Antibody-antigen-adjuvant conjugates enable co-delivery of antigen and adjuvant to dendritic cells in cis but only have partial targeting specificity.
Antibody-antigen conjugates, which promote antigen-presentation by dendritic cells (DC) by means of targeted delivery of antigen to particular DC subsets, represent a powerful vaccination approach. To ensure immunity rather than tolerance induction the co-administration of a suitable adjuvant is paramount. However, co-administration of unlinked adjuvant cannot ensure that all cells targeted by the antibody conjugates are appropriately activated. Furthermore, antigen-presenting cells (APC) that do not present the desired antigen are equally strongly activated and could prime undesired responses against self-antigens. We, therefore, were interested in exploring targeted co-delivery of antigen and adjuvant in cis in form of antibody-antigen-adjuvant conjugates for the induction of anti-tumour immunity. In this study, we report on the assembly and characterization of conjugates consisting of DEC205-specific antibody, the model antigen ovalbumin (OVA) and CpG oligodeoxynucleotides (ODN). We show that such conjugates are more potent at inducing cytotoxic T lymphocyte (CTL) responses than control conjugates mixed with soluble CpG. However, our study also reveals that the nucleic acid moiety of such antibody-antigen-adjuvant conjugates alters their binding and uptake and allows delivery of the antigen and the adjuvant to cells partially independently of DEC205. Nevertheless, antibody-antigen-adjuvant conjugates are superior to antibody-free antigen-adjuvant conjugates in priming CTL responses and efficiently induce anti-tumour immunity in the murine B16 pseudo-metastasis model. A better understanding of the role of the antibody moiety is required to inform future conjugate vaccination strategies for efficient induction of anti-tumour responses.
Peter Gorer Department of Immunobiology, King's College London, Guy's Hospital, London, United Kingdom.
Martin
M
Kreutz
Benoit
B
Giquel
Qin
Q
Hu
Ram
R
Abuknesha
Satoshi
S
Uematsu
Shizuo
S
Akira
Frank O
FO
Nestle
Sandra S
SS
Diebold
D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000595:Amino Acid Sequence; D000818:Animals; D000906:Antibodies / Q000276:immunology*; D000941:Antigens / Q000008:administration & dosage* / Q000276:immunology*; D015703:Antigens, CD / Q000276:immunology; D045142:Cross-Priming / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology*; D016503:Drug Delivery Systems; D018796:Immunoconjugates / Q000276:immunology*; D037181:Lectins, C-Type / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D015778:Minor Histocompatibility Antigens; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000276:immunology; D009838:Oligodeoxyribonucleotides / Q000276:immunology; D010047:Ovalbumin / Q000276:immunology; D010455:Peptides / Q000737:chemistry / Q000276:immunology; D011956:Receptors, Cell Surface / Q000276:immunology; D012995:Solubility; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000378:metabolism
D000276:Adjuvants, Immunologic; D000906:Antibodies; D000941:Antigens; D015703:Antigens, CD; C408982:CPG-oligonucleotide; C093569:DEC-205 receptor; D018796:Immunoconjugates; D037181:Lectins, C-Type; D015778:Minor Histocompatibility Antigens; D009838:Oligodeoxyribonucleotides; D010455:Peptides; D011956:Receptors, Cell Surface; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D010047:Ovalbumin