted alkaline phosphatase, or green fluorescent protein (see, Ui-Tel et al., 2000 FEBS Letters 479 :79-82).
  • Suitable expression systems are known and can be prepared by known techniques or obtained commercially.
  • the construct with the smallest 5' flanking region that exhibits the highest expression level of the reporter gene is considered a promoter.
  • Such a promoter region can be linked to a reporter gene and used to assess the ability of certain substances to regulate transcription driven by the promoter.
  • nucleic acids encoding any of the full-length anti-HBV pre-S1 antibodies described herein are provided.
  • the nucleic acid includes one or more nucleic acid sequences encoding full-length anti-HBV pre-S1 antibody heavy chain and light chain.
  • each of the one or more nucleic acid sequences is contained in a separate vector.
  • at least some of the nucleic acid sequences are contained within the same vector.
  • all nucleic acid sequences are contained within the same vector.
  • the vector can be selected, for example, from mammalian expression vectors and viral vectors (such as vectors derived from retroviruses, adenoviruses, adeno-associated viruses, herpesviruses, and lentiviruses).
  • mammalian expression vectors such as vectors derived from retroviruses, adenoviruses, adeno-associated viruses, herpesviruses, and lentiviruses.
  • vectors can be readily introduced into host cells, such as mammalian, bacterial, yeast or insect cells, by any method in the art.
  • expression vectors can be introduced into host cells by physical, chemical or biological methods.
  • polynucleotides are introduced into host cells by calcium phosphate transfection.
  • Biological methods for introducing polynucleotides of interest into host cells include the use of DNA and RNA vectors.
  • Viral vectors especially retroviral vectors, have become the most widely used method for inserting genes into mammalian cells, such as human cells.
  • Other viral vectors can be derived from lentiviruses, poxviruses, herpes simplex virus type 1, adenoviruses, and adeno-associated viruses, among others. See, eg, U.S. Pat. Nos. 5,350,674 and 5,585,362.
  • Chemical methods for introducing polynucleotides into host cells include colloidal dispersion systems such as polymer complexes, nanocapsules, microspheres, magnetic beads and lipid-based systems including oil-in-water emulsions, micelles, mixed gels clumps and liposomes.
  • colloidal dispersion systems such as polymer complexes, nanocapsules, microspheres, magnetic beads and lipid-based systems including oil-in-water emulsions, micelles, mixed gels clumps and liposomes.
  • An exemplary colloidal system used as a delivery vehicle in vivo and in vitro is a liposome (eg, an artificial membrane vesicle).
  • an exemplary delivery vehicle is a liposome.
  • lipid formulations to introduce nucleic acids into host cells (in vitro, ex vivo, or in vivo).
  • the nucleic acid can be bound to a lipid.
  • Lipid-bound nucleic acids can be encapsulated into the aqueous interior of liposomes, dispersed within the lipid bilayer of liposomes, attached to liposomes via linker molecules that bind liposomes and oligonucleotides, and include Buried in liposomes, complexed with liposomes, dispersed in lipid-containing solutions, mixed with lipids, associated with lipids, suspended in lipids, contained in or mixed with micelles , or otherwise bind to lipids.
  • Lipid, lipid/DNA or lipid/expression vector-related compositions are not limited to any particular structure in solution. For example, they may exist in bilayer structures, in micelles or in "collapsed" structures.
  • Lipids are fatty substances, either naturally occurring or synthetic.
  • lipids include fat droplets naturally present in the cytoplasm, as well as a class of compounds containing long-chain aliphatic hydrocarbons and their derivatives, such as fatty acids, alcohols, amines, aminoalcohols, and aldehydes.
  • experiments can be performed to confirm the presence of the recombinant DNA sequence in the host cell.
  • Such experiments include, for example, "molecular biology” experiments well known to those skilled in the art. Examples include Southern and Northern blotting, RT-PCR, and PCR; "biochemical” assays, such as detection of the presence or absence of a specific polypeptide, e.g. identified by immunological methods (ELISAs and Western blots) or by the assays described herein All fall within the scope of this application.
  • the anti-HBV pre-S1 antibody is or is derived from a monoclonal antibody. In some embodiments, the anti-HBV pre-S1 antibody comprises VH and VL from a monoclonal antibody, or a variant thereof. In some embodiments, the anti-HBV pre-S1 antibody further comprises CH1 and CL regions from a monoclonal antibody, or a variant thereof.
  • Monoclonal antibodies can be prepared using, for example, methods known in the art, including hybridoma cell methods, phage display methods, or using recombinant DNA methods. Additionally, exemplary phage display methods are described herein and in the Examples below.
  • lymphocytes In the hybridoma cell method, hamsters, mice or other suitable host animals are usually immunized with an immunizing agent to induce lymphocytes that produce or are capable of producing antibodies that specifically bind to the immunizing agent.
  • lymphocytes can be immunized in vitro. Immunizing agents may include polypeptides or fusion proteins of the protein of interest.
  • PBLs peripheral blood lymphocytes
  • splenocytes or lymph node cells are used if cells of non-human mammalian origin are desired.
  • Lymphocytes are fused with an immortal cell line using an appropriate fusion agent, such as polyethylene glycol, to form hybridoma cells.
  • Immortal cell lines are usually transformed mammalian cells, especially myeloma cells of rodent, bovine and human origin. Typically rat or mouse myeloma cell lines are used.
  • Hybridoma cells can be cultured in a suitable medium, which preferably contains one or more substances that inhibit the growth or survival of unfused immortalized cells.
  • a suitable medium which preferably contains one or more substances that inhibit the growth or survival of unfused immortalized cells.
  • the parental cells lack hypoxanthine-guanine phosphoribosyltransferase (HGPRT or HPRT)
  • the hybridoma cell culture medium usually includes hypoxanthine, aminopterin, and thymidine (HAT medium), which can Prevents the growth of HGPRT-deficient cells.
  • the immortalized cell lines fuse efficiently, ensure high-level stable expression of antibodies by the selected antibody-producing cells, and are sensitive to certain media, such as HAT media.
  • the immortal cell line is a mouse myeloma cell line available from, eg, the Salk Cell Collection, San Diego, California, and the American Type Culture Collection, Manassas, Virginia. Human myeloma and mouse-human hybrid myeloma cell lines are also described for the production of human monoclonal antibodies.
  • the medium in which the hybridoma cells are grown can then be assayed for the presence of monoclonal antibodies directed against the polypeptide.
  • the binding specificity of monoclonal antibodies produced by hybridoma cells can be determined by immunoprecipitation or in vitro binding assays, such as radioimmunoassay (RIA) or enzyme-linked immunosorbent assay (ELISA). Such techniques or analytical methods are known in the art.
  • the binding affinity of monoclonal antibodies can be determined by Scatchard analysis as described, for example, in Munson and Pollard, Anal. Biochem., 107:220 (1980).
  • hybridoma cells After the desired hybridoma cells have been identified, the clones of interest can be subcloned by limiting dilution and cultured by standard methods. Suitable media for this purpose include, for example, Modified Eagle's Medium (DMEM) and RPMI-1640 medium. Alternatively, hybridoma cells can be grown in ascites in mammals.
  • DMEM Modified Eagle's Medium
  • RPMI-1640 medium RPMI-1640
  • Monoclonal antibodies secreted by subclones can be isolated or purified from culture medium or ascitic fluid by conventional immunoglobulin purification methods, such as protein A-Sepharose, hydroxyapatite chromatography, gel electrophoresis, dialysis, or affinity chromatography.
  • the anti-HBV pre-S1 antibody comprises a sequence selected from a clone of an antibody library (eg, a phage library displaying scFv or Fab fragments).
  • a clone of an antibody library eg, a phage library displaying scFv or Fab fragments.
  • Such clones can be identified by screening a combinatorial library of antibody fragments having the desired activity. For example, various methods are known in the art for generating phage display libraries and screening these libraries for antibodies with desired binding properties.
  • the repertoires of the VH and VL genes are cloned separately by polymerase chain reaction (PCR), randomly recombined in a phage library, and then screened for antigen-binding phage, as in Winter et al. ., Ann. Rev. Immunol., 12:433-455 (1994).
  • Phage typically display antibody fragments as scFv fragments or as Fab fragments.
  • Immune-derived library phages provide high-affinity antibodies against the immunogen without the need to construct hybridoma cells.
  • natural repertoires e.g.
  • the anti-HBV pre-S1 antibody is prepared by phage display screening the anti-HBV pre-S1 antibody part in the library that can specifically bind to the target HBV pre-S1 antigen.
  • the library can be a human scFv phage display library with at least 1 ⁇ 10 9 (e.g. at least 1 ⁇ 10 9 , 2.5 ⁇ 10 9 , 5 ⁇ 10 9 , 7.5 ⁇ 10 9 , 1 ⁇ 10 10 , 2.5 ⁇ 10 10 , 5 ⁇ 10 10 , 7.5 ⁇ 10 10 , or 1 ⁇ 10 11 ) diversity of unique human antibody fragments.
  • the library is a natural human library constructed from DNA extracted from PMBCs and spleens of healthy subjects, comprising all human heavy and light chain subfamilies.
  • the library is a human natural library constructed by DNA extracted from PMBCs isolated from patients with various diseases, such as patients with autoimmune diseases, cancer patients and patients with infectious diseases.
  • the library is a semi-synthetic human library in which the heavy chain CDR3s are completely randomized, with all amino acids (except cysteine) present at any given position with equal probability. (See eg, Hoet, RM et al., Nat. Biotechnol. 23(3):344-348, 2005).
  • the semi-synthetic human library has a heavy chain CDR3 length of 5 to 24 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 , 19, 20, 21, 22, 23 or 24) amino acids.
  • the library is a fully synthetic phage display library.
  • the library is a non-human phage display library.
  • Phage clones with high affinity to target HBV pre-S1 can be screened by iterative binding of phage to target HBV pre-S1 antigen bound to a solid support (e.g., for solution panning). beads or mammalian cells for cell panning), followed by removal of unbound phage and elution of specifically bound phage. Subsequently, bound phage clones are eluted and used to infect suitable host cells, such as E. coli XL1-Blue, for expression and purification.
  • suitable host cells such as E. coli XL1-Blue
  • Multiple rounds of panning (for example, 2, 3, 4, 5, 6 or more rounds), such as solution panning, cell panning, or a combination of the two to enrich for phage clones specifically binding to HBV pre-S1, can be performed through multiple rounds of panning.
  • the specific binding of the enriched phage clones to the target HBV pre-S1 can be detected by any method known in the art, including, for example, ELISA and FACS.
  • Another way to screen antibody libraries is to display proteins on the surface of yeast cells.
  • Wittrup et al. (US Patents 6,699,658 and 6,696,251) developed a method for displaying libraries in yeast cells.
  • one component includes the yeast lectin protein (Aga1) anchored on the yeast cell wall, and the other component includes the second subunit of the lectin protein Aga2, which can Combined with Aga1 protein and displayed on the surface of yeast cells.
  • the Agal protein is expressed by integrating the Agal gene into the yeast chromosome. After transformation of a single-chain variable fragment (scFv) library fused to the Aga2 gene in a yeast display plasmid, the library is retained in yeast due to the presence of an additional nutritional marker. Both Aga1 and Aga2 proteins are expressed under the control of a galactose-inducible promoter.
  • scFv single-chain variable fragment
  • VH and VK fragments Human antibody V gene repertoires ( VH and VK fragments) were obtained by the PCR method using a set of degenerate primers (Sblattero, D. and Bradbury, A. Immunotechnology 3, 271-278 1998).
  • PCR templates were derived from commercially available RNA or cDNA, including PBMC, spleen, lymph node, bone marrow and tonsil. After combining independent VH and VK PCR libraries, they were assembled into scFv format by overlap extension PCR (Sheets, MD et al, Proc. Natl. Acad. Sci. USA 95, 6157-6162 1998).
  • yeast scFv display library To construct a yeast scFv display library, the resulting scFv PCR product was cloned into a yeast display plasmid in yeast by homologous recombination. (Chao, G, et al, Nat Protoc. 2006; 1(2):755-68. Miller KD, et al. Current Protocols in Cytometry 4.7.1-4.7.30, 2008).
  • Mammalian cell display system can be utilized to screen anti-HBV pre-S1 antibodies, wherein the antibody part is displayed on the cell surface and the antibody specifically targeting HBV pre-S1 is isolated by antigen-directed screening method (such as U.S.patent No.7,732,195 described in B2).
  • a library of Chinese hamster ovary (CHO) cells displaying a large number of human IgG antibody genes can be created and used to discover clones expressing high-affinity antibody genes.
  • An alternative display system has been developed that enables simultaneous cell surface display and secretion of the same protein through alternative splicing, where the displayed protein phenotype remains genotype-related, enabling simultaneous biophysical and cellular function-based analysis The secreted soluble antibody was characterized in .
  • This method overcomes many limitations of previous mammalian cell displays and enables direct screening and maturation of antibodies in the form of full-length, glycosylated IgGs (Peter M. Bowers, et al, Methods 2014, 65: 44-56) .
  • Transient expression systems are suitable for single rounds of antigen selection prior to antibody gene restoration and are therefore most useful for selecting antibodies from smaller libraries.
  • Stable exosome vectors offer an attractive option. Exosome vectors can be efficiently transfected and stably maintained at low copy numbers, allowing multiple rounds of panning and resolution of more complex antibody repertoires.
  • the IgG library is constructed based on the ligation of germline sequence V gene segments isolated from a panel of human donors with rearranged (D)J regions. RNA collected from 2000 human blood samples was reverse transcribed into cDNA, V H and V K fragments were amplified using V H and V K specific primers, and purified by gel extraction. IgG libraries were prepared by subcloning VH and VK fragments into display vectors containing IgG1 or K constant regions, respectively, and then electroporating or transducing 293T into cells.
  • VH and VK were ligated to generate scFv, which was then subcloned into a display vector, which was then electroporated or transduced into 293T cells.
  • IgG libraries are constructed based on germline sequence V gene fragments and rearranged (D)J regions isolated from a group of donors, such as mice, rats, rabbits or monkeys.
  • Monoclonal antibodies can also be prepared by recombinant DNA methods, such as described in U.S. Patent No. 4,816,567.
  • DNA encoding the monoclonal antibodies described in this application can be easily isolated and sequenced by conventional methods (eg, by oligonucleotide probes that can specifically bind to genes encoding the light and heavy chains of murine antibodies).
  • Hybridoma cells as mentioned above or the HBV pre-S1 specific phage clone of the present application can be used as the source of this DNA.
  • the DNA can be placed in an expression vector, which is then transfected into host cells, such as simian COS cells, Chinese hamster ovarian cancer (CHO) cells, or non-immunoglobulin-producing myeloma cells, to obtain Monoclonal antibodies synthesized in cells.
  • host cells such as simian COS cells, Chinese hamster ovarian cancer (CHO) cells, or non-immunoglobulin-producing myeloma cells.
  • the DNA can also be modified, for example by replacing human heavy and light chain constant regions with coding sequences and/or by replacing homologous non-human sequences with framework regions (U.S. Patent No. 4,816,567; Morrison et al., supra), or by A coding sequence of a non-immunoglobulin polypeptide covalently linked to all or part of a coding sequence of an immunoglobulin.
  • This non-immunoglobulin polypeptide can replace the constant region of the antibody of
  • the antibody can be a monovalent antibody.
  • Methods of making monovalent antibodies are known in the art. For example, one method involves recombinant expression of an immunoglobulin light chain and a modified heavy chain. Heavy chains are typically truncated anywhere in the Fc region to prevent cross-linking of the heavy chains to each other. Alternatively, the relevant cysteine residues are substituted with other amino acid residues or deleted to prevent cross-linking.
  • In vitro methods are also suitable for preparing monovalent antibodies. Digestion of antibodies to produce antibody fragments, particularly Fab fragments, can be accomplished using any method known in the art.
  • Antibody variable domains with the desired binding specificity can be fused to immunoglobulin constant regions.
  • the fusion is preferably to an immunoglobulin heavy chain constant region, which includes at least part of the hinge, CH2 and CH3 regions.
  • the first heavy chain constant region (CH1) comprising the site necessary for light chain binding is present in at least one fusion.
  • DNA encoding the fusion of the immunoglobulin heavy chain and, if desired, the DNA encoding the light chain of the immunoglobulin is inserted into a separate expression vector and co-transfected into a suitable host organism.
  • the anti-HBV pre-S1 antibody (such as a full-length anti-HBV pre-S1 antibody) can be a fully human antibody or a humanized antibody.
  • Humanized forms of non-human (e.g., mouse) antibody portions are chimeric immunoglobulins, immunoglobulin chains, or fragments thereof (e.g., Fv, Fab, Fab', F(ab') 2 , scFv, or other fragments of antibodies).
  • Antigen-binding subsequences which generally include minimal sequence derived from non-human immunoglobulins.
  • Humanized antibodies include human immunoglobulins, immunoglobulin chains or fragments thereof (recipient antibodies) in which residues from the recipient CDRs are replaced by non-human (donor antibody) CDRs having the desired specificity, affinity and properties. Residue substitutions, such as mouse, rat or rabbit CDRs. In some embodiments, human immunoglobulin Fv framework region residues are substituted by corresponding non-human residues. Humanized antibodies may also comprise amino acid residues that are found neither in the recipient antibody nor in imported CDR or framework region sequences.
  • humanized antibodies will comprise at least one, and usually two, variable domains in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and in which all or substantially all of the framework regions are common to human immunoglobulins. sequence.
  • humanized antibodies typically contain one or more amino acid residues that have been introduced from a non-human source. Those non-human amino acid residues are often referred to as "imported” residues, usually from an "imported” variable domain.
  • humanization can basically be carried out according to the following method of Winter and its colleagues (Jones et al., Nature, 321:522-525 (1986); Riechmann et al., Nature, 332:323-327 ( 1988); Verhoeyen et al., Science, 239:1534-1536 (1988)), by substituting rodent CDRs or CDR sequences for the corresponding sequences of human antibodies.
  • such "humanized” antibody portions U.S. Patent No.
  • a humanized antibody portion is that portion of a typically human antibody in which some CDR residues and possibly some framework region residues are substituted by residues from analogous sites in rodent antibodies.
  • Fully human antibodies are an alternative to humanization.
  • transgenic animals eg, mice
  • mice that are capable of producing a fully human antibody library upon immunization but not endogenous immunoglobulins are currently produced.
  • JH antibody heavy-chain joining region
  • human germline immunoglobulin gene arrays into such germline mutant mice produces human antibodies upon antigen stimulation, see, e.g., akobovits et al., PNAS USA, 90:2551 (1993); Jakobovits et al ., Nature, 362:255-258 (1993); Bruggemann et al., Year in Immunol., 7:33 (1993); U.S. Patent Nos. 5,545,806, 5,569,825, 5,591,669, 5,545,807; and WO 97/17852.
  • fully human antibodies can be prepared by introducing human immunoglobulin loci into transgenic animals (eg, mice in which endogenous immunoglobulin genes have been partially or fully silenced).
  • Fully human antibodies can also be produced by in vitro activation of B cells (see U.S. Patents 5,567,610 and 5,229,275) or by using various techniques known in the art, including phage display libraries. Hoogenboom and Winter, J.Mol.Biol., 227:381 (1991); Marks et al., J.Mol.Biol., 222:581 (1991). Techniques of Cole et al. and Boerner et al. It can also be used to prepare fully human monoclonal antibodies. See Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985) and Boerner et al., J. Immunol., 147(1):86-95 (1991).
  • the amino acid sequences of the anti-HBV pre-S1 antibody variants provided herein are also contemplated.
  • the amino acid sequences of antibody variants can be prepared by introducing appropriate modifications into the antibody-encoding nucleotide sequence or by peptide synthesis. Such modifications include, for example, deletions and/or insertions and/or substitutions of residues in the antibody amino acid sequence.
  • the final construction can be accomplished by any combination of amino acid residue deletions, insertions, and substitutions to impart the desired characteristics. For example, antigen binding.
  • anti-HBV pre-S1 antibody variants having one or more amino acid substitutions are provided.
  • Target sites for substitution mutations include hypervariable regions (HVRs) and framework regions (FRs).
  • Amino acid substitutions can be introduced in the antibody of interest and the product screened for desired activity, e.g., improved biological activity, retained/improved antigen binding ability, reduced immunogenicity, or improved ADCC, ADCP, or CDC.
  • Amino acids are divided into different classes according to their side chain properties:
  • Acidic amino acids aspartic acid Asp, glutamic acid Glu;
  • Aromatic amino acids tryptophan Trp, tyrosine Tyr, phenylalanine Phe.
  • Substitution of non-conservative amino acids involves substitution of one of the above classes for another class.
  • An exemplary substitution variant is an affinity matured antibody, which can be conveniently generated using, for example, phage display-based affinity maturation techniques. Briefly, one or more CDR residues are mutated, the variant antibody portions are displayed on phage, and the variants are screened for specific biological activities (eg, based on neutralizing activity or binding affinity). Alterations (eg, substitutions) in regions of the HVRs can be made to achieve improved neutralizing activity or binding affinity. Alterations can be made in HVR "hot spots", residues encoded by codons that are highly mutated during somatic maturation (see, e.g., Chowdhury, Methods Mol. Biol.
  • variable genes selected for affinity maturation are introduced into the variable genes selected for affinity maturation by any of a variety of methods (e.g., error-prone PCR, strand shuffling, or oligonucleotide-directed mutagenesis) . Secondary libraries are then created. This library is screened to identify antibody variants with the desired affinity. Another method of introducing diversity involves an HVR-mediated approach, in which several HVR residues (eg, 4-6 residues at a time) are randomized. HVR residues involved in antigen binding are specifically identified, for example, using alanine scanning mutagenesis or modeling. Often the CDR-H3 and CDR-L3 regions in particular are key targets.
  • HVR-mediated approach in which several HVR residues (eg, 4-6 residues at a time) are randomized. HVR residues involved in antigen binding are specifically identified, for example, using alanine scanning mutagenesis or modeling. Often the CDR-H3 and CDR-L3 regions in particular are key targets.
  • substitutions, insertions, or deletions may occur within one or more of the HVRs, so long as such alterations do not substantially reduce the ability of the antibody to bind antigen.
  • conservative changes eg, conservative substitutions provided herein
  • HVRs that do not substantially reduce binding affinity. These changes may occur outside of HVR "hot spots" or SDRs.
  • each HVR is either unchanged or comprises no more than 1, 2 or 3 amino acid substitutions.
  • a useful method for identifying amino acid residues or regions of an antibody that can be targeted for mutation is called "alanine scanning mutagenesis" as described in Cunningham and Wells (1989) Science, 244:1081-1085 .
  • target residues e.g., charged residues such as arginine, aspartic acid, histidine, lysine, and glutamic acid
  • neutral or negatively charged amino acids e.g., , alanine or glutamic acid
  • the contact sites between the antibody and the antigen are identified by the crystal structure of the antigen-antibody complex. These contact residues and neighboring residues can be targeted or eliminated as candidates for substitution. Variants are screened to determine whether they possess the desired properties.
  • Amino acid sequence insertions including amino-terminal and/or carboxy-terminal fusions, ranging in length from 1 residue to polypeptides containing 100 or more residues, also include intrasequence insertions of 1 or more amino acid residues base.
  • terminal insertions include antibodies with a methionyl residue at the N-terminus.
  • Other insertional variants of antibody molecules include fusions to the N-terminus or C-terminus of the antibody molecule of an enzyme (eg, ADEPT) or a polypeptide that increases the serum half-life of the antibody.
  • one or more amino acid modifications are introduced into the Fc region of an antibody described herein (e.g., a full-length anti-HBV pre-S1 antibody or an anti-HBV pre-S1 antibody fusion protein), thereby generating an Fc region variant .
  • the Fc region variants have enhanced ADCC or ADCP potency, generally associated with Fc-binding receptors (FcRs).
  • the Fc region variant has reduced ADCC or ADCP potency.
  • ADCC antibody-dependent cell-mediated cytotoxicity
  • ADCP antibody-dependent cell-mediated phagocytosis
  • NK cells activated by antibodies. NK cells express the Fc receptor CD16.
  • This receptor recognizes and binds the Fc portion of an antibody molecule bound to the surface of a target cell.
  • the most common Fc receptors on the surface of NK cells are CD16 or Fc ⁇ RIII. Binding of Fc receptors to the Fc region of an antibody results in activation of NK cells, release of cytolytic granules, and subsequent apoptosis of target cells.
  • the killing effect of ADCC on tumor cells can be determined by the specific experiment of NK-92 cells transfected with high-affinity FcR. The results were compared with wild-type NK-92 not expressing FcR.
  • the present application also provides anti-HBV pre-S1 antibody variants (such as full-length anti-HBV pre-S1 antibody variants), which comprise Fc regions with partial but not all effector functions, so that they have Prolonged half-life, however specific effector functions (such as CDC or ADCC) are dispensable or deleterious, making such anti-HBV pre-S1 antibodies ideal candidates for this application.
  • anti-HBV pre-S1 antibody variants such as full-length anti-HBV pre-S1 antibody variants
  • Fc regions with partial but not all effector functions so that they have Prolonged half-life, however specific effector functions (such as CDC or ADCC) are dispensable or deleterious, making such anti-HBV pre-S1 antibodies ideal candidates for this application.
  • the reduction/elimination of CDC and/or ADCC activity is confirmed by in vitro and/or in vivo cytotoxicity assays.
  • an Fc receptor (FcR) binding assay is used to confirm that the antibody lacks Fc ⁇
  • NK cells express only Fc ⁇ RIII, while monocytes express Fc ⁇ RI, Fc ⁇ RII, and Fc ⁇ RIII.
  • FcR expression on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet Annu. Rev. Immunol. 9:457-492 (1991).
  • Non-limiting examples of in vitro assessment of ADCC activity of target molecules are described in US Pat. ) and Hellstrom, I et al., Proc. Nat'l Acad. Sci. USA 82:1499-1502 (1985); US Pat. No. 5,821,337 (see Bruggemann, M. et al., J. Exp. Med.
  • nonradioactive detection methods can be used (see, for example, ACTI TM Flow Cytometry Nonradioactive Cytotoxicity Assay (Cell Technology, Inc. Mountain View, Calif.) and CYTOTOX 96 TM Nonradioactive Cell Toxicity assays (Promega, Madison, Wis.). Effector cells used in such assays include peripheral blood mononuclear cells (PBMC) and natural killer cells (NK). Alternatively, ADCC activity of the molecule of interest is performed in vivo Detection, for example, in an animal model, as described in Clynes et al.Proc.Nat'l Acad.Sci.USA95:652-656 (1998).
  • a C1q binding assay can also be performed to confirm that the antibody cannot bind to C1q, Thus lacking CDC activity. See, for example, C1q and C3c binding ELISA in WO 2006/029879 and WO 2005/100402.
  • a CDC assay can be performed (see, for example, Gazzano-Santoro et al., J. Immunol. Methods 202:163 (1996); Cragg, MS et al., Blood 101:1045-1052 (2003); and Cragg, MS and MJ Glennie, Blood 103:2738-2743 (2004)).
  • FcRn binding was determined using methods known in the art and in vivo clearance/half-life (see, eg, Petkova, SB et al., Int'l. Immunol. 18(12):1759-1769 (2006)).
  • Antibodies with reduced effector function include substitutions of one or more residues at residues 238, 265, 269, 270, 297, 327, and 329 of the Fc region (U.S. Pat. No. 6,737,056). These Fc variants include Fc variants with substitutions of two or more residues at positions 265, 269, 270, 297, and 327, including Fc variants known as "DANA", which have residues at positions 265 and 297 The base is substituted with alanine (U.S. Pat. No. 7,332,581).
  • an anti-HBV pre-S1 antibody variant (such as a full-length anti-HBV pre-S1 antibody) variant, which comprises an Fc region variant with one or more amino acid substitutions capable of enhancing the ADCC effect.
  • the Fc region variant comprises one or more amino substitutions capable of enhancing the ADCC effect, and these substitutions are at positions 298, 333 and/or 334 (EU residue numbering) of the Fc region.
  • the anti-HBV pre-S1 antibody (eg, full-length anti-HBV pre-S1 antibody) variant comprises amino acid substitutions at positions S298A, E333A and K334A in the Fc region.
  • alterations in the Fc region result in alterations (i.e., enhancement or attenuation) of Clq binding and/or complement-dependent cytotoxicity (CDC), see U.S. Pat. No. 6,194,551, WO 99/51642, and Idusogie et al. al., J. Immunol. 164:4178-4184 (2000).
  • CDC complement-dependent cytotoxicity
  • an anti-HBV pre-S1 antibody variant (such as a full-length anti-HBV pre-S1 antibody) variant, which comprises an Fc region variant with one or more amino acid substitutions capable of enhancing ADCP effect.
  • the alteration of the Fc region results in an alteration (ie, an increase or decrease) in binding to Fc ⁇ RIIa and/or antibody-dependent cell-mediated phagocytosis (ADCP).
  • an anti-HBV pre-S1 antibody (such as a full-length anti-HBV pre-S1 antibody) variant
  • which comprises an Fc region variant with one or more amino acid substitutions, which can prolong half-life or enhance Binding to Fc receptors (FcRn).
  • FcRn Fc receptors
  • Antibodies with extended half-life and improved FcRn binding are described in US 2005/0014934A1 (Hinton et al.). These antibody Fc regions contain one or more amino acid substitutions that enhance the binding of the Fc region to FcRn.
  • Fc variants comprise 238, 256, 265, 272, 286, 303, 305, 307, 311, 312, 317, 340, 356, 360, 362, 376, 378, 380, 382, 413, 424 or One or more substitutions in residue 434, eg, substitution of residue 434 in the Fc region (U.S. Pat. No. 7,371,826).
  • anti-HBV pre-S1 antibodies e.g., full-length anti-HBV pre-S1 antibodies
  • Fc variants described herein or combinations thereof any of the Fc variants described herein or combinations thereof.
  • an anti-HBV pre-S1 antibody provided herein is altered to increase or decrease the degree of glycosylation of the anti-NGF antibody. Adding or deleting glycosylation sites on the anti-HBV pre-S1 antibody can be conveniently achieved by changing the amino acid sequence of the anti-NGF antibody or its polypeptide portion to add or remove one or more glycosylation sites.
  • the anti-HBV pre-S1 antibody contains an Fc region, which can change the sugar attached to it.
  • Native antibodies produced by mammalian cells typically comprise branched biantennary oligosaccharides, usually N-linked to the Fc region CH2 domain Asn297, see e.g. Wright et al., TIBTECH 15:26-32 (1997) .
  • the oligosaccharides may comprise a variety of sugars such as mannose, N-acetylglucosamine (GlcNAc), galactose and sialic acid, as well as trehalose linked to the GlcNAc in the "stem" of the biantennary oligosaccharide structure.
  • the anti-HBV pre-S1 antibodies of the present application can be modified with oligosaccharides to produce anti-HBV pre-S1 antibody variants with certain improved properties.
  • N-glycans linked to the CH2 domain of the Fc region are heterogeneous.
  • Antibodies or Fc fusion proteins produced in CHO cells are fucosylated by fucosyltransferase activity, see Shoji-Hosaka et al., J. Biochem. 2006, 140:777-83.
  • a small fraction of naturally occurring non-fucosylated IgGs can be detected in human serum.
  • N-glycosylation of the Fc region is important for its binding to Fc ⁇ Rs; non-fucosylated N-glycans enhance the binding ability of Fc to Fc ⁇ RIIIa.
  • Enhanced binding to FcRIIIa results in enhanced ADCC effect, which is advantageous in certain antibody therapeutic applications where cytotoxicity is required.
  • enhanced effector functions may be detrimental when Fc-mediated cytotoxicity is not desired.
  • the Fc fragment or CH2 domain is aglycosylated.
  • glycosylation is prevented by mutating the N-glycosylation site in the CH2 domain.
  • anti-HBV pre-S1 antibody e.g., full-length anti-HBV pre-S1 antibody
  • variants comprise an Fc region, wherein the carbohydrate structure attached to the Fc region has reduced fucose or lacks Fucose, which may enhance ADCC function.
  • anti-HBV pre-S1 antibodies that have reduced fucose relative to the same anti-HBV pre-S1 antibodies produced by wild-type CHO cells. That is, they are characterized by having a lower amount of fucose than antibodies produced by native CHO cells (eg, CHO cells producing native glycosylated forms, CHO cells containing the native FUT8 gene).
  • the N-linked glycans of the anti-HBV pre-S1 antibody have less than 50%, 40%, 30%, 20%, 10%, or 5% fucose.
  • the fucose content of the anti-HBV pre-S1 antibody may be 1%-80%, 1%-65%, 5%-65%, or 20%-40%.
  • the N-linked glycans of the anti-HBV pre-S1 antibody do not contain fucose, i.e., wherein the anti-HBV pre-S1 antibody is completely fucose-free, fucose-free or fucose-depleted Fucosylation.
  • the content of fucose was calculated by calculating the average content of fucose in the sugar chain attached to Asn297 relative to the total of all sugar structures (such as complex, hybrid or mannose structures) attached to Asn297 measured by MALDI-TOF mass spectrometry. Quantities are determined as described in WO 2008/077546. Asn297 refers to the asparagine residue located at position 297 of the Fc region (EU Fc region residue numbering system). However, Asn297 can also be located ⁇ 3 amino acids upstream or downstream of position 297, ie between positions 294 and 300, due to minor sequence variations of the antibody. These fucosylated variants may have enhanced ADCC function. See, eg, US Patent Publication Nos.
  • Cell lines capable of producing afucosylated antibodies include Lec13CHO cells lacking protein fucosylation function (Ripka et al. Arch. Biochem. Biophys. 249:533-545 (1986); US Pat Appl No US 2003 /0157108A1, Presta, L; and WO 2004/056312A1, Adams et al., especially Example 11), and gene knockout cell lines, such as ⁇ -1,6-fucosyltransferase gene, FUT8 gene knockout Removed CHO cells (see Yamane-Ohnuki et al. Biotech. Bioeng. 87:614 (2004); Kanda, Y. et al., Biotechnol. Bioeng., 94 (4): 680-688 (2006); and WO2003 /085107).
  • Anti-HBV pre-S1 antibody (e.g., full-length anti-HBV pre-S1 antibody) variants further provide bisected oligosaccharides, e.g., wherein the biantennary oligosaccharide attached to the Fc region of the anti-HBV pre-S1 antibody is bisected by GlcNAc.
  • Such anti-HBV pre-S1 antibody (eg, full-length anti-HBV pre-S1 antibody) variants may have reduced fucosylation and/or enhanced ADCC function. Examples of such antibody variants are in WO 2003/011878 (Jean-Mairet et al.); U.S. Pat. No.
  • anti-HBV pre-S1 antibody e.g., full-length anti-HBV pre-S1 antibody
  • Such anti-HBV pre-S1 antibody variants may have enhanced CDC function.
  • Such variants are described, for example, in WO 1997/30087 (Patel et al.); WO 1998/58964 (Raju, S.); and WO 1999/22764 (Raju, S.).
  • the anti-HBV pre-S1 antibody (eg, full-length anti-HBV pre-S1 antibody) variant comprises an Fc region that binds Fc ⁇ RIII.
  • the anti-HBV pre-S1 antibody (e.g., full-length anti-HBV pre-S1 antibody) variant comprising an Fc region has ADCC activity in the presence of human effector cells (e.g., T cells), or in combination with human Compared with other identical anti-HBV pre-S1 antibodies (such as full-length anti-HBV pre-S1 antibodies) with wild-type IgG1 Fc region, it has enhanced ADCC activity in the presence of human effector cells.
  • cysteine-engineered anti-HBV pre-S1 antibodies e.g., full-length anti-HBV pre-S1 antibodies
  • the substituted residues occur at sites accessible to anti-HBV pre-S1 antibodies.
  • a reactive sulfhydryl group is located at the accessible site of the anti-HBV pre-S1 antibody and can be used to conjugate the anti-HBV pre-S1 antibody to other moieties, such as drug moieties or linker-drug moieties to prepare anti-HBV pre-S1 immunoconjugates as further described herein.
  • Cysteine-engineered anti-HBV pre-S1 antibodies eg, full-length anti-HBV pre-S1 antibodies
  • the anti-HBV pre-S1 antibodies provided herein can be further modified to include other non-protein moieties known in the art and readily available.
  • Moieties suitable for derivatizing anti-HBV pre-S1 antibodies include, but are not limited to, water-soluble polymers.
  • Non-limiting examples of water-soluble polymers include, but are not limited to, polyethylene glycol (PEG), ethylene glycol/propylene glycol copolymers, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone, poly-1 ,3-dioxolane, poly-1,3,6-trioxane, ethylene/maleic anhydride copolymer, polyamino acid (homopolymer or random copolymer), dextran or poly(n- vinylpyrrolidone) polyethylene glycol, propylene glycol homopolymer, propylene oxide/ethylene oxide copolymer, polyoxyethylated polyols (eg glycerol), polyvinyl alcohol and mixtures thereof.
  • PEG polyethylene glycol
  • ethylene glycol/propylene glycol copolymers carboxymethylcellulose
  • dextran polyvinyl alcohol
  • polyvinylpyrrolidone poly-1 ,3-dioxo
  • Polyethylene glycol propionaldehyde has advantages in manufacturing due to its stability in water.
  • the polymers can be of any molecular weight and can be branched or unbranched.
  • the number of polymers attached to the anti-HBV pre-S1 antibody can vary, and if more than one polymer is attached, they can be the same or different molecules.
  • the amount and/or type of polymers used for derivatization can be determined based on considerations including, but not limited to, the need to improve the properties or function of the anti-HBV pre-S1 antibody, whether the anti-HBV pre-S1 antibody derivative For the treatment of certain conditions, etc.
  • compositions comprising any anti-HBV pre-S1 antibody described herein and a pharmaceutically acceptable carrier.
  • anti-HBV pre-S1 antibody can be obtained by mixing anti-HBV pre-S1 antibody with desired purity and optional pharmaceutically acceptable carrier, excipient or stabilizer (Remington's Pharmaceutical Sciences 16th edition, Osol, A.Ed.(1980)).
  • the anti-HBV pre-S1 antibody preparation is prepared in the form of freeze-dried preparation or liquid preparation.
  • Acceptable carriers, excipients, or stabilizers that are nontoxic to recipients at the dosages and concentrations employed include buffers such as: phosphates, citric acid, and other organic acids; antioxidants, including ascorbic acid and methionine; preservatives such as Octadecyldimethylbenzylammonium chloride; Hexamethylammonium chloride; Benzalkonium chloride; Benzethonium chloride; Phenol; Butanol or benzyl alcohol; Alkylparabens such as p-hydroxybenzoate Methyl formate or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol and m-cresol); low molecular weight (less than 10 residues) polypeptides; proteins such as serum Albumin, gelatin, or immunoglobulin; hydrophilic polymers, such as polyvinylpyrrolidone; amino acids, such as glycine, glutamine,
  • Lyophilized formulations suitable for subcutaneous administration are described in WO97/04801. Such lyophilized formulations can be reconstituted with a suitable diluent into a high protein concentration formulation, and the reconstituted formulation can be administered subcutaneously to the individual to be treated herein. Cationic liposomes or liposomes can be used to deliver the anti-HBV pre-S1 antibodies of the present application to cells.
  • anti-HBV pre-S1 antibodies such as full-length anti-HBV pre-S1 antibodies
  • the preparations described herein can also include one or more other active substances necessary for the treatment of specific diseases, preferably with complementary activities and Substances that do not react adversely to each other.
  • anti-HBV pre-S1 antibodies it may be necessary to further include antiviral agents, antiallergic agents, antinausea agents (or antiemetic agents), analgesics, cytoprotective agents, immunosuppressants and combinations thereof.
  • the antiviral drugs may include but are not limited to interferon, nucleoside/nucleotide analogues, anti-HBV monoclonal antibodies, anti-HBV polyclonal antibodies, DNA polymerase inhibitors or therapeutic vaccines.
  • the nucleoside/nucleotide analogs may include, but are not limited to, lamivudine, entecavir, clevudine or adefovir dipivoxil. These molecules are present in combination in amounts effective for the intended purpose. Effective amounts of other substances depend on the amount of anti-HBV pre-S1 antibody in the formulation, the type of disease or disorder or treatment, and other factors as described above. These agents are generally used at the same doses and routes of administration as described herein, or at 1% to 99% of the currently employed doses.
  • the anti-HBV pre-S1 antibody (for example, full-length anti-HBV pre-S1 antibody) can also be embedded in microcapsules prepared by coacervation techniques and interfacial polymerization, for example, in colloidal drug delivery systems (for example, lipid hydroxymethylcellulose or gelatin-microcapsules and poly(methyl methacrylate) microcapsules in macroemulsions, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or macroemulsions. Sustained release formulations can be prepared.
  • colloidal drug delivery systems for example, lipid hydroxymethylcellulose or gelatin-microcapsules and poly(methyl methacrylate) microcapsules in macroemulsions, albumin microspheres, microemulsions, nanoparticles and nanocapsules
  • Sustained release formulations can be prepared.
  • Sustained-release formulations of anti-HBV pre-S1 antibodies can be prepared.
  • suitable examples of sustained release formulations include semipermeable matrices of solid hydrophobic polymers containing the antibody (or fragment thereof) in the form of shaped articles, eg, films or microcapsules.
  • sustained release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl methacrylate) or poly(vinyl alcohol)), polylactic acid (U.S. Pat. No.
  • L-glutamine Acid and ethyl L-glutamate copolymer non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymer such as LUPRON DEPOTTM (composed of lactic acid-glycolic acid copolymer and leuprolide acetate can injection microspheres) and poly-D(-)-3-hydroxybutyrate. While polymers such as ethylene-vinyl acetate and lactic acid-glycolic acid can release molecules for more than 100 days, certain hydrogels can release proteins for a shorter period of time.
  • the anti-HBV pre-S1 antibody (e.g., a full-length anti-HBV pre-S1 antibody) is formulated in the presence of citrate, sodium chloride, acetate, succinate, glycine, polysorbate 80 (Tween 80) or any combination of the above buffers.
  • Preparations for in vivo administration must be sterile. This is readily accomplished, for example, by filtration using sterile filtration membranes.
  • Anti-HBV pre-S1 antibodies for example, full-length anti-HBV pre-S1 antibodies
  • compositions described herein can be administered to individuals (for example, humans) to prevent, improve or treat HBV infection or infection with HBV Related diseases, including but not limited to hepatitis B, liver failure, cirrhosis or liver cancer.
  • the present application provides a method for preventing, improving or treating HBV infection or diseases associated with HBV infection, comprising administering to an individual an effective amount of an anti-HBV pre-S1 antibody (for example, a full-length Compositions (e.g., pharmaceutical compositions) of anti-HBV pre-S1 antibodies), such as any of the anti-HBV pre-S1 antibodies described herein (e.g., full-length anti-HBV pre-S1 antibodies), in some embodiments
  • the individual is a human.
  • a method for preventing, improving or treating HBV infection or diseases related to HBV infection comprising administering to an individual in need an effective amount of a structure comprising a specific binding HBV surface antigen pre-S1
  • the pharmaceutical composition of the antibody of domain for example, full-length anti-HBV pre-S1 antibody.
  • the anti-HBV pre-S1 antibody is a full length antibody.
  • the full-length anti-HBV pre-S1 antibody is an IgG1 or IgG4 antibody.
  • the disease or condition is selected from, for example, hepatitis B, liver failure, cirrhosis, or liver cancer.
  • the desired individual includes, but is not limited to, an individual infected with, exposed to, at risk of, or susceptible to HBV.
  • a method for preventing, improving or treating HBV infection or diseases associated with HBV infection comprising administering to an individual in need an effective amount of an anti-HBV pre-S1 antibody (for example, whole Long anti-HBV pre-S1 antibody) pharmaceutical composition, wherein said antibody comprises a heavy chain variable domain (V H ), said V H comprises: HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 1, HC - CDR2 comprising the amino acid sequence of SEQ ID NO: 19, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 39, or a variant of said VH comprising a substitution of up to about 5 amino acids in its HC-CDRs and a light chain variable domain (V L ), said V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO:58, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:79, and LC- CDR3 comprising the amino acid sequence of SEQ
  • the anti-HBV pre-S1 antibody is a full length antibody. In some embodiments, the full length anti-HBV pre-S1 antibody is an IgG1 or IgG4 antibody.
  • the disease or condition is selected from, for example, hepatitis B, liver failure, cirrhosis, or liver cancer.
  • the desired individual includes, but is not limited to, an individual infected with, exposed to, at risk of, or susceptible to HBV.
  • a method for preventing, improving or treating HBV infection or diseases related to HBV infection comprising administering to an individual in need an effective amount of a composition comprising an anti-HBV pre-S1 antibody, wherein the Said antibody comprises: VH , said VH comprises the amino acid sequence shown in SEQ ID NO:120 or its variant, and said variant has at least about 80% sequence identity with the amino acid sequence shown in SEQ ID NO:120 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 151 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO: 151.
  • the anti-HBV pre-S1 antibodies described herein are full-length anti-HBV pre-S1 antibodies comprising an IgG1 or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a method for preventing, improving or treating HBV infection or diseases associated with HBV infection comprising administering to an individual in need an effective amount of an anti-HBV pre-S1 antibody (for example, whole Long anti-HBV pre-S1 antibody) pharmaceutical composition, wherein said antibody comprises a heavy chain variable domain (V H ), said V H comprises: HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 2, HC - CDR2 comprising the amino acid sequence of SEQ ID NO: 20, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 40, or a variant of said VH comprising a substitution of up to about 5 amino acids in its HC-CDRs and a light chain variable domain (V L ), said V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO:59, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:79, and LC- CDR3 comprising the amino acid sequence of SEQ
  • the anti-HBV pre-S1 antibody is a full length antibody. In some embodiments, the full length anti-HBV pre-S1 antibody is an IgG1 or IgG4 antibody.
  • the disease or condition is selected from, for example, hepatitis B, liver failure, cirrhosis, or liver cancer.
  • the desired individual includes, but is not limited to, an individual infected with, exposed to, at risk of, or susceptible to HBV.
  • a method for preventing, improving or treating HBV infection or diseases related to HBV infection comprising administering to an individual in need an effective amount of a composition comprising an anti-HBV pre-S1 antibody, wherein the Said antibody comprises: VH , said VH comprises the amino acid sequence shown in SEQ ID NO:121 or its variant, and said variant has at least about 80% sequence identity with the amino acid sequence shown in SEQ ID NO:121 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 152 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO: 152.
  • the anti-HBV pre-S1 antibodies described herein are full-length anti-HBV pre-S1 antibodies comprising an IgG1 or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a method for preventing, improving or treating HBV infection or diseases associated with HBV infection comprising administering to an individual in need an effective amount of an anti-HBV pre-S1 antibody (for example, whole Long anti-HBV pre-S1 antibody) pharmaceutical composition, wherein said antibody comprises a heavy chain variable domain (V H ), said V H comprises: HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 3, HC - CDR2 comprising the amino acid sequence of SEQ ID NO: 21, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 41, or a variant of said VH comprising a substitution of up to about 5 amino acids in its HC-CDRs and a light chain variable domain (V L ), said V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO:60, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:80, and LC- CDR3 comprising the amino acid sequence of SEQ
  • the anti-HBV pre-S1 antibody is a full length antibody. In some embodiments, the full length anti-HBV pre-S1 antibody is an IgG1 or IgG4 antibody.
  • the disease or condition is selected from, for example, hepatitis B, liver failure, cirrhosis, or liver cancer.
  • the desired individual includes, but is not limited to, an individual infected with, exposed to, at risk of, or susceptible to HBV.
  • a method for preventing, improving or treating HBV infection or diseases related to HBV infection comprising administering to an individual in need an effective amount of a composition comprising an anti-HBV pre-S1 antibody, wherein the Said antibody comprises: VH , said VH comprising the amino acid sequence shown in SEQ ID NO: 122 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 122 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 153 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO: 153.
  • the anti-HBV pre-S1 antibodies described herein are full-length anti-HBV pre-S1 antibodies comprising an IgG1 or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a method for preventing, improving or treating HBV infection or diseases associated with HBV infection comprising administering to an individual in need an effective amount of an anti-HBV pre-S1 antibody (for example, whole Long anti-HBV pre-S1 antibody) pharmaceutical composition, wherein said antibody comprises a heavy chain variable domain (V H ), said V H comprises: HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 4, HC - CDR2 comprising the amino acid sequence of SEQ ID NO: 22, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 42, or a variant of said VH comprising a substitution of up to about 5 amino acids in its HC-CDRs and a light chain variable domain (V L ), said V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO:61, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:81, and LC- CDR3 comprising the amino acid sequence of SEQ
  • the anti-HBV pre-S1 antibody is a full length antibody. In some embodiments, the full length anti-HBV pre-S1 antibody is an IgG1 or IgG4 antibody.
  • the disease or condition is selected from, for example, hepatitis B, liver failure, cirrhosis, or liver cancer.
  • the desired individual includes, but is not limited to, an individual infected with, exposed to, at risk of, or susceptible to HBV.
  • a method for preventing, improving or treating HBV infection or diseases related to HBV infection comprising administering to an individual in need an effective amount of a composition comprising an anti-HBV pre-S1 antibody, wherein the Said antibody comprises: VH , said VH comprises the amino acid sequence shown in SEQ ID NO:123 or its variant, and said variant has at least about 80% sequence identity with the amino acid sequence shown in SEQ ID NO:123 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 154 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO: 154.
  • the anti-HBV pre-S1 antibodies described herein are full-length anti-HBV pre-S1 antibodies comprising an IgG1 or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a method for preventing, improving or treating HBV infection or diseases associated with HBV infection comprising administering to an individual in need an effective amount of an anti-HBV pre-S1 antibody (for example, whole Long anti-HBV pre-S1 antibody) pharmaceutical composition, wherein said antibody comprises a heavy chain variable domain (V H ), said V H comprises: HC-CDR1, which comprises the amino acid sequence SEQ ID NO:5, HC - CDR2 comprising the amino acid sequence of SEQ ID NO: 23, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 43, or a variant of said VH comprising a substitution of up to about 5 amino acids in its HC-CDRs and a light chain variable domain (V L ), said V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO:61, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:82, and LC- CDR3 comprising the amino acid sequence of SEQ
  • the anti-HBV pre-S1 antibody is a full length antibody. In some embodiments, the full length anti-HBV pre-S1 antibody is an IgG1 or IgG4 antibody.
  • the disease or condition is selected from, for example, hepatitis B, liver failure, cirrhosis, or liver cancer.
  • the desired individual includes, but is not limited to, an individual infected with, exposed to, at risk of, or susceptible to HBV.
  • a method for preventing, improving or treating HBV infection or diseases related to HBV infection comprising administering to an individual in need an effective amount of a composition comprising an anti-HBV pre-S1 antibody, wherein the Said antibody comprises: VH , said VH comprises the amino acid sequence shown in SEQ ID NO:124 or its variant, and said variant has at least about 80% sequence identity with the amino acid sequence shown in SEQ ID NO:124 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 155 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO: 155.
  • the anti-HBV pre-S1 antibodies described herein are full-length anti-HBV pre-S1 antibodies comprising an IgG1 or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a method for preventing, improving or treating HBV infection or diseases associated with HBV infection comprising administering to an individual in need an effective amount of an anti-HBV pre-S1 antibody (for example, whole Long anti-HBV pre-S1 antibody) pharmaceutical composition, wherein said antibody comprises a heavy chain variable domain (V H ), said V H comprises: HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 7, HC - CDR2 comprising the amino acid sequence of SEQ ID NO: 25, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 45, or a variant of said VH comprising a substitution of up to about 5 amino acids in its HC-CDRs and a light chain variable domain (V L ), said V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO:63, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:84, and LC- CDR3 comprising the amino acid sequence of SEQ
  • the anti-HBV pre-S1 antibody is a full length antibody. In some embodiments, the full length anti-HBV pre-S1 antibody is an IgG1 or IgG4 antibody.
  • the disease or condition is selected from, for example, hepatitis B, liver failure, cirrhosis, or liver cancer.
  • the desired individual includes, but is not limited to, an individual infected with, exposed to, at risk of, or susceptible to HBV.
  • a method for preventing, improving or treating HBV infection or diseases related to HBV infection comprising administering to an individual in need an effective amount of a composition comprising an anti-HBV pre-S1 antibody, wherein the Said antibody comprises: VH , said VH comprises the amino acid sequence shown in SEQ ID NO:126 or its variant, and said variant has at least about 80% sequence identity with the amino acid sequence shown in SEQ ID NO:126 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 157 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO: 157.
  • the anti-HBV pre-S1 antibodies described herein are full-length anti-HBV pre-S1 antibodies comprising an IgG1 or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a method for preventing, improving or treating HBV infection or diseases associated with HBV infection comprising administering to an individual in need an effective amount of an anti-HBV pre-S1 antibody (for example, whole Long anti-HBV pre-S1 antibody) pharmaceutical composition, wherein said antibody comprises a heavy chain variable domain (V H ), said V H comprises: HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 7, HC - CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 46, or a variant of said VH comprising a substitution of up to about 5 amino acids in its HC-CDRs and a light chain variable domain (VL), said VL comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO:64, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:79, and LC-CDR3 , which comprises the amino acid sequence of S
  • the anti-HBV pre-S1 antibody is a full length antibody. In some embodiments, the full length anti-HBV pre-S1 antibody is an IgG1 or IgG4 antibody.
  • the disease or condition is selected from, for example, hepatitis B, liver failure, cirrhosis, or liver cancer.
  • the desired individual includes, but is not limited to, an individual infected with, exposed to, at risk of, or susceptible to HBV.
  • a method for preventing, improving or treating HBV infection or diseases related to HBV infection comprising administering to an individual in need an effective amount of a composition comprising an anti-HBV pre-S1 antibody, wherein the Said antibody comprises: VH , said VH comprises the amino acid sequence shown in SEQ ID NO:128 or its variant, and said variant has at least about 80% sequence identity with the amino acid sequence shown in SEQ ID NO:128 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 158 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO: 158.
  • the anti-HBV pre-S1 antibodies described herein are full-length anti-HBV pre-S1 antibodies comprising an IgG1 or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a method for preventing, improving or treating HBV infection or diseases associated with HBV infection comprising administering to an individual in need an effective amount of an anti-HBV pre-S1 antibody (for example, whole Long anti-HBV pre-S1 antibody) pharmaceutical composition, wherein said antibody comprises a heavy chain variable domain (V H ), said V H comprises: HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 8, HC - CDR2 comprising the amino acid sequence of SEQ ID NO: 27, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 47, or a variant of said VH comprising a substitution of up to about 5 amino acids in its HC-CDRs and a light chain variable domain (V L ), said V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO:65, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:85, and LC- CDR3 comprising the amino acid sequence of SEQ
  • the anti-HBV pre-S1 antibody is a full length antibody. In some embodiments, the full length anti-HBV pre-S1 antibody is an IgG1 or IgG4 antibody.
  • the disease or condition is selected from, for example, hepatitis B, liver failure, cirrhosis, or liver cancer.
  • the desired individual includes, but is not limited to, an individual infected with, exposed to, at risk of, or susceptible to HBV.
  • a method for preventing, improving or treating HBV infection or diseases related to HBV infection comprising administering to an individual in need an effective amount of a composition comprising an anti-HBV pre-S1 antibody, wherein the Said antibody comprises: VH , said VH comprises the amino acid sequence shown in SEQ ID NO:130 or its variant, and said variant has at least about 80% sequence identity with the amino acid sequence shown in SEQ ID NO:130 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 159 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO: 159.
  • the anti-HBV pre-S1 antibodies described herein are full-length anti-HBV pre-S1 antibodies comprising an IgG1 or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a method for preventing, improving or treating HBV infection or diseases associated with HBV infection comprising administering to an individual in need an effective amount of an anti-HBV pre-S1 antibody (for example, whole Long anti-HBV pre-S1 antibody) pharmaceutical composition, wherein said antibody comprises a heavy chain variable domain (V H ), said V H comprises: HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 9, HC - CDR2 comprising the amino acid sequence of SEQ ID NO: 28, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 48, or a variant of said VH comprising a substitution of up to about 5 amino acids in its HC-CDRs and a light chain variable domain (V L ), said V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO:66, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:86, and LC- CDR3 comprising the amino acid sequence of SEQ
  • the anti-HBV pre-S1 antibody is a full length antibody. In some embodiments, the full length anti-HBV pre-S1 antibody is an IgG1 or IgG4 antibody.
  • the disease or condition is selected from, for example, hepatitis B, liver failure, cirrhosis, or liver cancer.
  • the desired individual includes, but is not limited to, an individual infected with, exposed to, at risk of, or susceptible to HBV.
