Chemokine-idiotype fusion DNA vaccines are potentiated by bivalency and xenogeneic sequences

Fredriksen, Agnete B.; Bogen, Bjarne

doi:10.1182/blood-2006-06-032938

Cited by 58 publications

(120 citation statements)

References 69 publications

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“…Initially, these experiments were performed with Ag that had been chemically conjugated to APCspecific Abs (5)(6)(7)(8)(9)(10). Later, genetic fusion of an APC-specific targeting unit and Ag has been a preferred method (11)(12)(13)(14)(15)(16)(17). Several different versions of APC-specific targeting units have been reported, including Ig-based formats (11,13), single-chain variable fragment (scFv) formats (14,15), and chemokines (12,16,17).…”

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confidence: 99%

Antigen Targeting to Human HLA Class II Molecules Increases Efficacy of DNA Vaccination

Grødeland

Fredriksen²,

Løset

et al. 2016

The Journal of Immunology

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It has been difficult to translate promising results from DNA vaccination in mice to larger animals and humans. Previously, DNA vaccines encoding proteins that target Ag to MHC class II (MHC-II) molecules on APCs have been shown to induce rapid, enhanced, and long-lasting Ag-specific Ab titers in mice. In this study, we describe two novel DNA vaccines that as proteins target HLA class II (HLA-II) molecules. These vaccine proteins cross-react with MHC-II molecules in several species of larger mammals. When tested in ferrets and pigs, a single DNA delivery with low doses of the HLA-II–targeted vaccines resulted in rapid and increased Ab responses. Importantly, painless intradermal jet delivery of DNA was as effective as delivery by needle injection followed by electroporation. As an indication that the vaccines could also be useful for human application, HLA-II–targeted vaccine proteins were found to increase human CD4+ T cell responses by a factor of ×103 in vitro. Thus, targeting of Ag to MHC-II molecules may represent an attractive strategy for increasing efficacy of DNA vaccines in larger animals and humans.

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confidence: 99%

Antigen Targeting to Human HLA Class II Molecules Increases Efficacy of DNA Vaccination

Grødeland

Fredriksen²,

Løset

et al. 2016

The Journal of Immunology

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“…Vaccibodies are homodimeric chimeric proteins consisting of a targeting unit, a hinge domain, and an Ag moiety (21). XCL1-based vaccibodies were developed recently to target Ags to XCR1 + DCs (22).…”

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confidence: 99%

Laser-Assisted Intradermal Delivery of Adjuvant-Free Vaccines Targeting XCR1+ Dendritic Cells Induces Potent Antitumoral Responses

Terhorst‐Molawi

Fossum

Barańska

et al. 2015

The Journal of Immunology

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The development of vaccines inducing efficient CD8+ T cell responses is the focus of intense research. Dendritic cells (DCs) expressing the XCR1 chemokine receptor, also known as CD103+ or CD8α+ DCs, excel in the presentation of extracellular Ags to CD8+ T cells. Because of its high numbers of DCs, including XCR1+ DCs, the skin dermis is an attractive site for vaccine administration. By creating laser-generated micropores through the epidermis, we targeted a model protein Ag fused to XCL1, the ligand of XCR1, to dermal XCR1+ DCs and induced Ag-specific CD8+ and CD4+ T cell responses. Efficient immunization required the emigration of XCR1+ dermal DCs to draining lymph nodes and occurred irrespective of TLR signaling. Moreover, a single intradermal immunization protected mice against melanoma tumor growth in prophylactic and therapeutic settings, in the absence of exogenous adjuvant. The mild inflammatory milieu created in the dermis by skin laser microporation itself most likely favored the development of potent T cell responses in the absence of exogenous adjuvants. The existence of functionally equivalent XCR1+ dermal DCs in humans should permit the translation of laser-assisted intradermal delivery of a tumor-specific vaccine targeting XCR1+ DCs to human cancer immunotherapy. Moreover, considering that the use of adjuvants in vaccines is often associated with safety issues, the possibility of inducing protective responses against melanoma tumor growth independently of the administration of exogenous adjuvants should facilitate the development of safer vaccines.

