Enhanced antitumor immunity by fusion of CTLA-4 to a self tumor antigen.
The idiotypic determinant (Id) of the immunoglobulin expressed by a B-cell malignancy can serve as an effective tumor-specific antigen but is only weakly immunogenic. This study demonstrates that the immunogenicity of the tumor Id protein can be dramatically increased by directing it to antigen-presenting cells (APCs). Cytotoxic T-lymphocyte antigen 4 (CTLA-4) present on activated T cells has a strong binding affinity to both B7-1 and B7-2 molecules, which are primarily expressed on APCs. After construction of a fusion protein consisting of Id and CTLA-4 (Id-CTLA4), mice immunized with the fusion protein induced high titers of Id-specific antibody and T-cell proliferative responses without adjuvants and were protected from lethal tumor challenge. The Id-CTLA4 fusion protein was so potent that even low doses (down to 0.1 microg) of the immunogen were able to elicit strong antibody responses. By using an Id-CTLA4 mutant protein, the ability to bind B7 molecules on APCs was shown to be required for the enhanced immunogenicity of Id-CTLA4. These findings demonstrate that fusing CTLA-4 to a potential tumor antigen represents an effective approach to prime antitumor immunities in vivo and may be applicable to the design of vaccines for a variety of other diseases. (Blood. 2000;96:3663-3670)
Huang
T H
TH
Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
Wu
P Y
PY
Lee
C N
CN
Huang
H I
HI
Hsieh
S L
SL
Kung
J
J
Tao
M H
MH
D000069594:Abatacept; D000818:Animals; D000917:Antibody Formation; D000938:Antigen-Presenting Cells / Q000276:immunology; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D000943:Antigens, Differentiation / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000276:immunology* / Q000378:metabolism; D018122:B7-1 Antigen / Q000276:immunology / Q000378:metabolism; D051940:B7-2 Antigen; D060908:CTLA-4 Antigen; D019496:Cancer Vaccines / Q000276:immunology / Q000592:standards; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007114:Immunization / Q000379:methods / Q000592:standards; D018796:Immunoconjugates; D007130:Immunoglobulin Idiotypes / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D016297:Mutagenesis, Site-Directed; D009368:Neoplasm Transplantation; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000138:chemical synthesis / Q000276:immunology / Q000378:metabolism; D014407:Tumor Cells, Cultured
D015703:Antigens, CD; D000943:Antigens, Differentiation; D000951:Antigens, Neoplasm; D018122:B7-1 Antigen; D051940:B7-2 Antigen; C497964:CD86 protein, human; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D019496:Cancer Vaccines; C497965:Cd86 protein, mouse; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D007130:Immunoglobulin Idiotypes; D008562:Membrane Glycoproteins; D011993:Recombinant Fusion Proteins; D000069594:Abatacept