  • a method for preventing, improving or treating HBV infection or diseases related to HBV infection comprising administering to an individual in need an effective amount of a composition comprising an anti-HBV pre-S1 antibody, wherein the Said antibody comprises: VH , said VH comprises the amino acid sequence shown in SEQ ID NO:131 or its variant, and said variant has at least about 80% sequence identity with the amino acid sequence shown in SEQ ID NO:131 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 160 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO: 160.
  • the anti-HBV pre-S1 antibodies described herein are full-length anti-HBV pre-S1 antibodies comprising an IgG1 or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a method for preventing, improving or treating HBV infection or diseases associated with HBV infection comprising administering to an individual in need an effective amount of an anti-HBV pre-S1 antibody (for example, whole Long anti-HBV pre-S1 antibody) pharmaceutical composition, wherein said antibody comprises a heavy chain variable domain (V H ), said V H comprises: HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 6, HC - CDR2 comprising the amino acid sequence of SEQ ID NO: 24, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 44, or a variant of said VH comprising a substitution of up to about 5 amino acids in its HC-CDRs and a light chain variable domain (V L ), said V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO:62, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:83, and LC- CDR3 comprising the amino acid sequence of SEQ
  • the anti-HBV pre-S1 antibody is a full length antibody. In some embodiments, the full length anti-HBV pre-S1 antibody is an IgG1 or IgG4 antibody.
  • the disease or condition is selected from, for example, hepatitis B, liver failure, cirrhosis, or liver cancer.
  • the desired individual includes, but is not limited to, an individual infected with, exposed to, at risk of, or susceptible to HBV.
  • a method for preventing, improving or treating HBV infection or diseases related to HBV infection comprising administering to an individual in need an effective amount of a composition comprising an anti-HBV pre-S1 antibody, wherein the Said antibody comprises: VH , said VH comprises the amino acid sequence shown in SEQ ID NO:132 or its variant, and said variant has at least about 80% sequence identity with the amino acid sequence shown in SEQ ID NO:132 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 161 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO: 161.
  • the anti-HBV pre-S1 antibodies described herein are full-length anti-HBV pre-S1 antibodies comprising an IgG1 or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a method for preventing, improving or treating HBV infection or diseases associated with HBV infection comprising administering to an individual in need an effective amount of an anti-HBV pre-S1 antibody (for example, whole Long anti-HBV pre-S1 antibody) pharmaceutical composition, wherein said antibody comprises a heavy chain variable domain (V H ), said V H comprises: HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 10, HC - CDR2 comprising the amino acid sequence of SEQ ID NO: 29, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 49, or a variant of said VH comprising a substitution of up to about 5 amino acids in its HC-CDRs and a light chain variable domain (V L ), said V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO:67, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:87, and LC- CDR3 comprising the amino acid sequence of SEQ
  • the anti-HBV pre-S1 antibody is a full length antibody. In some embodiments, the full length anti-HBV pre-S1 antibody is an IgG1 or IgG4 antibody.
  • the disease or condition is selected from, for example, hepatitis B, liver failure, cirrhosis, or liver cancer.
  • the desired individual includes, but is not limited to, an individual infected with, exposed to, at risk of, or susceptible to HBV.
  • a method for preventing, improving or treating HBV infection or diseases related to HBV infection comprising administering to an individual in need an effective amount of a composition comprising an anti-HBV pre-S1 antibody, wherein the Said antibody comprises: VH , said VH comprises the amino acid sequence shown in SEQ ID NO:133 or its variant, and said variant has at least about 80% sequence identity with the amino acid sequence shown in SEQ ID NO:133 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 162 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO: 162.
  • the anti-HBV pre-S1 antibodies described herein are full-length anti-HBV pre-S1 antibodies comprising an IgG1 or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a method for preventing, improving or treating HBV infection or diseases associated with HBV infection comprising administering to an individual in need an effective amount of an anti-HBV pre-S1 antibody (for example, whole Long anti-HBV pre-S1 antibody) pharmaceutical composition, wherein said antibody comprises a heavy chain variable domain (V H ), said V H comprises: HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 11, HC - CDR2 comprising the amino acid sequence of SEQ ID NO: 30, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 50, or a variant of said VH comprising a substitution of up to about 5 amino acids in its HC-CDRs and a light chain variable domain (V L ), said V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO:68, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:81, and LC- CDR3 comprising the amino acid sequence of SEQ
  • the anti-HBV pre-S1 antibody is a full length antibody. In some embodiments, the full length anti-HBV pre-S1 antibody is an IgG1 or IgG4 antibody.
  • the disease or condition is selected from, for example, hepatitis B, liver failure, cirrhosis, or liver cancer.
  • the desired individual includes, but is not limited to, an individual infected with, exposed to, at risk of, or susceptible to HBV.
  • a method for preventing, improving or treating HBV infection or diseases related to HBV infection comprising administering to an individual in need an effective amount of a composition comprising an anti-HBV pre-S1 antibody, wherein the Said antibody comprises: VH , said VH comprises the amino acid sequence shown in SEQ ID NO:134 or its variant, and said variant has at least about 80% sequence identity with the amino acid sequence shown in SEQ ID NO:134 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 163 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO: 163.
  • the anti-HBV pre-S1 antibodies described herein are full-length anti-HBV pre-S1 antibodies comprising an IgG1 or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a method for preventing, improving or treating HBV infection or diseases associated with HBV infection comprising administering to an individual in need an effective amount of an anti-HBV pre-S1 antibody (for example, whole Long anti-HBV pre-S1 antibody) pharmaceutical composition, wherein said antibody comprises a heavy chain variable domain (V H ), said V H comprises: HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 12, HC - CDR2 comprising the amino acid sequence of SEQ ID NO: 30, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 50, or a variant of said VH comprising a substitution of up to about 5 amino acids in its HC-CDRs and a light chain variable domain (V L ), said V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO:61, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:81, and LC- CDR3 comprising the amino acid sequence of SEQ
  • the anti-HBV pre-S1 antibody is a full length antibody. In some embodiments, the full length anti-HBV pre-S1 antibody is an IgG1 or IgG4 antibody.
  • the disease or condition is selected from, for example, hepatitis B, liver failure, cirrhosis, or liver cancer.
  • the desired individual includes, but is not limited to, an individual infected with, exposed to, at risk of, or susceptible to HBV.
  • a method for preventing, improving or treating HBV infection or diseases related to HBV infection comprising administering to an individual in need an effective amount of a composition comprising an anti-HBV pre-S1 antibody, wherein the Said antibody comprises: VH , said VH comprises the amino acid sequence shown in SEQ ID NO:135 or its variant, and said variant has at least about 80% sequence identity with the amino acid sequence shown in SEQ ID NO:135 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 164 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO: 164.
  • the anti-HBV pre-S1 antibodies described herein are full-length anti-HBV pre-S1 antibodies comprising an IgG1 or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a method for preventing, improving or treating HBV infection or diseases associated with HBV infection comprising administering to an individual in need an effective amount of an anti-HBV pre-S1 antibody (for example, whole Long anti-HBV pre-S1 antibody) pharmaceutical composition, wherein said antibody comprises a heavy chain variable domain (V H ), said V H comprises: HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 13, HC - CDR2 comprising the amino acid sequence of SEQ ID NO: 30, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 50, or a variant of said VH comprising a substitution of up to about 5 amino acids in its HC-CDRs and a light chain variable domain (V L ), said V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO:69, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:81, and LC- CDR3 comprising the amino acid sequence of SEQ
  • the anti-HBV pre-S1 antibody is a full length antibody. In some embodiments, the full length anti-HBV pre-S1 antibody is an IgG1 or IgG4 antibody.
  • the disease or condition is selected from, for example, hepatitis B, liver failure, cirrhosis, or liver cancer.
  • the desired individual includes, but is not limited to, an individual infected with, exposed to, at risk of, or susceptible to HBV.
  • a method for preventing, improving or treating HBV infection or diseases related to HBV infection comprising administering to an individual in need an effective amount of a composition comprising an anti-HBV pre-S1 antibody, wherein the Said antibody comprises: VH , said VH comprises the amino acid sequence shown in SEQ ID NO:136 or its variant, and said variant has at least about 80% sequence identity with the amino acid sequence shown in SEQ ID NO:136 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 165 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO: 165.
  • the anti-HBV pre-S1 antibodies described herein are full-length anti-HBV pre-S1 antibodies comprising an IgG1 or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a method for preventing, improving or treating HBV infection or diseases associated with HBV infection comprising administering to an individual in need an effective amount of an anti-HBV pre-S1 antibody (for example, whole Long anti-HBV pre-S1 antibody) pharmaceutical composition, wherein said antibody comprises a heavy chain variable domain (V H ), said V H comprises: HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 9, HC - CDR2 comprising the amino acid sequence of SEQ ID NO: 31, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 51, or a variant of said VH comprising a substitution of up to about 5 amino acids in its HC-CDRs and a light chain variable domain (V L ), said V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO:70, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:83, and LC- CDR3 comprising the amino acid sequence of SEQ
  • the anti-HBV pre-S1 antibody is a full length antibody. In some embodiments, the full length anti-HBV pre-S1 antibody is an IgG1 or IgG4 antibody.
  • the disease or condition is selected from, for example, hepatitis B, liver failure, cirrhosis, or liver cancer.
  • the desired individual includes, but is not limited to, an individual infected with, exposed to, at risk of, or susceptible to HBV.
  • a method for preventing, improving or treating HBV infection or diseases related to HBV infection comprising administering to an individual in need an effective amount of a composition comprising an anti-HBV pre-S1 antibody, wherein the Said antibody comprises: VH , said VH comprises the amino acid sequence shown in SEQ ID NO:137 or its variant, and said variant has at least about 80% sequence identity with the amino acid sequence shown in SEQ ID NO:137 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 167 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO: 167.
  • the anti-HBV pre-S1 antibodies described herein are full-length anti-HBV pre-S1 antibodies comprising an IgG1 or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a method for preventing, improving or treating HBV infection or diseases associated with HBV infection comprising administering to an individual in need an effective amount of an anti-HBV pre-S1 antibody (for example, whole Long anti-HBV pre-S1 antibody) pharmaceutical composition, wherein said antibody comprises a heavy chain variable domain (V H ), said V H comprises: HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 14, HC - CDR2 comprising the amino acid sequence of SEQ ID NO: 32, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 51, or a variant of said VH comprising a substitution of up to about 5 amino acids in its HC-CDRs and a light chain variable domain (V L ), said V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO:71, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:86, and LC- CDR3 comprising the amino acid sequence of S
  • the anti-HBV pre-S1 antibody is a full length antibody. In some embodiments, the full length anti-HBV pre-S1 antibody is an IgG1 or IgG4 antibody.
  • the disease or condition is selected from, for example, hepatitis B, liver failure, cirrhosis, or liver cancer.
  • the desired individual includes, but is not limited to, an individual infected with, exposed to, at risk of, or susceptible to HBV.
  • a method for preventing, improving or treating HBV infection or diseases related to HBV infection comprising administering to an individual in need an effective amount of a composition comprising an anti-HBV pre-S1 antibody, wherein the Said antibody comprises: VH , said VH comprises the amino acid sequence shown in SEQ ID NO:139 or its variant, and said variant has at least about 80% sequence identity with the amino acid sequence shown in SEQ ID NO:139 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 169 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO: 169.
  • the anti-HBV pre-S1 antibodies described herein are full-length anti-HBV pre-S1 antibodies comprising an IgG1 or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a method for preventing, improving or treating HBV infection or diseases associated with HBV infection comprising administering to an individual in need an effective amount of an anti-HBV pre-S1 antibody (for example, whole Long anti-HBV pre-S1 antibody) pharmaceutical composition, wherein said antibody comprises a heavy chain variable domain (V H ), said V H comprises: HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 11, HC - CDR2 comprising the amino acid sequence of SEQ ID NO: 30, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 50, or a variant of said VH comprising a substitution of up to about 5 amino acids in its HC-CDRs and a light chain variable domain (V L ), said V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO:72, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:81, and LC- CDR3 comprising the amino acid sequence of SEQ
  • the anti-HBV pre-S1 antibody is a full length antibody. In some embodiments, the full length anti-HBV pre-S1 antibody is an IgG1 or IgG4 antibody.
  • the disease or condition is selected from, for example, hepatitis B, liver failure, cirrhosis, or liver cancer.
  • the desired individual includes, but is not limited to, an individual infected with, exposed to, at risk of, or susceptible to HBV.
  • a method for preventing, improving or treating HBV infection or diseases related to HBV infection comprising administering to an individual in need an effective amount of a composition comprising an anti-HBV pre-S1 antibody, wherein the Said antibody comprises: VH , said VH comprises the amino acid sequence shown in SEQ ID NO:140 or its variant, and said variant has at least about 80% sequence identity with the amino acid sequence shown in SEQ ID NO:140 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 170 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO: 170.
  • the anti-HBV pre-S1 antibodies described herein are full-length anti-HBV pre-S1 antibodies comprising an IgG1 or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a method for preventing, improving or treating HBV infection or diseases associated with HBV infection comprising administering to an individual in need an effective amount of an anti-HBV pre-S1 antibody (for example, whole Long anti-HBV pre-S1 antibody) pharmaceutical composition, wherein said antibody comprises a heavy chain variable domain (V H ), said V H comprises: HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 13, HC - CDR2 comprising the amino acid sequence of SEQ ID NO: 33, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 52, or a variant of said VH comprising a substitution of up to about 5 amino acids in its HC-CDRs and a light chain variable domain (V L ), said V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO:61, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:81, and LC- CDR3 comprising the amino acid sequence of S
  • the anti-HBV pre-S1 antibody is a full length antibody. In some embodiments, the full length anti-HBV pre-S1 antibody is an IgG1 or IgG4 antibody.
  • the disease or condition is selected from, for example, hepatitis B, liver failure, cirrhosis, or liver cancer.
  • the desired individual includes, but is not limited to, an individual infected with, exposed to, at risk of, or susceptible to HBV.
  • a method for preventing, improving or treating HBV infection or diseases related to HBV infection comprising administering to an individual in need an effective amount of a composition comprising an anti-HBV pre-S1 antibody, wherein the Said antibody comprises: VH , said VH comprising the amino acid sequence shown in SEQ ID NO: 141 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 141 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 171 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO: 171.
  • the anti-HBV pre-S1 antibodies described herein are full-length anti-HBV pre-S1 antibodies comprising an IgG1 or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a method for preventing, improving or treating HBV infection or diseases associated with HBV infection comprising administering to an individual in need an effective amount of an anti-HBV pre-S1 antibody (for example, whole Long anti-HBV pre-S1 antibody) pharmaceutical composition, wherein said antibody comprises a heavy chain variable domain (V H ), said V H comprises: HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 10, HC - CDR2 comprising the amino acid sequence of SEQ ID NO: 30, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 50, or a variant of said VH comprising a substitution of up to about 5 amino acids in its HC-CDRs and a light chain variable domain (V L ), said V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO:61, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:81, and LC- CDR3 comprising the amino acid sequence of SEQ
  • the anti-HBV pre-S1 antibody is a full length antibody. In some embodiments, the full length anti-HBV pre-S1 antibody is an IgG1 or IgG4 antibody.
  • the disease or condition is selected from, for example, hepatitis B, liver failure, cirrhosis, or liver cancer.
  • the desired individual includes, but is not limited to, an individual infected with, exposed to, at risk of, or susceptible to HBV.
  • a method for preventing, improving or treating HBV infection or diseases related to HBV infection comprising administering to an individual in need an effective amount of a composition comprising an anti-HBV pre-S1 antibody, wherein the Said antibody comprises: VH , said VH comprises the amino acid sequence shown in SEQ ID NO:142 or its variant, and said variant has at least about 80% sequence identity with the amino acid sequence shown in SEQ ID NO:142 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 172 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO: 172.
  • the anti-HBV pre-S1 antibodies described herein are full-length anti-HBV pre-S1 antibodies comprising an IgG1 or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a method for preventing, improving or treating HBV infection or diseases associated with HBV infection comprising administering to an individual in need an effective amount of an anti-HBV pre-S1 antibody (for example, whole Long anti-HBV pre-S1 antibody) pharmaceutical composition, wherein said antibody comprises a heavy chain variable domain (V H ), said V H comprises: HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 15, HC - CDR2 comprising the amino acid sequence of SEQ ID NO: 34, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 53, or a variant of said VH comprising a substitution of up to about 5 amino acids in its HC-CDRs and a light chain variable domain (V L ), said V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO:73, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:81, and LC- CDR3 comprising the amino acid sequence of S
  • the anti-HBV pre-S1 antibody is a full length antibody. In some embodiments, the full length anti-HBV pre-S1 antibody is an IgG1 or IgG4 antibody.
  • the disease or condition is selected from, for example, hepatitis B, liver failure, cirrhosis, or liver cancer.
  • the desired individual includes, but is not limited to, an individual infected with, exposed to, at risk of, or susceptible to HBV.
  • a method for preventing, improving or treating HBV infection or diseases related to HBV infection comprising administering to an individual in need an effective amount of a composition comprising an anti-HBV pre-S1 antibody, wherein the Said antibody comprises: VH , said VH comprises the amino acid sequence shown in SEQ ID NO: 143 or its variant, and said variant has at least about 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 143 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 173 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO: 173.
  • the anti-HBV pre-S1 antibodies described herein are full-length anti-HBV pre-S1 antibodies comprising an IgG1 or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a method for preventing, improving or treating HBV infection or diseases associated with HBV infection comprising administering to an individual in need an effective amount of an anti-HBV pre-S1 antibody (for example, whole Long anti-HBV pre-S1 antibody) pharmaceutical composition, wherein said antibody comprises a heavy chain variable domain (V H ), said V H comprises: HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 16, HC - CDR2 comprising the amino acid sequence of SEQ ID NO: 35, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 54, or a variant of said VH comprising a substitution of up to about 5 amino acids in its HC-CDRs and a light chain variable domain (V L ), said V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO:74, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:88, and LC- CDR3 comprising the amino acid sequence of S
  • the anti-HBV pre-S1 antibody is a full length antibody. In some embodiments, the full length anti-HBV pre-S1 antibody is an IgG1 or IgG4 antibody.
  • the disease or condition is selected from, for example, hepatitis B, liver failure, cirrhosis, or liver cancer.
  • the desired individual includes, but is not limited to, an individual infected with, exposed to, at risk of, or susceptible to HBV.
  • a method for preventing, improving or treating HBV infection or diseases related to HBV infection comprising administering to an individual in need an effective amount of a composition comprising an anti-HBV pre-S1 antibody, wherein the Said antibody comprises: VH , said VH comprises the amino acid sequence shown in SEQ ID NO:144 or its variant, and said variant has at least about 80% sequence identity with the amino acid sequence shown in SEQ ID NO:144 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 174 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO: 174.
  • the anti-HBV pre-S1 antibodies described herein are full-length anti-HBV pre-S1 antibodies comprising an IgG1 or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a method for preventing, improving or treating HBV infection or diseases associated with HBV infection comprising administering to an individual in need an effective amount of an anti-HBV pre-S1 antibody (for example, whole Long anti-HBV pre-S1 antibody) pharmaceutical composition, wherein said antibody comprises a heavy chain variable domain (V H ), said V H comprises: HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 17, HC - CDR2 comprising the amino acid sequence of SEQ ID NO: 36, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 55, or a variant of said VH comprising a substitution of up to about 5 amino acids in its HC-CDRs and a light chain variable domain (V L ), said V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO:75, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:81, and LC- CDR3 comprising the amino acid sequence of S
  • the anti-HBV pre-S1 antibody is a full length antibody. In some embodiments, the full length anti-HBV pre-S1 antibody is an IgG1 or IgG4 antibody.
  • the disease or condition is selected from, for example, hepatitis B, liver failure, cirrhosis, or liver cancer.
  • the desired individual includes, but is not limited to, an individual infected with, exposed to, at risk of, or susceptible to HBV.
  • a method for preventing, improving or treating HBV infection or diseases associated with HBV infection comprising administering to an individual in need an effective amount of a composition comprising an anti-HBV pre-S1 antibody, comprising: VH , said VH comprising the amino acid sequence set forth in SEQ ID NO: 145 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO: 145; and VL , the V L comprises the amino acid sequence shown in SEQ ID NO: 175 or a variant thereof, and the variant has at least about 80% sequence identity to the amino acid sequence shown in SEQ ID NO: 175.
  • the anti-HBV pre-S1 antibodies described herein are full-length anti-HBV pre-S1 antibodies comprising an IgG1 or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a method for preventing, improving or treating HBV infection or diseases associated with HBV infection comprising administering to an individual in need an effective amount of an anti-HBV pre-S1 antibody (for example, whole A pharmaceutical composition of long anti-HBV pre-S1 antibody), wherein the antibody comprises a heavy chain variable domain ( VH ), and the VH comprises: HC-CDR1 comprising TYGIT (SEQ ID NO: 18); HC-CDR2, which comprises SRIPIX 1 GAALYAQKFQG (SEQ ID NO: 115), wherein X 1 is F or L; HC-CDR3, and which comprises NX 1 RGGFAAY (SEQ ID NO: 116), wherein X 1 is D or T and a light chain variable domain (V L ), said V L comprising: LC-CDR1 comprising RSSQSLX 1 HSNX 2 YNYLD (SEQ ID NO: 117), wherein X 1 is L or T, and X 2 is A or
  • the anti-HBV pre-S1 antibody is a full length antibody. In some embodiments, the full length anti-HBV pre-S1 antibody is an IgG1 or IgG4 antibody.
  • the disease or condition is selected from, for example, hepatitis B, liver failure, cirrhosis, or liver cancer.
  • the desired individual includes, but is not limited to, an individual infected with, exposed to, at risk of, or susceptible to HBV.
  • a method for preventing, improving or treating HBV infection or diseases related to HBV infection comprising administering to an individual in need an effective amount of a composition comprising an anti-HBV pre-S1 antibody, wherein the Said antibody comprises VH , and said VH comprises: HC-CDR1, which comprises the amino acid sequence shown in SEQ ID NO:18, HC-CDR2, which comprises the amino acid sequence shown in any one of SEQ ID NOs:37-38 , and HC-CDR3 comprising the amino acid sequence shown in any one of SEQ ID NOs: 56-57, or a variant of said VH comprising a substitution of up to about 5 amino acids in its HC-CDRs; and VL , the V L comprises: LC-CDR1, which comprises the amino acid sequence shown in any of SEQ ID NOs: 59 and 76-77, LC-CDR2, which comprises SEQ ID NOs: 79, and any of 89-91 A amino acid sequence as shown, and LC
  • a method for preventing, improving or treating HBV infection or diseases related to HBV infection comprising administering to an individual in need an effective amount of a composition comprising an anti-HBV pre-S1 antibody, wherein the Said antibody wherein said antibody comprises: V H , said V H comprises the amino acid sequence shown in any one of SEQ ID NOs:146-150 or its variant, said variant is identical to any of SEQ ID NOs:146-150 A shown amino acid sequence having at least about 80% sequence identity; and V L , said V L comprising any one of the amino acid sequences shown in SEQ ID NOs: 176-183 or a variant thereof, said variant being identical to SEQ ID NOs: 176-183
  • the amino acid sequences shown in any one of ID NOs: 176-183 have at least about 80% sequence identity.
  • the anti-HBV pre-S1 antibodies described herein are full-length anti-HBV pre-S1 antibodies comprising an IgG1 or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • a method for preventing, improving or treating HBV infection or diseases related to HBV infection comprising administering to an individual in need an effective amount of a composition comprising an anti-HBV pre-S1 antibody, wherein the Said antibody comprises VH , said VH comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 37, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 37 ID NO: 56, or a variant of said VH comprising a substitution of up to about 5 amino acids in its HC-CDRs; and a VL comprising: LC- CDR1 comprising the amino acid sequence SEQ ID NO: 59.
  • LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 79
  • LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 111
  • V L comprising at most about 5 of its LC-CDRs Amino acid substitutions.
  • the anti-HBV pre-S1 antibody described herein comprises: VH comprising the amino acid sequence of SEQ ID NO: 146 or a variant thereof having the amino acid sequence of SEQ ID NO: 146 at least about 80% sequence identity; and a VL comprising the amino acid sequence of SEQ ID NO: 176 or a variant thereof having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 176.
  • the anti-HBV pre-S1 antibody described herein is a full-length anti-HBV pre-S1 antibody comprising an IgG1 or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:186. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189.
  • a method for preventing, improving or treating HBV infection or diseases related to HBV infection comprising administering to an individual in need an effective amount of a composition comprising an anti-HBV pre-S1 antibody, wherein the Said antibody comprises: VH , said VH comprises: HC-CDR1, which comprises the amino acid sequence of SEQ ID NO: 18, HC-CDR2, which comprises the amino acid sequence of SEQ ID NO: 38, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 57, or a variant of said VH comprising a substitution of up to about 5 amino acids in its HC-CDRs; and a VL comprising: LC- CDR1 comprising the amino acid sequence of SEQ ID NO :76, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:79, and LC-CDR3, which comprises the amino acid sequence of SEQ ID NO:112, or variants of said V L comprising at most about 5 in its LC-CDRs
  • the anti-HBV pre-S1 antibody described herein comprises: VH comprising the amino acid sequence of SEQ ID NO: 147 or a variant thereof having the amino acid sequence of SEQ ID NO: 147 at least about 80% sequence identity; and a VL comprising the amino acid sequence of SEQ ID NO: 177 or a variant thereof having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 177.
  • the anti-HBV pre-S1 antibody described herein is a full-length anti-HBV pre-S1 antibody comprising an IgG1 or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:186. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189.
  • a method for preventing, improving or treating HBV infection or diseases related to HBV infection comprising administering to an individual in need an effective amount of a composition comprising an anti-HBV pre-S1 antibody, wherein the Said antibody comprises: VH , said VH comprises: HC-CDR1, which comprises the amino acid sequence of SEQ ID NO: 18, HC-CDR2, which comprises the amino acid sequence of SEQ ID NO: 37, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 57, or a variant of said VH comprising a substitution of up to about 5 amino acids in its HC-CDRs; and a VL comprising: LC- CDR1 comprising the amino acid sequence of SEQ ID NO :77, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:89, and LC-CDR3, which comprises the amino acid sequence of SEQ ID NO:111, or variants of said VL , comprising at most about 5 in its LC-C
  • the anti-HBV pre-S1 antibody described herein comprises: VH comprising the amino acid sequence of SEQ ID NO: 148 or a variant thereof having the amino acid sequence of SEQ ID NO: 148 at least about 80% sequence identity; and a VL comprising the amino acid sequence of SEQ ID NO: 178 or a variant thereof having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 178.
  • the anti-HBV pre-S1 antibody described herein is a full-length anti-HBV pre-S1 antibody comprising an IgG1 or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:186. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189.
  • a method for preventing, improving or treating HBV infection or diseases related to HBV infection comprising administering to an individual in need an effective amount of a composition comprising an anti-HBV pre-S1 antibody, wherein the Said antibody comprises: VH , said VH comprises: HC-CDR1, which comprises the amino acid sequence of SEQ ID NO: 18, HC-CDR2, which comprises the amino acid sequence of SEQ ID NO: 37, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 57, or a variant of said VH comprising a substitution of up to about 5 amino acids in its HC-CDRs; and a VL comprising: LC- CDR1 comprising the amino acid sequence of SEQ ID NO :77, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:90, and LC-CDR3, which comprises the amino acid sequence of SEQ ID NO:111, or variants of said VL comprising at most about 5 in its LC-CDRs
  • the anti-HBV pre-S1 antibody described herein comprises: VH comprising the amino acid sequence of SEQ ID NO: 149 or a variant thereof having the amino acid sequence of SEQ ID NO: 149 at least about 80% sequence identity; and a VL comprising the amino acid sequence of SEQ ID NO: 179 or a variant thereof having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 179.
  • the anti-HBV pre-S1 antibody described herein is a full-length anti-HBV pre-S1 antibody comprising an IgG1 or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:186. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189.
  • a method for preventing, improving or treating HBV infection or diseases related to HBV infection comprising administering to an individual in need an effective amount of a composition comprising an anti-HBV pre-S1 antibody, wherein the Said antibody comprises: VH , said VH comprises: HC-CDR1, which comprises the amino acid sequence of SEQ ID NO: 18, HC-CDR2, which comprises the amino acid sequence of SEQ ID NO: 38, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 57, or a variant of said VH comprising a substitution of up to about 5 amino acids in its HC-CDRs; and a VL comprising: LC- CDR1 comprising the amino acid sequence of SEQ ID NO :76, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:79, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO:111, or variants of said VL comprising at most about 5 in its LC-CDRs
  • the anti-HBV pre-S1 antibody described herein comprises: VH comprising the amino acid sequence of SEQ ID NO: 147 or a variant thereof having the amino acid sequence of SEQ ID NO: 147 at least about 80% sequence identity; and a VL comprising the amino acid sequence of SEQ ID NO: 180 or a variant thereof having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 180.
  • the anti-HBV pre-S1 antibody described herein is a full-length anti-HBV pre-S1 antibody comprising an IgG1 or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:186. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189.
  • a method for preventing, improving or treating HBV infection or diseases related to HBV infection comprising administering to an individual in need an effective amount of a composition comprising an anti-HBV pre-S1 antibody, wherein the Said antibody comprises: VH , said VH comprises: HC-CDR1, which comprises the amino acid sequence of SEQ ID NO: 18, HC-CDR2, which comprises the amino acid sequence of SEQ ID NO: 38, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 57, or a variant of said VH comprising a substitution of up to about 5 amino acids in its HC-CDRs; and a VL comprising: LC- CDR1 comprising the amino acid sequence of SEQ ID NO :77, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:79, and LC-CDR3, which comprises the amino acid sequence of SEQ ID NO:113, or variants of said V L comprising at most about 5 in its LC-CDRs
  • the anti-HBV pre-S1 antibody described herein comprises: VH comprising the amino acid sequence of SEQ ID NO: 147 or a variant thereof having the amino acid sequence of SEQ ID NO: 147 at least about 80% sequence identity; and a VL comprising the amino acid sequence of SEQ ID NO: 181 or a variant thereof having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 181.
  • the anti-HBV pre-S1 antibody described herein is a full-length anti-HBV pre-S1 antibody comprising an IgG1 or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:186. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189.
  • a method for preventing, improving or treating HBV infection or diseases related to HBV infection comprising administering to an individual in need an effective amount of a composition comprising an anti-HBV pre-S1 antibody, wherein the Said antibody comprises: VH , said VH comprises: HC-CDR1, which comprises the amino acid sequence of SEQ ID NO: 18, HC-CDR2, which comprises the amino acid sequence of SEQ ID NO: 37, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 57, or a variant of said VH comprising a substitution of up to about 5 amino acids in its HC-CDRs; and a VL comprising: LC- CDR1 comprising the amino acid sequence of SEQ ID NO :77, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:89, and LC-CDR3, which comprises the amino acid sequence of SEQ ID NO:114, or variants of said V L comprising at most about 5 in its LC-CDRs
  • the anti-HBV pre-S1 antibody described herein comprises: VH comprising the amino acid sequence of SEQ ID NO: 148 or a variant thereof having the amino acid sequence of SEQ ID NO: 148 at least about 80% sequence identity; and a VL comprising the amino acid sequence of SEQ ID NO: 182 or a variant thereof having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 182.
  • the anti-HBV pre-S1 antibody described herein is a full-length anti-HBV pre-S1 antibody comprising an IgG1 or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:186. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189.
  • a method for preventing, improving or treating HBV infection or diseases related to HBV infection comprising administering to an individual in need an effective amount of a composition comprising an anti-HBV pre-S1 antibody, wherein the Said antibody comprises: VH , said VH comprises: HC-CDR1, which comprises the amino acid sequence of SEQ ID NO: 18, HC-CDR2, which comprises the amino acid sequence of SEQ ID NO: 37, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 57, or a variant of said VH comprising a substitution of up to about 5 amino acids in its HC-CDRs; and a VL comprising: LC- CDR1 comprising the amino acid sequence of SEQ ID NO :77, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:91, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO:113, or variants of said VL comprising at most about 5 in its LC-CDRs
  • the anti-HBV pre-S1 antibody described herein comprises: VH comprising the amino acid sequence of SEQ ID NO: 150 or a variant thereof having the amino acid sequence of SEQ ID NO: 150 at least about 80% sequence identity; and a VL comprising the amino acid sequence of SEQ ID NO: 183 or a variant thereof having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 183.
  • the anti-HBV pre-S1 antibody described herein is a full-length anti-HBV pre-S1 antibody comprising an IgG1 or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:186. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:188. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:189.
  • a method for preventing, improving or treating HBV infection or diseases associated with HBV infection comprising administering to an individual in need an effective amount of an anti-HBV pre-S1 antibody (for example, whole Long anti-HBV pre-S1 antibody) pharmaceutical composition, wherein said antibody comprises a heavy chain variable domain (V H ), said V H comprises: HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 18, HC - CDR2 comprising the amino acid sequence of SEQ ID NO: 37, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 56, or a variant of said VH comprising a substitution of up to about 5 amino acids in its HC-CDRs and a light chain variable domain (V L ), said V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO:78, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:92, and LC- CDR3 comprising the amino acid sequence of S
  • the anti-HBV pre-S1 antibody is a full length antibody. In some embodiments, the full length anti-HBV pre-S1 antibody is an IgG1 or IgG4 antibody.
  • the disease or condition is selected from, for example, hepatitis B, liver failure, cirrhosis, or liver cancer.
  • the desired individual includes, but is not limited to, an individual infected with, exposed to, at risk of, or susceptible to HBV.
  • a method for preventing, improving or treating HBV infection or diseases related to HBV infection comprising administering to an individual in need an effective amount of a composition comprising an anti-HBV pre-S1 antibody, wherein the Said antibody comprises: VH , said VH comprises the amino acid sequence shown in SEQ ID NO:146 or its variant, and said variant has at least about 80% sequence identity with the amino acid sequence shown in SEQ ID NO:146 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 184 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO: 184.
  • the anti-HBV pre-S1 antibodies described herein are full-length anti-HBV pre-S1 antibodies comprising an IgG1 or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 186.
  • the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the individual is a mammal (eg, a human, non-human primate, rat, mouse, cow, horse, pig, sheep, goat, dog, cat, etc.). In some embodiments, the individual is a human. In some embodiments, the individual is a clinical patient, a clinical trial volunteer, an experimental animal, or the like. In some embodiments, the individual is less than 60 years old (including, for example, less than 50, 40, 30, 25, 20, 15, or 10 years old). In some embodiments, the individual is greater than 60 years old (including, for example, greater than 70, 80, 90, or 100 years old).
  • the individual is diagnosed with or is genetically predisposed to have one or more diseases or conditions described herein (eg, HBV infection or a disease associated with HBV infection). In some embodiments, the individual has one or more risk factors associated with one or more diseases or conditions described herein.
  • diseases or conditions described herein eg, HBV infection or a disease associated with HBV infection.
  • the individual has one or more risk factors associated with one or more diseases or conditions described herein.
  • the application provides a method for delivering an anti-HBV pre-S1 antibody (such as any anti-HBV pre-S1 antibody described herein, such as isolated Anti-HBV pre-S1 antibody), the method comprises administering to the individual a composition comprising an anti-HBV pre-S1 antibody.
  • an anti-HBV pre-S1 antibody such as any anti-HBV pre-S1 antibody described herein, such as isolated Anti-HBV pre-S1 antibody
  • HBV infection or any other manifestation of disease associated with HBV infection and the clinical description of these diseases are known in the art.
  • diagnostic methods include, but are not limited to, eg, immunohistochemistry, PCR, and fluorescence in situ hybridization (FISH).
  • FISH fluorescence in situ hybridization
  • anti-HBV pre-S1 antibodies described herein are combined with second, third or fourth agents (including, for example, other antiviral agents, Antiallergic agents, antinausea agents (or antiemetic agents), analgesics, cytoprotectants or immunosuppressants) are administered in combination to prevent, improve or treat HBV infection or diseases associated with HBV infection.
  • the other antiviral agents may include, but are not limited to, interferon, nucleoside/nucleotide analogs, anti-HBV monoclonal antibodies, anti-HBV polyclonal antibodies, DNA polymerase inhibitors or therapeutic vaccines.
  • the nucleoside/nucleotide analogs may include, but are not limited to, lamivudine, entecavir, clevudine or adefovir dipivoxil.
  • Dosages of anti-HBV pre-S1 antibody (e.g., isolated anti-HBV pre-S1 antibody) compositions administered to an individual may vary depending on the particular composition, mode of administration, and type of disease being treated.
  • the amount of the composition e.g., a composition comprising an anti-HBV pre-S1 antibody
  • an objective response e.g., a partial response or a complete response
  • the amount of the anti-HBV pre-S1 antibody composition is sufficient to produce a complete response in the individual.
  • the amount of the anti-HBV pre-S1 antibody composition is sufficient to generate a partial response in the individual.
  • the dose of the anti-HBV pre-S1 antibody composition administered is sufficient to produce greater than 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 64%, 65%, 70%, 75%, 80%, 85%, or 90% overall response rate.
  • An individual's response to the methods of treatment described herein can be determined, for example, by the levels of secreted HBV antigens in serum.
  • the amount of the composition is sufficient to prolong the progression-free survival of the individual. In some embodiments, the amount of the composition is sufficient to prolong the overall survival of the subject. In some embodiments, the amount of the composition (e.g. when administered alone) is sufficient to produce greater than 50%, 60%, 70% or 77% of the clinical outcome in a population of individuals treated with an anti-HBV pre-S1 antibody composition. benefit.
  • the amount of a composition is the amount indicated in the therapeutic An amount sufficient to control symptoms and reduce the risk of exacerbations compared with corresponding activity in other subjects not receiving treatment.
  • the magnitude of this therapeutic effect can be measured using standard methods, such as in vitro assays of purified enzymes, cell-based assays, animal models, or human trials.
  • the amount of anti-HBV pre-S1 antibody (e.g., full-length anti-HBV pre-S1 antibody) in the composition is lower than that causing a toxic effect (that is, a higher than clinically acceptable level of toxicity), or at a level at which potential side effects can be managed or tolerated.
  • the amount of the composition approximates the maximum tolerated dose (MTD) of the composition. In some embodiments, the amount of the composition is greater than 80%, 90%, 95%, or 98% of the MTD.
  • the content of the anti-HBV pre-S1 antibody (eg, full-length anti-HBV pre-S1 antibody) in the composition is in the range of 0.001 ⁇ g to 1000 ⁇ g.
  • the effective amount of the anti-HBV pre-S1 antibody (such as the full-length anti-HBV pre-S1 antibody) in the composition is 0.1 ⁇ g/kg to 100 mg/kg when calculated according to body weight within the range.
  • Anti-HBV pre-S1 antibody compositions can be administered to an individual (such as a human) by a variety of routes, including, for example, intravenous injection, intraarterial administration, intraperitoneal injection, intrapulmonary administration, oral administration, inhalation administration, intravascular administration Administration, intramuscular injection, intratracheal administration, subcutaneous injection, intraocular administration, intrathecal administration, mucosal administration or transdermal administration.
  • routes including, for example, intravenous injection, intraarterial administration, intraperitoneal injection, intrapulmonary administration, oral administration, inhalation administration, intravascular administration Administration, intramuscular injection, intratracheal administration, subcutaneous injection, intraocular administration, intrathecal administration, mucosal administration or transdermal administration.
  • a sustained release formulation of the composition is used.
  • the composition is administered intravenously.
  • the composition is administered arterially.
  • the composition is administered intraperitoneally.
  • the composition is administered intrahepatically.
  • the composition is administered by hepatic artery infusion.
  • a product which comprises a substance that can be used to prevent, improve or treat HBV infection or diseases related to HBV infection, or to deliver anti-HBV pre -S1 antibody (such as a full-length anti-HBV pre-S1 antibody) to HBV-infected individuals.
  • the article of manufacture may comprise a container and a label or package insert on or accompanying the container. Suitable containers include, for example, bottles, vials, syringes, and the like. Containers can be made from a variety of materials such as glass or plastic.
  • the container contains a composition effective to treat a disease or condition described herein and has a sterile port (eg, the container may be an IV bag or a vial with a hypodermic needle-pierceable cap).
  • a sterile port eg, the container may be an IV bag or a vial with a hypodermic needle-pierceable cap.
  • At least one active substance in the composition is the anti-HBV pre-S1 antibody described in this application.
  • the label or package insert identifies the particular condition that the composition may be used to treat.
  • the label or package insert further comprises instructions for administering the anti-HBV pre-S1 antibody composition to a patient. Articles of manufacture and kits comprising combination therapies are contemplated herein.
  • Package insert refers to the instructions commonly included in commercial packages of therapeutic products that contain indications, usage, dosage, administration, contraindications and/or warning information pertaining to the use of such therapeutic products.
  • the package insert indicates that the composition can be used to prevent, improve or treat HBV infection or diseases related to HBV infection.
  • the package insert indicates that the composition can be used to treat diseases including hepatitis B, liver failure, liver cirrhosis, or liver cancer.
  • the article of manufacture may further comprise a second container comprising a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate buffered saline, Greene's solution, or dextrose solution.
  • a pharmaceutically acceptable buffer such as bacteriostatic water for injection (BWFI), phosphate buffered saline, Greene's solution, or dextrose solution.
  • kits that can be used for various purposes, such as for preventing, ameliorating or treating HBV infection or diseases associated with HBV infection, or for delivering anti-HBV pre-S1 antibodies (such as full-length anti-HBV pre-S1 antibodies ) into an individual infected with HBV, optionally in combination with the preparation.
  • the test kit of the present application comprises one or more containers, and it comprises anti-HBV pre-S1 antibody composition (or single dose form and/or preparation), and in some embodiments, further comprises another kind of medicament (such as described herein agents described above) and/or instructions for use consistent with any of the methods described herein.
  • the kit may further include instructions for selecting an individual for treatment.
  • the instructions for use attached to the kit in the present application are usually written instructions on the label or package insert (such as paper sheets included in the kit), machine-readable instructions (such as instructions on a magnetic or optical storage disc) is also acceptable.
  • the kit includes a composition comprising an anti-HBV pre-S1 antibody (e.g., a full-length anti-HBV pre-S1 antibody).
  • the kit includes: a) a composition comprising any of the anti-HBV pre-S1 antibodies described herein, and b) at least one other agent in an effective amount that enhances anti-HBV pre-S1 Effects of antibodies (e.g. therapeutic effect, detection effect).
  • the kit includes: a) a composition comprising any of the anti-HBV pre-S1 antibodies described herein, and b) administering the anti-HBV pre-S1 antibody composition to an individual for preventing, ameliorating, or Instructions for use in the treatment of HBV infection or diseases associated with HBV infection.
  • the kit includes: a) a composition comprising any of the anti-HBV pre-S1 antibodies described herein, and b) at least one other agent in an effective amount that enhances anti-HBV pre-S1
  • the effect of the antibody (such as therapeutic effect, detection effect) and c) instructions for administering the anti-HBV pre-S1 antibody composition and other substances to individuals for preventing, improving or treating HBV infection or diseases related to HBV infection.
  • the anti-HBV pre-S1 antibody and other substances can be present in separate containers or in the same container.
  • the kit may include one particular composition or two or more compositions, one of which includes an anti-HBV pre-S1 antibody and the other of which includes another agent.
  • the kit comprises one (or a group) of nucleic acids encoding an anti-HBV pre-S1 antibody (eg, a full-length anti-HBV pre-S1 antibody).
  • the kit comprises: a) a nucleic acid (or a group) encoding an anti-HBV pre-S1 antibody (such as a full-length anti-HBV pre-S1 antibody), and b) an expressing nucleic acid (or A set of host cells for nucleic acids).
  • the kit comprises: a) a nucleic acid (or a group) encoding an anti-HBV pre-S1 antibody (such as a full-length anti-HBV pre-S1 antibody), and b) instructions for use, suitable for: i) express anti-HBV pre-S1 antibody in host cell, ii) prepare the composition that comprises anti-HBV pre-S1 antibody, and iii) prevent, ameliorate or treat to individual administration comprising the composition of anti-HBV pre-S1 antibody HBV infection or diseases associated with HBV infection.
  • an anti-HBV pre-S1 antibody such as a full-length anti-HBV pre-S1 antibody
  • the kit includes: a) a nucleic acid (or a group) encoding an anti-HBV pre-S1 antibody (such as a full-length anti-HBV pre-S1 antibody), b) an expressing nucleic acid (or a A host cell of group nucleic acid), and c) instructions for use, suitable for: i) expressing an anti-HBV pre-S1 antibody in the host cell, ii) preparing a composition comprising an anti-HBV pre-S1 antibody, and iii) administering to an individual
  • the composition comprising anti-HBV pre-S1 antibody is used to prevent, improve or treat HBV infection or diseases related to HBV infection.
  • kits described herein are packaged in a suitable form.
  • suitable packaging includes, but is not limited to, vials, bottles, jars, flexible packaging (eg, sealed mylar or plastic bags), and the like. Kits may optionally provide other components, such as buffers and instructional information. Accordingly, the present application also provides articles of manufacture including vials, bottles, jars, flexible packaging (eg, sealed mylar or plastic bags), and the like.
  • the instructions for use of the anti-HBV pre-S1 antibody composition usually include some information, such as dosage, administration cycle and administration route, etc.
  • the container can be unit dose, bulk (eg, multi-dose package) or subunit dose.
  • a kit comprising a sufficient dose of an anti-HBV pre-S1 antibody as described herein (e.g., a full-length anti-HBV pre-S1 antibody) is provided for long-term effective treatment of an individual, e.g., one week, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months or more.
  • the kit can also comprise multiple unit doses of the anti-HBV pre-S1 antibody, the pharmaceutical composition and instructions for use, and be packaged in quantities sufficient for storage and use in pharmacies, eg, hospital pharmacies and compounding pharmacies.
  • Embodiment 1 Recombinant protein preparation
  • pre-S1 domains of HBV A, B, C, D, E, F, G, H, I and J genotypes were respectively constructed into the pTT5 expression vector by subcloning, and expressed in HEK293 cells express in.
  • Add His tag and/or Avi tag and/or other tags commonly used by those skilled in the art on the cDNA encoding the HBV pre-S1 domain construct and express a fusion protein containing the HBV pre-S1 domain, such as X-preS1 -His, B-preS1-Avi-His.
  • His represents His tag
  • Avi represents avidin tag
  • X represents HBV genotype
  • X can be A, B, C, D, E, F, G, H, I or J, for example
  • B stands for HBV B genotype.
  • the cDNA encoding the extracellular region of Fc ⁇ RIIIa was constructed into pTT5 expression vector by subcloning, and expressed in HEK293 cells. Add His tag, Avi tag and/or other tags commonly used by those skilled in the art to the cDNA encoding the extracellular region of Fc ⁇ RIIIa to construct and express a fusion protein containing the extracellular region of Fc ⁇ RIIIa, such as Fc ⁇ RIIIa-ECD-Avi-His. Among them, “ECD” stands for extracellular domain, “His” stands for His tag, and "Avi” stands for avidin tag.
  • HBV pre-S1 fusion protein and Fc ⁇ RIIIa extracellular domain fusion protein including X-preS1-His, B-preS1-Avi-His and Fc ⁇ RIIIa-ECD-Avi-His, were expressed and purified respectively.
  • HEK293 cells were transfected with expression vectors containing the above fusion protein genes, and the cells were cultured at 37°C, 5% CO 2 , and 120rpm for 5 days. Cell culture fluid was collected separately.
  • Recombinant fusion proteins with His tags were purified using nickel columns (Ni) according to the manufacturer's instructions. The specific operation is as follows: centrifuge the cell culture solution at 20,000 rpm for 15 minutes, and take the supernatant. After the supernatant was filtered with a 0.45 ⁇ m filter membrane, it was purified using a HisCap 6FF column (Changzhou Tiandi Renhe Biotechnology Co., Ltd., SA005C55). The purified protein was concentrated and replaced with a 3kDa ultrafiltration tube (Millipore, UFC900396), and the solvent of the purified protein was replaced with PBS. BCA protein quantification kit (ThermoScientific, 23225) was used for protein quantification, and it was set aside.
  • B-preS1-Avi-His or Fc ⁇ RIIIa-ECD-Avi-His was biotinylated with biotinylated ligase B0101A (GeneCopoeia). Briefly, BufferA/B and BirA ligase were added to B-preS1-Avi-His or Fc ⁇ RIIIa-ECD-Avi-His and incubated at 30°C for 2 hours. Biotinylated B-preS1-Avi-His was named B-preS1-Bavih; biotinylated Fc ⁇ RIIIa-ECD-Avi-His was named Fc ⁇ RIIIa-ECD-Bavih. The biotinylation efficiency was detected by ELISA method, and it was determined that the biotinylation labeling efficiency of the above protein was at least 70%.
  • P2019-1 A polypeptide comprising amino acid residues 14-58 of the HBV L protein pre-S1 domain (SEQ NO.191) with N-terminal myristoylation modification and C-terminal biotin modification.
  • P2019-2 A polypeptide comprising amino acid residues 15-46 of the HBV L protein pre-S1 domain (SEQ NO.191) with biotin modification at the C-terminus.
  • P2019-1 Myr-TNLSVPNPLGFFPDHQLDPAFGANSNNPDWDFNPNKDHWPEANQV-K (biotin);
  • P2019-2 NLSVPNPLGFFPDHQLDPAFGANSNNPDWDFN-K (biotin).
  • Embodiment 2 Screen the single-chain Fv (scFv) of anti-HBV pre-S1
  • scFv single-chain Fv
  • Single-chain Fv (scFv) against HBV pre-S1 antigen was screened by FACS: The yeast enriched after panning by MACS was sorted by flow cytometry (FACS). Briefly, yeast cells induced in SGCAA medium were pelleted, the pellet was washed with 1 mL of PBSM, and centrifuged at 14,000 g for 30 s. Resuspend the yeast cells with 100 ⁇ L of PBSM buffer containing B-preS1-Bavih, P2019-1 or P2019-2, and incubate at room temperature for 1 h.
  • FACS flow cytometry
  • Example 3 Preparation and characterization of full-length anti-HBV pre-S1 antibodies
  • V L and V H were amplified from yeast expression vectors and constructed into eukaryotic expression vectors pTT5-L (containing kappa light chain constant region) and pTT5-H1 (containing IgG1 heavy chain constant region) or pTT5-H4 (containing IgG4 heavy chain constant region).
  • the extracted plasmids expressing the light chain or heavy chain were co-transfected into 293F cells, cultured at 37° C., 8% CO 2 , and 120 rpm for 5 days, and the culture solution was purified with Protein A affinity chromatography.
  • the protein A column was first equilibrated with 6 column volumes of 50 mM PBS buffer (containing 0.15M NaCl, pH 7.2) at a flow rate of 150 cm/h.
  • the culture supernatant (adjusted to pH 7.2) was passed through the column at a flow rate of 150 cm/h.
  • the obtained full-length antibody was further analyzed for biochemical and biological activity.
  • the screened full-length anti-HBV preS1 monoclonal antibody (reconstructed into human IgG1 form) was subjected to a binding test with the B-preS1-His antigen, which was used to identify the binding ability of the antibody to the pre-S1 antigen.
  • the B-preS1-His antigen prepared in Example 1 was dissolved in PBS solution, coated with 0.1 ⁇ g/well on a 96-well plate, and left overnight at 4°C. Before adding the antibody, the 96-well plate was washed with PBST solution, blocked with 5% milk at 37°C for 1 hour, and then washed with PBST solution.
  • Each antibody sample was diluted to 3 ⁇ g/mL followed by a 1:3 serial dilution.
  • the samples after serial dilution were added to 96-well plates, 100 ⁇ L per well, and incubated at 37° C. for 1 hour. It was subsequently washed 6 times with PBST solution.
  • 100 ⁇ L of secondary antibody (goat anti-human IgG-AP (Southern Biotech, A5912-PF77C)) was added to each well, and incubated at 37° C. for 1 hour. Wash 6 times with PBST solution.
  • Add 100 ⁇ L of pNPP chromogenic solution (Southern Biotech, L5519-2J39) to each well, and incubate at 37° C. for 10-20 minutes. Read the absorbance at 405 nm using a microplate reader. Binding curves were generated by Graphpad Prism and EC50 values were calculated.
  • sample name EC50 value (ng/mL) sample name EC50 value (ng/mL) K25 35.14 K80 27.73 K26 22.40 K82 34.05 K27 30.17 K118 22.37 K28 29.19 K119 36.83 K31 22.49 K121 12.90 K48 42.01 K122 14.24 K50 18.51 K123 24.58 K55 22.87 K127 20.01 K71 26.02 K128 21.12 K72 43.24 A14-8 32.98
  • the binding ability of the screened full-length anti-HBV preS1 antibody (reconstructed into human IgG1 form) and the control antibody A14-8 to the extracellular region of Fc ⁇ RIIIa (Fc receptor) was detected by ELISA assay, so as to determine the ADCC activity mediated by each antibody.
  • ELISA assay For the detection method of ADCC activity, please refer to the literature (Development of an ELISA based bridging assay as a surrogate measure of ADCC. J Immunol Methods. 2012 Nov 30; 385(1-2): 45-50.).
  • the B-preS1-His antigen prepared in Example 1 was dissolved in PBS solution, coated with 0.1 ⁇ g/well on a 96-well plate, and left overnight at 4°C. Before adding the antibody, the 96-well plate was washed with PBST solution, blocked with 5% milk at 37°C for 1 hour, and then washed with PBST solution. Each antibody sample was diluted to 10 ⁇ g/mL followed by a 1:3 serial dilution. The samples after serial dilution were respectively added to a 96-well plate, 100 ⁇ L per well, and incubated at 37° C. for 1 hour. It was subsequently washed 6 times with PBST solution.
  • Anti-HBV preS1 antibodies K23, K27, K50, K71, K80, K122, K127, etc. were all capable of binding to Fc ⁇ RIIIa, and exhibited better or comparable ADCC activity than the control antibody A14-8.
  • sample name EC50 value (ng/mL) sample name EC50 value (ng/mL) K23 776 K121 800 K27 712 K119 696 K28 648 K118 680 K31 728 K122 512 K50 840 K127 752 K71 560 A14-8 800 K80 536 the the
  • ADCC activity assay of anti-HBV preS1 antibody based on reporter gene
  • NFAT-CD16 Using Jurkat-Lucia TM NFAT-CD16 stably transfected with Fc receptor CD16A (Fc ⁇ RIIIA) and NFAT (nuclear factor of activated T-cells) response elements as effector cells, stably express HBV B genotype pre-S1 antigen 1-59 Amino acid 293T was used as the target cell.
  • the effector cells are connected to the target cells through the monoclonal antibody, and the binding of the Fc part of the antibody to the Fc receptor CD16A on the surface of the effector cells leads to the activation of the NFAT pathway, which in turn initiates the expression of the luciferase reporter gene. After adding the luciferase substrate solution, the antibody-mediated ADCC activity was indicated by the fluorescence intensity.
  • 293T cells (1 ⁇ 10 6 cells/mL) stably expressing the HBV B genotype pre-S1 antigen (1-59 amino acids) were seeded in 96-well plates, 90 ⁇ L per well.
  • K23, K27, K31, K41, K50, K123, K127 or K128 anti-HBV pre-S1 antibodies (reconstituted into human IgG1 form) with an initial concentration of 45 ⁇ g/mL were serially diluted at a ratio of 1:5, and added to Transfer to a 96-well culture plate and incubate for 1 h at 37°C, 5% CO 2 .
  • the relative light unit values measured when adding the negative control antibody (6G4103DT, our company’s antibody against the PcRV target) and adding A14-20m1 at a concentration of 4.5 ⁇ g/mL were set as 0% and 100% killing rate, respectively, so that To calculate the relative cell killing rate (cytotoxicity rate) of anti-HBV pre-S1 antibodies such as K23, K25, K27, K50, K80, K127, K128 and control antibody A14-20m1 at different concentrations.
  • Graphpad Prism software was used to draw graphs and calculate EC 50 values to determine the ADCC activity of each antibody.
  • anti-HBV preS1 antibodies such as K23, K27, K31, K41, K50, K123, K127, and K128 exhibit better or equivalent ADCC activity.
  • sample name EC50 value (ng/mL) sample name EC50 value (ng/mL) K23 8.76 K73 13.51 K27 14.55 K118 7.5 K28 14.17 K120 2.79 K31 4.57 K122 2.45 K41 7.03 K123 4.38 K50 13.22 K127 3.78 K70 7.55 K128 10.45 K71 5.93 A14-20m1 11.20
  • Embodiment 4 the broad spectrum of anti-HBV pre-S1 antibody binding HBV
  • Example 3 The ELISA binding test described in Example 3 was used to detect the full-length anti-pre-S1 antibodies K41, K50, K55, K80, K127, K128 (reconstructed into human IgG1 form) and the control antibody A14-8 respectively compared with those in Example 1.
