In vivo neutralization of hepatitis B virus infection by an anti-preS1 humanized antibody in chimpanzees

Hong, Hyo Jeong; Ryu, Chun Jeih; Hur, Hyangsuk; Kim, Se‐Ho; Oh, Han Kyu; Oh, Mee Sook; Park, Song Yong

doi:10.1016/j.virol.2003.09.014

Cited by 70 publications

(56 citation statements)

References 36 publications

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“…Alanine-scanning mutagenesis of residues 2P-10P of the preS1 epitope showed that mutations in residues 2P and 5P-10P caused a significant decrease in antibody binding, whereas mutations in Ser3P and Asp4P did not have any effect (16). In particular, mutations at Asp7P and Trp8P completely impaired the antibody binding (16).…”

Section: Resultsmentioning

confidence: 99%

“…Previously, we generated an anti-preS1 murine antibody KR127 that recognizes adr subtype preS1 (residues 37-45) (15). KR127 and the humanized version of KR127 antibody (HzKR127) bind to the preS1 domain of various clinical HBV isolates, including both adr and ayw subtypes, suggesting their broad neutralizing activity (15,16). HzKR127 also has been shown to exhibit in vivo neutralizing activity in chimpanzee and to protect the chimpanzee from HBV infection (16), indicating the high potential of the antibody for the immunoprophylaxis of HBV infection and therapy of hepatitis.…”

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confidence: 99%

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Broadly neutralizing anti-hepatitis B virus antibody reveals a complementarity determining region H3 lid-opening mechanism

Chi

Maeng²,

Kim

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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The humanized monoclonal antibody HzKR127 recognizes the preS1 domain of the human hepatitis B virus surface proteins with a broadly neutralizing activity in vivo. We present the crystal structures of HzKR127 Fab and its complex with a major epitope peptide. In the complex structure, the bound peptide forms a type IV ␤-turn followed by 310 helical turn, the looped-out conformation of which provides a structural basis for broad neutralization. Upon peptide binding, the antibody undergoes a dramatic complementarity determining region H3 lid opening. To understand the structural implication of the virus neutralization, we carried out comprehensive alanine-scanning mutagenesis of all complementarity determining region residues in HzKR127 Fab. The functional mapping of the antigen-combining site demonstrates the specific roles of major binding determinants in antigen binding, contributing to the rational design for maximal humanization and affinity maturation of the antibody.alanine-scanning mutagenesis ͉ crystal structure ͉ humanized antibody ͉ virus neutralization H uman hepatitis B virus (HBV) is a small enveloped DNA virus that causes acute and chronic hepatitis in humans (1-3). There are approximately 400 million carriers of HBV worldwide, posing a serious health threat. The current HBV vaccines have several limitations, including nonresponsiveness, escape mutants, and low immunogenicity (4). Recently, the potential of immunoprophylaxis for virus prevention has been increased by the discovery of monoclonal antibodies that have broad specificity toward various isolates of infectious viruses (5, 6).The HBV envelope consists of three surface glycoproteins called the large (L), middle (M), and small (S) proteins. All of these proteins are translated from a single ORF comprising preS1, preS2, and S domains (7). Translation of S, preS2ϩS, and preS1ϩpreS2ϩS domains results in S, M, and L proteins, respectively (Fig. 1). The L protein, preferentially localized in infectious HBV particles, plays an essential role in viral infection (7,8), and its preS1 domain is responsible for cell attachment in viral infection (9-12). In particular, the residue 21-47 region of preS1 has been suggested to contain a specific binding site for hepatocyte receptors and also has been shown to carry virusneutralizing epitopes (10-13).In the blood of HBV-infected persons, the noninfectious subviral particles with M and S proteins are present in excess amounts over the infectious virus particles containing L protein (7,8). Thus, neutralizing anti-preS1 antibodies are thought to have advantages over the neutralizing antibodies targeting S protein, which are currently undergoing clinical trials (4). Previously, we generated an anti-preS1 murine antibody KR127 that recognizes adr subtype preS1 (residues 37-45) (15). KR127 and the humanized version of KR127 antibody (HzKR127) bind to the preS1 domain of various clinical HBV isolates, including both adr and ayw subtypes, suggesting their broad neutralizing activity (15, 16). HzKR127 also has been sh...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Broadly neutralizing anti-hepatitis B virus antibody reveals a complementarity determining region H3 lid-opening mechanism