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“…To achieve this goal, we and others have tested various forms of recombinant Id vaccines (17,(19)(20)(21)(22)(23). A common approach is to produce fusions of Id sequences to targeting moieties that direct the construct to cytokine receptors or to other activating receptors on dendritic cells, macrophages, and other antigen-presenting cells (APCs) (19,22,23). The peptides derived from Id proteins would then be presented to T cells (24,25).…”

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confidence: 99%

A vaccine directed to B cells and produced by cell-free protein synthesis generates potent antilymphoma immunity

Jia

Patel³

et al. 2012

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

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Clinical studies of idiotype (Id) vaccination in patients with lymphoma have established a correlation between the induced anti-Id antibody responses and favorable clinical outcomes. To streamline the production of an Id vaccine, we engineered a small diabody (Db) molecule containing both a B-cell-targeting moiety (anti-CD19) and a lymphoma Id. This molecule (αCD19-Id) was designed to penetrate lymph nodes and bind to noncognate B cells to form an antigen presentation array. Indeed, the αCD19-Id molecule accumulated on B cells in vivo after s.c. administration. These noncognate B cells, decorated with the diabody, could then stimulate the more rare Id-specific B cells. Peptide epitopes present in the diabody linker augmented the response by activating CD4 + helper T cells. Consequently, the αCD19-Id molecule induced a robust Id-specific antibody response and protected animals from tumor challenge. Such diabodies are produced in a cell-free protein expression system within hours of amplification of the specific Ig genes from the B-cell tumor. This customized product can now be available to vaccinate patients before they receive other, potentially immunosuppressive, therapies.immunotherapy | tumor-specific antigen | bispecific antibody fragments I diotype (Id), the unique Ig molecule of each lymphoma tumor, is a good target for the immune system. Passively administered monoclonal antibodies (mAbs) against this target are effective in therapy (1). Furthermore, studies of Id vaccination had suggested a correlation between induced anti-Id antibody responses and progression-free survival and overall survival of patients (2-4). Despite these encouraging results, phase III trials have not established a clinical benefit from Id vaccination, except for a possible subset of patients who have prolonged remissions after initial chemotherapy (5-7). One possible problem may have been the chemical conjugation of Id to the carrier protein, keyhole limpet hemocyanin (KLH). Antigenic determinants on the Id could have been damaged in this process (8). Recombinant vaccines that do not require chemical conjugation may lead to improved immunogenicity and clinical outcomes.Recent studies on antigen (Ag) acquisition by B cells have provided new insights for vaccine design. The majority of B cells reside in follicles within secondary lymphoid organs. Foreign Ags in the form of immune complexes are transported into lymph node follicles by subcapsular sinus macrophages (9-11), and into spleen follicles by marginal zone B cells (12). In the follicles, nonspecific B cells retain immune complexes on their cell surfaces. Some complexes are transferred to follicular dendritic cells (9-11), whereas others may directly cross-link the Ag-specific receptors (BCRs) on cognate B cells (10, 11). These roles played by noncognate B cells in the generation of specific antibody responses were previously not appreciated. In addition to forming immune complexes that facilitate entering the follicles and presenting on the cell surface, foreign Ags may also b...

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Chemokine-idiotype fusion DNA vaccines are potentiated by bivalency and xenogeneic sequences

Cited by 58 publications

References 69 publications

Antigen Targeting to Human HLA Class II Molecules Increases Efficacy of DNA Vaccination

Antigen Targeting to Human HLA Class II Molecules Increases Efficacy of DNA Vaccination

Laser-Assisted Intradermal Delivery of Adjuvant-Free Vaccines Targeting XCR1+ Dendritic Cells Induces Potent Antitumoral Responses

A vaccine directed to B cells and produced by cell-free protein synthesis generates potent antilymphoma immunity

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