  • Anti-HBV pre-S1 antibodies can all be compared with at least 8 subtypes of HBV A, B, C, D, E, F, G, H, I and J genotype pre-S1 antigens. combined. Furthermore, K41 , K50, K55, K80, K127 or K128 bound better or comparable to the major genotypes of HBV (A, B, C, D or E) compared to the control antibody A14-8. It can be seen that the binding of anti-HBV pre-S1 antibodies K41, K50, K55, K80, K127 or K128 to HBV has a broad spectrum.
  • Embodiment 5 the affinity of anti-HBV pre-S1 antibody
  • Biacore 3000 (GE) was used to characterize the binding affinity of full-length anti-HBV pre-S1 antibodies K31, K50, K55, K80, K127 (reconstituted human IgG1 form) and control antibody A14-20m1 to pre-S1 antigen.
  • the B-preS1-Bavih antigen prepared in Example 1 was coated on the surface of a streptavidin chip (streptavidin chip), and the affinity of antibodies at different concentrations to B-preS1-Bavih was detected. The on-rate and off-rate of the antibody are measured using SPR technique and the binding affinity is determined.
  • Embodiment 6 the neutralizing activity of anti-HBV pre-S1 antibody
  • HBV Human cells expressing sodium taurocholate co-transporting polypeptide (NTCP) on the cell surface were infected with HBV, and the HBV neutralizing activity of each antibody was evaluated by detecting the content of HBV antigen (such as HBsAg or HBeAg) in the supernatant.
  • HBV antigen such as HBsAg or HBeAg
  • HepG2 cells stably expressing NTCP HepG2-NTCP, constructed by Shanghai WuXi AppTec
  • HepG2-NTCP constructed by Shanghai WuXi AppTec
  • the anti-HBV pre-S1 antibodies K31, K50, K55, K80, and K127 (reconstituted into human IgG1 form) with an initial concentration of 150 ⁇ g/mL were serially diluted at a ratio of 1:4, and respectively mixed with 600GE (genome , genome equivalent) of HBV (genotype D) were mixed and co-incubated at 37° C. for 1 h.
  • the above antibody-virus mixture was added to the HepG2-NTCP cell culture plate for culture, and the fresh medium without antibody and virus was replaced once on the 3rd, 5th, and 7th days. Supernatants were collected on day 9. The HBs antigen content in the supernatant was detected by HBsAg Elisa kit (Antu Bio, CL0310). The absorbance values measured without adding anti-pre-S1 antibody and without adding HBV virus infection were calculated as 0% and 100% inhibition rate respectively, and the experimental data were normalized to calculate the neutralizing activity of each antibody.
  • Embodiment 7 improve the affinity and biological activity of antibody
  • K127 was selected as the lead antibody for affinity maturation.
  • the sequence of K127 was analyzed, mutations were carried out in its CDR region, the corresponding phage scFv display library was constructed and produced, and the anti-HBV pre-S1 antibody with improved performance was screened out.
  • the above scFv antibody was reconstituted into a full-length antibody.
  • ELISA binding assay and ADCC assay were used for further biochemical and biological activity analysis.
  • an ELISA binding assay was performed on the affinity matured full-length antibody (reconstituted into a human IgG1 format) to detect the binding ability of the optimized antibody to the pre-S1 antigen.
  • the ADCC activity of the optimized antibody (reconstituted into human IgG1 format) was detected by ELISA assay.
  • the ADCC activity of each antibody was determined by displaying the cell killing rate (cytotoxicity rate) of the optimized antibody (reconstituted into a human IgG1 format) using a reporter gene system.
  • THP-1 cells human acute monocytic leukemia cells, derived from the National Laboratory Cell Resource Center
  • 293T stably expressing HBV B genotype pre-S1 antigen (1-59 amino acids) as target cells
  • anti-HBV pre-S1 antibody mediated ADCP effect Effector cells were labeled with CFSE
  • target cells were labeled with pHrodo Red AM
  • target cells, effector cells, and anti-HBV pre-S1 antibody were mixed and incubated
  • double-positive THP-1 cells were detected by flow cytometry (i.e. THP-1 cells after phagocytosis of target cells) and the number of total THP-1 cells, wherein the ratio of the number of double-positive THP-1 cells to the total number of THP-1 cells is the phagocytosis rate.
  • CFSE Invitrogen C34554
  • pHrodo Red AM Invitrogen P35372
  • Anti-HBV pre-S1 antibodies reconstituted into human IgG1 form
  • K127, K127-24, K127-42 or negative control antibody 6G4103DT with an initial concentration of 100ng/mL were serially diluted at a ratio of 1:5, and added to 96 Well culture plate, 100 ⁇ L per well.
  • target cells and effector cells After fully mixing the antibody, target cells and effector cells, incubate at 37°C, 5% CO 2 for 4.5h. At the same time, a blank control group containing only target cells and effector cells without adding antibodies was set. After washing with PBS, the cells were resuspended, and fluorescence detection was performed by flow cytometry. The number of double-positive THP-1 cells and total THP-1 cells was detected, and the phagocytosis rate was calculated. Graphpad Prism software was used to draw graphs to determine the ADCP activity of each antibody.
  • Embodiment 8 the effect of anti-HBV pre-S1 antibody in C57BL/6 mouse rAAV-HBV transfection model
  • C57BL/6 mice were infected with recombinant adeno-associated virus (rAAV) vector carrying HBV whole genome DNA, and the HBV infection model of C57BL/6 mice was established (Vitonda Company).
  • rAAV adeno-associated virus
  • rAAV-HBV hepatotropic rAAV type 8 as a vector
  • mice serum HBsAg, HBeAg and HBV DNA and liver tissue HBcAg expressed stably for more than 8 months, and the expression level increased with the injection dose of recombinant virus.
  • the anti-HBV pre-S1 antibodies K55, K80, K127, K127-10, K127-23, K127-24, and K127-42, which were modified by murineization of the Fc segment were taken as examples.
  • the above-mentioned antibodies were administered to the above-mentioned model mice by intraperitoneal injection, and a control group was set at the same time, wherein the mice in the positive control group were injected with A14-20m1 or VIR3434 (Vir Biotechnology, an antibody against the surface S antigen of HBV) murineized in the Fc segment, Mice in the negative control group were injected with PBS.
  • Embodiment 9 the effect of anti-HBV pre-S1 antibody in rAAV-HBV transfection model of Fc ⁇ RIIIa humanized mouse
  • Humanized Fc ⁇ RIIIa mice (Biocytogen, 111173) were infected with a recombinant adeno-associated virus (rAAV) vector carrying HBV whole genome DNA, and an HBV infection model of humanized Fc ⁇ RIIIa mice was established (Vitonda). Briefly, a DNA fragment approximately 1.3 times the length of the HBV genome was introduced into Fc ⁇ RIIIa humanized mice by infection (rAAV-HBV) using hepatotropic rAAV type 8 to replicate in the mouse liver to produce HBV virus particles. After injection of rAAV-HBV, mice serum HBsAg, HBeAg and HBV DNA and liver tissue HBcAg expressed stably for more than 8 months, and the expression level increased with the injection dose of recombinant virus.
  • rAAV adeno-associated virus
  • anti-HBV pre-S1 antibodies K127-9, K127-24, and K127-42 were administered to the above-mentioned model mice by intraperitoneal injection, and a control group was set at the same time , where the mice in the positive control group were injected with A14-20m1, and the mice in the negative control group were injected with antibody 6G4103DT (irrelevant antibody), administered twice a week, 20 mg/kg each time, for a total of 6 weeks.
  • the mouse blood samples were collected, and then the first administration was performed, and then the mouse blood samples were collected regularly, and the HBsAg content in the supernatant was detected using the HBsAg Elisa kit (Mike Bio).

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Abstract

提供一种特异性识别HBV表面抗原pre-S1的抗体，及其制备方法和用途。

Description

特异性结合乙型肝炎病毒表面抗原pre-S1的抗体及其应用
相关申请的交叉引用
本申请要求申请号为202111216677.5，申请日为2021.10.19，发明名称为“特异性结合乙型肝炎病毒表面抗原pre-S1的抗体及其应用”的中国专利申请的优先权，且该申请的全部内容以引用方式并入本文中。
对电子序列表的引用
电子序列表(文本名称：CN_202109093529_SEQLIST.xml，记录日期：2022.07.27，大小：171KB)的内容通过整体引用并入本文中。
技术领域
本申请涉及特异性结合乙型肝炎病毒表面抗原pre-S1的抗体或抗原结合片段，及其制备方法和用途。
背景技术
全世界约有20亿人感染乙型肝炎病毒(HBV)。目前有超过3.5亿人为慢性乙肝感染患者，并且有高风险发展为肝硬化、肝衰竭或肝癌。全世界50％以上的肝癌是由HBV感染引起的。HBV相关肝病仍然是一个主要的公共卫生问题，每年造成约100万人死亡(Lavanchy,D.Journal of viral hepatitis vol.11,2(2004):97-107.)。
HBV的基因组是长度约为3.2kb，部分双链、松弛型环状DNA(rcDNA)，其由一个完整的编码负链组成(-)和一个不完整的非编码正链(+)组成(Lamontagne,R Jason et al.Hepatoma research vol.2(2016):163-186.；Glebe,Dieter,and Corinna M Bremer.Seminars in liver disease vol.33,2(2013):103-12.)。编码负链包含四个重叠的开放阅读框(ORFs)(preC/C、P、preS/S和X)，其中preS/S开放阅读框编码大(L)、中(M)和小(S)包膜蛋白。L蛋白包含pre-S1、pre-S2和S结构域，M蛋白包含pre-S2和S结构域，S蛋白仅包含S结构域(Sheu,S Y,and S J Lo.Virology vol.188,1(1992):353-7.)。已知这3种表面抗原均可以刺激HBV病毒中和抗体的产生。L蛋白的pre-S1结构域被认为是HBV入侵的关键决定因素，并且介导病毒与肝细胞上的受体之间的相互作用(Gripon,P et al.Virology vol.213,2(1995):292-9.；Le Seyec,J et al.Journal of virology vol.73,3(1999):2052-7.；Chouteau,P et al.Journal of virology vol.75,23(2001):11565-72.；Le Duff,Yann et al.Journal of virology vol.83,23(2009):12443-51.)。现有研究表明，主要在肝脏中表达的牛磺胆酸钠共转运多肽(NTCP)是与HBV pre-S1结合的高亲和力功能受体(Yan,Huan et al.eLife vol.3 10.7554/eLife.00049.13Nov.2012)。因此，抑制pre-S1与其受体结合的抗体可以有效地抑制HBV的感染。
目前，已有针对HBV pre-S1的抗体，例如专利CN107614525B中披露了抗HBV pre-S1抗体2H5-A14及其改造后的变体A14-20m1、A14-8(在本申请实施例部分作为对照抗体)；专利申请 CN108064238A中披露了特异性结合HBV pre-S1的KR127的人源化抗体及其用途。现有治疗领域中仍需要高亲和力，高中和活性、和/或高ADCC活性的抗HBV pre-S1抗体。
本文提及的所有出版物、专利、专利申请和已公开的专利申请中披露的内容，以引用方式全部并入本文中。
申请概述
在一些实施例中，提供一种分离的特异性结合HBV表面抗原pre-S1结构域的抗体，包含：重链可变结构域(V H)，所述V H包含：重链互补决定区(HC-CDR)1，其包含TYGIT(SEQ ID NO:18)；HC-CDR2，其包含SRIPIX 1GAALYAQKFQG(SEQ ID NO:115)，其中X 1为F或L；和HC-CDR3，其包含NX 1RGGFAAY(SEQ ID NO:116)，其中X 1为D或T；以及轻链可变结构域(V L)，所述V L包含：LC-CDR1，其包含RSSQSLX 1HSNX 2YNYLD(SEQ ID NO:117)，其中X 1为L或T，X 2为A或G；LC-CDR2，其包含LGX 1X 2RAS(SEQ ID NO:118)，其中X 1为H或S，X 2为K、N或R；和LC-CDR3，其包含MQALX 1X 2PX 3T(SEQ ID NO:119)，其中X 1为Q或V，X 2为I或T，X 3为A或P。
在一些实施例中，提供一种分离的特异性结合HBV表面抗原pre-S1结构域的抗体，其包含：V H，所述V H包含：HC-CDR1，其包含SEQ ID NO:18所示的氨基酸序列或其变体，所述变体包含至多约3个氨基酸的取代；HC-CDR2，其包含SEQ ID NOs:37-38中任一所示的氨基酸序列或其变体，所述变体包含至多约3个氨基酸的取代；和HC-CDR3，其包含SEQ ID NOs:56-57中任一所示的氨基酸序列或其变体，所述变体包含至多约3个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含SEQ ID NOs:59、和76-77中任一所示的氨基酸序列或其变体，所述变体包含至多约3个氨基酸的取代；LC-CDR2，其包含SEQ ID NOs:79、和89-91中任一所示的氨基酸序列或其变体，所述变体包含至多约3个氨基酸的取代；和LC-CDR3，其包含SEQ ID NOs:111-114中任一所示的氨基酸序列或其变体，所述变体包含至多约3个氨基酸的取代。
在一些实施例中，提供一种分离的特异性结合HBV表面抗原pre-S1结构域的抗体，其包含：V H，所述V H包含如SEQ ID NOs:146-150中任一氨基酸序列所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3，以及V L，所述V L包含如SEQ ID NOs:176-183中任一氨基酸序列所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，提供一种分离的特异性结合HBV表面抗原pre-S1结构域的抗体，其包含：(i)V H，其包含如氨基酸序列SEQ ID NO:146所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:176所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3；(ii)V H，其包含如氨基酸序列SEQ ID NO:147所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:177所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3；(iii)V H，其包含如氨基酸序列SEQ ID NO:148所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:178所示的V L包含的LC- CDR1、LC-CDR2和LC-CDR3；(iv)V H，其包含如氨基酸序列SEQ ID NO:149所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:179所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3；(v)V H，其包含如氨基酸序列SEQ ID NO:147所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:180所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3；(vi)V H，其包含如氨基酸序列SEQ ID NO:147所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:181所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3；(vii)V H，其包含如氨基酸序列SEQ ID NO:148所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:182所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3；(viii)V H，其包含如氨基酸序列SEQ ID NO:150所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:183所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，提供一种分离的特异性结合HBV表面抗原pre-S1结构域的抗体，其包含：(i)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:18，HC-CDR2，其包含氨基酸序列SEQ ID NO:37，和HC-CDR3，其包含氨基酸序列SEQ ID NO:56，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:59，LC-CDR2，其包含氨基酸序列SEQ ID NO:79，和LC-CDR3，其包含氨基酸序列SEQ ID NO:111，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；(ii)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:18，HC-CDR2，其包含氨基酸序列SEQ ID NO:38，和HC-CDR3，其包含氨基酸序列SEQ ID NO:57，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:76，LC-CDR2，其包含氨基酸序列SEQ ID NO:79，和LC-CDR3，其包含氨基酸序列SEQ ID NO:112，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；(iii)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:18，HC-CDR2，其包含氨基酸序列SEQ ID NO:37，和HC-CDR3，其包含氨基酸序列SEQ ID NO:57，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:77，LC-CDR2，其包含氨基酸序列SEQ ID NO:89，和LC-CDR3，其包含氨基酸序列SEQ ID NO:111，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；(iv)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:18，HC-CDR2，其包含氨基酸序列SEQ ID NO:37，和HC-CDR3，其包含氨基酸序列SEQ ID NO:57，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:77，LC-CDR2，其包含氨基酸序列SEQ ID NO:90，和LC-CDR3，其包含氨基酸序列SEQ ID NO:111，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；(v)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:18，HC-CDR2，其包含氨基酸序列SEQ ID NO:38，和HC-CDR3，其包含氨基酸序列SEQ ID NO:57，或者所述V H的变体，其HC-CDRs中包含至多约5 个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:76，LC-CDR2，其包含氨基酸序列SEQ ID NO:79，和LC-CDR3，其包含氨基酸序列SEQ ID NO:111，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；(vi)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:18，HC-CDR2，其包含氨基酸序列SEQ ID NO:38，和HC-CDR3，其包含氨基酸序列SEQ ID NO:57，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:77，LC-CDR2，其包含氨基酸序列SEQ ID NO:79，和LC-CDR3，其包含氨基酸序列SEQ ID NO:113，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；(vii)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:18，HC-CDR2，其包含氨基酸序列SEQ ID NO:37，和HC-CDR3，其包含氨基酸序列SEQ ID NO:57，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:77，LC-CDR2，其包含氨基酸序列SEQ ID NO:89，和LC-CDR3，其包含氨基酸序列SEQ ID NO:114，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；(viii)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:18，HC-CDR2，其包含氨基酸序列SEQ ID NO:37，和HC-CDR3，其包含氨基酸序列SEQ ID NO:57，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:77，LC-CDR2，其包含氨基酸序列SEQ ID NO:91，和LC-CDR3，其包含氨基酸序列SEQ ID NO:113，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，提供一种分离的特异性结合HBV表面抗原pre-S1结构域的抗体，其包含：V H，其包含SEQ ID NOs:146-150中任一所示的氨基酸序列或其变体，所述变体与SEQ ID NOs:146-150中任一所示的氨基酸序列具有至少约80％序列同一性；以及V L，其包含SEQ ID NOs:176-183中任一所示的氨基酸序列或其变体，所述变体与SEQ ID NOs:176-183中任一所示的氨基酸序列具有至少约80％序列同一性。
在一些实施例中，提供一种分离的特异性结合HBV表面抗原pre-S1结构域的抗体，其包含：(i)V H，其包含氨基酸序列SEQ ID NO:146或其变体，所述变体与氨基酸序列SEQ ID NO:146具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:176或其变体，所述变体与氨基酸序列SEQ ID NO:176具有至少约80％序列同一性；(ii)V H，其包含氨基酸序列SEQ ID NO:147或其变体，所述变体与氨基酸序列SEQ ID NO:147具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:177或其变体，所述变体与氨基酸序列SEQ ID NO:177具有至少约80％序列同一性；(iii)V H，其包含氨基酸序列SEQ ID NO:148或其变体，所述变体与氨基酸序列SEQ ID NO:148具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:178或其变体，所述变体与氨基酸序列SEQ ID NO:178具有至少约80％序列同一性；(iv)V H，其包含氨基酸序列SEQ ID NO:149或其变体，所述变体与氨基酸序列SEQ ID NO:149具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:179或其变体，所述变体与氨基酸序列SEQ ID NO:179 具有至少约80％序列同一性；(v)V H，其包含氨基酸序列SEQ ID NO:147或其变体，所述变体与氨基酸序列SEQ ID NO:147具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:180或其变体，所述变体与氨基酸序列SEQ ID NO:180具有至少约80％序列同一性；(vi)V H，其包含氨基酸序列SEQ ID NO:147或其变体，所述变体与氨基酸序列SEQ ID NO:147具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:181或其变体，所述变体与氨基酸序列SEQ ID NO:181具有至少约80％序列同一性；(vii)V H，其包含氨基酸序列SEQ ID NO:148或其变体，所述变体与氨基酸序列SEQ ID NO:148具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:182或其变体，所述变体与氨基酸序列SEQ ID NO:182具有至少约80％序列同一性；(viii)V H，其包含氨基酸序列SEQ ID NO:150或其变体，所述变体与氨基酸序列SEQ ID NO:150具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:183或其变体，所述变体与氨基酸序列SEQ ID NO:183具有至少约80％序列同一性。
在一些实施例中，提供一种分离的特异性结合HBV表面抗原pre-S1结构域的抗体，其包含：(i)V H，其包含如氨基酸序列SEQ ID NO:120所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:151所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3；(ii)V H，其包含如氨基酸序列SEQ ID NO:121所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:152所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3；(iii)V H，其包含如氨基酸序列SEQ ID NO:122所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:153所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3；(iv)V H，其包含如氨基酸序列SEQ ID NO:123所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:154所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3；(v)V H，其包含如氨基酸序列SEQ ID NO:124所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:155所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3；(vi)V H，其包含如氨基酸序列SEQ ID NO:126所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:157所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3；(vii)V H，其包含如氨基酸序列SEQ ID NO:128所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:158所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3；(viii)V H，其包含如氨基酸序列SEQ ID NO:130所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:159所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3；(ix)V H，其包含如氨基酸序列SEQ ID NO:131所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:160所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3；(x)V H，其包含如氨基酸序列SEQ ID NO:132所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:161所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3；(xi)V H，其包含如氨基酸序列SEQ ID NO:133所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及 V L，其包含如氨基酸序列SEQ ID NO:162所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3；(xii)V H，其包含如氨基酸序列SEQ ID NO:134所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:163所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3；(xiii)V H，其包含如氨基酸序列SEQ ID NO:135所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:164所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3；(xiv)V H，其包含如氨基酸序列SEQ ID NO:136所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:165所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3；(xv)V H，其包含如氨基酸序列SEQ ID NO:137所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:167所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3；(xvi)V H，其包含如氨基酸序列SEQ ID NO:139所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:169所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3；(xvii)V H，其包含如氨基酸序列SEQ ID NO:140所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:170所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3；(xviii)V H，其包含如氨基酸序列SEQ ID NO:141所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:171所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3；(xix)V H，其包含如氨基酸序列SEQ ID NO:142所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:172所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3；(xx)V H，其包含如氨基酸序列SEQ ID NO:143所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:173所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3；(xxi)V H，其包含如氨基酸序列SEQ ID NO:144所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:174所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3；(xxii)V H，其包含如氨基酸序列SEQ ID NO:145所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:175所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3；或(xxiii)V H，其包含如氨基酸序列SEQ ID NO:146所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:184所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，提供一种分离的特异性结合HBV表面抗原pre-S1结构域的抗体，其包含：(i)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:1，HC-CDR2，其包含氨基酸序列SEQ ID NO:19，和HC-CDR3，其包含氨基酸序列SEQ ID NO:39，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:58，LC-CDR2，其包含氨基酸序列SEQ ID NO:79，和LC-CDR3，其包含氨基酸序列SEQ ID NO:93，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；(ii)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:2，HC-CDR2，其包含氨基酸序列SEQ  ID NO:20，和HC-CDR3，其包含氨基酸序列SEQ ID NO:40，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:59，LC-CDR2，其包含氨基酸序列SEQ ID NO:79，和LC-CDR3，其包含氨基酸序列SEQ ID NO:94，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；(iii)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:3，HC-CDR2，其包含氨基酸序列SEQ ID NO:21，和HC-CDR3，其包含氨基酸序列SEQ ID NO:41，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:60，LC-CDR2，其包含氨基酸序列SEQ ID NO:80，和LC-CDR3，其包含氨基酸序列SEQ ID NO:95，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；(iv)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:4，HC-CDR2，其包含氨基酸序列SEQ ID NO:22，和HC-CDR3，其包含氨基酸序列SEQ ID NO:42，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:61，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，和LC-CDR3，其包含氨基酸序列SEQ ID NO:96，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；(v)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:5，HC-CDR2，其包含氨基酸序列SEQ ID NO:23，和HC-CDR3，其包含氨基酸序列SEQ ID NO:43，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:61，LC-CDR2，其包含氨基酸序列SEQ ID NO:82，和LC-CDR3，其包含氨基酸序列SEQ ID NO:97，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；(vi)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:7，HC-CDR2，其包含氨基酸序列SEQ ID NO:25，和HC-CDR3，其包含氨基酸序列SEQ ID NO:45，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:63，LC-CDR2，其包含氨基酸序列SEQ ID NO:84，和LC-CDR3，其包含氨基酸序列SEQ ID NO:99，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；(vii)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:7，HC-CDR2，其包含氨基酸序列SEQ ID NO:26，和HC-CDR3，其包含氨基酸序列SEQ ID NO:46，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:64，LC-CDR2，其包含氨基酸序列SEQ ID NO:79，和LC-CDR3，其包含氨基酸序列SEQ ID NO:100，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；(viii)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:8，HC-CDR2，其包含氨基酸序列SEQ ID NO:27，和HC-CDR3，其包含氨基酸序列SEQ ID NO:47，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:65，LC-CDR2，其包含氨基酸序列SEQ ID NO:85，和LC-CDR3，其包含氨基酸序列SEQ ID NO:101，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；(ix)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:9， HC-CDR2，其包含氨基酸序列SEQ ID NO:28，和HC-CDR3，其包含氨基酸序列SEQ ID NO:48，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:66，LC-CDR2，其包含氨基酸序列SEQ ID NO:86，和LC-CDR3，其包含氨基酸序列SEQ ID NO:102，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；(x)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:6，HC-CDR2，其包含氨基酸序列SEQ ID NO:24，和HC-CDR3，其包含氨基酸序列SEQ ID NO:44，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:62，LC-CDR2，其包含氨基酸序列SEQ ID NO:83，和LC-CDR3，其包含氨基酸序列SEQ ID NO:98，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；(xi)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:10，HC-CDR2，其包含氨基酸序列SEQ ID NO:29，和HC-CDR3，其包含氨基酸序列SEQ ID NO:49，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:67，LC-CDR2，其包含氨基酸序列SEQ ID NO:87，和LC-CDR3，其包含氨基酸序列SEQ ID NO:103，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；(xii)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:11，HC-CDR2，其包含氨基酸序列SEQ ID NO:30，和HC-CDR3，其包含氨基酸序列SEQ ID NO:50，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:68，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，和LC-CDR3，其包含氨基酸序列SEQ ID NO:104，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；(xiii)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:12，HC-CDR2，其包含氨基酸序列SEQ ID NO:30，和HC-CDR3，其包含氨基酸序列SEQ ID NO:50，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:61，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，和LC-CDR3，其包含氨基酸序列SEQ ID NO:105，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；(xiv)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:13，HC-CDR2，其包含氨基酸序列SEQ ID NO:30，和HC-CDR3，其包含氨基酸序列SEQ ID NO:50，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:69，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，和LC-CDR3，其包含氨基酸序列SEQ ID NO:103，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；(xv)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:9，HC-CDR2，其包含氨基酸序列SEQ ID NO:31，和HC-CDR3，其包含氨基酸序列SEQ ID NO:51，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:70，LC-CDR2，其包含氨基酸序列SEQ ID NO:83，和LC-CDR3，其包含氨基酸序列SEQ ID NO:106，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；(xvi)V H，所述V H包含：HC-CDR1， 其包含氨基酸序列SEQ ID NO:14，HC-CDR2，其包含氨基酸序列SEQ ID NO:32，和HC-CDR3，其包含氨基酸序列SEQ ID NO:51，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:71，LC-CDR2，其包含氨基酸序列SEQ ID NO:86，和LC-CDR3，其包含氨基酸序列SEQ ID NO:107，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；(xvii)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:11，HC-CDR2，其包含氨基酸序列SEQ ID NO:30，和HC-CDR3，其包含氨基酸序列SEQ ID NO:50，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:72，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，和LC-CDR3，其包含氨基酸序列SEQ ID NO:108，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；(xviii)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:13，HC-CDR2，其包含氨基酸序列SEQ ID NO:33，和HC-CDR3，其包含氨基酸序列SEQ ID NO:52，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:61，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，和LC-CDR3，其包含氨基酸序列SEQ ID NO:97，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；(xix)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:10，HC-CDR2，其包含氨基酸序列SEQ ID NO:30，和HC-CDR3，其包含氨基酸序列SEQ ID NO:50，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:61，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，和LC-CDR3，其包含氨基酸序列SEQ ID NO:103，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；(xx))V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:15，HC-CDR2，其包含氨基酸序列SEQ ID NO:34，和HC-CDR3，其包含氨基酸序列SEQ ID NO:53，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:73，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，和LC-CDR3，其包含氨基酸序列SEQ ID NO:109，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；(xxi)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:16，HC-CDR2，其包含氨基酸序列SEQ ID NO:35，和HC-CDR3，其包含氨基酸序列SEQ ID NO:54，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:74，LC-CDR2，其包含氨基酸序列SEQ ID NO:88，和LC-CDR3，其包含氨基酸序列SEQ ID NO:110，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；(xxii)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:17，HC-CDR2，其包含氨基酸序列SEQ ID NO:36，和HC-CDR3，其包含氨基酸序列SEQ ID NO:55，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:75，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，和LC-CDR3，其包含氨基酸序列SEQ ID NO:97，或者所述V L的变体，其LC-CDRs中包含至多约5个 氨基酸的取代；或(xxiii)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:18，HC-CDR2，其包含氨基酸序列SEQ ID NO:37，和HC-CDR3，其包含氨基酸序列SEQ ID NO:56，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:78，LC-CDR2，其包含氨基酸序列SEQ ID NO:92，和LC-CDR3，其包含氨基酸序列SEQ ID NO:93，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，如上所述任一种分离的特异性结合HBV表面抗原pre-S1结构域的抗体，其包含：(i)V H，其包含SEQ ID NO:120所示的氨基酸序列或其变体，所述变体与SEQ ID NO:120所示的氨基酸序列具有至少约80％序列同一性；以及V L，其包含SEQ ID NO:151所示的氨基酸序列或其变体，所述变体与SEQ ID NO:151所示的氨基酸序列具有至少约80％序列同一性；(ii)V H，其包含SEQ ID NO:121所示的氨基酸序列或其变体，所述变体与SEQ ID NO:121所示的氨基酸序列具有至少约80％序列同一性；以及V L，其包含SEQ ID NO:152所示的氨基酸序列或其变体，所述变体与SEQ ID NO:152所示的氨基酸序列具有至少约80％序列同一性；(iii)V H，其包含SEQ ID NO:122所示的氨基酸序列或其变体，所述变体与SEQ ID NO:122所示的氨基酸序列具有至少约80％序列同一性；以及V L，其包含SEQ ID NO:153所示的氨基酸序列或其变体，所述变体与SEQ ID NO:153所示的氨基酸序列具有至少约80％序列同一性；(iv)V H，其包含SEQ ID NO:123所示的氨基酸序列或其变体，所述变体与SEQ ID NO:123所示的氨基酸序列具有至少约80％序列同一性；以及V L，其包含SEQ ID NO:154所示的氨基酸序列或其变体，所述变体与SEQ ID NO:154所示的氨基酸序列具有至少约80％序列同一性；(v)V H，其包含SEQ ID NO:124所示的氨基酸序列或其变体，所述变体与SEQ ID NO:124所示的氨基酸序列具有至少约80％序列同一性；以及V L，其包含SEQ ID NO:155所示的氨基酸序列或其变体，所述变体与SEQ ID NO:155所示的氨基酸序列具有至少约80％序列同一性；(vi)V H，其包含SEQ ID NO:126所示的氨基酸序列或其变体，所述变体与SEQ ID NO:126所示的氨基酸序列具有至少约80％序列同一性；以及V L，其包含SEQ ID NO:157所示的氨基酸序列或其变体，所述变体与SEQ ID NO:157所示的氨基酸序列具有至少约80％序列同一性；(vii)V H，其包含SEQ ID NO:128所示的氨基酸序列或其变体，所述变体与SEQ ID NO:128所示的氨基酸序列具有至少约80％序列同一性；以及V L，其包含SEQ ID NO:158所示的氨基酸序列或其变体，所述变体与SEQ ID NO:158所示的氨基酸序列具有至少约80％序列同一性；(viii)V H，其包含SEQ ID NO:130所示的氨基酸序列或其变体，所述变体与SEQ ID NO:130所示的氨基酸序列具有至少约80％序列同一性；以及V L，其包含SEQ ID NO:159所示的氨基酸序列或其变体，所述变体与SEQ ID NO:159所示的氨基酸序列具有至少约80％序列同一性；(ix)V H，其包含SEQ ID NO:131所示的氨基酸序列或其变体，所述变体与SEQ ID NO:131所示的氨基酸序列具有至少约80％序列同一性；以及V L，其包含SEQ ID NO:160所示的氨基酸序列或其变体，所述变体与SEQ ID NO:160所示的氨基酸序列具有至少约80％序列同一性；(x)V H，其包含SEQ ID NO:132所示的氨基酸序列或其变体，所述变体与SEQ ID NO:132所示的氨基酸序列具有至少 约80％序列同一性；以及V L，其包含SEQ ID NO:161所示的氨基酸序列或其变体，所述变体与SEQ ID NO:161所示的氨基酸序列具有至少约80％序列同一性；(xi)V H，其包含SEQ ID NO:133所示的氨基酸序列或其变体，所述变体与SEQ ID NO:133所示的氨基酸序列具有至少约80％序列同一性；以及V L，其包含SEQ ID NO:162所示的氨基酸序列或其变体，所述变体与SEQ ID NO:162所示的氨基酸序列具有至少约80％序列同一性；(xii)V H，其包含SEQ ID NO:134所示的氨基酸序列或其变体，所述变体与SEQ ID NO:134所示的氨基酸序列具有至少约80％序列同一性；以及V L，其包含SEQ ID NO:163所示的氨基酸序列或其变体，所述变体与SEQ ID NO:163所示的氨基酸序列具有至少约80％序列同一性；(xiii)V H，其包含SEQ ID NO:135所示的氨基酸序列或其变体，所述变体与SEQ ID NO:135所示的氨基酸序列具有至少约80％序列同一性；以及V L，其包含SEQ ID NO:164所示的氨基酸序列或其变体，所述变体与SEQ ID NO:164所示的氨基酸序列具有至少约80％序列同一性；(xiv)V H，其包含SEQ ID NO:136所示的氨基酸序列或其变体，所述变体与SEQ ID NO:136所示的氨基酸序列具有至少约80％序列同一性；以及V L，其包含SEQ ID NO:165所示的氨基酸序列或其变体，所述变体与SEQ ID NO:165所示的氨基酸序列具有至少约80％序列同一性；(xv)V H，其包含SEQ ID NO:137所示的氨基酸序列或其变体，所述变体与SEQ ID NO:137所示的氨基酸序列具有至少约80％序列同一性；以及V L，其包含SEQ ID NO:167所示的氨基酸序列或其变体，所述变体与SEQ ID NO:167所示的氨基酸序列具有至少约80％序列同一性；(xvi)V H，其包含SEQ ID NO:139所示的氨基酸序列或其变体，所述变体与SEQ ID NO:139所示的氨基酸序列具有至少约80％序列同一性；以及V L，其包含SEQ ID NO:169所示的氨基酸序列或其变体，所述变体与SEQ ID NO:169所示的氨基酸序列具有至少约80％序列同一性；(xvii)V H，其包含SEQ ID NO:140所示的氨基酸序列或其变体，所述变体与SEQ ID NO:140所示的氨基酸序列具有至少约80％序列同一性；以及V L，其包含SEQ ID NO:170所示的氨基酸序列或其变体，所述变体与SEQ ID NO:170所示的氨基酸序列具有至少约80％序列同一性；(xviii)V H，其包含SEQ ID NO:141所示的氨基酸序列或其变体，所述变体与SEQ ID NO:141所示的氨基酸序列具有至少约80％序列同一性；以及V L，其包含SEQ ID NO:171所示的氨基酸序列或其变体，所述变体与SEQ ID NO:171所示的氨基酸序列具有至少约80％序列同一性；(xix)V H，其包含SEQ ID NO:142所示的氨基酸序列或其变体，所述变体与SEQ ID NO:142所示的氨基酸序列具有至少约80％序列同一性；以及V L，其包含SEQ ID NO:172所示的氨基酸序列或其变体，所述变体与SEQ ID NO:172所示的氨基酸序列具有至少约80％序列同一性；(xx)V H，其包含SEQ ID NO:143所示的氨基酸序列或其变体，所述变体与SEQ ID NO:143所示的氨基酸序列具有至少约80％序列同一性；以及V L，其包含SEQ ID NO:173所示的氨基酸序列或其变体，所述变体与SEQ ID NO:173所示的氨基酸序列具有至少约80％序列同一性；(xxi)V H，其包含SEQ ID NO:144所示的氨基酸序列或其变体，所述变体与SEQ ID NO:144所示的氨基酸序列具有至少约80％序列同一性；以及V L，其包含SEQ ID NO:174所示的氨基酸序列或其变体，所述变体与SEQ ID NO:174所示的氨基酸序列具有至少约80％序列同一性；(xxii)V H，其包含SEQ ID NO:145所示的氨基酸序列或其变体，所述 变体与SEQ ID NO:145所示的氨基酸序列具有至少约80％序列同一性；以及V L，其包含SEQ ID NO:175所示的氨基酸序列或其变体，所述变体与SEQ ID NO:175所示的氨基酸序列具有至少约80％序列同一性；或(xxiii)V H，其包含SEQ ID NO:146所示的氨基酸序列或其变体，所述变体与SEQ ID NO:146所示的氨基酸序列具有至少约80％序列同一性；以及V L，其包含SEQ ID NO:184所示的氨基酸序列或其变体，所述变体与SEQ ID NO:184所示的氨基酸序列具有至少约80％序列同一性。
在一些实施例中，如上所述任一种分离的抗体与HBV pre-S1抗原结合的Kd值为约1pM至约100nM。
在一些实施例中，提供一种分离的特异性结合HBV表面抗原pre-S1结构域的抗体，其与上述任一种分离的抗HBV pre-S1抗体竞争与乙型肝炎病毒的特异性结合。在一些实施例中，提供一种分离的特异性结合HBV表面抗原pre-S1结构域的抗体，其与上述任一种分离的抗HBV pre-S1抗体特异性地结合相同的表位。
在一些实施例中，如上所述任一种分离的特异性结合HBV表面抗原pre-S1结构域的抗体，所述分离的抗体包含Fc片段。在一些实施例中，所述分离的特异性结合HBV表面抗原pre-S1结构域的抗体是全长的IgG抗体。在一些实施例中，所述分离的特异性结合HBV表面抗原pre-S1结构域的抗体是全长的IgG1、IgG2、IgG3或IgG4抗体。在一些实施例中，所述分离的特异性结合HBV表面抗原pre-S1结构域的抗体是嵌合的、全人的或人源化的。在一些实施例中，所述分离的特异性结合HBV表面抗原pre-S1结构域的抗体是抗原结合片段，所述抗原结合片段选自Fab、Fab’、F(ab)’ 2、Fab’-SH、单链Fv(scFv)、Fv片段、dAb、Fd、纳米抗体(nanobody)、双链抗体(diabody)和线性抗体。
在一些实施例中，提供一种分离的核酸分子，所述核酸分子编码如上所述任一种特异性结合HBV表面抗原pre-S1结构域的抗体。在一些实施例中，提供一种载体，所述载体包含如上所述任一种核酸分子。在一些实施例中，提供一种宿主细胞，所述宿主细胞包含如上所述任一种特异性结合HBV表面抗原pre-S1结构域的抗体、如上所述任一种核酸分子或如上所述任一种载体。在一些实施例中，提供一种制备特异性结合HBV表面抗原pre-S1结构域的抗体的方法，其包含：a)在能有效表达特异性结合HBV表面抗原pre-S1结构域的抗体的条件下培养上述任一种宿主细胞；和b)从宿主细胞中获得表达的特异性结合HBV表面抗原pre-S1结构域的抗体。
在一些实施例中，提供一种预防、改善或治疗所需个体疾病或病症的方法，包括向所述个体施用有效量的如上所述的任一种特异性结合HBV表面抗原pre-S1结构域的抗体。在一些实施例中，提供如上所述的任一种特异性结合HBV表面抗原pre-S1结构域的抗体在制备用于预防、改善或治疗所需个体疾病或病症的药物组合物中的用途。在一些实施例中，提供如上所述的任一种特异性结合HBV表面抗原pre-S1结构域的抗体或包含如上所述的任一种特异性结合HBV表面抗原pre-S1结构域的抗体的药物组合物在制备用于预防、改善或治疗疾病或病症的药物中的用途。在一些实施例中，所述所需个体包括但不限于已感染HBV、暴露于HBV、具有HBV感染风险或易感 HBV的个体。在一些实施例中，所述疾病或病症为HBV感染或与HBV感染相关。在一些实施例中，所述疾病或病症选自例如，乙型肝炎以及HBV感染相关的肝功能衰竭、肝硬化和肝癌。
在一些实施例中，提供如上所述的任一种特异性结合HBV表面抗原pre-S1结构域的抗体在制备用于预防、改善或治疗HBV感染或与HBV感染相关疾病的药物组合物中的用途。在一些实施例中，所述特异性结合HBV表面抗原pre-S1结构域的抗体(例如全长抗体)或其药物组合物与第二、第三或第四药剂(包括例如其他抗病毒剂、抗过敏剂、抗恶心剂(或抗呕剂)、镇痛药、细胞保护剂或免疫抑制剂)联合使用来预防、改善或治疗HBV感染或与HBV感染相关的疾病。在一些实施例中，所述其他抗病毒剂可包括但并不限于干扰素、核苷/核苷酸类似物、抗HBV的单克隆抗体、抗HBV的多克隆抗体、DNA聚合酶抑制剂或治疗性疫苗。所述核苷/核苷酸类似物可包括但并不限于拉米夫定、恩替卡韦、克来夫定或阿德福韦酯。
同时还提供包含如上所述的任一种特异性结合HBV表面抗原pre-S1结构域的抗体的药物组合物、试剂盒以及生产制品。
附图说明
图1A-1E所示结果为抗HBV pre-S1抗体的中和活性。图1A所示结果为抗HBV pre-S1抗体K31的中和活性。图1B所示结果为抗HBV pre-S1抗体K50的中和活性。图1C所示结果为抗HBV pre-S1抗体K55的中和活性。图1D所示结果为抗HBV pre-S1抗体K80的中和活性。图1E所示结果为抗HBV pre-S1抗体K127的中和活性。
图2所示结果为与对照抗体A14-20m1相比，优化后的抗HBV pre-S1抗体K127-9、K127-10、K127-23、K127-24、K127-29、K127-42、K127-53与HBV pre-S1抗原的结合曲线。
图3所示结果为通过ELISA方法检测的优化后的抗HBV pre-S1抗体K127-9、K127-10、K127-23、K127-24、K127-42、K127-53的ADCC活性。
图4所示结果为基于报告基因系统检测的优化后的抗HBV pre-S1抗体K127-10、K127-23、K127-24、K127-29、K127-42、K127-53的ADCC活性。
图5所示结果为抗HBV pre-S1抗体K127、K127-24和K127-42的ADCP活性。
图6所示结果为在HBV感染的C57BL/6小鼠体内，K127、K127-24、K127-42等抗pre-S1抗体能够有效抑制HBV感染。
图7所示结果为在HBV感染的FcγRIIIa人源化小鼠体内，K127-9、K127-24、K127-42等抗pre-S1抗体能够有效抑制HBV感染。
本申请的详细描述
本申请一方面提供特异性结合HBV表面抗原pre-S1结构域的抗体(既抗pre-S1抗体)。通过天然scFv酵母库筛选、亲和力成熟以及适当设计的生物化学及生物学实验的组合，已经鉴定出能够结合HBV pre-S1抗原和/或中和HBV感染的抗体分子。本文给出的结果表明，与已知的抗HBV pre-S1抗体相比，本申请中的抗体在各种生物学实验中甚至展现出更优的性能。
本申请所提供的抗HBV pre-S1抗体包括，例如，全长抗HBV pre-S1抗体、抗HBV pre-S1单链Fv(scFvs)、抗HBV pre-S1Fc融合蛋白、多特异性(如双特异性)抗HBV pre-S1抗体、抗HBV pre-S1免疫偶联物以及诸如此类的。
另一方面，本申请提供抗HBV pre-S1抗体，所述抗HBV pre-S1抗体包含：重链可变结构域(V H)，所述V H包含：重链互补决定区(HC-CDR)1，其包含TYGIT(SEQ ID NO:18)；HC-CDR2，其包含SRIPIX 1GAALYAQKFQG(SEQ ID NO:115)，其中X 1为F或L；和HC-CDR3，其包含NX 1RGGFAAY(SEQ ID NO:116)，其中X 1为D或T；以及轻链可变结构域(V L)，所述V L包含：轻链互补决定区(LC-CDR)1，其包含RSSQSLX 1HSNX 2YNYLD(SEQ ID NO:117)，其中X 1为L或T，X 2为A或G；LC-CDR2，其包含LGX 1X 2RAS(SEQ ID NO:118)，其中X 1为H或S，X 2为K、N或R；和LC-CDR3，其包含MQALX 1X 2PX 3T(SEQ ID NO:119)，其中X 1为Q或V，X 2为I或T，X 3为A或P。