Chi

Maeng²,

Kim

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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“…Chimpanzee is the only natural host that allows active replication of HBV. [5][6][7] Although this animal is a valuable model for the study of hepatitis viruses, 8 the practical use of chimpanzees is severely limited both ethically and economically.Several small animal models of HBV infection have been reported. The HBV transgenic mouse is a very useful model for the study of virology and evaluation of antiviral drugs.…”

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confidence: 99%

Infection of Human Hepatocyte Chimeric Mouse With Genetically Engineered Hepatitis B Virus *

et al. 2005

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H epatitis B virus (HBV) is a small enveloped DNA virus and causes chronic infection of the liver that often leads to chronic hepatitis, cirrhosis, and hepatocellular carcinoma. [1][2][3][4] The lack of a practical small animal model has impeded the study of the biology of this virus and the development of effective antiviral therapies. Chimpanzee is the only natural host that allows active replication of HBV. [5][6][7] Although this animal is a valuable model for the study of hepatitis viruses, 8 the practical use of chimpanzees is severely limited both ethically and economically.Several small animal models of HBV infection have been reported. The HBV transgenic mouse is a very useful model for the study of virology and evaluation of antiviral drugs. [9][10][11][12] However, the liver cells of this model are not permissive for HBV infection; therefore, studying virus-cell interactions such as receptor binding and entry is not possible. The HBVtrimera mouse is another useful mouse model. 13 In this model, ex vivo HBV-infected human liver fragments are implanted into lethally irradiated mice after SCID mouse bone marrow transplantation. Approximately 80% of the mice develop viremia 2 to 3 weeks after infection. However, the rate of positivity subsequently decreases to less than 20% 6 weeks after infection. The level viremia is approximately 10 5 copies/mL. More recently, HBV-containing human serum samples were used to infect human hepatocyte repopulated mice. 14 A high-level viremia (4.5 and 10 ϫ 10 8 copy/ mL) and HBs antigenemia are observed 8 weeks after injection. This mouse model is promising because HBV replicates in natural host cells, human hepatocytes. However,

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“…Previously, we generated HzKR127, a humanized version of anti-preS1 murine monoclonal antibody KR127 that binds adr subtype preS1 (residues 37-45) [10]. The antibody exhibits broadly neutralizing activity against various HBV isolates, including adr and ayw subtypes, and protected the chimpanzee from HBV infection [10].…”

Section: Introductionmentioning

confidence: 99%

“…Remodeling of the binding site through large conformational changes can significantly expand the structural diversity of the primary repertoire beyond a certain limit that calculated from sequence diversity alone, making it possible to bind an unlimited number of antigens in primary response. Although HzKR127 was originated from murine KR127 generated after multiple immunizations [10], the CDRs of HzKR127 still retain high sequence similarity with those of germline antibody for murine KR127. Furthermore, the HzKR127 Fab also shows very high sequence homology with other murine germline antibodies 48G7, 28B4, and 7G12.…”

Section: Introductionmentioning

confidence: 99%

Broadly neutralizing anti‐HBV antibody binds to non‐epitope regions of preS1

Chi

Kim

et al. 2009

FEBS Letters

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a b s t r a c tBroadly neutralizing anti-hepatitis B virus (HBV) antibody HzKR127 undergoes a fairly large conformational change of CDR H3 loop upon binding to HBV preS1 epitope peptide. In this study, we identified low-affinity antibody-binding sites in the largely unstructured preS1 region by nuclear magnetic resonance and biochemical studies, indicating that the antibody binds to the preS1 region outside the major immune epitope with low affinity. Surface plasma resonance experiments showed that the full-length preS1 has approximately three fold higher affinity for HzKR127 Fab than the preS1 epitope peptide, suggesting that the presence of low-affinity sites in the preS1 region increases the antibody-binding affinity. Therefore, the low-affinity binding of the antibody to non-epitope regions of preS1 may contribute to effective neutralization.

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In vivo neutralization of hepatitis B virus infection by an anti-preS1 humanized antibody in chimpanzees

Cited by 70 publications

References 36 publications

Broadly neutralizing anti-hepatitis B virus antibody reveals a complementarity determining region H3 lid-opening mechanism

Broadly neutralizing anti-hepatitis B virus antibody reveals a complementarity determining region H3 lid-opening mechanism

Infection of Human Hepatocyte Chimeric Mouse With Genetically Engineered Hepatitis B Virus *

Broadly neutralizing anti‐HBV antibody binds to non‐epitope regions of preS1

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