title: EpCAM-specific vaccine response by modified antigen and chimeric costimulatory molecule in cynomolgus monkeys.
abstract: Immunization against tumor-associated antigens is a promising approach to cancer therapy and prevention, but it faces several challenges and limitations, such as tolerance mechanisms associated with self-antigens expressed by the tumor cells. Costimulatory molecules B7.1 (CD80) and B7.2 (CD86) have improved the efficacy of gene-based and cell-based vaccines in animal models and are under investigation in clinical trials. However, their efficacy as vaccine adjuvants is likely limited by the fact that they mediate both stimulatory and inhibitory signals to T cells via CD28 and CTLA-4, respectively. To overcome these limitations, we have generated a B7.1-like, chimeric costimulatory molecule with preferential binding to CD28, named CD28-binding protein (CD28BP), which we combined with a modified, nonself tumor antigen variant of epithelial cell adhesion molecule (EpCAM), named TAg25. TAg25 induced a cross-reactive immune response against human wild-type EpCAM upon DNA vaccination in cynomolgus monkeys. However, TAg25 DNA immunization alone or in combination with human (h) B7.1 induced no detectable antigen-specific T cells in the peripheral blood of the animals. In contrast, TAg25 combined with CD28BP induced both CD4 and CD8 T cells specific for EpCAM. Moreover, TAg25 combined with CD28BP induced significantly higher levels of EpCAM-specific antibodies than TAg25 plus hB7.1. These improved adjuvant properties of CD28BP, when compared with hB7.1, illustrate the importance of CD28 costimulation in vaccine responses in nonhuman primates and warrant further studies on the potential of CD28BP in improving the efficacy of cancer vaccines.
authors.affiliation: Department of Biology and Pharmacology, Maxygen Inc, Redwood City, CA 94063, USA. margaret.neighbors@maxygen.com
authors.forename: Margaret
authors.initials: M
authors.lastname: Neighbors
authors.forename: Doris
authors.initials: D
authors.lastname: Apt
authors.forename: Jean C-C
authors.initials: JC
authors.lastname: Chang
authors.forename: Alice
authors.initials: A
authors.lastname: Brinkman
authors.forename: Isabelle
authors.initials: I
authors.lastname: Sipos-Solman
authors.forename: Randal
authors.initials: R
authors.lastname: Ong
authors.forename: Steven
authors.initials: S
authors.lastname: Leong
authors.forename: Juha
authors.initials: J
authors.lastname: Punnonen
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology*; D018122:B7-1 Antigen / Q000235:genetics / Q000276:immunology; D018106:CD28 Antigens / Q000276:immunology; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000276:immunology*; D049109:Cell Proliferation; D003429:Cross Reactions; D004357:Drug Synergism; D000071858:Epithelial Cell Adhesion Molecule; D006801:Humans; D007117:Immunization, Secondary; D007371:Interferon-gamma / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D008252:Macaca fascicularis; D009369:Neoplasms / Q000628:therapy; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D017634:Self Tolerance / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D018122:B7-1 Antigen; D018106:CD28 Antigens; C468140:CD28-binding protein, human; D019496:Cancer Vaccines; D002352:Carrier Proteins; D015815:Cell Adhesion Molecules; D000071858:Epithelial Cell Adhesion Molecule; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D007371:Interferon-gamma