另一方面，本申请提供抗HBV pre-S1抗体，所述抗HBV pre-S1抗体包含：(i)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:1，HC-CDR2，其包含氨基酸序列SEQ ID NO:19，和HC-CDR3，其包含氨基酸序列SEQ ID NO:39，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:58，LC-CDR2，其包含氨基酸序列SEQ ID NO:79，和LC-CDR3，其包含氨基酸序列SEQ ID NO:93，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；(ii)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:2，HC-CDR2，其包含氨基酸序列SEQ ID NO:20，和HC-CDR3，其包含氨基酸序列SEQ ID NO:40，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:59，LC-CDR2，其包含氨基酸序列SEQ ID NO:79，和LC-CDR3，其包含氨基酸序列SEQ ID NO:94，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；(iii)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:3，HC-CDR2，其包含氨基酸序列SEQ ID NO:21，和HC-CDR3，其包含氨基酸序列SEQ ID NO:41，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:60，LC-CDR2，其包含氨基酸序列SEQ ID NO:80，和LC-CDR3，其包含氨基酸序列SEQ ID NO:95，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；(iv)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:4，HC-CDR2，其包含氨基酸序列SEQ ID NO:22，和HC-CDR3，其包含氨基酸序列SEQ ID NO:42，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:61，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，和LC-CDR3，其包含氨基酸序列SEQ ID NO:96，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；(v)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:5，HC-CDR2，其包含氨基酸序列SEQ ID NO:23，和HC-CDR3，其包含氨基酸序列SEQ ID NO:43，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所 述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:61，LC-CDR2，其包含氨基酸序列SEQ ID NO:82，和LC-CDR3，其包含氨基酸序列SEQ ID NO:97，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；(vi)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:7，HC-CDR2，其包含氨基酸序列SEQ ID NO:25，和HC-CDR3，其包含氨基酸序列SEQ ID NO:45，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:63，LC-CDR2，其包含氨基酸序列SEQ ID NO:84，和LC-CDR3，其包含氨基酸序列SEQ ID NO:99，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；(vii)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:7，HC-CDR2，其包含氨基酸序列SEQ ID NO:26，和HC-CDR3，其包含氨基酸序列SEQ ID NO:46，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:64，LC-CDR2，其包含氨基酸序列SEQ ID NO:79，和LC-CDR3，其包含氨基酸序列SEQ ID NO:100，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；(viii)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:8，HC-CDR2，其包含氨基酸序列SEQ ID NO:27，和HC-CDR3，其包含氨基酸序列SEQ ID NO:47，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:65，LC-CDR2，其包含氨基酸序列SEQ ID NO:85，和LC-CDR3，其包含氨基酸序列SEQ ID NO:101，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；(ix)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:9，HC-CDR2，其包含氨基酸序列SEQ ID NO:28，和HC-CDR3，其包含氨基酸序列SEQ ID NO:48，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:66，LC-CDR2，其包含氨基酸序列SEQ ID NO:86，和LC-CDR3，其包含氨基酸序列SEQ ID NO:102，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；(x)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:6，HC-CDR2，其包含氨基酸序列SEQ ID NO:24，和HC-CDR3，其包含氨基酸序列SEQ ID NO:44，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:62，LC-CDR2，其包含氨基酸序列SEQ ID NO:83，和LC-CDR3，其包含氨基酸序列SEQ ID NO:98，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；(xi)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:10，HC-CDR2，其包含氨基酸序列SEQ ID NO:29，和HC-CDR3，其包含氨基酸序列SEQ ID NO:49，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:67，LC-CDR2，其包含氨基酸序列SEQ ID NO:87，和LC-CDR3，其包含氨基酸序列SEQ ID NO:103，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；(xii)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:11，HC-CDR2，其包含氨基酸序列SEQ ID NO:30，和HC-CDR3，其包含氨基酸序列SEQ ID NO:50，或者所述V H的变体，其HC-CDRs中包含 至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:68，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，和LC-CDR3，其包含氨基酸序列SEQ ID NO:104，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；(xiii)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:12，HC-CDR2，其包含氨基酸序列SEQ ID NO:30，和HC-CDR3，其包含氨基酸序列SEQ ID NO:50，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:61，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，和LC-CDR3，其包含氨基酸序列SEQ ID NO:105，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；(xiv)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:13，HC-CDR2，其包含氨基酸序列SEQ ID NO:30，和HC-CDR3，其包含氨基酸序列SEQ ID NO:50，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:69，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，和LC-CDR3，其包含氨基酸序列SEQ ID NO:103，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；(xv)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:9，HC-CDR2，其包含氨基酸序列SEQ ID NO:31，和HC-CDR3，其包含氨基酸序列SEQ ID NO:51，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:70，LC-CDR2，其包含氨基酸序列SEQ ID NO:83，和LC-CDR3，其包含氨基酸序列SEQ ID NO:106，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；(xvi)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:14，HC-CDR2，其包含氨基酸序列SEQ ID NO:32，和HC-CDR3，其包含氨基酸序列SEQ ID NO:51，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:71，LC-CDR2，其包含氨基酸序列SEQ ID NO:86，和LC-CDR3，其包含氨基酸序列SEQ ID NO:107，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；(xvii)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:11，HC-CDR2，其包含氨基酸序列SEQ ID NO:30，和HC-CDR3，其包含氨基酸序列SEQ ID NO:50，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:72，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，和LC-CDR3，其包含氨基酸序列SEQ ID NO:108，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；(xviii)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:13，HC-CDR2，其包含氨基酸序列SEQ ID NO:33，和HC-CDR3，其包含氨基酸序列SEQ ID NO:52，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:61，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，和LC-CDR3，其包含氨基酸序列SEQ ID NO:97，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；(xix)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:10，HC-CDR2，其包含氨基酸序列SEQ ID NO:30，和HC-CDR3，其包含氨基酸序列 SEQ ID NO:50，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:61，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，和LC-CDR3，其包含氨基酸序列SEQ ID NO:103，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；(xx))V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:15，HC-CDR2，其包含氨基酸序列SEQ ID NO:34，和HC-CDR3，其包含氨基酸序列SEQ ID NO:53，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:73，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，和LC-CDR3，其包含氨基酸序列SEQ ID NO:109，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；(xxi)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:16，HC-CDR2，其包含氨基酸序列SEQ ID NO:35，和HC-CDR3，其包含氨基酸序列SEQ ID NO:54，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:74，LC-CDR2，其包含氨基酸序列SEQ ID NO:88，和LC-CDR3，其包含氨基酸序列SEQ ID NO:110，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；(xxii)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:17，HC-CDR2，其包含氨基酸序列SEQ ID NO:36，和HC-CDR3，其包含氨基酸序列SEQ ID NO:55，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:75，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，和LC-CDR3，其包含氨基酸序列SEQ ID NO:97，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；或(xxiii)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:18，HC-CDR2，其包含氨基酸序列SEQ ID NO:37，和HC-CDR3，其包含氨基酸序列SEQ ID NO:56，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:78，LC-CDR2，其包含氨基酸序列SEQ ID NO:92，和LC-CDR3，其包含氨基酸序列SEQ ID NO:93，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
同时还提供编码抗HBV pre-S1抗体的核酸，包含抗HBV pre-S1抗体的组合物，以及制备和使用抗HBV pre-S1抗体的方法。
定义
如本文所述，“治疗(treatment)”或“治疗(treating)是一种获得有益的或期望的结果的方法，包括临床结果。鉴于本申请的目的，所述有益的或期望的临床结果，包括但不限于以下一种或多种：缓解由疾病引起的一种或多种症状，减轻疾病程度，稳定疾病(例如，预防或延迟疾病恶化)，预防或延迟疾病的扩散(例如，病毒的扩散)，预防或延迟疾病复发，延迟或减缓疾病进展，改善疾病状态，缓解疾病(部分或全部)，减少治疗疾病所需的一种或多种其他药物的剂量，延迟疾病进展，改善或提高生活质量，增加体重，和/或延长生存期。同时，“治疗”还包括疾病病 理结果的减少(例如，对HBV病毒感染而言，病毒载量、肝损伤程度)。本申请的方法考虑了这些治疗的任何一个或多个方面。
术语“预防”指的是包括防止发病的防止措施或降低发病风险的预防措施。
术语“抗体”包括全长抗体及其抗原结合片段。全长抗体包括两条重链和两条轻链。轻链和重链的可变区负责抗原的结合。两条链中的可变区通常包括3个高变的环，被称为互补决定区(CDRs)(轻链(LC)CDRs包括LC-CDR1、LC-CDR2和LC-CDR3，重链(HC)CDRs包括HC-CDR1、HC-CDR2和HC-CDR3)。本文所披露的抗体或抗原结合片段的CDR边界可以通过Kabat，Chothia或Al-Lazikani惯例来定义或识别(Al-Lazikani 1997；Chothia 1985；Chothia 1987；Chothia 1989；Kabat 1987；Kabat 1991)。重链或轻链的3个CDR区插入到被称为框架区(FRs)的侧翼区段之间，所述框架区比CDR区具有更高的保守性，并形成支撑高变环的支架。重链和轻链的恒定区并不参与抗原结合，但展示出多种效应功能。抗体是基于它们重链恒定区的氨基酸序列进行分类的。抗体的五种主要类别或同种型是IgA、IgD、IgE、IgG和IgM，其特征在于分别具有α、δ、ε、γ和μ型重链。几种主要的抗体类别被分为亚类，如IgG1(γ1重链)、IgG2(γ2重链)、IgG3(γ3重链)、IgG4(γ4重链)、IgA1(α1重链)或IgA2(α2重链)。
如本文所述，术语“抗原结合片段”包括抗体片段，例如，双链抗体(diabody)、Fab、Fab’、F(ab’) 2、Fv片段、二硫键稳定的Fv片段(dsFv)、(dsFv) 2、双特异性dsFv(dsFv-dsFv’)、二硫键稳定的双链抗体(ds双链抗体)、单链Fv(scFv)、scFv二聚体(二价双链抗体)，由包含一个或多个CDRs的抗体片段组成的多特异性抗体、单域抗体、纳米抗体(nanobady)、域抗体、二价域抗体或者能够与抗原结合但不包含完整抗体结构的任何其他抗体片段。抗原结合片段能够与亲本抗体或亲本抗体片段(如亲本scFv)结合相同的抗原。抗原结合片段还包括包含上述抗体片段的融合蛋白。在一些实施例中，抗原结合片段可能包括来自特定人抗体的一个或多个CDRs，该CDRs被移植到来自一个或多个不同人抗体的框架区。
如本文所述，术语“表位”是指抗体或抗体部分结合的抗原上特定的原子或氨基酸组。如果两种抗体或抗体部分表现出与某抗原竞争性结合，则它们可能结合抗原上的相同表位。
如本文所用，当第一抗体在等摩尔浓度下抑制第二抗体与HBV pre-S1靶标结合至少50％(例如至少55％、60％、65％、70％、75％、80％、85％、90％、95％、98％或99％)时，第一抗体与第二抗体“竞争”结合HBV pre-S1靶标，反之亦然。PCT出版物WO 03/48731描述了基于交叉竞争的高通量抗体“表位归类”方法。
如本文所述，术语“特异性地结合”、“特异性地识别”或“对..来说是特异性的”是指可测量的和可再现的相互作用，例如抗体与靶标的结合可以确定在异质分子群，包括生物分子中存在该靶标。例如，抗体能够特异性地识别某靶标(可以是表位)是指，与其它靶标结合相比，该抗体与该靶标的结合具有更高的亲和力，亲合力，更容易和/或更持久。在一些实施例中，特异性地识别抗原的抗体与抗原的一个或多个抗原决定簇反应，其结合亲和力是其与其它靶标结合亲和力的至少10倍。
如本文所述，一种“分离的”抗HBV pre-S1抗体是指一种抗HBV pre-S1抗体，其(1)与天然存在的蛋白无关，(2)不含相同来源的其他蛋白，(3)由不同种属的细胞所表达，或(4)自然界中不存在。
如本文所述，术语“分离的核酸”，是指基因组、cDNA或合成来源的核酸或其组合。根据其来源，所述“分离的核酸”是指(1)与自然界中发现的“分离的核酸”中的全部或部分多核苷酸无关，(2)可与自然状态下不与之相连的多核苷酸可操作性地连接，或(3)在自然界中不作为较长序列的一部分而存在。
如本文所用，术语“CDR”或“互补决定区”意指重链和轻链多肽的可变结构域内发现的非连续抗原结合位点。在文献Kabat et al.,J.Biol.Chem.252:6609-6616(1977)；Kabat et al.,U.S.Dept.of Health and Human Services,“Sequences of proteins of immunological interest”(1991)；Chothia et al.,J.Mol.Biol.196:901-917(1987)；Al-Lazikani B.et al.,J.Mol.Biol.,273:927-948(1997)；MacCallum et al.,J.Mol.Biol.262:732-745(1996)；Abhinandan and Martin,Mol.Immunol.,45:3832-3839(2008)；Lefranc M.P.et al.,Dev.Comp.Immunol.,27:55-77(2003)；和Honegger and Plückthun,J.Mol.Biol.,309:657-670(2001)中已经描述这些特殊的区域，其中当彼此之间互相比较时，这些定义包括氨基酸残基的重合或子集。然而，采用任何一种定义方式来指示抗体或移植抗体或其变体的CDR，均包括在本文所定义和使用的术语范围之内。表1中列了由上述引用的各篇参考文献所定义的CDR所包括的氨基酸残基的位置，以示比较。CDR预测的算法和结合界面在本领域是已知的，包括，例如Abhinandan and Martin,Mol.Immunol.,45:3832-3839(2008)；Ehrenmann F.et al.,Nucleic Acids Res.,38:D301-D307(2010)；和Adolf-Bryfogle J.et al.,Nucleic Acids Res.,43:D432-D438(2015)中均有描述。本段中所引用的参考文献的内容以其整体引用并入本文中，以用于本申请和可能包含在本文中的一个或多个权利要求中。
表1:CDR定义
  Kabat 1 Chothia 2 MacCallum 3 IMGT 4 AHo 5
V H CDR1 31-35 26-32 30-35 27-38 25-40
V H CDR2 50-65 53-55 47-58 56-65 58-77
V H CDR3 95-102 96-101 93-101 105-117 109-137
V L CDR1 24-34 26-32 30-36 27-38 25-40
V L CDR2 50-56 50-52 46-55 56-65 58-77
V L CDR3 89-97 91-96 89-96 105-117 109-137
1氨基酸残基编号参照上述Kabat et al.中的命名方法
2氨基酸残基编号参照上述Chothia et al.中的命名方法
3氨基酸残基编号参照上述MacCallum et al.中的命名方法
4氨基酸残基编号参照上述Lefranc et al.中的命名方法
5氨基酸残基编号参照上述Honegger and Plückthun中的命名方法
术语“嵌合抗体”是指，重链和/或轻链的一部分与来自特定种属或属于特定抗体种类或亚类的抗体中的相应序列一致或具有同源性，而这个(些)链的剩余部分与来自另一种属或属于其它抗体种类或亚类的抗体中的相应序列一致或具有同源性的抗体，以及此类抗体的片段，只要其具有本申请中的生物学活性(见U.S.Patent No.4,816,567；and Morrison et al.,Proc.Natl.Acad.Sci.USA,81:6851-6855(1984))。
“Fv”是包含完整抗原识别及结合位点的最小抗体片段。该片段是由一个重链可变结构域和一个轻链可变结构域紧密非共价连接形成的二聚体。通过这两个域的折叠衍生出6个高变环(轻链和重链中各3个环)，所述高变环为抗体提供了用于结合抗原的氨基酸残基，并且赋予抗体与抗原结合的特异性。然而，即使单个可变结构域(或Fv片段的一半，其仅包含对抗原具有特异性的3个CDRs)也具有识别和结合抗原的能力，尽管其亲和力低于完整的结合位点。
“单链Fv”，也可简写成“sFv”或“scFv”，是包含被连接成单一多肽链的V H和V L抗体域的抗体片段。在一些实施例中，scFv多肽进一步包括V H和V L域之间的连接多肽，该连接多肽使得scFv形成抗原结合的理想结构。关于scFv的概述，见Pluckthun in The Pharmacology of Monoclonal Antibodies,vol.113,Rosenburg and Moore eds.,Springer-Verlag,New York,pp.269-315(1994)。
术语“双链抗体(diabody)”是在V H和V L域之间采用短接头(例如5～10个残基)，构建scFv片段(见上段内容)制备而成的一种小抗体片段，这样就使得可变结构域在链间而不是链内进行配对，产生一个双价片段，即具有两个抗原结合位点的片段。双特异性的双链抗体是两个“交叉”scFv片段的异二聚体，其中两个抗体的V H和V L域位于不同的多肽链上。在EP 404,097；WO 93/11161；Hollinger et al.,Proc.Natl.Acad.Sci.USA,90:6444-6448(1993)中全面描述了双链抗体。
非人源(如啮齿类)抗体的“人源化”形式是嵌合抗体，其包括最少的来自非人源抗体的序列。大多数情况下，人源化抗体是人源免疫球蛋白(受体抗体)，其中受体抗体的高变区(HVR)残基被来自非人源种属例如小鼠、大鼠、兔或非人类哺乳动物的且具有理想的抗体特异性，亲和力和性能的高变区残基所取代(供体抗体)。在某些情况下，人源免疫球蛋白框架区中的残基被相应的非人源残基所取代。另外，人源化抗体可以包括在受体抗体或供体抗体中均不存在的残基。这些修饰能够进一步改善抗体的性能。通常，人源化抗体会包含基本上所有，至少一个，通常两个可变结构域，其中所有或基本上所有的高变环均与非人免疫球蛋白的高变环相对应，以及所有或基本上所有的框架区均是人免疫球蛋白序列。人源抗体任选地也还包括免疫球蛋白恒定区(Fc)的至少一部分，通常是人免疫球蛋白的恒定区。具体细节可以参考Jones et al.,Nature 321:522-525(1986)；Riechmann et al.,Nature 332:323-329(1988)；和Presta,Curr.Op.Struct.Biol.2:593-596(1992)。
本文所鉴定的多肽和抗体序列的“氨基酸序列同一性百分比(％)”或“同源性”被定义：在认为保守性取代属于序列同一性的一部分的情况下进行序列对比，候选序列与待比较多肽序列中相同氨基酸残基所占的百分比。可以通过本领域技术范围内的多种比对方式来确定氨基酸序列同一性 百分比，例如，使用如BLAST、BLAST-2、ALIGN、Megalign(DNASTAR)、或MUSCLE软件等可公开获得的计算机软件。本领域技术人员可以确定用于测量比对的合适的参数，包括在所比较序列的全长上实现最大化比对所需的任何算法。然而，为了本文的目的，氨基酸序列同一性百分比数值是使用序列比对电脑程序MUSCLE(Edgar,R.C.,Nucleic Acids Research 32(5):1792-1797,2004；Edgar,R.C.,BMC Bioinformatics 5(1):113,2004)生成的。
术语“Fc受体”或“FcR”用于描述结合抗体Fc区的受体。在一些实施例中，本申请所述的FcR是结合IgG抗体(一种γ受体)的FcR，包括FcγRI、FcγRII和FcγRIII亚类的受体，包括这些受体的等位基因变体和可变剪接形式。FcγRII受体包括FcγRIIA(“激活受体”)和FcγRIIB(“抑制受体”)，它们具有相似的氨基酸序列，主要在细胞质结构域有所不同。激活受体FcγRIIA的胞质结构域中含有免疫受体酪氨酸活化基序(ITAM)。抑制受体FcγRIIB的胞质结构域中含有免疫受体酪氨酸抑制基序(ITIM)(见M.in
Figure PCTCN2022125558-appb-000001
Annu.Rev.Immunol.15:203-234(1997))。所述术语还包括同种异型，例如FcγRIIIA同种异型：FcγRIIIA-Phe158、FcγRIIIA-Val158、FcγRIIA-R131和/或FcγRIIA-H131。在Ravetch and Kinet,Annu.Rev.Immunol 9:457-92(1991)和Capel et al.,Immunomethods 4:25-34(1994)；以及de Haas et al.,J.Lab.Clin.Med.126:330-41(1995)中对FcRs进行了描述。本申请中术语FcR涵盖其他类型的FcRs，包括将来鉴定的FcRs。术语FcR同时还包括新生儿受体FcRn，其负责向新生儿转移母体IgGs(Guyer et al.,J.Immunol.117:587(1976)以及Kim et al.,J.Immunol.24:249(1994))。
术语“FcRn”指新生儿Fc受体(FcRn)。FcRn与主要组织相容性复合体(MHC)在结构上相似，由α链非共价结合到β2微球蛋白上组成。新生儿Fc受体FcRn的多种功能在Ghetie and Ward(2000)Annu.Rev.Immunol.18,739-766.中进行了综述。FcRn在免疫球蛋白IgGs从母体向新生儿的被动转运和调控血清IgG水平中起到重要作用。FcRn作为一种救助受体，可以在细胞内和细胞间以完整的形式结合和运输胞吞化的IgG，并使它们免于经受默认的降解途径。
人IgG重链恒定区的“CH1结构域”通常从118位氨基酸延伸到215位氨基酸(EU编号系统)。
“铰链区”通常被定义为从人IgG1的216位Glu延伸到230位Pro(Burton,Molec.Immunol.22:161-206(1985))。通过将形成重链间二硫键的第一个和最后一个半胱氨酸残基置于与IgG1相同位置后，可以使得其他IgG同种型的铰链区与IgG1序列比对。
人IgG Fc区的“CH2结构域”通常从231位氨基酸延伸到340位氨基酸。CH2结构域的独特之处在于，它不会与另一个区域紧密配对，而是在完整的天然IgG分子的两个CH2结构域之间插入了两条N端连接的支链糖链。据推测，糖类可能作为域与域间配对的替代，有助于保持CH2结构域稳定。Burton,Molec.Immunol.22:161-206(1985)。
“CH3”结构域包括在Fc区内从C末端残基延伸到CH2结构域(从341位氨基酸到抗体序列的C末端，通常为IgG的第446或447位氨基酸残基)。
“功能性Fc片段”具有天然Fc区序列所具有的“效应功能”。示例性的“效应功能”包括C1q结合；补体依赖的细胞毒作用(CDC)；Fc受体结合；抗体依赖的细胞介导的细胞毒作用(ADCC)； 抗体依赖性细胞介导的吞噬作用(ADCP)；吞噬作用；细胞表面受体的下调(如B细胞受体；BCR)等。这类效应功能通常需要Fc区与结合结构域(如抗体可变区)结合，并且可以使用本领域公知的多种实验方法进行评估。
具有“改变的”FcR结合亲和力或ADCC活性的IgG Fc变体的抗体，与亲本多肽或包含天然Fc序列的多肽相比，其FcR结合活性和/或ADCC活性增强或减弱。表现出与FcR“结合增强”的Fc变体与亲本多肽或包含天然IgG Fc序列的多肽相比，其与至少一种FcR具有更高的结合亲和力(例如更低的表观Kd或IC 50值)。在一些实施例中，与亲本多肽相比，结合能力增强3倍，例如5、10、25、50、60、100、150、200，甚至高达500倍或结合力提高25％到1000％。表现出与FcR“结合降低”的Fc变体，与亲本多肽相比，其与至少一种FcR具有更低的亲和力(例如更高的表观Kd或IC 50值)。与亲本多肽相比，其结合能力下降40％或更多。
“抗体依赖的细胞介导的细胞毒作用”或“ADCC”是一种细胞毒性形式，指分泌型的Ig与存在于某些细胞毒性细胞(例如自然杀伤细胞(NK)、中性粒细胞、和巨噬细胞)上的Fc受体(FcRs)结合，使这些细胞毒性效应细胞能够特异性结合携带抗原的靶细胞，随后使用细胞毒素杀死靶细胞。抗体“武装”细胞毒性细胞并且是这种杀伤所必需的。介导ADCC的主要细胞类型中，NK细胞只表达FcγRIII，而单核细胞表达FcγRI、FcγRII和FcγRIII。在Ravetch and Kinet,Annu.Rev.Immunol 9:457-92(1991)第464页的Table 3中总结了在造血细胞上FcR的表达。评估目标分子的ADCC活性，可以进行体外ADCC实验，在美国专利No.5,500,362或5,821,337中进行了描述。适用于此类实验的效应细胞包括外周血单核细胞(PBMC)和自然杀伤性细胞(NK)。可选地，或者此外，目标分子的ADCC活性也可以在体内进行评估，例如在如Clynes et al.PNAS(USA)95:652-656(1998)中所公开的动物模型中进行了描述。
包含Fc区变体的多肽与包含野生型IgG Fc多肽或亲本多肽相比，在人体效应细胞存在下表现出“增强的ADCC活性”或能够更有效的介导ADCC效应，所述包含Fc区变体的多肽在实验时与包含野生型IgG Fc多肽(或亲本多肽)数量上基本相同时，无论在体外或体内均能更有效的介导ADCC。通常采用本领域已知的任何体外ADCC实验方法来鉴定此类变体，例如用于鉴定ADCC活性的实验或方法，例如在动物模型中等。在一些实施例中，此类变体与野生型Fc(或亲代多肽)相比，介导ADCC的效率提高5到100倍，例如25到50倍。
“抗体依赖性细胞介导的吞噬作用”或“ADCP”是指细胞介导的反应，其中表达FcγRs的非特异性细胞毒性细胞识别结合在靶细胞上的抗体，并随后引起对靶细胞的吞噬作用。
“补体依赖的细胞毒作用”或“CDC”是指在补体存在的情况下裂解靶细胞。经典的补体途径的激活是由补体系统第一组分(C1q)与结合同源抗原的抗体(具有适宜结构的亚类)相结合而启动的。为了评估补体激活，可以进行CDC实验，如Gazzano-Santoro et al.,J.Immunol.Methods 202:163(1996)中所描述的。在美国专利No.6,194,551B1和WO99/51642中描述了具有改变的Fc区氨基酸序列并增加或降低的C1q结合能力的多肽变体。这些专利出版物的内容通过引用明确地并入本文中。另见Idusogie et al.J.Immunol.164:4178-4184(2000)。
“中和”是指抑制病毒感染宿主细胞。在不依赖任何一种理论的情况下，特定抗体的中和机制可以包括阻断病毒衣壳蛋白与细胞表面受体的相互作用，或在将病毒基因组递送到宿主细胞的细胞核之前破坏进入和运输过程中的任何阶段。
除非另有说明，一种“编码氨基酸序列的核苷酸序列”包括相互之间互为简并形式且编码相同氨基酸序列的所有核苷酸序列。编码蛋白质或RNA的核苷酸序列也可包括内含子，例如编码蛋白质的核苷酸序列在某些形式中包含内含子。
术语“可操作性地连接”是指调控序列与异源核苷酸序列之间的功能性连接，从而使后者表达。例如，当第一个核苷酸序列与第二个核苷酸序列处于功能性关系时，第一个核苷酸序列与第二个核苷酸序列为可操作性地连接。例如，如果启动子影响编码序列的转录或表达，该启动子与编码序列为可操作性地连接。通常，可操作性连接的DNA序列是连续的，并且在必要时，可以在同一个阅读框中连接两个蛋白质编码区。
“同源”是指两个多肽之间或两个核酸分子之间的序列相似性或序列同一性。如果两个比较序列的同一位置为相同的碱基或氨基酸单体亚基时，例如两个DNA分子的同一位置均为腺嘌呤，则这两个DNA分子在该位置是同源的。两个序列间的同源百分比是指两个序列中共有的匹配或同源位置的数量与位置总数之比再乘以100所得函数。例如，两个序列中如果10个位置中有6个位置是相匹配或同源的，则这两个序列的同源性为60％。举例来说，DNA序列ATTGCC和TATGGC具有50％的同源性。通常来说，在比对两个序列时，以得到最大同源性为目的来进行对比。
本文所公开的抗HBV pre-S1抗体或组合物的“有效量”是指足以实现特定目的的量。“有效量”可以凭经验和通过已知的与所述目的相关的方法确定。
术语“治疗有效量”是指本文所公开的抗HBV pre-S1抗体或其组合物能够有效治疗个体的疾病或者症状的用量。例如在HBV感染的情况中，抗HBV pre-S1抗体或其组合物的治疗有效量是指能够有效预防或治疗由于HBV感染造成的病情的结合分子的用量。本文所公开的抗HBV pre-S1抗体或其组合物在某种程度上能够阻止和/或杀死现有的感染HBV的细胞，它可以是细胞抑制性的或细胞毒性的。在一些实施例中，治疗有效量是指能够延长患者生存期的用量。在一些实施例中，治疗有效量是指能够改善患者无进展生存期的用量。
如本文所用的，“药学上可接受的”或“药理学上相容的”是指无生物学活性或者其它不期望性质的材料，例如该材料能够加入到给予患者的药物组合物中，而不会引起显著的不良生物反应，或者，不与组合物中包含的任何其它组分以有害的方式相互作用。药学上可接受的载体或赋形剂优选满足毒理学或制造检测的所需标准和/或包含在美国食品和药品管理局编制的非活性成分指南中。
本文中描述的本申请的实施例应理解为包含“由……组成”和/或“基本上由……组成”的实施例。
本文中提及“约”为一个数值或参数，包含(和描述)针对该值或参数本身的变体。例如，涉及“约X”的描述，包括“X”的描述。
如本文所用的，提及“不是(not)”一个数值或参数，通常表示并描述“除了(other than)”某一数值或参数之外。例如，该方法不能用于治疗X型癌症，意味着该方法通常用于治疗除X型癌症之外的其他类型的癌症。
除非上下文另有明确说明，本文和所述权利要求中所采用的单数形式“一”，“一个”和“该”包括复数对象。
抗HBV pre-S1抗体
一方面，本申请提供特异性结合HBV表面抗原pre-S1结构域的抗HBV pre-S1抗体。所述抗HBV pre-S1抗体包括，但不限于，人源化抗体，嵌合抗体，小鼠抗体，人抗体，以及本文所述的包含重链和/或轻链CDRs的抗体分子。一方面，本申请提供与HBV pre-S1抗原结合的分离的抗体。预期的抗HBV pre-S1抗体包括，例如，全长抗HBV pre-S1抗体(如全长IgG1或IgG4)，抗HBV pre-S1单链Fv，抗HBV pre-S1Fc融合蛋白，多特异性(如双特异性)抗HBV pre-S1抗体，抗HBV pre-S1免疫偶联物，以及诸如此类的。在一些实施例中，抗HBV pre-S1抗体是全长抗体(如全长IgG1或IgG4)或其抗原结合片段，其特异性结合HBV pre-S1结构域。在一些实施例中，抗HBV pre-S1抗体是Fab、Fab’、F(ab)’ 2、Fab’-SH、单链Fv(scFv)、Fv片段、dAb、Fd、纳米抗体(nanobody)、双链抗体(diabody)或线性抗体。在一些实施例中，特异性结合HBV pre-S1结构域的抗体是指抗体与HBV pre-S1抗原结合的亲和力至少是与非靶标结合亲和力的10倍以上(包括例如10、10 2、10 3、10 4、10 5、10 6、或10 7倍)。在一些实施例中，非靶标是指不是HBV pre-S1的抗原。结合亲和力可通过本领域已知的方法来测定，如ELISA，荧光激活细胞分选(FACS)分析或放射免疫沉淀分析(RIA)。Kd值可以通过本领域已知的方法来测定，如表面等离子共振(SPR)技术或生物层干涉技术(BLI)。
尽管本文广泛地讨论了包含人序列的抗HBV pre-S1抗体(例如，包含人CDR序列的人重链和轻链可变结构域)，但同时也考虑了非人抗HBV pre-S1抗体。在一些实施例中，非人抗HBV pre-S1抗体包括本文所述的抗HBV pre-S1抗体的人CDR序列和非人框架区序列，在一些实施例中，非人框架区序列包括任何的用于使用如本文所述的一种或多种人CDR序列产生重链和/或轻链可变结构域的序列，包括例如哺乳动物，例如小鼠、大鼠、兔子、猪、牛(例如，牛、公牛、水牛)、鹿、绵羊、山羊、鸡、猫、狗、雪貂、灵长类(例如，小猿，猕猴)等。在一些实施例中，非人抗HBV pre-S1抗体包括将一种或多种本文所述的人CDR序列移植到非人框架区中(例如，鼠或鸡的框架区序列)所产生的抗HBV pre-S1抗体。
示例性HBV B基因型pre-S1抗原的完整氨基酸序列包含SEQ ID NO：190所示的氨基酸序列或由SEQ ID NO：190所示的氨基酸序列组成。示例性HBV C基因型pre-S1抗原的完整氨基酸序列包含SEQ ID NO：191所示的氨基酸序列或由SEQ ID NO：191所示的氨基酸序列组成。
在一些实施例中，本文所述抗HBV pre-S1抗体特异性识别HBV pre-S1结构域中的表位。在一些实施例中，所述抗HBV pre-S1抗体可与多种HBV基因型的pre-S1抗原的结合，其与HBV的结合具有广谱型。
在一些实施例中，如本文所述的任一抗HBV pre-S1抗体，所述抗HBV pre-S1抗体包括抗体重链恒定区和抗体轻链恒定区。在一些实施例中，所述抗HBV pre-S1抗体包括IgG1型重链恒定区。在一些实施例中，所述抗HBV pre-S1抗体包括IgG2型重链恒定区。在一些实施例中，所述抗HBV pre-S1抗体包括IgG3型重链恒定区。在一些实施例中，所述抗HBV pre-S1抗体包括IgG4型重链恒定区。在一些实施例中，所述重链恒定区包含(包括由…组成或基本上由…组成)氨基酸序列SEQ ID NO:186。在一些实施例中，所述重链恒定区包含(包括由…组成或基本上由…组成)氨基酸序列SEQ ID NO:187。在一些实施例中，所述抗HBV pre-S1抗体包含κ轻链恒定区。在一些实施例中，所述轻链恒定区包含(包括由…组成或基本上由…组成)氨基酸序列SEQ ID NO:188。在一些实施例中，所述抗HBV pre-S1抗体包含λ轻链恒定区。在一些实施例中，所述轻链恒定区包含(包括由…组成或基本上由…组成)氨基酸序列SEQ ID NO:189。在一些实施例中，所述抗HBV pre-S1抗体包括抗体重链可变结构域和抗体轻链可变结构域。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:1，HC-CDR2，其包含氨基酸序列SEQ ID NO:19，HC-CDR3，其包含氨基酸序列SEQ ID NO:39，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:58，LC-CDR2，其包含氨基酸序列SEQ ID NO:79，LC-CDR3，其包含氨基酸序列SEQ ID NO:93，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:1，HC-CDR2，其包含氨基酸序列SEQ ID NO:19，和HC-CDR3，其包含氨基酸序列SEQ ID NO:39；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:58，LC-CDR2，其包含氨基酸序列SEQ ID NO:79，和LC-CDR3，其包含氨基酸序列SEQ ID NO:93。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，其包含如氨基酸序列SEQ ID NO:120所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:151所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗HBV pre-S1抗体包含：V H，所述V H包含氨基酸序列SEQ ID NO:120或其变体，所述变体与氨基酸序列SEQ ID NO:120具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:151或其变体，所述变体与氨基酸序列SEQ ID NO:151具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含氨基酸序列SEQ ID NO:120，以及V L，所述V L包含氨基酸序列SEQ ID NO:151。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:2，HC-CDR2，其包含氨基酸序列SEQ ID NO:20，HC-CDR3，其包含氨基酸序列SEQ ID NO:40，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:59，LC-CDR2，其包含氨基酸序列SEQ ID NO:79，LC-CDR3，其包含氨基酸序列SEQ ID NO:94，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:2，HC-CDR2，其包含氨基酸序列SEQ ID NO:20，和HC-CDR3，其包含氨基酸序列SEQ ID NO:40；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:59，LC-CDR2，其包含氨基酸序列SEQ ID NO:79，和LC-CDR3，其包含氨基酸序列SEQ ID NO:94。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，其包含如氨基酸序列SEQ ID NO:121所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:152所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗HBV pre-S1抗体包含：V H，所述V H包含氨基酸序列SEQ ID NO:121或其变体，所述变体与氨基酸序列SEQ ID NO:121具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:152或其变体，所述变体与氨基酸序列SEQ ID NO:152具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含氨基酸序列SEQ ID NO:121，以及V L，所述V L包含氨基酸序列SEQ ID NO:152。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:3，HC-CDR2，其包含氨基酸序列SEQ ID NO:21，HC-CDR3，其包含氨基酸序列SEQ ID NO:41，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:60，LC-CDR2，其包含氨基酸序列SEQ ID NO:80，LC-CDR3，其包含氨基酸序列SEQ ID NO:95，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:3，HC-CDR2，其包含氨基酸序列SEQ ID NO:21，和HC-CDR3，其包含氨基酸序列SEQ ID NO:41；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:60，LC-CDR2，其包含氨基酸序列SEQ ID NO:80，和LC-CDR3，其包含氨基酸序列SEQ ID NO:95。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，其包含如氨基酸序列SEQ ID NO:122所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:153所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗HBV pre-S1抗体包含：V H，所述V H包含氨基酸序列SEQ ID NO:122或其变体，所述变体与氨基酸序列SEQ ID NO:122具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:153或其变体，所述变体与氨基酸序列SEQ ID NO:153具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含氨基酸序列SEQ ID NO:122，以及V L，所述V L包含氨基酸序列SEQ ID NO:153。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:4，HC-CDR2，其包含氨基酸序列SEQ ID NO:22，HC-CDR3，其包含氨基酸序列SEQ ID NO:42，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:61，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，LC-CDR3，其包含氨基酸序列SEQ ID NO:96，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:4，HC-CDR2，其包含氨基酸序列SEQ ID NO:22，和HC-CDR3，其包含氨基酸序列SEQ ID NO:42；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:61，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，和LC-CDR3，其包含氨基酸序列SEQ ID NO:96。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，其包含如氨基酸序列SEQ ID NO:123所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:154所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗HBV pre-S1抗体包含：V H，所述V H包含氨基酸序列SEQ ID NO:123或其变体，所述变体与氨基酸序列SEQ ID NO:123具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:154或其变体，所述变体与氨基酸序列SEQ ID NO:154具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含氨基酸序列SEQ ID NO:123，以及V L，所述V L包含氨基酸序列SEQ ID NO:154。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:5，HC-CDR2，其包含氨基酸序列SEQ ID NO:23，HC-CDR3，其包含氨基酸序列SEQ ID NO:43，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:61，LC-CDR2，其包含氨基酸序列SEQ ID NO:82，LC-CDR3，其包含氨基酸序列SEQ ID NO:97，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:5，HC-CDR2，其包含氨基酸序列SEQ ID NO:23，和HC-CDR3，其包含氨基酸序列SEQ ID NO:43；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:61，LC-CDR2，其包含氨基酸序列SEQ ID NO:82，和LC-CDR3，其包含氨基酸序列SEQ ID NO:97。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，其包含如氨基酸序列SEQ ID NO:124所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:155所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗HBV pre-S1抗体包含：V H，所述V H包含氨基酸序列SEQ ID NO:124或其变体，所述变体与氨基酸序列SEQ ID NO:124具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:155或其变体，所述变体与氨基酸序列SEQ ID NO:155具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含氨基酸序列SEQ ID NO:124，以及V L，所述V L包含氨基酸序列SEQ ID NO:155。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:7，HC-CDR2，其包含氨基酸序列SEQ ID NO:25，HC-CDR3，其包含氨基酸序列SEQ ID NO:45，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:63，LC-CDR2，其包含氨基酸序列SEQ ID NO:84，LC-CDR3，其包含氨基酸序列SEQ ID NO:99，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:7，HC-CDR2，其包含氨基酸序列SEQ ID NO:25，和HC-CDR3，其包含氨基酸序列SEQ ID NO:45；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:63，LC-CDR2，其包含氨基酸序列SEQ ID NO:84，和LC-CDR3，其包含氨基酸序列SEQ ID NO:99。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，其包含如氨基酸序列SEQ ID NO:126所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:157所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗HBV pre-S1抗体包含：V H，所述V H包含氨基酸序列SEQ ID NO:126或其变体，所述变体与氨基酸序列SEQ ID NO:126具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:157或其变体，所述变体与氨基酸序列SEQ ID NO:157具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含氨基酸序列SEQ ID NO:126，以及V L，所述V L包含氨基酸序列SEQ ID NO:157。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:7，HC-CDR2，其包含氨基酸序列SEQ ID NO:26，HC-CDR3，其包含氨基酸序列SEQ ID NO:46，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:64，LC-CDR2，其包含氨基酸序列SEQ ID NO:79，LC-CDR3，其包含氨基酸序列SEQ ID NO:100，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:7，HC-CDR2，其包含氨基酸序列SEQ ID NO:26，和HC-CDR3，其包含氨基酸序列SEQ ID NO:46；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:64，LC-CDR2，其包含氨基酸序列SEQ ID NO:79，和LC-CDR3，其包含氨基酸序列SEQ ID NO:100。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，其包含如氨基酸序列SEQ ID NO:128所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:158所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗HBV pre-S1抗体包含：V H，所述V H包含氨基酸序列SEQ ID NO:128或其变体，所述变体与氨基酸序列SEQ ID NO:128具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:158或其变体，所述变体与氨基酸序列SEQ ID NO:158具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含氨基酸序列SEQ ID NO:128，以及V L，所述V L包含氨基酸序列SEQ ID NO:158。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:8，HC-CDR2，其包含氨基酸序列SEQ ID NO:27，HC-CDR3，其包含氨基酸序列SEQ ID NO:47，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:65，LC-CDR2，其包含氨基酸序列SEQ ID NO:85，LC-CDR3，其包含氨基酸序列SEQ ID NO:101，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:8，HC-CDR2，其包含氨基酸序列SEQ ID NO:27，和HC-CDR3，其包含氨基酸序列SEQ ID NO:47；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:65，LC-CDR2，其包含氨基酸序列SEQ ID NO:85，和LC-CDR3，其包含氨基酸序列SEQ ID NO:101。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，其包含如氨基酸序列SEQ ID NO:130所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:159所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗HBV pre-S1抗体包含：V H，所述V H包含氨基酸序列SEQ ID NO:130或其变体，所述变体与氨基酸序列SEQ ID NO:130具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:159或其变体，所述变体与氨基酸序列SEQ ID NO:159具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含氨基酸序列SEQ ID NO:130，以及V L，所述V L包含氨基酸序列SEQ ID NO:159。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:9，HC-CDR2，其包含氨基酸序列SEQ ID NO:28，HC-CDR3，其包含氨基酸序列SEQ ID NO:48，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:66，LC-CDR2，其包含氨基酸序列SEQ ID NO:86，LC-CDR3，其包含氨基酸序列SEQ ID NO:102，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:9，HC-CDR2，其包含氨基酸序列SEQ ID NO:28，和HC-CDR3，其包含氨基酸序列SEQ ID NO:48；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:66，LC-CDR2，其包含氨基酸序列SEQ ID NO:86，和LC-CDR3，其包含氨基酸序列SEQ ID NO:102。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，其包含如氨基酸序列SEQ ID NO:131所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:160所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗HBV pre-S1抗体包含：V H，所述V H包含氨基酸序列SEQ ID NO:131或其变体，所述变体与氨基酸序列SEQ ID NO:131具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:160或其变体，所述变体与氨基酸序列SEQ ID NO:160具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含氨基酸序列SEQ ID NO:131，以及V L，所述V L包含氨基酸序列SEQ ID NO:160。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:6，HC-CDR2，其包含氨基酸序列SEQ ID NO:24，HC-CDR3，其包含氨基酸序列SEQ ID NO:44，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:62，LC-CDR2，其包含氨基酸序列SEQ ID NO:83，LC-CDR3，其包含氨基酸序列SEQ ID NO:98，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:6，HC-CDR2，其包含氨基酸序列SEQ ID NO:24，和HC-CDR3，其包含氨基酸序列SEQ ID NO:44；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:62，LC-CDR2，其包含氨基酸序列SEQ ID NO:83，和LC-CDR3，其包含氨基酸序列SEQ ID NO:98。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，其包含如氨基酸序列SEQ ID NO:132所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:161所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗HBV pre-S1抗体包含：V H，所述V H包含氨基酸序列SEQ ID NO:132或其变体，所述变体与氨基酸序列SEQ ID NO:132具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:161或其变体，所述变体与氨基酸序列SEQ ID NO:161具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含氨基酸序列SEQ ID NO:132，以及V L，所述V L包含氨基酸序列SEQ ID NO:161。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:10，HC-CDR2，其包含氨基酸序列SEQ ID NO:29，HC-CDR3，其包含氨基酸序列SEQ ID NO:49，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:67，LC-CDR2，其包含氨基酸序列SEQ ID NO:87，LC-CDR3，其包含氨基酸序列SEQ ID NO:103，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:10，HC-CDR2，其包含氨基酸序列SEQ ID NO:29，和HC-CDR3，其包含氨基酸序列SEQ ID NO:49；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:67，LC-CDR2，其包含氨基酸序列SEQ ID NO:87，和LC-CDR3，其包含氨基酸序列SEQ ID NO:103。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，其包含如氨基酸序列SEQ ID NO:133所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:162所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗HBV pre-S1抗体包含：V H，所述V H包含氨基酸序列SEQ ID NO:133或其变体，所述变体与氨基酸序列SEQ ID NO:133具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:162或其变体，所述变体与氨基酸序列SEQ ID NO:162具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含氨基酸序列SEQ ID NO:133，以及V L，所述V L包含氨基酸序列SEQ ID NO:162。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:11，HC-CDR2，其包含氨基酸序列SEQ ID NO:30，HC-CDR3，其包含氨基酸序列SEQ ID NO:50，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:68，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，LC-CDR3，其包含氨基酸序列SEQ ID NO:104，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:11，HC-CDR2，其包含氨基酸序列SEQ ID NO:30，和HC-CDR3，其包含氨基酸序列SEQ ID NO:50；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:68，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，和LC-CDR3，其包含氨基酸序列SEQ ID NO:104。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，其包含如氨基酸序列SEQ ID NO:134所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:163所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗HBV pre-S1抗体包含：V H，所述V H包含氨基酸序列SEQ ID NO:134或其变体，所述变体与氨基酸序列SEQ ID NO:134具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:163或其变体，所述变体与氨基酸序列SEQ ID NO:163具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含氨基酸序列SEQ ID NO:134，以及V L，所述V L包含氨基酸序列SEQ ID NO:163。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:12，HC-CDR2，其包含氨基酸序列SEQ ID NO:30，HC-CDR3，其包含氨基酸序列SEQ ID NO:50，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:61，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，LC-CDR3，其包含氨基酸序列SEQ ID NO:105，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:12，HC-CDR2，其包含氨基酸序列SEQ ID NO:30，和HC-CDR3，其包含氨基酸序列SEQ ID NO:50；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:61，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，和LC-CDR3，其包含氨基酸序列SEQ ID NO:105。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，其包含如氨基酸序列SEQ ID NO:135所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:164所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗HBV pre-S1抗体包含：V H，所述V H包含氨基酸序列SEQ ID NO:135或其变体，所述变体与氨基酸序列SEQ ID NO:135具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:164或其变体，所述变体与氨基酸序列SEQ ID NO:164具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含氨基酸序列SEQ ID NO:135，以及V L，所述V L包含氨基酸序列SEQ ID NO:164。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:13，HC-CDR2，其包含氨基酸序列SEQ ID NO:30，HC-CDR3，其包含氨基酸序列SEQ ID NO:50，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:69，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，LC-CDR3，其包含氨基酸序列SEQ ID NO:103，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:13，HC-CDR2，其包含氨基酸序列SEQ ID NO:30，和HC-CDR3，其包含氨基酸序列SEQ ID NO:50；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:69，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，和LC-CDR3，其包含氨基酸序列SEQ ID NO:103。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，其包含如氨基酸序列SEQ ID NO:136所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:165所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗HBV pre-S1抗体包含：V H，所述V H包含氨基酸序列SEQ ID NO:136或其变体，所述变体与氨基酸序列SEQ ID NO:136具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:165或其变体，所述变体与氨基酸序列SEQ ID NO:165具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含氨基酸序列SEQ ID NO:136，以及V L，所述V L包含氨基酸序列SEQ ID NO:165。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:9，HC-CDR2，其包含氨基酸序列SEQ ID NO:31，HC-CDR3，其包含氨基酸序列SEQ ID NO:51，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:70，LC-CDR2，其包含氨基酸序列SEQ ID NO:83，LC-CDR3，其包含氨基酸序列SEQ ID NO:106，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:9，HC-CDR2，其包含氨基酸序列SEQ ID NO:31，和HC-CDR3，其包含氨基酸序列SEQ ID NO:51；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:70，LC-CDR2，其包含氨基酸序列SEQ ID NO:83，和LC-CDR3，其包含氨基酸序列SEQ ID NO:106。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，其包含如氨基酸序列SEQ ID NO:137所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:167所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗HBV pre-S1抗体包含：V H，所述V H包含氨基酸序列SEQ ID NO:137或其变体，所述变体与氨基酸序列SEQ ID NO:137具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:167或其变体，所述变体与氨基酸序列SEQ ID NO:167具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含氨基酸序列SEQ ID NO:137，以及V L，所述V L包含氨基酸序列SEQ ID NO:167。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:14，HC-CDR2，其包含氨基酸序列SEQ ID NO:32，HC-CDR3，其包含氨基酸序列SEQ ID NO:51，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:71，LC-CDR2，其包含氨基酸序列SEQ ID NO:86，LC-CDR3，其包含氨基酸序列SEQ ID NO:107，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:14，HC-CDR2，其包含氨基酸序列SEQ ID NO:32，和HC-CDR3，其包含氨基酸序列SEQ ID NO:51；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:71，LC-CDR2，其包含氨基酸序列SEQ ID NO:86，和LC-CDR3，其包含氨基酸序列SEQ ID NO:107。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，其包含如氨基酸序列SEQ ID NO:139所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:169所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗HBV pre-S1抗体包含：V H，所述V H包含氨基酸序列SEQ ID NO:139或其变体，所述变体与氨基酸序列SEQ ID NO:139具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:169或其变体，所述变体与氨基酸序列SEQ ID NO:169具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含氨基酸序列SEQ ID NO:139，以及V L，所述V L包含氨基酸序列SEQ ID NO:169。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:11，HC-CDR2，其包含氨基酸序列SEQ ID NO:30，HC-CDR3，其包含氨基酸序列SEQ ID NO:50，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:72，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，LC-CDR3，其包含氨基酸序列SEQ ID NO:108，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:11，HC-CDR2，其包含氨基酸序列SEQ ID NO:30，和HC-CDR3，其包含氨基酸序列SEQ ID NO:50；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:72，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，和LC-CDR3，其包含氨基酸序列SEQ ID NO:108。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，其包含如氨基酸序列SEQ ID NO:140所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:170所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗HBV pre-S1抗体包含：V H，所述V H包含氨基酸序列SEQ ID NO:140或其变体，所述变体与氨基酸序列SEQ ID NO:140具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:170或其变体，所述变体与氨基酸序列SEQ ID NO:170具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含氨基酸序列SEQ ID NO:140，以及V L，所述V L包含氨基酸序列SEQ ID NO:170。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:13，HC-CDR2，其包含氨基酸序列SEQ ID NO:33，HC-CDR3，其包含氨基酸序列SEQ ID NO:52，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:61，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，LC-CDR3，其包含氨基酸序列SEQ ID NO:97，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:13，HC-CDR2，其包含氨基酸序列SEQ ID NO:33，和HC-CDR3，其包含氨基酸序列SEQ ID NO:52；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:61，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，和LC-CDR3，其包含氨基酸序列SEQ ID NO:97。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，其包含如氨基酸序列SEQ ID NO:141所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:171所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗HBV pre-S1抗体包含：V H，所述V H包含氨基酸序列SEQ ID NO:141或其变体，所述变体与氨基酸序列SEQ ID NO:141具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:171或其变体，所述变体与氨基酸序列SEQ ID NO:171具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含氨基酸序列SEQ ID NO:141，以及V L，所述V L包含氨基酸序列SEQ ID NO:171。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:10，HC-CDR2，其包含氨基酸序列SEQ ID NO:30，HC-CDR3，其包含氨基酸序列SEQ ID NO:50，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:61，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，LC-CDR3，其包含氨基酸序列SEQ ID NO:103，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:10，HC-CDR2，其包含氨基酸序列SEQ ID NO:30，和HC-CDR3，其包含氨基酸序列SEQ ID NO:50；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:61，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，和LC-CDR3，其包含氨基酸序列SEQ ID NO:103。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，其包含如氨基酸序列SEQ ID NO:142所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:172所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗HBV pre-S1抗体包含：V H，所述V H包含氨基酸序列SEQ ID NO:142或其变体，所述变体与氨基酸序列SEQ ID NO:142具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:172或其变体，所述变体与氨基酸序列SEQ ID NO:172具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含氨基酸序列SEQ ID NO:142，以及V L，所述V L包含氨基酸序列SEQ ID NO:172。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:15，HC-CDR2，其包含氨基酸序列SEQ ID NO:34，HC-CDR3，其包含氨基酸序列SEQ ID NO:53，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:73，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，LC-CDR3，其包含氨基酸序列SEQ ID NO:109，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:15，HC-CDR2，其包含氨基酸序列SEQ ID NO:34，和HC-CDR3，其包含氨基酸序列SEQ ID NO:53；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:73，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，和LC-CDR3，其包含氨基酸序列SEQ ID NO:109。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，其包含如氨基酸序列SEQ ID NO:143所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:173所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗HBV pre-S1抗体包含：V H，所述V H包含氨基酸序列SEQ ID NO:143或其变体，所述变体与氨基酸序列SEQ ID NO:143具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:173或其变体，所述变体与氨基酸序列SEQ ID NO:173具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含氨基酸序列SEQ ID NO:143，以及V L，所述V L包含氨基酸序列SEQ ID NO:173。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:16，HC-CDR2，其包含氨基酸序列SEQ ID NO:35，HC-CDR3，其包含氨基酸序列SEQ ID NO:54，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:74，LC-CDR2，其包含氨基酸序列SEQ ID NO:88，LC-CDR3，其包含氨基酸序列SEQ ID NO:110，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:16，HC-CDR2，其包含氨基酸序列SEQ ID NO:35，和HC-CDR3，其包含氨基酸序列SEQ ID NO:54；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:74，LC-CDR2，其包含氨基酸序列SEQ ID NO:88，和LC-CDR3，其包含氨基酸序列SEQ ID NO:110。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，其包含如氨基酸序列SEQ ID NO:144所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:174所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗HBV pre-S1抗体包含：V H，所述V H包含氨基酸序列SEQ ID NO:144或其变体，所述变体与氨基酸序列SEQ ID NO:144具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:174或其变体，所述变体与氨基酸序列SEQ ID NO:174具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含氨基酸序列SEQ ID NO:144，以及V L，所述V L包含氨基酸序列SEQ ID NO:174。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:17，HC-CDR2，其包含氨基酸序列SEQ ID NO:36，HC-CDR3，其包含氨基酸序列SEQ ID NO:55，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:75，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，LC-CDR3，其包含氨基酸序列SEQ ID NO:97，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:17，HC-CDR2，其包含氨基酸序列SEQ ID NO:36，和HC-CDR3，其包含氨基酸序列SEQ ID NO:55；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:75，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，和LC-CDR3，其包含氨基酸序列SEQ ID NO:97。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，其包含如氨基酸序列SEQ ID NO:145所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:175所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗HBV pre-S1抗体包含：V H，所述V H包含氨基酸序列SEQ ID NO:145或其变体，所述变体与氨基酸序列SEQ ID NO:145具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:175或其变体，所述变体与氨基酸序列SEQ ID NO:175具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含氨基酸序列SEQ ID NO:145，以及V L，所述V L包含氨基酸序列SEQ ID NO:175。
