Construction of a humanized antibody to hepatitis B surface antigen by specificity-determining residues (SDR)-grafting and de-immunization.
We previously constructed a humanized antibody, HuS10, by grafting the complementarity-determining regions (CDRs) of a parental murine monoclonal antibody into the homologous human antibody sequences. This process is termed CDR grafting. Some residues that were thought to affect the CDR loops and stabilize the structure of the variable regions were retained in the framework region. HuS10 exhibited in vivo virus-neutralizing activity, but its murine content had the potential to elicit immune responses in patients. In this study, to minimize the immunogenic potential of HuS10, we replaced 17 mouse residues in HuS10 with the comparable human residues using specificity-determining residue (SDR)-grafting and de-immunization methods. The resultant humanized antibody, HzS-III, had the same affinity and epitope specificity as HuS10 and had reduced immunogenic potential, as assessed by T-cell epitope analysis. Thus, SDR grafting in combination with de-immunization may be a useful strategy for minimizing the immunogenicity of humanized antibodies. In addition, HzS-III may be a good candidate for immunoprophylaxis of HBV infection.
Kim
Keun-Soo
KS
College of Pharmacy, Chungnam National University, Daejeon 305-764, Republic of Korea.
Kim
Hyun-Jung
HJ
Han
Byung Woo
BW
Myung
Pyung-Keun
PK
Hong
Hyo Jeong
HJ
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D000915:Antibody Affinity; D018604:Epitope Mapping; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D006509:Hepatitis B / Q000276:immunology* / Q000517:prevention & control; D006510:Hepatitis B Antibodies / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D006514:Hepatitis B Surface Antigens / Q000276:immunology*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D017433:Protein Structure, Secondary
D000911:Antibodies, Monoclonal; D018984:Epitopes, T-Lymphocyte; D006510:Hepatitis B Antibodies; D006514:Hepatitis B Surface Antigens