在一些实施例中，所述抗HBV pre-S1抗体，包含重链可变结构域(V H)，所述V H包含：重链互补决定区(HC-CDR)1，其包含TYGIT(SEQ ID NO:18)；HC-CDR2，其包含SRIPIX 1GAALYAQKFQG(SEQ ID NO:115)，其中X 1为F或L；和HC-CDR3，其包含NX 1RGGFAAY(SEQ ID NO:116)，其中X 1为D或T；以及轻链可变结构域(V L)，所述V L包含：轻链互补决定区(LC-CDR)1，其包含RSSQSLX 1HSNX 2YNYLD(SEQ ID NO:117)，其中X 1为L或T，X 2为A或G；LC-CDR2，其包含LGX 1X 2RAS(SEQ ID NO:118)，其中X 1为H或S，X 2为K、N或R；和LC-CDR3，其包含序列MQALX 1X 2PX 3T(SEQ ID NO:119)，其中X 1为Q或V，X 2为I或T，X 3为A或P
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含SEQID NO:18所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；HC-CDR2，其包含SEQ ID NOs:37-38中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；和HC-CDR3，其包含SEQ ID NOs:56-57中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含SEQ ID NO:18所示的氨基酸序列，HC-CDR2，其包含SEQ ID NOs:37-38中任一所示的氨基酸序列，HC-CDR3，其包含SEQ ID NOs:56-57中任一所示的氨基酸序列。
在一些实施例中，所述抗HBV pre-S1抗体包含V L，所述V L包含：LC-CDR1，其包含SEQ ID NOs:59、和76-77中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；LC-CDR2，其包含SEQ ID NOs:79、和89-91中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；和LC-CDR3，其包含SEQ ID NOs:111-114中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代。
在一些实施例中，所述抗HBV pre-S1抗体包含V L，所述V L包含：LC-CDR1，其包含SEQ ID NOs:59、和76-77中任一所示的氨基酸序列，LC-CDR2，其包含SEQ ID NOs:79、和89-91中任一所示的氨基酸序列，LC-CDR3，其包含SEQ ID NOs:111-114中任一所示的氨基酸序列。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含SEQ ID NO:18所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；HC-CDR2，其包含SEQ ID NOs:37-38中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；和HC-CDR3，其包含SEQ ID NOs:56-57中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含SEQ ID NOs:59、和76-77中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；LC-CDR2，其包含SEQ ID NOs:79、和89-91中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；和LC-CDR3，其包含SEQ ID NOs:111-114中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含SEQ ID NO:18所示的氨基酸序列，HC-CDR2，其包含SEQ ID NOs:37-38中任一所示的氨基酸序列，和HC-CDR3，其包含SEQ ID NOs:56-57中任一所示的氨基酸序列；以及V L，所述V L包含：LC-CDR1，其包含SEQ ID NOs:59、和76-77中任一所示的氨基酸序列，LC-CDR2，其包含SEQ ID NOs:79、和89-91中任一所示的氨基酸序列，和LC-CDR3，其包含SEQ ID NOs:111-114中任一所示的氨基酸序列。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:18，HC-CDR2，其包含氨基酸序列SEQ ID NO:37，HC-CDR3，其包含氨基酸序列SEQ ID NO:56，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:59，LC-CDR2，其包含氨基酸序列SEQ ID NO:79，LC-CDR3，其包含氨基酸序列SEQ ID NO:111，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:18，HC-CDR2，其包含氨基酸序列SEQ ID NO:37，和HC-CDR3，其包含氨基酸序列SEQ ID NO:56；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:59，LC-CDR2，其包含氨基酸序列SEQ ID NO:79，和LC-CDR3，其包含氨基酸序列SEQ ID NO:111。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:18，HC-CDR2，其包含氨基酸序列SEQ ID NO:38，HC-CDR3，其包含氨基酸序列SEQ ID NO:57，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:76，LC-CDR2，其包含氨基酸序列SEQ ID NO:79，LC-CDR3，其包含氨基酸序列SEQ ID NO:112，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:18，HC-CDR2，其包含氨基酸序列SEQ ID NO:38，和HC-CDR3，其包含氨基酸序列SEQ ID NO:57；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:76，LC-CDR2，其包含氨基酸序列SEQ ID NO:79，和LC-CDR3，其包含氨基酸序列SEQ ID NO:112。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:18，HC-CDR2，其包含氨基酸序列SEQ ID NO:37，HC-CDR3，其包含氨基酸序列SEQ ID NO:57，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:77，LC-CDR2，其包含氨基酸序列SEQ ID NO:89，LC-CDR3，其包含氨基酸序列SEQ ID NO:111，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:18，HC-CDR2，其包含氨基酸序列SEQ ID NO:37，和HC-CDR3，其包含氨基酸序列SEQ ID NO:57；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:77，LC-CDR2，其包含氨基酸序列SEQ ID NO:89，和LC-CDR3，其包含氨基酸序列SEQ ID NO:111。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:18，HC-CDR2，其包含氨基酸序列SEQ ID NO:37，HC-CDR3，其包含氨基酸序列SEQ ID NO:57，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:77，LC-CDR2，其包含氨基酸序列SEQ ID NO:90，LC-CDR3，其包含氨基酸序列SEQ ID NO:111，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:18，HC-CDR2，其包含氨基酸序列SEQ ID NO:37，和HC-CDR3，其包含氨基酸序列SEQ ID NO:57；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:77，LC-CDR2，其包含氨基酸序列SEQ ID NO:90，和LC-CDR3，其包含氨基酸序列SEQ ID NO:111。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:18，HC-CDR2，其包含氨基酸序列SEQ ID NO:38，HC-CDR3，其包含氨基酸序列SEQ ID NO:57，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:76，LC-CDR2，其包含氨基酸序列SEQ ID NO:79，LC-CDR3，其包含氨基酸序列SEQ ID NO:111，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:18，HC-CDR2，其包含氨基酸序列SEQ ID NO:38，和HC-CDR3，其包含氨基酸序列SEQ ID NO:57；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:76，LC-CDR2，其包含氨基酸序列SEQ ID NO:79，和LC-CDR3，其包含氨基酸序列SEQ ID NO:111。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:18，HC-CDR2，其包含氨基酸序列SEQ ID NO:38，HC-CDR3，其包含氨基酸序列SEQ ID NO:57，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:77，LC-CDR2，其包含氨基酸序列SEQ ID NO:79，LC-CDR3，其包含氨基酸序列SEQ ID NO:113，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:18，HC-CDR2，其包含氨基酸序列SEQ ID NO:38，和HC-CDR3，其包含氨基酸序列SEQ ID NO:57；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:77，LC-CDR2，其包含氨基酸序列SEQ ID NO:79，和LC-CDR3，其包含氨基酸序列SEQ ID NO:113。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:18，HC-CDR2，其包含氨基酸序列SEQ ID NO:37，HC-CDR3，其包含氨基酸序列SEQ ID NO:57，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:77，LC-CDR2，其包含氨基酸序列SEQ ID NO:89，LC-CDR3，其包含氨基酸序列SEQ ID NO:114，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:18，HC-CDR2，其包含氨基酸序列SEQ ID NO:37，和HC-CDR3，其包含氨基酸序列SEQ ID NO:57；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:77，LC-CDR2，其包含氨基酸序列SEQ ID NO:89，和LC-CDR3，其包含氨基酸序列SEQ ID NO:114。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:18，HC-CDR2，其包含氨基酸序列SEQ ID NO:37，HC-CDR3，其包含氨基酸序列SEQ ID NO:57，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:77，LC-CDR2，其包含氨基酸序列SEQ  ID NO:91，LC-CDR3，其包含氨基酸序列SEQ ID NO:113，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:18，HC-CDR2，其包含氨基酸序列SEQ ID NO:37，和HC-CDR3，其包含氨基酸序列SEQ ID NO:57；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:77，LC-CDR2，其包含氨基酸序列SEQ ID NO:91，和LC-CDR3，其包含氨基酸序列SEQ ID NO:113。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含如SEQ ID NOs:146-150中任一氨基酸序列所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，所述V L包含如SEQ ID NOs:176-183中任一氨基酸序列所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，其包含如氨基酸序列SEQ ID NO:146所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:176所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，其包含如氨基酸序列SEQ ID NO:147所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:177所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，其包含如氨基酸序列SEQ ID NO:148所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:178所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，其包含如氨基酸序列SEQ ID NO:149所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:179所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，其包含如氨基酸序列SEQ ID NO:147所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:180所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，其包含如氨基酸序列SEQ ID NO:147所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:181所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，其包含如氨基酸序列SEQ ID NO:148所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:182所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，其包含如氨基酸序列SEQ ID NO:150所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:183所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗HBV pre-S1抗体包含：V H，所述V H包含SEQ ID NOs:146-150中任一所示的氨基酸序列或其变体，所述变体与SEQ ID NOs:146-150中任一所示的氨基酸序列具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及V L，所述V L包含SEQ ID NOs:176-183中任一所示的氨基酸序列或其变体，所述变体与SEQ ID NOs:176-183中任一所示的氨基酸序列具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含SEQ ID NOs:146-150中任一所示的氨基酸序列，以及V L，所述V L包含SEQ ID NOs:176-183中任一所示的氨基酸序列。
在一些实施例中，所述抗HBV pre-S1抗体包含：V H，所述V H包含氨基酸序列SEQ ID NO:146或其变体，所述变体与氨基酸序列SEQ ID NO:146具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:176或其变体，所述变体与氨基酸序列SEQ ID NO:176具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含氨基酸序列SEQ ID NO:146，以及V L，所述V L包含氨基酸序列SEQ ID NO:176。
在一些实施例中，所述抗HBV pre-S1抗体包含：V H，所述V H包含氨基酸序列SEQ ID NO:147或其变体，所述变体与氨基酸序列SEQ ID NO:147具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:177或其变体，所述变体与氨基酸序列SEQ ID NO:177具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含氨基酸序列SEQ ID NO:147，以及V L，所述V L包含氨基酸序列SEQ ID NO:177。
在一些实施例中，所述抗HBV pre-S1抗体包含：V H，所述V H包含氨基酸序列SEQ ID NO:148或其变体，所述变体与氨基酸序列SEQ ID NO:148具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:178或其变体，所述变体与氨基酸序列SEQ ID NO:178具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含氨基酸序列SEQ ID NO:148，以及V L，所述V L包含氨基酸序列SEQ ID NO:178。
在一些实施例中，所述抗HBV pre-S1抗体包含：V H，所述V H包含氨基酸序列SEQ ID NO:149或其变体，所述变体与氨基酸序列SEQ ID NO:149具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:179或其变体，所述变体与氨基酸序列SEQ ID NO:179具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗HBV pre-S1 抗体包含V H，所述V H包含氨基酸序列SEQ ID NO:149，以及V L，所述V L包含氨基酸序列SEQ ID NO:179。
在一些实施例中，所述抗HBV pre-S1抗体包含：V H，所述V H包含氨基酸序列SEQ ID NO:147或其变体，所述变体与氨基酸序列SEQ ID NO:147具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:180或其变体，所述变体与氨基酸序列SEQ ID NO:180具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含氨基酸序列SEQ ID NO:147，以及V L，所述V L包含氨基酸序列SEQ ID NO:180。
在一些实施例中，所述抗HBV pre-S1抗体包含：V H，所述V H包含氨基酸序列SEQ ID NO:147或其变体，所述变体与氨基酸序列SEQ ID NO:147具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:181或其变体，所述变体与氨基酸序列SEQ ID NO:181具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含氨基酸序列SEQ ID NO:147，以及V L，所述V L包含氨基酸序列SEQ ID NO:181。
在一些实施例中，所述抗HBV pre-S1抗体包含：V H，所述V H包含氨基酸序列SEQ ID NO:148或其变体，所述变体与氨基酸序列SEQ ID NO:148具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:182或其变体，所述变体与氨基酸序列SEQ ID NO:182具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含氨基酸序列SEQ ID NO:148，以及V L，所述V L包含氨基酸序列SEQ ID NO:182。
在一些实施例中，所述抗HBV pre-S1抗体包含：V H，所述V H包含氨基酸序列SEQ ID NO:150或其变体，所述变体与氨基酸序列SEQ ID NO:150具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:183或其变体，所述变体与氨基酸序列SEQ ID NO:183具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含氨基酸序列SEQ ID NO:150，以及V L，所述V L包含氨基酸序列SEQ ID NO:183。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:18，HC-CDR2，其包含氨基酸序列SEQ ID NO:37，HC-CDR3，其包含氨基酸序列SEQ ID NO:56，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:78，LC-CDR2，其包含氨基酸序列SEQ  ID NO:92，LC-CDR3，其包含氨基酸序列SEQ ID NO:93，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:18，HC-CDR2，其包含氨基酸序列SEQ ID NO:37，和HC-CDR3，其包含氨基酸序列SEQ ID NO:56；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:78，LC-CDR2，其包含氨基酸序列SEQ ID NO:92，和LC-CDR3，其包含氨基酸序列SEQ ID NO:93。
在一些实施例中，所述抗HBV pre-S1抗体包含V H，其包含如氨基酸序列SEQ ID NO:146所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:184所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗HBV pre-S1抗体包含：V H，所述V H包含氨基酸序列SEQ ID NO:146或其变体，所述变体与氨基酸序列SEQ ID NO:146具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:184或其变体，所述变体与氨基酸序列SEQ ID NO:184具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗HBV pre-S1抗体包含V H，所述V H包含氨基酸序列SEQ ID NO:146，以及V L，所述V L包含氨基酸序列SEQ ID NO:184。
在一些实施例中，上述氨基酸取代限于本文表4中所示的“示例性取代”。在一些实施例中，氨基酸取代限于本文表4中所示的“优选取代”。
在一些实施例中，功能性表位可通过组合丙氨酸扫描法来解析。在此过程中，组合丙氨酸扫描技术可用于鉴定HBV pre-S1蛋白中与抗HBV pre-S1抗体相互作用所必需的氨基酸。在一些实施例中，该表位是构象的，同时可以采用与HBV pre-S1蛋白结合的抗HBV pre-S1抗体的晶体结构来鉴定表位。
在一些实施例中，本申请提供与本文所述的任一种抗HBV pre-S1抗体竞争性结合HBV pre-S1抗原的抗体。在一些实施例中，提供能够与本文所述的任一种抗HBV pre-S1抗体竞争性地结合HBV pre-S1抗原上的表位的抗体。在一些实施例中，提供抗HBV pre-S1抗体，其与包含V H和V L的抗HBV pre-S1抗体分子结合相同的表位，其中所述V H包含SEQ ID NOs:120-150中任一所示的氨基酸序列，以及所述V L包含SEQ ID NOs:151-185中任一所示的氨基酸序列。在一些实施例中，提供抗HBV pre-S1抗体，其与包含V H和V L的抗HBV pre-S1抗体竞争性地结合HBV pre-S1，其中所述V H包含SEQ ID NOs:120-150中任一所示的氨基酸序列，以及所述V L包含SEQ ID NOs:151-185中任一所示的氨基酸序列。
在一些实施例中，可以利用竞争实验来鉴定与本文所述的抗HBV pre-S1抗体竞争性结合HBV pre-S1的单克隆抗体。竞争实验可以通过识别相同的或空间上重叠的表位或者通过一个抗体竞争性抑制另一抗体与抗原结合来确定两个抗体是否结合相同的表位。在某些实施例中，这种竞争性抗体与本文所述的抗体结合相同的表位。一些示例性的竞争实验包括，但不限于如Harlow and Lane (1988)Antibodies:A Laboratory Manual ch.14(Cold Spring Harbor Laboratory，Cold Spring Harbor,N.Y.)中所提到的常规实验。用于解析抗体结合的表位的详细示例性方法如Morris(1996)"Epitope Mapping Protocols,"in Methods in Molecular Biology vol.66(Humana Press,Totowa,N.J.)中所述。在一些实施例中，如果每种抗体阻断另一种抗体结合的50％或更多，则称其结合相同的表位。在一些实施例中，与本文所述的抗HBV pre-S1抗体竞争的抗体是嵌合抗体、人源化抗体或全人抗体。
示例性抗HBV pre-S1抗体序列如表2、表3所示，其中根据Kabat定义方式进行CDR编号。本领域技术人员将认识到有多种已知算法来预测CDR的位置以及界定抗体轻、重链可变区。包含如本文所述抗体的CDRs、V H和/或V L序列，但基于预测算法而非下表中所示例的抗体也在本申请的范围内。
表2 示例性抗HBV pre-S1抗体CDR序列
Figure PCTCN2022125558-appb-000002
Figure PCTCN2022125558-appb-000003
Figure PCTCN2022125558-appb-000004
Figure PCTCN2022125558-appb-000005
表3 示例性序列
Figure PCTCN2022125558-appb-000006
Figure PCTCN2022125558-appb-000007
Figure PCTCN2022125558-appb-000008
Figure PCTCN2022125558-appb-000009
Figure PCTCN2022125558-appb-000010
全长抗HBV pre-S1抗体
在一些实施例中，所述抗HBV pre-S1抗体是全长抗HBV pre-S1抗体。在一些实施例中，所述全长抗HBV pre-S1抗体是IgA、IgD、IgE、IgG或IgM。在一些实施例中，所述全长抗HBV pre-S1抗体包含IgG恒定区域，例如IgG1、IgG2、IgG3、IgG4或其变体的恒定区域。在一些实施例中，所述全长抗HBV pre-S1抗体包含λ轻链恒定区。在一些实施例中，所述全长抗HBV pre-S1抗体包含κ轻链恒定区。在一些实施例中，所述全长抗HBV pre-S1抗体是全长的人抗HBV pre-S1抗体。在一些实施例中，所述全长抗HBV pre-S1抗体包含小鼠免疫球蛋白Fc序列。在一些实施例中，所述全长抗HBV pre-S1抗体包含已经改变的或以其他方式改变的Fc序列，使得其具有增强的抗体依赖的细胞介导的细胞毒作用(ADCC)、抗体依赖性细胞介导的吞噬作用(ADCP)或补体依赖的细胞毒作用(CDC)的效应功能。
因此，例如，在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，所述抗HBV pre-S1抗体与HBV pre-S1抗原特异性结合。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG2恒定区的全长抗HBV pre-S1抗体，所述抗HBV pre-S1抗体与HBV pre-S1特异性结合。在一些实施例中，所述IgG2是人IgG2。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG3恒定区的全长抗HBV pre-S1抗体，所述抗HBV pre-S1抗体与HBV pre-S1特异性结合。在一些实施例中，所述IgG3是人IgG3。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，所述抗HBV pre-S1抗体与HBV pre-S1特异性结合。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含SEQ ID NOs:1-18中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；HC-CDR2，其包含SEQ ID NOs:19-38中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；和HC-CDR3，其包含SEQ ID NOs:39-57中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含SEQ ID NOs:58-78中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代，LC-CDR2，其包含SEQ ID NOs:79-92中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；和LC-CDR3，其包含SEQ ID NOs:93-114中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG2恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含SEQ ID NOs: 1-18中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；HC-CDR2，其包含SEQ ID NOs:19-38中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；和HC-CDR3，其包含SEQ ID NOs:39-57中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含SEQ ID NOs:58-78中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；LC-CDR2，其包含SEQ ID NOs:79-92中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；和LC-CDR3，其包含SEQ ID NOs:93-114中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代。在一些实施例中，所述IgG2是人IgG2。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG3恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含SEQ ID NOs:1-18中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代，HC-CDR2，其包含SEQ ID NOs:19-38中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；和HC-CDR3，其包含SEQ ID NOs:39-57中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含SEQ ID NOs:58-78中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；LC-CDR2，其包含SEQ ID NOs:79-92中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；和LC-CDR3，其包含SEQ ID NOs:93-114中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代。在一些实施例中，所述IgG3是人IgG3。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含SEQ ID NOs:1-18中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；HC-CDR2，其包含SEQ ID NOs:19-38中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；和HC-CDR3，其包含SEQ ID NOs:39-57中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含SEQ ID NOs:58-78中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代，LC-CDR2，其包含SEQ ID NOs:79-92中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代，和LC-CDR3，其包含SEQ ID NOs:93-114中任一所示的氨基酸序列或 其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含SEQ ID NOs:1-18中任一所示的氨基酸序列，HC-CDR2，其包含SEQ ID NOs:19-38中任一所示的氨基酸序列，和HC-CDR3，其包含SEQ ID NOs:39-57中任一所示的氨基酸序列，或者所述重链可变结构域的变体，其HC-CDR序列中包含至多约5个(例如1、2、3、4或5个)氨基酸的取代；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含SEQ ID NOs:58-78中任一所示的氨基酸序列，LC-CDR2，其包含SEQ ID NOs:79-92中任一所示的氨基酸序列，和LC-CDR3，其包含SEQ ID NOs:93-114中任一所示的氨基酸序列，或者所述轻链可变结构域的变体，其LC-CDR序列中包含至多约5个(例如1、2、3、4或5个)氨基酸的取代。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含SEQ ID NOs:1-18中任一所示的氨基酸序列，HC-CDR2，其包含SEQ ID NOs:19-38中任一所示的氨基酸序列，和HC-CDR3，其包含SEQ ID NOs:39-57中任一所示的氨基酸序列，或者所述重链可变结构域的变体，其HC-CDR序列中包含至多约5个(例如1、2、3、4或5个)氨基酸的取代；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含SEQ ID NOs:58-78中任一所示的氨基酸序列，LC-CDR2，包含SEQ ID NOs:79-92中任一所示的氨基酸序列，和LC-CDR3，其包含SEQ ID NOs:93-114中任一所示的氨基酸序列，或者所述轻链可变结构域的变体，其LC-CDR序列中包含至多约5个(例如1、2、3、4或5个)氨基酸的取代。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO: 187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含SEQ ID NOs:1-18中任一所示的氨基酸序列，HC-CDR2，其包含SEQ ID NOs:19-38中任一所示的氨基酸序列，和HC-CDR3，其包含SEQ ID NOs:39-57中任一所示的氨基酸序列；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含SEQ ID NOs:58-78中任一所示的氨基酸序列，LC-CDR2，其包含SEQ ID NOs:79-92中任一所示的氨基酸序列，和LC-CDR3，其包含SEQ ID NOs:93-114中任一所示的氨基酸序列。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含SEQ ID NOs:1-18中任一所示的氨基酸序列，HC-CDR2，其包含SEQ ID NOs:19-38中任一所示的氨基酸序列，和HC-CDR3，其包含SEQ ID NOs:39-57中任一所示的氨基酸序列；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含SEQ ID NOs:58-78中任一所示的氨基酸序列，LC-CDR2，其包含SEQ ID NOs:79-92中任一所示的氨基酸序列，和LC-CDR3，其包含SEQ ID NOs:93-114中任一所示的氨基酸序列。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:1，HC-CDR2，其包含氨基酸序列SEQ ID NO:19，和HC-CDR3，其包含氨基酸序列SEQ ID NO:39；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:58，LC-CDR2，其包含氨基酸序列SEQ ID NO:79，和LC-CDR3，其包含氨基酸序列SEQ ID NO:93。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID  NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:2，HC-CDR2，其包含氨基酸序列SEQ ID NO:20，和HC-CDR3，其包含氨基酸序列SEQ ID NO:40；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:59，LC-CDR2，其包含氨基酸序列SEQ ID NO:79，和LC-CDR3，其包含氨基酸序列SEQ ID NO:94。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:3，HC-CDR2，其包含氨基酸序列SEQ ID NO:21，和HC-CDR3，其包含氨基酸序列SEQ ID NO:41；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:60，LC-CDR2，其包含氨基酸序列SEQ ID NO:80，和LC-CDR3，其包含氨基酸序列SEQ ID NO:95。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:4，HC-CDR2，其包含氨基酸序列SEQ ID NO:22，和HC-CDR3，其包含氨基酸序列SEQ ID NO:42；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:61，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，和LC-CDR3，其包含氨基酸序列SEQ ID NO:96。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些 实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:5，HC-CDR2，其包含氨基酸序列SEQ ID NO:23，和HC-CDR3，其包含氨基酸序列SEQ ID NO:43；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:61，LC-CDR2，其包含氨基酸序列SEQ ID NO:82，和LC-CDR3，其包含氨基酸序列SEQ ID NO:97。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:7，HC-CDR2，其包含氨基酸序列SEQ ID NO:25，和HC-CDR3，其包含氨基酸序列SEQ ID NO:45；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:63，LC-CDR2，其包含氨基酸序列SEQ ID NO:84，和LC-CDR3，其包含氨基酸序列SEQ ID NO:99。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:7，HC-CDR2，其包含氨基酸序列SEQ ID NO:26，和HC-CDR3，其包含氨基酸序列SEQ ID NO:46；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:64，LC-CDR2，其包含氨基酸序列SEQ ID NO:79，和LC-CDR3，其包含氨基酸序列SEQ ID NO:100。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸 序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:8，HC-CDR2，其包含氨基酸序列SEQ ID NO:27，和HC-CDR3，其包含氨基酸序列SEQ ID NO:47；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:65，LC-CDR2，其包含氨基酸序列SEQ ID NO:85，和LC-CDR3，其包含氨基酸序列SEQ ID NO:101。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:9，HC-CDR2，其包含氨基酸序列SEQ ID NO:28，和HC-CDR3，其包含氨基酸序列SEQ ID NO:48；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:66，LC-CDR2，其包含氨基酸序列SEQ ID NO:86，和LC-CDR3，其包含氨基酸序列SEQ ID NO:102。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:6，HC-CDR2，其包含氨基酸序列SEQ ID NO:24，和HC-CDR3，其包含氨基酸序列SEQ ID NO:44；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:62，LC-CDR2，其包含氨基酸序列SEQ ID NO:83，和LC-CDR3，其包含氨基酸序列SEQ ID NO:98。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸 序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:10，HC-CDR2，其包含氨基酸序列SEQ ID NO:29，和HC-CDR3，其包含氨基酸序列SEQ ID NO:49；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:67，LC-CDR2，其包含氨基酸序列SEQ ID NO:87，和LC-CDR3，其包含氨基酸序列SEQ ID NO:103。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:11，HC-CDR2，其包含氨基酸序列SEQ ID NO:30，和HC-CDR3，其包含氨基酸序列SEQ ID NO:50；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:68，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，和LC-CDR3，其包含氨基酸序列SEQ ID NO:104。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:12，HC-CDR2，其包含氨基酸序列SEQ ID NO:30，和HC-CDR3，其包含氨基酸序列SEQ ID NO:50；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:61，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，和LC-CDR3，其包含氨基酸序列SEQ ID NO:105。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸 序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:13，HC-CDR2，其包含氨基酸序列SEQ ID NO:30，和HC-CDR3，其包含氨基酸序列SEQ ID NO:50；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:69，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，和LC-CDR3，其包含氨基酸序列SEQ ID NO:103。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:9，HC-CDR2，其包含氨基酸序列SEQ ID NO:31，和HC-CDR3，其包含氨基酸序列SEQ ID NO:51；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:70，LC-CDR2，其包含氨基酸序列SEQ ID NO:83，和LC-CDR3，其包含氨基酸序列SEQ ID NO:106。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:14，HC-CDR2，其包含氨基酸序列SEQ ID NO:32，和HC-CDR3，其包含氨基酸序列SEQ ID NO:51；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:71，LC-CDR2，其包含氨基酸序列SEQ ID NO:86，和LC-CDR3，其包含氨基酸序列SEQ ID NO:107。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸 序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:11，HC-CDR2，其包含氨基酸序列SEQ ID NO:30，和HC-CDR3，其包含氨基酸序列SEQ ID NO:50；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:72，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，和LC-CDR3，其包含氨基酸序列SEQ ID NO:108。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:13，HC-CDR2，其包含氨基酸序列SEQ ID NO:33，和HC-CDR3，其包含氨基酸序列SEQ ID NO:52；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:61，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，和LC-CDR3，其包含氨基酸序列SEQ ID NO:97。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:10，HC-CDR2，其包含氨基酸序列SEQ ID NO:30，和HC-CDR3，其包含氨基酸序列SEQ ID NO:50；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:61，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，和LC-CDR3，其包含氨基酸序列SEQ ID NO:103。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸 序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:15，HC-CDR2，其包含氨基酸序列SEQ ID NO:34，和HC-CDR3，其包含氨基酸序列SEQ ID NO:53；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:73，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，和LC-CDR3，其包含氨基酸序列SEQ ID NO:109。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:16，HC-CDR2，其包含氨基酸序列SEQ ID NO:35，和HC-CDR3，其包含氨基酸序列SEQ ID NO:54；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:74，LC-CDR2，其包含氨基酸序列SEQ ID NO:88，和LC-CDR3，其包含氨基酸序列SEQ ID NO:110。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:17，HC-CDR2，其包含氨基酸序列SEQ ID NO:36，和HC-CDR3，其包含氨基酸序列SEQ ID NO:55；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:75，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，和LC-CDR3，其包含氨基酸序列SEQ ID NO:97。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸 序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:18，HC-CDR2，其包含氨基酸序列SEQ ID NO:37，和HC-CDR3，其包含氨基酸序列SEQ ID NO:56；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:59，LC-CDR2，其包含氨基酸序列SEQ ID NO:79，和LC-CDR3，其包含氨基酸序列SEQ ID NO:111。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:18，HC-CDR2，其包含氨基酸序列SEQ ID NO:38，和HC-CDR3，其包含氨基酸序列SEQ ID NO:57；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:76，LC-CDR2，其包含氨基酸序列SEQ ID NO:79，和LC-CDR3，其包含氨基酸序列SEQ ID NO:112。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:18，HC-CDR2，其包含氨基酸序列SEQ ID NO:37，和HC-CDR3，其包含氨基酸序列SEQ ID NO:57；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:77，LC-CDR2，其包含氨基酸序列SEQ ID NO:89，和LC-CDR3，其包含氨基酸序列SEQ ID NO:111。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸 序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:18，HC-CDR2，其包含氨基酸序列SEQ ID NO:37，和HC-CDR3，其包含氨基酸序列SEQ ID NO:57；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:77，LC-CDR2，其包含氨基酸序列SEQ ID NO:90，和LC-CDR3，其包含氨基酸序列SEQ ID NO:111。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:18，HC-CDR2，其包含氨基酸序列SEQ ID NO:38，和HC-CDR3，其包含氨基酸序列SEQ ID NO:57；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:76，LC-CDR2，其包含氨基酸序列SEQ ID NO:79，和LC-CDR3，其包含氨基酸序列SEQ ID NO:111。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:18，HC-CDR2，其包含氨基酸序列SEQ ID NO:38，和HC-CDR3，其包含氨基酸序列SEQ ID NO:57；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:77，LC-CDR2，其包含氨基酸序列SEQ ID NO:79，和LC-CDR3，其包含氨基酸序列SEQ ID NO:113。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸 序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:18，HC-CDR2，其包含氨基酸序列SEQ ID NO:37，和HC-CDR3，其包含氨基酸序列SEQ ID NO:57；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:77，LC-CDR2，其包含氨基酸序列SEQ ID NO:89，和LC-CDR3，其包含氨基酸序列SEQ ID NO:114。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:18，HC-CDR2，其包含氨基酸序列SEQ ID NO:37，和HC-CDR3，其包含氨基酸序列SEQ ID NO:57；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:77，LC-CDR2，其包含氨基酸序列SEQ ID NO:91，和LC-CDR3，其包含氨基酸序列SEQ ID NO:113。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:18，HC-CDR2，其包含氨基酸序列SEQ ID NO:37，和HC-CDR3，其包含氨基酸序列SEQ ID NO:56；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:78，LC-CDR2，其包含氨基酸序列SEQ ID NO:92，和LC-CDR3，其包含氨基酸序列SEQ ID NO:93。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸 序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:1，HC-CDR2，其包含氨基酸序列SEQ ID NO:19，和HC-CDR3，其包含氨基酸序列SEQ ID NO:39；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:58，LC-CDR2，其包含氨基酸序列SEQ ID NO:79，和LC-CDR3，其包含氨基酸序列SEQ ID NO:93。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:2，HC-CDR2，其包含氨基酸序列SEQ ID NO:20，和HC-CDR3，其包含氨基酸序列SEQ ID NO:40；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:59，LC-CDR2，其包含氨基酸序列SEQ ID NO:79，和LC-CDR3，其包含氨基酸序列SEQ ID NO:94。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:3，HC-CDR2，其包含氨基酸序列SEQ ID NO:21，和HC-CDR3，其包含氨基酸序列SEQ ID NO:41；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:60，LC-CDR2，其包含氨基酸序列SEQ ID NO:80，和LC-CDR3，其包含氨基酸序列SEQ ID NO:95。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸 序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:4，HC-CDR2，其包含氨基酸序列SEQ ID NO:22，和HC-CDR3，其包含氨基酸序列SEQ ID NO:42；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:61，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，和LC-CDR3，其包含氨基酸序列SEQ ID NO:96。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:5，HC-CDR2，其包含氨基酸序列SEQ ID NO:23，和HC-CDR3，其包含氨基酸序列SEQ ID NO:43；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:61，LC-CDR2，其包含氨基酸序列SEQ ID NO:82，和LC-CDR3，其包含氨基酸序列SEQ ID NO:97。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:7，HC-CDR2，其包含氨基酸序列SEQ ID NO:25，和HC-CDR3，其包含氨基酸序列SEQ ID NO:45；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:63，LC-CDR2，其包含氨基酸序列SEQ ID NO:84，和LC-CDR3，其包含氨基酸序列SEQ ID NO:99。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸 序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:7，HC-CDR2，其包含氨基酸序列SEQ ID NO:26，和HC-CDR3，其包含氨基酸序列SEQ ID NO:46；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:64，LC-CDR2，其包含氨基酸序列SEQ ID NO:79，和LC-CDR3，其包含氨基酸序列SEQ ID NO:100。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:8，HC-CDR2，其包含氨基酸序列SEQ ID NO:27，和HC-CDR3，其包含氨基酸序列SEQ ID NO:47；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:65，LC-CDR2，其包含氨基酸序列SEQ ID NO:85，和LC-CDR3，其包含氨基酸序列SEQ ID NO:101。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:9，HC-CDR2，其包含氨基酸序列SEQ ID NO:28，和HC-CDR3，其包含氨基酸序列SEQ ID NO:48；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:66，LC-CDR2，其包含氨基酸序列SEQ ID NO:86，和LC-CDR3，其包含氨基酸序列SEQ ID NO:102。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸 序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:6，HC-CDR2，其包含氨基酸序列SEQ ID NO:24，和HC-CDR3，其包含氨基酸序列SEQ ID NO:44；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:62，LC-CDR2，其包含氨基酸序列SEQ ID NO:83，和LC-CDR3，其包含氨基酸序列SEQ ID NO:98。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:10，HC-CDR2，其包含氨基酸序列SEQ ID NO:29，和HC-CDR3，其包含氨基酸序列SEQ ID NO:49；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:67，LC-CDR2，其包含氨基酸序列SEQ ID NO:87，和LC-CDR3，其包含氨基酸序列SEQ ID NO:103。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:11，HC-CDR2，其包含氨基酸序列SEQ ID NO:30，和HC-CDR3，其包含氨基酸序列SEQ ID NO:50；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:68，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，和LC-CDR3，其包含氨基酸序列SEQ ID NO:104。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸 序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:12，HC-CDR2，其包含氨基酸序列SEQ ID NO:30，和HC-CDR3，其包含氨基酸序列SEQ ID NO:50；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:61，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，和LC-CDR3，其包含氨基酸序列SEQ ID NO:105。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:13，HC-CDR2，其包含氨基酸序列SEQ ID NO:30，和HC-CDR3，其包含氨基酸序列SEQ ID NO:50；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:69，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，和LC-CDR3，其包含氨基酸序列SEQ ID NO:103。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:9，HC-CDR2，其包含氨基酸序列SEQ ID NO:31，和HC-CDR3，其包含氨基酸序列SEQ ID NO:51；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:70，LC-CDR2，其包含氨基酸序列SEQ ID NO:83，和LC-CDR3，其包含氨基酸序列SEQ ID NO:106。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸 序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:14，HC-CDR2，其包含氨基酸序列SEQ ID NO:32，和HC-CDR3，其包含氨基酸序列SEQ ID NO:51；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:71，LC-CDR2，其包含氨基酸序列SEQ ID NO:86，和LC-CDR3，其包含氨基酸序列SEQ ID NO:107。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:11，HC-CDR2，其包含氨基酸序列SEQ ID NO:30，和HC-CDR3，其包含氨基酸序列SEQ ID NO:50；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:72，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，和LC-CDR3，其包含氨基酸序列SEQ ID NO:108。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:13，HC-CDR2，其包含氨基酸序列SEQ ID NO:33，和HC-CDR3，其包含氨基酸序列SEQ ID NO:52；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:61，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，和LC-CDR3，其包含氨基酸序列SEQ ID NO:97。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸 序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:10，HC-CDR2，其包含氨基酸序列SEQ ID NO:30，和HC-CDR3，其包含氨基酸序列SEQ ID NO:50；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:61，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，和LC-CDR3，其包含氨基酸序列SEQ ID NO:103。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:15，HC-CDR2，其包含氨基酸序列SEQ ID NO:34，和HC-CDR3，其包含氨基酸序列SEQ ID NO:53；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:73，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，和LC-CDR3，其包含氨基酸序列SEQ ID NO:109。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:16，HC-CDR2，其包含氨基酸序列SEQ ID NO:35，和HC-CDR3，其包含氨基酸序列SEQ ID NO:54；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:74，LC-CDR2，其包含氨基酸序列SEQ ID NO:88，和LC-CDR3，其包含氨基酸序列SEQ ID NO:110。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸 序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:17，HC-CDR2，其包含氨基酸序列SEQ ID NO:36，和HC-CDR3，其包含氨基酸序列SEQ ID NO:55；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:75，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，和LC-CDR3，其包含氨基酸序列SEQ ID NO:97。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:18，HC-CDR2，其包含氨基酸序列SEQ ID NO:37，和HC-CDR3，其包含氨基酸序列SEQ ID NO:56；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:59，LC-CDR2，其包含氨基酸序列SEQ ID NO:79，和LC-CDR3，其包含氨基酸序列SEQ ID NO:111。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:18，HC-CDR2，其包含氨基酸序列SEQ ID NO:38，和HC-CDR3，其包含氨基酸序列SEQ ID NO:57；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:76，LC-CDR2，其包含氨基酸序列SEQ ID NO:79，和LC-CDR3，其包含氨基酸序列SEQ ID NO:112。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸 序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:18，HC-CDR2，其包含氨基酸序列SEQ ID NO:37，和HC-CDR3，其包含氨基酸序列SEQ ID NO:57；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:77，LC-CDR2，其包含氨基酸序列SEQ ID NO:89，和LC-CDR3，其包含氨基酸序列SEQ ID NO:111。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:18，HC-CDR2，其包含氨基酸序列SEQ ID NO:37，和HC-CDR3，其包含氨基酸序列SEQ ID NO:57；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:77，LC-CDR2，其包含氨基酸序列SEQ ID NO:90，和LC-CDR3，其包含氨基酸序列SEQ ID NO:111。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:18，HC-CDR2，其包含氨基酸序列SEQ ID NO:38，和HC-CDR3，其包含氨基酸序列SEQ ID NO:57；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:76，LC-CDR2，其包含氨基酸序列SEQ ID NO:79，和LC-CDR3，其包含氨基酸序列SEQ ID NO:111。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸 序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:18，HC-CDR2，其包含氨基酸序列SEQ ID NO:38，和HC-CDR3，其包含氨基酸序列SEQ ID NO:57；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:77，LC-CDR2，其包含氨基酸序列SEQ ID NO:79，和LC-CDR3，其包含氨基酸序列SEQ ID NO:113。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:18，HC-CDR2，其包含氨基酸序列SEQ ID NO:37，和HC-CDR3，其包含氨基酸序列SEQ ID NO:57；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:77，LC-CDR2，其包含氨基酸序列SEQ ID NO:89，和LC-CDR3，其包含氨基酸序列SEQ ID NO:114。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:18，HC-CDR2，其包含氨基酸序列SEQ ID NO:37，和HC-CDR3，其包含氨基酸序列SEQ ID NO:57；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:77，LC-CDR2，其包含氨基酸序列SEQ ID NO:91，和LC-CDR3，其包含氨基酸序列SEQ ID NO:113。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸 序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中所述抗HBV pre-S1抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:18，HC-CDR2，其包含氨基酸序列SEQ ID NO:37，和HC-CDR3，其包含氨基酸序列SEQ ID NO:56；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:78，LC-CDR2，其包含氨基酸序列SEQ ID NO:92，和LC-CDR3，其包含氨基酸序列SEQ ID NO:93。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包含：重链可变结构域(V H)，所述V H包含SEQ ID NOs:120-150中任一所示的氨基酸序列或其变体，所述变体与SEQ ID NOs:120-150中任一所示的氨基酸序列具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及轻链可变结构域(V L)，所述V L包含SEQ ID NOs:151-185中任一所示的氨基酸序列或其变体，所述变体与SEQ ID NOs:151-185中任一所示的氨基酸序列具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG2恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包含：重链可变结构域(V H)，所述V H包含SEQ ID NOs:120-150中任一所示的氨基酸序列或其变体，所述变体与SEQ ID NOs:120-150中任一所示的氨基酸序列具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及轻链可变结构域(V L)，所述V L包含SEQ ID NOs:151-185中任一所示的氨基酸序列或其变体，所述变体与SEQ ID NOs:151-185中任一所示的氨基酸序列具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述IgG2是人IgG2。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG3恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包含：重链可变结构域(V H)，所述V H包含SEQ ID NOs:120-150中任一所示的氨基酸序列或其变体，所述变体与SEQ ID NOs:120-150中任一所示的氨基酸序列具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及轻链可变结构域(V L)，所述V L包含SEQ ID NOs:151-185中任一所示的氨基酸序列或其变体，所述变体与SEQ ID NOs:151-185中任一所示的氨基酸序列具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述IgG3是人IgG3。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包含：重链可变结构域(V H)，所述V H包含SEQ ID NOs:120-150中任一所示的氨基酸序列或其变体，所述变体与SEQ ID NOs:120-150中任一所示的氨基酸序列具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及轻链可变结构域(V L)，所述V L包含SEQ ID NOs:151-185中任一所示的氨基酸序列或其变体，所述变体与SEQ ID NOs:151-185中任一所示的氨基酸序列具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包含：重链可变结构域(V H)，所述V H包含SEQ ID NOs:120-150中任一所示的氨基酸序列，以及轻链可变结构域(V L)，所述V L包含SEQ ID NOs:151-185中任一所示的氨基酸序列。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包括：重链可变结构域(V H)，所述V H包含SEQ ID NOs:120-150中任一所示的氨基酸序列，以及轻链可变结构域(V L)，所述V L包含SEQ ID NOs:151-185中任一所示的氨基酸序列。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO: 187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包含：V H，其包含氨基酸序列SEQ ID NO:120或其变体，所述变体与氨基酸序列SEQ ID NO:120具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:151或其变体，所述变体与氨基酸序列SEQ ID NO:151具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包含：V H，其包含氨基酸序列SEQ ID NO:121或其变体，所述变体与氨基酸序列SEQ ID NO:121具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:152或其变体，所述变体与氨基酸序列SEQ ID NO:152具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包含：V H，其包含氨基酸序列SEQ ID NO:122或其变体，所述变体与氨基酸序列SEQ ID NO:122具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:153或其变体，所述变体与氨基酸序列SEQ ID NO:153具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定 区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包含：V H，其包含氨基酸序列SEQ ID NO:123或其变体，所述变体与氨基酸序列SEQ ID NO:123具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:154或其变体，所述变体与氨基酸序列SEQ ID NO:154具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包含：V H，其包含氨基酸序列SEQ ID NO:124或其变体，所述变体与氨基酸序列SEQ ID NO:124具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:155或其变体，所述变体与氨基酸序列SEQ ID NO:155具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包含：V H，其包含氨基酸序列SEQ ID NO:126或其变体，所述变体与氨基酸序列SEQ ID NO:126具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:157或其变体，所述变体与氨基酸序列SEQ ID NO:157具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包含：V H，其包含氨基酸序列SEQ ID NO:128或其变体，所述变体与氨基酸序列SEQ ID NO: 128具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:158或其变体，所述变体与氨基酸序列SEQ ID NO:158具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包含：V H，其包含氨基酸序列SEQ ID NO:130或其变体，所述变体与氨基酸序列SEQ ID NO:130具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:159或其变体，所述变体与氨基酸序列SEQ ID NO:159具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包含：V H，其包含氨基酸序列SEQ ID NO:131或其变体，所述变体与氨基酸序列SEQ ID NO:131具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:160或其变体，所述变体与氨基酸序列SEQ ID NO:160具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包含：V H，其包含氨基酸序列SEQ ID NO:132或其变体，所述变体与氨基酸序列SEQ ID NO:132具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:161或其变体，所述变体与氨基酸序列SEQ ID NO:161具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨 基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包含：V H，其包含氨基酸序列SEQ ID NO:133或其变体，所述变体与氨基酸序列SEQ ID NO:133具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:162或其变体，所述变体与氨基酸序列SEQ ID NO:162具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包含：V H，其包含氨基酸序列SEQ ID NO:134或其变体，所述变体与氨基酸序列SEQ ID NO:134具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:163或其变体，所述变体与氨基酸序列SEQ ID NO:163具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包含：V H，其包含氨基酸序列SEQ ID NO:135或其变体，所述变体与氨基酸序列SEQ ID NO:135具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:164或其变体，所述变体与氨基酸序列SEQ ID NO:164具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包含：V H，其包含氨基酸序列SEQ ID NO:136或其变体，所述变体与氨基酸序列SEQ ID NO:136具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:165或其变体，所述变体与氨基酸序列SEQ ID NO:165具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包含：V H，其包含氨基酸序列SEQ ID NO:137或其变体，所述变体与氨基酸序列SEQ ID NO:137具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:167或其变体，所述变体与氨基酸序列SEQ ID NO:167具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包含：V H，其包含氨基酸序列SEQ ID NO:139或其变体，所述变体与氨基酸序列SEQ ID NO:139具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:169或其变体，所述变体与氨基酸序列SEQ ID NO:169具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包含：V H，其包含氨基酸序列SEQ ID NO:140或其变体，所述变体与氨基酸序列SEQ ID NO:140具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:170或其变体，所述变体与氨基酸序列SEQ ID NO:170具有至少约80％序列同一性。在一些实施例中，所述IgG1是人 IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包含：V H，其包含氨基酸序列SEQ ID NO:141或其变体，所述变体与氨基酸序列SEQ ID NO:141具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:171或其变体，所述变体与氨基酸序列SEQ ID NO:171具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包含：V H，其包含氨基酸序列SEQ ID NO:142或其变体，所述变体与氨基酸序列SEQ ID NO:142具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:172或其变体，所述变体与氨基酸序列SEQ ID NO:172具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包含：V H，其包含氨基酸序列SEQ ID NO:143或其变体，所述变体与氨基酸序列SEQ ID NO:143具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:173或其变体，所述变体与氨基酸序列SEQ ID NO:173具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定 区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包含：V H，其包含氨基酸序列SEQ ID NO:144或其变体，所述变体与氨基酸序列SEQ ID NO:144具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:174或其变体，所述变体与氨基酸序列SEQ ID NO:174具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包含：V H，其包含氨基酸序列SEQ ID NO:145或其变体，所述变体与氨基酸序列SEQ ID NO:145具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:175或其变体，所述变体与氨基酸序列SEQ ID NO:175具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包含：V H，其包含氨基酸序列SEQ ID NO:146或其变体，所述变体与氨基酸序列SEQ ID NO:146具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:176或其变体，所述变体与氨基酸序列SEQ ID NO:176具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包含：V H，其包含氨基酸序列SEQ ID NO:147或其变体，所述变体与氨基酸序列SEQ ID NO: 147具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:177或其变体，所述变体与氨基酸序列SEQ ID NO:177具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包含：V H，其包含氨基酸序列SEQ ID NO:148或其变体，所述变体与氨基酸序列SEQ ID NO:148具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:178或其变体，所述变体与氨基酸序列SEQ ID NO:178具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包含：V H，其包含氨基酸序列SEQ ID NO:149或其变体，所述变体与氨基酸序列SEQ ID NO:149具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:179或其变体，所述变体与氨基酸序列SEQ ID NO:179具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包含：V H，其包含氨基酸序列SEQ ID NO:147或其变体，所述变体与氨基酸序列SEQ ID NO:147具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:180或其变体，所述变体与氨基酸序列SEQ ID NO:180具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨 基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包含：V H，其包含氨基酸序列SEQ ID NO:147或其变体，所述变体与氨基酸序列SEQ ID NO:147具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:181或其变体，所述变体与氨基酸序列SEQ ID NO:181具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包含：V H，其包含氨基酸序列SEQ ID NO:148或其变体，所述变体与氨基酸序列SEQ ID NO:148具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:182或其变体，所述变体与氨基酸序列SEQ ID NO:182具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包含：V H，其包含氨基酸序列SEQ ID NO:150或其变体，所述变体与氨基酸序列SEQ ID NO:150具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:183或其变体，所述变体与氨基酸序列SEQ ID NO:183具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包含：V H，其包含氨基酸序列SEQ ID NO:146或其变体，所述变体与氨基酸序列SEQ ID NO:146具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:184或其变体，所述变体与氨基酸序列SEQ ID NO:184具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包括：V H，其包含氨基酸序列SEQ ID NO:120或其变体，所述变体与氨基酸序列SEQ ID NO:120具有至少约80％序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:151或其变体，所述变体与氨基酸序列SEQ ID NO:151具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包括：V H，其包含氨基酸序列SEQ ID NO:121或其变体，所述变体与氨基酸序列SEQ ID NO:121具有至少约80％序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:152或其变体，所述变体与氨基酸序列SEQ ID NO:152具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包括：V H，其包含氨基酸序列SEQ ID NO:122或其变体，所述变体与氨基酸序列SEQ ID NO:122具有至少约80％序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:153或其变体，所述变体与氨基酸序列SEQ ID NO:120具有至少约80％序列同一性。在一些实施例中，所述IgG4 是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包括：V H，其包含氨基酸序列SEQ ID NO:123或其变体，所述变体与氨基酸序列SEQ ID NO:123具有至少约80％序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:154或其变体，所述变体与氨基酸序列SEQ ID NO:154具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包括：V H，其包含氨基酸序列SEQ ID NO:124或其变体，所述变体与氨基酸序列SEQ ID NO:124具有至少约80％序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:155或其变体，所述变体与氨基酸序列SEQ ID NO:155具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包括：V H，其包含氨基酸序列SEQ ID NO:126或其变体，所述变体与氨基酸序列SEQ ID NO:126具有至少约80％序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:157或其变体，所述变体与氨基酸序列SEQ ID NO:157具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链 恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包括：V H，其包含氨基酸序列SEQ ID NO:128或其变体，所述变体与氨基酸序列SEQ ID NO:128具有至少约80％序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:158或其变体，所述变体与氨基酸序列SEQ ID NO:158具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包括：V H，其包含氨基酸序列SEQ ID NO:130或其变体，所述变体与氨基酸序列SEQ ID NO:130具有至少约80％序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:159或其变体，所述变体与氨基酸序列SEQ ID NO:159具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包括：V H，其包含氨基酸序列SEQ ID NO:131或其变体，所述变体与氨基酸序列SEQ ID NO:131具有至少约80％序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:160或其变体，所述变体与氨基酸序列SEQ ID NO:160具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包括：V H，其包含氨基酸序列SEQ ID NO:132或其变体，所述变体与氨基酸序列SEQ ID NO: 132具有至少约80％序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:161或其变体，所述变体与氨基酸序列SEQ ID NO:161具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包括：V H，其包含氨基酸序列SEQ ID NO:133或其变体，所述变体与氨基酸序列SEQ ID NO:133具有至少约80％序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:162或其变体，所述变体与氨基酸序列SEQ ID NO:162具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包括：V H，其包含氨基酸序列SEQ ID NO:134或其变体，所述变体与氨基酸序列SEQ ID NO:134具有至少约80％序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:163或其变体，所述变体与氨基酸序列SEQ ID NO:163具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包括：V H，其包含氨基酸序列SEQ ID NO:135或其变体，所述变体与氨基酸序列SEQ ID NO:135具有至少约80％序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:164或其变体，所述变体与氨基酸序列SEQ ID NO:164具有至少约80％序列同一性在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或 由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包括：V H，其包含氨基酸序列SEQ ID NO:136或其变体，所述变体与氨基酸序列SEQ ID NO:136具有至少约80％序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:165或其变体，所述变体与氨基酸序列SEQ ID NO:165具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包括：V H，其包含氨基酸序列SEQ ID NO:137或其变体，所述变体与氨基酸序列SEQ ID NO:137具有至少约80％序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:167或其变体，所述变体与氨基酸序列SEQ ID NO:167具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包括：V H，其包含氨基酸序列SEQ ID NO:139或其变体，所述变体与氨基酸序列SEQ ID NO:139具有至少约80％序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:169或其变体，所述变体与氨基酸序列SEQ ID NO:169具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包括：V H，其包含氨基酸序列SEQ ID NO:140或其变体，所述变体与氨基酸序列SEQ ID NO:140具有至少约80％序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:170或其变体，所述变体与氨基酸序列SEQ ID NO:170具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包括：V H，其包含氨基酸序列SEQ ID NO:141或其变体，所述变体与氨基酸序列SEQ ID NO:141具有至少约80％序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:171或其变体，所述变体与氨基酸序列SEQ ID NO:171具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包括：V H，其包含氨基酸序列SEQ ID NO:142或其变体，所述变体与氨基酸序列SEQ ID NO:142具有至少约80％序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:172或其变体，所述变体与氨基酸序列SEQ ID NO:172具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包括：V H，其包含氨基酸序列SEQ ID NO:143或其变体，所述变体与氨基酸序列SEQ ID NO:143具有至少约80％序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:173或其变体，所述变体与氨基酸序列SEQ ID NO:173具有至少约80％序列同一性。在一些实施例中，所述IgG4 是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包括：V H，其包含氨基酸序列SEQ ID NO:144或其变体，所述变体与氨基酸序列SEQ ID NO:144具有至少约80％序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:174或其变体，所述变体与氨基酸序列SEQ ID NO:174具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包括：V H，其包含氨基酸序列SEQ ID NO:145或其变体，所述变体与氨基酸序列SEQ ID NO:145具有至少约80％序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:175或其变体，所述变体与氨基酸序列SEQ ID NO:175具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包括：V H，其包含氨基酸序列SEQ ID NO:146或其变体，所述变体与氨基酸序列SEQ ID NO:146具有至少约80％序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:176或其变体，所述变体与氨基酸序列SEQ ID NO:176具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链 恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包括：V H，其包含氨基酸序列SEQ ID NO:147或其变体，所述变体与氨基酸序列SEQ ID NO:147具有至少约80％序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:177或其变体，所述变体与氨基酸序列SEQ ID NO:177具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包括：V H，其包含氨基酸序列SEQ ID NO:148或其变体，所述变体与氨基酸序列SEQ ID NO:148具有至少约80％序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:178或其变体，所述变体与氨基酸序列SEQ ID NO:178具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包括：V H，其包含氨基酸序列SEQ ID NO:149或其变体，所述变体与氨基酸序列SEQ ID NO:149具有至少约80％序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:179或其变体，所述变体与氨基酸序列SEQ ID NO:179具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包括：V H，其包含氨基酸序列SEQ ID NO:147或其变体，所述变体与氨基酸序列SEQ ID NO: 147具有至少约80％序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:180或其变体，所述变体与氨基酸序列SEQ ID NO:180具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包括：V H，其包含氨基酸序列SEQ ID NO:147或其变体，所述变体与氨基酸序列SEQ ID NO:147具有至少约80％序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:181或其变体，所述变体与氨基酸序列SEQ ID NO:181具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包括：V H，其包含氨基酸序列SEQ ID NO:148或其变体，所述变体与氨基酸序列SEQ ID NO:148具有至少约80％序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:182或其变体，所述变体与氨基酸序列SEQ ID NO:182具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包括：V H，其包含氨基酸序列SEQ ID NO:150或其变体，所述变体与氨基酸序列SEQ ID NO:150具有至少约80％序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:183或其变体，所述变体与氨基酸序列SEQ ID NO:183具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含 或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗HBV pre-S1抗体，其中抗HBV pre-S1抗体包括：V H，其包含氨基酸序列SEQ ID NO:146或其变体，所述变体与氨基酸序列SEQ ID NO:146具有至少约80％序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:184或其变体，所述变体与氨基酸序列SEQ ID NO:184具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
结合亲和力
结合亲和力采用Kd、Koff、Kon或Ka表示。如本文所用，术语Koff是指抗体从抗原/抗体复合物中解离的速率常数，通过动力学选择装置测定。术语Kon是指抗体与抗原结合形成抗原/抗体复合物的结合速率常数。本文所用的平衡解离常数Kd是指特定抗体抗原相互作用时的解离常数，是指在抗体分子溶液中，抗原占据所有抗体结合位点的一半并且达到平衡时所需的抗原浓度，等于Koff/Kon。Kd的测定假设所有的结合分子均在溶液中。抗体与细胞壁连接的情况，例如在酵母表达系统中，相应的平衡解离速率常数采用EC 50来表示，其是Kd的一个良好的近似值。亲和结合常数Ka是解离常数Kd的倒数。
解离常数(Kd)可以作为反应抗体部分与抗原亲和力的指标。例如，可以通过Scatchard方法使用标记有各种标记物的抗体，和Biacore仪器(由Amersham Biosciences制造)进行简单分析，根据用户手册或附带试剂盒，通过表面等离子体共振来分析生物分子间的相互作用。使用这些方法得到的Kd值，用单位M来表示。与靶标特异性结合的抗体可能具有，例如≤10 -7M、≤10 -8M、≤10 -9M、≤10 -10M、≤10 -11M、≤10 -12M或≤10 -13M的Kd值。
抗体的结合特异性可以通过本领域已知的方法进行实验测定。这些方法包括，但不限于Western blots、ELISA-、RIA-、ECL-、IRMA-、EIA-、BIAcore测试和肽扫描等。
在一些实施例中，所述抗HBV pre-S1抗体特异性结合HBV pre-S1靶标，其Kd值为10 -7M至10 -13M(例如10 -7M至10 -13M、10 -8M至10 -13M、10 -9M至10 -13M或10 -10M至10 -12M)。因此，在一些实施例中，抗HBV pre-S1抗体与HBV pre-S1之间结合的Kd值为10 -7M至10 -13M、1×10 - 7M至5×10 -13M、10 -7M至10 -12M、10 -7M至10 -11M、10 -7M至10 -10M、10 -7M至10 -9M、10 - 8M至10 -13M、1×10 -8M至5×10 -13M、10 -8M至10 -12M、10 -8M至10 -11M、10 -8M至10 -10M、 10 -8M至10 -9M、5×10 -9M至1×10 -13M、5×10 -9M至1×10 -12M、5×10 -9M至1×10 -11M、5×10 -9M至1×10 -10M、10 -9M至10 -13M、10 -9M至10 -12M、10 -9M至10 -11M、10 -9M至10 -10M、5×10 - 10M至1×10 -13M、5×10 -10M至1×10 -12M、5×10 -10M至1×10 -11M、10 -10M至10 -13M、1×10 -10M至5×10 -13M、1×10 -10M至1×10 -12M、1×10 -10M至5×10 -12M、1×10 -10M至1×10 -11M、10 -11M至10 -13M、1×10 -11M至5×10 -13M、10 -11M至10 -12M、10 -12M至10 -13M。在一些实施例中，抗HBV pre-S1抗体与HBV pre-S1之间结合的Kd值为10 -7M至10 -13M。
在一些实施例中，抗HBV pre-S1抗体与非靶标之间结合的Kd值高于抗HBV pre-S1抗体与靶标的Kd值，并且本文中引用的一些实施例中，抗HBV pre-S1抗体与靶标(例如，HBV pre-S1抗原)的结合亲和力高于抗HBV pre-S1抗体与非靶标的结合亲和力。一些实施例中，非靶标是指非HBV pre-S1的抗原。在一些实施例中，抗HBV pre-S1抗体(针对HBV pre-S1)与非HBV pre-S1靶标结合的Kd值间至少相差10倍，例如10-100倍、100-1000倍、10 3-10 4倍、10 4-10 5倍、10 5-10 6倍、10 6-10 7倍、10 7-10 8倍、10 8-10 9倍、10 9-10 10倍、10 10-10 11倍、10 11-10 12倍。
在一些实施例中，所述抗HBV pre-S1抗体与非靶标结合的Kd值为10 -1M至10 -6M(例如10 - 1M至10 -6M、10 -1M至10 -5M、10 -2M至10 -4M)。在一些实施例中，所述非靶标是指非HBV pre-S1的抗原。因此，在一些实施例中，抗HBV pre-S1抗体与非HBV pre-S1靶标之间结合的Kd值为10 -1M至10 -6M、1×10 -1M至5×10 -6M、10 -1M至10 -5M、1×10 -1M至5×10 -5M、10 -1M至10 -4M、1×10 -1M至5×10 -4M、10 -1M至10 -3M、1×10 -1M至5×10 -3M、10 -1M至10 -2M、10 -2M至10 -6M、1×10 -2M至5×10 -6M、10 -2M至10 -5M、1×10 -2M至5×10 -5M、10 -2M至10 -4M、1×10 - 2M至5×10 -4M、10 -2M至10 -3M、10 -3M至10 -6M、1×10 -3M至5×10 -6M、10 -3M至10 -5M、1×10 -3M至5×10 -5M、10 -3M至10 -4M、10 -4M至10 -6M、1×10 -4M至5×10 -6M、10 -4M至10 -5M、10 -5M至10 -6M。
在一些实施例中，当提及抗HBV pre-S1抗体以高结合亲和力特异性地识别HBV pre-S1靶标，并以低结合亲和力结合非靶标时，所述抗HBV pre-S1抗体与HBV pre-S1靶标结合的Kd值为10 -7M至10 -13M(例如10 -7M至10 -13M、10 -8M至10 -13M、10 -9M至10 -13M、10 -10M至10 -12M)，并且与非靶标结合的Kd值为10 -1M至10 -6M(例如10 -1M至10 -6M、10 -1M至10 -5M、10 -2M至10 -4M)。
在一些实施例中，当提及抗HBV pre-S1抗体特异性地识别HBV pre-S1时，将所述抗HBV pre-S1抗体的结合亲和力与对照抗HBV pre-S1抗体(例如A14-20m1或A14-8)的结合亲和力进行比较。在一些实施例中，对照抗HBV pre-S1抗体与HBV pre-S1之间结合的Kd值可以是本申请所述的抗HBV pre-S1抗体与HBV pre-S1之间结合的Kd值的至少2倍，例如2倍、3倍、4倍、5倍、6倍、7倍、8倍、9倍、10倍、10-100倍、100-1000倍、10 3-10 4倍。
核酸
编码抗HBV pre-S1抗体的核酸分子也被考虑在内。在一些实施例中，提供一种(或一组)编码全长抗HBV pre-S1抗体的核酸，包括本文所述的任一种全长抗HBV pre-S1抗体。在一些实施例 中，本文所述的抗HBV pre-S1抗体的核酸(或一组核酸)还可以包括编码多肽标签的核酸序列(例如蛋白纯化标签，His标签、HA标签)。
同时本文还考虑了包含抗HBV pre-S1抗体的分离的宿主细胞，编码抗HBV pre-S1抗体多肽组分的分离的核酸，或者包含编码本文所述的抗HBV pre-S1抗体多肽组分的核酸的载体。
本申请还包括这些核酸序列的变体。例如，变体包括至少在中等严格杂交条件下与编码本申请的抗HBV pre-S1抗体的核酸序列杂交的核苷酸序列。
本申请同时还提供可将本申请中核酸序列插入到其中的载体。
简言之，将编码抗HBV pre-S1抗体的天然或合成的核酸插入到合适的表达载体中，使得核酸可操作性的连接到5’和3’端调控元件，例如包括启动子(例如淋巴细胞特异性启动子)和3’非翻译区(UTR)，可表达抗HBV pre-S1抗体(例如全长的抗HBV pre-S1抗体)。所述载体可适用于在真核宿主细胞中复制和整合。典型的克隆与表达载体包含调控目标核酸序列的表达的转录和翻译终止子、起始序列和启动子。
本申请所述的核酸也可以通过使用标准的基因递送方案，用于核酸免疫和基因治疗。核酸递送方法是本领域已知的。例如参见U.S.Pat.Nos.5,399,346、5,580,859、5,589,466，通过引用其全部内容并入本文。在一些实施例中，本申请还提供基因治疗载体。
可以将核酸克隆到许多类型的载体中。例如，可以将核酸克隆到载体中，所述载体包括，但不限于，质粒、噬菌粒、噬菌体衍生物、动物病毒和柯斯质粒。特别感兴趣的载体包括表达载体、复制载体、探针生成载体和测序载体。
此外，表达载体可以以病毒载体的形式提供给细胞。病毒载体技术是本领域熟知的，并且描述于例如Green and Sambrook(2013,Molecular Cloning:A Laboratory Manual,Cold Spring Harbor Laboratory,New York)，以及其它病毒学或分子生物学手册中。可用作载体的病毒包括，但不限于，逆转录病毒、腺病毒、腺相关病毒、疱疹病毒和慢病毒。通常，合适的载体包括一个在至少一种生物体中起作用的复制起点、启动子序列、方便的限制性内切酶位点以及一个或多个选择标记物(参见例如，WO 01/96584；WO 01/29058；和U.S.Pat.No.6,326,193)。
已经开发了许多基于病毒的系统，用于将基因转移到哺乳动物细胞中。例如，逆转录病毒为基因递送系统提供了便利的平台。可以应用本领域已知的技术，将选择的基因插入载体中并包装在逆转录病毒颗粒中。然后分离重组病毒，在体内或体外递送至受试者的细胞中。许多逆转录病毒系统在本领域中是已知的。在一些实施例中，使用腺病毒载体。许多腺病毒载体在本领域中是已知的。在一些实施例中，使用慢病毒载体。衍生自逆转录病毒的载体，例如慢病毒，是实现长期基因转移的合适工具，因为它们使得转基因长期稳定的整合以及在子代细胞中繁殖。慢病毒载体相对于衍生自肿瘤的逆转录病毒例如小鼠白血病病毒具有额外的优势，因为它们可以转导非分裂细胞，例如肝细胞。同时，其还具有低免疫原性的额外优势。
其它的启动子元件，例如，增强子，调控转录起始频率。通常它们位于起始位点上游30-110bp处，虽然最近发现很多启动子也包含起始位点下游的功能元件。启动子元件之间的间隔通常 是灵活的，所以当元件彼此之间位置互换或移动时仍保持启动子的功能。在胸苷激酶(tk)启动子中，启动子元件之间的间隔增加到50bp活性才会开始下降。
合适启动子的一个示例是即时早期巨细胞病毒(CMV)启动子序列。该启动子序列是一个很强的组成型启动子序列，可以驱动任何与其可操作性连接的多核苷酸序列高水平表达。合适启动子的另一个示例是延伸因子1α(EF-1α)启动子。然而，也可以使用其它组成型启动子，包括但不限于猿猴病毒40(SV40)早期启动子、小鼠乳腺肿瘤病毒(MMTV)、人免病缺陷病毒长末端重复序列(HIV-LTR)启动子、MoMuLV启动子、禽类白血病病毒启动子、Epstein-Barr病毒即刻早期启动子、劳斯氏肉瘤病毒启动子以及人类基因启动子，例如包括但不限于肌动蛋白启动子、肌球蛋白启动子、血红蛋白启动子和肌酸激酶启动子。此外，不应将本申请局限在仅使用组成型启动子，诱导型启动子也是本申请考虑的部分。诱导型启动子的使用提供了一种分子开关，当需要这种表达时，能启动其与之可操作性连接的多核苷酸序列表达，当不需要时，则关闭表达。诱导型启动子包含，但不局限于，金属硫蛋白启动子、糖皮质激素启动子、孕酮启动子和四环素启动子。
在一些实施例中，抗HBV pre-S1抗体的表达是可诱导的。在一些实施例中，编码抗HBV pre-S1抗体的核酸序列可操作的连接到诱导型启动子上，包括本文所述的任一诱导型启动子。
诱导型启动子
诱导型启动子的使用提供了一种分子开关，当需要表达时，可启动与之可操作性连接的多核苷酸序列表达，而在不需要表达时，则关闭表达。真核细胞中适用的示例性诱导型启动子包括，但不限于，激素调节元件(例如，参见Mader,S.and White,J.H.(1993)Proc.Natl.Acad.Sci.USA90:5603-5607)、合成配体调节元件(参见Spencer,D.M.et al(1993)Science 262:1019-1024)以及电离辐射调控元件(参见Manome,Y.et al.(1993)Biochemistry 32:10607-10613；Datta,R.et al.(1992)Proc.Natl.Acad.Sci.USA 89:1014-10153)。其它适用于体内或体外哺乳动物系统的示例性诱导型启动子参见Gingrich et al.(1998)Annual Rev.Neurosci 21:377-405。在一些实施例中，用于表达抗HBV pre-S1抗体的诱导型启动子系统为Tet系统。在一些实施例中，用于表达抗HBV pre-S1抗体的诱导型启动子系统为大肠杆菌lac抑制系统。
本申请所采用的一个示例性诱导型启动子系统为Tet系统。该系统是基于Gossen等(1993)描述的Tet系统。在一个示例性实施例中，目标多核苷酸由包含一个或多个Tet操纵子(TetO)位点的启动子控制。在非激活状态，Tet阻遏物(TetR)与TetO位点结合并抑制启动子的转录。在激活状态，例如，在存在诱导剂如四环素(Tc)、无水四环素、多西环素(Dox)或其活性类似物的情况下，诱导剂会使TetR从TetO上释放，从而导致转录发生。多西环素是四环素抗生素家族中的一员，其化学名为1-二甲氨基-2,4a,5,7-五羟基-11-甲基-4,6-二氧基-1,4a,11,11a,12,12a-六氢四烯-3-甲酰胺。
在一个实施例中，TetR经密码子优化适用于在哺乳动物细胞中表达，例如小鼠或人类细胞。由于遗传密码的简并性，大多数氨基酸由不止一个密码子编码，从而使得给定核酸的序列具有大 量的变体，而其编码的氨基酸序列没有任何改变。然而，许多生物体在密码子使用方面存在差异，也称为“密码子偏好”(即，给定氨基酸使用特定密码子的偏好)。密码子偏好通常与特定密码子的优势tRNA种类的存在有关，反过来又提高了mRNA翻译的效率。因此可以通过密码子优化来定制源自特定物种的编码序列(例如，原核生物)，以提高其在不同物种(例如，真核生物)中的表达。
Tet系统的其它具体变体，包括以下的“Tet-Off”和“Tet-On”系统。在Tet-off系统中，转录在Tc或Dox存在下是失活的。在该系统中，由TetR与单纯疱疹病毒VP16强转录激活结构域融合组成的四环素调控的转录激活蛋白(tTA)，在四环素反应启动子元件(TRE)转录控制下调控靶核酸的表达。TRE元件由TetO序列串联与启动子(通常是来源于人巨细胞病毒即刻早期启动子的最小启动子序列)融合组成。在不存在Tc或Dox的情况下，tTA结合TRE并激活靶基因的转录。在存在Tc或Dox的情况下，tTA不能结合TRE，靶基因不能表达。
相反，在Tet-On系统中，转录在Tc或Dox存在下是激活的。Tet-On系统是基于反向四环素调控的转录激活因子rtTA。与tTA一样，rtTA是由TetR阻遏物与VP16转录激活结构域组成的融合蛋白。然而，TetR的DNA结合区中4个氨基酸的变化改变了rtTA的结合特性，使其在存在Dox的情况下只能识别靶转基因TRE上的tetO序列。所以在Tet-On系统中，只有在存在Dox的情况下，rtTA才能激活TRE调控的靶基因的转录。
另一种诱导型启动子系统是大肠杆菌的lac阻遏物系统(参见Brown et al.,Cell 49:603-612(1987))。Lac阻遏物系统通过调控与包含lac操纵子(lacO)的启动子可操作性连接的目标多核苷酸的转录发挥功能。Lac阻遏物(lacR)与LacO结合，进而阻止目标多核苷酸的转录。通过合适的诱导剂来诱导目标多核苷酸的表达，例如，异丙基-β-D硫代半乳糖吡喃苷(IPTG)。
为了评估多肽或其部分的表达，待导入细胞的表达载体还可包含选择标记基因或报告基因或二者都有，以便于从病毒载体转染或感染的细胞群体中识别和选择表达细胞。在其他方面，选择标记可以携带在单独的DNA片段上并在共转染实验中使用。选择标记基因或报告基因都可侧接于合适的调控序列，使其在宿主细胞中能够表达。有用的选择标记包括，例如，抗生素耐药基因，如neo以及类似基因。
报告基因可用于鉴定潜在的转染细胞和评价调控序列的功能。通常，报告基因是不存在于受体生物体或组织中或不由受体生物体或组织表达的基因，其编码一种多肽，其表达表现为一些易于检测的特性，例如酶活性。当DNA导入受体细胞后，在合适的时间检测报告基因的表达。合适的报告基因可包括编码荧光素酶、β-半乳糖苷酶、氯霉素乙酰转移酶、分泌碱性磷酸酶或绿色荧光蛋白的基因(参见,Ui-Tel et al.,2000 FEBS Letters 479:79-82)。合适的表达系统是公知的，可以通过已知的技术制备或通过商业途径获得。通常，把可显示报告基因最高表达水平的最小5’侧翼区的构建体认定为启动子。此类启动子区可以与报告基因连接，并用于评估某些物质在调节启动子驱动的转录中能力。
在一些实施例中，提供编码本文所述的任一种全长抗HBV pre-S1抗体的核酸。在一些实施例中，所述核酸包括编码全长抗HBV pre-S1抗体重链和轻链的一个或多个核酸序列。在一些实施例中，所述一个或多个核酸序列中的每一个包含在单独的载体中。在一些实施例中，至少有一些核酸序列包含在同一载体中。在一些实施例中，所有核酸序列包含在同一载体中。载体可以选自，例如，哺乳动物表达载体和病毒载体(如源自逆转录病毒、腺病毒、腺相关病毒、疱疹病毒和慢病毒的载体)。
将基因导入细胞并表达的方法在本领域是已知的。在涉及表达载体的上下文中，通过本领域的任何方法载体可以很容易地导入宿主细胞中，如哺乳动物细胞、细菌、酵母或昆虫细胞。例如表达载体可以通过物理、化学或生物方法导入宿主细胞。
将多核苷酸导入宿主细胞的物理方法包括磷酸钙沉淀、脂质体转染、基因枪法、显微注射、电穿孔法以及诸如此类。制备包含载体和/或外源核酸的细胞的方法在本领域是熟知的。参见例如Green and Sambrook(2013,Molecular Cloning:A Laboratory Manual,Cold Spring Harbor Laboratory,New York)。在一些实施例中，通过磷酸钙转染法将多核苷酸导入宿主细胞。
将目标多核苷酸导入宿主细胞的生物学方法包括使用DNA和RNA载体。病毒载体，特别是逆转录病毒载体，已成为将基因插入哺乳动物细胞，例如人类细胞中的最广泛使用的方法。其它病毒载体可以源自慢病毒、痘病毒、单纯疱疹病毒1型、腺病毒和腺相关病毒等。参见如U.S.Pat.Nos.5,350,674和5,585,362。
将多核苷酸导入宿主细胞的化学方法包括胶体分散系统，例如高分子复合物、纳米胶囊、微球、磁珠和以脂质为基础的系统，其包括水包油乳剂、胶团、混合胶团和脂质体。一种在体内和体外被用作递送载体的示例性胶体系统是脂质体(例如，人工膜囊)。
在使用非病毒递送系统的情况下，示例性的递送载体是脂质体。考虑使用脂质制剂将核酸导入宿主细胞(体外、离体或体内)。在另一方面，所述核酸可以与脂质结合。与脂质结合的核酸可被包裹进脂质体的水性内部，散布在脂质体的脂质双层内，通过与脂质体和寡核苷酸结合的连接分子连接在脂质体，包埋在脂质体中，与脂质体形成复合物，分散在含有脂质的溶液中，与脂质混合，与脂质结合，悬浮在脂质中，包含在胶束中或与胶束混合，或以其它方式与脂质结合。脂质、脂质/DNA或脂质/表达载体相关的组合物在溶液中不限于任何特定结构。例如，它们可能以双分子层结构、以胶束或以“塌陷”结构存在。它们也可以简单的分散在溶液中，可能形成大小或形状不均匀的聚集体。脂质是脂肪物质，可以是天然存在的或是合成的脂质。例如，脂质包括天然存在于细胞质中的脂肪滴，以及含有长链脂肪烃及其衍生物的一类化合物，例如脂肪酸、醇、胺、氨基醇和醛。
无论采用何种方法将外源核酸导入宿主细胞中或以其他方式将细胞暴露于本申请的抑制剂中，为了确认重组DNA序列存在于宿主细胞中，可以进行多种实验。这类实验包括例如本领域技术人员熟知的“分子生物学”实验。例如Southern和Northern blotting，RT-PCR和PCR；“生物化学”实验， 例如检测某一特定多肽存在或不存在，例如通过免疫学方法(ELISAs和Western blots)或者通过本文所述的实验来进行鉴定均落入本申请范围内。
抗HBV pre-S1抗体的制备
在一些实施例中，所述抗HBV pre-S1抗体是单克隆抗体或源于单克隆抗体。在一些实施例中，所述抗HBV pre-S1抗体包括来自单克隆抗体的V H和V L，或者其变体。在一些实施例中，所述抗HBV pre-S1抗体进一步包括来自单克隆抗体的CH1和CL区域，或者其变体。单克隆抗体可以应用例如本领域已知的方法制备，包括杂交瘤细胞法、噬菌体展示方法或应用重组DNA法。此外，示例性的噬菌体展示法在本文及以下的实施例中进行了描述。
在杂交瘤细胞法中，通常采用免疫剂免疫仓鼠、小鼠或其他适合的宿主动物，以引发产生或能够产生与免疫剂特异性结合的抗体的淋巴细胞。或者，可以在体外免疫淋巴细胞。免疫剂可包括目标蛋白的多肽或融合蛋白。通常，如果需要人源细胞，采用外周血淋巴细胞(PBLs)，而如果需要非人哺乳动物来源细胞，则会使用脾细胞或淋巴结细胞。使用适当的融合剂将淋巴细胞与永生细胞系进行融合，例如聚乙二醇，以形成杂交瘤细胞。永生细胞系通常是转化的哺乳动物细胞，尤其是啮齿类、牛科和人源的骨髓瘤细胞。通常采用大鼠或小鼠骨髓瘤细胞系。杂交瘤细胞可以在合适的培养基中进行培养，所述培养基优选含有一种或多种抑制未融合永生细胞生长或存活的物质。例如，如果亲本细胞缺乏次黄嘌呤-鸟嘌呤磷酸核糖转移酶(HGPRT或HPRT)，则杂交瘤细胞培养基通常包括次黄嘌呤、氨蝶呤和胸苷(HAT培养基)，该培养基能阻止HGPRT缺陷细胞生长。
在一些实施例中，永生化细胞系有效融合，通过所选择的抗体生产细胞保证抗体高水平稳定表达，并且对某些培养基敏感，例如HAT培养基。在一些实施例中，永生细胞系是小鼠骨髓瘤细胞系，可以从例如，加利福尼亚圣地亚哥的索尔克细胞保藏中心和弗吉尼亚马纳萨斯的美国典型培养物保藏中心获得。同时还描述了人骨髓瘤和鼠-人杂交骨髓瘤细胞系用于制备人源单克隆抗体。
然后可以测定培养杂交瘤细胞的培养基中是否存在针对多肽的单克隆抗体。由杂交瘤细胞产生的单克隆抗体的结合特异性可以通过免疫沉淀法或体外结合实验确定，如放射性免疫测定法(RIA)或酶联免疫吸附法(ELISA)。此类技术或分析方法在本领域是已知的。单克隆抗体的结合亲和力可以通过例如Munson and Pollard,Anal.Biochem.,107:220(1980)中所述的斯卡查德(Scatchard)分析确定。
在鉴定出所需的杂交瘤细胞后，可以通过有限稀释法对目标克隆进行亚克隆，并通过标准方法进行培养。基于此目的适合的培养基包括，例如改良Eagle培养基(DMEM)和RPMI-1640培养基。或者，杂交瘤细胞可以在哺乳动物体内以腹水的形式生长。
亚克隆分泌的单克隆抗体可以通过常规免疫球蛋白纯化方法从培养基或腹水中分离或纯化，例如蛋白A-琼脂糖凝胶、羟基磷灰石色谱层析、凝胶电泳、透析或亲和层析。
在一些实施例中，根据本文所述的任一抗HBV pre-S1抗体，所述抗HBV pre-S1抗体包含选自抗体文库(例如展示scFv或Fab片段的噬菌体文库)的克隆的序列。所述克隆可以通过筛选具有 所需活性的抗体片段组合文库的方法进行鉴定。例如，本领域已知多种方法用于产生噬菌体展示文库以及筛选这些文库来获得所需结合特性的抗体。这些方法在例如Hoogenboom et al.,Methods in Molecular Biology 178:1-37(O'Brien et al.,ed.,Human Press,Totowa,N.J.,2001)中进行了综述，并且在例如McCafferty et al.,Nature 348:552-554；Clackson et al.,Nature 352:624-628(1991)；Marks et al.,J.Mol.Biol.222:581-597(1992)；Marks and Bradbury,Methods in Molecular Biology 248:161-175(Lo,ed.,Human Press,Totowa,N.J.,2003)；Sidhu et al.,J.Mol.Biol.338(2):299-310(2004)；Lee et al.,J.Mol.Biol.340(5):1073-1093(2004)；Fellouse,Proc.Natl.Acad.Sci.USA 101(34):12467-12472(2004)；and Lee et al.,J.Immunol.Methods 284(1-2):119-132(2004)中进行了进一步描述。
在某些噬菌体展示方法中，通过聚合酶链式反应(PCR)分别克隆V H和V L基因的所有组成成分，并在噬菌体文库中随机重组，然后筛选能够结合抗原的噬菌体，如Winter et al.,Ann.Rev.Immunol.,12:433-455(1994)中所述。噬菌体通常以scFv片段或以Fab片段形式展示抗体片段。免疫来源的文库噬菌体提供针对免疫原的高亲和力抗体而不需要构建杂交瘤细胞。或者，可以克隆天然库(例如来自人)，来提供针对多种非自身抗原和自身抗原的单一抗体来源，而不需任何免疫，如Griffiths et al.,EMBO J,12:725-734(1993)中所述。最后，天然文库也可以通过克隆来自干细胞的非重排V-gene片段，并使用包含随机序列的PCR引物编码CDR3高变区并且在体外完成重排的方法进行制备，如Hoogenboom and Winter,J.Mol.Biol.,227:381-388(1992)中所述。描述人抗体噬菌体文库的专利出版物包括，例如U.S.Pat.No.5,750,373和US Patent Publication Nos.2005/0079574、2005/0119455、2005/0266000、2007/0117126、2007/0160598、2007/0237764、2007/0292936和2009/0002360。
通过噬菌体展示筛选文库中能够特异性结合靶标HBV pre-S1抗原的抗HBV pre-S1抗体部分的方法来制备所述的抗HBV pre-S1抗体。该文库可以是人scFv噬菌体展示文库，具有至少1×10 9(例如至少1×10 9、2.5×10 9、5×10 9、7.5×10 9、1×10 10、2.5×10 10、5×10 10、7.5×10 10或1×10 11)种多样性的独特的人抗体片段。在一些实施例中，所述文库是人天然文库，通过从健康受试者的PMBCs和脾脏中提取的DNA构建，包含所有人重链和轻链亚家族。在一些实施例中，所述文库是人天然文库，通过从各种疾病患者体内分离的PMBCs中提取的DNA构建，例如自身免疫病的患者、癌症患者和感染性疾病的患者。在一些实施例中，所述文库是半合成的人文库，其中重链CDR3完全是随机的，所有氨基酸(除了半胱氨酸)以相同的概率存在于任何给定的位置。(参见例如,Hoet,R.M.et al.,Nat.Biotechnol.23(3):344-348,2005)。在一些实施例中，半合成的人文库的重链CDR3长度在5到24个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23或24个)氨基酸之间。在一些实施例中，所述文库是全合成的噬菌体展示文库。在一些实施例中，所述文库是非人噬菌体展示文库。
与靶标HBV pre-S1具有高亲和力的噬菌体克隆可以通过噬菌体与靶标HBV pre-S1抗原的迭代结合进行筛选，所述靶标HBV pre-S1抗原与固相支持物结合(例如用于溶液淘选的珠子或用于细胞淘选的哺乳动物细胞)，接下来去除未结合的噬菌体，并洗脱特异性结合噬菌体。随后，洗脱 结合的噬菌体克隆并用于感染合适的宿主细胞，例如E.coli XL1-Blue，进行表达和纯化。可以通过多轮淘选(例如，2、3、4、5、6或更多轮)，例如溶液淘选、细胞淘选或两者结合以富集特异性结合HBV pre-S1的噬菌体克隆。富集的噬菌体克隆与靶标HBV pre-S1的特异性结合可以通过本领域已知的任何方法进行检测，包括例如ELISA和FACS。
筛选抗体文库的另一种方法是在酵母细胞表面展示蛋白质。Wittrup等(美国专利6,699,658和6,696,251)开发了一种酵母细胞展示文库的方法。在此酵母展示系统中，一个组分包括锚定在酵母细胞壁上的酵母凝集素蛋白(Aga1)，另一个组分包括凝集素蛋白Aga2的第二个亚基，该亚基可以通过二硫键与Aga1蛋白结合进而展示在酵母细胞表面上。通过将Aga1基因整合到酵母染色体中来表达Aga1蛋白。将单链可变片段(scFv)文库与酵母展示质粒中的Aga2基因融合，将其转化后，该文库由于附加的营养标记的存在可保留在酵母中。Aga1和Aga2蛋白均在半乳糖诱导型启动子的控制下表达。
人抗体V基因库(V H和V K片段)是使用一组简并引物通过PCR方法获得(Sblattero，D.and Bradbury,A.Immunotechnology 3,271-278 1998)。PCR模板来自可商购的RNA或cDNA，包括PBMC，脾脏，淋巴结，骨髓和扁桃体。将独立的V H和V K PCR文库合并后，通过重叠延伸PCR将其组装成scFv形式(Sheets，M.D.et al,Proc.Natl.Acad.Sci.USA 95,6157–6162 1998)。为了构建酵母scFv展示文库，通过同源重组将所得的scFv PCR产物克隆到酵母中的酵母展示质粒中。(Chao,G,et al,Nat Protoc.2006；1(2):755-68.Miller KD,et al.Current Protocols in Cytometry 4.7.1-4.7.30,2008)。
可以利用哺乳动物细胞展示系统来筛选抗HBV pre-S1抗体，其中抗体部分展示在细胞表面上并通过抗原导向的筛选方法分离出特异性靶向HBV pre-S1的抗体(如U.S.patent No.7,732,195B2中所述)。可以建立展示大量人类IgG抗体基因的中国仓鼠卵巢(CHO)细胞文库，并将其用于发现表达高亲和力抗体基因的克隆。已开发出另一种展示系统，该系统通过可变剪接使同一蛋白同时在细胞表面展示和分泌，其中展示的蛋白表型保持与基因型相关，使得可同时在生物物理和基于细胞功能的分析中表征该分泌的可溶性抗体。该方法克服了先前哺乳动物细胞展示的许多局限性，能够直接筛选和成熟化全长的、糖基化的IgGs形式的抗体(Peter M.Bowers,et al,Methods 2014,65：44-56)。瞬时表达系统适用于在抗体基因恢复之前进行的单轮抗原选择，因此对于从较小文库中选择抗体最有用。稳定的外显体载体提供了一种有吸引力的选择。外显体载体可以高效转染并稳定地维持在低拷贝数，从而允许多轮淘选以及更复杂抗体库的解析。
IgG文库是基于分离自一群人类供体的种系序列V基因片段与重排的(D)J区域的连接构建而成。将从2000个人体血液样本中收集的RNA反转录为cDNA，使用V H和V K特异性引物扩增V H和V K片段，并通过凝胶提取纯化。将V H和V K片段分别亚克隆到包含IgG1或K恒定区的展示载体中，然后电穿孔或转导293T到细胞，从而制备IgG文库。为了制备scFv抗体展示文库，连接V H和V K以产生scFv，然后亚克隆到展示载体中，再将其电穿孔或转导293T细胞。众所周知， IgG文库是基于分离自一群供体的种系序列V基因片段与重排的(D)J区域构建而成，供体可以是小鼠，大鼠，兔或猴。
单克隆抗体也可以通过重组DNA方法进行制备，例如U.S.Patent No.4,816,567中所述。编码本申请中所述单克隆抗体的DNA可以通过常规方法(例如通过能特异性结合编码鼠源抗体轻链和重链基因的寡聚核苷酸探针)轻易的分离和测序。如上所述的杂交瘤细胞或本申请的HBV pre-S1特异性噬菌体克隆可以作为这种DNA的来源。分离后，可将DNA置于表达载体中，然后该载体转染入宿主细胞，例如猿猴COS细胞、中华仓鼠卵巢癌(CHO)细胞或不产生免疫球蛋白的骨髓瘤细胞中，获得在重组宿主细胞中合成的单克隆抗体。所述DNA也可以被修饰，例如用编码序列取代人重链和轻链恒定区和/或用框架区替换同源非人序列(U.S.Patent No.4,816,567；Morrison et al.,supra)，或通过共价键连接免疫球蛋白的编码序列的全部或部分非免疫球蛋白多肽的编码序列。这种非免疫球蛋白多肽可以取代本申请中抗体的恒定区，或可以取代本申请中抗体可变结构域中的一个抗原结合位点，形成嵌合的二价抗体。
所述抗体可以是单价抗体。制备单价抗体的方法是本领域已知的。例如，一种涉及免疫球蛋白轻链和修饰重链的重组表达方法。通常在Fc区的任意位置截短重链，以阻止重链相互交联。或者，相关的半胱氨酸残基被其它氨基酸残基取代或被缺失以防止交联。
体外方法也适用于制备单价抗体。消化抗体产生抗体片段，特别是Fab片段，可以使用任何本领域已知的方法完成。
具有所需结合特异性(抗体-抗原结合位点)的抗体可变结构域可以与免疫球蛋白恒定区融合。优选与免疫球蛋白重链恒定区进行融合，其包括至少部分铰链，CH2和CH3区。在一些实施例中，包含轻链结合必要位点的第一重链恒定区(CH1)至少出现在一种融合体中。编码免疫球蛋白重链融合体的DNA，如果需要，还可以包括编码免疫球蛋白轻链的DNA，被插入进独立的表达载体中，并共转染至合适的宿主生物中。
全人和人源化抗体
所述抗HBV pre-S1抗体(如全长的抗HBV pre-S1抗体)可以是全人抗体或人源化抗体。非人(如小鼠)抗体部分的人源化形式是嵌合的免疫球蛋白、免疫球蛋白链或其片段(例如Fv、Fab、Fab’、F(ab’) 2、scFv或抗体的其他抗原结合子序列)，其通常包括最少的源于非人免疫球蛋白的序列。人源化抗体包括人免疫球蛋白、免疫球蛋白链或其片段(受体抗体)，其中受体CDR的残基被具有所需特异性、亲和力和性能的非人源(供体抗体)CDR残基取代，例如小鼠、大鼠或兔子的CDR。在一些实施例中，人免疫球蛋白Fv框架区残基被相应的非人源残基取代。人源化抗体还可以包含既不属于受体抗体也不在引入的CDR或框架区序列中的氨基酸残基。通常，人源化抗体包含至少一个，通常两个可变结构域，其中全部或基本上全部CDR区对应于非人免疫球蛋白的CDR区，全部或基本上全部框架区是人免疫球蛋白共有序列。
通常，人源化抗体含有一个或多个从非人源引入的氨基酸残基。那些非人源氨基酸残基通常被称为“移入”残基，通常来自“移入”可变结构域。根据一些实施例，人源化基本上可以按照Winter 和其同事的如下方法进行(Jones et al.,Nature,321:522-525(1986)；Riechmann et al.,Nature,332:323-327(1988)；Verhoeyen et al.,Science,239:1534-1536(1988))，通过用啮齿动物CDRs或CDR序列取代人源抗体的相应序列。因此，这种“人源化”抗体部分(U.S.Patent No.4,816,567)，其基本上少于完整的人源抗体，其可变结构域已被来自非人源的相应序列所取代。在实际中，人源化抗体部分是典型的人源抗体部分，其中一些CDR残基和可能的一些框架区残基被来自啮齿类抗体中类似位点的残基所取代。
全人抗体是人源化的一种替代方式。例如，目前可以制备在免疫后能够产生完整的全人抗体文库而不产生内源性免疫球蛋白的转基因动物(例如，小鼠)。例如，已有报道，嵌合和种系突变小鼠中抗体重链连接区(JH)基因的纯合子缺失，完全抑制了内源性抗体的产生。将人种系免疫球蛋白基因阵列转移到这种种系突变小鼠体内，可在抗原刺激下产生人源抗体，参见，例如akobovits et al.,PNAS USA,90:2551(1993)；Jakobovits et al.,Nature,362:255-258(1993)；Bruggemann et al.,Year in Immunol.,7:33(1993)；U.S.Patent Nos.5,545,806,5,569,825,5,591,669,5,545,807；和WO 97/17852。或者，可以通过将人类免疫球蛋白基因座引入转基因动物中(例如内源性免疫球蛋白基因已经被部分或全部沉默的小鼠)来制备全人抗体。抗原刺激后，可以发现全人抗体的产生在各个方面都与其在人类中的产生非常相似，包括基因重排、组装和抗体文库。这种方法在例如U.S.Patent Nos.5,545,807；5,545,806；5,569,825；5,625,126；5,633,425；and 5,661,016,and Marks et al.,Bio/Technology,10:779-783(1992)；Lonberg et al.,Nature,368:856-859(1994)；Morrison,Nature,368:812-813(1994)；Fishwild et al.,Nature Biotechnology,14:845-851(1996)；Neuberger,Nature Biotechnology,14:826(1996)；Lonberg and Huszar,Intern.Rev.Immunol.,13:65-93(1995)中进行了描述。
全人抗体也以通过体外活化B细胞(见U.S.Patents 5,567,610and 5,229,275)或通过使用本领域已知的各种技术来产生，包括噬菌体展示文库。Hoogenboom and Winter,J.Mol.Biol.,227:381(1991)；Marks et al.,J.Mol.Biol.,222:581(1991).Cole et al.和Boerner et al.等人的技术也可以用于制备全人单克隆抗体。见Cole et al.,Monoclonal Antibodies and Cancer Therapy,Alan R.Liss,p.77(1985)and Boerner et al.,J.Immunol.,147(1):86-95(1991)。
抗HBV pre-S1抗体变体
在一些实施例中，本文提供的抗HBV pre-S1抗体变体(例如，全长的抗HBV pre-S1抗体)的氨基酸序列也在考虑中。例如，可能需要改善抗体的结合亲和力和/或其它生物学活性。抗体变体的氨基酸序列可以通过在编码抗体的核苷酸序列中引入适当的修饰或通过肽合成来制备。此类修饰包括例如，抗体氨基酸序列中残基的缺失和/或插入和/或取代。可以通过氨基酸残基缺失、插入和取代的任一组合来完成最终的构建，使其具有所需的特征。例如，抗原结合性。
在一些实施例中，提供具有一个或多个氨基酸取代的抗HBV pre-S1抗体变体。取代突变的目标位点包括高变区(HVRs)和框架区(FRs)。可以在目标抗体中引入氨基酸取代，筛选所需活 性的产物，例如，改善的生物活性，保持/改善抗原结合能力，降低的免疫原性，或改善的ADCC、ADCP或CDC。
保守取代如下表4所示。
表4 保守取代
原始残基 示例性取代 优选取代
Ala(A) Val；Leu；Ile Val
Arg(R) Lys；Gln；Asn Lys
Asn(N) Gln；His；Asp,Lys；Arg Gln
Asp(D) Glu；Asn Glu
Cys(C) Ser；Ala Ser
Gln(Q) Asn；Glu Asn
Glu(E) Asp；Gln Asp
Gly(G) Ala Ala
His(H) Asn；Gln；Lys；Arg Arg
Ile(I) Leu；Val；Met；Ala；Phe；Norleucine Leu
Leu(L) Norleucine；Ile；Val；Met；Ala；Phe Ile
Lys(K) Arg；Gln；Asn Arg
Met(M) Leu；Phe；Ile Leu
Phe(F) Trp；Leu；Val；Ile；Ala；Tyr Tyr
Pro(P) Ala Ala
Ser(S) Thr Thr
Thr(T) Val；Ser Ser
Trp(W) Tyr；Phe Tyr
Tyr(Y) Trp；Phe；Thr；Ser Phe
Val(V) Ile；Leu；Met；Phe；Ala；Norleucine Leu
根据侧链性质将氨基酸分为不同类别：
a、疏水氨基酸：去甲亮氨酸Norleucine、蛋氨酸Met、丙氨酸Ala、缬氨酸Val、亮氨酸Leu、异亮氨酸Ile；
b、中性亲水性氨基酸：半胱氨酸Cys、丝氨酸Ser、苏氨酸Thr、天冬酰胺Asn、谷氨酰胺Gln；
c、酸性氨基酸：天冬氨酸Asp、谷氨酸Glu；
d、碱性氨基酸：组氨酸His、赖氨酸Lys、精氨酸Arg；
e、含有影响链方向的氨基酸：甘氨酸Gly、脯氨酸Pro；
f、芳香族氨基酸：色氨酸Trp、酪氨酸Tyr、苯丙氨酸Phe。
非保守氨基酸的取代包含将以上一种类别取代为另一种类别。
一种示例性的取代变体是亲和力成熟的抗体，可采用例如以噬菌体展示为基础的亲和力成熟技术而方便地产生。简言之，将一个或多个CDR残基进行突变，变体抗体部分展示在噬菌体上，并筛选具有特定生物活性(例如，基于中和活性或结合亲和力)的变体。可以在HVRs区进行改变(例如，取代)来获得改善的中和活性或结合亲和力。可以在HVR的“热点区”产生改变，即在体细胞成熟过程中发生高频突变的密码子编码的残基(参见，例如Chowdhury,Methods Mol.Biol.207:179-196(2008))，和/或在特异的决定性残基(SDRs)，检测所得变体V H和V L的结合亲和 力。从二级文库中构建和重新选择亲和力成熟的方法已经在一些文献中进行描述，例如，Hoogenboom et al.in Methods in Molecular Biology 178:1-37(O'Brien et al.,ed.,Human Press,Totowa,NJ,(2001))。
在一些亲和力成熟的实施例中，通过多种方法中的任一种(例如易错PCR，链改组或寡核苷酸定向突变)，将多样性引入选择的用于亲和力成熟的可变基因中。然后创建二级文库。对该文库进行筛选，鉴定出具有所需亲和力的抗体变体。另一种引入多样性的方法包括HVR介导的方式，其中几个HVR残基(例如，一次4-6个残基)被随机化。涉及抗原结合的HVR残基被特异性地识别，例如，采用丙氨酸扫描诱变或建模。通常CDR-H3和CDR-L3区域尤其是重点靶标。
在一些实施例中，取代、插入或缺失可能发生在一个或多个HVRs内，只要这种改变基本上不降低抗体结合抗原的能力。例如，可以在HVRs中产生基本上不降低结合亲和力的保守性改变(例如，本文中提供的保守性取代)。这些改变可能发生在HVR“热点区”或SDRs区域之外。在一些实施例中上文提供的变体V H和V L序列，每一个HVR或者是未发生改变，或者包含不超过1个、2个或3个氨基酸取代。
一种有用的可以鉴定出抗体中能被靶向性突变的氨基酸残基或区域的方法称为“丙氨酸扫描突变”，如Cunningham and Wells(1989)Science,244:1081-1085中所述。在该方法中，一个或一组目标残基(例如，带电残基如精氨酸、天冬氨酸、组氨酸、赖氨酸和谷氨酸)被中性或带负电荷氨基酸(例如，丙氨酸或谷氨酸)取代，以此来确定抗体与抗原相互作用是否受到影响。可以在氨基酸的位置进一步引入取代，来证明该位置对初始取代具有功能敏感性。或者/另外，通过抗原-抗体复合物的晶体结构来鉴定抗体和抗原之间的接触位点。这些接触位点残基和邻近残基可作为取代候选物而被靶向或消除。筛选变体，确定它们是否具有所需要的性质。
氨基酸序列的插入，包括在氨基端和/或羧基末端的融合，长度范围从1个残基到包含100个或更多个残基的多肽，还包括在序列内插入1个或多个氨基酸残基。末端插入的例子包括N末端具有甲硫氨酰残基的抗体。抗体分子的其它插入变体，包括在抗体分子N-末端或C-末端融合一个酶(例如，ADEPT)或增加抗体血清半衰期的多肽。
Fc区变体
在一些实施例中，将一个或多个氨基酸修饰引入本文所述的抗体(例如，全长抗HBV pre-S1抗体或抗HBV pre-S1抗体融合蛋白)的Fc区，从而产生Fc区变体。在一些实施例中，Fc区变体具有增强的ADCC或ADCP效能，通常与结合Fc的受体(FcRs)有关。在一些实施例中，Fc区变体具有降低的ADCC或ADCP效能。有很多关于Fc序列的改变或突变影响其效能的例子，例如，WO 00/42072、Shields et al.J Biol.Chem.9(2):6591-6604(2001)中描述了与FcRs的结合增强或减弱的抗体变体。这些出版物的内容通过引用并入本文。
抗体依赖的细胞介导的细胞毒作用(ADCC)和抗体依赖性细胞介导的吞噬作用(ADCP)是抗体破坏靶细胞的潜在机制。ADCC是细胞介导的免疫防御，当靶细胞膜表面的抗原被特异性抗体(例如，抗HBV pre-S1抗体)结合，免疫系统的效应细胞主动裂解靶细胞(例如，感染细胞)。 ADCP是细胞介导的免疫防御反应，表达FcγRs的非特异性细胞毒性细胞识别结合在靶细胞上的抗体，进而引起对靶细胞的吞噬作用。通常ADCC效应涉及由抗体激活的NK细胞。NK细胞表达Fc受体CD16。该受体识别并结合与靶细胞表面相结合的抗体分子的Fc部分。NK细胞表面最常见的Fc受体为CD16或FcγRIII。Fc受体与抗体Fc区的结合导致NK细胞的活化，释放细胞裂解颗粒，随后靶细胞凋亡。ADCC对肿瘤细胞的杀伤作用可以通过转染高亲和力FcR的NK-92细胞的特异性实验来测定。其结果与不表达FcR的野生型NK-92进行比较。
在一些实施例中，本申请还提供抗HBV pre-S1抗体变体(例如全长抗HBV pre-S1抗体变体)，其包含具有部分但不是全部的效应功能Fc区，使得其在体内具有延长的半衰期，然而特定的效应功能(例如CDC或ADCC)是非必需的或有害的，这种抗HBV pre-S1抗体成为本申请理想的候选。通过在体外和/或体内进行细胞毒性检测来确认CDC和/或ADCC活性的减少/消除。例如，通过Fc受体(FcR)结合试验来确认抗体缺乏FcγR结合能力(因此可能缺乏ADCC活性)但依然保留FcRn的结合能力。介导ADCC的主要细胞中，NK细胞仅表达FcγRIII，而单核细胞表达FcγRI、FcγRII和FcγRIII。Ravetch and Kinet Annu.Rev.Immunol.9:457-492(1991)第464页的表3中总结了FcR在造血细胞上的表达。在体外评估目标分子的ADCC活性的非限制性实例在U.S.Pat.No.5,500,362中进行了描述(参见例如Hellstrom,I.et al.Proc.Nat'l Acad.Sci.USA 83:7059-7063(1986)and Hellstrom,I et al.,Proc.Nat'l Acad.Sci.USA 82:1499-1502(1985)；U.S.Pat.No.5,821,337(see Bruggemann,M.et al.,J.Exp.Med.166:1351-1361(1987))。或者，可以采用非放射性检测方法(参见，例如ACTI TM流式细胞术非放射性细胞毒性检测(CellTechnology,Inc.Mountain View,Calif.)和CYTOTOX 96 TM非放射性细胞毒性检测(Promega,Madison,Wis.))。此类检测实验采用的效应细胞包括外周血单核细胞(PBMC)和自然杀伤细胞(NK)。或者，另外地，目标分子的ADCC活性在体内进行检测，例如，在动物模型中，如Clynes et al.Proc.Nat'l Acad.Sci.USA95:652-656(1998)中所述。同时还可以进行C1q结合试验来确认抗体不能与C1q结合，从而缺乏CDC活性。参见，例如WO 2006/029879和WO 2005/100402中C1q和C3c结合ELISA。为了评估补体激活情况，可进行CDC检测(参见，例如Gazzano-Santoro et al.,J.Immunol.Methods 202:163(1996)；Cragg,M.S.et al.,Blood 101:1045-1052(2003)；和Cragg,M.S.and M.J.Glennie,Blood103:2738-2743(2004))。使用本领域已知的方法来测定FcRn结合和体内清除/半衰期(参见，例如，Petkova,S.B.et al.,Int'l.Immunol.18(12):1759-1769(2006))。
具有降低的效应功能的抗体，包括在Fc区残基238、265、269、270、297、327和329位进行一个或多个残基的取代(U.S.Pat.No.6,737,056)。这些Fc变体包括在265、269、270、297和327位进行两个或多个残基的取代的Fc变体，包括被称为“DANA”的Fc变体，其在265和297位残基取代为丙氨酸(U.S.Pat.No.7,332,581)。
这类与FcRs结合能力提高或降低的抗体变体已有描述(参见例如U.S.Pat.No.6,737,056；WO 2004/056312，和Shields et al.,J.Biol.Chem.9(2):6591-6604(2001))。
在一些实施例中，提供一种抗HBV pre-S1抗体(例如全长的抗HBV pre-S1抗体)变体，其包含具有一个或多个能够增强ADCC效应的氨基酸取代的Fc区变体。在一些实施例中，Fc区变体包含一个或多个能够增强ADCC效应的氨基取代，这些取代的位置在Fc区的298、333和/或334位(EU残基编号)。在一些实施例中，所述抗HBV pre-S1抗体(例如，全长的抗HBV pre-S1抗体)变体包括在Fc区的S298A，E333A和K334A位氨基酸取代。
在一些实施例中，Fc区的改变导致C1q结合和/或补体依赖性细胞毒作用(CDC)的改变(即增强或减弱)，参见U.S.Pat.No.6,194,551,WO 99/51642，和Idusogie et al.,J.Immunol.164:4178-4184(2000)中所述。
在一些实施例中，提供一种抗HBV pre-S1抗体(例如全长的抗HBV pre-S1抗体)变体，其包含具有一个或多个能够增强ADCP效应的氨基酸取代的Fc区变体。在一些实施例中，Fc区的改变导致与FcγRIIa的结合和/或抗体依赖性细胞介导的吞噬作用(ADCP)的改变(即增强或减弱)。
在一些实施例中，提供一种抗HBV pre-S1抗体(例如全长的抗HBV pre-S1抗体)变体，其包含具有一个或多个氨基酸取代的Fc区变体，能够延长半衰期或增强与Fc受体(FcRn)的结合。具有延长半衰期和改善FcRn结合的抗体在US 2005/0014934A1(Hinton等)中有所描述。这些抗体Fc区包含一个或多个氨基酸取代，增强了Fc区与FcRn的结合。这些Fc变体在Fc区包含238、256、265、272、286、303、305、307、311、312、317、340、356、360、362、376、378、380、382、413、424或434位的残基中的一个或多个取代，例如Fc区434位残基的取代(U.S.Pat.No.7,371,826)。
同时参见Duncan & Winter,Nature 322:738-40(1988)；U.S.Pat.No.5,648,260；U.S.Pat.No.5,624,821和WO 94/29351中提供其它Fc区变体的例子。
本申请考虑了包括本文所述的任一种Fc变体或其组合的抗HBV pre-S1抗体(例如全长抗HBV pre-S1抗体)。
糖基化变体
在一些实施例中，对本文所提供的抗HBV pre-S1抗体(例如全长抗HBV pre-S1抗体)进行改变，以增加或降低抗NGF抗体糖基化的程度。通过改变抗NGF抗体或其多肽部分的氨基酸序列以此来增加或去除一个或多个糖基化位点，可以方便地实现添加或删除抗HBV pre-S1抗体上的糖基化位点。
其中抗HBV pre-S1抗体包含Fc区，可以改变与其连接的糖。由哺乳动物细胞产生的天然抗体通常包含分支的双触角寡糖，该寡糖通常通过N-连接与Fc区CH2结构域Asn297连接，参见例如Wright et al.，TIBTECH 15:26-32(1997)。所述寡糖可包含多种糖类，例如甘露糖、N-乙酰氨基葡萄糖苷(GlcNAc)、半乳糖和唾液酸，以及与双触角寡糖结构“茎”部的GlcNAc相连接的海藻糖。在一些实施例中，可对本申请的抗HBV pre-S1抗体进行寡糖修饰，从而产生具有某些改进特性的抗HBV pre-S1抗体变体。
与Fc区的CH2结构域连接的N-聚糖是异质的。CHO细胞中产生的抗体或Fc融合蛋白通过岩藻糖基转移酶活性被岩藻糖基化，参见Shoji-Hosaka et al.,J.Biochem.2006,140:777-83。通常，可以在人血清中检测出一小部分天然存在的非岩藻糖基化IgGs。Fc区的N-糖基化对于其与FcγR结合很重要；而非岩藻糖基化的N-聚糖增强了Fc与FcγRIIIa的结合能力。与FcRIIIa结合能力增强使得ADCC效应增强，这在需要细胞毒性的某些抗体治疗应用中是有利的。
在一些实施例中，当不需要Fc介导的细胞毒作用时，增强的效应功能可能是有害的。在一些实施例中，Fc片段或CH2结构域是非糖基化的。在一些实施例中，通过对CH2结构域中的N-糖基化位点进行突变以阻止其糖基化。
在一些实施例中，提供抗HBV pre-S1抗体(例如全长的抗HBV pre-S1抗体)变体，其包含Fc区，其中连接于Fc区的糖类结构具有减少的岩藻糖或缺乏岩藻糖，这可能会增强ADCC功能。具体地，本文提供抗HBV pre-S1抗体，其相对于野生型CHO细胞产生的相同抗HBV pre-S1抗体具有减少的岩藻糖。也就是说，它们的特征在于，与天然CHO细胞(例如，产生天然糖基化形式的CHO细胞，含有天然FUT8基因的CHO细胞)产生的抗体相比，具有更少量的岩藻糖。在一些实施例中，所述抗HBV pre-S1抗体的N-连接聚糖具有少于50％、40％、30％、20％、10％或5％的岩藻糖。例如，该抗HBV pre-S1抗体的岩藻糖含量可能是1％-80％、1％-65％、5％-65％或20％-40％。在一些实施例中，所述抗HBV pre-S1抗体的N-连接聚糖不包含岩藻糖，即，其中抗HBV pre-S1抗体完全不含岩藻糖，或没有岩藻糖或是去岩藻糖基化。岩藻糖的含量是通过计算连接到Asn297上的糖链内岩藻糖平均含量相对于通过MALDI-TOF质谱测量的所有连接在Asn297上的糖结构(如复合、杂交或甘露糖结构)的总量来确定的，如WO 2008/077546所述。Asn297是指位于Fc区297位的天冬酰胺残基(EU Fc区残基编号体系)。然而，由于抗体的微小序列变化，Asn297也可位于297位的上游或下游±3个氨基酸，即在294和300位之间。这些岩藻糖基化变体可能具有增强的ADCC功能。参见例如US Patent Publication Nos.US 2003/0157108(Presta,L.)，US 2004/0093621(Kyowa Hakko Kogyo Co.,Ltd)。与“去岩藻糖基化”或“岩藻糖缺乏”的抗体变体相关的出版物的实例包括，US 2003/0157108；WO 2000/61739；WO 2001/29246；US 2003/0115614；US 2002/0164328；US 2004/0093621；US 2004/0132140；US 2004/0110704；US 2004/0110282；US 2004/0109865；WO 2003/085119；WO 2003/084570；WO 2005/035586；WO 2005/035778；WO 2005/053742；WO 2002/031140；Okazaki et al.J.Mol.Biol.336:1239-1249(2004)；Yamane-Ohnuki et al.Biotech.Bioeng.87:614(2004)。能够产生去岩藻糖基化抗体的细胞系包括缺乏蛋白岩藻糖基化功能的Lec13CHO细胞(Ripka et al.Arch.Biochem.Biophys.249:533-545(1986)；US Pat Appl No US 2003/0157108A1,Presta,L；和WO 2004/056312A1,Adams et al.,尤其是实施例11)，和基因敲除细胞系，例如α-1,6-岩藻糖基转移酶基因，FUT8基因敲除的CHO细胞(参见Yamane-Ohnuki et al.Biotech.Bioeng.87:614(2004)；Kanda,Y.et al.,Biotechnol.Bioeng.,94(4):680-688(2006)；和WO2003/085107)。
抗HBV pre-S1抗体(例如全长抗HBV pre-S1抗体)变体进一步提供二等分寡糖，例如，其中连接于抗HBV pre-S1抗体Fc区的双触角寡糖被GlcNAc等分。这种抗HBV pre-S1抗体(例如全长的抗HBV pre-S1抗体)变体可能具有减少的岩藻糖基化和/或增强的ADCC功能。这类抗体变体的实例在WO 2003/011878(Jean-Mairet et al.)；U.S.Pat.No.6,602,684(Umana et al.)；US 2005/0123546(Umana et al.)，和Ferrara et al.,Biotechnology and Bioengineering,93(5):851-861(2006)中有所描述。还提供抗HBV pre-S1抗体(例如全长的抗HBV pre-S1抗体)变体，其在与Fc区连接的寡糖中具有至少一个半乳糖残基。这类抗HBV pre-S1抗体变体可能具有增强的CDC功能。这类变体在例如WO 1997/30087(Patel et al.)；WO 1998/58964(Raju,S.)；和WO 1999/22764(Raju,S.)中有所描述。
在一些实施例中，所述抗HBV pre-S1抗体(例如全长抗HBV pre-S1抗体)变体包含能与FcγRIII结合的Fc区。在一些实施例中，包含Fc区的所述抗HBV pre-S1抗体(例如全长抗HBV pre-S1抗体)变体在人效应细胞(例如T细胞)存在下具有ADCC活性，或者与具有人野生型IgG1Fc区的其他相同抗HBV pre-S1抗体(例如全长抗HBV pre-S1抗体)相比，在人效应细胞存在下，具有增强的ADCC活性。
半胱氨酸工程变体
在一些实施例中，需要制备半胱氨酸工程化的抗HBV pre-S1抗体(例如全长抗HBV pre-S1抗体)，在该抗体中一个或多个氨基酸残基被半胱氨酸残基取代。在一些实施例中，取代残基出现在抗HBV pre-S1抗体的可及位点。通过用半胱氨酸取代那些残基，具有活性的巯基基团位于抗HBV pre-S1抗体的可及位点，可以用于将该抗HBV pre-S1抗体与其它部分偶联，例如药物部分或接头-药物部分，来制备如本文中进一步描述的抗HBV pre-S1免疫偶联物。半胱氨酸工程化的抗HBV pre-S1抗体(例如，全长抗HBV pre-S1抗体)可以按照例如U.S.Pat.No.7,521,541所述进行制备。
衍生物
在一些实施例中，本文所提供的抗HBV pre-S1抗体(例如全长抗HBV pre-S1抗体)可进一步修饰以包含本领域已知并且容易获得的其它非蛋白部分。适用于衍生化抗HBV pre-S1抗体的部分包括，但不限于，水溶性聚合物。水溶性聚合物的非限制性实例包括，但不限于，聚乙二醇(PEG)、乙二醇/丙二醇共聚物、羧甲基纤维素、右旋糖酐、聚乙烯醇、聚乙烯吡咯烷酮、聚-1,3-二氧戊烷、聚-1,3,6-三氧杂环已烷、乙烯/马来酸酐共聚物、聚氨基酸(均聚物或无规共聚物)、右旋糖酐或聚(n-乙烯基吡咯烷酮)聚乙二醇、丙二醇均聚物、环氧丙烷/环氧乙烷共聚物、聚氧乙基化多元醇(例如甘油)、聚乙烯醇及其混合物。聚乙二醇丙醛由于其在水中的稳定性，在制造中具有优势。聚合物可以具有任意分子量，可以是支链或非支链的。连接在抗HBV pre-S1抗体上的聚合物数量可以变化，并且如果连接多于一个多聚物，它们可以是相同的或不同的分子。通常，用于衍生化的聚合物的数量和/或类型可基于以下考虑因素来确定，包括但不限于，需要改进抗HBV pre-S1抗体的特性或功能，抗HBV pre-S1抗体衍生物是否用于特定条件下的治疗等。
药物组合物
本文还提供包含任一种抗HBV pre-S1抗体(例如全长抗HBV pre-S1抗体)、编码抗体的核酸、包含编码抗体的核酸的载体或者包含本文所述的核酸或载体的宿主细胞的组合物(例如药物组合物，在这里也称为制剂)。在一些实施例中，提供一种药物组合物，包含本文所述的任一种抗HBV pre-S1抗体和药学上可接受的载体。
可通过混合具有所需纯度的抗HBV pre-S1抗体与任选的药学上可接受的载体、赋形剂或稳定剂(Remington's Pharmaceutical Sciences 16th edition,Osol,A.Ed.(1980))获得合适的抗HBV pre-S1抗体制剂，制备成冻干制剂或液体制剂形式。可接受的载体、赋形剂或稳定剂在所用剂量和浓度下对接受者无毒，包括缓冲剂如：磷酸盐、柠檬酸和其它有机酸；抗氧化剂，包括抗坏血酸和蛋氨酸；防腐剂(例如十八烷基二甲基苄基氯化铵；六甲基氯化铵；苯扎氯铵；苄索氯铵；苯酚；丁醇或苄醇；对羟基苯甲酸烷基酯，如对羟基苯甲酸甲酯或对羟基苯甲酸丙酯；邻苯二酚；间苯二酚；环己醇；3-戊醇和间甲酚)；低分子量(少于10个残基)多肽；蛋白质，例如血清白蛋白、明胶或免疫球蛋白；亲水性聚合物，如聚乙烯吡咯烷酮；氨基酸，例如甘氨酸、谷氨酰胺、天冬酰胺、组氨酸、精氨酸或赖氨酸；单糖、二糖和其它碳水化合物，包括葡萄糖、甘露糖或糊精；螯合剂如EDTA；糖类，如蔗糖、甘露醇、海藻糖或山梨糖醇；成盐反离子如钠；金属复合物(如锌-蛋白复合物)；和/或非离子表面活性剂如TWEEN TM，PLURONICS TM或聚乙二醇(PEG)；示例性制剂如WO98/56418中所述，并通过引用明确并入本文。适合皮下给药的冻干制剂在WO97/04801中有所描述。这类冻干制剂可通过合适的稀释剂重构成高蛋白浓度的制剂，并且重构的制剂可以通过皮下给药的方式给予本文中待治疗个体。阳离子脂质体或脂质体可以用于将本申请中的抗HBV pre-S1抗体递送至细胞。
本文所述的制剂除包含抗HBV pre-S1抗体(例如全长抗HBV pre-S1抗体)之外，还可以包含一种或多种治疗特定病症所必要的其它活性物质，优选具有活性互补且彼此无不良反应的物质。例如，除了抗HBV pre-S1抗体之外，可能需要进一步包含抗病毒剂、抗过敏剂、抗恶心剂(或抗呕剂)、镇痛药、细胞保护剂、免疫抑制剂及其组合。所述抗病毒药物可包括但并不限于干扰素、核苷/核苷酸类似物、抗HBV的单克隆抗体、抗HBV的多克隆抗体、DNA聚合酶抑制剂或治疗性疫苗。所述核苷/核苷酸类似物可包括但并不限于拉米夫定、恩替卡韦、克来夫定或阿德福韦酯。这些分子以对预期目的有效的量组合存在。其它物质的有效量取决于制剂中的抗HBV pre-S1抗体的含量，疾病或病症或治疗的类型，以及如上所述的其它因素。这些药物通常以与本文描述的相同剂量和给药途径使用，或者以目前应用剂量的1％至99％使用。
所述抗HBV pre-S1抗体(例如，全长抗HBV pre-S1抗体)也可以包埋在例如通过凝聚技术和界面聚合制备的微胶囊中，例如分别在胶体药物递送系统(例如，脂质体、白蛋白微球、微乳液、纳米颗粒和纳米胶囊)中或粗乳液中的羟甲基纤维素或明胶-微胶囊和聚(甲基丙烯酸甲酯)微胶囊。可以制备缓释制剂。
可以制备抗HBV pre-S1抗体(例如，全长抗HBV pre-S1抗体)的缓释制剂。缓释制剂的适合的实例包括含有抗体(或其片段)的固体疏水聚合物半透性基质，这些基质是成型制品的形式，例如，薄膜或微胶囊。缓释基质的实例包括聚酯、水凝胶(例如，聚(2-羟乙基甲基丙烯酸酯)或聚(乙烯醇))、聚乳酸(U.S.Pat.No.3,773,919)，L-谷氨酸和L-谷氨酸乙酯共聚物，不可降解的乙烯-醋酸乙烯酯，可降解的乳酸-乙醇酸共聚物如LUPRON DEPOTTM(由乳酸-乙醇酸共聚物和醋酸亮丙瑞林组成的可注射微球)以及聚-D(-)-3-羟基丁酸。虽然诸如乙烯-醋酸乙烯酯和乳酸-乙醇酸之类的聚合物可以使分子的释放超过100天，某些水凝胶可以在更短的时间内释放蛋白质。当包封的抗体在体内长时间停留时，它们会因暴露于37℃的潮湿环境中发生变性或聚集，可能导致生物活性的丧失或免疫原性的改变。可以根据相应的机制，设计合理的策略来稳定抗HBV pre-S1抗体。例如，如果发现聚集机制是通过硫代二硫化物交换形成分子间S-S键，则可以通过修饰巯基残基、在酸性溶液中冻干、控制含水量、使用适当的添加剂、以及开发特定的聚合物基质组合物来实现稳定化。
在一些实施例中，所述抗HBV pre-S1抗体(例如全长抗HBV pre-S1抗体)配制在含有柠檬酸盐、氯化钠、乙酸盐、琥珀酸盐、甘氨酸、聚山梨酯80(吐温80)或上述任何组合的缓冲液中。
用于体内给药的制剂必须是无菌的。这可以通过例如应用无菌过滤膜过滤而容易地实现。
使用抗HBV pre-S1抗体的治疗方法
抗HBV pre-S1抗体(例如，全长的抗HBV pre-S1抗体)和/或本申请所述的组合物可以施用于个体(例如，人类)来预防、改善或治疗HBV感染或与HBV感染相关的疾病，这些疾病包括但不限于乙型肝炎、肝功能衰竭、肝硬化或肝癌。因此，本申请在一些实施例中，提供一种预防、改善或治疗HBV感染或与HBV感染相关的疾病的方法，包括向个体施用有效量的包含抗HBV pre-S1抗体(例如，全长的抗HBV pre-S1抗体)的组合物(例如，药物组合物)，例如本文所述的任一种抗HBV pre-S1抗体(例如，全长的抗HBV pre-S1抗体)，在一些实施例中，所述个体是人类。
例如，在一些实施例中，提供一种用于预防、改善或治疗HBV感染或与HBV感染相关的疾病的方法，包括向所需个体施用有效量的包含特异性结合HBV表面抗原pre-S1结构域的抗体(例如，全长抗HBV pre-S1抗体)的药物组合物。在一些实施例中，所述抗HBV pre-S1抗体是全长抗体。在一些实施例中，所述全长抗HBV pre-S1抗体是IgG1或IgG4抗体。在一些实施例中，所述疾病或病症选自例如，乙型肝炎、肝功能衰竭、肝硬化或肝癌。在一些实施例中，所述所需个体包括但不限于已感染HBV、暴露于HBV、具有HBV感染风险或易感HBV的个体。
例如，在一些实施例中，提供一种用于预防、改善或治疗HBV感染或与HBV感染相关的疾病的方法，包括向所需个体施用有效量的包含抗HBV pre-S1抗体(例如，全长抗HBV pre-S1抗体)的药物组合物，其中所述抗体包含重链可变结构域(V H)，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:1，HC-CDR2，其包含氨基酸序列SEQ ID NO:19，和HC-CDR3，其包含氨 基酸序列SEQ ID NO:39，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及轻链可变结构域(V L)，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:58，LC-CDR2，其包含氨基酸序列SEQ ID NO:79，和LC-CDR3，其包含氨基酸序列SEQ ID NO:93，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。在一些实施例中，所述抗HBV pre-S1抗体是全长抗体。在一些实施例中，所述全长抗HBV pre-S1抗体是IgG1或IgG4抗体。在一些实施例中，所述疾病或病症选自例如，乙型肝炎、肝功能衰竭、肝硬化或肝癌。在一些实施例中，所述所需个体包括但不限于已感染HBV、暴露于HBV、具有HBV感染风险或易感HBV的个体。
在一些实施例中，提供一种用于预防、改善或治疗HBV感染或与HBV感染相关的疾病的方法，包括向所需个体施用有效量的包含抗HBV pre-S1抗体的组合物，其中所述抗体包含：V H，所述V H包含SEQ ID NO:120所示的氨基酸序列或其变体，所述变体与SEQ ID NO:120所示的氨基酸序列具有至少约80％序列同一性；以及V L，所述V L包含SEQ ID NO:151所示的氨基酸序列或其变体，所述变体与SEQ ID NO:151所示的氨基酸序列具有至少约80％序列同一性。
在一些实施例中，本文所述抗HBV pre-S1抗体是包含IgG1或IgG4恒定区的全长抗HBV pre-S1抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
例如，在一些实施例中，提供一种用于预防、改善或治疗HBV感染或与HBV感染相关的疾病的方法，包括向所需个体施用有效量的包含抗HBV pre-S1抗体(例如，全长抗HBV pre-S1抗体)的药物组合物，其中所述抗体包含重链可变结构域(V H)，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:2，HC-CDR2，其包含氨基酸序列SEQ ID NO:20，和HC-CDR3，其包含氨基酸序列SEQ ID NO:40，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及轻链可变结构域(V L)，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:59，LC-CDR2，其包含氨基酸序列SEQ ID NO:79，和LC-CDR3，其包含氨基酸序列SEQ ID NO:94，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。在一些实施例中，所述抗HBV pre-S1抗体是全长抗体。在一些实施例中，所述全长抗HBV pre-S1抗体是IgG1或IgG4抗体。在一些实施例中，所述疾病或病症选自例如，乙型肝炎、肝功能衰竭、肝硬化或肝癌。在一些实施例中，所述所需个体包括但不限于已感染HBV、暴露于HBV、具有HBV感染风险或易感HBV的个体。
在一些实施例中，提供一种用于预防、改善或治疗HBV感染或与HBV感染相关的疾病的方法，包括向所需个体施用有效量的包含抗HBV pre-S1抗体的组合物，其中所述抗体包含：V H，所述V H包含SEQ ID NO:121所示的氨基酸序列或其变体，所述变体与SEQ ID NO:121所示的氨基 酸序列具有至少约80％序列同一性；以及V L，所述V L包含SEQ ID NO:152所示的氨基酸序列或其变体，所述变体与SEQ ID NO:152所示的氨基酸序列具有至少约80％序列同一性。
在一些实施例中，本文所述抗HBV pre-S1抗体是包含IgG1或IgG4恒定区的全长抗HBV pre-S1抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
例如，在一些实施例中，提供一种用于预防、改善或治疗HBV感染或与HBV感染相关的疾病的方法，包括向所需个体施用有效量的包含抗HBV pre-S1抗体(例如，全长抗HBV pre-S1抗体)的药物组合物，其中所述抗体包含重链可变结构域(V H)，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:3，HC-CDR2，其包含氨基酸序列SEQ ID NO:21，和HC-CDR3，其包含氨基酸序列SEQ ID NO:41，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及轻链可变结构域(V L)，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:60，LC-CDR2，其包含氨基酸序列SEQ ID NO:80，和LC-CDR3，其包含氨基酸序列SEQ ID NO:95，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。在一些实施例中，所述抗HBV pre-S1抗体是全长抗体。在一些实施例中，所述全长抗HBV pre-S1抗体是IgG1或IgG4抗体。在一些实施例中，所述疾病或病症选自例如，乙型肝炎、肝功能衰竭、肝硬化或肝癌。在一些实施例中，所述所需个体包括但不限于已感染HBV、暴露于HBV、具有HBV感染风险或易感HBV的个体。
在一些实施例中，提供一种用于预防、改善或治疗HBV感染或与HBV感染相关的疾病的方法，包括向所需个体施用有效量的包含抗HBV pre-S1抗体的组合物，其中所述抗体包含：V H，所述V H包含SEQ ID NO:122所示的氨基酸序列或其变体，所述变体与SEQ ID NO:122所示的氨基酸序列具有至少约80％序列同一性；以及V L，所述V L包含SEQ ID NO:153所示的氨基酸序列或其变体，所述变体与SEQ ID NO:153所示的氨基酸序列具有至少约80％序列同一性。
在一些实施例中，本文所述抗HBV pre-S1抗体是包含IgG1或IgG4恒定区的全长抗HBV pre-S1抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
例如，在一些实施例中，提供一种用于预防、改善或治疗HBV感染或与HBV感染相关的疾病的方法，包括向所需个体施用有效量的包含抗HBV pre-S1抗体(例如，全长抗HBV pre-S1抗体)的药物组合物，其中所述抗体包含重链可变结构域(V H)，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:4，HC-CDR2，其包含氨基酸序列SEQ ID NO:22，和HC-CDR3，其包含氨基酸序列SEQ ID NO:42，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以 及轻链可变结构域(V L)，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:61，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，和LC-CDR3，其包含氨基酸序列SEQ ID NO:96，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。在一些实施例中，所述抗HBV pre-S1抗体是全长抗体。在一些实施例中，所述全长抗HBV pre-S1抗体是IgG1或IgG4抗体。在一些实施例中，所述疾病或病症选自例如，乙型肝炎、肝功能衰竭、肝硬化或肝癌。在一些实施例中，所述所需个体包括但不限于已感染HBV、暴露于HBV、具有HBV感染风险或易感HBV的个体。
在一些实施例中，提供一种用于预防、改善或治疗HBV感染或与HBV感染相关的疾病的方法，包括向所需个体施用有效量的包含抗HBV pre-S1抗体的组合物，其中所述抗体包含：V H，所述V H包含SEQ ID NO:123所示的氨基酸序列或其变体，所述变体与SEQ ID NO:123所示的氨基酸序列具有至少约80％序列同一性；以及V L，所述V L包含SEQ ID NO:154所示的氨基酸序列或其变体，所述变体与SEQ ID NO:154所示的氨基酸序列具有至少约80％序列同一性。
在一些实施例中，本文所述抗HBV pre-S1抗体是包含IgG1或IgG4恒定区的全长抗HBV pre-S1抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
例如，在一些实施例中，提供一种用于预防、改善或治疗HBV感染或与HBV感染相关的疾病的方法，包括向所需个体施用有效量的包含抗HBV pre-S1抗体(例如，全长抗HBV pre-S1抗体)的药物组合物，其中所述抗体包含重链可变结构域(V H)，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:5，HC-CDR2，其包含氨基酸序列SEQ ID NO:23，和HC-CDR3，其包含氨基酸序列SEQ ID NO:43，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及轻链可变结构域(V L)，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:61，LC-CDR2，其包含氨基酸序列SEQ ID NO:82，和LC-CDR3，其包含氨基酸序列SEQ ID NO:97，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。在一些实施例中，所述抗HBV pre-S1抗体是全长抗体。在一些实施例中，所述全长抗HBV pre-S1抗体是IgG1或IgG4抗体。在一些实施例中，所述疾病或病症选自例如，乙型肝炎、肝功能衰竭、肝硬化或肝癌。在一些实施例中，所述所需个体包括但不限于已感染HBV、暴露于HBV、具有HBV感染风险或易感HBV的个体。
在一些实施例中，提供一种用于预防、改善或治疗HBV感染或与HBV感染相关的疾病的方法，包括向所需个体施用有效量的包含抗HBV pre-S1抗体的组合物，其中所述抗体包含：V H，所述V H包含SEQ ID NO:124所示的氨基酸序列或其变体，所述变体与SEQ ID NO:124所示的氨基酸序列具有至少约80％序列同一性；以及V L，所述V L包含SEQ ID NO:155所示的氨基酸序列或其变体，所述变体与SEQ ID NO:155所示的氨基酸序列具有至少约80％序列同一性。
在一些实施例中，本文所述抗HBV pre-S1抗体是包含IgG1或IgG4恒定区的全长抗HBV pre-S1抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
例如，在一些实施例中，提供一种用于预防、改善或治疗HBV感染或与HBV感染相关的疾病的方法，包括向所需个体施用有效量的包含抗HBV pre-S1抗体(例如，全长抗HBV pre-S1抗体)的药物组合物，其中所述抗体包含重链可变结构域(V H)，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:7，HC-CDR2，其包含氨基酸序列SEQ ID NO:25，和HC-CDR3，其包含氨基酸序列SEQ ID NO:45，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及轻链可变结构域(V L)，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:63，LC-CDR2，其包含氨基酸序列SEQ ID NO:84，和LC-CDR3，其包含氨基酸序列SEQ ID NO:99，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。在一些实施例中，所述抗HBV pre-S1抗体是全长抗体。在一些实施例中，所述全长抗HBV pre-S1抗体是IgG1或IgG4抗体。在一些实施例中，所述疾病或病症选自例如，乙型肝炎、肝功能衰竭、肝硬化或肝癌。在一些实施例中，所述所需个体包括但不限于已感染HBV、暴露于HBV、具有HBV感染风险或易感HBV的个体。
在一些实施例中，提供一种用于预防、改善或治疗HBV感染或与HBV感染相关的疾病的方法，包括向所需个体施用有效量的包含抗HBV pre-S1抗体的组合物，其中所述抗体包含：V H，所述V H包含SEQ ID NO:126所示的氨基酸序列或其变体，所述变体与SEQ ID NO:126所示的氨基酸序列具有至少约80％序列同一性；以及V L，所述V L包含SEQ ID NO:157所示的氨基酸序列或其变体，所述变体与SEQ ID NO:157所示的氨基酸序列具有至少约80％序列同一性。
在一些实施例中，本文所述抗HBV pre-S1抗体是包含IgG1或IgG4恒定区的全长抗HBV pre-S1抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
例如，在一些实施例中，提供一种用于预防、改善或治疗HBV感染或与HBV感染相关的疾病的方法，包括向所需个体施用有效量的包含抗HBV pre-S1抗体(例如，全长抗HBV pre-S1抗体)的药物组合物，其中所述抗体包含重链可变结构域(V H)，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:7，HC-CDR2，其包含氨基酸序列SEQ ID NO:26，和HC-CDR3，其包含氨基酸序列SEQ ID NO:46，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及轻链可变结构域(VL)，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:64，LC-CDR2，其包含氨基酸序列SEQ ID NO:79，和LC-CDR3，其包含氨基酸序列SEQ ID NO:100，或 者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。在一些实施例中，所述抗HBV pre-S1抗体是全长抗体。在一些实施例中，所述全长抗HBV pre-S1抗体是IgG1或IgG4抗体。在一些实施例中，所述疾病或病症选自例如，乙型肝炎、肝功能衰竭、肝硬化或肝癌。在一些实施例中，所述所需个体包括但不限于已感染HBV、暴露于HBV、具有HBV感染风险或易感HBV的个体。
在一些实施例中，提供一种用于预防、改善或治疗HBV感染或与HBV感染相关的疾病的方法，包括向所需个体施用有效量的包含抗HBV pre-S1抗体的组合物，其中所述抗体包含：V H，所述V H包含SEQ ID NO:128所示的氨基酸序列或其变体，所述变体与SEQ ID NO:128所示的氨基酸序列具有至少约80％序列同一性；以及V L，所述V L包含SEQ ID NO:158所示的氨基酸序列或其变体，所述变体与SEQ ID NO:158所示的氨基酸序列具有至少约80％序列同一性。
在一些实施例中，本文所述抗HBV pre-S1抗体是包含IgG1或IgG4恒定区的全长抗HBV pre-S1抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
例如，在一些实施例中，提供一种用于预防、改善或治疗HBV感染或与HBV感染相关的疾病的方法，包括向所需个体施用有效量的包含抗HBV pre-S1抗体(例如，全长抗HBV pre-S1抗体)的药物组合物，其中所述抗体包含重链可变结构域(V H)，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:8，HC-CDR2，其包含氨基酸序列SEQ ID NO:27，和HC-CDR3，其包含氨基酸序列SEQ ID NO:47，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及轻链可变结构域(V L)，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:65，LC-CDR2，其包含氨基酸序列SEQ ID NO:85，和LC-CDR3，其包含氨基酸序列SEQ ID NO:101，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。在一些实施例中，所述抗HBV pre-S1抗体是全长抗体。在一些实施例中，所述全长抗HBV pre-S1抗体是IgG1或IgG4抗体。在一些实施例中，所述疾病或病症选自例如，乙型肝炎、肝功能衰竭、肝硬化或肝癌。在一些实施例中，所述所需个体包括但不限于已感染HBV、暴露于HBV、具有HBV感染风险或易感HBV的个体。
在一些实施例中，提供一种用于预防、改善或治疗HBV感染或与HBV感染相关的疾病的方法，包括向所需个体施用有效量的包含抗HBV pre-S1抗体的组合物，其中所述抗体包含：V H，所述V H包含SEQ ID NO:130所示的氨基酸序列或其变体，所述变体与SEQ ID NO:130所示的氨基酸序列具有至少约80％序列同一性；以及V L，所述V L包含SEQ ID NO:159所示的氨基酸序列或其变体，所述变体与SEQ ID NO:159所示的氨基酸序列具有至少约80％序列同一性。
在一些实施例中，本文所述抗HBV pre-S1抗体是包含IgG1或IgG4恒定区的全长抗HBV pre-S1抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些 实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
例如，在一些实施例中，提供一种用于预防、改善或治疗HBV感染或与HBV感染相关的疾病的方法，包括向所需个体施用有效量的包含抗HBV pre-S1抗体(例如，全长抗HBV pre-S1抗体)的药物组合物，其中所述抗体包含重链可变结构域(V H)，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:9，HC-CDR2，其包含氨基酸序列SEQ ID NO:28，和HC-CDR3，其包含氨基酸序列SEQ ID NO:48，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及轻链可变结构域(V L)，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:66，LC-CDR2，其包含氨基酸序列SEQ ID NO:86，和LC-CDR3，其包含氨基酸序列SEQ ID NO:102，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。在一些实施例中，所述抗HBV pre-S1抗体是全长抗体。在一些实施例中，所述全长抗HBV pre-S1抗体是IgG1或IgG4抗体。在一些实施例中，所述疾病或病症选自例如，乙型肝炎、肝功能衰竭、肝硬化或肝癌。在一些实施例中，所述所需个体包括但不限于已感染HBV、暴露于HBV、具有HBV感染风险或易感HBV的个体。
在一些实施例中，提供一种用于预防、改善或治疗HBV感染或与HBV感染相关的疾病的方法，包括向所需个体施用有效量的包含抗HBV pre-S1抗体的组合物，其中所述抗体包含：V H，所述V H包含SEQ ID NO:131所示的氨基酸序列或其变体，所述变体与SEQ ID NO:131所示的氨基酸序列具有至少约80％序列同一性；以及V L，所述V L包含SEQ ID NO:160所示的氨基酸序列或其变体，所述变体与SEQ ID NO:160所示的氨基酸序列具有至少约80％序列同一性。
在一些实施例中，本文所述抗HBV pre-S1抗体是包含IgG1或IgG4恒定区的全长抗HBV pre-S1抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
例如，在一些实施例中，提供一种用于预防、改善或治疗HBV感染或与HBV感染相关的疾病的方法，包括向所需个体施用有效量的包含抗HBV pre-S1抗体(例如，全长抗HBV pre-S1抗体)的药物组合物，其中所述抗体包含重链可变结构域(V H)，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:6，HC-CDR2，其包含氨基酸序列SEQ ID NO:24，和HC-CDR3，其包含氨基酸序列SEQ ID NO:44，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及轻链可变结构域(V L)，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:62，LC-CDR2，其包含氨基酸序列SEQ ID NO:83，和LC-CDR3，其包含氨基酸序列SEQ ID NO:98，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。在一些实施例中，所述抗HBV pre-S1抗体是全长抗体。在一些实施例中，所述全长抗HBV pre-S1抗体是IgG1或IgG4抗体。在 一些实施例中，所述疾病或病症选自例如，乙型肝炎、肝功能衰竭、肝硬化或肝癌。在一些实施例中，所述所需个体包括但不限于已感染HBV、暴露于HBV、具有HBV感染风险或易感HBV的个体。
在一些实施例中，提供一种用于预防、改善或治疗HBV感染或与HBV感染相关的疾病的方法，包括向所需个体施用有效量的包含抗HBV pre-S1抗体的组合物，其中所述抗体包含：V H，所述V H包含SEQ ID NO:132所示的氨基酸序列或其变体，所述变体与SEQ ID NO:132所示的氨基酸序列具有至少约80％序列同一性；以及V L，所述V L包含SEQ ID NO:161所示的氨基酸序列或其变体，所述变体与SEQ ID NO:161所示的氨基酸序列具有至少约80％序列同一性。
在一些实施例中，本文所述抗HBV pre-S1抗体是包含IgG1或IgG4恒定区的全长抗HBV pre-S1抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
例如，在一些实施例中，提供一种用于预防、改善或治疗HBV感染或与HBV感染相关的疾病的方法，包括向所需个体施用有效量的包含抗HBV pre-S1抗体(例如，全长抗HBV pre-S1抗体)的药物组合物，其中所述抗体包含重链可变结构域(V H)，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:10，HC-CDR2，其包含氨基酸序列SEQ ID NO:29，和HC-CDR3，其包含氨基酸序列SEQ ID NO:49，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及轻链可变结构域(V L)，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:67，LC-CDR2，其包含氨基酸序列SEQ ID NO:87，和LC-CDR3，其包含氨基酸序列SEQ ID NO:103，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。在一些实施例中，所述抗HBV pre-S1抗体是全长抗体。在一些实施例中，所述全长抗HBV pre-S1抗体是IgG1或IgG4抗体。在一些实施例中，所述疾病或病症选自例如，乙型肝炎、肝功能衰竭、肝硬化或肝癌。在一些实施例中，所述所需个体包括但不限于已感染HBV、暴露于HBV、具有HBV感染风险或易感HBV的个体。
在一些实施例中，提供一种用于预防、改善或治疗HBV感染或与HBV感染相关的疾病的方法，包括向所需个体施用有效量的包含抗HBV pre-S1抗体的组合物，其中所述抗体包含：V H，所述V H包含SEQ ID NO:133所示的氨基酸序列或其变体，所述变体与SEQ ID NO:133所示的氨基酸序列具有至少约80％序列同一性；以及V L，所述V L包含SEQ ID NO:162所示的氨基酸序列或其变体，所述变体与SEQ ID NO:162所示的氨基酸序列具有至少约80％序列同一性。
在一些实施例中，本文所述抗HBV pre-S1抗体是包含IgG1或IgG4恒定区的全长抗HBV pre-S1抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，重链恒定区 包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
例如，在一些实施例中，提供一种用于预防、改善或治疗HBV感染或与HBV感染相关的疾病的方法，包括向所需个体施用有效量的包含抗HBV pre-S1抗体(例如，全长抗HBV pre-S1抗体)的药物组合物，其中所述抗体包含重链可变结构域(V H)，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:11，HC-CDR2，其包含氨基酸序列SEQ ID NO:30，和HC-CDR3，其包含氨基酸序列SEQ ID NO:50，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及轻链可变结构域(V L)，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:68，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，和LC-CDR3，其包含氨基酸序列SEQ ID NO:104，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。在一些实施例中，所述抗HBV pre-S1抗体是全长抗体。在一些实施例中，所述全长抗HBV pre-S1抗体是IgG1或IgG4抗体。在一些实施例中，所述疾病或病症选自例如，乙型肝炎、肝功能衰竭、肝硬化或肝癌。在一些实施例中，所述所需个体包括但不限于已感染HBV、暴露于HBV、具有HBV感染风险或易感HBV的个体。
在一些实施例中，提供一种用于预防、改善或治疗HBV感染或与HBV感染相关的疾病的方法，包括向所需个体施用有效量的包含抗HBV pre-S1抗体的组合物，其中所述抗体包含：V H，所述V H包含SEQ ID NO:134所示的氨基酸序列或其变体，所述变体与SEQ ID NO:134所示的氨基酸序列具有至少约80％序列同一性；以及V L，所述V L包含SEQ ID NO:163所示的氨基酸序列或其变体，所述变体与SEQ ID NO:163所示的氨基酸序列具有至少约80％序列同一性。
在一些实施例中，本文所述抗HBV pre-S1抗体是包含IgG1或IgG4恒定区的全长抗HBV pre-S1抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
例如，在一些实施例中，提供一种用于预防、改善或治疗HBV感染或与HBV感染相关的疾病的方法，包括向所需个体施用有效量的包含抗HBV pre-S1抗体(例如，全长抗HBV pre-S1抗体)的药物组合物，其中所述抗体包含重链可变结构域(V H)，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:12，HC-CDR2，其包含氨基酸序列SEQ ID NO:30，和HC-CDR3，其包含氨基酸序列SEQ ID NO:50，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及轻链可变结构域(V L)，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:61，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，和LC-CDR3，其包含氨基酸序列SEQ ID NO:105，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。在一些实施例中，所述抗HBV pre-S1抗体是全长抗体。在一些实施例中，所述全长抗HBV pre-S1抗体是IgG1或IgG4抗体。在一些实施例中，所述疾病或病症选自例如，乙型肝炎、肝功能衰竭、肝硬化或肝癌。在一些实施 例中，所述所需个体包括但不限于已感染HBV、暴露于HBV、具有HBV感染风险或易感HBV的个体。
在一些实施例中，提供一种用于预防、改善或治疗HBV感染或与HBV感染相关的疾病的方法，包括向所需个体施用有效量的包含抗HBV pre-S1抗体的组合物，其中所述抗体包含：V H，所述V H包含SEQ ID NO:135所示的氨基酸序列或其变体，所述变体与SEQ ID NO:135所示的氨基酸序列具有至少约80％序列同一性；以及V L，所述V L包含SEQ ID NO:164所示的氨基酸序列或其变体，所述变体与SEQ ID NO:164所示的氨基酸序列具有至少约80％序列同一性。
在一些实施例中，本文所述抗HBV pre-S1抗体是包含IgG1或IgG4恒定区的全长抗HBV pre-S1抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
例如，在一些实施例中，提供一种用于预防、改善或治疗HBV感染或与HBV感染相关的疾病的方法，包括向所需个体施用有效量的包含抗HBV pre-S1抗体(例如，全长抗HBV pre-S1抗体)的药物组合物，其中所述抗体包含重链可变结构域(V H)，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:13，HC-CDR2，其包含氨基酸序列SEQ ID NO:30，和HC-CDR3，其包含氨基酸序列SEQ ID NO:50，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及轻链可变结构域(V L)，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:69，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，和LC-CDR3，其包含氨基酸序列SEQ ID NO:103，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。在一些实施例中，所述抗HBV pre-S1抗体是全长抗体。在一些实施例中，所述全长抗HBV pre-S1抗体是IgG1或IgG4抗体。在一些实施例中，所述疾病或病症选自例如，乙型肝炎、肝功能衰竭、肝硬化或肝癌。在一些实施例中，所述所需个体包括但不限于已感染HBV、暴露于HBV、具有HBV感染风险或易感HBV的个体。
在一些实施例中，提供一种用于预防、改善或治疗HBV感染或与HBV感染相关的疾病的方法，包括向所需个体施用有效量的包含抗HBV pre-S1抗体的组合物，其中所述抗体包含：V H，所述V H包含SEQ ID NO:136所示的氨基酸序列或其变体，所述变体与SEQ ID NO:136所示的氨基酸序列具有至少约80％序列同一性；以及V L，所述V L包含SEQ ID NO:165所示的氨基酸序列或其变体，所述变体与SEQ ID NO:165所示的氨基酸序列具有至少约80％序列同一性。
在一些实施例中，本文所述抗HBV pre-S1抗体是包含IgG1或IgG4恒定区的全长抗HBV pre-S1抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
例如，在一些实施例中，提供一种用于预防、改善或治疗HBV感染或与HBV感染相关的疾病的方法，包括向所需个体施用有效量的包含抗HBV pre-S1抗体(例如，全长抗HBV pre-S1抗体)的药物组合物，其中所述抗体包含重链可变结构域(V H)，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:9，HC-CDR2，其包含氨基酸序列SEQ ID NO:31，和HC-CDR3，其包含氨基酸序列SEQ ID NO:51，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及轻链可变结构域(V L)，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:70，LC-CDR2，其包含氨基酸序列SEQ ID NO:83，和LC-CDR3，其包含氨基酸序列SEQ ID NO:106，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。在一些实施例中，所述抗HBV pre-S1抗体是全长抗体。在一些实施例中，所述全长抗HBV pre-S1抗体是IgG1或IgG4抗体。在一些实施例中，所述疾病或病症选自例如，乙型肝炎、肝功能衰竭、肝硬化或肝癌。在一些实施例中，所述所需个体包括但不限于已感染HBV、暴露于HBV、具有HBV感染风险或易感HBV的个体。
在一些实施例中，提供一种用于预防、改善或治疗HBV感染或与HBV感染相关的疾病的方法，包括向所需个体施用有效量的包含抗HBV pre-S1抗体的组合物，其中所述抗体包含：V H，所述V H包含SEQ ID NO:137所示的氨基酸序列或其变体，所述变体与SEQ ID NO:137所示的氨基酸序列具有至少约80％序列同一性；以及V L，所述V L包含SEQ ID NO:167所示的氨基酸序列或其变体，所述变体与SEQ ID NO:167所示的氨基酸序列具有至少约80％序列同一性。
在一些实施例中，本文所述抗HBV pre-S1抗体是包含IgG1或IgG4恒定区的全长抗HBV pre-S1抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
例如，在一些实施例中，提供一种用于预防、改善或治疗HBV感染或与HBV感染相关的疾病的方法，包括向所需个体施用有效量的包含抗HBV pre-S1抗体(例如，全长抗HBV pre-S1抗体)的药物组合物，其中所述抗体包含重链可变结构域(V H)，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:14，HC-CDR2，其包含氨基酸序列SEQ ID NO:32，和HC-CDR3，其包含氨基酸序列SEQ ID NO:51，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及轻链可变结构域(V L)，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:71，LC-CDR2，其包含氨基酸序列SEQ ID NO:86，和LC-CDR3，其包含氨基酸序列SEQ ID NO:107，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。在一些实施例中，所述抗HBV pre-S1抗体是全长抗体。在一些实施例中，所述全长抗HBV pre-S1抗体是IgG1或IgG4抗体。在一些实施例中，所述疾病或病症选自例如，乙型肝炎、肝功能衰竭、肝硬化或肝癌。在一些实施例中，所述所需个体包括但不限于已感染HBV、暴露于HBV、具有HBV感染风险或易感HBV的个体。
在一些实施例中，提供一种用于预防、改善或治疗HBV感染或与HBV感染相关的疾病的方法，包括向所需个体施用有效量的包含抗HBV pre-S1抗体的组合物，其中所述抗体包含：V H，所述V H包含SEQ ID NO:139所示的氨基酸序列或其变体，所述变体与SEQ ID NO:139所示的氨基酸序列具有至少约80％序列同一性；以及V L，所述V L包含SEQ ID NO:169所示的氨基酸序列或其变体，所述变体与SEQ ID NO:169所示的氨基酸序列具有至少约80％序列同一性。
在一些实施例中，本文所述抗HBV pre-S1抗体是包含IgG1或IgG4恒定区的全长抗HBV pre-S1抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
例如，在一些实施例中，提供一种用于预防、改善或治疗HBV感染或与HBV感染相关的疾病的方法，包括向所需个体施用有效量的包含抗HBV pre-S1抗体(例如，全长抗HBV pre-S1抗体)的药物组合物，其中所述抗体包含重链可变结构域(V H)，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:11，HC-CDR2，其包含氨基酸序列SEQ ID NO:30，和HC-CDR3，其包含氨基酸序列SEQ ID NO:50，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及轻链可变结构域(V L)，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:72，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，和LC-CDR3，其包含氨基酸序列SEQ ID NO:108，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。在一些实施例中，所述抗HBV pre-S1抗体是全长抗体。在一些实施例中，所述全长抗HBV pre-S1抗体是IgG1或IgG4抗体。在一些实施例中，所述疾病或病症选自例如，乙型肝炎、肝功能衰竭、肝硬化或肝癌。在一些实施例中，所述所需个体包括但不限于已感染HBV、暴露于HBV、具有HBV感染风险或易感HBV的个体。
在一些实施例中，提供一种用于预防、改善或治疗HBV感染或与HBV感染相关的疾病的方法，包括向所需个体施用有效量的包含抗HBV pre-S1抗体的组合物，其中所述抗体包含：V H，所述V H包含SEQ ID NO:140所示的氨基酸序列或其变体，所述变体与SEQ ID NO:140所示的氨基酸序列具有至少约80％序列同一性；以及V L，所述V L包含SEQ ID NO:170所示的氨基酸序列或其变体，所述变体与SEQ ID NO:170所示的氨基酸序列具有至少约80％序列同一性。
在一些实施例中，本文所述抗HBV pre-S1抗体是包含IgG1或IgG4恒定区的全长抗HBV pre-S1抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
例如，在一些实施例中，提供一种用于预防、改善或治疗HBV感染或与HBV感染相关的疾病的方法，包括向所需个体施用有效量的包含抗HBV pre-S1抗体(例如，全长抗HBV pre-S1抗体) 的药物组合物，其中所述抗体包含重链可变结构域(V H)，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:13，HC-CDR2，其包含氨基酸序列SEQ ID NO:33，和HC-CDR3，其包含氨基酸序列SEQ ID NO:52，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及轻链可变结构域(V L)，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:61，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，和LC-CDR3，其包含氨基酸序列SEQ ID NO:97，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。在一些实施例中，所述抗HBV pre-S1抗体是全长抗体。在一些实施例中，所述全长抗HBV pre-S1抗体是IgG1或IgG4抗体。在一些实施例中，所述疾病或病症选自例如，乙型肝炎、肝功能衰竭、肝硬化或肝癌。在一些实施例中，所述所需个体包括但不限于已感染HBV、暴露于HBV、具有HBV感染风险或易感HBV的个体。
在一些实施例中，提供一种用于预防、改善或治疗HBV感染或与HBV感染相关的疾病的方法，包括向所需个体施用有效量的包含抗HBV pre-S1抗体的组合物，其中所述抗体包含：V H，所述V H包含SEQ ID NO:141所示的氨基酸序列或其变体，所述变体与SEQ ID NO:141所示的氨基酸序列具有至少约80％序列同一性；以及V L，所述V L包含SEQ ID NO:171所示的氨基酸序列或其变体，所述变体与SEQ ID NO:171所示的氨基酸序列具有至少约80％序列同一性。
在一些实施例中，本文所述抗HBV pre-S1抗体是包含IgG1或IgG4恒定区的全长抗HBV pre-S1抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
例如，在一些实施例中，提供一种用于预防、改善或治疗HBV感染或与HBV感染相关的疾病的方法，包括向所需个体施用有效量的包含抗HBV pre-S1抗体(例如，全长抗HBV pre-S1抗体)的药物组合物，其中所述抗体包含重链可变结构域(V H)，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:10，HC-CDR2，其包含氨基酸序列SEQ ID NO:30，和HC-CDR3，其包含氨基酸序列SEQ ID NO:50，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及轻链可变结构域(V L)，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:61，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，和LC-CDR3，其包含氨基酸序列SEQ ID NO:103，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。在一些实施例中，所述抗HBV pre-S1抗体是全长抗体。在一些实施例中，所述全长抗HBV pre-S1抗体是IgG1或IgG4抗体。在一些实施例中，所述疾病或病症选自例如，乙型肝炎、肝功能衰竭、肝硬化或肝癌。在一些实施例中，所述所需个体包括但不限于已感染HBV、暴露于HBV、具有HBV感染风险或易感HBV的个体。
在一些实施例中，提供一种用于预防、改善或治疗HBV感染或与HBV感染相关的疾病的方法，包括向所需个体施用有效量的包含抗HBV pre-S1抗体的组合物，其中所述抗体包含：V H，所 述V H包含SEQ ID NO:142所示的氨基酸序列或其变体，所述变体与SEQ ID NO:142所示的氨基酸序列具有至少约80％序列同一性；以及V L，所述V L包含SEQ ID NO:172所示的氨基酸序列或其变体，所述变体与SEQ ID NO:172所示的氨基酸序列具有至少约80％序列同一性。
在一些实施例中，本文所述抗HBV pre-S1抗体是包含IgG1或IgG4恒定区的全长抗HBV pre-S1抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
例如，在一些实施例中，提供一种用于预防、改善或治疗HBV感染或与HBV感染相关的疾病的方法，包括向所需个体施用有效量的包含抗HBV pre-S1抗体(例如，全长抗HBV pre-S1抗体)的药物组合物，其中所述抗体包含重链可变结构域(V H)，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:15，HC-CDR2，其包含氨基酸序列SEQ ID NO:34，和HC-CDR3，其包含氨基酸序列SEQ ID NO:53，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及轻链可变结构域(V L)，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:73，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，和LC-CDR3，其包含氨基酸序列SEQ ID NO:109，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。在一些实施例中，所述抗HBV pre-S1抗体是全长抗体。在一些实施例中，所述全长抗HBV pre-S1抗体是IgG1或IgG4抗体。在一些实施例中，所述疾病或病症选自例如，乙型肝炎、肝功能衰竭、肝硬化或肝癌。在一些实施例中，所述所需个体包括但不限于已感染HBV、暴露于HBV、具有HBV感染风险或易感HBV的个体。
在一些实施例中，提供一种用于预防、改善或治疗HBV感染或与HBV感染相关的疾病的方法，包括向所需个体施用有效量的包含抗HBV pre-S1抗体的组合物，其中所述抗体包含：V H，所述V H包含SEQ ID NO:143所示的氨基酸序列或其变体，所述变体与SEQ ID NO:143所示的氨基酸序列具有至少约80％序列同一性；以及V L，所述V L包含SEQ ID NO:173所示的氨基酸序列或其变体，所述变体与SEQ ID NO:173所示的氨基酸序列具有至少约80％序列同一性。
在一些实施例中，本文所述抗HBV pre-S1抗体是包含IgG1或IgG4恒定区的全长抗HBV pre-S1抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
例如，在一些实施例中，提供一种用于预防、改善或治疗HBV感染或与HBV感染相关的疾病的方法，包括向所需个体施用有效量的包含抗HBV pre-S1抗体(例如，全长抗HBV pre-S1抗体)的药物组合物，其中所述抗体包含重链可变结构域(V H)，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:16，HC-CDR2，其包含氨基酸序列SEQ ID NO:35，和HC-CDR3，其包含 氨基酸序列SEQ ID NO:54，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及轻链可变结构域(V L)，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:74，LC-CDR2，其包含氨基酸序列SEQ ID NO:88，和LC-CDR3，其包含氨基酸序列SEQ ID NO:110，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。在一些实施例中，所述抗HBV pre-S1抗体是全长抗体。在一些实施例中，所述全长抗HBV pre-S1抗体是IgG1或IgG4抗体。在一些实施例中，所述疾病或病症选自例如，乙型肝炎、肝功能衰竭、肝硬化或肝癌。在一些实施例中，所述所需个体包括但不限于已感染HBV、暴露于HBV、具有HBV感染风险或易感HBV的个体。
在一些实施例中，提供一种用于预防、改善或治疗HBV感染或与HBV感染相关的疾病的方法，包括向所需个体施用有效量的包含抗HBV pre-S1抗体的组合物，其中所述抗体包含：V H，所述V H包含SEQ ID NO:144所示的氨基酸序列或其变体，所述变体与SEQ ID NO:144所示的氨基酸序列具有至少约80％序列同一性；以及V L，所述V L包含SEQ ID NO:174所示的氨基酸序列或其变体，所述变体与SEQ ID NO:174所示的氨基酸序列具有至少约80％序列同一性。
在一些实施例中，本文所述抗HBV pre-S1抗体是包含IgG1或IgG4恒定区的全长抗HBV pre-S1抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
例如，在一些实施例中，提供一种用于预防、改善或治疗HBV感染或与HBV感染相关的疾病的方法，包括向所需个体施用有效量的包含抗HBV pre-S1抗体(例如，全长抗HBV pre-S1抗体)的药物组合物，其中所述抗体包含重链可变结构域(V H)，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:17，HC-CDR2，其包含氨基酸序列SEQ ID NO:36，和HC-CDR3，其包含氨基酸序列SEQ ID NO:55，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及轻链可变结构域(V L)，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:75，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，和LC-CDR3，其包含氨基酸序列SEQ ID NO:97，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。在一些实施例中，所述抗HBV pre-S1抗体是全长抗体。在一些实施例中，所述全长抗HBV pre-S1抗体是IgG1或IgG4抗体。在一些实施例中，所述疾病或病症选自例如，乙型肝炎、肝功能衰竭、肝硬化或肝癌。在一些实施例中，所述所需个体包括但不限于已感染HBV、暴露于HBV、具有HBV感染风险或易感HBV的个体。
在一些实施例中，提供一种用于预防、改善或治疗HBV感染或与HBV感染相关的疾病的方法，包括向所需个体施用有效量的包含抗HBV pre-S1抗体的组合物，包含：V H，所述V H包含SEQ ID NO:145所示的氨基酸序列或其变体，所述变体与SEQ ID NO:145所示的氨基酸序列具有 至少约80％序列同一性；以及V L，所述V L包含SEQ ID NO:175所示的氨基酸序列或其变体，所述变体与SEQ ID NO:175所示的氨基酸序列具有至少约80％序列同一性。
在一些实施例中，本文所述抗HBV pre-S1抗体是包含IgG1或IgG4恒定区的全长抗HBV pre-S1抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
例如，在一些实施例中，提供一种用于预防、改善或治疗HBV感染或与HBV感染相关的疾病的方法，包括向所需个体施用有效量的包含抗HBV pre-S1抗体(例如，全长抗HBV pre-S1抗体)的药物组合物，其中所述抗体包含重链可变结构域(V H)，所述V H包含：HC-CDR1，其包含TYGIT(SEQ ID NO:18)；HC-CDR2，其包含SRIPIX 1GAALYAQKFQG(SEQ ID NO:115)，其中X 1为F或L；HC-CDR3，和其包含NX 1RGGFAAY(SEQ ID NO:116)，其中X 1为D或T；以及轻链可变结构域(V L)，所述V L包含：LC-CDR1，其包含RSSQSLX 1HSNX 2YNYLD(SEQ ID NO:117)，其中X 1为L或T，X 2为A或G；LC-CDR2，其包含LGX 1X 2RAS(SEQ ID NO:118)，其中X 1为H或S，X 2为K、N或R；和LC-CDR3，其包含MQALX 1X 2PX 3T(SEQ ID NO:119)，其中X 1为Q或V，X 2为I或T，X 3为A或P。在一些实施例中，所述抗HBV pre-S1抗体是全长抗体。在一些实施例中，所述全长抗HBV pre-S1抗体是IgG1或IgG4抗体。在一些实施例中，所述疾病或病症选自例如，乙型肝炎、肝功能衰竭、肝硬化或肝癌。在一些实施例中，所述所需个体包括但不限于已感染HBV、暴露于HBV、具有HBV感染风险或易感HBV的个体。
在一些实施例中，提供一种用于预防、改善或治疗HBV感染或与HBV感染相关的疾病的方法，包括向所需个体施用有效量的包含抗HBV pre-S1抗体的组合物，其中所述抗体包含V H，所述V H包含：HC-CDR1，其包含SEQ ID NO:18所示的氨基酸序列，HC-CDR2，其包含SEQ ID NOs:37-38中任一所示的氨基酸序列，和HC-CDR3，其包含SEQ ID NOs:56-57中任一所示的氨基酸序列，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含SEQ ID NOs:59、和76-77中任一所示的氨基酸序列，LC-CDR2，其包含SEQ ID NOs:79、和89-91中任一所示的氨基酸序列，和LC-CDR3，其包含SEQ ID NOs:111-114中任一所示的氨基酸序列，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，提供一种用于预防、改善或治疗HBV感染或与HBV感染相关的疾病的方法，包括向所需个体施用有效量的包含抗HBV pre-S1抗体的组合物，其中所述抗体其中所述抗体包含：V H，所述V H包含SEQ ID NOs:146-150中任一所示的氨基酸序列或其变体，所述变体与SEQ ID NOs:146-150中任一所示的氨基酸序列具有至少约80％序列同一性；以及V L，所述V L包含SEQ ID NOs:176-183中任一所示的氨基酸序列或其变体，所述变体与SEQ ID NOs:176-183中任一所示的氨基酸序列具有至少约80％序列同一性。
在一些实施例中，本文所述抗HBV pre-S1抗体是包含IgG1或IgG4恒定区的全长抗HBV pre-S1抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种用于预防、改善或治疗HBV感染或与HBV感染相关的疾病的方法，包括向所需个体施用有效量的包含抗HBV pre-S1抗体的组合物，其中所述抗体包含V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:18，HC-CDR2，其包含氨基酸序列SEQ ID NO:37，和HC-CDR3，其包含氨基酸序列SEQ ID NO:56，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:59，LC-CDR2，其包含氨基酸序列SEQ ID NO:79，和LC-CDR3，其包含氨基酸序列SEQ ID NO:111，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，本文所述抗HBV pre-S1抗体包含：V H，所述V H包含氨基酸序列SEQ ID NO:146或其变体，所述变体与氨基酸序列SEQ ID NO:146具有至少约80％序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:176或其变体，所述变体与氨基酸序列SEQ ID NO:176具有至少约80％序列同一性。在一些实施例中，本文所述抗HBV pre-S1抗体是包含IgG1或IgG4恒定区的全长抗HBV pre-S1抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种用于预防、改善或治疗HBV感染或与HBV感染相关的疾病的方法，包括向所需个体施用有效量的包含抗HBV pre-S1抗体的组合物，其中所述抗体包含：V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:18，HC-CDR2，其包含氨基酸序列SEQ ID NO:38，和HC-CDR3，其包含氨基酸序列SEQ ID NO:57，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:76，LC-CDR2，其包含氨基酸序列SEQ ID NO:79，和LC-CDR3，其包含氨基酸序列SEQ ID NO:112，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，本文所述抗HBV pre-S1抗体包含：V H，所述V H包含氨基酸序列SEQ ID NO:147或其变体，所述变体与氨基酸序列SEQ ID NO:147具有至少约80％序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:177或其变体，所述变体与氨基酸序列SEQ ID NO:177具有至少约80％序列同一性。在一些实施例中，本文所述抗HBV pre-S1抗体是包含IgG1或IgG4恒定区的全长抗HBV pre-S1抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些 实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种用于预防、改善或治疗HBV感染或与HBV感染相关的疾病的方法，包括向所需个体施用有效量的包含抗HBV pre-S1抗体的组合物，其中所述抗体包含：V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:18，HC-CDR2，其包含氨基酸序列SEQ ID NO:37，和HC-CDR3，其包含氨基酸序列SEQ ID NO:57，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:77，LC-CDR2，其包含氨基酸序列SEQ ID NO:89，和LC-CDR3，其包含氨基酸序列SEQ ID NO:111，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，本文所述抗HBV pre-S1抗体包含：V H，所述V H包含氨基酸序列SEQ ID NO:148或其变体，所述变体与氨基酸序列SEQ ID NO:148具有至少约80％序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:178或其变体，所述变体与氨基酸序列SEQ ID NO:178具有至少约80％序列同一性。在一些实施例中，本文所述抗HBV pre-S1抗体是包含IgG1或IgG4恒定区的全长抗HBV pre-S1抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种用于预防、改善或治疗HBV感染或与HBV感染相关的疾病的方法，包括向所需个体施用有效量的包含抗HBV pre-S1抗体的组合物，其中所述抗体包含：V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:18，HC-CDR2，其包含氨基酸序列SEQ ID NO:37，和HC-CDR3，其包含氨基酸序列SEQ ID NO:57，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:77，LC-CDR2，其包含氨基酸序列SEQ ID NO:90，和LC-CDR3，其包含氨基酸序列SEQ ID NO:111，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，本文所述抗HBV pre-S1抗体包含：V H，所述V H包含氨基酸序列SEQ ID NO:149或其变体，所述变体与氨基酸序列SEQ ID NO:149具有至少约80％序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:179或其变体，所述变体与氨基酸序列SEQ ID NO:179具有至少约80％序列同一性。在一些实施例中，本文所述抗HBV pre-S1抗体是包含IgG1或IgG4恒定区的全长抗HBV pre-S1抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区 包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种用于预防、改善或治疗HBV感染或与HBV感染相关的疾病的方法，包括向所需个体施用有效量的包含抗HBV pre-S1抗体的组合物，其中所述抗体包含：V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:18，HC-CDR2，其包含氨基酸序列SEQ ID NO:38，和HC-CDR3，其包含氨基酸序列SEQ ID NO:57，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:76，LC-CDR2，其包含氨基酸序列SEQ ID NO:79，和LC-CDR3，其包含氨基酸序列SEQ ID NO:111，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，本文所述抗HBV pre-S1抗体包含：V H，所述V H包含氨基酸序列SEQ ID NO:147或其变体，所述变体与氨基酸序列SEQ ID NO:147具有至少约80％序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:180或其变体，所述变体与氨基酸序列SEQ ID NO:180具有至少约80％序列同一性。在一些实施例中，本文所述抗HBV pre-S1抗体是包含IgG1或IgG4恒定区的全长抗HBV pre-S1抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种用于预防、改善或治疗HBV感染或与HBV感染相关的疾病的方法，包括向所需个体施用有效量的包含抗HBV pre-S1抗体的组合物，其中所述抗体包含：V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:18，HC-CDR2，其包含氨基酸序列SEQ ID NO:38，和HC-CDR3，其包含氨基酸序列SEQ ID NO:57，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:77，LC-CDR2，其包含氨基酸序列SEQ ID NO:79，和LC-CDR3，其包含氨基酸序列SEQ ID NO:113，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，本文所述抗HBV pre-S1抗体包含：V H，所述V H包含氨基酸序列SEQ ID NO:147或其变体，所述变体与氨基酸序列SEQ ID NO:147具有至少约80％序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:181或其变体，所述变体与氨基酸序列SEQ ID NO:181具有至少约80％序列同一性。在一些实施例中，本文所述抗HBV pre-S1抗体是包含IgG1或IgG4恒定区的全长抗HBV pre-S1抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种用于预防、改善或治疗HBV感染或与HBV感染相关的疾病的方法，包括向所需个体施用有效量的包含抗HBV pre-S1抗体的组合物，其中所述抗体包含：V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:18，HC-CDR2，其包含氨基酸序列SEQ ID NO:37，和HC-CDR3，其包含氨基酸序列SEQ ID NO:57，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:77，LC-CDR2，其包含氨基酸序列SEQ ID NO:89，和LC-CDR3，其包含氨基酸序列SEQ ID NO:114，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，本文所述抗HBV pre-S1抗体包含：V H，所述V H包含氨基酸序列SEQ ID NO:148或其变体，所述变体与氨基酸序列SEQ ID NO:148具有至少约80％序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:182或其变体，所述变体与氨基酸序列SEQ ID NO:182具有至少约80％序列同一性。在一些实施例中，本文所述抗HBV pre-S1抗体是包含IgG1或IgG4恒定区的全长抗HBV pre-S1抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，提供一种用于预防、改善或治疗HBV感染或与HBV感染相关的疾病的方法，包括向所需个体施用有效量的包含抗HBV pre-S1抗体的组合物，其中所述抗体包含：V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:18，HC-CDR2，其包含氨基酸序列SEQ ID NO:37，和HC-CDR3，其包含氨基酸序列SEQ ID NO:57，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:77，LC-CDR2，其包含氨基酸序列SEQ ID NO:91，和LC-CDR3，其包含氨基酸序列SEQ ID NO:113，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，本文所述抗HBV pre-S1抗体包含：V H，所述V H包含氨基酸序列SEQ ID NO:150或其变体，所述变体与氨基酸序列SEQ ID NO:150具有至少约80％序列同一性；以及V L，所述V L包含氨基酸序列SEQ ID NO:183或其变体，所述变体与氨基酸序列SEQ ID NO:183具有至少约80％序列同一性。在一些实施例中，本文所述抗HBV pre-S1抗体是包含IgG1或IgG4恒定区的全长抗HBV pre-S1抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
例如，在一些实施例中，提供一种用于预防、改善或治疗HBV感染或与HBV感染相关的疾病的方法，包括向所需个体施用有效量的包含抗HBV pre-S1抗体(例如，全长抗HBV pre-S1抗体) 的药物组合物，其中所述抗体包含重链可变结构域(V H)，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:18，HC-CDR2，其包含氨基酸序列SEQ ID NO:37，和HC-CDR3，其包含氨基酸序列SEQ ID NO:56，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及轻链可变结构域(V L)，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:78，LC-CDR2，其包含氨基酸序列SEQ ID NO:92，和LC-CDR3，其包含氨基酸序列SEQ ID NO:93，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。在一些实施例中，所述抗HBV pre-S1抗体是全长抗体。在一些实施例中，所述全长抗HBV pre-S1抗体是IgG1或IgG4抗体。在一些实施例中，所述疾病或病症选自例如，乙型肝炎、肝功能衰竭、肝硬化或肝癌。在一些实施例中，所述所需个体包括但不限于已感染HBV、暴露于HBV、具有HBV感染风险或易感HBV的个体。
在一些实施例中，提供一种用于预防、改善或治疗HBV感染或与HBV感染相关的疾病的方法，包括向所需个体施用有效量的包含抗HBV pre-S1抗体的组合物，其中所述抗体包含：V H，所述V H包含SEQ ID NO:146所示的氨基酸序列或其变体，所述变体与SEQ ID NO:146所示的氨基酸序列具有至少约80％序列同一性；以及V L，所述V L包含SEQ ID NO:184所示的氨基酸序列或其变体，所述变体与SEQ ID NO:184所示的氨基酸序列具有至少约80％序列同一性。
在一些实施例中，本文所述抗HBV pre-S1抗体是包含IgG1或IgG4恒定区的全长抗HBV pre-S1抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:186组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:187组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:188组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:189组成。
在一些实施例中，所述个体是哺乳动物(例如人、非人灵长类、大鼠、小鼠、牛、马、猪、绵羊、山羊、狗、猫等)。在一些实施例中，所述个体是人类。在一些实施例中，所述个体是临床患者、临床试验志愿者、实验动物等。在一些实施例中，所述个体年龄小于60岁(包括例如小于50、40、30、25、20、15或10岁)。在一些实施例中，所述个体年龄大于60岁(包括例如大于70、80、90或100岁)。在一些实施例中，所述个体是被诊断为或在遗传角度上易患本文所描述的一种或多种疾病或病症(例如HBV感染或与HBV感染相关的疾病)。在一些实施例中，所述个体具有一种或多种与本文所述的一种或多种疾病或病症相关的风险因子。
在一些实施例中，本申请提供一种向个体中在其表面表达HBV pre-S1的细胞递送抗HBV pre-S1抗体(例如本文所述的任一种抗HBV pre-S1抗体，例如分离的抗HBV pre-S1抗体)的方法，所述方法包括向该个体施用包含抗HBV pre-S1抗体的组合物。
HBV感染或其它任何表现出与HBV感染相关疾病的许多诊断方法和这些疾病的临床描述在本领域是已知的。这类方法包括，但不限于，例如免疫组化、PCR以及荧光原位杂交(FISH)。
在一些实施例中，本申请所述抗HBV pre-S1抗体(例如全长抗HBV pre-S1抗体)和/或组合物与第二、第三或第四药剂(包括例如其他抗病毒剂、抗过敏剂、抗恶心剂(或抗呕剂)、镇痛药、 细胞保护剂或免疫抑制剂)组合施用来预防、改善或治疗HBV感染或与HBV感染相关的疾病。在一些实施例中，所述其他抗病毒剂可包括但并不限于干扰素、核苷/核苷酸类似物、抗HBV的单克隆抗体、抗HBV的多克隆抗体、DNA聚合酶抑制剂或治疗性疫苗。所述核苷/核苷酸类似物可包括但并不限于拉米夫定、恩替卡韦、克来夫定或阿德福韦酯。
抗HBV pre-S1抗体的给药剂量和方法
施用于个体(例如人)的抗HBV pre-S1抗体(例如分离的抗HBV pre-S1抗体)组合物的剂量可能因特定组合物、给药方式和治疗疾病类型的不同而不同。在一些实施例中，组合物(例如，包含抗HBV pre-S1抗体的组合物)的量可在HBV感染或与HBV感染相关疾病的治疗中有效产生客观响应(例如，部分响应或完全响应)。在一些实施例中，抗HBV pre-S1抗体组合物的量足以在个体中产生完全响应。在一些实施例中，抗HBV pre-S1抗体组合物的量足以在个体中产生部分响应。在一些实施例中，抗HBV pre-S1抗体组合物的给药剂量(例如当单独施用时)足以在使用抗HBV pre-S1抗体组合物治疗的个体群体中产生高于20％、25％、30％、35％、40％、45％、50％、55％、60％、64％、65％、70％、75％、80％、85％或90％的总响应率。个体对本文所述治疗方法的响应可通过，例如，血清中分泌性HBV抗原的水平来确定。
在一些实施例中，组合物(例如包含分离的抗HBV pre-S1抗体的组合物)的量足以延长个体的无进展生存期。在一些实施例中，组合物的量足以延长个体的总体生存期。在一些实施例中，在使用抗HBV pre-S1抗体组合物治疗的个体群体中，组合物的量(例如当单独施用时)足以产生高于50％、60％、70％或77％的临床益处。
在一些实施例中，组合物(例如包含分离的抗HBV pre-S1抗体的组合物)的量，单独使用或与第二，第三、和/或第四药剂联合使用时，是指在治疗前或与未接受治疗的其他受试者的相应活性相比，足以控制症状和减少病情加重的风险的量。可以采用标准方法来测量该疗效的大小，例如纯化酶的体外检测、基于细胞的检测、动物模型或人体试验。
在一些实施例中，当将组合物施用于个体时，组合物中抗HBV pre-S1抗体(例如全长的抗HBV pre-S1抗体)的量低于引起毒性效应(即，一种高于临床可接受毒性水平的效应)的水平，或者处于潜在副作用可以控制或耐受的水平。
在一些实施例中，遵循相同的给药方案，组合物的量接近的组合物的最大耐受剂量(MTD)。在一些实施例中，组合物的量高于MTD的80％、90％、95％或98％。
在一些实施例中，组合物中抗HBV pre-S1抗体(例如全长的抗HBV pre-S1抗体)的含量在0.001μg到1000μg的范围之内。
在如上所述任一个实施例中，组合物中的抗HBV pre-S1抗体(例如全长的抗HBV pre-S1抗体)的有效量，按照体重时计算，为0.1μg/kg到100mg/kg的范围之内。
抗HBV pre-S1抗体组合物可通过多种途径施用于个体(如人类)，包括，例如静脉注射、动脉内给药、腹腔注射、肺内给药、口服给药、吸入给药、血管内给药、肌肉注射、气管内给药、皮下注射、眼内给药、鞘内给药、粘膜给药或经皮给药。在一些实施例中，使用组合物的缓释制 剂。在一些实施例中，组合物通过静脉给药。在一些实施例中，组合物通过动脉给药。在一些实施例中，组合物通过腹膜内给药。在一些实施例中，组合物通过肝内给药。在一些实施例中，组合物通过肝动脉输注给药。在一些实施例中，组合物施用于远离第一病灶的部位。
制品及试剂盒
在本申请的一些实施例中，提供一种制品，所述制品包含一种物质，所述物质能够用于预防、改善或治疗HBV感染或与HBV感染相关的疾病，或者用于递送抗HBV pre-S1抗体(例如一种全长抗HBV pre-S1抗体)到感染HBV的个体。所述制品可以包括一种容器以及在容器上或随该容器附带的标签或包装说明书。合适的容器包括，例如瓶子、小瓶、注射器等。容器可以由多种材料制成，例如玻璃或塑料。通常，该容器内装有能够有效治疗本文所述疾病或病症的组合物，并且具有一个无菌端口(例如该容器可以是一个静脉输液袋或是一个具有皮下注射针头可刺穿盖子的小瓶)。组合物中的至少一种活性物质即为本申请所述的抗HBV pre-S1抗体。标签或包装说明书标示了该组合物可以用于治疗的特定病症。标签或包装说明书进一步包含给患者施用抗HBV pre-S1抗体组合物的说明书。包括联合治疗的制品和试剂盒均在本文的考虑范围之内。
包装说明书是指通常包含在治疗产品的商业包装内的说明书，其包含关于与这些治疗产品使用有关的适应症、用法、剂量、施用、禁忌症和/或警告信息。在一些实施例中，包装说明书标明该组合物可以用于预防、改善或治疗HBV感染或与HBV感染相关的疾病。在一些实施例中，包装说明书标明该组合物可以用于治疗以下的疾病，包括乙型肝炎、肝功能衰竭、肝硬化或肝癌。
此外，所述制品还可以包括第二容器，其包含药学上可接受的缓冲液，例如抑菌性注射用水(BWFI)、磷酸盐缓冲液、格林氏溶液或葡萄糖溶液。还可以包括从商业和用户角度而言所需的其他材料，包括其他缓冲液、稀释液、过滤器、针头和注射器。
同时还涉及可用于各种目的的试剂盒，例如用于预防、改善或治疗HBV感染或与HBV感染相关的疾病，或者用于递送抗HBV pre-S1抗体(例如全长抗HBV pre-S1抗体)到感染HBV的个体中，任选与制品组合。本申请的试剂盒包括一个或多个容器，其包含抗HBV pre-S1抗体组合物(或单剂量形式和/或制品)，并且在一些实施例中，进一步包含另一种药剂(例如本文所述的药剂)和/或与本文所述任一方法相一致的使用说明书。该试剂盒可进一步包括选择适合治疗个体的描述。本申请中试剂盒中所附带的使用说明书通常是标签或包装说明书上的书面说明(例如包含在试剂盒内的纸页)，机器可读的说明(例如，磁性或光学储存光盘上的说明)也是可以接受的。
例如，在一些实施例中，试剂盒包括一种包含抗HBV pre-S1抗体(例如全长的抗HBV pre-S1抗体)的组合物。在一些实施例中，试剂盒包括：a)包含本文所述的任一种抗HBV pre-S1抗体的组合物，和b)至少一种有效量的其它药剂，其能够增强抗HBV pre-S1抗体的效果(如治疗效果、检测效果)。在一些实施例中，试剂盒包括：a)包含本文所述的任一种抗HBV pre-S1抗体的组合物，和b)向个体施用抗HBV pre-S1抗体组合物用于预防、改善或治疗HBV感染或与HBV感染相关疾病的使用说明书。在一些实施例中，试剂盒包括：a)包含本文所述的任一种抗HBV pre-S1抗 体的组合物，和b)至少一种有效量的其它药剂，其能够增强抗HBV pre-S1抗体的效果(如治疗效果、检测效果)和c)向个体施用抗HBV pre-S1抗体组合物和其它物质用于预防、改善或治疗HBV感染或与HBV感染相关疾病的使用说明书。所述抗HBV pre-S1抗体和其他物质可以存在于独立的容器或同一个容器中。例如，该试剂盒可以包括一种特定组合物或两种或更多种组合物，其中一种组合物包括抗HBV pre-S1抗体，另一种组合物包括另一种药剂。
在一些实施例中，试剂盒包含一种(或一组)编码抗HBV pre-S1抗体(例如全长的抗HBV pre-S1抗体)的核酸。在一些实施例中，试剂盒包含：a)一种(或一组)编码抗HBV pre-S1抗体(例如全长的抗HBV pre-S1抗体)的核酸，和b)一种表达核酸(或一组核酸)的宿主细胞。在一些实施例中，试剂盒包含：a)一种(或一组)编码抗HBV pre-S1抗体(例如全长的抗HBV pre-S1抗体)的核酸，和b)使用说明书，适用于：i)在宿主细胞中表达抗HBV pre-S1抗体，ii)制备包含抗HBV pre-S1抗体的组合物，和iii)向个体施用包含抗HBV pre-S1抗体的组合物来预防、改善或治疗HBV感染或与HBV感染相关的疾病。在一些实施例中，试剂盒包括：a)一种(或一组)编码抗HBV pre-S1抗体(例如全长的抗HBV pre-S1抗体)的核酸，b)一种表达核酸(或一组核酸)的宿主细胞，和c)使用说明书，适用于：i)在宿主细胞中表达抗HBV pre-S1抗体，ii)制备包含抗HBV pre-S1抗体的组合物，和iii)向个体施用包含抗HBV pre-S1抗体的组合物来预防、改善或治疗HBV感染或与HBV感染相关的疾病。
本申请所述的试剂盒以合适的形式进行包装。合适的包装包括，但不限于，小瓶、瓶子、广口瓶、软包装(例如密封的聚酯薄膜或塑料袋)等。试剂盒可以任选地提供其它的组分，例如缓冲液和说明信息。因此，本申请还提供制品，其包括小瓶、瓶子、广口瓶、软包装(例如密封的聚酯薄膜或塑料袋)等。
关于抗HBV pre-S1抗体组合物的使用说明书，通常包括一些信息，诸如，剂量，给药周期和给药途径等。容器可以是单位剂量的，大包装的(如，多剂量包装)或亚单位剂量的。例如，提供一种包含足够剂量的如本文所述的抗HBV pre-S1抗体(例如全长的抗HBV pre-S1抗体)的试剂盒以对个体进行长期有效的治疗，例如一周、8天、9天、10天、11天、12天、13天、2周、3周、4周、6周、8周、3个月、4个月、5个月、7个月、8个月、9个月或更长时间。试剂盒还可包含多单位剂量的抗HBV pre-S1抗体、药物组合物和使用说明书，并且以足够在药房中储存和使用的量进行包装，例如，医院药房和复方药房。
本领域的技术人员将认识到在本申请的范围和宗旨内可能的若干实施例。现在将通过参考以下非限制性实施例来更详细地描述本申请。以下实施例进一步阐明本申请，但不应解释为以任何方式进行限制其范围。
具体实施方式
实施例1：重组蛋白制备
制备重组HBV pre-S1抗原
通过亚克隆分别将编码HBV A、B、C、D、E、F、G、H、I和J基因型的pre-S1(preS1)结构域的cDNA构建到pTT5表达载体中，并在HEK293细胞中进行表达。在编码HBV pre-S1结构域的cDNA上添加His标签和/或Avi标签和/或其它的本领域技术人员常用标签，构建并表达出含有HBV pre-S1结构域的融合蛋白，例如X-preS1-His、B-preS1-Avi-His。其中，“His”代表His标签，“Avi”代表亲和素标签，“X”代表HBV基因型，X可以是A、B、C、D、E、F、G、H、I或J，例如，“B”代表HBV B基因型。
制备重组FcγRIIIa胞外区抗原
通过亚克隆将编码FcγRIIIa胞外区的cDNA构建到pTT5表达载体中，并在HEK293细胞中进行表达。在编码FcγRIIIa胞外区的cDNA上添加His标签、Avi标签和/或其它的本领域技术人员常用标签，构建并表达出含有FcγRIIIa胞外区的融合蛋白，例如FcγRIIIa-ECD-Avi-His。其中，“ECD”代表胞外区，“His”代表His标签，“Avi”代表亲和素标签。
将重组HBV pre-S1融合蛋白和FcγRIIIa胞外区融合蛋白，包括X-preS1-His、B-preS1-Avi-His以及FcγRIIIa-ECD-Avi-His，分别表达和纯化。简言之，将含有上述融合蛋白基因的表达载体分别转染HEK293细胞，并将上述细胞在37℃、5％CO 2、120rpm条件下培养5天。分别收集细胞培养液。
根据制造商的操作说明，采用镍柱(Ni)纯化具有His标签的重组融合蛋白。具体操作如下：将细胞培养液在20000rpm条件下离心15分钟，取上清。将上清用0.45μm滤膜过滤后，采用HisCap 6FF柱(常州天地人和生物科技有限公司，SA005C55)进行纯化。纯化后的蛋白采用3kDa超滤管(Millipore，UFC900396)进行浓缩换液，将纯化后蛋白的溶剂更换为PBS。采用BCA蛋白定量试剂盒(ThermoScientific，23225)进行蛋白定量，备用。
制备生物素化标记的抗原
按照操作说明书，采用生物素化连接酶B0101A(GeneCopoeia)对B-preS1-Avi-His或FcγRIIIa-ECD-Avi-His进行生物素化标记。简言之，向B-preS1-Avi-His或FcγRIIIa-ECD-Avi-His中加入BufferA/B和BirA连接酶后在30℃下孵育2小时。生物素化的B-preS1-Avi-His被命名为B-preS1-Bavih；生物素化的FcγRIIIa-ECD-Avi-His被命名为FcγRIIIa-ECD-Bavih。通过ELISA方法检测生物素化效率，确定上述蛋白的生物素化标记效率至少为70％。
合成的HBV pre-S1抗原
委托北京中科亚光生物科技有限公司合成HBV pre-S1抗原P2019-1和P2019-2，这些抗原用于后续抗体筛选。P2019-1:具有N末端肉豆蔻酰化修饰和C末端生物素修饰的包含HBV L蛋白pre-S1结构域(SEQ NO.191)第14-58位氨基酸残基的多肽。P2019-2:在C末端具有生物素修饰的包含HBV L蛋白pre-S1结构域(SEQ NO.191)第15-46位氨基酸残基的多肽。
P2019-1：Myr-TNLSVPNPLGFFPDHQLDPAFGANSNNPDWDFNPNKDHWPEANQV-K(biotin)；
P2019-2：NLSVPNPLGFFPDHQLDPAFGANSNNPDWDFN-K(biotin)。
实施例2：筛选抗HBV pre-S1的单链Fv(scFv)
构建scFv抗体酵母展示文库：从2000份人血液样本中提取RNA，经逆转录获得cDNA。采用V H和V K特异性引物扩增V H和V K片段，经过胶回收纯化后，连接V H和V K，构建scFv。将其克隆到酵母展示质粒PYD1中，随后将该质粒电转至酵母菌中，获得scFv抗体酵母展示文库。
筛选抗HBV pre-S1抗原的单链Fv(scFv)：经几轮淘选后，从酵母展示文库中分离结合HBV B基因型pre-S1抗原的scFvs。简言之，采用MACS磁珠分选，对结合HBV B基因型pre-S1抗原的酵母细胞进行富集。将1000OD的酵母细胞在2500g下离心5分钟，获得的细胞沉淀按照OD600＝1的起始浓度，用1L SGCAA培养基进行重悬，并于20℃、250rpm培养条件下诱导表达40-48小时。将细胞培养液离心，并用PBSM溶液清洗后，用5-10倍体积的含有1μM B-preS1-Bavih的PBSM溶液重悬细胞沉淀，4℃孵育1小时。经过离心和PBSM洗涤后，未结合的抗原被PBSM溶液洗去。加入磁珠后，充分混匀，随后置于4℃悬转仪上孵育30分钟。2500g离心5分钟，弃去上清，用5-10倍体积的PBSM溶液重悬沉淀。每次取7mL细胞悬液加入到柱子上，直到所有的细胞悬液流穿柱子。洗脱并收集结合到柱子上的细胞，用于培养以及后续FACS分选。
采用FACS筛选抗HBV pre-S1抗原的单链Fv(scFv)：对经MACS淘选后富集的酵母进行流式细胞术分选(FACS)。简言之，将SGCAA培养基中诱导的酵母细胞沉淀，用1mL PBSM洗涤沉淀，14000g离心30秒。用100μL含有B-preS1-Bavih、P2019-1或P2019-2的PBSM缓冲液重悬酵母细胞，室温孵育1h。洗涤后，用SA-PE(BD，554061)和抗V5抗体(GenScript，A01803)对细胞进行染色，将其加入100μL PBSM缓冲液中，冰上孵育20分钟，筛选出前1％的双阳性染色细胞。经由B-preS1-Bavih和/或P2019-1和/或P2019-2指导的筛选分别重复2-3个循环，将分选到的酵母细胞接种到琼脂固体培养基中，进行扩增。通过进一步的FACS分析，对单个克隆进行检测。在筛选过程结束后，获得一系列阳性scFv抗体，并对其进行测序。
实施例3：制备和表征全长的抗HBV pre-S1抗体
制备全长的抗HBV pre-S1抗体
将获得的阳性scFv抗体重构成具有人IgG1或IgG4的重链恒定区和人kappa轻链恒定区的嵌合抗体分子。从酵母表达载体中扩增V L和V H，分别构建入真核表达载体pTT5-L(包含kappa轻链恒定区)和pTT5-H1(包含IgG1重链恒定区)或pTT5-H4(包含IgG4重链恒定区)中。将分别提取的表达轻链或重链的质粒，共转染293F细胞，37℃、8％CO 2、120rpm培养5天，用Protein A亲和层析柱纯化培养液。简言之，首先采用6倍柱体积50mM PBS缓冲液(包含0.15M NaCl，pH7.2)以150cm/h的流速平衡蛋白A柱。培养液上清(调节pH至7.2)以150cm/h流速流 穿柱子。进一步平衡该柱后，采用50mM柠檬酸钠缓冲液(pH3.5)洗脱，收集洗脱液。将获得的全长抗体进行进一步的生化和生物活性分析。
ELISA结合试验
将筛选得到的全长抗HBV preS1单克隆抗体(重构成人IgG1形式)分别与B-preS1-His抗原进行结合试验，该试验用于鉴定抗体与pre-S1抗原的结合能力。简言之，将实施例1制备的B-preS1-His抗原溶解在PBS溶液中，按照0.1μg/孔包被96孔板，4℃过夜。在加入抗体之前，用PBST溶液洗涤96孔板，用5％牛奶37℃封闭1小时，再用PBST溶液洗涤。将每个抗体样品稀释至3μg/mL，随后以1：3的比例进行梯度稀释。将梯度稀释后的样品分别加入96孔板中，每孔100μL，37℃孵育1小时。随后用PBST溶液洗涤6次。向各孔中加入100μL二抗(山羊抗人IgG-AP(Southern Biotech公司，A5912-PF77C))，37℃孵育1小时。用PBST溶液洗涤6次。每孔加入100μL pNPP显色液(Southern Biotech公司，L5519-2J39)，37℃孵育10-20分钟。利用酶标仪读取405nm处的吸光值。通过Graphpad Prism生成结合曲线，计算EC 50值。
结果如表5所示，与对照抗体A14-8相比，所选的抗HBV pre-S1抗体K25、K27、K31、K55、K71、K80、K121、K127等均能较好的结合HBV pre-S1抗原。
表5 抗HBV pre-S1抗体与pre-S1抗原的结合能力
样品名称 EC 50值(ng/mL) 样品名称 EC 50值(ng/mL)
K25 35.14 K80 27.73
K26 22.40 K82 34.05
K27 30.17 K118 22.37
K28 29.19 K119 36.83
K31 22.49 K121 12.90
K48 42.01 K122 14.24
K50 18.51 K123 24.58
K55 22.87 K127 20.01
K71 26.02 K128 21.12
K72 43.24 A14-8 32.98
ELISA方法检测抗HBV preS1抗体ADCC活性：
通过ELISA试验检测筛选得到的全长抗HBV preS1抗体(重构成人IgG1形式)以及对照抗体A14-8与FcγRIIIa(Fc受体)胞外区的结合能力，从而确定各抗体介导的ADCC活性。ADCC活性的检测方法参见文献(Development of an ELISA based bridging assay as a surrogate measure of ADCC.J Immunol Methods.2012 Nov 30；385(1-2):45-50.)。简言之，首先将实施例1制备的B-preS1-His抗原溶解在PBS溶液中，按照0.1μg/孔包被96孔板，4℃过夜。在加入抗体之前，用PBST溶液洗涤96孔板，用5％牛奶37℃封闭1小时，再用PBST溶液洗涤。将每个抗体样品稀释至10μg/mL，随后以1：3的比例进行梯度稀释。将梯度稀释后的样品分别加入96孔板中，每孔100μL，37℃ 孵育1小时。随后用PBST溶液洗涤6次。向各孔中加入100μL实施例1中制备的FcγRIIIa-ECD-Bavih重组蛋白(5μg/mL)，37℃孵育1小时。用PBST溶液洗涤6次。每孔加入100μL SA-HRP(Invitrogen,SNN2004)，37℃孵育1小时。用PBST溶液洗涤6次。每孔加入100μL TMB(碧云天，P0209-100mL)，37℃孵育10-20分钟。用2M H 2SO 4终止反应。利用酶标仪读取450nm处的吸光值。通过Graphpad Prism生成结合曲线，计算EC 50值。
结果如表6所示，抗HBV preS1抗体K23、K27、K50、K71、K80、K122、K127等均能够与FcγRIIIa结合，且展示出比对照抗体A14-8更优或与之相当的ADCC活性。
表6 ELISA方法检测抗HBV preS1抗体的ADCC活性
样品名称 EC 50值(ng/mL) 样品名称 EC 50值(ng/mL)
K23 776 K121 800
K27 712 K119 696
K28 648 K118 680
K31 728 K122 512
K50 840 K127 752
K71 560 A14-8 800
K80 536    
基于报告基因的抗HBV preS1抗体ADCC活性测定：
利用稳定转染Fc受体CD16A(FcγRIIIA)以及NFAT(nuclear factorof activated T-cells)反应元件的Jurkat-Lucia TM NFAT-CD16作为效应细胞，稳定表达HBV B基因型pre-S1抗原第1-59位氨基酸的293T作为靶细胞。通过单抗将效应细胞与靶细胞连接起来，同时抗体的Fc部分与效应细胞表面Fc受体CD16A的结合导致NFAT通路激活，进而启动荧光素酶报告基因的表达。加入荧光素酶底物溶液后，以荧光强度指示抗体介导的ADCC活性。
简言之，将稳定表达HBV B基因型pre-S1抗原(1-59位氨基酸)的293T细胞(1×10 6个细胞/mL)接种于96孔板中，每孔90μL。将起始浓度为45μg/mL的K23、K27、K31、K41、K50、K123、K127或K128等抗HBV pre-S1抗体(重构成人IgG1形式)以1：5的比例进行梯度稀释，分别加入到96孔培养板中，在37℃、5％CO 2条件下孵育1h。将密度为2×10 6个细胞/mL的效应细胞Jurkat-Lucia TM NFAT-CD16(InvivoGen，jktl-nfat-cd16)接种于上述96孔板中，每孔90μL，并在37℃、5％CO 2条件下孵育6h。每孔取20μL上清，分别加入50μL QUANTI-Luc检测液。利用酶标仪测量相对光单位的数值。将加入阴性对照抗体(6G4103DT，本公司针对PcRV靶点的抗体)和加入浓度为4.5μg/mL的A14-20m1时测定得到的相对光单位数值分别设为0％和100％杀伤率，以此来计算不同浓度下K23、K25、K27、K50、K80、K127、K128等抗HBV pre-S1抗体以及对照抗体A14-20m1的相对细胞杀伤率(细胞毒性率)。利用Graphpad Prism软件绘图，计算EC 50值，从而确定各抗体的ADCC活性。
结果如表7所示，与对照抗体A14-20m1相比，K23、K27、K31、K41、K50、K123、K127、 K128等抗HBV preS1抗体展示出更优或与之相当的ADCC活性。
表7 基于报告基因的抗HBV preS1抗体ADCC活性测定
样品名称 EC 50值(ng/mL) 样品名称 EC 50值(ng/mL)
K23 8.76 K73 13.51
K27 14.55 K118 7.5
K28 14.17 K120 2.79
K31 4.57 K122 2.45
K41 7.03 K123 4.38
K50 13.22 K127 3.78
K70 7.55 K128 10.45
K71 5.93 A14-20m1 11.20
实施例4:抗HBV pre-S1抗体结合HBV的广谱性
采用实施例3中所述的ELISA结合试验，检测全长抗pre-S1抗体K41、K50、K55、K80、K127、K128(重构成人IgG1形式)以及对照抗体A14-8分别与实施例1中制备的HBV A、B、C、D、E、F、G、H、I或J基因型pre-S1抗原的结合情况，以判断抗HBV pre-S1抗体对HBV的结合是否具有广谱性。
结果如表8所示，抗HBV pre-S1抗体均可以与HBV A、B、C、D、E、F、G、H、I和J基因型pre-S1抗原中的至少8种亚型相结合。此外，与对照抗体A14-8相比，K41、K50、K55、K80、K127或K128与HBV的主要基因型(A、B、C、D或E)的结合更优或与之相当。由此可见，抗HBV pre-S1抗体K41、K50、K55、K80、K127或K128与HBV的结合具有广谱性。
表8 抗HBV pre-S1抗体结合HBV的广谱性
Figure PCTCN2022125558-appb-000011
实施例5:抗HBV pre-S1抗体的亲和力
采用Biacore 3000(GE)表征全长抗HBV pre-S1抗体K31、K50、、K55、K80、K127(重构 成人IgG1形式)以及对照抗体A14-20m1与pre-S1抗原的结合亲和力。将实施例1中制备的B-preS1-Bavih抗原包被在链霉亲和素芯片(streptavidin chip)的表面，检测不同浓度下的抗体与B-preS1-Bavih的亲和力。用SPR技术测量抗体的结合速率和解离速率，并确定结合亲和力。
结果如表9所示，与对照抗体A14-20m1相比，K31、K50、K55、K80抗体的亲和力更优，而K127抗体的亲和力稍弱，后续可进行优化。
表9 抗HBV pre-S1抗体的亲和力
抗体名称 Kon(1/Ms) Koff(1/s) Kd(M)
K31 5.167E+5 1.953E-3 3.779E-9
K50 2.852E+5 1.575E-3 5.524E-9
K55 9.156E+5 7.719E-3 8.430E-9
K80 1.243E+6 3.566E-3 2.870E-9
K127 2.128E+5 3.692E-3 1.735E-8
A14-20m1 3.477E+6 3.397E-2 9.770E-9
实施例6:抗HBV pre-S1抗体的中和活性
采用HBV感染细胞表面表达牛磺胆酸钠共转运多肽(NTCP)的人类细胞，通过检测上清中的HBV抗原(例如HBsAg或HBeAg)的含量来评估各抗体的HBV中和活性。
简言之，将稳定表达NTCP的HepG2细胞(HepG2-NTCP，由上海药明康德公司构建)接种于48孔板中，每孔7.5×10 4个细胞。第2天，将起始浓度为150μg/mL的抗HBV pre-S1抗体K31、K50、K55、K80、K127(重构成人IgG1形式)以1：4的比例进行梯度稀释，分别与600GE(genome，基因组当量)的HBV(D基因型)混合，37℃条件下共孵育1h。将上述抗体-病毒混合液加入HepG2-NTCP细胞培养板中进行培养，第3、5、7天分别更换一次不含抗体和病毒的新鲜培养基。在第9天收集上清。采用HBsAg Elisa试剂盒(安图生物，CL0310)检测上清中HBs抗原含量。将不加入抗pre-S1抗体和不加入HBV病毒感染时测定的吸光度值分别计为0％和100％抑制率，归一化实验数据，计算各抗体的中和活性。
结果如图1A—1E所示，随着K31、K50、K55、K80或K127抗体浓度的增加，上清中HBsAg含量逐渐降低，这表明上述抗体均具有良好的HBV中和活性。
实施例7:提高抗体的亲和力和生物学活性
为了提高抗HBV pre-S1抗体的亲和力和活性，选择K127作为先导抗体进行亲和力成熟。分析K127的序列，在其CDR区进行突变，构建并产生相应的噬菌体scFv展示文库，筛选出性能提高的抗HBV pre-S1抗体。按照实施例3所述方法，将上述scFv抗体重构成全长抗体。采用ELISA结合试验、ADCC试验进一步进行生化和生物活性分析。
ELISA结合试验
采用实施例3中所述的方案，对亲和力成熟后的全长抗体(重构成人IgG1形式)进行ELISA结合试验，以检测优化后的抗体与pre-S1抗原的结合能力。
结果如图2所示，与对照抗体A14-20m1相比，亲本抗体K127及优化后的抗体K127-9、K127-10、K127-23、K127-24、K127-29、K127-42、K127-53均展示出较好的结合HBV pre-S1抗原的能力；且与母本K127相比，优化后的抗体K127-9、K127-10、K127-23、K127-24、K127-29、K127-42、K127-53与pre-S1的结合能力得以提高。
ELISA方法检测抗HBV pre-S1抗体ADCC活性：
根据实施例3中所述的方案，采用ELISA试验检测优化后抗体(重构成人IgG1形式)的ADCC活性。
结果如图3所示，优化后的抗体K127-9、K127-10、K127-23、K127-24、K127-42、K127-53均能够与FcγRIIIa结合，且与其母本K127相比，优化后的抗体ADCC活性增强。
基于报告基因的抗HBV pre-S1抗体ADCC活性测定：
根据实施例3中所述的方案，利用报告基因系统展示优化后抗体(重构成人IgG1形式)的细胞杀伤率(细胞毒性率)，从而确定各抗体的ADCC活性。
结果如图4所示，优化后的抗体K127-10、K127-23、K127-24、K127-29、K127-42和K127-53展示出良好的ADCC活性。
抗HBV pre-S1抗体的ADCP活性测定:
利用THP-1细胞(人急性单核细胞白血病细胞，来源于国家实验室细胞资源中心)作为效应细胞，稳定表达HBV B基因型pre-S1抗原(1-59位氨基酸)的293T作为靶细胞，加入抗HBV pre-S1抗体介导ADCP作用。以CFSE标记效应细胞，以pHrodo Red AM标记靶细胞，然后将靶细胞、效应细胞以及抗HBV pre-S1抗体三者混合后孵育，通过流式细胞仪检测出双阳性的THP-1细胞(即吞噬靶细胞后的THP-1细胞)及总THP-1细胞的数量，其中双阳性THP-1细胞与总THP-1细胞数量的比值即为吞噬率。
简言之，向THP-1细胞中加入CFSE(Invitrogen C34554)制备CFSE标记的效应细胞，向稳定表达HBV B基因型pre-S1抗原(1-59位氨基酸)的293T细胞中加入pHrodo Red AM(Invitrogen P35372)制备pHrodo Red AM标记的靶细胞。将起始浓度为100ng/mL的抗HBV pre-S1抗体(重构成人IgG1形式)K127、K127-24、K127-42或阴性对照抗体6G4103DT以1：5的比例进行梯度稀释，分别加入到96孔培养板中，每孔100μL。向各96孔板中加入pHrodo Red AM标记的靶细胞(1×10 5个细胞/孔)和CFSE标记的效应细胞(5×10 4个细胞/孔)。将抗体、靶细胞和效应细胞充分混合后，在37℃、5％CO 2条件下孵育4.5h。同时设置不加抗体，仅含有靶细胞和效应细胞的空白对照组。用PBS洗涤后，再将细胞重悬，利用流式细胞仪进行荧光检测。检测出双阳性THP-1细胞及总THP-1细胞的数量，并计算吞噬率。利用Graphpad Prism软件绘图，从而确定各抗体的ADCP活性。
结果如图5所示，抗HBV preS1抗体K127、K127-24、K127-42均展示出良好的ADCP活性，而阴性对照抗体未展示出ADCP活性。
实施例8:抗HBV pre-S1抗体在C57BL/6小鼠rAAV-HBV转染模型中的作用
利用携带HBV全基因组DNA的重组腺相关病毒(rAAV)载体感染C57BL/6小鼠，建立C57BL/6小鼠HBV感染模型(维通达公司)。简言之，以嗜肝性的8型rAAV为载体，将约1.3倍HBV基因组长度的DNA片段通过感染(rAAV-HBV)导入C57BL/6小鼠体内，可以在小鼠肝内复制产生HBV病毒粒子。注射rAAV-HBV后，小鼠血清HBsAg、HBeAg和HBV DNA以及肝组织HBcAg稳定表达超过8个月，其表达水平随重组病毒注射剂量的增加而升高。
为了测定抗HBV pre-S1抗体的治疗作用，以Fc段鼠源化改造的抗HBV pre-S1抗体K55、K80、K127、K127-10、K127-23、K127-24、K127-42为例，通过腹腔注射向上述模型小鼠分别施用上述抗体，同时设置对照组，其中阳性对照组小鼠注射Fc段鼠源化改造的A14-20m1或VIR3434(Vir Biotechnology，抗HBV表面S抗原的抗体)，阴性对照组小鼠注射PBS。每周给药两次，每次20mg/kg，共给药6周。首次给药当天(记为第0天)采集小鼠血液样品，然后进行首次给药，之后定期采集小鼠血液样品，采用HBsAg Elisa试剂盒(迈克生物)检测上清中HBsAg含量。
结果如图6所示，在rAAV-HBV转染的C57BL/6小鼠模型中，施用抗pre-S1抗体K127、K127-24或K127-42后，小鼠血清中的HBsAg含量下降，其效果与对照抗体A14-20m1相当，优于对照抗体VIR3434。K55、K80、K127-10、K127-23也表现出相似的效果(数据未显示)。上述结果表明，本发明的抗pre-S1抗体能够在体内有效抑制HBV感染。
实施例9:抗HBV pre-S1抗体在FcγRIIIa人源化小鼠rAAV-HBV转染模型中的作用
利用携带HBV全基因组DNA的重组腺相关病毒(rAAV)载体感染FcγRIIIa人源化小鼠(百奥赛图，111173)，建立FcγRIIIa人源化小鼠HBV感染模型(维通达公司)。简言之，以嗜肝性的8型rAAV为载体，将约1.3倍HBV基因组长度的DNA片段通过感染(rAAV-HBV)导入FcγRIIIa人源化小鼠体内，以在小鼠肝内复制产生HBV病毒粒子。注射rAAV-HBV后，小鼠血清HBsAg、HBeAg和HBV DNA以及肝组织HBcAg稳定表达超过8个月，其表达水平随重组病毒注射剂量的增加而升高。
为了测定抗HBV pre-S1抗体的治疗作用，以抗HBV pre-S1抗体K127-9、K127-24、K127-42为例，通过腹腔注射向上述模型小鼠分别施用上述抗体，同时设置对照组，其中阳性对照组小鼠注射A14-20m1，阴性对照组小鼠注射抗体6G4103DT(无关抗体)，每周给药两次，每次20mg/kg，共给药6周。首次给药的当天(记为第0天)采集小鼠血液样品，然后进行首次给药，之后定期采集小鼠血液样品，采用HBsAg Elisa试剂盒(迈克生物)检测上清中HBsAg含量。
结果如图7所示，在rAAV-HBV转染的FcγRIIIa人源化小鼠模型中，施用抗pre-S1抗体K127-9、K127-24或K127-42后，小鼠血清中的HBsAg含量下降，且其效果优于对照抗体A14- 20m1。上述结果再一次证明，本发明的抗pre-S1抗体能够在体内有效抑制HBV感染。

Claims (27)

  1. 一种分离的特异性结合HBV表面抗原pre-S1结构域的抗体，其中所述抗体包含：重链可变结构域(V H)，所述V H包含：
    重链互补决定区(HC-CDR)1，其包含TYGIT(SEQ ID NO:18)；
    HC-CDR2，其包含SRIPIX 1GAALYAQKFQG(SEQ ID NO:115)，其中X 1为F或L；和
    HC-CDR3，其包含NX 1RGGFAAY(SEQ ID NO:116)，其中X 1为D或T；
    以及轻链可变结构域(V L)，所述V L包含：
    轻链互补决定区(LC-CDR)1，其包含RSSQSLX 1HSNX 2YNYLD(SEQ ID NO:117)，其中X 1为L或T，X 2为A或G；
    LC-CDR2，其包含LGX 1X 2RAS(SEQ ID NO:118)的，其中X 1为H或S，X 2为K、N或R；和
    LC-CDR3，其包含序列MQALX 1X 2PX 3T(SEQ ID NO:119)，其中X 1为Q或V，X 2为I或T，X 3为A或P。
  2. 一种分离的特异性结合HBV表面抗原pre-S1结构域的抗体，其包含：
    V H，所述V H包含：
    HC-CDR1，其包含SEQ ID NO:18所示的氨基酸序列或其变体，所述变体包含至多约3个氨基酸的取代；
    HC-CDR2，其包含SEQ ID NOs:37-38中任一所示的氨基酸序列或其变体，所述变体包含至多约3个氨基酸的取代；和
    HC-CDR3，其包含SEQ ID NOs:56-57中任一所示的氨基酸序列或其变体，所述变体包含至多约3个氨基酸的取代；
    以及V L，所述V L包含：
    LC-CDR1，其包含SEQ ID NOs:59和76-77中任一所示的氨基酸序列或其变体，所述变体包含至多约3个氨基酸的取代；
    LC-CDR2，其包含SEQ ID NOs:79和89-91中任一所示的氨基酸序列或其变体，所述变体包含至多约3个氨基酸的取代；和
    LC-CDR3，其包含SEQ ID NOs:111-114中任一所示的氨基酸序列或其变体，所述变体包含至多约3个氨基酸的取代。
  3. 一种分离的特异性结合HBV表面抗原pre-S1结构域的抗体，其包含V H，所述 V H包含如SEQ ID NOs:146-150中任一氨基酸序列所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，所述V L包含如SEQ ID NOs:176-183中任一氨基酸序列所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3。
  4. 根据权利要求3中所述的分离的特异性结合HBV表面抗原pre-S1结构域的抗体，其包含：
    (i)V H，其包含如氨基酸序列SEQ ID NO:146所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:176所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3；
    (ii)V H，其包含如氨基酸序列SEQ ID NO:147所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:177所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3；
    (iii)V H，其包含如氨基酸序列SEQ ID NO:148所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:178所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3；
    (iv)V H，其包含如氨基酸序列SEQ ID NO:149所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:179所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3；
    (v)V H，其包含如氨基酸序列SEQ ID NO:147所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:180所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3；
    (vi)V H，其包含如氨基酸序列SEQ ID NO:147所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:181所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3；
    (vii)V H，其包含如氨基酸序列SEQ ID NO:148所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:182所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3；或
    (viii)V H，其包含如氨基酸序列SEQ ID NO:150所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:183所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3。
  5. 根据权利要求1-4中任一项所述的分离的特异性结合HBV表面抗原pre-S1结构域的抗体，其包含：
    (i)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:18，HC-CDR2，其包含氨基酸序列SEQ ID NO:37，和HC-CDR3，其包含氨基酸序列SEQ ID NO:56，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:59，LC-CDR2，其包含氨基酸序列SEQ ID NO:79，和LC-CDR3，其包含氨基酸序列SEQ ID NO:111，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；
    (ii)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:18，HC-CDR2，其包含氨基酸序列SEQ ID NO:38，和HC-CDR3，其包含氨基酸序列SEQ ID NO:57，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:76，LC-CDR2，其包含氨基酸序列SEQ ID NO:79，和LC-CDR3，其包含氨基酸序列SEQ ID NO:112，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；
    (iii)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:18，HC-CDR2，其包含氨基酸序列SEQ ID NO:37，和HC-CDR3，其包含氨基酸序列SEQ ID NO:57，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:77，LC-CDR2，其包含氨基酸序列SEQ ID NO:89，和LC-CDR3，其包含氨基酸序列SEQ ID NO:111，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；
    (iv)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:18，HC-CDR2，其包含氨基酸序列SEQ ID NO:37，和HC-CDR3，其包含氨基酸序列SEQ ID NO:57，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:77，LC-CDR2，其包含氨基酸序列SEQ ID NO:90，和LC-CDR3，其包含氨基酸序列SEQ ID NO:111，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸 的取代；
    (v)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:18，HC-CDR2，其包含氨基酸序列SEQ ID NO:38，和HC-CDR3，其包含氨基酸序列SEQ ID NO:57，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:76，LC-CDR2，其包含氨基酸序列SEQ ID NO:79，和LC-CDR3其包含氨基酸序列SEQ ID NO:111，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；
    (vi)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:18，HC-CDR2，其包含氨基酸序列SEQ ID NO:38，和HC-CDR3，其包含氨基酸序列SEQ ID NO:57，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:77，LC-CDR2，其包含氨基酸序列SEQ ID NO:79，和LC-CDR3，其包含氨基酸序列SEQ ID NO:113，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；
    (vii)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:18，HC-CDR2，其包含氨基酸序列SEQ ID NO:37，和HC-CDR3，其包含氨基酸序列SEQ ID NO:57，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:77，LC-CDR2，其包含氨基酸序列SEQ ID NO:89，和LC-CDR3，其包含氨基酸序列SEQ ID NO:114，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；或
    (viii)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:18，HC-CDR2，其包含氨基酸序列SEQ ID NO:37，和HC-CDR3，其包含氨基酸序列SEQ ID NO:57，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:77，LC-CDR2，其包含氨基酸序列SEQ ID NO:91，和LC-CDR3，其包含氨基酸序列SEQ ID NO:113，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
  6. 根据权利要求1-5中任一项所述的分离的特异性结合HBV表面抗原pre-S1结构域的抗体，其包含：
    V H，其包含SEQ ID NOs:146-150中任一所示的氨基酸序列或其变体，所述变体与SEQ ID NOs:146-150中任一氨基酸序列具有至少约80％序列同一性；以及V L，其包含SEQ ID NOs:176-183中任一所示的氨基酸序列或其变体，所述变体与SEQ ID NOs:176-183中任一氨基酸序列具有至少80％序列同一性。
  7. 根据权利要求6中所述的分离的特异性结合HBV表面抗原pre-S1结构域的抗体，其包含：
    (i)V H，其包含氨基酸序列SEQ ID NO:146或其变体，所述变体与氨基酸序列SEQ ID NO:146具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:176或其变体，所述变体与氨基酸序列SEQ ID NO:176具有至少约80％序列同一性；
    (ii)V H，其包含氨基酸序列SEQ ID NO:147或其变体，所述变体与氨基酸序列SEQ ID NO:147具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:177或其变体，所述变体与氨基酸序列SEQ ID NO:177具有至少约80％序列同一性；
    (iii)V H，其包含氨基酸序列SEQ ID NO:148或其变体，所述变体与氨基酸序列SEQ ID NO:148具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:178或其变体，所述变体与氨基酸序列SEQ ID NO:178具有至少约80％序列同一性；
    (iv)V H，其包含氨基酸序列SEQ ID NO:149或其变体，所述变体与氨基酸序列SEQ ID NO:149具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:179或其变体，所述变体与氨基酸序列SEQ ID NO:179具有至少约80％序列同一性；
    (v)V H，其包含氨基酸序列SEQ ID NO:147或其变体，所述变体与氨基酸序列SEQ ID NO:147具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:180或其变体，所述变体与氨基酸序列SEQ ID NO:180具有至少约80％序列同一性；
    (vi)V H，其包含氨基酸序列SEQ ID NO:147或其变体，所述变体与氨基酸序列 SEQ ID NO:147具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:181或其变体，所述变体与氨基酸序列SEQ ID NO:181具有至少约80％序列同一性；
    (vii)V H，其包含氨基酸序列SEQ ID NO:148或其变体，所述变体与氨基酸序列SEQ ID NO:148具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:182或其变体，所述变体与氨基酸序列SEQ ID NO:182具有至少约80％序列同一性；或
    (viii)V H，其包含氨基酸序列SEQ ID NO:150或其变体，所述变体与氨基酸序列SEQ ID NO:150具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:183或其变体，所述变体与氨基酸序列SEQ ID NO:183具有至少约80％序列同一性。
  8. 一种分离的特异性结合HBV表面抗原pre-S1结构域的抗体，其包含：
    (i)V H，其包含如氨基酸序列SEQ ID NO:120所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:151所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3；
    (ii)V H，其包含如氨基酸序列SEQ ID NO:121所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:152所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3；
    (iii)V H，其包含如氨基酸序列SEQ ID NO:122所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:153所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3；
    (iv)V H，其包含如氨基酸序列SEQ ID NO:123所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:154所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3；
    (v)V H，其包含如氨基酸序列SEQ ID NO:124所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:155所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3；
    (vi)V H，其包含如氨基酸序列SEQ ID NO:126所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:157所示的V L 包含的LC-CDR1、LC-CDR2和LC-CDR3；
    (vii)V H，其包含如氨基酸序列SEQ ID NO:128所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:158所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3；
    (viii)V H，其包含如氨基酸序列SEQ ID NO:130所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:159所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3；
    (ix)V H，其包含如氨基酸序列SEQ ID NO:131所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:160所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3；
    (x)V H，其包含如氨基酸序列SEQ ID NO:132所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:161所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3；
    (xi)V H，其包含如氨基酸序列SEQ ID NO:133所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:162所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3；
    (xii)V H，其包含如氨基酸序列SEQ ID NO:134所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:163所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3；
    (xiii)V H，其包含如氨基酸序列SEQ ID NO:135所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:164所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3；
    (xiv)V H，其包含如氨基酸序列SEQ ID NO:136所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:165所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3；
    (xv)V H，其包含如氨基酸序列SEQ ID NO:137所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:167所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3；
    (xvi)V H，其包含如氨基酸序列SEQ ID NO:139所示的V H包含的HC-CDR1、HC- CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:169所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3；
    (xvii)V H，其包含如氨基酸序列SEQ ID NO:140所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:170所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3；
    (xviii)V H，其包含如氨基酸序列SEQ ID NO:141所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:171所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3；
    (xix)V H，其包含如氨基酸序列SEQ ID NO:142所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:172所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3；
    (xx)V H，其包含如氨基酸序列SEQ ID NO:143所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:173所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3；
    (xxi)V H，其包含如氨基酸序列SEQ ID NO:144所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:174所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3；
    (xxii)V H，其包含如氨基酸序列SEQ ID NO:145所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:175所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3；或
    (xxiii)V H，其包含如氨基酸序列SEQ ID NO:146所示的V H包含的HC-CDR1、HC-CDR2和HC-CDR3；以及V L，其包含如氨基酸序列SEQ ID NO:184所示的V L包含的LC-CDR1、LC-CDR2和LC-CDR3。
  9. 一种分离的特异性结合HBV表面抗原pre-S1结构域的抗体，其包含：
    (i)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:1，HC-CDR2，其包含氨基酸序列SEQ ID NO:19，和HC-CDR3，其包含氨基酸序列SEQ ID NO:39，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:58，LC-CDR2，其包含氨基酸序列SEQ ID NO:79，和LC-CDR3，其包含氨基酸序列 SEQ ID NO:93，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；
    (ii)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:2，HC-CDR2，其包含氨基酸序列SEQ ID NO:20，和HC-CDR3，其包含氨基酸序列SEQ ID NO:40，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:59，LC-CDR2，其包含氨基酸序列SEQ ID NO:79，和LC-CDR3，其包含氨基酸序列SEQ ID NO:94，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；
    (iii)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:3，HC-CDR2，其包含氨基酸序列SEQ ID NO:21，和HC-CDR3，其包含氨基酸序列SEQ ID NO:41，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:60，LC-CDR2，其包含氨基酸序列SEQ ID NO:80，和LC-CDR3，其包含氨基酸序列SEQ ID NO:95，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；
    (iv)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:4，HC-CDR2，其包含氨基酸序列SEQ ID NO:22，和HC-CDR3，其包含氨基酸序列SEQ ID NO:42，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:61，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，和LC-CDR3，其包含氨基酸序列SEQ ID NO:96，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；
    (v)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:5，HC-CDR2，其包含氨基酸序列SEQ ID NO:23，和HC-CDR3，其包含氨基酸序列SEQ ID NO:43，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:61，LC-CDR2，其包含氨基酸序列SEQ ID NO:82，和LC-CDR3，其包含氨基酸序列SEQ ID NO:97，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的 取代；
    (vi)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:7，HC-CDR2，其包含氨基酸序列SEQ ID NO:25，和HC-CDR3，其包含氨基酸序列SEQ ID NO:45，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:63，LC-CDR2，其包含氨基酸序列SEQ ID NO:84，和LC-CDR3，其包含氨基酸序列SEQ ID NO:99，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；
    (vii)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:7，HC-CDR2，其包含氨基酸序列SEQ ID NO:26，和HC-CDR3，其包含氨基酸序列SEQ ID NO:46，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:64，LC-CDR2，其包含氨基酸序列SEQ ID NO:79，和LC-CDR3，其包含氨基酸序列SEQ ID NO:100，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；
    (viii)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:8，HC-CDR2，其包含氨基酸序列SEQ ID NO:27，和HC-CDR3，其包含氨基酸序列SEQ ID NO:47，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:65，LC-CDR2，其包含氨基酸序列SEQ ID NO:85，和LC-CDR3，其包含氨基酸序列SEQ ID NO:101，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；
    (ix)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:9，HC-CDR2，其包含氨基酸序列SEQ ID NO:28，和HC-CDR3，其包含氨基酸序列SEQ ID NO:48，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:66，LC-CDR2，其包含氨基酸序列SEQ ID NO:86，和LC-CDR3，其包含氨基酸序列SEQ ID NO:102，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；
    (x)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:6，HC-CDR2，其包含氨基酸序列SEQ ID NO:24，和HC-CDR3，其包含氨基酸序列SEQ ID NO:44，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:62，LC-CDR2，其包含氨基酸序列SEQ ID NO:83，和LC-CDR3，其包含氨基酸序列SEQ ID NO:98，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；
    (xi)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:10，HC-CDR2，其包含氨基酸序列SEQ ID NO:29，和HC-CDR3，其包含氨基酸序列SEQ ID NO:49，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:67，LC-CDR2，其包含氨基酸序列SEQ ID NO:87，和LC-CDR3，其包含氨基酸序列SEQ ID NO:103，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；
    (xii)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:11，HC-CDR2，其包含氨基酸序列SEQ ID NO:30，和HC-CDR3，其包含氨基酸序列SEQ ID NO:50，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:68，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，和LC-CDR3，其包含氨基酸序列SEQ ID NO:104，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；
    (xiii)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:12，HC-CDR2，其包含氨基酸序列SEQ ID NO:30，和HC-CDR3，其包含氨基酸序列SEQ ID NO:50，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:61，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，和LC-CDR3，其包含氨基酸序列SEQ ID NO:105，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；
    (xiv)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:13，HC-CDR2， 其包含氨基酸序列SEQ ID NO:30，和HC-CDR3，其包含氨基酸序列SEQ ID NO:50，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:69，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，和LC-CDR3，其包含氨基酸序列SEQ ID NO:103，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；
    (xv)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:9，HC-CDR2，其包含氨基酸序列SEQ ID NO:31，和HC-CDR3，其包含氨基酸序列SEQ ID NO:51，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:70，LC-CDR2，其包含氨基酸序列SEQ ID NO:83，和LC-CDR3，其包含氨基酸序列SEQ ID NO:106，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；
    (xvi)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:14，HC-CDR2，其包含氨基酸序列SEQ ID NO:32，和HC-CDR3，其包含氨基酸序列SEQ ID NO:51，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:71，LC-CDR2，其包含氨基酸序列SEQ ID NO:86，和LC-CDR3，其包含氨基酸序列SEQ ID NO:107，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；
    (xvii)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:11，HC-CDR2，其包含氨基酸序列SEQ ID NO:30，和HC-CDR3，其包含氨基酸序列SEQ ID NO:50，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:72，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，和LC-CDR3，其包含氨基酸序列SEQ ID NO:108，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；
    (xviii)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:13，HC-CDR2，其包含氨基酸序列SEQ ID NO:33，和HC-CDR3，其包含氨基酸序列 SEQ ID NO:52，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:61，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，和LC-CDR3，其包含氨基酸序列SEQ ID NO:97，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；
    (xix)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:10，HC-CDR2，其包含氨基酸序列SEQ ID NO:30，和HC-CDR3，其包含氨基酸序列SEQ ID NO:50，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:61，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，和LC-CDR3，其包含氨基酸序列SEQ ID NO:103，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；
    (xx)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:15，HC-CDR2，其包含氨基酸序列SEQ ID NO:34，和HC-CDR3，其包含氨基酸序列SEQ ID NO:53，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:73，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，和LC-CDR3，其包含氨基酸序列SEQ ID NO:109，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；
    (xxi)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:16，HC-CDR2，其包含氨基酸序列SEQ ID NO:35，和HC-CDR3，其包含氨基酸序列SEQ ID NO:54，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:74，LC-CDR2，其包含氨基酸序列SEQ ID NO:88，和LC-CDR3，其包含氨基酸序列SEQ ID NO:110，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；
    (xxii)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:17，HC-CDR2，其包含氨基酸序列SEQ ID NO:36，和HC-CDR3，其包含氨基酸序列SEQ ID NO:55，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸 的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:75，LC-CDR2，其包含氨基酸序列SEQ ID NO:81，和LC-CDR3，其包含氨基酸序列SEQ ID NO:97，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代；或
    (xxiii)V H，所述V H包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:18，HC-CDR2，其包含氨基酸序列SEQ ID NO:37，和HC-CDR3，其包含氨基酸序列SEQ ID NO:56，或者所述V H的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及V L，所述V L包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:78，LC-CDR2，其包含氨基酸序列SEQ ID NO:92，和LC-CDR3，其包含氨基酸序列SEQ ID NO:93，或者所述V L的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
  10. 根据权利要求8或9中所述的分离的特异性结合HBV表面抗原pre-S1结构域的抗体，其包含：
    (i)V H，其包含氨基酸序列SEQ ID NO:120或其变体，所述变体与氨基酸序列SEQ ID NO:120具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:151或其变体，所述变体与氨基酸序列SEQ ID NO:151具有至少约80％序列同一性；
    (ii)V H，其包含氨基酸序列SEQ ID NO:121或其变体，所述变体与氨基酸序列SEQ ID NO:121具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:152或其变体，所述变体与氨基酸序列SEQ ID NO:152具有至少约80％序列同一性；
    (iii)V H，其包含氨基酸序列SEQ ID NO:122或其变体，所述变体与氨基酸序列SEQ ID NO:122具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:153或其变体，所述变体与氨基酸序列SEQ ID NO:153具有至少约80％序列同一性；
    (iv)V H，其包含氨基酸序列SEQ ID NO:123或其变体，所述变体与氨基酸序列SEQ ID NO:123具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:154或其变体，所述变体与氨基酸序列SEQ ID NO:154具有至少约80％序列同一性；
    (v)V H，其包含氨基酸序列SEQ ID NO:124或其变体，所述变体与氨基酸序列SEQ ID NO:124具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:155或其变体，所述变体与氨基酸序列SEQ ID NO:155具有至少约80％序列同一性；
    (vi)V H，其包含氨基酸序列SEQ ID NO:126或其变体，所述变体与氨基酸序列SEQ ID NO:126具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:157或其变体，所述变体与氨基酸序列SEQ ID NO:157具有至少约80％序列同一性；
    (vii)V H，其包含氨基酸序列SEQ ID NO:128或其变体，所述变体与氨基酸序列SEQ ID NO:128具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:158或其变体，所述变体与氨基酸序列SEQ ID NO:158具有至少约80％序列同一性；
    (viii)V H，其包含氨基酸序列SEQ ID NO:130或其变体，所述变体与氨基酸序列SEQ ID NO:130具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:159或其变体，所述变体与氨基酸序列SEQ ID NO:159具有至少约80％序列同一性；
    (ix)V H，其包含氨基酸序列SEQ ID NO:131或其变体，所述变体与氨基酸序列SEQ ID NO:131具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:160或其变体，所述变体与氨基酸序列SEQ ID NO:160具有至少约80％序列同一性；
    (x)V H，其包含氨基酸序列SEQ ID NO:132或其变体，所述变体与氨基酸序列SEQ ID NO:132具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:161或其变体，所述变体与氨基酸序列SEQ ID NO:161具有至少约80％序列同一性；
    (xi)V H，其包含氨基酸序列SEQ ID NO:133或其变体，所述变体与氨基酸序列SEQ ID NO:133具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:162或其变体，所述变体与氨基酸序列SEQ ID NO:162具有至少约80％序列同一性；
    (xii)V H，其包含氨基酸序列SEQ ID NO:134或其变体，所述变体与氨基酸序列 SEQ ID NO:134具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:163或其变体，所述变体与氨基酸序列SEQ ID NO:163具有至少约80％序列同一性；
    (xiii)V H，其包含氨基酸序列SEQ ID NO:135或其变体，所述变体与氨基酸序列SEQ ID NO:135具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:164或其变体，所述变体与氨基酸序列SEQ ID NO:164具有至少约80％序列同一性；
    (xiv)V H，其包含氨基酸序列SEQ ID NO:136或其变体，所述变体与氨基酸序列SEQ ID NO:136具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:165或其变体，所述变体与氨基酸序列SEQ ID NO:165具有至少约80％序列同一性；
    (xv)V H，其包含氨基酸序列SEQ ID NO:137或其变体，所述变体与氨基酸序列SEQ ID NO:137具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:167或其变体，所述变体与氨基酸序列SEQ ID NO:167具有至少约80％序列同一性；
    (xvi)V H，其包含氨基酸序列SEQ ID NO:139或其变体，所述变体与氨基酸序列SEQ ID NO:139具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:169或其变体，所述变体与氨基酸序列SEQ ID NO:169具有至少约80％序列同一性；
    (xvii)V H，其包含氨基酸序列SEQ ID NO:140或其变体，所述变体与氨基酸序列SEQ ID NO:140具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:170或其变体，所述变体与氨基酸序列SEQ ID NO:170具有至少约80％序列同一性；
    (xviii)V H，其包含氨基酸序列SEQ ID NO:141或其变体，所述变体与氨基酸序列SEQ ID NO:141具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:171或其变体，所述变体与氨基酸序列SEQ ID NO:171具有至少约80％序列同一性；
    (xix)V H，其包含氨基酸序列SEQ ID NO:142或其变体，所述变体与氨基酸序列SEQ ID NO:142具有至少约80％序列同一性；以及V L，其包含氨基酸序列 SEQ ID NO:172或其变体，所述变体与氨基酸序列SEQ ID NO:172具有至少约80％序列同一性；
    (xx)V H，其包含氨基酸序列SEQ ID NO:143或其变体，所述变体与氨基酸序列SEQ ID NO:143具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:173或其变体，所述变体与氨基酸序列SEQ ID NO:173具有至少约80％序列同一性；
    (xxi)V H，其包含氨基酸序列SEQ ID NO:144或其变体，所述变体与氨基酸序列SEQ ID NO:144具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:174或其变体，所述变体与氨基酸序列SEQ ID NO:174具有至少约80％序列同一性；
    (xxii)V H，其包含氨基酸序列SEQ ID NO:145或其变体，所述变体与氨基酸序列SEQ ID NO:145具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:175或其变体，所述变体与氨基酸序列SEQ ID NO:175具有至少约80％序列同一性；或
    (xxiii)V H，其包含氨基酸序列SEQ ID NO:146或其变体，所述变体与氨基酸序列SEQ ID NO:146具有至少约80％序列同一性；以及V L，其包含氨基酸序列SEQ ID NO:184或其变体，所述变体与氨基酸序列SEQ ID NO:184具有至少约80％序列同一性。
  11. 根据权利要求1-10中任一项的分离的特异性结合HBV表面抗原pre-S1结构域的抗体，其中所述抗体包含Fc片段。
  12. 根据权利要求11中的分离的特异性结合HBV表面抗原pre-S1结构域的抗体，其中所述抗体是全长的IgG抗体。
  13. 根据权利要求12中的分离的特异性结合HBV表面抗原pre-S1结构域的抗体，其中所述抗体是全长的IgG1、IgG2、IgG3或IgG4抗体。
  14. 根据权利要求1-13中任一项的分离的特异性结合HBV表面抗原pre-S1结构域的抗体，其中所述抗体是嵌合的、人源化的或全人的抗体。
  15. 根据权利要求1-14中任一项的分离的特异性结合HBV表面抗原pre-S1结构域的抗体是抗原结合片段，其中所述抗原结合片段选自Fab、Fab’、F(ab)’ 2、Fab’-SH、单链抗体(scFv)、Fv片段、dAb、Fd、纳米抗体(nanobody)、双链抗体(diabody)和线性抗体。
  16. 一种核酸分子，其编码权利要求1-15中任一项所述的特异性结合HBV表面抗原pre-S1结构域的抗体。
  17. 一种包含权利要求16中所述的核酸分子的载体。
  18. 一种分离的宿主细胞，其包含权利要求1-15中任一项所述的特异性结合HBV表面抗原pre-S1结构域的抗体、权利要求16中所述的核酸分子或权利要求17中所述的载体。
  19. 一种制备特异性结合HBV表面抗原pre-S1结构域的抗体的方法，其包含：
    a)在能有效表达特异性结合HBV表面抗原pre-S1结构域的抗体的条件下培养权利要求18中所述的宿主细胞；和
    b)从宿主细胞中获得所表达的特异性结合HBV表面抗原pre-S1结构域的抗体。
  20. 一种药物组合物，其包含权利要求1-15中任一项所述的特异性结合HBV表面抗原pre-S1结构域的抗体、权利要求16中所述的核酸分子、权利要求17中所述的载体、权利要求18中所述的分离的宿主细胞或由权利要求19中所述的方法制备得到的抗体，以及药学上可接受的载体。
  21. 权利要求1-15中任一项所述的抗体、权利要求16中所述的核酸分子、权利要求17中所述的载体、权利要求18中所述的分离的宿主细胞、由权利要求19中所述方法制备得到的抗体、或权利要求20中所述的药物组合物在制备治疗、预防或改善有此需求的个体疾病或病症的药物中的用途。
  22. 一种治疗疾病或病症的方法，所述方法包括向所需个体施用有效量的如权利要求1-15中任一项所述的抗体、权利要求16中所述的核酸分子、权利要求17中所述的载体、权利要求18中所述的分离的宿主细胞、由权利要求19中所述方法制备得到的抗体、或权利要求20中所述的药物组合物。
  23. 根据权利要求21中所述的用途或权利要求22中所述的方法，其中所述疾病或病症为HBV感染或与HBV感染相关。
  24. 根据权利要求23中所述的用途或方法，其中所述疾病或病症选自乙型肝炎、肝功能衰竭、肝硬化和肝癌。
  25. 根据权利要求23或24中所述的用途或方法，其与另一种药剂组合施用。
  26. 根据权利要求25中所述的用途或方法，其中所述另一种药剂选自抗病毒剂、抗过敏剂、抗恶心剂(或抗呕剂)、镇痛药、细胞保护剂和免疫抑制剂。
  27. 根据权利要求26中所述的用途或治疗方法，其中所述抗病毒剂选自干扰素、核苷 /核苷酸类似物、抗HBV的单克隆抗体、抗HBV的多克隆抗体、DNA聚合酶抑制剂和治疗性疫苗。
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